U.S. patent application number 12/437049 was filed with the patent office on 2009-11-05 for novel hypocholesterolemic compounds.
This patent application is currently assigned to LIPIDEON BIOTECHNOLOGY AG. Invention is credited to Erick Carreira, Helmut Hauser, Lisbet Kvaerno, Tobias Ritter, Moritz Werder.
Application Number | 20090275524 12/437049 |
Document ID | / |
Family ID | 34307063 |
Filed Date | 2009-11-05 |
United States Patent
Application |
20090275524 |
Kind Code |
A1 |
Carreira; Erick ; et
al. |
November 5, 2009 |
NOVEL HYPOCHOLESTEROLEMIC COMPOUNDS
Abstract
The present invention relates to novel hypocholesterolemic
compounds of formula (I) useful in the treatment and prevention of
atherosclerosis and for the reduction of cholesterol levels as well
as to pharmaceutical compositions comprising said compounds alone
or in combination with other active agents ##STR00001##
Inventors: |
Carreira; Erick; (Zumikon,
CH) ; Hauser; Helmut; (Uerikon, CH) ; Kvaerno;
Lisbet; (Zurich, CH) ; Ritter; Tobias;
(Zurich, CH) ; Werder; Moritz; (Bremgarten,
CH) |
Correspondence
Address: |
THE WEBB LAW FIRM, P.C.
700 KOPPERS BUILDING, 436 SEVENTH AVENUE
PITTSBURGH
PA
15219
US
|
Assignee: |
LIPIDEON BIOTECHNOLOGY AG
|
Family ID: |
34307063 |
Appl. No.: |
12/437049 |
Filed: |
May 7, 2009 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10575025 |
Apr 25, 2007 |
7544667 |
|
|
PCT/CH2004/000584 |
Sep 15, 2004 |
|
|
|
12437049 |
|
|
|
|
Current U.S.
Class: |
514/24 ;
514/210.01; 514/210.02; 514/311; 514/35; 514/403; 536/17.4;
546/173; 548/379.4; 548/950; 548/952 |
Current CPC
Class: |
C07H 15/00 20130101;
C07D 205/08 20130101; A61P 9/10 20180101; C07D 215/14 20130101;
A61P 3/06 20180101; C07D 205/04 20130101; A61P 9/00 20180101 |
Class at
Publication: |
514/24 ; 548/950;
548/952; 536/17.4; 546/173; 548/379.4; 514/210.01; 514/210.02;
514/35; 514/311; 514/403 |
International
Class: |
A61K 31/397 20060101
A61K031/397; C07D 205/04 20060101 C07D205/04; C07H 15/22 20060101
C07H015/22; C07D 215/04 20060101 C07D215/04; C07D 231/06 20060101
C07D231/06; A61K 31/7052 20060101 A61K031/7052; A61K 31/47 20060101
A61K031/47; A61K 31/415 20060101 A61K031/415; A61P 9/00 20060101
A61P009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 7, 2003 |
EP |
03405719.0 |
Claims
1-17. (canceled)
18: A compound according to formula I ##STR00032## wherein P
represents --N<, x represents --CO--, --CS--, --CH.sub.2-- or
--NH--, n represents 1, R.sub.a represents H, lower alkyl,
--OR.sub.3, --O(CO)R.sub.3, --O(CO)OR.sub.3,
--O(CO)NR.sub.3R.sub.4, --NR.sub.3R.sub.4, --NR.sub.3(CO)R.sub.4,
--COOR.sub.3, --CONR.sub.3R.sub.4, --CH.dbd.CHCOOR.sub.3,
--CF.sub.3, --CN, --NO.sub.2, SO.sub.3H, PO.sub.3H or halogen,
wherein R.sub.3 and R.sub.4 represent H or lower alkyl, R.sub.b
represents H, OH, --OSO.sub.2Me, --OSO.sub.2W wherein W represents
optionally substituted aryl or heteroaryl,
--OCO(CHOH).sub.2COOR.sub.5 wherein R.sub.5 represents H or lower
alky; or represents the formula -Sp.sub.3-R.sub.6, wherein SP3
represents a covalent bond, --O--, --OCH.sub.2--,
--OSO.sub.2CH.sub.2--, --OSO.sub.2--, --OSO.sub.2-- (p)
C.sub.6H.sub.4O-- and R.sub.6 represents one of carbohydrate
structures A-D: ##STR00033## wherein R.sub.7, R.sub.8, R.sub.9,
R.sub.11, R.sub.12, R.sub.13 and R.sub.14 represent independently
of each other H, lower allyl, aryl(lower alkyl), --CO-lower alkyl,
--CO-aryl, --SO.sub.3.sup.- or --PO.sub.3.sup.-, R.sub.10
represents --CH.sub.2OR.sub.16 or --COOR.sub.17, and R.sub.15
represents --CH.sub.2OR.sub.16, --COOR.sub.17, --CH.sub.2NH.sub.2,
--CH.sub.2OPO.sub.3-- or --CH.sub.2OSO.sub.3--, wherein R.sub.16
and R.sub.17 independently of each other represent H, lower alkyl,
aryl(lower alkyl), --CO-- lower alkyl, --CO-aryl, --SO.sub.3.sup.-
or --PO.sub.3.sup.-, Z represents optionally substituted aryl or
heteroaryl, Sp.sub.1 represents a spacer unit, such as a
straight-chain or branched lower alkyl group --(CH.sub.2).sub.p,
wherein p is from 2-6, which is unsubstituted, mono or
poly-substituted by --OH, --OR.sub.18, halogen or cyano group,
wherein one or more --CH.sub.2-- groups may independently be
replaced by --O--, --CO--, --CO--O--, --O--CO--, --NR.sub.19,
--NR.sub.19--CO--, --CO--NR.sub.19--, --CH.dbd.CH--, --C.ident.C--
and wherein R.sub.18 and R.sub.19 represent a hydrogen atom or
lower alkyl; Sp.sub.2 represents an optional spacer unit, such as a
covalent bond or a straight-chain or branched lower alkyl group
--(CH.sub.2).sub.q, wherein q is from 1-6, which is unsubstituted,
mono or poly-substituted by --OH, --OR.sub.20, halogen or cyano
group, wherein one or more --CH.sub.2-- groups may independently be
replaced by --O--, --CO--, --CO--O--, --O--CO--, --NR.sub.21--,
NR.sub.21--CO--, --CO--NR.sub.21--, --CH.dbd.CH--, --C.ident.C--
and wherein R.sub.20 and R.sub.21 represents a hydrogen atom or
lower alkyl; Y represents optionally substituted aryl or
heteroaryl, with the proviso, that if X.dbd.--CO-- and Sp.sub.2
represents a covalent bond, R.sub.b may not represent H or OH and
Sp.sub.3 may not represent a covalent bond, --O-- or
--OCH.sub.2--.
19: A compound according to claim 18 having the formula IIa
##STR00034## wherein Ra represents H, lower alkyl, --OR.sub.3,
--O(CO)R.sub.3, --O(CO)OR.sub.3, --O(CO)NR.sub.3R.sub.4,
--NR.sub.3R.sub.4, --NR.sub.3(CO)R.sub.4, --COOR.sub.3,
--CONR.sub.3R.sub.4, --CH.dbd.CHCOOR.sub.3, --CF.sub.3, --CN,
--NO.sub.2, SO.sub.3H, PO.sub.3H or halogen, wherein R.sub.3 and
R.sub.4 represent H or lower alkyl, Rb represents H, OH,
--OSO.sub.2Me, --OSO.sub.2W wherein W represents optionally
substituted aryl or heteroaryl, --OCO(CHOH).sub.2COOR.sub.5 wherein
R.sub.5 represents H or lower alkyl; or represents the formula
-Sp.sub.3-R.sub.6, wherein Sp.sub.3 represents a covalent bond,
--O--, --OCH.sub.2--, --OSO.sub.2CH.sub.2--, --OSO.sub.2--,
--OSO.sub.2-- (p) C.sub.6H.sub.4O-- and R.sub.6 represents one of
carbohydrate structures A-D: ##STR00035## wherein R.sub.7, R.sub.8,
R.sub.9, R.sub.11, R.sub.12, R.sub.13 and R.sub.14 represent
independently of each other H, lower alkyl, alyl(lower allyl),
--CO-lower allyl, --CO-aryl, --SO.sub.3.sup.- or --PO.sub.3.sup.-,
R10 represents-CH.sub.2OR.sub.16 or --COOR.sub.17, and R15
represents --CH.sub.2OR.sub.16, --COOR.sub.17, --CH.sub.2NH.sub.2,
--CH.sub.2OPO.sub.3-- or --CH.sub.2OSO.sub.3--, wherein R.sub.16
and R.sub.17 independently of each other represent H, lower allyl,
aryl(lower alkyl), --CO-lower alkyl, --CO-aryl, --SO.sub.3.sup.- or
--PO.sub.3.sup.-, Z represents optionally substituted aryl or
heteroaryl, Sp.sub.1 represents a spacer unit, such as a
straight-chain or branched lower alkyl group --(CH.sub.2)--,
wherein p is from 2-6, which is unsubstituted, mono or
poly-substituted by --OH, --OR18, halogen or cyano group, wherein
one or more --CH.sub.2-- groups may independently be replaced by
--O--, --CO--, --CO--O--, --O--CO--, --NR.sub.19--,
--NR.sub.19--CO--, --CO--NR.sub.19--, --CH.dbd.CH--, --C.ident.C--
and wherein R.sub.18 and R.sub.19 represent a hydrogen atom or
lower alkyl; Sp.sub.2 represents an optional spacer unit, such as a
covalent bond or a straight-chain or branched lower alkyl group
--(CH.sub.2).sub.q--, wherein q is from 1-6, which is
unsubstituted, mono or poly-substituted by --OH, --OR.sub.20,
halogen or cyano group, wherein one or more --CH.sub.2-- groups may
independently be replaced by --O--, --CO--, --CO--O--, --O--CO--,
--NR.sub.21--, --NR.sub.21--CO--, --CO--NR.sub.21--, --CH.dbd.CH--,
--C.ident.C-- and wherein R.sub.20 and R.sub.21 represents a
hydrogen atom or lower alkyl; Y represents optionally substituted
aryl or heteroaryl, with the proviso, that if Sp.sub.2 represents a
covalent bond R.sub.b may not represent H or OH and Sp.sub.3 may
not represent a covalent bond, --O-- or --OCH.sub.2--.
20: A compound according to claim 19 wherein R.sub.a is in the
meta-position and R.sub.b is in the para-position.
21: A compound according to claim 19 wherein R.sub.a is H,
straight-chain or branched C(1-8)allyl, --OR.sub.3,
--NR.sub.3R.sub.4, --COOR.sub.3, --CONR.sub.3R.sub.4 or halogen,
wherein R.sub.3 and R.sub.4 represent independently of each other H
or straight-chain or branched C(1-8)allyl.
22: A compound according to claim 19 wherein R.sub.b is H, OH,
--OSO.sub.2Me, --OSO.sub.2Ph; or the formula -Sp.sub.3-R.sub.6,
wherein Sp.sub.3 preferably represents a covalent bond, --O--,
--OCH.sub.2-- or --OSO.sub.2CH.sub.2-- and R.sub.6 represents one
of carbohydrate structures A-D, preferably carbohydrate structures
A, B or D.
23: A compound according to claim 19 wherein Sp.sub.1 represents a
straight-chain or branched --(CH.sub.2).sub.m-- group, which is
unsubstituted, mono or poly-substituted by --OH, --OR.sub.18,
halogen or cyano group, wherein R.sub.18 represents hydrogen or
straight-chain or branched C(1-8)allyl and m is 1 to 3.
24: A compound according to claim 19 wherein Y represents an
optionally substituted phenyl group.
25: A compound according to claim 19 wherein Z represents an
optionally substituted phenyl group.
26: A compound according to claim 18 having the formula IIc
##STR00036## wherein R.sub.a represents H, lower alkyl, --OR.sub.3,
--O(CO)R.sub.3, --O(CO)OR.sub.3, --O(CO)NR.sub.3R.sub.4,
--NR.sub.3R.sub.4, --NR.sub.3(CO)R.sub.4, --COOR.sub.3,
--CONR.sub.3R.sub.4, --CH.dbd.CHCOOR.sub.3, --CF.sub.3, --CN,
--NO.sub.2, SO.sub.3H, PO.sub.3H or halogen, wherein R.sub.3 and
R.sub.4 represent H or lower alkyl, R.sub.b represents H, OH,
--OSO.sub.2Me, --OSO.sub.2W wherein W represents optionally
substituted aryl or heteroaryl, --OCO(CHOH).sub.2COOR.sub.5 wherein
R.sub.5 represents H or lower alkyl; or represents the formula
-Sp.sub.3-R.sub.6, wherein SP3 represents a covalent bond, --O--,
--OCH.sub.2--, --OSO.sub.2CH.sub.2--, --OSO.sub.2--, --OSO.sub.2--
(p) C.sub.6H.sub.4O-- and R.sub.6 represents one of carbohydrate
structures A-D: ##STR00037## wherein R.sub.7, R.sub.8, R.sub.9,
R.sub.11, R.sub.12, R.sub.13 and R.sub.14 represent independently
of each other H, lower alkyl, aryl(lower allyl), --CO-lower alkyl,
--CO-aryl, --SO.sub.3.sup.- or --PO.sub.3.sup.-, R.sub.10
represents --CH.sub.2OR.sub.16 or --COOR.sub.17, and R.sub.15
represents --CH.sub.2OR.sub.16, --COOR.sub.17, --CH.sub.2NH.sub.2,
--CH.sub.2OPO.sub.3 or --CH.sub.2OSO.sub.3.sup.-, wherein R.sub.16
and R.sub.17 independently of each other represent H, lower alkyl,
aryl(lower alkyl), --CO-- lower alkyl, --CO-alyl, --SO.sub.3.sup.-
or --PO.sub.3.sup.-, Z represents optionally substituted aryl or
heteroaryl, Sp.sub.1 represents a spacer unit, such as a
straight-chain or branched lower alkyl group --(CH.sub.2).sup.p--,
wherein p is from 2-6, which is unsubstituted, mono or
poly-substituted by --OH, --OR.sub.18, halogen or cyano group,
wherein one or more --CH.sub.2-- groups may independently be
replaced by --O--, --CO--, --CO--O--, --O--CO--, --NR.sub.19--,
--NR.sub.19--CO--, --CO--NR.sub.19--, --CH.dbd.CH--, --C.ident.C--
and wherein R.sub.18 and R.sub.19 represent a hydrogen atom or
lower allyl; Sp.sub.2 represents an optional spacer unit, such as a
covalent bond or a straight-chain or branched lower alkyl group
--(CH.sub.2).sub.q--, wherein q is from 1-6, which is
unsubstituted, mono or poly-substituted by --OH, --OR.sub.20,
halogen or cyano group, wherein one or more --CH.sub.2-- groups may
independently be replaced by --O--, --CO--, --CO--O--, --O--CO--,
--NR.sub.21--, --NR.sub.21--CO--, --CO--NR.sub.21--, --CH.dbd.CH--,
--C.ident.C-- and wherein R.sub.20 and R.sub.21 represents a
hydrogen atom or lower alkyl; Y represents optionally substituted
aryl or heteroaryl.
27: A compound according to claim 26 wherein R.sub.a is in the
meta-position and R.sub.b is in the para-position.
28: A compound according to claim 26 wherein R.sub.a is H,
straight-chain or branched C(1-8)alkyl, --OR.sub.3,
--NR.sub.3R.sub.4, --COOR.sub.3, --CONR.sub.3R.sub.4 or halogen,
wherein R.sub.3 and R.sub.4 represent independently of each other H
or straight-chain or branched C(1-8)alkyl.
29: A compound according to claim 26 wherein R.sub.b is H, OH,
--OSO.sub.2Me, --OSO.sub.2Ph; or the formula -Sp.sub.3-R.sub.6,
wherein Sp.sub.3 preferably represents a covalent bond, --O--,
--OCH.sub.2-- or --OSO.sub.2CH.sub.2-- and R.sub.r represents one
of carbohydrate structures A-D, preferably carbohydrate structures
A, B or D.
30: A compound according to claim 26 wherein S.sub.p1 represents a
straight-chain or branched --(CH.sub.2).sub.m group, which is
unsubstituted, mono or poly-substituted by --OH, --OR.sub.18,
halogen or cyano group, wherein R.sub.18 represents hydrogen or
straight-chain or branched C(1-8) alkyl and m is 1 to 3.
31: A compound according to claim 26 wherein Y represents an
optionally substituted phenyl group.
32: A compound according to claim 26 wherein Z represents an
optionally substituted phenyl group.
33: A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 18 with a pharmaceutically
acceptable carrier.
34: A pharmaceutical composition according to claim 33 for the
treatment of artheriosclerosis or for the reduction of cholesterol
levels.
35: A kit comprising a pharmaceutical composition according to
claim 33 for use in the treatment of artheriosclerosis or for the
reduction of cholesterol levels.
36: A method for the treatment of artheriosclerosis or for the
reduction of cholesterol levels comprising administering to a
subject in need of such treatment an effective amount of a compound
according to claim 18.
Description
[0001] The present invention relates to novel hypocholesterolemic
compounds useful in the treatment and prevention of atherosclerosis
and for the reduction of cholesterol levels as well as to
pharmaceutical compositions comprising said compounds alone or in
combination with other active agents.
[0002] Atherosclerotic coronary heart disease represents the major
cause for death and cardiovascular morbidity in the western world.
Risk factors for atherosclerotic coronary heart disease include
hypertension, diabetes mellitus, family history, male gender,
cigarette smoke as well as serum cholesterol. Elevated
concentrations of serum cholesterol have been demonstrated by a
number of clinical studies to be a major contributing factor in the
development and progression of atherosclerosis, which is
characterized by the formation of cholesterol-containing plaques in
the aorta and lesser arteries.
[0003] In mammals, 1/3 of the serum cholesterol is derived from
exogenous dietary sources which enters the body through absorption
in the intestine and 2/3 of the serum cholesterol are derived
through endogenous de novo synthesis in the liver involving a
complex set of enzyme-catalyzed reactions and regulatory
mechanisms.
[0004] Recently it has been shown that intestinal cholesterol
absorption is an energy-independent, protein-mediated process
(Hauser, H. et al, Biochemistry 1998, 37, 17843-17850; Schulthess,
G. et al, Biochemistry 2000, 39, 12623-12631; Werder, M. et al,
Biochemistry 2001, 40, 11643-11650) rather than a passive diffusion
process. The proteins facilitating intestinal cholesterol
absorption were identified as two brush border membrane-resident
scavenger receptors (Hauser, H. et al, Biochemistry 1998, 37,
17843-17850; Werder, M. et al, Biochemistry 2001, 40, 11643-11650).
Both in vitro and in vivo animal experiments confirmed the presence
of these two scavenger receptors in the intestinal BBM and proved
that they are responsible for the protein-mediated cholesterol
uptake.
[0005] Various 2-azetidinone compounds have been reported as being
useful in lowering cholesterol and/or in inhibiting the formation
of cholesterol-containing lesions in mammalian arterial walls: For
example WO 93/02048, WO 94/17038, WO 95/08532, PCT/US95/03196, U.S.
Pat. No. 5,633,246 describe 2-azetidinone compounds with different
substituents at the 3-position, and U.S. Pat. No. 5,756,470
discloses 2-azetidinones having varying substituents at the 4
position. Other azetidinone derivatives include for example
elastase inhibitory substituted azetidinones disclosed in European
Patent 199,630B1 and European Patent Application 337,549A1. The
most prominent representative of these 2-azetidinones, Ezetimibe
(also known under trade names Zetia.TM. and Ezetrol.RTM.), has been
in use as a cholesterol-lowering drug in monotherapy and in dual
therapy combined with a statin. It is the first representative of
the new class of cholesterol-lowering drugs that inhibit intestinal
cholesterol absorption by targeting the two scavenger receptors in
the intestinal brush border membrane described above.
[0006] However, it has been shown that the 2-azetidinones upon
administration are readily absorbed and extensively metabolized
into the pharmalogically active glucuronide of which over 95%
remained in the intestinal wall upon direct administration as the
glucuronide (van Heek, M. et al. Br. J. Pharmacol. 2000, 129,
1748-1754). In addition side effects such as allergic reactions
including rash and angiodema have been reported.
[0007] Applicants have now discovered that the compounds of the
present invention with the structural characteristics as depicted
in formula I and in particular formulas II and III are able to
inhibit the protein-mediated process mentioned above by which
cholesterol absorption is mediated, while overcoming the above
described disadvantages of compounds known in the art. Thus the
compounds of the present invention are particularly useful in the
treatment and prevention of atherosclerosis and for the reduction
of cholesterol levels.
[0008] In a first aspect, the present invention thus relates to
novel hypocholesterolemic compounds of formula I, and in particular
to compounds of formulas II and III having a four- or five-membered
ring, respectively.
[0009] In one embodiment, the present invention is directed to a
compound of formula I, or a pharmaceutically acceptable salt or
solvate thereof,
##STR00002##
wherein [0010] P represents --N< or --C.dbd., [0011] X
represents independently of each other --CH.sub.2--, CR.sub.1
(sp.sub.2-hybridised), O, --NH--, .dbd.N--, --CO-- or --CS--,
wherein R.sub.1 represents H or NR.sub.2, wherein R.sub.2
represents H or lower alkyl, which optionally is linked to Z such
that a bicyclic structure is formed; [0012] n represents 1 or 2,
[0013] R.sub.a represents H, lower alkyl, --OR.sub.3,
--O(CO)R.sub.3, --O(CO)OR.sub.3, --O(CO)NR.sub.3R.sub.4,
--NR.sub.3R.sub.4, --NR.sub.3(CO)R.sub.4, --COOR.sub.3,
--CONR.sub.3R.sub.4, --CH.dbd.CHCOOR.sub.3, --CF.sub.3, --CN,
--NO.sub.2, SO.sub.3H, PO.sub.3H or halogen, wherein R.sub.3 and
R.sub.4 represent H or lower alkyl, [0014] R.sub.b represents H,
OH, --OSO.sub.2Me, --OSO.sub.2W wherein W represents optionally
substituted aryl or heteroaryl, --OCO(CHOH).sub.2COOR.sub.5 wherein
R.sub.5 represents H or lower alkyl; or represents the formula
-Sp.sub.3-R.sub.6, [0015] wherein Sp.sub.3 represents a covalent
bond, --O--, --OCH.sub.2--, --OSO.sub.2CH.sub.2--, --OSO.sub.2--,
--OSO.sub.2-- (p)C.sub.6H.sub.4O-- and R.sub.6 represents one of
carbohydrate structures A-D:
[0015] ##STR00003## [0016] wherein [0017] R.sub.7, R.sub.8,
R.sub.9, R.sub.11, R.sub.12, R.sub.13 and R.sub.14 represent
independently of each other H, lower alkyl, aryl(lower alkyl),
--CO-lower alkyl, --CO-aryl, --SO.sub.3.sup.- or --PO.sub.3.sup.-,
[0018] R.sub.10 represents --CH.sub.2OR.sub.16 or --COOR.sub.17,
and [0019] R.sub.15 represents --CH.sub.2OR.sub.16, --COOR.sub.17,
--CH.sub.2NH.sub.2, --CH.sub.2OPO.sub.3.sup.- or
--CH.sub.2OSO.sub.3.sup.-, wherein R.sub.16 and R.sub.17
independently of each other represent H, lower alkyl, aryl(lower
alkyl), --CO-lower alkyl, --CO-aryl, --SO.sub.3.sup.- or
--PO.sub.3.sup.-, [0020] Z represents optionally substituted aryl
or heteroaryl, [0021] Sp.sub.1 represents a spacer unit, such as a
straight-chain or branched lower alkyl group --(CH.sub.2).sub.p--,
wherein p is from 2-6, which is unsubstituted, mono or
poly-substituted by --OH, --OR.sub.18, halogen or cyano group,
wherein one or more --CH.sub.2-- groups may independently be
replaced by --O--, --CO--, --CO--O--, --O--CO--, --NR.sub.19--,
--NR.sub.19--CO--, --CO--NR.sub.19--, --CH.dbd.CH--,
--C.ident.C--and wherein R.sub.18 and R.sub.19 represent a hydrogen
atom or lower alkyl; [0022] Sp.sub.2 represents an optional spacer
unit, such as a covalent bond or a straight-chain or branched lower
alkyl group --(CH.sub.2).sub.q--, wherein g is from 1-6, which is
unsubstituted, mono or poly-substituted by --OH, --OR.sub.20,
halogen or cyano group, wherein one or more --CH.sub.2-- groups may
independently be replaced by --O--, --CO--, --CO--O--, --O--CO--,
--NR.sub.21--, --NR.sub.21-- CO--, --CO--NR.sub.21--,
--CH.dbd.CH--, --C.ident.C-- and wherein R.sub.20 and R.sub.21
represents a hydrogen atom or lower alkyl; [0023] Y represents
optionally substituted aryl or heteroaryl, with the proviso, that
if P.dbd.--N<, n=1, X.dbd.CO-- and Sp.sub.2 represents a
covalent bond, R.sub.6 may not represent carbohydrate structures A
or D for Sp.sub.3=--O-- and R.sub.6 may not represent carbohydrate
B for Sp.sub.3.dbd.--OCH.sub.2--.
[0024] Preferably, if P.dbd.N<, n=1, X.dbd.CO-- and Sp.sub.2
represents a covalent bond, R.sub.b may not represent H or OH and
Sp.sub.3 may not represent a covalent bond, --O-- or
--OCH.sub.2--.
[0025] In a preferred embodiment, the present invention is directed
towards compounds of formula I wherein P.dbd.N<, n=1 and
X.dbd.CO--, --CS--, --CH.sub.2-- or --NH--.
[0026] Thus, the present invention is preferably directed towards
compounds of formula IIa-d
##STR00004##
or a pharmaceutically acceptable salt or solvate thereof, wherein
the groups R.sub.a, R.sub.b, Sp.sub.1, Sp.sub.2, Y and Z are as
defined above.
[0027] In another preferred embodiment, the present invention is
directed towards compounds of formula I wherein for P.dbd.N<,
--(X).sub.n-- represents --OOC--, --COO--, --CONH--, --CH.dbd.N--,
and for P.dbd.--C.dbd., --(X).sub.n-- represents --NH--N.dbd. or
--O--N.dbd..
[0028] Thus, the present invention is directed towards compounds of
formula IIIa-f:
##STR00005##
or a pharmaceutically acceptable salt or solvate thereof, wherein
the groups R.sub.a, R.sub.b, Sp.sub.1, Sp.sub.2, Y and Z are as
defined above.
[0029] In a further preferred embodiment, the present invention is
directed towards compounds of formula I with P.dbd.N< where
--(X).sub.n-- represents --CH--C.dbd.NR-- or --CH--NH--CR-- or
wherein ring Z is coupled to --(X).sub.n-- to form bicylic
compounds.
[0030] Thus, the present invention is further directed towards
compounds of formula IIIg-h:
##STR00006##
[0031] R.sub.a preferably represents H, lower alkyl, --OR.sub.3,
--NR.sub.3R.sub.4, --COOR.sub.3, CONR.sub.3R.sub.4,
--CH.dbd.CHCOOR.sub.3, --CF.sub.3, --CN, --NO.sub.2, SO.sub.3H,
PO.sub.3H or halogen, more preferably H, lower alkyl, --OR.sub.3,
--NR.sub.3R.sub.4, --COOR.sub.3, --CONR.sub.3R.sub.4 or halogen,
most preferably H, lower alkyl, --OR.sub.19 or halogen, wherein
R.sub.3 and R.sub.4 represent independently of each other H or
lower alkyl.
[0032] R.sub.b preferably represents H, OH, --OSO.sub.2Me,
--OSO.sub.2W wherein W represents Phenyl (Ph) or isomers of
salicylic acid (all combinations of disubstituted phenyl with OH
and COOH substituents); or the formula -Sp.sub.3-R.sub.6, wherein
Sp.sub.3 preferably represents a covalent bond, --O--,
--OCH.sub.2-- or --OSO.sub.2CH.sub.2-- and R.sub.6 represents one
of carbohydrate structures A-D, preferably carbohydrate structures
A, B or D. More preferably R.sub.b represents H, OH, --OSO.sub.2Me,
--OSO.sub.2Ph; or the formula -Sp.sub.3-R.sub.6, wherein Sp.sub.3
preferably represents a covalent bond, --O--, --OCH.sub.2-- or
--OSO.sub.2CH.sub.2-- and R.sub.6 represents one of carbohydrate
structures A-D, preferably carbohydrate structures A, B or D.
[0033] Sp.sub.1 preferably represents a straight-chain or branched
--(CH.sub.2).sub.m-- group, which is unsubstituted, mono or
poly-substituted by --OH, --OR.sub.18, halogen or cyano group,
wherein R.sub.18 represents hydrogen or lower alkyl and m is 1 to
3. More preferably Sp.sub.1 represents a --(CH.sub.2).sub.3--,
which is unsubstituted or substituted by --OH or halogen.
[0034] Sp.sub.2 preferably represents a straight-chain or branched
--(CH.sub.2).sub.p-- group, which is unsubstituted, mono or
poly-substituted by --OH, --OR.sub.20, halogen or cyano group,
wherein R.sub.20 represents hydrogen or lower alkyl and p is 1 to
3. More preferably Sp.sub.1 represents an unsubstituted
--(CH.sub.2).sub.p--, wherein p is 1 to 3, most preferably a
covalent bond.
[0035] R.sub.15 preferably represents --CH.sub.2OR.sub.16, --COOP17
or --CH.sub.2NH.sub.2, wherein R.sub.16 and R.sub.17 independently
of each other represent H, lower alkyl, aryl(lower alkyl),
--CO-lower alkyl, --CO-aryl, --SO.sub.3.sup.- or --PO.sub.3.sup.-,
preferably H, acetyl or benzyl.
[0036] R.sub.7, R.sub.8, R.sub.9, R.sub.11, R.sub.12, R.sub.13, and
R.sub.14 preferably represent independently of each other H, lower
alkyl, aryl-lower alkyl, --CO-lower alkyl, --CO-aryl, more
preferably, H, acetyl or benzyl.
[0037] The term "optionally substituted aryl group" should be
understood to include an aromatic ring system having 4 to 10,
preferably 5, 6 or 10 ring atoms. The aryl group can be substituted
with one or more substituents, which may be the same or different,
and are selected from a group as defined hereinafter. Non-limiting
examples of suitable aryl groups include phenyl, naphthalene or
tetraline groups, most preferably phenyl groups substituted by
halogeno, preferably fluoro.
[0038] The term "optionally substituted heteroaryl" should be
understood to include an aromatic ring system of 5 to 14,
preferably 5 to 10, more preferably 5 to 6 or 10 ring atoms, in
which one or more of the atoms in the ring system is/are atoms
other than carbon, for example nitrogen, oxygen or sulfur. The
heteroaryl can be optionally substituted by one or more
substituents, which may be the same or different, and are selected
from a group as defined hereinafter. Examples of suitable
6-membered heteroaryl groups include pyridyl, pyrimidinyl,
pyrazinyl, pyridazinyl and the like. Examples of useful 5-membered
heteroaryl rings include furyl, thienyl, pyrrolyl, thiazolyl,
isothiazolyl, imidazolyl, pyrazolyl, oxazolyl and isoxazolyl.
Useful bicyclic groups are benzo-fused ring systems derived from
the heteroaryl groups named above, e.g., quinolyl, phthalazinyl,
quinazolinyl, benzofuranyl, benzothienyl and indolyl.
[0039] The term "lower alkyl" should be understood to include
straight chain and branched hydrocarbon groups having from 1 to 8,
preferably 1 to 6, more preferably from 1 to 3 carbon atoms, which
may be optionally substituted. Non-limiting examples of suitable
lower alkyl groups include methyl, ethyl, n-propyl, isopropyl,
n-butyl, t-butyl, n-pentyl, fluoromethyl and trifluoromethyl.
[0040] The term "branched" should be understood to represent a
linear straight chain hydrocarbon group having one or more lower
alkyl groups such as methyl, ethyl or propyl, attached to it.
[0041] The term "lower alkoxy" should be understood to include
"lower alkyl-O-- "-groups, wherein the lower alkyl groups are as
described above and have from 1 to 8, preferably 1 to 6, more
preferably from 1 to 3 carbon atoms. Methoxy, ethoxy and isopropoxy
groups are especially preferred.
[0042] The term "aryl(lower alkyl)" should be understood to include
an aryl(lower alkyl) group in which the aryl and lower alkyl are as
previously described. Non-limiting examples of suitable aryl(lower
alkyl) groups include benzyl, phenethyl and naphthlenylmethyl.
[0043] If not otherwise indicated, the term "optionally
substituted" should be understood to represent substituents
independently selected from the group consisting of aryl,
heteroaryl, aryl(lower alkyl), (lower alkyl)aryl, aralkenyl,
heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy,
hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halogen,
nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,
aralkoxycarbonyl, aminoalkyl, alkylthio, arylthio, heteroarylthio,
aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl,
heterocyclyl, heterocyclenyl, preferably lower alkyl, hydroxy,
lower alkoxy, cyano, alkylthio, amino, --NH(lower alkyl), --N(lower
alkyl).sub.2 (which alkyls can be the same or different), carboxy,
--C(O)O-(lower alkyl) and halogen. Those skilled in the art will
recognize that the size and nature of the substituent(s) will
affect the number of substituents which can be present.
[0044] The term "halogen" should be understood to include fluoro,
chloro, bromo. iodo, preferably, fluoro and chloro, most
preferably, fluoro.
[0045] It is understood that all isomers, including enantiomers,
stereoisomers, rotamers, tautomers and racemates of the compounds
of formula I and in particular the compounds of formulas II and III
are contemplated as being part of this invention. The invention
includes stereoisomers in optically pure form and in admixture,
including racemic mixtures. Isomers can be prepared using
conventional techniques, either by reacting optically pure or
optically enriched starting materials or by separating isomers of a
compound of formula I and in particular the compounds of formulas
II and III. In a preferred embodiment the stereochemistry in the
central ring is such that the substituents at the 3- and 4-position
are in trans configuration to each other.
[0046] In yet a further embodiment, preferred combinations of
groups R.sub.a and R.sub.b include combinations wherein R.sub.b is
as defined hereinabove and is in para-position (in relation to the
linker Sp.sub.2) and R.sub.a is as defined hereinabove, most
preferably H, and is in meta-position.
[0047] Thus in a further preferred embodiment the present invention
is directed towards a compound of formula IVa,
##STR00007##
wherein R.sub.a, R.sub.b, Sp.sub.1, Sp.sub.2, P, X, Y, Z and n are
as defined herein-above.
[0048] Such preferred combinations are thus compounds of formulas
IIa-f and IIIa-h wherein R.sub.b is as defined hereinabove and is
in para-position (in relation to the linker Sp.sub.2) and R.sub.a
is as defined hereinabove, most preferably H, and is in
meta-position.
[0049] Further preferred embodiments include combinations, wherein
Sp.sub.2 is a covalent bond and Y and Z represent optionally
substituted phenyl rings.
[0050] Thus in a further preferred embodiment the present invention
is directed towards a compound of formula IVb,
##STR00008##
wherein R.sub.a, R.sub.b, Sp.sub.1, P and X are as defined
hereinabove and wherein R.sub.21 and R.sub.22 preferably represent
H, lower alkyl, lower alkoxy or halogen, most preferably in
para-position.
[0051] Such combinations are thus compounds of formulas IIa-f and
IIIa-h wherein Sp.sub.2 is a covalent bond and Y and Z represent
optionally substituted phenyl rings.
[0052] Compounds of formula I and in particular compounds of
formulas II and III may be prepared using methods of preparation
known in the art and are described in the following paragraphs:
[0053] The 2-azetidinone portions of the compounds of formula II
can be prepared by known methods, such as are disclosed in U.S.
Pat. Nos. 5,631,365, 5,756,470, 5,767,115, 5,846,966, 6,207,822,
U.S. Provisional Patent Application No. 60/279,288 filed Mar. 28,
2001, and PCT Patent Application WO 93/02048, each of which is
incorporated herein by reference. Compounds of formula Ia according
to the invention may then be obtained by further linkage to
appropriate carbohydrate structures using literature procedures as
illustrated by the Examples.
[0054] Compounds of formula IIb may be obtained through conversion
of .beta.-lactams to thiolactams, most commonly performed with
Lawesson's reagent (Verkoyen, C. and Rademacher, P. Chem. Ber.
1985, 118, 653-660; Yde, B. et al. Tetrahedron 1984, 40, 2047-2052;
Steliou, K.; Mrani, M. J. Am. Chem. Soc. 1982, 104, 3104-3106;
Clader, J. W. et al. J. Med. Chem. 1996, 39, 3684-3693).
[0055] Compounds of formula IIc may be obtained through conversion
of .beta.-lactams to azetidines, which may be achieved by a number
of wellknown methods in the art, such as (1) direct one-step
reduction with reducing agents of the composition
AlH.sub.xCl.sub.3-x, such as chlorodihydroalane or alane (Jackson,
M. B. et al. Aust. J. Chem. 1983, 36, 779), or diborane (Jackson,
M. B. et al.; Aust. J. Chem. 1983, 36, 779-788), AlHCl.sub.2 and
DIBAL-H (Yamashita, M. and Ojima, I. J. Am. Chem. Soc. 1983, 105,
6339-6342; Ojima, I. et al. J. Org. Chem. 1991, 56, 5263-5277); and
(2) cyclodehydration of 1,3-amino alcohols using various methods
(Sohar, P. et al. Chem. Soc. Perkin Trans. 2 2000, 287-293; Suga,
H. et al. S. J. Am. Chem. Soc. 1994, 116, 11197-11198; Barluenga,
J. et al. Tetrahedron 1996, 52, 3095-3106; Obika, S. et al.
Tetrahedron Lett. 2003, 44, 5267-5270) as also outlined in the
Examples.
[0056] The preparation of compounds of formula IIIa is effected as
outlined in Scheme I through initial Sharpless asymmetric amino
hydroxylation reaction of the desired trans-1,2-disubstituted
alkenes (Demko, Z. P. et al. Org. Lett. 2000, 2, 2221-2223;
O'Brien, P. Angew. Chem. Int. Edit. Engl. 1999, 38, 326-329;
Bodkin, J. A.; McLeod, M. D. J. Chem. Soc. Perkin Trans. 1 2002,
2733-2746), followed by chromatographic separation to obtain the
desired regioisomeric product. Subsequent cleavage of the
para-toluene sulfonamide group furnishes a primary amine which upon
Buchwald-Hartwig arylation reaction (Hartwig, J. F. Acc. Chem. Res.
1998, 31, 852-860; Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818) and subsequent
exposure to triphosgene eventually leads to the formation of the
desired oxazolidinones of formula IIIa. Alternatively, they can be
accessed as outlined in the Examples.
##STR00009##
[0057] Compounds of formula IIIe may be obtained e.g. as
illustrated in Scheme II using known methods in the art (Mish, M.
R. et al. J. Am. Chem. Soc. 1997, 119, 8379-8380; Guerra, F. M. et
al. Org. Lett. 2000, 2, 4265-4267). Alternatively, compounds in
which sp.sub.2 is not a covalent bond can be synthesized as
demonstrated in the Examples.
##STR00010##
[0058] The preparation of pyrazolidinones of formula IIIC proceeds
in an analogous strategy to that reported in the literature as
illustrated in Scheme III (Lou, B. S. et al. J. Org. Chem. 1995,
60, 5509-5514; Tomkinson, N.C. O. Rodd's Chemistry of Carbon
Compounds (2nd Edition), Asymetric Catalysis, Ed. M. Sainsbury
2001, 5, 199-258).
##STR00011##
[0059] It has been found that the use of sulfonate linkages in e.g.
the Rb or Sp3 group, i.e. linking carbohydrates to the phenylene
ring is particularly beneficial in that the S.dbd.O double bonds in
the linkages may function as hydrogen bond acceptors compared to
the more non-polar nature of a C-glycoside linkage. Such linkages
have not yet been reported to link carbohydrates to other kinds of
molecules. Furthermore the linkages are non-hydrolyzable, i.e. the
carbohydrates are not hydrolyzed off.
[0060] It has further been shown that the compounds of the
invention display superior pharmacological activities and are able
to overcome the drawbacks of known cholesterol-lowering agents
using well-established methods in the art, e.g. evaluation of their
IC.sub.50 value for cholesterol uptake in rabbit brush border
membrane vesicles (BBMV) as well as in Caco-2 cells (Hauser, H. et
al, Biochemistry 1998, 37, 17843-17850; Schulthess, G. et al,
Biochemistry 2000, 39, 12623-12631; Werder, M. et al, Biochemistry
2001, 40, 11643-11650; Boffelli, D. et al. FEBS Lett. 1997, 411,
7-11) (see also Table I).
[0061] Thus, the compounds of the invention, e.g. compounds of
formula I and their pharmaceutically acceptable acid addition
salts, exhibit pharmacological activity and are, therefore, useful
as pharmaceuticals. The compounds of the invention have been shown
to effectively inhibit cholesterol absorption and are therefore
useful in the treatment and/or prevention of atherosclerosis and of
the reduction of cholesterol levels.
[0062] Thus in yet a further aspect, the present invention is
directed to a method of treatment and/or prevention of
atherosclerosis, of the reduction of cholesterol levels and of
treating or preventing a vascular condition, comprising
administering to a mammal in need of such treatment an effective
amount of a compound of formula I and in particular a compound of
formulas II and III.
[0063] The novel compounds of formula I can be used, for example,
in the form of pharmaceutical compositions containing a
therapeutically effective amount of the active ingredient, if
appropriate together with inorganic or organic, solid or liquid,
pharmaceutically acceptable carriers suitable for enteral, e.g.
oral, or parenteral administration. Accordingly, tablets or gelatin
capsules are used that contain the active ingredient together with
diluents, typically lactose, dextrose, saccharose, mannitol,
sorbitol, cellulose and/or lubricants, e.g. diatomaceous earth,
talcum, stearic acid or salts thereof, such as magnesium stearate
or calcium stearate, and/or polyethylene glycol. Tablets may also
contain binders, typically magnesium aluminium silicate, starches,
typically corn starch, wheat starch, rice starch or arrow root
starch, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose and/or polyvinylpyrrolidone, and, if
desired, disintegrators, typically starches, agar, alginic acid or
a salt thereof, e.g. sodium alginate, and/or effervescent mixtures,
or absorbents, colourants, flavourings and sweeteners.
[0064] Thus in another aspect, the invention relates to a
pharmaceutical composition comprising a compound of formula I, and
in particular a compound of formulas II and III (and optionally
other therapeutically effective agents), and a pharmaceutically
acceptable carrier for the treatment or prevention of
artheriosclerosis or for the reduction of cholesterol levels.
[0065] The terms "effective amount" and "therapeutically effective
amount" mean that amount of a compound of formula I and in
particular compounds of formulas II and III (and optionally other
therapeutically effective agents), that will elicit a biological or
medical response of a tissue, system, animal or mammal, which
includes alleviation of the symptoms of the condition or disease
being treated and the prevention, slowing or halting of progression
of one or more conditions, for example atherosclerosis,
hypercholesterolemia.
[0066] The pharmaceutical compositions so obtained which, if
desired, contain further pharmacologically active substances, are
prepared in a manner known per se by conventional mixing,
granulating, sugar-coating, solution or lyophilising methods and
contain from about 0.1- to 100%, preferably from about 1% to about
50%, lyophilisate to about 100%, of active ingredient.
[0067] The compounds, compositions and treatments of the present
invention can be administered by any suitable means which produce
contact of these compounds with the site of action in the body, for
example in the plasma, liver or small intestine of a mammal or
human. Thus the novel compounds of formula I may also be used in
the form of compositions for parenteral, oral, transdermal
administration or infusion solutions. Such solutions are preferably
isotonic aqueous solutions or suspension which, e.g. in the case of
lyophilised compositions that contain the active ingredient by
itself or together with a carrier, such as mannitol, can be
prepared before use. The pharmaceutical compositions can be
sterilised and/or can contain excipients, typically preservatives,
stabilisers, wetting agents and/or emulsifiers, solubilisers, salts
for regulating the osmotic pressure and/or buffers.
[0068] In yet a further aspect, the invention relates to a kit
comprising an effective amount of a compound of formula I and in
particular a compound of formulas II and III in a pharmaceutically
acceptable carrier (and optionally an effective amount of another
therapeutically effective agent), optionally in separate
compartments.
[0069] The following non-limiting Examples illustrate the
above-described invention in more detail.
EXAMPLES
[0070] Materials and Methods: Reactions in anhydrous solvents were
all performed using oven dried glassware under an atmosphere of
argon. Reagent grade solvents were all purchased from chemical
companies and used without prior purification. For chromatic
purification, technical grade solvents were distillated prior to
use. TLC was performed using Machery-Nagel Alugram Sil G/UV.sub.254
TLC plates and visualized with ultraviolet light at 254 nm and 12 g
phosphor molybdic acid in 250 m-L EtOH or 10% H.sub.2SO.sub.4 in
MeOH (v/v). chromatographic purification of products was
accomplished using dry column vacuum chromatography on Merck Silica
Gel 60 (15-40 .mu.m) according to literature procedures (Pedersen,
D. S, and Rosenbohm, C. Synthesis 2001, 2431-2434); fractions
containing product were pooled, the solvents were evaporated under
reduced pressure and the residue was dried under high vacuum to
give the product. NMR spectra were recorded on a Varian Mercury 300
MHz apparatus operating at 300 MHz and 75 MHz for .sup.1H and
.sup.13C, respectively, and chemical shifts (.delta.) were
referenced to the internal solvent signals. IR-Spectra were
recorded in CHCl.sub.3 on a Perkin Elmer Spectrum RX I FT-IR
apparatus (thin films on NaCl plates) and are reported as
absorption maxima in cm.sup.-3. Elemental analysis was performed by
the Mikroelementaranalytisches Laboratorium at the ETH, Zurich.
High resolution matrix-assisted laser desorption ionization mass
spectrometry (MALDI-MS) was recorded in positive ion mode.
Example 1
##STR00012##
[0072] LiAlH.sub.4 (114 mg, 3.0 mmol) and AlCl.sub.3 (390 mg, 2.9
mmol) were suspended in anhydrous ether (15 mL) and refluxed for 30
min.
Trans-1-(4-fluorophenyl)-3-[(3-phenyl)-propyl]-4-phenyl-2-azetidinone
(361 mg, 1.00 mmol; prepared according to Browne, M. et al.
Tetrahedron Lett. 1995, 36, 2555-2558) dissolved in anhydrous ether
(15 mL) was added and after stirring at reflux for 30 min, the
suspension was cooled and H.sub.2O (5 mL) was added dropwise
followed by addition of 50% sat. aq. NaHCO.sub.3 (30 mL). The
layers were separated, the aqueous layer was extracted with
EtOAc/hexane and ether and the combined organic layer was washed
successively with sat. aq. NaHCO.sub.3 (20 mL) and H.sub.2O (20
mL), evaporated on celite and purified by dry column vacuum
chromatography (3.7.times.3.3 cm) on silica gel eluting with a
gradient of 0-10% EtOAc in hexane (v/v) to give the desired
compound V (281 mg, 81%) as a colourless oil.
[0073] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.51-7.14 (10H,
m), 6.87 (2H, t, J=8.7 Hz), 6.38 (2H, dd, J=4.7, 9.0 Hz), 4.46 (1H,
d, J=6.8 Hz), 4.17 (1H, t, J=6.8 Hz), 3.35 (1H, dd, J=6.8, 7.5 Hz),
2.69-2.58 (3H, m), 1.85-1.56 (4H, m). .sup.13C-NMR (75 MHz,
CDCl.sub.3) .delta.: 157.64, 154.52, 148.53, 142.69, 141.95 (C),
128.66, 128.25, 127.47, 125.99, 125.73, 115.41, 115.12, 113.04,
112.94 (CH), 74.37 (CH), 56.05 (CH.sub.2), 42.09 (CH), 35.85,
33.52, 28.92 (CH.sub.2). IR (cm.sup.-1): 3026, 2933, 2852, 1603,
1508, 1473, 1453, 1321, 1222, 1120, 823, 773, 747, 699. MALDI-MS
(C.sub.24H.sub.24FN) [MH].sup.+ 346.1982 (calcd. 346.1971). Anal.
Calcd for C.sub.24H.sub.24FN: C, 83.44; H, 7.00; N, 4.05. Found: C,
83.45; H, 7.06; N, 4.27.
Example 2
##STR00013##
[0075] Ezetimibe (commercially obtained or synthesized according to
Wu, G. Z. et al., J. Org. Chem. 1999, 64, 3714-3718) (5.530 g, 13.5
mmol) was suspended in 2-propanol (70 mL), aq. NaOH (2M, 15 mL)
followed by Ac.sub.2O (3.0 mL, 32 mmol) were added and the solution
was stirred for 5 h followed by addition of sat. aq. NaHCO.sub.3
(200 mL). After extraction with EtOAc (4.times.50 mL), the combined
organic layer was washed successively with sat. aq. NaHCO.sub.3 (50
mL) and H.sub.2O (50 mL), evaporated on celite and purified by dry
column vacuum chromatography (5.2.times.5.5 cm) on silica gel
eluting with a gradient of 0-100% EtOAc in hexane (v/v) to give the
corresponding azetidinone acetate (5.930 g, 97%) as a white
foam.
[0076] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.31 (2H, d,
J=8.7 Hz), 7.29-7.18 (4H, m), 7.09 (2H, d, T 8.7 Hz), 6.99 (2H, t,
J=8.7 Hz), 6.92 (2H, t, J=8.7 Hz), 4.67 (1H, bs), 4.61 (1H, d,
J=2.5 Hz), 3.08-3.04 (1H, m), 2.75 (1H, bs), 2.29 (3H, s),
1.97-1.85 (4H, m). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.:
169.16, 167.23, 163.56, 160.46, 160.32, 157.24, 150.58, 139.94,
139.90, 134.85, 133.53, 133.50 (C), 127.32, 127.21, 126.78, 122.38,
118.34, 118.23, 115.95, 115.65, 115.35, 115.07 (CH), 72.95, 60.81,
60.33 (CH), 36.61, 25.07 (CH.sub.2), 21.19 (CH.sub.3). IR
(cm.sup.-1): 3443, 3019, 2936, 2862, 1747, 1605, 1509, 1427, 1388,
1370, 1221, 1198, 1157, 1016, 835, 757, 668. MALDI-MS
(C.sub.26H.sub.23F.sub.2NO.sub.4): [MH--H.sub.2O].sup.+ 434.1556
(calcd. 434.1568); [Ma].sup.+474.1485 (calcd. 474.1493))
[0077] Subsequently the acetate (1.864 g, 4.13 mmol) was dissolved
in anhydrous DMF (25 mL), imidazole (939 mg, 13.8 mmol) and TBDMSCl
(1.853 g, 12.3 mmol) were added sequentially and the solution was
stirred for 3 h followed by addition of 50% sat. aq. NaHCO.sub.3
(150 mL). After extraction with EtOAc (4.times.40 mL), the combined
organic layer was washed successively with sat. aq. NaHCO.sub.3 (40
mL) and H.sub.2O (40 mL), evaporated on celite and purified by dry
column vacuum chromatography (4.2.times.5.5 cm) on silica gel
eluting with a gradient of 0-30% EtOAc in hexane (v/v) to give the
corresponding silylated azetidinone acetate (2.137 g, 91%) as a
colourless oil.
[0078] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.31 (2H, d,
J=8.7 Hz), 7.26-7.20 (4H, m), 7.10 (2H, d, J=8.7 Hz), 6.98 (2H, t,
J=8.7 Hz), 6.91 (2H, t, J=8.7 Hz), 4.67 (1H, t, J=5.3 Hz), 4.58
(1H, d, J=1.9 Hz), 3.06-3.02 (1H, m), 2.28 (3H, s), 1.96-1.80 (4H,
m), 0.88 (9H, s), 0.02 (3H, s), -0.16 (3H, s). .sup.13C-NMR (75
MHz, CDCl.sub.3) .delta.: 169.16, 167.06, 163.42, 160.47, 160.16,
157.23, 150.62, 140.50, 135.10, 133.74, 133.70 (C), 127.26, 127.14,
126.77, 122.37, 118.27, 118.16, 115.89, 115.58, 115.03, 114.76
(CH), 73.74, 60.67, 60.53 (CH), 37.94 (CH.sub.2), 25.73 (CH.sub.3),
24.55 (CH.sub.2), 20.99 (CH.sub.3), 18.07 (C), -4.74, -5.05
(CH.sub.3). IR (cm.sup.-1): 2953, 2930, 2857, 1752, 1606, 1510,
1472, 1426, 1385, 1370, 1252, 1219, 1197, 1166, 1140, 1102, 1086,
1015, 912, 835, 777, 736. MALDI-MS: [MH-TBDMSOH].sup.+ 434.1556
(calcd. 434.1568); [MNa].sup.+ 588.2347 (calcd. 588.2358). Anal.
Calcd for C.sub.32H.sub.37F.sub.2NO.sub.4Si: C, 67.94; H, 6.59; N,
2.48. Found: C, 67.94; H. 6.64; N, 2.37)
[0079] The silylated azetidinone acetate (5.123 g, 9.06 mmol) was
dissolved in CH.sub.2Cl.sub.2 (200 mL), neutral alumina (50 g) was
added and the suspension was evaporated to dryness. The coated
alumina was dried shortly under vacuum and then heated to
70.degree. C. for 5.5 h. After cooling, the alumina was extracted
with 10% MeOH in CH.sub.2Cl.sub.2 (8.times.50 mL) and the combined
organic extracts were evaporated on celite and purified by dry
column vacuum chromatography (5.4.times.5.5 cm) on silica gel
eluting with a gradient of 0-30% EtOAc in hexane (v/v) to give the
silylated azetidinone phenol VIa (3.919 g, 83%) as a white
foam.
[0080] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.26-7.14 (6H,
m), 6.99-6.83 (6H, m), 6.16 (1H, bs), 4.65 (1H, t, J=5.3 Hz), 4.52
(1H, d, J=1.9 Hz), 3.04-2.98 (1H, m), 1.92-1.76 (4H, m), 0.86 (9H,
s), 0.00 (3H, s), -0.17 (3H, s). .sup.13C-NMR (75 MHz, CDCl.sub.3)
.delta.: 167.82, 163.28, 160.42, 156.12, 140.50, 140.45, 133.57
(C), 128.92, 127.19, 127.15, 127.08, 118.43, 118.32, 116.05,
115.85, 115.55, 115.01, 114.72 (CH), 73.82, 61.17, 60.35 (CH),
38.07 (CH.sub.2), 25.89 (CH.sub.3), 24.68 (CH.sub.2), 18.25 (C),
-4.54, -4.84 (CH.sub.3). IR (cm.sup.-3): 3351, 2953, 2938, 2857,
1722, 1615, 1604, 1510, 1450, 1391, 1361, 1252, 1223, 1156, 1103,
1087, 863, 834, 776, 760. MALDI-MS: [MH-TBDMSOH].sup.+ 392.1451
(calcd. 392.1462); [MH].sup.+ 524.2409 (calcd. 524.2433);
[MNa].sup.+ 546.2242 (calcd. 546.2252). Anal. Calcd for
C.sub.30H.sub.35F.sub.2NO.sub.3Si: C, 68.81; H, 6.74; N, 2.67.
Found: C, 68.61; H, 6.82; N, 2.66.
##STR00014##
[0081] The silylated azetidinone phenol VIa (176 mg, 0.336 mmol)
was dissolved in anhydrous CH.sub.2Cl.sub.2 (10 mL), anhydrous
pyridine (0.5 mL) followed by MsCl (0.1 mL, 1.29 mmol) were added
and the solution was stirred for 22 h, diluted with EtOAc (50 mL)
and washed sequentially with sat. aq. NaHCO.sub.3 (20 mL) and
H.sub.2O (20 mL). The organic layer was evaporated on celite and
purified by dry column vacuum chromatography (4.2.times.3.3 cm) on
silica gel eluting with a gradient of 0-50% EtOAc in hexane (v/v)
to give the intermediate mesylate VIb (195.5 mg, 92%) as a
colourless oil.
[0082] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.35 (2H, d,
J=8.7 Hz), 7.28 (2H, d, J=8.7 Hz), 7.26-7.18 (4H, m), 6.98 (2H, t,
J=8.7 Hz), 6.93 (2H, t, J=8.7 Hz), 4.67 (1H, dd, J=4.4, 6.2 Hz),
4.59 (1H, d, J=1.9 Hz), 3.16 (3H, s), 3.04-3.00 (1H, m), 1.93-1.79
(4H, m), 0.87 (9H, s), 0.01 (3H, s), -0.16 (3H, s). .sup.13C-NMR
(75 MHz, CDCl.sub.3) .delta.: 166.83, 163.46, 160.57, 160.21,
157.34, 148.88, 140.53, 140.49, 137.07, 133.59, 133.56 (C), 127.36,
127.28, 127.18, 122.94, 118.26, 118.16, 116.04, 115.73, 115.10,
114.81 (CH), 73.79, 60.67, 60.41 (CH), 37.97 (CH.sub.2), 37.59,
25.76 (CH.sub.3), 24.60 (CH.sub.2), 18.11 (C), -4.71, -5.02
(CH.sub.3). IR (cm.sup.-1): 2952, 2931, 2857, 1752, 1605, 1509,
1371, 1252, 1220, 1176, 1153, 1102, 1086, 971, 871, 835, 777.
MALDI-MS: [MH-TBDMSOH].sup.+ 470.1228 (calcd. 470.12376);
[MNa].sup.+ 624.2029 (calcd. 624.2027). Anal. Calcd for
C.sub.33H.sub.37F.sub.2NO.sub.5SiS: C, 61.87; H, 6.20; N, 2.33.
Found: C, 61.69; H, 6.19; N. 2.15).
c)
[0083] The intermediate mesylate received in the previous step
(67.7 mg, 0.112 mmol) was dissolved in THF (2 mL), TBAF (0.2 mL, 1M
in THF) was added and the solution was stirred for 1.5 h, diluted
with EtOAc (20 mL) and washed successively with sat. aq.
NaHCO.sub.3 (10 mL) and H.sub.2O (10 mL). The organic layer was
evaporated on celite and purified by dry column vacuum
chromatography (4.2.times.2.0 cm) on silica gel eluting with a
gradient of 0-90% EtOAc in hexane (v/v) to give the desired
mesylated azetidinone VI (37.0 mg, 68%) as a white solid after
coevaporation with hexane (10 mL).
[0084] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.37-7.17 (8H,
m), 7.03-6.91 (4H, m), 4.69 (1H, t, J=5.9 Hz), 4.65 (1H, d, J=1.9
Hz), 3.16 (3H, s), 3.07-3.01 (1H, m), 2.63 (1H, bs), 2.03-1.84 (4H,
m). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 167.11, 163.76,
160.68, 160.50, 157.44, 148.89, 139.92, 136.86, 133.41 (C), 127.40,
127.27, 122.98, 118.35, 118.24, 116.10, 115.79, 115.45, 115.18,
115.11 (CH), 73.03, 60.48, 60.41 (CH), 37.63 (CH.sub.3), 36.48,
25.00 (CH.sub.2). IR (cm.sup.-1): 3428, 2937, 1744, 1604, 1510,
1426, 1369, 1221, 1176, 1152, 1103, 1016, 971, 912, 872, 835, 788,
734. MALDI-MS: [MH--H.sub.2O].sup.+ 470.1239 (calcd. 470.1238);
[MNa].sup.+ 510.1164 (calcd. 510.1163). Anal. Calcd for
C.sub.25H.sub.23F.sub.2NO.sub.5S: C, 61.59; H, 4.75; N, 2.87.
Found: C, 61.79; H, 4.89; N, 2.76.
Example 3
##STR00015##
[0086] LiAlH.sub.4 (58 mg, 1.5 mmol) and AlCl.sub.3 (202 mg, 1.5
mmol) were suspended in anhydrous ether (15 mL), refluxed for 30
min and cooled to 0.degree. C. The mesylate VIb obtained in step
2b) (195.5 mg, 0.325 mmol) dissolved in anhydrous ether (5 ml) was
added and after stirring at 0.degree. C. for 15 min, sat. aq.
NaHCO.sub.3 (1 mL) was added dropwise. The suspension was
evaporated on celite and purified by dry column vacuum
chromatography (4.6.times.3.3 cm) on silica gel eluting with a
gradient of 0-50% EtOAc in hexane (v/v) to give the intermediate
silylated azetidine (146.4 mg, 77%) as a colourless oil.
[0087] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.49 (2H, d,
J=8.7 Hz), 7.30 (2H, d, J=8.7 Hz), 7.18 (2H, dd, J=5.0, 8.7 Hz),
6.98 (2H, t, J=8.7 Hz), 6.85 (2H, t, J=8.7 Hz), 6.31 (2H, dd,
J=4.4, 9.3 Hz), 4.58 (1H, t, J=5.3 Hz), 4.40 (1H, d, J=6.8 Hz),
4.11 (1H, t, J=7.2 Hz), 3.28 (1H, t, J=7.2 Hz), 3.17 (3H, s),
2.56-2.49 (1H, m), 1.77-1.50 (4H, m), 0.88 (9H, s), 0.01 (3H, s),
-0.15 (3H, s). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 163.22,
159.99, 157.69, 154.57, 148.23, 148.07, 141.97, 140.62 (C), 127.41,
127.13, 127.03, 122.25, 115.43, 115.13, 114.96, 114.68, 113.00,
112.90 (CH), 73.86, 73.29 (CH), 55.88 (CH.sub.2), 41.88 (CH), 37.90
(CH.sub.2), 37.43 (CH.sub.3), 29.43 (CH.sub.2), 25.85 (CH.sub.3),
18.24 (C), -4.53, -4.88 (CH.sub.3). IR (cm.sup.-1): 2932, 2856,
1605, 1509, 1473, 1372, 1331, 1252, 1222, 1198, 1171, 1151, 1090,
970, 870, 836, 776. MALDI-MS: [MH-TBDMSOH].sup.+ 456.1442 (calcd.
456.14449); [MNa].sup.+ 610.2236 (calcd. 610.22348). Anal. Calcd
for C.sub.31H.sub.39F.sub.2NO.sub.4SiS: C, 63.34; H, 6.69; N, 2.38.
Found: C, 63.49; H, 6.87; N, 2.33.
[0088] This intermediate silylated azetidine (146.3 mg, 0.249 mmol)
was dissolved in anhydrous THF (5.0 mL, teflon-bottle) at 0.degree.
C., anhydrous pyridine (1.0 mL) followed by HF-pyridine complex
(1.0 mL) were added and the solution was stirred at 0.degree. C.
for 1 h and at room temperature for 7 h, diluted with ether (30 mL)
and washed with sat. aq. NaHCO.sub.3 (3.times.10 mL). The organic
layer was evaporated on celite and purified by dry column vacuum
chromatography (4.2.times.2.0 cm) on silica gel eluting with a
gradient of 0-90% EtOAc in hexane (v/v) to give the desired
mesylated azetidine VII (100.0 mg, 85%) as a white foam.
[0089] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.50 (2H, d,
J=8.7 Hz), 7.28 (2H, d, J=8.7 Hz), 7.22 (2H, dd, J=5.6, 8.7 Hz),
7.01 (2H, t, J=8.7 Hz), 6.84 (2H, t, J=8.7 Hz), 6.30 (2H, dd,
J=4.3, 9.3 Hz), 4.57 (1H, t, J=5.6 Hz), 4.41 (1H, d, J=6.8 Hz),
4.12 (1H, t, J=6.8 Hz), 3.30 (1H, dd, J=6.8, 7.5 Hz), 3.16 (3H, s),
2.55 (1H, dt, J=6.8, 7.5 Hz), 1.93 (1H, bs), 1.88-1.53 (4H, m).
.sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 163.62, 160.37, 157.74,
154.61, 148.22, 148.01, 141.89, 139.95, 139.91 (C), 127.46, 127.28,
127.17, 122.29, 115.46, 115.42, 115.13, 113.02, 112.92 (CH), 73.43,
73.28 (CH), 55.92 (CH.sub.2), 41.81 (CH), 37.49 (CH.sub.3), 36.28,
29.85 (CH.sub.2). IR (cm.sup.-1): 3416, 2938, 2853, 1508, 1367,
1221, 1196, 1171, 1149, 970, 871, 823. MALDI-MS
(C.sub.25H.sub.25F.sub.2NO.sub.4S): [MH--H.sub.2O].sup.+ 456.1447
(calcd. 456.1445); [M].sup.+ 473.1481 (calcd. 473.1472);
[MNa].sup.+ 496.1380 (calcd. 496.1370).
Example 4
##STR00016##
[0091] The silylated azetidinone phenol VIa obtained in step 2a)
(143 mg, 0.273 mmol) and
C-(hydroxymethyl)-2,3,4,6-tetra-O-benzyl-.beta.-D-glucopyranoside
(prepared according to RajanBabu, T. V. and Reddy, G. S. J. Org.
Chem. 1986, 51, 5458-5461; 180 mg, 0.325 mmol) were dissolved in
anhydrous THIF (10 mL) at 0.degree. C., Bu.sub.3P (0.20 mL, 0.80
mmol) and 1,1'-(azodicarbonyl)dipiperidine (206 mg, 0.82 mmol) were
added sequentially and the suspension was allowed to warm to
ambient temperature over several hours and stirred for 24 h.
EtOAc/hexane (1:4 (v/v), 20 mL) was added, the suspension was
filtered through celite (2.times.10 mL EtOAc/hexane (1:4 (v/v))
washings) and the filtrate was evaporated on celite and purified by
dry column vacuum chromatography (4.1.times.3.3 cm) on silica gel
eluting with a gradient of 0-50% EtOAc in hexane (v/v) to give the
corresponding C-glycoside (60.1 mg, 21%) as a colourless oil.
[0092] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.37-7.17 (26H,
m), 7.04-6.89 (6H, m), 4.96 (2H, bs), 4.89 (1H, d, J=9.3 Hz), 4.86
(1H, d, J=8.7 Hz), 4.69 (1H, t, T=5.3 Hz), 4.63-4.53 (5H, m), 4.21
(1H, d, J=10.6 Hz), 4.10 (1H, dd, J=5.0, 10.6 Hz), 3.85-3.52 (7H,
m), 3.07-3.02 (1H, m), 2.01-1.78 (4H, m), 0.91 (9H, s), 0.05 (3H,
s), -0.13 (3H, s). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.:
167.25, 158.74, 140.53, 140.49, 138.29, 137.85, 137.79, 137.65,
133.81 (C), 129.53, 128.32, 128.28, 128.18, 127.96, 127.81, 127.78,
127.74, 127.66, 127.54, 127.48, 127.18, 127.08, 126.90, 118.22,
118.12, 115.77, 115.47, 115.30, 114.98, 114.70 (CH), 87.12, 79.14,
78.25, 77.87, 77.71 (CH), 75.56, 75.11, 75.03 (CH.sub.2), 73.82
(CH), 73.44, 68.93, 67.23 (CH.sub.2), 61.02, 60.47 (CH), 38.10
(CH.sub.2), 25.89 (CH.sub.3), 24.71 (CH.sub.2), 18.24 (C), -4.54,
-4.83 (CH.sub.3). IR (cm.sup.-1): 2951, 2929, 2858, 1749, 1608,
1510, 1454, 1386, 1361, 1250, 1223, 1156, 1141, 1101, 1028, 911,
835, 777, 735, 699. MALDI-MS (C.sub.65H.sub.71F.sub.2NO.sub.8Si):
[MNa].sup.+ 1082.4831 (calcd. 1082.4815).
[0093] This C-Glycoside (72 mg, 0.068 mmol) was subsequently
dissolved in EtOH (5 mL), Pd (OH).sub.2/C (20% (w/w), 40 mg) was
added and the suspension was evacuated 4 times with H.sub.2 and
stirred under an H.sub.2-atmosphere for 17 h. The suspension was
evaporated on celite and purified by dry column vacuum
chromatography (3.8.times.2.0 cm) on silica gel eluting with a
gradient of 0-100% EtOAc in hexane followed by 10% MeOH in
CH.sub.2Cl.sub.2 (v/v) to give the debenzylated C-glycoside (28 mg,
59%) as colourless oil.
[0094] .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 167.22, 163.28,
160.05, 158.36, 157.03, 140.57, 133.75, 130.30, 129.52, 127.22,
127.11, 118.23, 115.83, 115.54, 116.35, 115.05, 114.91, 114.76,
79.16, 78.33, 77.70, 73.88, 70.18, 69.52, 67.75, 61.54, 60.79,
60.57, 38.14, 25.91, 24.81, 18.27, -4.51, -4.80. IR (cm.sup.-):
3391, 2930, 2858, 1747, 1609, 1510, 1387, 1362, 1223, 1140, 1086,
1043, 1014, 835, 758. MALDI-MS (C.sub.37H.sub.47F.sub.2NO.sub.8Si):
[MH-TBDMSOH].sup.+ 568.2132 (calcd. 568.2147); [MNa].sup.+ 722.2939
(calcd. 722.2937).
[0095] Subsequently, the debenzylated C-Glycoside (27.0 mg, 0.039
mmol) was dissolved in THF (1.0 mL), TBAF (0.2 mL, 1M in THF) was
added and the solution was stirred for 15 h, diluted with
CH.sub.2Cl.sub.2, evaporated on celite and purified by dry column
vacuum chromatography (3.5.times.2.0 cm) on silica gel eluting with
a gradient of 0-18% MeOH in CH.sub.2Cl.sub.2 (v/v) to give the
desired C-glycoside VIII (14.0 mg, 62%) as a white solid after
coevaporation with hexane (10 mL).
[0096] .sup.1H-NMR (300 MHz, CD.sub.3OD) .delta.: 7.33-7.23 (6H,
m), 7.05-6.94 (6H, m), 4.78 (1H, d, J=1.9 Hz), 4.59 (1H, t, J=5.3
Hz), 4.29 (1H, dd, J=1.5, 10.3 Hz), 4.13 (1H, dd, J=5.6, 10.6 Hz),
3.85 (1H, d, J=11.2 Hz), 3.67-3.61 (1H, m), 3.57-3.51 (1H, m),
3.44-3.37 (2H, m), 3.31-3.28 (2H, m), 3.11-3.06 (1H, m), 1.97-1.81
(4H, m). .sup.13C-NMR (75 MHz, CD.sub.3OD) .delta.: 169.20, 160.12,
130.69, 128.36, 128.25, 128.14, 119.52, 119.41, 116.35, 116.04,
115.93, 115.63, 115.35, 81.55, 79.49, 79.39, 73.35, 71.30, 71.23,
68.77, 62.66, 61.74, 60.86, 37.22, 25.84. MALDI-MS
(C.sub.31H.sub.33F.sub.2NO.sub.8): [MH-TBDMSOH].sup.+ 568.2143
(calcd. 568.2147); [MNa].sup.+ 608.2073 (calcd. 608.2072).
Example 5
##STR00017##
[0098] Methyl 2,3,4-Tri-O-benzyl-.alpha.-D-glucopyranoside
(prepared according to Jaramillo, C. et al; Chiara, J. L.;
Martinlomas, M. J. Org. Chem. 1994, 59, 3135-3141; 1.181 g, 2.54
mmol) was dissolved in anhydrous CH.sub.2Cl.sub.2 (25 mL) at
0.degree. C., anhydrous pyridine (3.0 mL) followed by MsCl (0.50
mL, 6.4 mmol) were added and the solution was stirred at 0.degree.
C. for 1 h and at room temperature for 7 h followed by addition of
sat. aq. NaHCO.sub.3 (50 mL). The layers were separated and the
aqueous layer extracted with EtOAc (3.times.25 mL). The combined
organic layer was washed successively with sat. aq. NaHCO.sub.3 (25
mL) and H.sub.2O (25 ml), evaporated on celite and purified by dry
column vacuum chromatography (4.1.times.3.3 cm) on silica gel
eluting with a gradient of 0-100% CH.sub.2Cl.sub.2 in hexane (v/v)
followed by 0.25-1.0% MeOH in CH.sub.2Cl.sub.2 (v/v) to give the
corresponding mesylate (1.303 g, 94%) as a colourless oil after
coevaporation with acetonitrile (3.times.10 mL).
[0099] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.39-7.26 (15H,
m), 5.02 (1H, d, J=10.6 Hz), 4.92 (1H, d, J=10.6 Hz), 4.84 (1H, d,
J=10.6 Hz), 4.80 (1H, d, J=12.5 Hz), 4.66 (1H, d, J=11.8 Hz), 4.63
(1H, d, J=10.6 Hz), 4.60 (1H, d, J=3.7 Hz), 4.41-4.32 (2H, m), 4.02
(1H, t, J=9.3 Hz), 3.85 (1H, dt, J=3.7, 10.0 Hz), 3.52 (1H, dt,
J=3.7, 6.2 Hz), 3.50 (1H, bs), 3.39 (3H, s), 2.98 (3H, s).
.sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 138.30, 137.75, 137.56
(C), 128.36, 128.30, 127.94, 127.84, 127.76, 127.57 (CH), 98.06,
81.73, 79.69, 76.86 (CH), 75.73, 75.09, 73.44 (CH.sub.2), 68.59
(CH), 68.36 (CH.sub.2), 55.46, 37.54 (CH.sub.3). IR (cm.sup.-1):
3031, 2913, 1497, 1454, 1359, 1177, 1089, 1074, 1046, 1003, 965,
931, 813, 739, 699. MALDI-MS: [MNa].sup.+ 565.1873 (calcd.
565.1872). Anal. Calcd for C.sub.29H.sub.34O.sub.8S: C, 64.19; H,
6.32. Found: C, 63.99; H. 6.27.
[0100] Subsequently, this mesylate (1.290 g, 2.38 mmol) was
dissolved in EtOH (25 mL), KOSCMe (869 mg, 7.61 mmol) was added and
the unclear solution was stirred at reflux for 4 h (orange
precipitate). After cooling, 50% sat. aq. NaHCO.sub.3 (100 mL) was
added and the suspension was extracted with EtOAc (3.times.50 mL).
The combined organic layer was washed successively with sat. aq.
NaHCO.sub.3 (50 mL) and H.sub.2O (50 mL), evaporated on celite and
purified by dry column vacuum chromatography (4.1.times.3.3 cm) on
silica gel eluting with a gradient of 0-30% EtOAc in hexane (v/v)
to give the corresponding thioacetate (1.189 g, 96%) as a light
orange solid.
[0101] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.41-7.32 (15H,
m), 5.03 (1H, d, J=10.6 Hz), 4.94 (1H, d, J=10.6 Hz), 4.86 (1H, d,
J=10.6 Hz), 4.82 (1H, d, J=11.8 Hz), 4.69 (1H, d, J=11.8 Hz), 4.66
(1H, d, J=10.6 Hz), 4.58 (1H, d, J=3.1 Hz), 4.02 (1H, t, J=9.0 Hz),
3.81 (1H, dt, J=2.5, 7.5 Hz), 3.55 (1H, dd, J=3.7, 9.3 Hz), 3.48
(1H, dd, J=3.1, 13.7 Hz), 3.40 (3H, s), 3.35 (1H, t, J=9.5 Hz),
3.08 (1H, dd, J=7.5, 13.7 Hz), 2.36 (3H, s). .sup.13C-NMR (75 MHz,
CDCl.sub.3) .delta.: 194.67, 138.46, 137.90, 137.78 (C), 128.33,
128.29, 128.03, 127.94, 127.85, 127.81, 127.74, 127.53 (CH), 97.72,
81.69, 80.36, 79.78 (CH), 75.64, 75.04, 73.22 (CH.sub.2), 69.23
(CH), 55.02 (CH.sub.3), 30.73 (CH.sub.2), 30.39 (CH.sub.3). IR
(cm.sup.-1): 3063, 3031, 2908, 1694, 1497, 1454, 1358, 1201, 1156,
1136, 1092, 1072, 1050, 1029, 999, 955, 737, 698, 630. MALDI-MS:
[MNa].sup.+ 545.1974 (calcd. 545.1974). Anal. Calcd for
C.sub.30H.sub.34O.sub.6S: C, 68.94; H, 6.56. Found: C, 68.77; H.
6.63.
[0102] The thioacetate received above (1.180 g, 2.26 mmol) was then
dissolved in ACOH (25 mL), KOAc (4.082 g, 41.6 mmol) followed by
Oxone (2KHSO.sub.5.KHSO.sub.4.K.sub.2SO.sub.4, 4.019 g, 8.69 mmol)
were added and after stirring for 15 h, sat. aq. NaHCO.sub.3 (100
mL), H.sub.2O (50 mL) and sat. aq. Na.sub.2CO.sub.3 (50 mL) were
carefully added. After extraction with EtOAc (4.times.40 mL), the
combined organic layer was washed with sat. aq. Na.sub.2CO.sub.3
(50 mL), evaporated on celite and purified by dry column vacuum
chromatography (4.0.times.3.3 cm) on silica gel eluting with a
gradient of 0-90% EtOAc in hexane (v/v) followed by 0-50% MeOH in
EtOAc (v/v) to give the corresponding sulfonate salt (1.116 g, 90%)
as a white solid.
[0103] .sup.1H-NMR (300 MHz, CD.sub.3OD) .delta.: 7.37-7.21 (15H,
m), 4.90 (1H, d, J=11.2 Hz), 4.86 (1H, d, J=10.6 Hz), 4.84 (1H, d,
J=11.2 Hz), 4.73 (1H, d, J=3.1 Hz), 4.72 (1H, d, J=11.2 Hz), 4.64
(1H, d, J=12.5 Hz), 4.60 (1H, d, J=11.2 Hz), 4.16 (1H, t, J=9.2
Hz), 3.90 (1H, t, J=9.3 Hz), 3.55 (1H, dd, J=3.4, 9.3 Hz), 3.48
(3H, s), 3.30-3.22 (2H, m), 2.92 (1H, dd, J=10.0, 14.3 Hz).
.sup.13C-NMR (75 MHz, CD.sub.3OD) .delta.: 140.03, 139.57, 139.55
(C), 129.42, 129.31, 129.15, 128.93, 128.89, 128.84, 128.67, 128.59
(CH), 98.53, 83.03, 81.65, 81.52 (CH), 76.44, 75.83, 73.85
(CH.sub.2), 68.52 (CH), 55.95 (CH.sub.3), 53.65 (CH.sub.2). IR
(cm.sup.-1): 3484, 3030, 2922, 1497, 1454, 1360, 1230, 1198, 1177,
1156, 1093, 1058, 1028, 736, 696. MALDI-MS
(C.sub.28H.sub.31NaO.sub.8S) [MNa].sup.+ 573.1536 (calcd.
573.1535).
[0104] Finally, the obtained sulfonate salt (696 mg, 1.26 mmol) was
suspended in anhydrous acetonitrile/CH.sub.2Cl.sub.2 (10 mL, 1:1
(v/v)) at 0.degree. C., Ph.sub.3P (1.002 g, 3.8 mmol) and thionyl
chloride (0.40 mL, 5.5 mmol) were added sequentially and the
suspension was stirred at room temperature for 13 h. EtOAc/hexane
(1:4 (v/v), 100 mL) was added, the suspension was filtered through
celite (4.times.15 mL EtOAc/hexane (1:3 (v/v)) washings) and the
filtrate was evaporated and dried shortly under vacuum to give the
desired sulfonyl chloride IXa (657 mg, 95%) as a yellowish oil.
[0105] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.42-7.28 (15H,
m), 5.05 (1H, d, J=10.6 Hz), 4.96 (1H, d, J=11.8 Hz), 4.85 (1H, d,
J=10.6 Hz), 4.83 (1H, d, J=11.8 Hz), 4.67 (1H, d, J=12.5 Hz), 4.60
(1H, d, J=11.2 Hz), 4.60 (1H, d, J=3.1 Hz), 4.33 (1H, t, J=9.6 Hz),
4.07 (1H, t, J=9.0 Hz), 3.85 (1H, dd, J=1.2, 13.7 Hz), 3.55 (1H, d,
J=9.3 Hz), 3.52 (1H, t, J=10.0 Hz), 3.46 (3H, s), 3.26 (1H, t,
J=9.5 Hz). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 138.02,
137.57, 137.06 (C), 128.58, 128.36, 128.30, 128.23, 128.12, 127.92,
127.66 (CH), 98.00, 81.56, 79.41, 78.49 (CH), 75.85, 74.76, 73.38,
66.75 (CH.sub.2), 65.93 (CH), 55.90 (CH.sub.3). MALDI-MS
(C.sub.28H.sub.33ClO.sub.7S): [MNa].sup.+ 569.1378 (calcd.
569.1377).
##STR00018##
[0106] The sulfonyl chloride IXa obtained in step 5a) (197 mg, 0.36
mmol) was suspended in anhydrous CH.sub.2Cl.sub.2 (5 mL), anhydrous
pyridine (0.5 mL) followed by the silylated azetidinone phenol VIa
obtained in step 2a) (70.0 mg, 0.13 mmol) were added and the
solution was stirred for 22 h, diluted with EtOAc (25 mL) and
washed sequentially with sat. aq. NaHCO.sub.3 (10 mL) and H.sub.2O
(10 mL). The organic layer was evaporated on celite and purified by
dry column vacuum chromatography (4.3.times.2.0 cm) on silica gel
eluting with a gradient of 0-35% EtOAc in hexane (v/v) to give the
corresponding glycosylated azetidinone (125.5 mg, 91%) as a
colourless oil/glass.
[0107] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.37-7.14 (23H,
m), 7.00 (2H, t, J=8.7 Hz), 6.95 (2H, t, J=8.7 Hz), 5.05 (1H, d,
J=11.2 Hz), 4.97 (1H, d, J=11.2 Hz), 4.84 (1H, d, J=11.8 Hz), 4.82
(1H, d, J=10.6 Hz), 4.69 (1H, t, J=6.8 Hz), 4.67 (1H, d, J=12.5
Hz), 4.60 (1H, d, J=3.7 Hz), 4.56 (1H, d, J=12.5 Hz), 4.54 (1H, d,
J=10.6 Hz), 4.29 (1H, t, J=9.5 Hz), 4.06 (1H, t, J=9.0 Hz), 3.57
(1H, t, J=3.1 Hz), 3.53 (1H, d, J=3.1 Hz), 3.46 (3H, s), 3.26 (1H,
t, J=9.3 Hz), 3.14 (1H, dd, J=10.0, 14.3 Hz), 2.96 (1H, dt, J=1.9,
6.8 Hz), 1.97-1.78 (4H, m), 0.90 (9H, s), 0.04 (3H, s), -0.13 (3H,
s). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 166.62, 163.27,
160.37, 160.03, 157.14, 148.91, 140.33, 138.05, 137.63, 137.29,
136.67, 133.45, 133.42 (C), 128.44, 128.31, 128.18, 128.04, 127.96,
127.86, 127.65, 127.15, 127.03, 126.97, 123.15, 118.13, 118.03,
115.93, 115.64, 115.02, 114.75 (CH), 97.92, 81.67, 79.60, 79.23
(CH), 75.78, 74.86 (CH.sub.2), 73.78 (CH), 73.37 (CH.sub.2), 65.64,
60.66, 60.48 (CH), 55.73 (CH.sub.3), 51.63, 38.06 (CH.sub.2), 25.85
(CH.sub.3), 24.69 (CH.sub.2), 18.22 (C), -4.54, -4.87 (CH.sub.3).
IR (cm.sup.-1): 3032, 2930, 2858, 1750, 1605, 1510, 1455, 1386,
1252, 1220, 1153, 1086, 1073, 1048, 870, 836, 755, 699. MALDI-MS:
[MNa].sup.+ 1056.3969 (calcd. 1056.3964). Anal. Calcd for
C.sub.58H.sub.65F.sub.2NO.sub.10SiS: C, 67.3.5; H, 6.33; N, 1.35.
Found: C, 67.43; H, 6.44; N, 1.33.
[0108] Subsequently the glycosylated azetidinone (105.1 mg, 0.102
mmol) was dissolved in EtOH (5 mL), Pd(OH).sub.2/C (20% (w/w), 33
mg) was added and the suspension was evacuated 4 times with H.sub.2
and stirred under an H.sub.2-atmosphere for 6 h. The suspension was
evaporated on celite and purified by dry column vacuum
chromatography (4.2.times.2.0 cm) on silica gel eluting with a
gradient of 0-10% MeOH in CH.sub.2Cl.sub.2 (v/v) to give the
debenzylated azetidinone (63.2 mg, 81%) as a colourless oil.
[0109] .sup.1H-NMR (300 MHz, acetone-d.sub.6) .delta.: 7.55 (2H, d,
J=8.7 Hz), 7.42 (2H, d, J=8.7 Hz), 7.37 (2H, dd, J=5.9, 8.4 Hz),
7.28 (2H, dd, J=5.0, 9.3 Hz), 7.11-7.01 (4H, m), 4.96 (1H, d, J=1.9
Hz), 4.84 (1H, t, J=5.3 Hz), 4.69 (1H, d, J=3.7 Hz), 4.61 (1H, d,
J=5.0 Hz), 4.35 (1H, d, J=3.1. Hz), 4.16 (1H, dt, J=1.2, 10.0 Hz),
3.87 (1H, dd, J=1.2, 14.9 Hz), 3.79 (1H, d, J=7.5 Hz), 3.65 (1H, t,
J=9.0 Hz), 3.56 (1H, dd, J=10.0, 14.9 Hz), 3.45-3.40 (1H, m), 3.38
(3H, s), 3.27-3.14 (2H, m), 2.00-1.88 (4H, m), 0.87 (9H, s), 0.05
(3H, s), -0.15 (3H, s). .sup.13C-NMR (75 MHz, acetone-d.sub.6)
.delta.: 167.25, 163.96, 160.84, 160.75, 157.65, 150.14, 141.91,
141.87, 138.13, 134.95, 134.91 (C), 128.32, 128.23, 123.84, 118.98,
118.88, 116.43, 116.12, 115.49, 115.21 (CH), 100.74, 74.77, 74.42,
73.55, 73.04, 68.01, 61.25, 60.50 (CH), 55.56 (CH.sub.3), 52.83,
38.50 (CH.sub.2), 26.16 (CH.sub.3), 25.34 (CH.sub.2), 18.65 (C),
-4.47, -4.71 (CH.sub.3). IR (cm.sup.-1) 3396, 2951, 2931, 2857,
1754, 1701, 1605, 1510, 1426, 1385, 1250, 1220, 1151, 1103, 1088,
1053, 1015, 988, 872, 836, 778. MALDI-MS
(C.sub.37H.sub.47F.sub.2NO.sub.10SSi): [MNa].sup.+ 786.2559 (calcd.
786.2556).
[0110] This debenzylated azetidinone (58.9 mg, 0.077 mmol) was
dissolved in anhydrous THF (2.5 mL, teflon bottle), anhydrous
pyridine (0.5 mL) followed by HF.pyridine complex (0.5 mL) were
added and the solution was stirred for 14.5 h, diluted with ether
(20 mL) and washed with sat. aq. NaHCO.sub.3 (3.times.5 mL). The
organic layer was evaporated on celite and purified by dry column
vacuum chromatography (4.2.times.2.0 cm) on silica gel eluting with
a gradient of 0-10% MeOH in CH.sub.2Cl.sub.2 (v/v) to give the
desired azetidinone IXb (44.9 mg; 90%) as a white solid.
[0111] .sup.1H-NMR (300 Mz, acetone-d.sub.6) .delta.: 7.56 (2H, d,
J=8.7 Hz), 7.43 (2H, d, J=8.7 Hz), 7.37 (2H, dd, J=5.6, 8.7 Hz),
7.30 (2H, dd, J=4.7, 9.0 Hz), 7.06 (2H, d, J=9.3 Hz), 7.03 (2H, d,
J=8.7 Hz), 4.99 (1H, d, J=2.5 Hz), 4.69 (1H, d, J=3.7 Hz), 4.61
(1H, d, J=5.0 Hz), 4.42 (1H, d, J=3.7 Hz), 4.34 (1H, bs), 4.15 (1H,
dt, J=1.2, 8.7 Hz), 3.86 (1H, dd, J=1.2, 14.9 Hz), 3.79 (1H, d,
J=8.1 Hz), 3.65 (1H, t, J=8.7 Hz), 3.57 (1H, dd, J=10.0, 14.9 Hz),
3.44-3.38 (1H, m), 3.38 (3H, s), 3.32-3.14 (2H, m), 2.08-1.86 (4H,
m). .sup.13C-NMR (75 MHz, acetone-d.sub.6) .delta.: 167.42, 163.87,
160.85, 157.67, 150.13, 142.52, 138.18, 134.93 (C), 128.35, 128.22,
128.13, 123.83, 119.01, 118.89, 116.44, 116.13, 115.40, 115.11
(CH), 100.74, 74.77, 73.56, 73.04, 72.77, 68.01, 61.27, 60.56 (CH),
55.56 (CH.sub.3), 52.83, 37.54, 25.70 (CH.sub.2). IR (cm.sup.-1):
3395, 2925, 1732, 1604, 1509, 1365, 1219, 1148, 1103, 1051, 1014,
871, 834, 752. MALDI-MS: [MNa].sup.+ 672.1693 (calcd. 672.1691).
Anal. Calcd for C.sub.31H.sub.33F.sub.2NO.sub.10S: C, 57.31; H,
5.12; N, 2.16. Found: C, 57.34; H. 5.26; N, 2.21.
c)
[0112] LiAlH.sub.4 (57 mg, 1.5 mmol) and AlCl.sub.3 (200 mg, 1.5
mmol) were suspended in anhydrous ether (15 mL), refluxed for 30
min and cooled to 0.degree. C. The azetidinone IXb obtained under
step 5b) (26.8 mg, 0.041 mmol) dissolved in anhydrous THF (1 mL,
2.times.0.5 mL rinse) was added and after stirring at 0.degree. C.
for 10 min, sat. aq. NaHCO.sub.3 (1 mL) was added dropwise. The
suspension was evaporated on celite and purified by dry column
vacuum chromatography (4.7.times.2.0 cm) on silica gel eluting with
a gradient of 0-12% MeOH in CH.sub.2Cl.sub.2 (v/v) to give the
desired azetidine IX (20.4 mg, 78%) as a colourless oil.
[0113] .sup.1H-NMR (300 MHz, acetone-d.sub.6) .delta.: 7.63-7.59
(2H, m), 7.49-7.42 (2H, m), 7.36-7.29 (2H, m), 7.10-7.01 (2H, m),
6.92-6.77 (2H, m), 6.40-6.35 (2H, m), 4.72 (1H, d, J=3.7 Hz), 4.62
(1H, d, T=5.0 Hz), 4.61 (1H, bs), 4.52 (1H, d, T=6.9 Hz), 4.31 (2H,
t, J=4.4 Hz), 4.21-4.15 (2H, m), 3.90 (1H, dd, J=1.2, 14.9 Hz),
3.76 (1H, d, j=8.1 Hz), 3.68 (1H, dd, J=3.7, 9.3 Hz), 3.66-3.57
(2H, m), 3.41 (3H, s, OMe), 3.38-3.31 (1H, m), 3.25 (1H, dt, J=5.0,
13.7 Hz), 2.62 (1H, dd, J=6.8, 14.3 Hz), 1.92-1.84 (1H, m),
1.74-1.57 (3H, m). .sup.13C-NMR (75 MHz, acetone-d.sub.6) .delta.:
163.90, 160.69, 158.31, 155.22, 149.93, 149.72, 149.52, 142.90,
142.84 (C), 129.60, 129.44, 128.30, 128.24, 128.13, 123.51, 122.99,
115.95, 115.91, 115.66, 115.40, 115.11, 113.87, 113.77, 113.67,
113.57 (CH), 100.84, 74.86, 74.03, 73.68, 73.14, 72.87, 68.09 (CH),
56.67 (CH.sub.2), 55.63 (CH.sub.3), 52.83 (CH.sub.2), 42.78 (CH),
37.60, 29-83 (CH.sub.2). IR (cm.sup.-1): 3390, 2935, 2850, 1605,
1508, 1474, 1366, 1221, 1147, 1052, 1015, 874, 824, 755. MALDI-MS
(C.sub.31H.sub.35F.sub.2NO.sub.9S) [MH--H.sub.2O].sup.+ 618.1968
(calcd. 618.1973); [MH].sup.+ 636.2045 (calad. 636.2079);
[MNa].sup.+ 658.1901 (calcd. 658.1898).
Example 6
##STR00019##
[0115] The above sulfonyl chloride Xa was prepared according to the
methods described under step 5a) using
C-(Hydroxymethyl)-2,3,4,6-tetra-O-benzyl-.beta.-D-glucopyranoside
(prepared according to RajanBabu, T. V.; Reddy, G. S. J. Org. Chem.
1986, 51, 5458-5461) as the starting material.
b)
[0116] The sulfonyl chloride Xa obtained under step 6a) (871 mg,
1.26 mmol) was suspended in anhydrous CH.sub.2Cl.sub.2 (10 mL),
anhydrous pyridine (1.0 mL) followed by the silylated azetidinone
phenol VIa obtained in step 2a) (334 mg, 0.634 mmol) were added and
the solution was stirred for 13 h, diluted with EtOAc (50 mL) and
washed sequentially with sat. aq. NaHCO.sub.3 (20 mL) and H.sub.2O
(20 mL). The organic layer was evaporated on celite and purified by
dry column vacuum chromatography (4.3.times.3.3 cm) on silica gel
eluting with a gradient of 0-100% CH.sub.2Cl.sub.2 in hexane (v/v)
to give the corresponding glycosylated azetidinone (657 mg, 92%) as
a white foam.
[0117] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.37-7.15 (28H,
m), 7.01 (2H, t, J=8.7 Hz), 6.96 (2H, t, J=8.7 Hz), 5.03-4.81 (4H,
m), 4.73-4.51 (6H, m), 3.95 (1H, t, J=8.4 Hz), 3.78 (4H, bs),
3.57-3.53 (1H, m), 3.48 (1H, d, J=1.2 Hz), 3.40 (1H, t, J=9.0 Hz),
3.24 (1H, dd, J=9.3, 14.9 Hz), 3.02-2.95, (1H, m), 1.97-1.80 (4H,
m), 0.92 (9H, s), 0.06 (3H, s), -0.11 (3H, s). .sup.13C-NMR (75
MHz, CDCl.sub.3) .delta.: 166.72, 163.24, 160.35, 160.01, 157.13,
149.25, 140.37, 140.33, 137.90, 137.65, 137.58, 137.1.2, 136.97,
136.52, 133.52, 133.48 (C), 128.46, 128.32, 128.28, 128.17, 128.02,
127.97, 127.81, 127.76, 127.67, 127.63, 127.52, 127.13, 127.02,
123.32, 118.13, 118.02, 115.90, 115.60, 115.01, 114.72 (CH), 86.83,
79.13, 78.83, 77.73 (CH), 75.56, 75.00, 74.85 (CH.sub.2), 74.19,
73.77 (CH), 73.31 (CH.sub.2), 68.36, 60.57, 60.53 (CH), 51.31,
38.03 (CH.sub.2), 25.85 (CH.sub.3), 24.67 (CH.sub.2), 18.20 (C),
-4.57, -4.87 (CH.sub.3). IR (cm.sup.-1): 2951; 2929, 2858, 1751,
1605, 1510, 1454, 1386, 1362, 1251, 1220, 1151, 1102, 871, 835,
776, 754, 699. MALDI-MS: [MNa].sup.+ 1146.4440 (calcd. 1146.4434).
Anal. Calcd for C.sub.65H.sub.71F.sub.2NO.sub.10SiS: C, 69.43; H,
6.36; N, 1.25. Found: C, 69.27; H, 6.47; N, 1.28.
[0118] The glycosylated azetidinone obtained above (236 mg, 0.210
mmol) was then dissolved in EtOH/EtOAc (10 mL, 1:1 (v/v)),
Pd(OH).sub.2/C (20% (w/w), 73 mg) was added and the suspension was
evacuated 4 times with H.sub.2 and stirred under an
H.sub.2-atmosphere for 3.5 h. The suspension was evaporated on
celite and purified by dry column vacuum chromatography
(4.6.times.2.0 cm) on silica gel eluting with a gradient of 0-20%
MeOH in CH.sub.2Cl.sub.2 (v/v) to give the debenzylated azetidinone
(145 mg, 90%) as a white foam.
[0119] .sup.1H-NMR (300 MHz, acetone-d.sub.6) .delta.: 7.55 (2H,
dd, J=6.5, 8.7 Hz), 7.47 (2H, d, J=8.4 Hz), 7.40-7.20 (4H, m),
7.11-6.98 (4H, m), 4.97 (1H, dd, J=2.3, 10.5 Hz), 4.83 (1H, bs),
4.61 (1H, bs), 4.48 (1H, bs), 4.30 (1H, bs), 3.90-3.81 (3H, m),
3.71-3.64 (1H, m), 3.56-3.38 (5H, m), 3.25-3.14 (2H, m), 2.66 (1H,
t, J=7.2 Hz), 1.98-1.81 (4H, m), 0.88 (9H, s), 0.05 (3H, s), -0.15
(3H, s). .sup.13C-NMR (75 MHz, acetone-d.sub.6) .delta.: 168.30,
161.88, 158.69, 151.25, 142.96, 139.63, 139.16, 139.13, 135.98 (C),
131.66, 131.56, 129.36, 129.28, 124.92, 120.00, 119.90, 117.46,
117.16, 116.62, 116.52 (CH), 82.13, 80.16, 76.75, 75.44, 74.46,
72.35 (CH), 63.64 (CH.sub.2), 61.60, 61.55 (CH), 54.03, 39.52
(CH.sub.2), 27.20 (CH.sub.3), 26.35 (CH.sub.2), 19.68 (C), -3.44,
-3.69 (CH.sub.3). IR (cm.sup.-3): 3380, 2930, 2858, 1749, 1604,
1510, 1385, 1363, 1220, 1172, 1149, 1088, 1032, 1016, 872, 835,
757. MALDI-MS: [MNa].sup.+ 786.2563 (calcd. 786.2556). Anal. Calcd
for C.sub.37H.sub.47F.sub.2Nl.sub.10SiS: C, 58.17; H, 6.20; N,
1.83. Found: C, 58.02; H, 6.26; N, 1.85.
[0120] The debenzylated azetidinone (31.5 mg, 0.041 mmol) was then
dissolved in anhydrous THF (2.5 mL, teflon bottle), anhydrous
pyridine (0.5 mL) followed by HF-pyridine complex (0.5 mL) were
added and the solution was stirred for 24 h, diluted with ether (20
mL) and washed with sat. aq. NaHCO.sub.3 (3.times.5 mL). The
organic layer was evaporated on celite and purified by dry column
vacuum chromatography (4.3.times.2.0 cm) on silica gel eluting with
a gradient of 0-20% MeOH in CH.sub.2Cl.sub.2 (v/v) to give the
desired azetidinone X (9.8 mg, 37%) as a white solid.
[0121] .sup.1H-NMR (300 Mz, acetone-d.sub.6) .delta.: 7.55 (2H, d,
J=8.7 Hz), 7.47 (2H; d, J=8.7 Hz), 7.36 (2H, dd, J=5.6, 8.7 Hz),
7.29 (2H, dd, J=4.8, 9.2 Hz), 7.06 (2H, d, L=8.7 Hz), 7.03 (2H, d,
J=9.0 Hz), 4.98 (1H, d, J=2.5 Hz), 4.68 (1H, bs), 4.58 (1H, bs),
4.38 (1H, bs), 4.27 (1H, bs), 3.89-3.80 (3H, m), 3.66 (1H, d,
J=10.6 Hz), 3.54-3.36 (5H, m), 3.24-3.14 (2H, m), 2.00-1.86 (4H, m)
.sup.13C-NMR (75 MHz, acetone-d.sub.6) .delta.: 168.48, 151.29,
143.63, 139.23, 136.09 (C), 129.37, 129.29, 129.19, 124.97, 120.05,
119.94, 117.49, 117.18, 116.46, 116.18 (CH), 82.17, 80.18, 76.78,
74.49, 73.79, 72.42 (CH), 63.67 (CH.sub.2), 62.35, 61.63 (CH),
54.06, 38.62, 26.75 (CH.sub.2). IR (cm.sup.-1): 3364, 2924, 1734,
1509, 1388, 1220, 1148, 1102, 872, 835, 769. MALDI-MS
(C.sub.31H.sub.33F.sub.2NO.sub.10S) [Na].sup.+ 672.1744 (calcd.
672.1691).
Example 7
##STR00020##
[0123] LiAlH.sub.4 (57 mg, 1.5 mmol) and AlCl.sub.3 (200 mg, 1.5
mmol) were suspended in anhydrous ether (15 mL), refluxed for 30
min and cooled to 0.degree. C. The azetidinone X obtained in
Example 6 (41.3 mg, 0.054 mmol) dissolved in anhydrous ether (5 mL)
was added and after stirring at 0.degree. C. for 10 min, sat. aq.
NaHCO.sub.3 (1 mL) was added dropwise. The suspension was
evaporated on celite and purified by dry column vacuum
chromatography (4.2.times.2.0 cm) on silica gel eluting with a
gradient of 0-20% MeOH in CH.sub.2Cl.sub.2 (v/v) to give the
corresponding azetidine (38.2 mg, 94%) as a white foam.
[0124] .sup.1H-NMR (300 MHz, acetone-d.sub.6) .delta.: 7.58 (2H, d,
J=8.7 Hz), 7.47 (2H, d, J=8.7 Hz), 7.29 (2H, dd, J=5.6, 8.7 Hz),
7.05 (2H, t, J=8.7 Hz), 6.88 (2H, t, J=9.0 Hz), 6.37 (2H, dd, J
4.7, 9.0 Hz), 4.71 (1H, t, J=5.5 Hz), 4.61 (1H, d, J=5.0 Hz), 4.49
(2H, d, J=6.8 Hz), 4.30 (1H, bs), 4.17 (1H, t, J=7.2 Hz), 3.92-3.83
(3H, m), 3.74-3.66 (1H, m), 3.57-3.40 (5H, m), 3.32-3.15 (2H, m),
2.63-2.56 (1H, m), 1.82-1.56 (4H, m), 0.87 (9H, s), 0.04 (3H, s),
-0.17 (3H, s). .sup.13C-NMR (75 MHz, acetone-d.sub.6) .delta.:
164.97, 161.76, 159.31, 156.21, 150.76, 150.47, 150.45, 143.77,
143.11, 143.07 (C), 129.35, 129.22, 124.60, 116.95, 116.65, 116.48,
116.19, 114.86, 114.75 (CH), 82.15, 80.21, 76.81, 75.43, 74.99,
74.52, 72.41 (CH), 63.70, 57.54, 53.95 (CH.sub.2), 43.62 (CH),
39.47, 31.22 (CH.sub.2), 27.20 (CH.sub.3), 19.70 (C), -3.40, -3.68
(CH.sub.3). IR (cm.sup.-1): 3377, 2930, 2856, 1605, 1508, 1472,
1361, 1252, 1222, 1147, 1090, 1015, 871, 836, 776, 760. MALDI-MS
(C.sub.37H.sub.49F.sub.2NO.sub.9SSi): [MNa].sup.+ 772.2767 (calcd.
772.2763).
[0125] The azetidine obtained above (34.3 mg, 0.046 mmol) was
dissolved in anhydrous THF (2.5 mL, teflon bottle), anhydrous
pyridine (0.5 mL) followed by HF-pyridine complex (0.5 mL) were
added and the solution was stirred for 14 h, diluted with ether (20
mL) and washed with sat. aq. NaHCO.sub.3 (3.times.5 mL). The
organic layer was evaporated on celite and purified by dry column
vacuum chromatography (4.9.times.2.0 cm) on silica gel eluting with
a gradient of 0-18% MeOH in CH.sub.2Cl.sub.2 (v/v) to give the
desired azetidine XI (20.2 mg, 69%) as a colourless oil.
[0126] .sup.1H-NMR (300 MHz, acetone-d.sub.6) .delta.: 7.61 (2H, d,
J=8.1 Hz), 7.48 (2H, d, J=8.7 Hz), 7.30 (2H, dd, J=5.6, 8.7 Hz),
7.04 (2H, t, J=8.7 Hz), 6.89 (2H, m), 6.38 (2H, dd, J=4.4, 8.7 Hz),
4.60 (2H, d, J=4.4 Hz), 4.52 (1H, d, J=6.8 Hz), 4.45 (1H, d, J=2.5
Hz), 4.29 (2H, d, J=4.4 Hz), 4.19 (1H, t, J=6.8 Hz), 4.03-3.83 (3H,
m), 3.80-3.67 (1H, m), 3.60-3.31 (6H, m), 3.25, (1H, p, L=4.4 Hz),
2.62 (1H, dd, J=7.5, 14.3 Hz), 1.92-1.82 (1H, m), 1.78-1.61 (3H,
m). .sup.13C-NMR (75 MHz, acetone-d.sub.6) .delta.: 164.04, 155.14,
149.92, 149.71, 149.47, 142.77, 129.48 (C), 128.19, 128.16, 128.05,
123.52, 123.03, 115.87, 115.58, 115.39, 115.32, 115.05, 113.78,
113.69, 113.61, 113.51 (CH), 81.09, 79.15, 75.76, 73.98, 73.46,
72.75, 71.36 (CH), 62.63, 56.60, 52.88 (CH.sub.2), 42.68 (CH),
37.52, 29.61 (CH.sub.2). IR (cm.sup.-1): 3370, 2933, 1605, 1508,
1474, 1360, 1220, 1146, 1087, 10-15, 873, 823, 771. MALDI-MS
(C.sub.3H.sub.35F.sub.2NOgS): [MH--H.sub.2O].sup.+ 618.1973 (calcd.
618.1973); [M].sup.+ 635.1996 (calcd. 635.2001); [MNa].sup.+
658.1900 (calcd. 658.1898).
Example 8
##STR00021##
[0128] Ezetimibe (commercially obtained or synthesized according to
Wu, G. Z. et al., J. Org. Chem. 1999; 279 mg, 0.681 mmol) was
dissolved in anhydrous DMF (5 mL), imidazole (262 mg, 3.84 mmol)
and TBDMSC1 (500 mg, 3.32 mmol) were added sequentially and the
solution was stirred for 5 h followed by addition of 509 sat. aq.
NaHCO.sub.3 (50 mL) After extraction with EtOAc (4.times.20 mL),
the combined organic layer was washed successively with sat. aq.
Ma-HCO.sub.3 (20 mL) and H.sub.2O (20 mL), evaporated on celite and
purified by dry column vacuum chromatography (3.8.times.3.3 cm) on
silica gel eluting with a gradient of 0-10% EtOAc in hexane (v/v)
to give the fully silylated azetidinone XIIa (424 mg, 97%) as a
colourless oil.
[0129] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.25-7.21 (4H,
m), 7.17 (2H, d, J=8.1 Hz), 6.98 (2H, t, J=8.7 Hz), 6.91 (2H, t,
J=8.7 Hz), 6.83 (2H, d, J=8.1 Hz), 4.66 (1H, t, J=5.6 Hz), 4.51
(1H, d, J=2.5 Hz), 3.08-3.02 (1H, m), 1.96-1.78 (4H, m), 0.98 (9H,
s), 0.88 (9H, s), 0.20 (6H, s), 0.02 (3H, s), -0.16 (3H, s).
.sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 167.27, 163.28, 160.27,
160.04, 157.06, 155.71, 140.58, 140.54, 133.89, 133.86 (C), 129.99,
127.22, 127.11, 126.94, 120.56, 118.24, 118.15, 115.74, 115.44,
114.99, 114.72 (CH), 73.84, 61.08, 60.44 (CH), 38.08 (CH.sub.2),
25.90, 25.68 (CH.sub.3), 24.75 (CH.sub.2), 18.26, 18.24 (C), -4.28,
-4.52, -4.83 (CH.sub.3). IR (cm.sup.-1): 2954, 2930, 2858, 1752,
1607, 1510, 1385, 1259, 1223, 1101, 1085, 914, 834, 778. MALDI-MS:
[MH-TBDMSOH].sup.+ 506.2329 (calcd. 506.2327); [MH].sup.+ 638.3289
(calcd. 638.3297); [MNa].sup.+ 660.3117 (calcd. 660.3117). Anal.
Calcd for C.sub.36H.sub.49F.sub.2NO.sub.3Si.sub.2: C, 67.78; H,
7.74; N. 2.20. Found: C, 67.70; H. 7.60; N, 2.02.
##STR00022##
[0130] LiAlH.sub.4 (57 mg, 1.5 mmol) and AlC13 (200 mg, 1.5 mmol)
were suspended in anhydrous ether (15 mL), refluxed for 40 min and
cooled to 0.degree. C. The fully silylated azetidinone ZIIa
obtained under step 8a) (180.8 mg, 0.283 mmol) dissolved in
anhydrous ether (5 mL) was added and after stirring at 0.degree. C.
for 30 min, H.sub.2O (1 mL) was added dropwise. The suspension was
evaporated on celite and purified by dry column vacuum
chromatography (3.5.times.3.3 cm) on silica gel eluting with a
gradient of 0-50% CH.sub.2Cl.sub.2 in hexane (v/v) to give the
desired bicyclic amine XIIb (110.8 mg, 63%) as a colourless
oil.
[0131] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.18-7.14 (2H,
m), 6.95 (2H, t, J=8.7 Hz), 6.88 (2H, d, J=8.7 Hz), 6.74 (2H, d,
J=8.1 Hz), 6.68 (1H, dd, J=2.8, 8.4 Hz), 6.44 (1H, dd, J=6.5, 8.7
Hz), 6.38 (1H, dd, J=2.8, 9.6 Hz), 4.48 (1H, dd, J=5.0, 6.8 Hz),
3.78 (1H, bs), 3.61 (1H, d, J=7.5 Hz), 3.26 (1H, dd, J=3.1, 11.2
Hz), 2.91 (1H, dd, J=7.8, 11.5 Hz), 1.91-1.85 (1H, m), 1.68-1.44
(3H, m), 1.16-1.04 (1H, m), 0.99 (9H, s), 0.80 (9H, s), 0.20 (6H,
s), 0.06 (3H, s), -0.21 (3H, s). 10-NMR (75 MHz, CDCl.sub.3)
.delta.: 163.60, 160.36, 157.37, 154.27, 141.53, 141.01, 138.13
(C), 130.07, 127.56, 127.46, 125.58, 125.50, 120.01, 117.27,
116.98, 115.17, 114.89, 114.78, 114.08, 113.79 (CH), 74.64, 48.97
(CH), 44.52 (CH.sub.2), 39.89 (CH), 38.67, 28.28 (CH.sub.2), 26.00,
25.90 (CH.sub.3), 18.38, 18.32 (C), -4.16, -4.43, -4.77 (CH.sub.3).
IR (cm.sup.-1): 2955, 2930, 2858, 1607, 1506, 1472, 1408, 1361,
1258, 1222, 1170, 1144, 1085, 1006, 915, 837, 808, 779, 735, 667.
MALDI-MS (C.sub.36H.sub.51F.sub.2NO.sub.2Si.sub.2):
[MH-TBDMSOH].sup.+ 492.2517 (calcd. 492.2534); [M].sup.+ 623.3414
(calcd. 623.3426). Anal. Calcd for
C.sub.36H.sub.51F.sub.2NO.sub.2Si.sub.2: C, 69.30; H, 8.24; N,
2.24. Found: C, 69.47; H, 8.32; N, 2.15.
c)
[0132] The bicyclic amine XIIb obtained under step 8b) (39.8 mg,
0.064 mmol) was dissolved in THF (5 mL), TBAF (0.5 mL, 1M in THF)
was added and the solution was stirred for 21 h, evaporated on
celite and purified by dry column vacuum chromatography
(3.7.times.2.0 cm) on silica gel eluting with a gradient of 0-100%
EtOAc in hexane (v/v) to give the desired amine XII (27.7 mg,
quant.) as a yellowish solid.
[0133] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.19-7.15 (2H,
m), 6.97 (2H, t, J=8.7 Hz), 6.87 (2H, d, J=8.4 Hz), 6.74-6.66 (3H,
m), 6.46 (1H, dd, J=5.0, 8.7 Hz), 6.38 (1H, dd, J=2.2, 9.0 Hz),
5.54 (1H, bs), 4.52 (1H, t, J=6.5 Hz), 3.61 (1H, d, J=7.2 Hz), 3.26
(1H, dd, J=3.4, 11.5 Hz), 2.90 (1H, dd, J=7.5, 11.5 Hz), 1.95-1.86
(1H, m), 1.78-1.68 (2H, m), 1.52-1.41 (1H, m), 1.19-1.06 (1H, m).
.sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 163.55, 160.30, 157.10,
154.25, 154.00, 140.44, 139.95, 139.90, 137.07 (C), 129.90, 127.46,
127.36, 125.24, 116.99, 116.70, 115.28, 115.26, 115.21, 115.15,
115.00, 114.95, 114.84, 113.91, 113.61 (CH), 73.94, 48.53 (CH),
43.98 (CH.sub.2), 39.73 (CH), 36.43, 27.95 (CH.sub.2). IR
(cm.sup.-1): 3335, 2925, 2853, 1607, 1511, 1223, 913, 836, 744.
MALDI-MS (d.sub.24H.sub.23F.sub.2NO.sub.2): [MH-H.sub.2O].sup.+
378.1661 (calcd. 378.1670); [M].sup.+ 395.1689 (calcd.
395.1670)
Example 9
##STR00023##
[0135] The bicyclic amine XIIb obtained in step 8b) (503 mg, 0.806
mmol) was dissolved in THF (15 mL) at 0.degree. C., TBAF (1.5 mL,
1M in THF) was added and the solution was stirred at 0.degree. C.
for 1.5 h, diluted with EtOAc (50 mL) and washed successively with
sat. aq. NaHCO.sub.3 (20 mL) and H.sub.2O (20 mL). The organic
layer was evaporated on celite and purified by dry column vacuum
chromatography (3.4.times.3.3 cm) on silica gel eluting with a
gradient of 0-300 EtOAc in hexane (v/v) to give the corresponding
phenol (344.2 mg, 84%) as a light yellow foam.
[0136] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.16 (2H, dd,
J=5.6, 8.1 Hz), 6.95 (2H, t, J=8.7 Hz), 6.90 (2H, d, J=8.7 Hz),
6.72 (2H, d, J=8.7 Hz), 6.72-6.67 (1H, m), 6.48 (1H, dd, J=4.4, 8.7
Hz), 6.39 (1H, dd, J=2.7, 9.6 Hz), 4.49 (1H, dd, J=5.6, 6.8 Hz),
4.40 (1H, bs), 3.61 (1H, d, J=7.5 Hz), 3.28 (1H, dd, J=2.7, 11.2
Hz), 2.92 (1H, dd, J=8.1, 11.2 Hz), 1.93-1.87 (1H, m), 1.73-1.47
(3H, m), 1.20-1.15 (1H, m), 0.81 (9H, s), 0.06 (3H, s), -0.20 (3H,
s). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 163.16, 159.93,
157.15, 154.03, 141.13, 141.09, 140.43, 140.40, 137.05 (C), 129.95,
127.21, 127.11, 125.69, 125.62, 116.92, 116.62, 115.23, 114.98,
114.87, 114.83, 114.55, 113.83, 113.53 (CH), 74.36, 48.77 (CH),
44.49 (CH.sub.2), 39.78 (CH), 38.46, 28.07 (CH.sub.2), 25.81
(CH.sub.3), 18.17 (C), -4.52, -4.90 (CH.sub.3). IR (cm.sup.-1):
3338, 2954, 2929, 2857, 1606, 1508, 1475, 1462, 1361, 1251, 1221,
1084, 836, 775, 760. MALDI-MS (C.sub.30H.sub.37F.sub.2NO.sub.2Si):
[MH-TBDMSOH].sup.+ 378.1657 (calcd. 378.1670); [M].sup.+ 509.2553
(calcd. 509.2562).
[0137] The phenol obtained above (79 mg, 0.15 mmol) and
2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-.beta.-D-glucopyranosyl)-.alpha.--
D-glucopyranosyl 1-(2,2,2-trichloroacetimidate) (prepared according
to Buijsman, R. C. et al., Bioorg. Med. Chem. 1999, 7, 1881-1890;
267 mg, 0.34 mmol) were then dissolved in anhydrous
CH.sub.2Cl.sub.2 (2 mL) at -25.degree. C. and BF.sub.3.OEt.sub.2 in
CH.sub.2Cl.sub.2 (1:9 (v/v), 0.10 mL, 0.08 mmol) was added. After
stirring for 2.5 h at -25 to -20.degree. C., additional
BF.sub.3--OEt.sub.2 (0.05 mL, 0.39 mmol) was added and after
additional 1 h at -25 to -20.degree. C., sat. aq. NH.sub.4Cl (10
mL) and EtOAc (10 mL) were added. The layers were separated and the
aqueous phase was extracted with EtOAc (3.times.10 mL). The
combined organic layer was washed successively with sat. aq.
NaHCO.sub.3 (10 mL) and H.sub.2O (10 mL), evaporated on celite and
purified by dry column vacuum chromatography (4.5.times.2.0 cm) on
silica gel eluting with a gradient of 0-70% EtOAc in hexane (v/v)
to give the glycosylated amine (169 mg, 97%) as a white foam.
[0138] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.12 (2H, dd,
L=5.6, 8.7 Hz), 6.94-6.84 (6H, m), 6.66 (1H, dt, J=2.5, 8.1 Hz),
6.42 (1H, dd, J=4.4, 8.7 Hz), 6.29 (1H, dd, J=2.7, 9.6 Hz),
5.29-4.90 (6H, m), 4.54-4.43 (3H, m), 4.37 (1H, dd, J=4.4, 12.5
Hz), 4.16-4.02 (2H, m), 3.86 (1H, t, J=9.0 Hz), 3.77-3.64 (2H, m),
3.60 (1H, d, J=7.5 Hz), 3.23 (1H, dd, J=2.7, 11.5 Hz), 2.88 (1H,
dd, J=8.1, 11.2 Hz), 2.07-1.96 (21H, m), 1.87-1.75 (1H, m),
1.70-1.38 (3H, m), 1.13-0.97 (1H, m), 0.76 (9H, s), -0.10 (3H, s),
-0.25 (3H, s). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 170.38,
170.09, 169.67, 169.47, 169.20, 168.96, 163.25, 160.01, 156.95,
155.27, 153.85, 141.10, 140.73, 140.10 (C), 129.91, 127.21, 127.11,
124.80, 116.68, 114.83, 114.56, 113.62 (CH), 100.71, 98.80, 76.33,
74.20, 72.81, 72.69, 72.42, 71.89, 71.48, 71.27, 67.63 (CH), 61.84,
61.42 (CH.sub.2), 48.71 (CH), 44.19 (CH.sub.2), 39.61 (CH), 38.27,
27.85 (CH.sub.2), 25.64, 20.67, 20.58, 20.43 (CH.sub.3), 17.96 (C),
-4.76, -5.14 (CH.sub.3). IR (cm.sup.-1): 2955, 2858, 1756, 1506,
1368, 1223, 1049, 837, 770. MALDI-MS
(C.sub.56H.sub.71F.sub.2NO.sub.19Si): [MNa].sup.+ 1150.4235 (calcd.
1150.4255).
[0139] The glycosylated amine obtained above (370 mg, 0.328 mmol)
was then dissolved in THF (10 mL), TBAF (1.0 mL, 1M in THF) was
added and the solution was stirred for 27 h, diluted with EtOAc (40
mL) and washed successively with sat. aq. NaHCO.sub.3 (15 mL) and
H.sub.2O (15 mL). The organic layer was evaporated and the crude
intermediate [MALDI-MS (C.sub.50H.sub.57F.sub.2NO.sub.19):
[MNa].sup.+ 1036.3394 (calcd. 1036.3391)] was dissolved in
MeOH/Et.sub.3N/THF (12 mL, 1:1:2 (v/v/v)), H.sub.2O (10.5 mL) was
added dropwise and the solution was stirred for 18 h. sat. aq.
NaHCO.sub.3 (1 mL) was added dropwise and the suspension was
evaporated on celite and purified by dry column vacuum
chromatography (4.0.times.3.3 cm) on silica gel eluting with a
gradient of 0-25% MeOH in EtOAc (v/v) to give the desired bicyclic
amine XIII (80.5 mg, 34%) as a white solid after coevaporation with
hexane (20 mL).
[0140] .sup.1H-NMR (300 MHz, CD.sub.3OD) .delta.: 7.20 (2H, dd,
J=5.6, 8.7 Hz), 7.02-6.93 (6H, m), 6.65 (1H, dt, J=2.5, 8.7 Hz),
6.54 (1H, dd, J=5.0, 8.7 Hz), 6.23 (1H, dd, J=2.5, 10.0 Hz), 4.94
(1H, d, J=7.5 Hz), 4.47-4.43 (2H, m), 3.92 (2H, bs), 3.90 (1H, d,
J=10.6 Hz), 3.72-3.52 (6H, m), 3.43-3.22 (5H, m), 2.86 (1H, dd,
L=8.1, 11.8 Hz), 1.96-1.84 (1H, m), 1.80-1.68 (2H, m), 1.50-1.35
(1H, m), 1.17-1.03 (1H, m). .sup.13C-NMR (75 MHz, CD.sub.3OD)
.delta.: 164.71, 161.49, 157.30, 155.12, 142.58, 141.98, 141.95,
140.78 (C), 130.89, 128.83, 128.72, 126.64, 126.56; 117.52, 117.36,
117.09, 115.86, 115.57 (CH), 104.44, 101.98, 80.21, 78.01, 77.76,
76.49, 76.22, 74.83, 74.58, 74.41, 71.29 (CH), 62.39, 61.63
(CH.sub.2), 50.00 (CH), 45.09 (CH.sub.2), 40.95 (CH), 37.38, 29.09
(CH.sub.2). MALDI-MS (C.sub.36H.sub.43F.sub.2NO.sub.12):
[MNa].sup.+ 742.2654 (calcd. 742.2651).
Example 10
##STR00024##
[0142] The silylated azetidinone phenol VIa obtained in step 2a)
(104.0 mg, 0.199 mmol) was dissolved in anhydrous CH.sub.2Cl.sub.2
(10 mL), anhydrous pyridine (0.5 mL) followed by PhSO.sub.2Cl (0.10
mL, 0.7.8 mmol) were added and the solution was stirred for 19 h.
Additional PhSO.sub.2Cl (0.10 mL, 0.78 mmol) was added and the
solution was stirred for further 69 h, diluted with EtOAc (50 mL)
and washed sequentially with sat. aq. NaHCO.sub.3 (20 mL) and
H.sub.2O (20 mL). The organic layer was evaporated on celite and
purified by dry column vacuum chromatography (4.2.times.3.3 cm) on
silica gel eluting with a gradient of 0-100% CH.sub.2Cl.sub.2 in
hexane (v/v) followed by 0.5-1.0% MeOH in CH.sub.2Cl.sub.2 (v/v) to
give the corresponding benzene sulfonate (92.0 mg, 70%) as a
colourless oil.
[0143] R.sub.f (10 MeOH in CH.sub.2Cl.sub.2 (v/v)) 0.72;
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.83 (2H, d, T=7.5 Hz),
7.66 (1H, t, J=7.5 Hz), 7.51 (2H, t, J=7.5 Hz), 7.25-7.14 (6H, m),
7.00 (2H, d, J=8.7 Hz), 6.97 (2H, d, J=8.7 Hz), 6.91 (2H, t, J=8.7
Hz), 4.66 (1H, dd, J=4.4, 6.2 Hz), 4.55 (1H, d, J=1.9 Hz),
3.02-2.96 (1H, m), 1.94-1.75 (4H, m), 0.87 (9H, s), 0.00 (3H, s),
-0.16 (3H, s). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 166.82,
163.44, 160.51, 157.29, 149.35, 140.54 (C), 136.77 (CH), 135.26,
134.32, 133.56, 129.13 (C), 128.31, 127.27, 127.17, 127.08, 123.15,
118.23, 118.12, 115.93, 115.63, 115.09, 114.82, 73.76, 60.53, 60.40
(CH), 37.92 (CH.sub.2), 25.75 (CH.sub.3), 24.59 (CH.sub.2), 18.10
(C), -4.71, -5.03 (CH.sub.3). IR (cm.sup.-1) 2953, 2930, 2857,
1752, 1605, 1510, 1450, 1382, 1252, 1221, 1202, 1181, 1155, 1093,
1016, 868, 835, 776, 753, 700, 687. MALDI-MS
(C.sub.36H.sub.39F.sub.2NO.sub.5SSi): [MH-TBDMSOH].sup.+ 532.1395
(calcd. 532.1394); [MNa].sup.+ 686.2185 (calcd. 686.2184).
[0144] This benzene sulfonate (90.0 mg, 0.136 mmol) was dissolved
in anhydrous THF (2.5 mL, teflon bottle) at 0.degree. C., anhydrous
pyridine (0.5 mL) followed by HF-pyridine complex (0.5 mL) were
added and the solution allowed slowly to warm to room temperature.
After 14 h, the mixture was diluted with ether (20 mL) and washed
with sat. aq. NaHCO.sub.3 (3.times.5 mL)). The organic layer was
evaporated on celite and purified by dry column vacuum
chromatography (5.0.times.2.0 cm) on silica gel eluting with a
gradient of 0-100% CH.sub.2Cl.sub.2 in hexane (v/v) followed by
1-7% MeOH in CH.sub.2Cl.sub.2 (v/v) to give plactam XIV (69.2 mg,
93%) as a white foam.
[0145] R.sub.f (3%; MeOH in CH.sub.2Cl.sub.2 (v/v)) 0.33;
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.82 (2H, dd, J=1.2, 7.5
Hz), 7.67 (1H, tt, J=1.2, 7.5 Hz), 7.51 (2H, t, J=7.5 Hz),
7.29-7.22 (4H, m), 7.15 (2H, dd, J=4.4, 8.7 Hz), 6.99 (2H, t, J=8.7
Hz), 6.98 (2H, d, J=8.7 Hz), 6.92 (2H, t, J=8.7 Hz), 4.68 (1H, dd,
J=5.6, 6.2 Hz), 4.60 (1H, d, J=1.9 Hz), 3.06-2.98 (1H, m), 2.55
(1H, bs), 2.04-1.84 (4H, m). .sup.13C-NMR (75 MHz, CDCl.sub.3)
.delta.: 166.87, 163.56, 160.44, 160.31, 157.22, 149.23, 139.84,
139.79 (C), 136.46 (CH), 135.10, 134.26, 133.37 (C), 129.07,
128.22, 127.26, 127.16, 127.02, 123.07, 118.21, 118.11, 115.93,
115.62, 115.36, 115.07, 72.98, 60.50, 60.32 (CH), 36.54, 25.09
(CH.sub.2). IR (cm.sup.-1): 3440, 3069, 3017, 2927, 2862, 1747,
1604, 1510, 1450, 1426, 1378, 1221, 1201, 1180, 1154, 1094, 1016,
868, 835, 753, 700, 687, 668. MALDI-MS
(C.sub.30H.sub.25F.sub.2NO.sub.5S): [MH--H.sub.2O].sup.+ 532.1388
(calcd. 532.1394); [MNa].sup.+ 572.1302 (calcd. 572.1319).
Example 11
##STR00025##
[0147] LiAlH.sub.4 (57 mg, 1.5 mmol) and AlCl.sub.3 (202 mg, 1.5
mmol) were suspended in anhydrous ether (15 mL), refluxed for 30
min and cooled to 0.degree. C. .beta.-Lactam XIV obtained in
example 10 (62.8 mg, 0.114 mmol) dissolved in anhydrous ether (5
mL) was added and after stirring at 0.degree. C. for 20 min, sat.
aq. NaHCO.sub.3 (1, mL) was added dropwise. The suspension was
evaporated on celite and purified by dry column vacuum
chromatography (4.8.times.2.0 cm) on silica gel eluting with a
gradient of 0-50% EtOAc in hexane (v/v) to give azetidine XV (24.5
mg, 40%) as a white foam.
[0148] R.sub.f (1:1 EtOAc/hexane (v/v)) 0.46; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.88-7.82 (2H, m), 7.70-7.63 (1H, m),
7.55-7.47 (2H, m), 7.38-7.30 (2H, m), 7.24-7.19 (2H, m), 7.05-6.98
(4H, m).sub., 6.83 (2H, t, J=8.7 Hz), 6.26 (2H, dd, J=4.4, 9.3 Hz),
4.56 (1H, dd, J=5.0, 7.5 Hz), 4.36 (1H, d, J=6.8 Hz), 4.09 (1H, dd,
LT 6.8, 7.5 Hz), 3.27 (1H, dd, J=6.8, 7.5 Hz), 2.79 (1H, d, J=5.6
Hz), 2.52 (1H, dd, J=6.8, 7.5 Hz), 1.89-1.52 (4H, m). .sup.13C-NMR
(75 MHz, CDCl.sub.3) .delta.: 163.65, 160.40, 157.73, 154.61,
148.65, 148.07, 141.59, 139.94, 135.36 (C), 134.11, 129.24, 129.03,
128.30, 127.28, 127.17, 122.54, 115.45, 115.15, 112.99, 112.90,
73.47, 73.32 (CH), 55.89 (CH.sub.2), 41.74 (CH), 36.30, 29.93
(CH.sub.2). IR (cm.sup.-1): 3411, 2937, 2853, 1604, 1508, 1474,
1450, 1374, 1221, 1198, 1175, 1151, 1093, 1016, 867, 823, 752, 700,
686. MALDI-MS (C.sub.30H.sub.27F.sub.2NO.sub.4S):
[MH--H.sub.2O].sup.+ 518.1596 (calcd. 518.1601); [M].sup.+ 535.1619
(calcd. 535.1629); [Mqa].sup.+ 558.1512 (calcd. 558.1527).
Example 12
##STR00026##
[0150] The silylated azetidinone phenol VIa obtained in step 2a)
(105 mg, 0.201 mmol) was dissolved in anhydrous CH.sub.2Cl.sub.2 (5
mL), anhydrous pyridine (0.5 mL, 5.0 mmol) and
3-carboxy-4-hydroxybenzene sulfonyl chloride (prepared according to
Stewart, J. J. Chem. Soc. 1922, 121, 2555-2561; 223 mg, 0.94 mmol)
were added sequentially and the suspension was stirred at room
temperature for 63 h. The mixture was evaporated on celite and
purified by dry column vacuum chromatography (4.7.times.2.0 cm) on
silica gel eluting with a gradient of 0-15% MeOH in
CH.sub.2Cl.sub.2 (v/v) to give the corresponding silylated
sulfonate (76.2 mg, 53%) as a colourless oil.
[0151] R.sub.f (20% MeOH in CH.sub.2Cl.sub.2 (v/v)) 0.68;
.sup.1H-NMR (300 MHz, CD.sub.3CN) .delta.: 10.36 (1H, bs), 8.31
(1H, bs), 7.69 (1H, bs), 7.31-7.13 (8H, m), 7.00 (2H, t, J=7.5 Hz),
6.89 (2H, t, J=8.1 Hz), 6.57 (1H, bs), 4.72 (1H, bs), 4.65 (1H,
bs), 3.12 (1H, bs), 2.98 (1H, bs), 1.88-1.72 (4H, m), 0.84 (9H, s),
0.01 (3H, s), -0.18 (3H, s). .sup.13C-NMR (75 MHz, CD.sub.3CN)
.delta.: 168.91, 167.92, 163.57, 160.97, 157.89, 150.74, 142.17,
142.14, 137.17, 134.89 (C), 128.57, 128.45, 128.16, 123.34, 119.23,
119.17, 118.18, 116.68, 116.38, 115.71, 115.43, 74.39, 61.14, 60.64
(CH), 38.40 (CH.sub.2), 26.12 (CH.sub.3), 25.10 (CH.sub.2), 18.65
(C), -4.53, -4.69 (CH.sub.3). IR (cm.sup.-1): 3450, 2954, 2930,
2858, 1751, 1696, 1606, 1585, 1510, 1478, 1386, 1339, 1293, 1220,
1194, 1126, 1103, 1087, 1063, 1042, 835, 777, 758. MALDI-MS
(C.sub.37H.sub.39F.sub.2NO.sub.8SSi): [M-H+2Na].sup.+ 768.1851
(calcd. 768.1851).
[0152] This silylated sulfonate (74.2 mg, 62.5 mmol) was dissolved
in anhydrous THF (2.5 mL, teflon bottle) at 0.degree. C., anhydrous
pyridine (0.5 mL) followed by HF.pyridine complex (0.5 mL) were
added and the solution allowed slowly to warm to room temperature.
After 15 h, sat. aq. NaHCO.sub.3 (15 mL) was added and the
suspension was evaporated on celite and purified by dry column
vacuum chromatography (4.4.times.2.0 cm) on silica gel eluting with
a gradient of 0-25% MeOH in EtOAc (v/v) to give sulfonate XVI (43.6
mg, 70%) as a white solid.
[0153] R.sub.f (1:3 MeOH/EtOAc (v/v)) 0.44; .sup.1H-NMR (300 MHz,
CD.sub.3OD) Z: 8.53 (1H, d, J=1.9 Hz), 7.99 (1H, dd, J=2.5, 8.7
Hz), 7.48 (1H, d, J=8.7 Hz), 7.35-7.28 (6H, m), 7.07-6.97 (5H, m),
4.93 (1H, d, J=2.5 Hz), 4.62 (1H, dd, J=5.0, 6.2 Hz), 3.17-3.08
(1H, m), 1.97-1.84 (4H, m). .sup.13C-NMR (75 MHz, CD.sub.3OD)
.delta.: 169.19, 164.04, 151.43, 142.04, 142.01, 138.00 (C), 137.35
(CH), 134.92 (C), 129.46, 128.72, 128.62, 128.44, 123.54, 119.86,
119.76, 118.63, 116.82, 116.51, 115.98, 115.68 (CH), 112.37 (C),
73.73, 61.65, 61.39 (CH), 37.49, 26.18 (CH.sub.2). MALDI-MS
(C.sub.31H.sub.25F.sub.2NO.sub.8S): [M-H+2Na].sup.+654.1000 (calcd.
654.0986).
Example 13
##STR00027##
[0155] The silylated azetidinone phenol VIa obtained in step 2a)
(80.3 mg, 0.153 mmol) and alcohol XVIIa (prepared according to
Spak, S. J.; Martin, O. R. Tetrahedron 2000, 56, 217-224; 101.5 mg,
0.103 mmol) were dissolved in anhydrous THF (10 mL) at 0.degree.
C., Bu.sub.3P (50 mg, 0.20 mmol) and
1,1'-(azodicarbonyl)dipiperidine (39.5 mg, 0.17 mmol) were added
sequentially and the suspension was allowed to warm to ambient
temperature over several hours. After stirring at room temperature
for 26 h, EtOAc/hexane (1:4 (v/v), 30 mL) was added and the
suspension was filtered through celite (2.times.10 mL EtOAc/hexane
(1:4 (v/v)) washings). The filtrate was evaporated on celite and
purified by dry column vacuum chromatography (4.5.times.2.0 cm) on
silica gel eluting with a gradient of 0-25% EtOAc in hexane (v/v)
to give a 1:1 mixture of the corresponding C-glycoside and
unreacted phenol VIa (49.7 mg) as a white foam.
[0156] R.sub.f (1:1 EtOAc/hexane (v/v)) 0.64; .sup.13C-NMR (75 MHz,
CDCl.sub.3) .delta.: 167.39, 163.27, 160.31, 158.82, 157.09,
140.54, 140.49, 139.05, 138.37, 138.29, 138.19, 137.85, 133.78,
133.73, 129.40, 128.96, 128.23, 128.12, 128.04, 127.94, 127.86,
127.73, 127.63, 127.57, 127.49, 127.41, 127.20, 127.10, 126.87,
118.30, 118.19, 116.01, 115.78, 115.49, 115.30, 114.99, 114.71,
102.41, 85.35, 84.84, 82.70, 79.29, 78.01, 77.82, 77.19, 75.64,
75.25, 75.10, 75.02, 74.96, 74.81, 73.84, 73.26, 68.99, 68.15,
67.49, 61.07, 60.44, 38.09, 25.90, 24.72, 18.25, -4.53, -4.83.
MALDI-MS (C.sub.92H.sub.99F.sub.2NO.sub.13Si): [MNa].sup.+
1514.6763 (calcd. 1514.6751).
[0157] This mixture of the C-glycoside and phenol VIa (49.7 mg) was
dissolved in EtOH/EtOAc (10 mL, 1:1 (v/v)), Pd(OH).sub.2/C (20%
(w/w), 31 mg) was added and the suspension was evacuated 4 times
with H.sub.2 and stirred under an H.sub.2-atmosphere for 3 h. The
suspension was evaporated on celite and purified by dry column
vacuum chromatography (4.6.times.2.0 cm) on silica gel eluting with
a gradient of 0-20% MeOH in CH.sub.2Cl.sub.2 (v/v) to give the
corresponding debenzylated C-glycoside (18.7 mg, 21% from VIa) as a
colourless oil.
[0158] R.sub.f (20% MeOH in CH.sub.2Cl.sub.2 (v/v)) 0.44;
.sup.1H-NMR (300 Mz, CD.sub.3OD) .delta.: 7.31-7.23 (6H, m),
7.04-6.94 (6H, m), 4.71 (1H, d, J=1.9 Hz), 4.41 (1H, d, J=7.5 Hz),
4.12 (1H, dd, J=5.3, 10.9 Hz), 3.91-3.81 (3H, m), 3.66 (1H, d,
J=5.6, 11.8 Hz), 3.57-3.47 (3H, m), 3.40-3.20 (7H, m), 3.07 (1H, t,
J=5.9 Hz), 1.92-1.78 (4H, m), 0.87 (9H, s), 0.02 (3H, s), -0.18
(3H, s). .sup.13C-NMR (75 MHz, CD.sub.3OD) .delta.: 169.71, 160.66,
145.96, 142.43, 131.16, 131.05, 128.89, 128.80, 128.62, 120.00,
119.89, 116.83, 116.54, 116.41, 116.02, 115.74, 115.58, 104.65,
80.78, 80.43, 79.64, 78.16, 77.90, 75.13, 74.99, 71.43, 62.50,
62.08, 61.29, 38.96, 26.38, 25.75, 19.06, -4.40. MALDI-MS
(C.sub.43H.sub.57F.sub.2NO.sub.13Si) [MNa].sup.+ 884.3668 (calcd.
884.3465).
[0159] This debenzylated C-glycoside (18.3 mg, 0.021 mmol) was
dissolved in anhydrous THF (2.5 mL, teflon bottle) at 0.degree. C.,
anhydrous pyridine (0.50 mL) followed by HF-pyridine complex (0.50
mL) were added and the solution was stirred for 17 h. NaHCO.sub.3
(S) was added and the suspension was evaporated on celite and
purified by dry column vacuum chromatography (4.6.times.2.0 cm) on
silica gel eluting with a gradient of 0-20% MeOH in
CH.sub.2Cl.sub.2 (v/v) to give the desired C-glycoside XVII (10.3
mg, 65%) as a white solid.
[0160] R.sub.f (20% MeOH in CH.sub.2Cl.sub.2 (v/v)) 0.31;
.sup.1H-NMR (300 Mz, CD.sub.3OD) .delta.: 7.33-7.24 (6H, m),
7.05-6.94 (6H, m), 4.78 (1H, d, J=1.9 Hz), 4.60 (1H, t, J=4.4 Hz),
4.41 (1H, d, J=7.5 Hz), 4.30 (1H, d, J=10.0 Hz), 4.12 (1H, dd,
J=5.0, 10.6 Hz), 3.91-3.84 (3H, m), 3.66 (1H, d, J=5.6, 11.8 Hz),
3.57-3.49 (3H, m), 3.40-3.20 (6H, m), 3.10-3.06 (1H, m), 1.97-1.82
(4H, m). .sup.13C-NMR (75 MHz, CD.sub.3OD) .delta.: 169.52, 164.87,
160.42, 142.07, 133.18 (C), 131.03, 130.87, 128.68, 128.59, 128.47,
123.36, 119.86, 119.74, 116.69, 116.38, 116.25, 116.22, 115.96,
115.88, 115.68, 104.54, 80.71, 80.36, 79.58, 78.11, 77.85, 74.94,
73.70, 71.38 (CH), 69.02, 62.47 (CH.sub.2), 62.09 (CH.sub.2+CH),
61.20 (CH), 37.54, 26.18 (CH.sub.2). MALDI-MS
(C.sub.37H.sub.43F.sub.2NO.sub.13): [MNa].sup.+ 770.2589 (calcd.
770.2600).
Example 14
##STR00028##
[0162] Alcohol XVIIa (prepared according to Spak, S. J.; Martin, O.
R. Tetrahedron 2000, 56, 217-224; 895.3 mg, 0.907 mmol) was
dissolved in anhydrous CH.sub.2Cl.sub.2 (10 ml), anhydrous pyridine
(1.0 mL) followed by MsCl (0.20 mL, 2.6 mmol) were added and after
stirring for 1 h, sat. aq. NaHCO.sub.3 (40 mL) was added. The
layers were separated and the aqueous layer extracted with EtOAc
(3.times.20 mL). The combined organic layer was washed successively
with sat. aq. NaHCO.sub.3 (20 mL) and H.sub.2O (20 mL), evaporated
on celite and purified by dry column vacuum chromatography
(4.2.times.3.3 cm) on silica gel eluting with a gradient of 0-50%
EtOAc in hexane (v/v) to give the corresponding mesylate (830.7 mg,
86%) as a white solid.
[0163] R.sub.f (1:1 EtOAc/hexane (v/v)) 0.67; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.49-7.24 (35H, m), 5.31 (1H, d, J=11.2 Hz),
5.00 (1H, d, J=11.2 Hz), 4.98-4.79 (6H, m), 4.66-4.36 (9H, m), 4.09
(1H, t, J=9.3 Hz), 3.90 (1H, dd, J=2.8, 10.9 Hz), 3.83 (1H, d,
J=10.0 Hz), 3.75-3.62 (5H, m), 3.55-3.39 (5H, m), 2.97 (3H, s).
.sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 138.97, 138.37, 138.21,
138.04, 137.61 (C), 128.37, 128.29, 128.18, 128.08, 127.93, 127.84,
127.76, 127.38, 127.34, 127.24, 102.51, 84.86, 82.64, 78.70, 77.94,
76.84, 76.53, 76.38, 75.57 (CH), 75.22, 75.09 (CH.sub.2), 74.96,
74.78 (CH.sub.2, CH), 73.21, 73.02, 69.22, 68.89, 67.76 (CH.sub.2),
37.74 (CH.sub.3). IR (cm.sup.-): 3063, 3030, 2867, 1497, 1454,
1358, 1277, 1209, 1174, 1150, 1092, 1071, 1028, 984, 922, 812, 737,
698, 527. MALDI-MS (C.sub.63H.sub.68O.sub.13S): [MNa].sup.+
1087.4284 (calcd. 1087.4278). Anal. Calcd for
C.sub.63H.sub.68O.sub.13S: C, 71.03; H, 6.43. Found: C, 70.94; H,
6.62.
[0164] Subsequently, this mesylate (825 mg, 0.774 mmol) was
dissolved in EtOH (20 mL), KOSCMe (278 mg, 2.43 mmol), iPrOH (10
mL) and THF (10 mL) were added and the orange solution was stirred
at reflux for 3 h (orange precipitate). Additional KOSCMe (512 mg,
4.48 mmol) was added and the suspension was stirred at reflux for
16 h. After cooling, 500 sat. aq. NaHCO.sub.3 (100 mL) was added
and the suspension was extracted with ether (4.times.30 mL). The
combined organic layer was washed successively with sat. aq.
Na--HCO.sub.3 (50 mL) and H.sub.2O (50 mL), evaporated on celite
and purified by dry column vacuum chromatography (4.2.times.3.3 cm)
on silica gel elutiug with a gradient of 0-50% E-OAc in hexane
(v/v) to give the corresponding thioacetate (637 mg, 79%) as a
light orange solid.
[0165] R.sub.f (1:3 EtOAc/hexane (v/v)) 0.45; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.43-7.19 (35H, m), 5.22 (1H, d, J=11.2 Hz),
4.92 (1H, d, J=11.2 Hz), 4.88 (1H, d, J=11.2 Hz), 4.87-4.71 (5H,
m), 4.62 (1H, d, J=12.5 Hz), 4.60-4.43 (5H, m), 4.41 (1H, d, J=11.8
Hz), 4.06 (1H, t, J=9.3 Hz), 3.86 (1H, dd, J=3.7, 11.2 Hz), 3.75
(1H, dd, J=1.6, 10.9 Hz), 3.69-3.55 (5H, m), 3.51-3.31 (6H, m),
3.05 (1H, dd, J=6.8, 13.7 Hz), 2.34 (3H, s). .sup.13C-NMR (75 MHz,
CDCl.sub.3) .delta.: 195.04, 139.19, 138.53, 138.30, 138.24,
138.17, 137.96 (C), 128.33, 128.26, 128.20, 128.04, 127.79, 127.71,
127.63, 127.55, 127.47, 127.29, 127.19, 102.40, 85.12, 84.88,
82.71, 79.85, 79.30, 78.05, 77.87 (CH), 75.62, 75.18 (CH.sub.2),
75.09 (CH), 74.94, 74.81, 73.26, 73.21, 68.96, 67.86, 31.12
(CH.sub.2), 30.49 (CH.sub.3). IR (cm.sup.-1): 3030, 2868, 1692,
1496, 1454, 1358, 1210, 1067, 1028, 773, 735, 698, 626. MALDI-MS
(C.sub.64H.sub.68O.sub.11S): [Ma].sup.+ 1067.4365 (calcd.
1067.4380). Anal. Calcd for C.sub.64H.sub.66O.sub.11S: C, 73.54; H,
8.56. Found: C, 73.50; H, 6.60.
[0166] The thioacetate received above (631 mg, 0.604 mmol) was
suspended in AcOH (10 mL), ROAc (933 mg, 9.5 mmol) followed by
Oxone (2KHSO.sub.5.KHSO.sub.4.K.sub.2SO.sub.4, 1.179 g, 2.55 mmol)
were added and after stirring for 18 h, sat. aq. Na.sub.2CO.sub.3
(50 mL) and H.sub.2O (50 mL) were carefully added. After extraction
with CHCl.sub.3 (4.times.25 mL), the combined organic layer was
washed with sat. aq. Na.sub.2CO.sub.3 (25 mL), evaporated on celite
and purified by dry column vacuum chromatography (4.1.times.3.3 cm)
on silica gel eluting with a gradient of 0-20% MeOH in
CH.sub.2Cl.sub.2 (v/v) to give the corresponding sulfinate salt
(622 mg, 96%) as a colourless oil.
[0167] R.sub.f (10% MeOH in CH.sub.2Cl.sub.2 (v/v)) 0.29;
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.: 7.40-7.14 (35H, m),
5.19-4.34 (15H, m), 4.17-3.22 (15H, m). .sup.13C-NMR (75 MHz,
CDCl.sub.3) .delta.: 138.97, 138.32, 138.21, 138.06, 137.88,
137.84, 128.70, 128.36, 128.18, 128.05, 127.86, 127.76, 127.63,
127.57, 127.44, 127.29, 127.20, 126.94, 84.53, 84.45, 82.01, 79.48,
77.96, 77.75, 76.06, 76.01, 75.46, 74.94, 74.79, 74.67, 74.57,
73.28, 73.08, 73.02, 53.42. IR (cm.sup.-1): 3478, 3063, 3030, 2870,
1497, 1454, 1361, 1315, 1210, 1174, 1069, 1048, 1028, 736, 698,
621. MALDI-MS (C.sub.62H65NaO.sub.13S): [MH].sup.+ 1073.4098
(calcd. 1073.4122); [MNa].sup.+ 1095.3926 (calcd. 1095.3941).
[0168] Finally, the obtained sulfinate salt (334 mg, 0.311 mmol)
was dissolved in anhydrous acetonitrile/CH.sub.2Cl.sub.2 (4 mL, 1:1
(v/v)) at 0.degree. C., Ph.sub.3P (264 mg, 1.01 mmol) and thionyl
chloride (0.10 mL, 1.37 mmol) were added sequentially at 0.degree.
C. and the suspension was stirred at room temperature for 6 h.
EtOAc/hexane (1:4 (v/v), 30 mL) was added, the suspension was
filtered through a short pad of silica gel (4.times.5 mL
EtOAc/hexane (1:3 (v/v)) washings) and the filtrate was evaporated
and dried shortly under vacuum to give the desired sulfonyl
chloride XVIIIa (220 mg, 66%) as a light yellow foam.
[0169] R.sub.f (1:3 EtOAc/hexane (v/v)) 0.38; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.50-7.26 (35H, m), 5.30 (1H, d, J=11.2 Hz),
4.98 (1H, d, J=10.6 Hz), 4.96-4.81 (5H, m), 4.79 (1H, d, J=10.6
Hz), 4.67-4.50 (6H, m), 4.48 (1H, d, J=11.8 Hz), 4.23-4.15 (1H, m),
3.98-3.91 (2H, m), 3.85-3.57 (8H, m), 3.51-3.38 (3H, m), 3.30 (1H,
t J=9.0 Hz). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 138.77,
138.45, 138.17, 138.11, 137.78, 137.27 (C), 128.63, 128.38, 128.31,
128.18, 128.12, 127.94, 127.78, 127.70, 127.63, 127.55, 127.42,
127.29, 102.32, 84.98, 84.80, 82.66, 79.23, 77.95, 77.82, 75.78
(CH), 75.60, 75.38 (CH.sub.2), 75.12 (CH), 74.99, 74.78, 74.70
(CH.sub.2), 74.21 (CH), 73.24, 68.95, 67.35, 66.79 (CH.sub.2). IR
(cm.sup.-1): 3089, 3063, 3030, 2868, 1496, 1454, 1362, 1313, 1280,
1209, 1167, 1091, 1067, 1028, 913, 771, 736, 698, 601. MALDI-MS
(C.sub.62H.sub.65ClO.sub.12S): [MNa].sup.+ 1091.3767 (calcd.
1091.3783).
[0170] The sulfonyl chloride XVIIIa (271 mg, 0.253 mmol) was
dissolved in anhydrous CH.sub.2Cl.sub.2 (3 mL), anhydrous pyridine
(0.5 mL) followed by the silylated azetidinone phenol VIa obtained
in step 2a) (75.7 mg, 0.145 mmol) were added and the solution was
stirred for 38 h, diluted with EtOAc (50 mL) and washed
sequentially with sat. aq. NaHCO.sub.3 (15 ml) and H.sub.2O (15
mL). The organic layer was evaporated on celite and purified by dry
column vacuum chromatography (4.5.times.3.3 cm) on silica gel
eluting with a gradient of 0-20% EtoAc in toluene (v/v) to give the
corresponding sulfonate mixed with unreacted phenol VIa (166 mg,
4:1 mixture) as a white foam.
[0171] R.sub.f (1:1 EtOAc/hexane (v/v)) 0.73; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.49-7.17 (41H, m), 7.06 (2H, d, J=8.7 Hz),
7.02 (2H, t, J=8.1 Hz), 6.96 (2H, d, J=8.7 Hz), 5.31 (1H, d, J=11.2
Hz), 5.01-4.74 (7H, m), 4.65-4.45 (8H, m), 4.21 (1H, t, J=9.3 Hz),
4.02-3.96 (2H, m), 3.86-3.60 (6H, m), 3.53-3.47 (4H, m), 3.33 (1H,
d, J=9.3 Hz), 3.26 (1H, t, J=9.0 Hz), 3.19 (1H, d, J=9.3 Hz),
3.06-3.00 (1H, m), 2.06-1.84 (4H, m), 0.96 (9H, s), 0.10 (3H, s),
-0.07 (3H, s). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 166.70,
160.35, 160.00, 156.27, 149.33, 140.35, 140.31, 138.63, 138.26,
138.00, 137.90, 137.59, 137.45, 137.29, 136.51, 133.47 (C), 128.82,
128.73, 128.34, 128.19, 128.08, 127.98, 127.85, 127.66, 127.56,
127.45, 127.30, 127.25, 127.12, 127.01, 125.10, 123.32, 118.11,
118.01, 115.91, 115.60, 115.00, 114.93, 114.72, 102.39, 84.93,
84.80, 82.56, 78.82, 78.55, 77.95, 75.99 (CH), 75.60, 75.31
(CH.sub.2), 75.15 (CH), 74.96, 74.76 (CH.sub.2), 74.23, 73.77 (CH),
73.21, 73.08, 68.97, 67.62 (CH.sub.2), 61.02, 60.57, 60.39 (CH),
51.26, 38.02 (CH.sub.2), 25.85 (CH.sub.3), 24.67 (CH.sub.2), 18.19
(C), -4.56, -4.87 (CH.sub.3). .sup.19F-NMR (282 MHz, CDCl.sub.3)
.delta.: -114.94 (1F, septet, J=4.3 Hz), -117.10 (1F, septet, J=4.3
Hz). MALDI-MS (C.sub.92H.sub.99F.sub.2NO.sub.15SiS): [MNa].sup.+
1578.6365 (calcd. 1578.6370).
[0172] Subsequently, this sulfonate (166 mg 4:1 mixture) was
dissolved in EtOH (5 mL), Pd(OH).sub.2/C (20% (w/w), 94 mg) was
added and the suspension was evacuated 4 times with H.sub.2 and
stirred under an H.sub.2-atmosphere for 11.5 h. The suspension was
evaporated on celite and purified by dry column vacuum
chromatography (4.3.times.2.0 cm) on silica gel eluting with a
gradient of 0-10% MeOH in CH.sub.2Cl.sub.2 (v/v) to give the
corresponding debenzylated .beta.-lactam (69.5 mg, 52% from phenol
VIa) as a colourless oil.
[0173] R.sub.f (20% MeOH in CH.sub.2Cl.sub.2 (v/v)) 0.46; 3H-NMR
(300 MHz, CD.sub.3OD) .delta.: 7.46-7.38 (4H, m), 7.31-7.23 (4H,
m), 7.04-6.95 (4H, m), 4.75-4.68 (1H, m), 4.44 (1H, d, J=8.1 Hz),
3.92-3.80 (5H, m), 3.69-3.18 (11H, m), 3.10-3.05 (1H, m), 1.95-1.75
(4H, m), 0.86 (9H, s), 0.01 (3H, s), -0.19 (3H, s). .sup.13C-NMR
(75 MHz, CD.sub.3OD) .delta.: 169.31, 169.21, 161.76, 158.91,
150.96, 142.28, 138.45, 135.01, 134.98, 131.06, 130.95 (C), 128.83,
124.50, 119.92, 119.83, 116.99, 116.68, 116.10, 116.04, 115.81,
115.74, 104.54, 80.33, 80.10, 78.11, 77.81, 77.72, 76.30, 75.13,
74.89, 73.61, 71.38 (CH), 62.47, 61.63 (CH.sub.2), 61.56, 61.47
(CH), 53.26, 38.83 (CH.sub.2), 26.38 (CH.sub.3), 25.75 (CH.sub.2),
19.04 (a), -4.40, -4.70 (CH.sub.3). .sup.19F-NMR (282 MHz,
CD.sub.3OD) .delta.: -117.94 (1F, septet, J=4.3 Hz), -120.10 (1F,
septet, J=4.3 Hz). MALDI-MS (C.sub.43H.sub.57F.sub.2NO.sub.15SiS)
[MNa].sup.+ 948.3088 (calcd. 948.3084).
[0174] This debenzylated .beta.-Lactam (59.5 mg, 0.073 mmol) was
dissolved in anhydrous THF (2.0 mL, teflon bottle), anhydrous
pyridine (0.40 mL) followed by HF-pyridine complex (0.40 mL) were
added and the solution was stirred for 14 h. Sat. aq. NaHCO.sub.3
(5 mL) was added and the suspension was evaporated on celite and
purified by dry column vacuum chromatography (4.4.times.2.0 cm) on
silica gel eluting with a gradient of 10-20% MeOH in
CH.sub.2Cl.sub.2 (v/v) to give the desired .beta.-lactam XVIII
(38.1 mg, 64%) as a white solid.
[0175] R.sub.f (10% MeOH in CH.sub.2Cl.sub.2 (v/v)) 0.17 (eluted
thrice); .sup.1H-NMR (300 MHz, CD.sub.3OD) .delta.: 7.45 (2H, t,
J=9.3 Hz), 7.40 (2H, d, J=8.7 Hz), 7.33-7.24 (4H, m), 7.02 (2H, t,
J=8.1 Hz), 6.98 (2H, d, J=8.7 Hz), 4.90 (1H, d, J=1.9 Hz), 4.60
(1H, dd, J=5.0, 6.2 Hz), 4.43 (1H, d, J=7.5 Hz), 3.92-3.79 (5H, m),
3.69-3.49 (4H, m), 3.44-3.18 (6H, m), 3.12-3.06 (1H, m), 1.99-1.82
(4H, m). .sup.13C-NMR (75 MHz, CD.sub.3OD) .delta.: 169.31, 165.08,
162.17, 161.85, 158.96, 150.98, 142.15, 138.51, 135.01 (C), 128.88,
128.76, 124.46, 119.97, 119.86, 116.99, 116.68, 116.13, 115.84,
104.54, 80.35, 80.06, 78.11, 77.81, 77.71, 76.31, 74.91, 73.77,
73.63, 71.39 (CH), 62.45, 61.50 (CH.sub.2), 61.42 (CH), 53.26,
37.45, 26.12 (CH.sub.2).
[0176] .sup.19F-NMR (282 MHz, CD.sub.3OD) .delta.: -118.08 (1F,
septet, J=4.3 Hz), -120.21 (1F, septet, J=4.3 Hz). MALDI-MS
(C.sub.37H.sub.43F.sub.2NO.sub.15S): [MNa].sup.+ 834.2223 (calcd.
834.2219).
Example 15
##STR00029##
[0178] A 50 mL Schlenk flask was charged with Zn(OTf).sub.2 (12.647
g, 34.79 mmol) and heated to 120.degree. C. under high-vacuum (0.2
Torr) for 3.5 h. After cooling, (+)--N-methylephedrine (6.595 g,
36.79 mmol) was added and the flask was purged with Ar for 15 min.
Anhydrous toluene (14 mL) followed by Et.sub.3N (3.874 g, 38.3
mmol) were added and after 3 h stirring, benzyl propargyl ether
(prepared according to Ren, X. F.; Turos, E.; Lake, C. H.;
Churchill, M. R. J. Org. Chem. 1995, 60, 6468-6483; 5.556 g, 38.00
mmol) was added in one portion. After 20 min stirring, the mixture
was trans-ferred to a precooled acetone bath (8.degree. C.),
stirred for 5 min and p-FC.sub.6H.sub.4CHO (3.632 g, 29.26 mmol)
was added in one portion. After 15 h stirring at 9 to 120.degree.
C., the suspension was diluted with EtOAc (125 mL) and washed with
sat. aq. NH.sub.4Cl (2.times.30 mL) and brine (30 mL). The organic
layer was evaporated on celite and purified by dry column vacuum
chromatography (5.4.times.5.5 cm) on silica gel eluting with a
gradient of 0-50% EtOAc in hexane (v/v) to give propargyl alcohol
XIXa (5.896 g, 75%) as a light yellow oil. Enantiomeric excess as
determined by HPLC analysis: 960 ee; R.sub.t 20 min (R-XIXa), 28
min (S-XIXa) (Chiracel OD-H 25 cm, 6% iPrOH in hexane, flow 1.0
mL/min, 254 nm). R.sub.f (1:3 EtOAc/hexane (v/v)) 0.28; .sup.1H-NMR
(300 MNz, CDCl.sub.3) .delta.: 7.50 (2H, dd, J=5.6, 8.7 Hz),
7.38-7.32 (5H, m), 7.06 (2H, t, J=8.7 Hz), 5.48 (1H, s), 4.60 (2H,
s), 4.26 (2H, s), 2.84 (1H, s). .sup.13C-NMR (75 MHz, CDCl.sub.3)
.delta.: 164.01, 160.75, 136.95, 136.04 (C), 128.30, 128.21,
127.92, 127.81, 115.43, 115.13 (CH), 86.13, 82.62 (C), 71.74
(CH.sub.2), 63.74 (CH), 57.35 (CH.sub.2). .sup.19F-NMR (282 MHz,
CDCl.sub.3) .delta.: -113.28 (1F, septet, J=4.3 Hz). IR
(cm.sup.-1): 3390, 3066, 3032, 2859, 1604, 1508, 1455, 1413, 1386,
1355, 1224, 1158, 1121, 1096, 1072, 1028, 1014, 842, 772, 744, 699,
592, 561, 498. MALDI-MS (C.sub.17H.sub.15FO.sub.2): [MNa].sup.+
293.0947 (calcd. 293.0954). Anal. Calcd for
C.sub.17H.sub.15FO.sub.2: C, 75.54; H, 5.59. Found: C, 75.39; H,
5.62.
[0179] Subsequently this propargyl alcohol (4.108 g, 15.20 mmol)
was dissolved in anhydrous DMF (50 mL), imidazole (2.123 g, 31.1
mmol) and TBDMSCl (3.590 mg, 23.8 mmol) were added sequentially and
the solution was stirred for 3.5 h followed by addition of 500 sat.
aq. NaHCO.sub.3 (150 mL). After extraction with ether (4.times.50
mL), the combined organic layer was washed successively with sat.
aq. NaHCO.sub.3 (50 mL) and H.sub.2O (50 mL), evaporated and dried
shortly under high vacuum. The residue was dissolved in EtOH (40
mL), Na.sub.2CO.sub.3 (3.229 g, 30.5 mmol) and Pd/C (10% (w/w), 223
mg) were added and the suspension was evacuated 4 times with
H.sub.2 and stirred under an H.sub.2-atmosphere for 19 h. The
suspension was diluted with 10% EtOAc/hexane (250 mL (v/v)) and
filtered through a short plug of silica gel (2.times.25 mL 200
EtOAc/hexane washings (v/v)), evaporated and dried shortly under
high vacuum. The residue was dissolved in EtOH (40 mL), Pd/C
(10%(w/w), 142 mg) was added and the suspension was evacuated 4
times with H.sub.2 and stirred under an H.sub.2-atmosphere for 1 h.
Additional Pd/C (10% (w/w), 190 mg) was added and the suspension
was evacuated 4 times with H.sub.2 and stirred under an
H.sub.2-atmosphere for 1.25 h. The suspension was evaporated on
celite and purified by dry column vacuum chromatography
(5.2.times.5.5 cm) on silica gel eluting with a gradient of 0-25%
EtOAc in hexane (v/v) to give the corresponding alcohol (3.643 g,
80%) as a light yellow oil.
[0180] R.sub.f (1:3 EtOAc/hexane (v/v)) 0.37; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.24 (2H, dd, J=5.6, 8.7 Hz), 6.97 (2H, t,
J=8.7 Hz), 4.69 (1H, dt, L=1.2, 5.0 Hz), 3.59 (2H, dt, J=1.2, 6.2
Hz), 2.18 (1H, bs), 1.77-1.45 (4H, m), 0.87 (9H, s), 0.02 (3H, s),
-0.15 (3H, s): .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 163.37,
160.13, 140.96, 140.91 (C), 127.32, 127.23, 114.94, 114.64, 74.16
(CH), 62.76, 37.19, 28.47 (CH.sub.2), 25.76 (CH.sub.3), 18.15 (C),
-4.71, -5.05 (CH.sub.3). IR (cm.sup.-1): 3339, 2954, 2930, 2885,
2858, 1606, 1510, 1472, 1463, 1362, 1252, 1223, 1156, 1092, 1060,
984, 890, 836, 776, 668, 560. MALDI-MS
(C.sub.16H.sub.27FO.sub.2Si): [MNa].sup.+ 321.1643 (calcd.
321.1662). Anal. Calcd for C.sub.16H.sub.27FO.sub.2Si: C, 64.39; H,
9.12. Found: C, 64.36; H, 9.15.
[0181] The alcohol obtained above was dissolved in CH.sub.2Cl.sub.2
(50 mL), Dess-Martin periodinane (5.658 g, 13.3 mmol) was added and
the milky solution was stirred at room temperature for 1.5 h. Sat.
aq. Na.sub.2SO.sub.3 (100 mL) was added and the layers were swirled
until the solid had dissolved. The layers were separated and the
aqueous phase was extracted with CH.sub.2Cl.sub.2 (2.times.40 mL).
The combined organic phase was evaporated on celite and purified by
dry column vacuum chromatography (5.1.times.5.5 cm) on silica gel
eluting with a gradient of 0-10% EtOAc in hexane (v/v) to give the
corresponding aldehyde XIXb (2.093 g, 80%) as a light yellow
oil.
[0182] R.sub.f (1:3 EtOAc/hexene (v/v)) 0.63; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 9.73 (1H, d, J=1.5 Hz), 7.25 (2H, dd, J=5.6,
8.7 Hz), 6.99 (2H, t, J=9.0 Hz), 4.74 (1H, dt, J=5.0, 6.8 Hz),
2.52-2.35 (2H, m), 2.06-1.88 (2H, m), 0.88 (9H, 6), 0.02 (3H, s),
-0.16 (3H, s). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 201.91
(CH), 163.35, 160.10, 140.13 (C), 127.20, 127.10, 115.04, 114.75,
73.03 (CH), 39.69, 33.11 (CH.sub.2), 25.85 (CH.sub.3), 18.21 (C),
-4.61, -4.95 (CH.sub.3). IR (cm.sup.-1): 2955, 2938, 2888, 2858,
2720, 1727, 1606, 1509, 1472, 1464, 1412, 1390, 1362, 1254, 1223,
1156, 1090, 1014, 837, 776, 670, 540. Anal. Calcd for
C.sub.16H.sub.25FO.sub.2Si: C, 64.82; H, 8.50. Found: C, 64.95; H,
8.36.
[0183] LiCl (140.8 mg, 3.32 mmol) was heated shortly with a heat
gun under high-vacuum and after cooling, anhydrous CH.sub.3CN (5
mL), phosphonate XIXc (prepared according to Melekhov, A.; Fallis,
A. G. Tetrahedron Lett. 1999, 40, 7867-7870; 660 mg, 1.68 mmol) and
DBU (221 mg, 1.45 mmol) were added sequentially. After 3 min
stirring, the aldehyde XIXb (407.3 mg, 1.3.7 mmol) was added and
the suspension was stirred at room temperature for 2.5 h followed
by addition of 50% sat. aq. NaHCO.sub.3 (60 mL). After extraction
with ether/hexane (1:1 (v/v), 4.times.25 ml), the combined organic
layer was washed with brine (25 mL), evaporated on celite and
purified by dry column vacuum chromatography (4.6.times.3.3 cm) on
silica gel eluting with a gradient of 0-20% EtOAc in hexane (v/v)
to give olefin XIXd (520.7 mg, 71%) as a colourless oil.
[0184] R.sub.f (1:3 EtOAc/hexane (v/v)) 0.43; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.25 (2H, dd, J=5.6, 8.7 Hz), 7.10-6.94 (3H,
m), 6.53 (1H, d, J=14.9 Hz), 4.65 (1H, dd, J=5.0, 7.5 Hz), 3.91
(1H, dd, J=5.6, 6.8 Hz), 3.50 (1H, d, J=13.7 Hz), 3.42 (1H, d,
J=13.7 Hz), 2.30-2.23 (2H, m), 2.09-2.02 (2H, m), 1.90-1.70 (5H,
m), 1.43-1.30 (2H, m), 1.15 (3H, s), 0.95 (3H, s), 0.85 (9H, s),
0.01 (3H, s), -0.20 (3H, s). .sup.13C-NMR (75 MHz, CDCl.sub.3)
.delta.: 163.88, 163.39, 160.14, 150.06, 140.63 (C), 127.35,
127.26, 120.91, 114.98, 114.69, 73.24, 64.99 (CH), 53.04
(CH.sub.2), 48.33, 47.67 (C), 44.58 (CH), 38.61, 38.39, 32.71,
28.32, 26.40 (CH.sub.2), 25.72, 20.72, 19.78 (CH.sub.3), 18.04 (C),
-4.74, -5.10 (CH.sub.3). IR (cm.sup.-1): 2956, 2885, 2859, 1684,
1640, 1605, 1509, 1472, 1414, 1374, 1332, 1295, 1250, 1220, 1165,
1134, 1083, 1049, 995, 970, 860, 836, 774, 544. MALDI-MS
(C.sub.28H.sub.42FNO.sub.4SSi): [MNa].sup.+ 558.2479 (calcd.
558.2486). Anal. Calcd for C.sub.28H.sub.42FNO.sub.4SSi: C, 62.77;
H, 7.90; N, 2.61. Found: C, 62.84; H, 7.78; N, 2.58.
[0185] Olefin XIXd was dissolved in anhydrous toluene (2.0 mL),
TMSCHN.sub.2 (2 M in hexanes, 1.50 mL, 3.0 mmol) was added and the
solution was stirred at room temperature for 64 h. After
evaporation, the residue was dissolved in CH.sub.2Cl.sub.2 (10 ml),
TFA (202 mg, 1.77 mmol) was added and the solution was stirred for
20 min. Sat. aq. Na--HCO.sub.3 (1.5 ml) was added and the mixture
was evaporated on celite and purified by dry column vacuum
chromatography (4.5.times.3.3 cm) on silica gel eluting with a
gradient of 0-40% EtOAc in hexane (v/v) to give the corresponding
pyrazoline (468 mg, 84%) as a light yellow foam.
[0186] R.sub.f (1:3 EtOAc/hexane (v/v)) 0.25; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.21 (2H, dd, J=5.6, 8.7 Hz), 6.95 (2H, t,
J=8.7 Hz), 6.60 (1H, s), 6.16 (1H, d, J=5.6 Hz), 4.65 (1H, t, J=5.0
Hz), 4.33 (1H, dd, J=5.9, 9.7 Hz), 3.87 (1H, dd, J=5.0, 7.5 Hz),
3.67-3.62 (1H, bs), 3.53 (1H, d, J=13.7 Hz), 3.44 (1H, d, J=13.7
Hz), 2.15-1.99 (2H, m), 1.91-1.86 (3H, m), 1.66-1.51 (3H, m),
1.47-1.21 (3H, m), 1.14 (3H, s), 0.95 (3H, s), 0.86 (9H, s), 0.01
(3H, s), -0.17 (3H, s). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.:
167.96, 163.12, 159.89 (C), 146.91 (CH), 140.52, 140.49 (C),
127.15, 127.05, 114.83, 114.54, 73.37, 66.44, 65.09 (CH), 52.81
(CH.sub.2), 48.91 (C), 48.04 (CH), 47.79 (C), 44.33 (CH), 37.98,
37.79, 32.55, 26.76, 26.45 (CH.sub.2), 25.82, 20.68, 19.84
(CH.sub.3), 18.16 (C), -4.64, -4.90 (CH.sub.3). IR (cm.sup.-1):
3360, 2955, 2857, 1700, 1604, 1509, 1472, 1390, 1329, 1273, 1250,
1236, 1221, 1166, 1134, 1086, 1066, 994, 939, 836, 775, 694, 542.
MALDI-MS (C.sub.29HA.sub.4FN.sub.3O.sub.4BSi): [MNa].sup.+ 600.2691
(calcd. 600.2704). Anal. Calcd for
C.sub.29H.sub.44FN.sub.3O.sub.4SSi: C, 60.28; H, 7.67; N, 7.27.
Found: C, 60.25; Hr 7.83; N, 7.16.
[0187] This pyrazoline (409.8 mg, 0.709 mmol), Cu(OAc).sub.2 (296
mg, 1.63 mmol) and (p-FC.sub.6H.sub.4).sub.3Bi (prepared according
to Banfi, A.; Bartoletti, M.; Bellora, E.; Bignotti, M.; Turconi,
M. Synthesis 1994, 775-776; 950 mg, 1.92 mmol) were dissolved in
anhydrous CH.sub.2Cl.sub.2 (5 mL), anhydrous Et.sub.3N (165 mg,
1.63 mmol) was added and the dark green suspension was stirred at
room temperature for 12.5 h. After evaporation on celite the
residue was purified by dry column vacuum chromatography
(4.5.times.3.3 cm) on silica gel eluting with a gradient of 0-30%
EtOAc in hexane (v/v) to give N-arylated pyrazoline XIXe (320.8 mg,
63%) as a light yellow foam.
[0188] R.sub.f (1:3 EtOAc/hexane (v/v)) 0.33; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.24 (2H, dd, J=5.3, 8.4 Hz), 7.01-6.94 (4H,
m), 6.89 (2H, t, J=8.7 Hz), 6.68 (1H, d, J=1.9 Hz), 5.05 (1H, d,
J=3.7 Hz), 4.62 (1H, t, J=5.3 Hz), 3.85 (1H, dd, J=4.4, 7.5 Hz),
3.59 (1H, d, J=14.3 Hz), 3.58 (1H, d, J=14.3 Hz), 3.41-3.35 (1H,
m), 1.98-1.78 (5H, m), 1.72-1.60 (3H, m), 1.41-1.23 (3H, m), 1.21
(3H, s), 0.98 (3H, s), 0.88 (9H, s), 0.04 (3H, s), -0.17 (3H, s).
.sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 169.54, 163.38, 160.14,
158.46, 155.30 (C), 142.10 (CH), 140.75 (C), 127.32, 127.22,
115.71, 115.40, 114.96, 114.67, 114.22, 114.12, 73.99, 65.48, 64.93
(CH), 53.02 (CH, CH.sub.2), 49.05, 47.77 (C), 44.31 (CH), 37.98,
36.95, 32.76, 27.79, 26.25 (CH.sub.2), 25.75, 20.37, 19.77
(CH.sub.3), 18.07 (C), -4.77, -5.01 (CH.sub.3). .sup.19F (282 MHz,
CDCl.sub.3) .delta.: -116.27 (1F, m), -125.73 (iF, septet, J=4.3
Hz). IR (cm.sup.-1): 2957, 2857, 1699, 1606, 1510, 1471, 1413,
1362, 1334, 1268, 1250, 1221, 1166, 1136, 1113, 1088, 1063, 987,
836, 776, 759, 538. MALDI-MS
(C.sub.35H.sub.47F.sub.2N.sub.3O.sub.4SSi): [MH-TBDMSOH].sup.+
540.2127 (calcd. 540.2132); [MNa].sup.+694.2909 (calcd. 694.2922).
Anal. Calcd for C.sub.35H.sub.17F.sub.2N.sub.3O.sub.4SSi: C, 62.56;
H, 7.05; N, 6.25. Found: C, 62.37; H, 7.05; N, 6.03.
[0189] The N-arylated pyrazoline XIXe (101.5 mg, 0.151 mmol) was
dissolved in anhydrous THF (5 mL)-78.degree. C., LiAlH.sub.4 (33
mg, 0.87 mmol) was added and the suspension was stirred at
-78.degree. C. for 4.5 h. Sat. ag. NaHCO.sub.3 (1 mL) was added and
the mixture was evaporated on celite and purified twice by dry
column vacuum chromatography (4.6.times.2.0 cm) on silica gel
eluting with a gradient of 0-30% EtOAc in hexane (v/v) to give the
corresponding alcohol (52.7 mg, 76%) as a light yellow oil.
[0190] R.sub.f (1:3 EtoAc/hexane (v/v)) 0.23; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.23, (2H, dd, J=5.6, 8.7 Hz), 7.04-6.92 (6H,
m), 6.67 (1H, d, J=1.2 Hz), 4.64 (1H, t, J=5.9 Hz), 3.81 (1H, dd,
J=4.0, 11.5 Hz), 3.68-3.58 (2H, m), 3.12 (1H, dd, J=6.2, 6.8 Hz),
1.86 (1H, bs), 1.77-1.67 (2H, m), 1.58-1.48 (2H, m), 0.86 (9H, s),
0.00 (3H, s), -0.17 (3H, s). .sup.13C-NMR (75 MHz, CDCl.sub.3)
.delta.: 163.47, 160.22, 158.83, 155.68 (C), 144.84 (CH), 142.35,
140.67, 140.62 (C), 127.26, 127.16, 115.75, 115.46, 115.11, 115.06,
114.96, 114.83, 73.76, 66.81 (CH), 62.37 (CH.sub.2), 50.05 (CH),
37.72, 28.28 (CH.sub.2), 25.75 (CH.sub.3), 18.12 (C), -4.67, -5.01
(CH.sub.3). .sup.19F (282 MHz, CDCl.sub.3) .delta.: -115.25 (1F,
septet, T=4.3 Hz), -124.25 (1F, septet, J=4.3 Hz). IR (cm.sup.-1):
3401, 2953, 2930, 2885, 2858, 1672, 1605, 1509, 1472, 1463, 1416,
1362, 1296, 1252, 1223, 1156, 1086, 1006, 979, 938, 861, 835, 776,
666, 608, 554. MALDI-MS (C.sub.25H.sub.34F.sub.2N.sub.2O.sub.2Si):
[MH-CH.sub.2O] 429.2175 (calcd. 429.2174); [M-H].sup.+ 459.2279
(calcd. 459.2279).
[0191] Subsequently this alcohol (70.8 mg, 0.154 mmol) was
dissolved in anhydrous CH.sub.2Cl.sub.2 (5 mL), anhydrous Et.sub.3N
(0.50 mL, 3.9 mmol), DMAP (6.8 mg, 0.056 mmol) and TsCl (69 mg,
0.36 mmol) were added and the solution was stirred at room
temperature for 12.5 h, evaporated on celite and purified by dry
column vacuum chromatography (4.4.times.2.0 cm) on silica gel
eluting with a gradient of 0-20% EtOAc in hexane (v/v) to give the
corresponding tosylate (78.4 mg, 83%) as a colourless oil.
[0192] R.sub.f (1:3 EtOAc/hexane (v/v)) 0.44; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.68 (2H, d, J=8.7 Hz), 7.25 (4H, t, J=8.1
Hz), 6.99 (2H, t, J=8.7 Hz), 6.92-6.80 (4H, m), 6.64 (1H, d, J=1.2
Hz), 4.65 (1H, dd, J=4.4, 6.8 Hz), 4.12 (1H, dd, J=2.5, 9.3 Hz),
3.92-3.81 (2H, m), 3.08-3.01 (1H, m), 2.42 (3H, s), 1.80-1.43 (4H,
m), 0.87 (9H, s), 0.01 (3H, s), -0.17 (3H, s). .sup.13C-NMR (75
MHz, CDCl.sub.3) .delta.: 163.49, 160.24, 158.59, 155.43, 145.16
(C), 143.40 (CH), 140.54, 132.21 (C), 129.84, 127.82, 127.32,
127.21, 115.79, 115.48, 115.12, 114.83, 114.31, 114.22, 73.50 (CH),
67.45 (CH.sub.2), 62.42, 50.74 (CH), 37.35, 27.87 (CH.sub.2),
25.77, 21.59 (CH.sub.3), 18.10 (C), -4.67, -5.01 (CH.sub.3).
.sup.19F (282 MHz, CDCl.sub.3) .delta.: -116.01 (1F, m), -125.40
(1F, septet, J=4.3 Hz). IR (cmri): 3055, 3034, 2953, 2930, 2886,
2857, 1603, 1509, 1472, 1463, 1365, 1307, 1294, 1252, 1223, 1190,
1177, 1156, 1096, 979, 862, 835, 775, 666, 608, 555. MALDI-MS
(C.sub.32H.sub.40F.sub.2N.sub.2O.sub.4SSi): [MH-TBDMSOH].sup.+
483.1559 (calcd. 483.1554); [MNa].sup.+ 637.2330 (calcd.
637.2344).
[0193] The tosylate received above was dissolved in anhydrous DMF
(2.5 mL), hydroquinone (263 mg, 2.39 mmol) and Cs.sub.2CO.sub.3
(102.1 mg, 0.313 mmol) were added and the suspension was stirred at
80.degree. C. for 12 h. EtOAc (30 mL) was added and the organic
phase was washed with sat. aq. NaHCO.sub.3 (10 mL) and H.sub.2O (10
mL), evaporated on celite and purified by dry column vacuum
chromatography (4.5.times.2.0 cm) on silica gel eluting with a
gradient of 0-30% EtOAc in hexane (v/v) to give the corresponding
phenol XIXE (70.9 mg, 86%) as a colourless oil.
[0194] R.sub.f (1:3 EtOAc/hexane (v/v)) 0.33; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.24 (2H, dd, J=5.3, 8.4 Hz), 7.06-6.93 (6H,
m), 6.75-6.68 (5H, m), 4.67 (1H, dd, J=4.4, 6.8 Hz), 4.10-3.98 (2H,
m), 3.74 (1H, dd, J=1.2, 7.5 Hz), 3.17-3.11 (1H, m), 1.86-1.54 (4H,
m), 0.88 (9H, s), 0.02 (3H, s), -0.15 (3H, s). .sup.13C-NMR (75
MHz, CDCl.sub.3) .delta.: 163.32, 160.08, 158.48, 155.35, 152.31,
149.86 (C), 143.85 (CH), 141.52, 141.49, 140.63 (C), 127.23,
127.12, 115.99, 115.73, 115.51, 115.44, 115.04, 114.75, 114.67,
114.57, 73.78 (CH), 67.79 (CH.sub.2), 63.88, 51.51 (CH), 37.77,
28.38 (CH.sub.2), 25.89 (CH.sub.3), 18.25 (C), -4.46, -4.80
(CH.sub.3). .sup.19F (282 MHz, CDCl.sub.3) .delta.: -115.31 (1F,
m), -124.71 (1F, septet, J=4.3 Hz). IR (cm.sup.-1): 3350, 3056,
2953, 2930, 2885, 2858, 1605, 1509, 1472, 1462, 1362, 1297, 1226,
1156, 1100, 1086, 1050, 1006, 939, 828, 776, 667, 609, 553, 518.
MALDI-MS (C.sub.31H.sub.38F.sub.2N.sub.2O.sub.3Si):
[MH-TBDMSOH].sup.+ 421.1720 (calcd. 421.1728); [MH].sup.+ 553.2677
(calcd. 553.2698); [MNa].sup.+ 575.2505 (calcd. 575.2517).
[0195] The phenol XIXf (18.4 mg, 0.0333 mmol) was dissolved in
anhydrous THF (1.0 mL, teflon bottle) at 0.degree. C., anhydrous
pyridine (0.20 ml) followed by HF.pyridine complex (0.20 mL) were
added and the solution was allowed to warm to room temperature over
several h and stirred at room temperature for 22 h. Ether (20 mL)
was added and the solution was washed with sat. aq. NaHCO.sub.3
(2.times.5 mL), evaporated on celite and purified by dry column
vacuum chromatography (4.5.times.2.0 cm) on silica gel eluting with
a gradient of 0-60% EtOAc in hexane (v/v) to give the desired diol
XIX (14.4 mg, 99%) as a colourless oil.
[0196] R.sub.f (1:1 EtoAc/hexane (v/v)) 0.27; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.29 (2H, dd, J=5.3, 8.4 Hz), 7.06-6.93 (6H,
m), 6.75-6.67 (5H, m), 4.70 (1H, t, J=6.5 Hz), 4.09-4.03 (2H, m),
3.72 (1H, t, J=10.0 Hz), 3.18 (1H, dd, J=4.4, 6.2 Hz), 1.99-1.50
(4H, m). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 163.72, 160.47,
155.31, 152.26, 149.95 (C), 143.53 (CH), 141.41, 139.78 (C),
127.41, 127.29, 116.01, 115.77, 115.51, 115.23, 114.54, 114.42,
73.49 (CH), 67.60 (CH.sub.2), 63.67, 51.35 (CH), 35.89, 28.70
(CH.sub.2). .sup.19F (282 MHz, CDCl.sub.3) .delta.: -114.89 (1F,
septet, J=4.3 Hz), -124.64 (1F, septet, J=4.3 Hz). IR (cm.sup.-1):
3320, 2927, 1604, 1508, 1453, 1366, 1225, 1157, 1102, 1044, 910,
826, 733, 609. MALDI-MS (C.sub.25H.sub.24F.sub.2N.sub.2O.sub.3)
[MH--H.sub.2O].sup.+ 421.1717 (calcd. 421.1728); [M].sup.+ 438.1755
(calcd. 438.1755); [MH] 439.1825 (calcd. 439.1833); [MNa].sup.+
461.1650 (calcd. 461.1653).
Example 16
##STR00030##
[0198] The phenol XIXf obtained in step 15a) (28.4 mg, 0.0514 mmol)
was dissolved in anhydrous CH.sub.2Cl.sub.2 (2 mL), anhydrous
pyridine (0.10 mL, 1.3 mmol) and MsCl (0.05 mL, 0.51 mmol) were
added and the solution was stirred at room temperature for 22.5 h,
evaporated on celite and purified by dry column vacuum
chromatography (4.5.times.2.0 cm) on silica gel eluting with a
gradient of 0-50% EtOAc in hexane (v/v) to give the corresponding
mesylate (29.2 mg, 90%) as a colourless oil.
[0199] R.sub.f (1:1 EtOAc/hexane (v/v)) 0.64; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.26-7.17 (6H, m), 7.06-6.94 (6H, m), 6.83
(2H, d, J=9.3 Hz), 6.71 (1H, d, J=1.2 Hz), 4.66 (1H, dd, J=4.4, 6.8
Hz), 4.11 (1H, dd, J=4.0, 9.0 Hz), 4.04 (1H, dt, J=4.4, 7.5 Hz),
3.81 (1H, dd, J=7.5, 8.7 Hz), 3.11 (3H, s), 3.19-3.08 (1H, m),
1.85-1.52 (4H, m), 0.87 (9H, s), 0.01 (3H, s), -0.16 (3H, s).
.sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.: 160.25, 158.65, 157.92,
157.23, 155.50 (C), 143.67 (CH), 142.93, 141.52, 140.67 (C),
127.30, 127.19, 123.18, 115.85, 115.56, 115.45, 115.14, 114.85,
114.64, 114.53, 73.76 (CH), 67.53 (CH.sub.2), 63.54, 51.60 (CH),
37.75 (CH.sub.2), 37.09 (CH.sub.3), 28.29 (CH.sub.2), 25.78
(CH.sub.3), 18.13 (C), -4.63, -4.98 (CH.sub.3). .sup.19F (282 MHz,
CDCl.sub.3) .delta.: -116.00 (1F, m), -125.47 (1F, septet, J=4.3
Hz). IR (cm.sup.-1): 2930, 2857, 1605, 1508, 1472, 1369, 1299,
1251, 1223, 1197, 1168, 1152, 1086, 1009, 970, 868, 836, 776, 609,
527. MALDT-MS (C.sub.32H.sub.40F.sub.2N.sub.2O.sub.5SSi)
[MH-TBDMSOH].sup.+ 499.1504 (calcd. 499.1503); [MNa].sup.+ 653.2298
(calcd. 653.2293).
[0200] This mesylate (29.0 mg, 0.0460 mmol) was dissolved in
anhydrous THF (1.0 mL, teflon bottle) at 0.degree. C., anhydrous
pyridine (0.20 mL) followed by HF-pyridine complex (0.20 mL) were
added and the solution was allowed to warm to room temperature over
several h and stirred at room temperature for 10 h. Ether (20 mL)
was added and the solution was washed with sat. aq. NaHCO.sub.3
(2.times.5 mL), evaporated on celite and purified by dry column
vacuum chromatography (4.6.times.2.0 cm) on silica gel eluting with
a gradient of 0-90% EtOAc in hexane (v/v) to give the desired
mesylate XX (23.0 mg, 97%) as a colourless oil.
[0201] R.sub.f (1:1 EtOAc/hexane (v/v)) 0.18; .sup.1H-NMR (300 MHz,
CDCl.sub.3) .delta.: 7.30 (2H, dd, J=5.6, 8.7 Hz), 7.18 (2H, d,
J=9.3 Hz), 7.06-6.94 (6H, m), 6.83 (2H, d, J=9.3 Hz), 6.73 (1H, d,
J=1.2 Hz), 4.70 (1H, dd, J=5.6, 6.8 Hz), 4.14-4.07 (2H, m),
3.84-3.77 (1H, m), 3.19-3.14 (1H, m), 3.10 (3H, s), 1.94 (1H, bs),
1.92-1.54 (4H, m). .sup.13C-NMR (75 MHz, CDCl.sub.3) .delta.:
163.72, 160.47, 158.50, 157.04, 155.35 (C), 143.35 (CH), 142.82,
141.30, 141.26, 139.84 (C), 127.36, 127.26, 123.11, 115.81, 115.52,
115.41, 115.25, 114.52, 114.42, 73.44 (CH), 67.37 (CH.sub.2),
63.44, 51.43 (CH), 37.20 (CH.sub.3), 35.97, 28.73 (CH.sub.2).
.sup.19F (282 MHz, CDCl.sub.3) .delta.: -114.06 (1F, m), -124.49
(1F, septet, J=4.3 Hz). IR (cm.sup.-1): 3550, 3404, 2936, 1604,
1508, 1366, 1299, 1249, 1223, 1196, 1168, 1151, 1039, 970, 913,
870, 835, 743, 528. MADI-MS
(C.sub.26H.sub.26F.sub.2N.sub.2O.sub.5S):
[MH--H.sub.2O].sup.+499.1500 (calcd. 499.1503); [M].sup.+ 516.1536
(calcd. 516.1504); [MH].sup.+ 517.1606 (calcd. 517.1609);
[Ma].sup.+ 539.1428 (calcd. 539.1428).
Example 17
##STR00031##
[0203] To a solution of acid XXIa (prepared according to B. A.
Shinkre, V. G. Puranik, B. M. Bhawal, A. Deshmukh, Tetrahedron:
Asymmetry 2003, 14, 453; 30.0 g, 102 mmol, 1.11 equiv) in
CH.sub.2Cl.sub.2 (600 ml) is added triethylamine (64.0 ml, 461
mmol, 5.00 equiv) followed by imine XXIb (prepared according to T.
Kambara, X. Tomioka, J. Org. Chem. 1999, 64, 9282; 28.1 g, 92.1
mmol, 1.00 equiv). The solution is cooled to -20.degree. C. and
triphosgene (16.4 g, 55.8 mmol, 0.600 equiv) is added in 50 ml
CH.sub.2Cl.sub.2 over a period of 20 min. The solution is warmed to
23.degree. C. over a period of 8 h and stirred for additional 10 h
at this temperature. The solution is poured onto 600 ml ice water
and 200 ml CH.sub.2Cl.sub.2. The aqueous phase is extracted with
CH.sub.2Cl.sub.2 (3*100 ml). The combined organic phases are washed
with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The
residue is purified by chromatography on silica gel eluting with
hexane/ethyl acetate (3/2 to 1/2 gradient) and then chromatography
on silica gel eluting with EtOAc/CH.sub.2Cl.sub.2 (7/1 to 3/1
gradient) to afford .beta.-lactam XXIc as a colorless solid in 40 W
yield along with 35% yield of the undesired diastereomer.
[0204] mp: 132.degree. C. R.sub.f=0.38 (hexane/ethyl acetate 1/1).
.alpha..sub.D=+77.degree., (CHCl.sub.3, c=1.075, 30.5.degree. C.).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 7.46-7.07 (m, 16H),
6.92-6.84 (m, 2H), 5.34 (d, J=5.3, Hz, 1H), 5.06 (s, 2H), 4.95 (d,
J=5.3 Hz, 1H), 4.60 (d, J=2.5 Hz), 3.23-3.14 (m, 1H), 2.90 (s, 3H),
1.70 (s, 3H), 0.83 (d, J=6.2 Hz) .sup.13C-NMR (75 MHz, CDCl.sub.3):
.delta. 165.4, 165.0, 159.3 (J=244 Hz), 159.1, 137.1 (L=5 Hz),
133.7, 129.9, 128.9, 128.6, 128.3, 128.0, 127.7, 125.7, 119.0 (J=8
Hz), 116.0 (J=23 Hz), 115.1, 100.1, 76.9, 71.2, 70.1, 62.2, 59.0,
33.8, 23.6, 12.4. IR (thin film): 2938, 1756, 1667, 1612, 1511,
1382, 1223, 1177, 1112, 1092, 834, 734. HEMS (EI): Calcd' for
(C.sub.35H.sub.33FN.sub.2O.sup.+), 580.2374, found, 580.2369.
[0205] To a solution of .beta.-lactam XXIc (17.0 g, 29.0 mmol, 1.00
equiv) in THF (242 ml) and water (48 ml) is added p-toluenesulfonic
acid hydrate (55.7 g, 293 mmol, 10.0 equiv). The solution is heated
to reflux for 5 h. The solution is concentrated to an approximate
volume of 60 ml and then poured onto EtOAc (150 ml) and water (250
ml). The aqueous phase is extracted with EtOAc (4*100 ml). The
combined organic phases are washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated in vacuo. The residue is
purified by chromatography on silica gel eluting with hexane/ethyl
acetate (3/2 to 2/3 gradient) to afford the corresponding
3-hydroxy-p-lactam as a colorless solid in 51% yield.
[0206] mp: 168.degree. C. R.sub.f=0.26 (hexane/ethyl acetate 3/2).
.alpha..sub.D=-129.degree., (acetone, c=1.22, 29.5.degree. C.).
.sup.1H-NMR (300 MHz, acetone): .delta. 7.50-7.47 (m, 2H),
7.42-7.29 (m, 5H), 7.10-7.01 (m, 4H), 5.33 (d, J=5.3 Hz, 1H), 5.27
(dd, J=7.2 Hz, 5.3 Hz, 1H), 5.11 (s, 2H), 5.07 (d, J=7.2 Hz, 1H).
.sup.13C-MR (75 MHz, acetone): .delta. 166.5, 159.2, 159.0 (J=241
Hz), 137.7, 134.7, 129.6, 128.6, 128.0, 127.8, 118.9 (J=8 Hz),
115.8 (J=23 Hz), 114.8, 78.0, 69.8, 62.3. IR (thin film): 3120,
1756, 1667, 1612, 1511, 1382, 1223, 1177, 1112, 1092, 834, 734.
HRMS (EI): Calcd' for (C.sub.22H.sub.18FNO.sub.3.sup.+), 363.1271,
found, 363.1268. Anal. Calcd. for C.sub.22H.sub.11FNO.sub.3: C,
72.72; H, 4.99; N, 3.85; found: C, 77.73; H, 5.20; N, 3.91.
[0207] To a suspension of this 3-hydroxy-.beta.-lactam (2.00 g,
5.50 mmol, 1.00 equiv) in methanol (55.0 ml) is added sodium
methoxide (1.49 g, 27.5 mmol, 5.00 equiv). The suspension is
stirred at 23.degree. C. for 2 h. To the forming solution is added
NH.sub.4Cl.sub.(s) and the suspension is concentrated in vacuo. To
the solid is added EtOAc (50 ml) and water (50 ml). The aqueous
phase is extracted with EtOAc (3*20 ml). The combined organic
phases are washed with brine, dried (Na.sub.2SO.sub.4) and
concentrated in vacuo. The residue is purified by chromatography on
silica gel eluting with hexane/ethyl acetate (3/2 to 1/1 gradient)
to afford the corresponding amino alcohol as a colorless solid in
89% yield.
[0208] mp: 103.degree. C. R.sub.f=0.45 (hexane/ethyl acetate 3/2).
.alpha..sub.D=+13.9.degree., (CH.sub.2Cl.sub.2, c=1.10,
25.3.degree. C. .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta.
7.44-7.24 (m, 4H), 6.97-6.91 (m, 2H), 6.84-6.76 (m, 2H), 6.53-6.46
(m, 2H), 5.02 (s, 2H), 4.81 (s, 1H), 4.60 (s, 1H), 4.46 (m, 1H),
3.79 (s, 3H), 3.07 (d, J=3.7 Hz, 1H). .sup.13C-NMR (75 MHz,
CDCl.sub.3), .delta. 158.2, 155.8 (L=233 Hz), 142.5, 136.8, 131.0,
128.5, 127.9, 127.9, 127.4, 155.5 (J=22 Hz), 114.9, 114.8, 74.6,
70.0, 59.1, 53.1, 114.8, 78.0, 69.8, 62.3. IR (thin film): 3390,
1737, 1610, 1510, 1221, 1113, 823. MS (EI): 306.1748 (2.54 W),
186.2356 (18.8%, 91.0908 (100%). Anal. Calcd. for
C.sub.23H.sub.22FNO.sub.4: C, 69.86; H, 5.61; N, 3.54; found: C,
69.88; H, 5.78; N, 3.54.
[0209] To a solution of the amino alcohol received above (1.92 g,
4.86 mmol, 1.00 equiv) in CH.sub.2Cl.sub.2 (24.0 ml) is added
diisopropylethyl-amine (2.54 ml, 14.6 mmol, 3.00 equiv) and
4-N,N-dimethylaminopyridine (59.0 mg, 0.486 mmol, 0.10 eguiv). The
solution is cooled to -78.degree. C. and triphosgene (1.44 g, 4.86
mmol, 1.00 equiv) in CH.sub.2Cl.sub.2 (4.0 ml) is added over a
period of 5 min. The solution is warmed to 23.degree. C. over 8 h
and stirred at this temperature for additional 5 h. To this
solution is added water (50 ml) and concentrated aqueous ammonium
hydroxide solution (3 ml). The aqueous phase is extracted with
CH.sub.2Cl.sub.2 (3*20 ml). The combined organic phases are washed
with brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The
residue is purified by chromatography on silica gel eluting with
hexane/ethyl acetate (2/1 to 1/1 gradient) to afford methyl ester
XXId as a colourless solid in 82% yield.
[0210] mp: 118.degree. C. R.sub.f=0.54 (hexane/ethyl acetate 3/2).
.alpha..sub.D=+18.degree., (CHCl.sub.3, c=1.10, 29.3.degree. C.).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 7.40-7.32 (m, 7H),
7.29-7.22 (m, 2H), 6.98-6.93 (m, 4H), 5.33 (d, J=4.4 Hz, 1H), 5.03
(s, 2H), 4.73 (d, J=4.4 Hz, 1H), 3.89 (s, 3H). .sup.13C-NMR (75
MHz, CDCl.sub.3): .delta. 168.9, 160.1 (d, J=244 Hz), 159.7, 154.3,
136.7, 132.7, 129.5, 128.9, 128.4, 127.8, 127.7, 123.2 (d, J=8 Hz),
116.1 (d, J=22 Hz), 116.0, 77.9, 70.3, 36.6, 53.5. IR (thin film):
1769, 1552, 1388, 1227, 1099, 834. HRMS (MALDI): Calcd' for
(C.sub.24H.sub.20FNO.sub.5Na.sup.+), 444.1224, found, 444.1224.
Anal. Calcd. for C.sub.24H.sub.20FNO.sub.5: C, 68.40; H. 4.78; N,
3.32; found: C, 68.18; H, 4.91; N, 3.38.
[0211] To a suspension of methyl ester XXId (1.68 g, 3.99 mmol,
1.00 equiv) in ethanol (27.0 ml) is added at 23.degree. C. sodium
cyanoborohydride (226 mg, 5.98 mmol, 1.50 equiv). The suspension is
stirred for 2 h at this temperature at which point all solids were
dissolved. To this solution is added NH.sub.4Cl.sub.(s) and the
volume is concentrated in vacuo to 5 ml. To this suspension is
added water (50 ml) and EtOAc (50 ml). The aqueous phase is
extracted with EtOAc. The combined organic phases are washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The
residue is purified by chromatography on silica gel eluting with
hexane/ethyl acetate (1/1 to 2/3 gradient) to afford the
corresponding alcohol as a colorless solid in 92% yield.
[0212] mp: 143.degree. C. R.sub.f=0.40 (hexane/ethyl acetate 2/3).
.alpha..sub.D=-16.degree., (CHCl.sub.3, c=1.54, 32.4.degree. C.).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 7.42-7.19 (m, 9H),
6.97-6.90 (m, 4H), 5.26 (d, J=6.5 Hz, 1H), 5.02 (s, 2H), 4.39 (m,
1H), 3.99 (d, J=12.5 Hz, 1H), 3.74 (d, J=12.5 Hz, 1H), 2.77 (s,
1H). .sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 159.7 (d, J=245
Hz), 159.0, 136.4, 132.7, 129.4, 128.5, 128.0, 127.9, 127.4, 123.6
(d, J=8 Hz), 115.6 (d, J=22 Hz), 115.6, 82.0, 70.1, 61.6, 61.2. IR
(thin film): 3418, 2930, 2871, 1748, 1611, 1512, 1394, 1234. HRMS
(EI): Calcd' for (C.sub.23H.sub.20FNO.sub.4.sup.+), 393.1376,
found, 393.1389. Anal. Calcd. for C.sub.23H.sub.20FNO.sub.4: C,
70.22; H, 5.12; N, 3.56; found: C, 70.26; H, 5.21; N, 3.61.
[0213] To a solution of oxalylchloride (508 mg, 4.00 mmol, 2.00
equiv) in CH.sub.2Cl.sub.2 (15.0 ml) is added at -78.degree. C.
dimethylsulfoxide (0.355 ml, 5.00 mmol, 2.50 equiv). After 10 min
at -78.degree. C. is added the alcohol received above (787 mg, 2.00
mmol, 1.00 equiv) in CH.sub.2Cl.sub.2 (15.0 ml) over a period of 5
min. After additional 5 min at this temperature triethylamine (1.14
ml, 8.00 mmol, 8.00 equiv) is added. After 5 min
1-(4-Fluoro-phenyl)-2-(triphenyl-.lamda..sup.5-phosphanylidene)-ethanone
is added and the resulting suspension is warmed to 20.degree. C.
and stirred for additional 30 min. To the solution is added
saturated aqueous Na.sub.2HCO.sub.3 solution. The aqueous phase is
extracted with CH.sub.2Cl.sub.2. The combined organic phases are
washed with brine, dried (Na.sub.2SO.sub.4) and concentrated in
vacuo. The residue is purified by chromatography on silica gel
eluting with hexane/ethyl acetate (2/1 to 1/1 gradient) to afford
the corresponding enone as a colorless solid in 89% yield.
[0214] mp: 152.degree. C. R.sub.f 0.56 (hexane/ethyl acetate 3/2).
.alpha..sub.D=+100.degree., (CHCl.sub.3, c=0.60, 25.6.degree. C.).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.06-7.99 (m, 2H),
7.42-7.06 (m, 14H), 7.00-6.92 (m, 4H), 5.05-5.00 (m, 4H).
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 187.1, 165.9 (d, J=254
Hz), 159.8 (d, J=243 Hz), 159.4, 154.8, 140.0, 136.2, 133.2, 132.3,
131.4 (d, J=9 Hz), 128.6, 128.1, 128.1, 127.9, 127.4, 125.8, 123.5
(d, J=9 Hz), 115.9 (d, J=24 Hz), 115.8 (d, J=24 Hz), 115.8, 80.5,
70.2, 66.0. IR (thin film): 1760, 1675, 1597, 1511, 1385, 1227.
HRMS (MALDI): Calcd' for (C.sub.31H.sub.23F.sub.2NO.sub.4Na.sup.+),
534.1493, found, 534.1482. Anal. Calcd. for
C.sub.31H.sub.23F.sub.2NO.sub.4: C, 72.79; H, 4.53; N, 2.74; found:
C, 72.51; H, 4.78; N, 2.73.
[0215] To this enone (910 mg, 1.78 mmol, 1.00 equiv) in ethanol
(15.0 ml) is added at 23.degree. C. palladium on carbon (10 (100
mg). The suspension is vigorously stirred under 1 atm of hydrogen
gas for 3 h. The suspension is filtered through a pad of celite
eluting with EtOAc concentrated and the residue is purified by
chromatography on silica gel eluting with hexane/ethyl acetate (2/1
to 1/1 gradient). A portion of the resulting benzyl ether (310 mg,
0.604 mmol, 1.00 equiv) is dissolved in CH.sub.2Cl.sub.2 and cooled
to -20.degree. C.
(R)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo-oxazaborole2-methyl-oxazab-
orolidin (solution in toluene (0.5 M) 0.600 ml, 0.302 mmol, 0.50
equiv) is added followed by borane dimethylsulfide complex (0.080
ml, 0.905 mmol, 1.50 equiv). The solution is stirred at -20.degree.
C. for 2 h, then warmed to 0.degree. C. and quenched with methanol.
To the solution is added saturated aqueous Na.sub.2HCO.sub.3
solution and CH.sub.2Cl.sub.2. The aqueous phase is extracted with
CH.sub.2Cl.sub.2. The combined organic phases are washed with
brine, dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The
residue is purified by chromatography on silica gel eluting with
hexane/ethyl acetate (3/2 to 1/1 gradient). A portion of the
resulting alcohol (53 mg, 0.10 mmol, 1.0 equiv) is dissolved in
ethanol and palladium on carbon (10 mg) is added. The suspension is
vigorously stirred under an atmosphere of hydrogen for 2.5 h. The
suspension is filtered through a plug of celite eluting with EtOAc.
The residue is purified by chromatography on silica gel eluting
with hexane/ethyl acetate (1/1 to 1/2 gradient) to afford the
desired oxazolidinone XXI as a colorless solid in 57% yield from
the starting enone.
[0216] mp: 98.degree. C. R.sub.f=0.41 (hexane/ethyl acetate 2/3).
.alpha..sub.D=-1, (CHCl.sub.3, c=0.84, 27.6.degree. C.).
.sup.1H-NMR (300 MHz, acetone d.sub.6): .delta. 7.47-7.35 (m, 4H),
7.29-7.24 (m, 2H), 7.09-6.97 (m, 4H), 6.85-6.79 (m, 2H), 5.15 (d,
J=6.7 Hz, 1H), 4.76-4.68 (m, 1H), 4.43-4.34 (m, 2H), 2.02-1.76 (m,
4H). .sup.13C-NMR (75 MHz, acetone d.sub.6): 162.0 (d, J=243 Hz),
159.5 (d, J=242 Hz), 157.9, 155.3, 142.2 (d, J=3 Hz), 134.3 (d, J=2
Hz), 129.1, 128.7, 127.8 (d, J=8 Hz), 123.8 (d, J=9 Hz), 116.1,
115.2 (d, J=23 Hz), 114.9 (d, J=21 Hz), 82.4, 72.3, 65.6, 35.0,
30.3. IR (thin film): 3316, 2925, 1726, 1603, 1511, 1224, 835. HRMS
(MALDI) Calcd' for (C.sub.24H.sub.21F.sub.2NO.sub.4Na.sup.+),
448.1337, found, 448.1326.
Example 18
[0217] The compounds of the invention and ezetimibe (commercially
obtained or prepared according to Wu, G. Z. et al., J. Org. Chem.
1999) together with the glucuronide (the metabolite of ezetimibe,
prepared according to Vaccaro, W. D.; Davis, H. R. Bioorg. Med.
Chem. Lett. 1998, 8, 313-318) as appropriate reference compounds
were evaluated by well-established methods to determine their
inhibition of cholesterol uptake in rabbit brush border membrane
vesicles (BBMV) (Table 1). Briefly, the scavenger receptor-mediated
uptake of radiolabelled cholesterol ester from the loaded donor
particles into the BBMV bilayer was measured in the presence of
various compounds of the invention and appropriate reference
compounds (Hauser, H. et al., Biochemistry 1998, 37, 17843-17850;
Werder, M. et al., Biochemistry 2001, 40, 11643-11650; Boffelli, D.
et al., FBBS Lett. 1997, 411, 7-11.)
TABLE-US-00001 TABLE 1 applied in donor SUV (9 mol %) Compound
Inhibition in (%) Ezetimibe 16 .+-. 4 Glucuronide 19 .+-. 4 VI 30
.+-. 4 VII 22 .+-. 2 VIII 15 .+-. 3 IXb 20 .+-. 5 IX 27 .+-. 4 X 15
.+-. 3 XI 20 .+-. 5 XIV 26 .+-. 3 XV 19 .+-. 3 XVI 21 .+-. 5 XVII
28 .+-. 4 XVIII 41 .+-. 4 XXI 19 .+-. 2
* * * * *