U.S. patent application number 09/860772 was filed with the patent office on 2002-01-03 for processes and novel intermediates for 11-oxa prostaglandin synthesis.
Invention is credited to Conrow, Raymond E., Dean, William D., Delgado, Pete, Gaines, Michael S..
Application Number | 20020002284 09/860772 |
Document ID | / |
Family ID | 26900672 |
Filed Date | 2002-01-03 |
United States Patent
Application |
20020002284 |
Kind Code |
A1 |
Delgado, Pete ; et
al. |
January 3, 2002 |
Processes and novel intermediates for 11-oxa prostaglandin
synthesis
Abstract
Novel processes and intermediates useful in the preparation of
11-oxa prostaglandin analogs are disclosed.
Inventors: |
Delgado, Pete; (Fort Worth,
TX) ; Conrow, Raymond E.; (Crowley, TX) ;
Dean, William D.; (Arlington, TX) ; Gaines, Michael
S.; (Fort Worth, TX) |
Correspondence
Address: |
ALCON RESEARCH, LTD.
R&D COUNSEL, Q-148
6201 SOUTH FREEWAY
FORT WORTH
TX
76134-2099
US
|
Family ID: |
26900672 |
Appl. No.: |
09/860772 |
Filed: |
May 18, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60205692 |
May 19, 2000 |
|
|
|
Current U.S.
Class: |
546/152 ;
548/465; 549/475; 549/49; 549/499 |
Current CPC
Class: |
C07D 307/20 20130101;
C07D 407/04 20130101; C07F 7/1892 20130101 |
Class at
Publication: |
546/152 ;
549/499; 549/475; 549/49; 548/465 |
International
Class: |
C07D 409/02; C07D
333/72; C07D 37/32 |
Claims
We claim:
1. A process for the preparation of 11-oxa prostaglandin analogs of
formula I: 10wherein: R is H or a pharmaceutically acceptable
cationic salt moiety, or CO.sub.2R forms a pharmaceutically
acceptable ester moiety R.sup.9O and R.sup.15O are the same or
different and constitute a free or functionally modified hydroxy
group; --- is a single or trans double bond; X=(CH.sub.2).sub.q or
(CH.sub.2).sub.qO; q=1-6; and Y=a phenyl ring optionally
substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, or a
free or functionally modified hydroxy or amino group; or
X--Y=(CH.sub.2).sub.mY.sup.1, m=0-6, 11wherein: W=CH.sub.2, O,
S(O).sub.m, NR.sup.10, CH.sub.2CH.sub.2, CH.dbd.CH, CH.sub.2O,
CH.sub.2S(O).sub.m, CH.dbd.N, or CH.sub.2NR.sup.10; m=0-2; R=H,
alkyl, acyl; Z=H, alkyl, alkoxy, acyl, acyloxy, halo,
trihalomethyl, amino, alkylamino, acylamino, OH; and ----=single or
double bond; comprising: a) converting 1,4-anhydro-D-glucitol to
the corresponding ortho ester; b) silylating the ortho ester to
yield to the corresponding silyl ether; c) removing the ortho ester
group of the silyl ether to yield to the corresponding triol; d)
converting the triol to the corresponding acetonide; e) oxidizing
the free OH group of the acetonide to yield to the corresponding
ketone; f) converting the ketone to the corresponding unsaturated
ester; g) hydrogenating the unsaturated ester to yield the
saturated ester; h) reducing the saturated ester to yield to the
corresponding alcohol; i) converting the alcohol to the
corresponding sulfonate; j) reacting the sulfonate with cyanide to
yield to the corresponding nitrile; k) oxidatively cleaving the
acetonide grouping of the nitrile to yield to the corresponding
nitrile aldehyde; l) converting the nitrile aldehyde to the
corresponding enone; m) reducing the enone to yield to the
corresponding alcohol having desirable and undesirable epimeric
forms; n) silylating the alcohol to yield to the corresponding bis
silyl ether; o) reducing the bis silyl ether to yield to the
corresponding aldehyde; p) condensing the aldehyde to yield to the
corresponding ester; q) desilylating the ester to yield to the
corresponding end product; and r) removing undesirable epimeric
form.
2. The process of claim 1, wherein removal of the undesirable
epimeric form occurs before silylating the alcohol produced in step
(m) above.
3. The process of claim 2, wherein the alcohol produced in step (m)
above is desilylated before removal of the undesirable epimeric
form.
4. The process of claim 1, wherein removal of the undesirable
epimeric form occurs after desilylating the ester produced in step
(p) above.
5. A process for the preparation of 11-oxa prostaglandin analogs,
comprising the use of one or more intermediates selected from the
group consisting of: 12wherein: R4, R5, R6=same or different=alkyl,
cycloalkyl, or aryl X=(CH.sub.2).sub.q or (CH.sub.2).sub.qO; q=1-6;
and Y=a phenyl ring optionally substituted with alkyl halo,
trihalomethyl, alkoxy, acyl, or a free or functionally modified
hydroxy or amino group; or X--Y=(CH.sub.2).sub.mY.sup.1, m=0-6,
13wherein: W=CH.sub.2, O, S(O).sub.m, NR.sup.10, CH.sub.2CH.sub.2,
CH.dbd.CH, CH.sub.2O, CH.sub.2S(O).sub.m, CH.dbd.N, or
CH.sub.2NR.sup.10; m=0-2; R.sup.10=H, alkyl, acyl; Z=H, alkyl,
alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino,
acylamino, OH; and ----=single or double bond.
6. The process of claim 5, where the one or more intermediates are
selected from the group consisting of: 14
Description
FIELD OF THE INVENTION
[0001] The present invention relates to novel compounds and
processes useful in the synthesis of certain prostaglandin analogs.
Specifically, the invention relates to intermediates and processes
useful in the synthesis of certain 11-oxa prostaglandins.
BACKGROUND OF THE INVENTION
[0002] Substituted tetrahydrofuran analogs of D and F series
prostaglandins for use in treating glaucoma and ocular hypertension
are disclosed in commonly assigned U.S. Pat. No. 5,994,397, the
entire contents of which are by this reference incorporated herein.
11-oxa PGF.sub.2.alpha. analogs and/or synthetic schemes for their
preparation are disclosed in Hanessian, et al., Carbohydrate
Research, 141:221-238 (1985); Thiem et al., Liebigs Ann. Chem.,
2151-2164 (1985); Arndt, et al., S. African J. Chem. 34:121-127
(1981); and U.S. Pat. No. 4,133,817. The entire contents of these
references are hereby incorporated herein.
[0003] Previous routes to 11-oxa prostaglandins employ a C1-C2
olefination reaction of a tetrahydrofuran-2-carboxaldehyde for the
introduction of the .omega.-chain. The cc-chain may be introduced
before or after this step. The tetrahydrofuran-2-carboxaldehyde may
be prepared from several readily available carbohydrates, which
provide the four carbons of the tetrahydrofuran core and C1 of the
.omega.-chain. The following carbohydrates have been used as
starting materials in this approach: D-sorbitol (J. Thiem and H.
Luders, Liebigs Ann. Chem., 2151 (1985) and S. Hanessian, Y.
Guindon, P. Lavalle and P. Dextraze, Carbohydrate Research, 141,
221 (1985)), D-xylose and D-glucose (G. J. Lourens and J. M.
Koekemoer, Tetrahedron Letters, 43:3719 (1975) and R. R. Arndt, J.
M. Koekemoer, G. J. Lourens and E. M. Venter, S.-Afri. Tydskr.
Chem., 34:121 (1981)).
[0004] It is desirable, especially to improve therapeutic effect,
to isolate the active isomer of the desired compound. In order for
development of a pharmaceutical product comprising the
enantiomerically enriched compound to be feasible, an economically
viable synthetic route that will yield commercial quantities of the
material is required.
[0005] Previously known syntheses of 11-oxa prostaglandins have
suffered from various drawbacks that limit their usefulness for
production of commercial quantities of the desired material. Such
drawbacks include, without limitation, low yields, costly, time
consuming, or inefficient synthetic sequences, and/or difficult or
inadequate separation of the undesired enantiomer or epimer. A need
exists, therefore, for an improved, commercially viable synthetic
approach for 11-oxa prostaglandin analogs.
SUMMARY OF THE INVENTION
[0006] The present invention is directed to novel processes and
intermediates useful in the preparation of preferred enantiomers of
certain 11-oxa prostaglandins. The processes and intermediates of
the present invention are particularly useful in the preparation of
[2R(1E,3R),3S(4Z),4R]-7-[Tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-bu-
tenyl]-4-hydroxy-3-furanyl]-4-heptenoic acid and its C1 esters.
DETAILED DESCRIPTION OF THE INVENTION
[0007] The present invention is directed to improved processes and
intermediates for the preparation of certain 11-oxa prostaglandin
analogs, including salt, ester, ether, alcohol, amine and amide
derivatives thereof, and especially the 11-oxa prostaglandin
analogs of formula I: 1
[0008] wherein:
[0009] R is H or a pharmaceutically acceptable cationic salt
moiety, or CO.sub.2R forms a pharmaceutically acceptable ester
moiety.
[0010] R.sup.9O and R.sup.15O are the same or different and
constitute a free or functionally modified hydroxy group;
[0011] --- is a single or trans double bond;
[0012] X=(CH2).sub.q or (CH2).sub.qO; q=1-6; and
[0013] Y=a phenyl ring optionally substituted with alkyl, halo,
trihalomethyl, alkoxy, acyl, or a free or functionally modified
hydroxy or amino group;
[0014] or X--Y=(CH.sub.2).sub.mY.sup.1, m=0-6, 2
[0015] wherein:
[0016] W=CH.sub.2, O, S(O).sub.m, NR.sup.10, CH.sub.2CH.sub.2,
CH.dbd.CH, CH.sub.2O, CH.sub.2S(O)m, CH.dbd.N, or
CH.sub.2NR.sup.10;
[0017] m=0-2;
[0018] R.sup.10=H, alkyl, acyl;
[0019] Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl,
amino, alkylamino, acylamino, OH; and
[0020] ----=single or double bond.
[0021] The inventive processes and intermediates are preferably
used to prepare the 11-oxa prostaglandin analogs of formula II:
3
[0022] wherein:
[0023] R=H or alkyl;
[0024] X=CH.sub.2CH.sub.2 or CH.sub.2O; and
[0025] Y=phenyl, optionally substituted with halo or
trihalomethyl.
[0026] The most preferred product of the presently claimed
processes is isopropyl
[2R(1E,3R),3S(4Z),4R]-7-[Tetrahydro-2-[4-(3-chlorophenoxy)-3-hy-
droxy-1-butenyl]-4-hydroxy-3-furanyl]-4-heptenoate as provided by
formula II, wherein R=isopropyl, X=CH.sub.2O, and
Y=3-chlorophenyl.
[0027] It has now been discovered that by utilizing novel
intermediates and by making certain modifications and additions to
known synthetic processes, yields and purity of intermediates and
ultimately the desired end product are significantly improved. The
improved processes of the present invention thus provide a
commercially viable route for the preparation of therapeutically
useful 11-oxa prostaglandin analogs.
[0028] The novel process comprises conversion of D-sorbitol (1) to
anhydro-D-glucitol (2) using acid and heat. Treatment of 2 with a
trialkyl orthoalkanoate (preferred is trimethyl orthoacetate)
affords ortho ester III (R.sup.3 is alkyl or cycloalkyl, preferred
is R.sup.3=CH.sub.3), which is silylated on the free hydroxy group
using a silyl halide or triflate R.sup.4R.sup.5R.sup.6SiX (R.sup.4,
R.sup.5, R.sup.6=same or different =alkyl, cycloalkyl, or aryl,
preferred is R.sup.4 and R.sup.5=Ph and R.sup.6=tert-butyl; X=Cl,
Br, I, or OSO.sub.2CF.sub.3, preferred is X=Cl or
OSO.sub.2CF.sub.3) in the presence of an amine base (e.g.,
NEt.sub.3 or imidazole) to give silyl ether IV (R.sup.4, R.sup.5,
R.sup.6=same or different=alkyl, cycloalkyl, or aryl, preferred is
R.sup.4 and R.sup.5=Ph and R.sup.6=tert-butyl). 4
[0029] Treatment of IV with acid and a hydroxylic solvent provides
triol V, which is treated with dimethoxypropane in the presence of
catalytic acid to yield acetonide VI. Oxidation of VI with, for
example, DMSO/carbodiimide/acid affords ketone VII, which is
condensed with Ph.sub.3P.dbd.CHCO.sub.2R.sup.7 (R.sup.7=alkyl,
aryl, or cycloalkyl; R.sup.7=alkyl is preferred) to give enoate
VIII (R.sup.7=alkyl, aryl, or cycloalkyl, R.sup.7=alkyl is
preferred). 5
[0030] Unsaturated ester VIII is reduced with hydrogen gas over a
metal catalyst (e.g., Pd/C) to provide saturated ester IX, which is
reduced with a metal hydride reagent (e.g., lithium aluminum
hydride or lithium borohydride; preferred is lithium aluminum
hydride) to give alcohol X. Treatment of alcohol X with
R.sup.8SO.sub.2X (R.sup.8=alkyl, aryl, or trifluoromethyl,
preferred is methyl, 4-methylphenyl, or trifluoromethyl; X=halide,
preferably chloride, or OSO.sub.2R.sup.8 (i. e., R.sup.8SO.sub.2X
forms an anhydride)) in the presence of an amine base (such as
pyridine, triethylamine, or DBU) yields sulfonate XI, which is
reacted with a metal cyanide (preferably NaCN) in DMSO to afford
nitrile XI. Oxidative deprotection of XII with H.sub.5IO.sub.6
gives aldehyde XIII, which is condensed with
(MeO).sub.2P(O)CH.sub.2C(O)--X--Y (X and Y are as defined for
formula I; preferred is X=O and Y=3-chlorophenyl) in the presence
of an amine base (preferred are triethylamine and DBU) and LiCl or
LiBr to provide trans-enone XIV. Alternatively, aldehyde XIII can
be condensed with Ph.sub.3P.dbd.CHC(O)--X--Y (X and Y are as
defined for formula I) to afford XIV. 6
[0031] Reduction of enone XIV to the corresponding allylic alcohol
can be performed under several conditions. Reduction using
NaBH.sub.4/CeCl.sub.3 affords the alcohol XV as a nearly 1:1
mixture of diastereomers. More efficient production of the
15.alpha. diastereomer can be achieved by using stoichiometric
(-)-B-chlorodiisopinocampheylborane, or catalytic
(3aR)-Tetrahydro-1-methyl-3,3-diphenyl-(1H,3H)-pyrrolo
[1,2-c][1,3,2]oxazaborole [(R)-2-methyl-CBS-oxazaborolidine, which
is commercially available from Aldrich Chemical Co., Milwaukee,
Wis.] with stoichiometric BH.sub.3 as the reducing agent.
Similarly, use of stoichiometric
(+)-B-chlorodiisopinocampheylborane, or catalytic
(3aS)-Tetrahydro-1-methyl-3,3-diphenyl-(1H,3H)-pyrrolo[1,2-c][1,3,2]oxaza-
borole [(S)-2-methyl-CBS-oxazaborolidine, which is commercially
available from Aldrich Chemical Co., Milwaukee, Wis.] with
stoichiometric BH.sub.3 affords the 15.beta. diastereomer
predominantly. Optionally, desilylation of XV using
tetra-n-butylammonium fluoride affords diol XVI, for which the
normal phase silica gel chromatographic separation of the two
carbon 15 epimers is most efficiently achieved. Protection of XV or
XVI using a silyl halide or triflate R.sup.4R.sup.5R.sup.6SiX
(R.sup.4, R.sup.5, R.sup.6=same or different=alkyl, cycloalkyl, or
aryl, preferred is R.sup.4 and R.sup.5 =Ph and R.sup.6=tert-butyl;
X=Cl, Br, I, or OSO.sub.2CF.sub.3, preferred is X=Cl or
OSO.sub.2CF.sub.3) in the presence of an amine base (e.g.,
NEt.sub.3 or imidazole) provides XVII. 7
[0032] Nitrile XVII is treated with diisobutylaluminum hydride
below -20.degree. C. followed by addition of aqueous acid to give
aldehyde XVIII. Wittig condensation of XVIII with Ph.sub.3P.sup.+
(CH.sub.2).sub.3CO.sub.2R Br.sup.- (R=H, alkyl, aryl, cycloalkyl,
etc.; preferred is alkyl) in a suitable solvent (preferred are
toluene and THF and mixtures thereof) in the presence of a strong
base [e.g., MN(SiMe.sub.3).sub.2 (M=Na, Li, or K), KOBu.sup.t, or
n-butyllithium, preferred is NaN(SiMe.sub.3).sub.2] in the
temperature range -78.degree. C. to 25.degree. C. (preferred is the
range -40.degree. C. to 0.degree. C.) affords XIX, which is
deprotected using tetra-n-butylammonium fluoride to yield a
compound of formula I where R.sup.9=R.sup.15=H. One skilled in the
art will appreciate that production of such compound with R.sup.9
and R.sup.15 equal to groups other than H is possible by
introduction of said groups at the appropriate time; for example,
reaction of alcohol XV with CH.sub.3OSO.sub.2CF.sub.3 in
CH.sub.2Cl.sub.2 in the presence of 2,6-di-t-butylpyridine,
followed by the rest of the reaction sequence, would afford I with
R.sup.9=H and R.sup.15=CH.sub.3. 8
[0033] The term "acyl" represents a group that is linked by a
carbon atom that has a double bond to an oxygen atom and single
bond to another carbon atom.
[0034] The term "acylamino" represents a group that is linked by an
amino atom that is connected to a carbon atom that has a double
bond to an oxygen group and a single bond to a carbon atom or
hydrogen atom.
[0035] The term "acyloxy" represents a group that is linked by an
oxygen atom that is connected to a carbon atom that has a double
bond to an oxygen atom and single bond to another carbon atom.
[0036] The term "alkenyl" includes straight or branched chain
hydrocarbon groups having 1 to 15 carbon atoms with at least one
carbon-carbon double bond. The chain hydrogens may be substituted
with other groups, such as halogen. Preferred straight or branched
alkenyl groups include, allyl, 1-butenyl, 1-methyl-2-propenyl and
4-pentenyl.
[0037] The term "alkoxy" represents an alkyl group attached through
an oxygen linkage.
[0038] The term "alkyl" includes straight or branched chain
aliphatic hydrocarbon groups that are saturated and have 1 to 15
carbon atoms. The alkyl groups may be substituted with other
groups, such as halogen, hydroxyl or alkoxy. Preferred straight or
branched chain alkyl groups include methyl, ethyl, propyl,
isopropyl, butyl and t-butyl.
[0039] The term "alkylamino" represents an alkyl group attached
through a nitrogen linkage.
[0040] The term "aryl" refers to carbon-based rings which are
aromatic. The rings may be isolated, such as phenyl, or fused, such
as naphthyl. The ring hydrogens may be substituted with other
groups, such as lower alkyl, or halogen.
[0041] The term "cationic salt moiety" includes alkali and alkaline
earth metal salts as well as ammonium salts.
[0042] The term "cycloalkyl" includes straight or branched chain,
saturated or unsaturated aliphatic hydrocarbon groups which connect
to form one or more rings, which can be fused or isolated. The
rings may be substituted with other groups, such as halogen,
hydroxyl or lower alkyl. Preferred cycloalkyl groups include
cyclopropyl, cyclobutyl, cylopentyl and cyclohexyl.
[0043] The term "halogen" and "halo" represents fluoro, chloro,
bromo, or iodo.
[0044] The term "lower alkyl" represents alkyl groups containing
one to six carbons (C1-C6).
[0045] The term "free hydroxy group" means an OH. The term
"functionally modified hydroxy group" means an OH which has been
functionalized to form: an ether, in which an alkyl, aryl,
cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,
heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for
the hydrogen; an ester, in which an acyl group is substituted for
the hydrogen; a carbamate, in which an aminocarbonyl group is
substituted for the hydrogen; or a carbonate, in which an aryloxy-,
heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-,
alkenyloxy-, cycloalkenyloxy-, heterocycloalkenyloxy-, or
alkynyloxy-carbonyl group is substituted for the hydrogen.
Preferred moieties include OH,
OCH.sub.2C(O)CH.sub.3,OCH.sub.2C(O)C.sub.2H.sub.5, OCH.sub.3,
OCH.sub.2CH.sub.3, OC(O)CH.sub.3, and OC(O)C.sub.2H.sub.5.
[0046] The term "free amino group" means an NH.sub.2. The term
"functionally modified amino group" means an NH.sub.2 which has
been functionalized to form: an aryloxy-, heteroaryloxy-, alkoxy-,
cycloalkoxy-, heterocycloalkoxy-, alkenyl-, cycloalkenyl-,
heterocycloalkenyl-, alkynyl-, or hydroxy-amino group, wherein the
appropriate group is substituted for one of the hydrogens; an
aryl-, heteroaryl-, alkyl-, cycloalkyl-, heterocycloalkyl-,
alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-amino
group, wherein the appropriate group is substituted for one or both
of the hydrogens; an amide, in which an acyl group is substituted
for one of the hydrogens; a carbamate, in which an aryloxy-,
heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-,
alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-carbonyl
group is substituted for one of the hydrogens; or a urea, in which
an aminocarbonyl group is substituted for one of the hydrogens.
Combinations of these substitution patterns, for example an
NH.sub.2 in which one of the hydrogens is replaced by an alkyl
group and the other hydrogen is replaced by an alkoxycarbonyl
group, also fall under the definition of a functionally modified
amino group and are included within the scope of the present
invention. Preferred moieties include NH.sub.2, NHCH.sub.3,
NHC.sub.2H.sub.5, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHOH, and
NH(OCH.sub.3).
[0047] For purposes of the foregoing and following definitions, the
term "alkyl" or "pharmaceutically acceptable ester moiety" means
any ester moiety that would be suitable for therapeutic
administration to a patient by any conventional means without
significant deleterious health consequences. Similarly, the term
"ophthalmically acceptable ester moiety" means any pharmaceutically
acceptable ester moiety that would be suitable for ophthalmic
application, i.e. non-toxic and non-irritating. Preferred are
ophthalmically acceptable esters such as alkyl and alkylcycloalkyl
esters of carboxylic acids. Most preferred are C2-C5 alkyl esters
of carboxylic acids, and especially isopropyl esters.
[0048] In the foregoing illustrations, as well as those provided
hereinafter, wavy line attachments indicate that the configuration
may be either alpha (.alpha.) or beta (.beta.). Dashed lines on
bonds indicate a single or double bond. Two solid lines between
carbons specify the configuration of the relevant double bond.
Hatched lines indicate the .alpha. configuration. A solid
triangular line indicates the .beta. configuration.
[0049] In the following Examples, the following standard
abbreviations are used: g=grams (kg=kilograms; mg=milligrams);
mol=moles (mmol=millimoles); mL=milliliters; mm Hg=millimeters of
mercury; mp=melting point; bp=boiling point; h=hours; and
min=minutes. In addition, "NMR" refers to nuclear magnetic
resonance spectroscopy and "MS" refers to mass spectrometry.
[0050] The preparations exemplified below are depicted
schematically in the following Scheme I. All reactions were
performed under a nitrogen atmosphere. 9
[0051] Preparation of 1,4-Anhydro-D-glucitol
(1,4-anhydro-D-sorbitol) (2). A mixture of D-sorbitol (1) (4.0 kg),
water (560 mL) and H.sub.2SO.sub.4 (50 mL) was heated to a melt
(104.degree. C.) and stirred. After 20 h, 25 mL of H.sub.2SO.sub.4
was added. After a further 22 h, 25 mL of H.sub.2SO.sub.4 was
added. After a fiurther 32 h, the mixture was cooled to ambient
temperature, neutralized carefully with solid Na.sub.2CO.sub.3 and
stirred for 30 min. i-PrOH (12 L) was added, followed by anhydrous
Na.sub.2SO.sub.4 (4 kg). The mixture was filtered and the solid was
washed with i-PrOH (6 L) and EtOH (3 L). The filtrate was treated
with activated charcoal (100 g), filtered through Celite, rinsing
with 1.2 L each of i-PrOH and EtOH, then concentrated. Toluene (6
L) was added to the residue, and the mixture was concentrated in
vacuo with heating to effect azeotropic removal of water. EtOH (10
L) was added to the solid residue with heating to effect
dissolution. The solution was concentrated and cooled to ambient
temperature to give a suspension (6 L). The solid was isolated by
filtration, washed with cold EtOH (4 L) and dried.
Recrystallization of the crude product (1.9 kg) from hot EtOH
provided 2 (1693 g) as a white solid, mp 112-112.5.degree. C.,
[.alpha.].sup.23.sub.D-22.9.degree. (c 0.5, H.sub.2O). The .sup.13C
NMR spectrum of this compound agreed with that reported by Duclos
et al., Synthesis, page 1087 (1994).
[0052] Preparation of 1,4-Anhydro-3,5,6-O-orthoacetyl-D-glucitol
(3). Trimethyl orthoacetate (1513 mL) and p-TsOH H.sub.2O (15 g)
were added to a stirred solution of 2 (1.5 kg) in MeCN (15 L).
After 13 h, Na.sub.2CO.sub.3 (50 g) was added. After 15 min the
mixture was filtered through Celite and the filtrate concentrated
to give 3 (1760 g). The 1H and .sup.13C NMR spectra of this
compound agreed with those reported by Duclos et al., Synthesis,
page 1087 (1994).
[0053] Preparation of
1,4-Anhydro-2-O-t-butyldiphenylsilyl-3,5,6-O-orthoac-
etyl-D-glucitol (4). t-BuPh.sub.2SiCl (2495 mL) was added to a
stirred solution of 3 (1720 g) and imidazole (1555 g) in DMF (3.0
L). After 19 h the mixture was poured into brine and extracted with
2:1 ether-hexane (4.times.6 L). The organic extract was washed with
brine, dried (Na.sub.2SO.sub.4), filtered and concentrated to give
4 (4115 g) as a viscous oil. 1H NMR (CDCl.sub.3): .delta. 1.06
(s,9H), 1.52 (s, 3H), 3.77-4.06 (m, 5H), 4.27 (br s, 2H), 4.74 (m,
1H), 7.34-7.48 (m, 6H), 7.60-7.64 (m, 4H).
[0054] Preparation of
1,4-Anhydro-2-O-t-butyldiphenylsilyl-D-glucitol (5). Amberlyst-15
resin (1 kg) and water (20 mL) were added to a stirred solution of
4 (1947 g) in MeOH (35 L). After 19 h the mixture was treated with
activated charcoal (50 g) and filtered through Celite, rinsing with
MeOH (6 L). The filtrate was combined with that from an identical
run and concentrated in vacuo to give 5 (3948 g) as a solid.
.sup.1H NMR (CDCl.sub.3): 6 1.05 (s, 9H), 3.05 (br s, 1H),
3.37-4.22 (m, 10H), 7.31-7.46 (m, 6H), 7.57-7.70 (m, 4H).
[0055] Preparation of
1,4-Anhydro-2-O-t-butyldiphenylsilyl-5,6-O-isopropyl-
idene-D-glucitol (6). 2,2-Dimethoxypropane (842 mL) and
p-TsOHH.sub.20 (3.4 g) were added to a stirred solution of 5 (918
g) in acetone (41 L) at 0.degree. C. After 2 h the solution was
eluted through Florisil (1 kg) and the filtrate was combined with
those from three identical runs and concentrated. The solid residue
was treated with hexane (12 L) and the resulting suspension was
concentrated to 8 L. Crystalline 6 (2817 g) was obtained by
filtration and drying in vacuo at 40.degree. C. The .sup.1H NMR
spectrum of this compound agreed with that reported by Hanessian et
al., Carbohydrate Research, Volume 141, page 221 (1985).
[0056] Preparation of
1,4-Anhydro-2-O-t-butyldiphenylsilyl-5,6-O-isopropyl-
idene-D-ribo-3-hexulose (7). Dichloroacetic acid (263 mL) was added
over 15 min to a stirred mixture of 6 (2815 g) and
1-(3-(dimethylamino)propyl)- -3-ethylcarbodiimide hydrochloride
(3663 g) in DMSO (25 L). After 4 h the mixture was poured into 5%
NaHCO.sub.3 (37 L) and extracted with 1:1 ether-hexane (4.times.12
L). The organic extract was washed with water (9 L), brine (9 L),
dried over a mixture of MgSO.sub.4 and activated carbon, filtered
and concentrated. The residue was dissolved in ether (1 L) and
eluted through silica gel with ether (12 L). Concentration in vacuo
gave 7 (2783 g) as a yellow oil. The .sup.1H NMR spectrum of this
compound agreed with that reported by Hanessian et al.,
Carbohydrate Research, Volume 141, page 221 (1985).
[0057] Preparation of
1,4-Anhydro-2-(t-butyldiphenysilyl)oxy-3-deoxy-3-C-(-
ethoxycarbonylmethylene)-5,6-O-isopropylidene-D-ribo-hexitol (8).
Ph.sub.3P.dbd.CHCO.sub.2Et (3.5 kg) was added to a stirred solution
of 7 (2782 g) in CH.sub.2Cl.sub.2 (25 L). After 48 h the mixture
was applied to a silica gel pad and eluted with 20% EtOAc-hexane.
Concentration in vacuo gave 8 (3337 g). The .sup.1H NMR spectrum of
this compound agreed with that reported by Hanessian et al.,
Carbohydrate Research, Volume 141, page 221 (1985).
[0058] Preparation of
1,4-Anhydro-2-(t-butyidiphenysilyl)oxy-3-deoxy-3-C-(-
ethoxycarbonylmethyl)-5,6-O-isopropylidene-D-allitol (9). A
solution of 8 (1622 g) in EtOH (2.6 L) was added to a suspension of
Raney Ni (2 kg, washed with 3.times.3 L of water) in EtOH (4 L).
After stirring for 30 min, the mixture was filtered through Celite,
rinsing with hot EtOH (12 L). The filtrate was charged into a 20-L
steel reactor. Pd on carbon (10%, 50 g) was added as a suspension
in EtOH-water, and the reactor was then purged with H.sub.2. The
mixture was stirred at ambient temperature under 1.5-2 atm of
H.sub.2 pressure for 24 h. Pd on carbon (10%, 100 g) was added and
the hydrogenation was resumed under the foregoing conditions until
complete by NMR analysis. The mixture plus reactor rinse (4 L of
EtOH) was filtered through Celite, rinsing with additional EtOH.
Toluene was added to the filtrate and the solution was concentrated
in vacuo to give 9 (1602 g). The .sup.1H NMR spectrum of this
compound agreed with that reported by Hanessian et al.,
Carbohydrate Research, Volume 141, page 221 (1985).
[0059] Preparation of 1
,4-Anhydro-2-(t-butyldiphenysilyl)oxy-3-deoxy-3-C--
(2-hydroxyethyl)-5,6-O-isopropylidene-D-allitol (10). LiAlH.sub.4
(1 M in THF, 2.4 L) was added over 40 min to a stirred, ice-cooled
solution of 9 (1602 g) in ether (24 L), keeping the reaction
temperature below 5.degree. C. After stiffing for a flirther 2 h
with ice cooling, the reaction was carefuilly quenched by
sequential addition of water (91 mL), 15% NaOH (91 mL), and water
(273 mL) The mixture was stirred until the solid separated in
granular form, then filtered through Celite. The filter cake was
rinsed with hot EtOAc (30 L), the filtrate was concentrated and the
residue was eluted through a silica gel pad with 25% EtOAc-hexane
followed by EtOAc. Concentration in vacuo gave 10 (1229 g) as an
oil. .sup.1H NMR (CDCl.sub.3): .delta. 1.07 (s, 911), 1.34 (s,
311), 1.43 (s,3H), 1.79-1.86 (m, 1H), 2.02-2.16 (m, 2H), 3.45-4.39
(m, 911), 7.33-7.45 (m, 6H), 7.62-7.69 (m, 4H).
[0060] Preparation of
1,4-Anhydro-2-(t-butyldiphenysilyl)oxy-3-deoxy-3-C-(-
2-(mesyloxy)ethyl)-5,6-O-isopropylidene-D-allitol (11). MsCl (202
ML) was added to a stirred, ice-cooled solution of 10 (1226 g) and
Et.sub.3N (726 mL) in CH.sub.2Cl.sub.2 (12 L), keeping the reaction
temperature below 10.degree. C. After stirring for a further 1 h
with ice cooling, the mixture was quenched into water (6 L) a nd
the organic solution was separated . The aqueous solution was
extracted with CH.sub.2Cl.sub.2 (3.times.4 L) and the combined o
rganic extract was washed with saturated KH .sub.2P0.sub.4
(3.times.2 L) and brine (2 L), dried (Na.sub.2SO.sub.4) and
concentrated to provide 11 (1445 g) as an oil. .sup.1H NMR
(CDCl.sub.3): .delta. 1.07 (s, 9H), 1.33 (s, 3H), 1.42 (s, 3H),
2.00-2.25 (m, 2H), 2.92 (s, 3H), 3.53-4.37 (m, 7H), 7.36-7.49 (m,
6H), 7.62-7.68 (m, 4H).
[0061] Preparation of
1,4-Anhydro-2-(t-butyidiphenysilyl)oxy-3-deoxy-3-C-(-
2-cyanoethyl)-5,6-O-isopropylidene-D-allitol (12). NaCN (166 g) was
added to a stirred solution of 11 (1445 g) in DMSO (8 L) at
35.degree. C. After 24 h, NaCN (38 g) was added and the temperature
was raised to 45.degree. C. After a further 24 h, the mixture was
cooled to ambient temperature and poured into water (30 L)
containing 5 kg of ice. NaCl (5 kg) was added and the mixture was
extracted with ether (4.times.8 L). The organic extract was washed
with brine (15 L), dried (Na.sub.2SO.sub.4) and concentrated. The
residue (1.2 kg) was dissolved in 5% EtOAc-hexane (4 L) and this
solution was injected into a Biotage Kiloprep 250 chromatographic
instrument (run 1,400 g; run 2,800 g) eluting with 5% EtOAc-hexane,
then 20% EtOAc-hexane, and finally EtOAc, to provide 12 (1025 g) as
a clear oil. .sup.1H NMR (CDCl.sub.3): .delta. 1.08 (s, 9H), 1.33
(s, 3H), 1.42 (s, 3H), 1.96-2.28 (m, 5H), 3.52-3.58 (dd, 1H),
3.67-3.79 (m, 2H), 3.88-3.93 (m, 2H), 4.05-4.10 (m, 1H), 4.32 (s,
1H), 7.34-7.47 (m, 6H), 7.61-7.67 (m, 4H).
[0062] Preparation of (2S, 3R,
4R)-4-(t-Butyldiphenylsilyl)oxy-3-(2-cyanoe-
thyl)tetrahydrofuran-2-carboxaldehyde (13). H.sub.5IO.sub.6 (625 g)
was added to a stirred solution of 12 (1024 g) in ether (20 L).
After 18 h the mixture was applied to a 25-cm pad of Florisil and
eluted with 1:1 EtOAc-hexane. Concentration in vacuo gave 13 (870
g) largely as the hydrate. .sup.1H NMR (CDCl.sub.3): .delta. 1.08
(s, 9H), 2.08-2.25 (m, 5H), 3.69-3.76 (dd, 1H), 3.89-3.94 (d, 1H),
4.13-4.19 (m, 1H), 4.38 (t, 1H), 7.37-7.48 (m, 6H), 7.62-7.68 (m,
4H), 9.69 (d, 35% of 1H).
[0063] Preparation of (2R (1E), 3R,
4R)-3-[Tetrahydro-(2-(4-(3-chloropheno-
xy)-3-oxo-1-butenyl)-4-(t-butyldiphenylsilyl)oxy)-3-furanyllpropanenitrile
(14).
[0064] Method 1. N,N-Diisopropylethylamine (408 mL) was added
dropwise to a stirred solution of 13 (870 g), dimethyl
3-(3-chlorophenoxy)-2-oxopropy- l phosphonate (640 g) and LiCl (102
g) in MeCN (10 L). After complete reaction, hexane-ether (1:4, 40
L) was added and the solution was washed with saturated
KH.sub.2PO.sub.4 (2.times.4 L) and brine (2.times.4 L), dried
(Na.sub.2SO.sub.4) filtered and concentrated. The residue was
chromatographed on a Biotage Kiloprep 250, eluting with a step
gradient of 5% to 15% EtOAc-hexane to give 14 (173 g) of 75%
purity. .sup.1H NMR (CDCl.sub.3): .delta. 1.09 (s, 9H), 1.64-1.87
(m ,2H), 2.05-2.15 (m, 2H), 3.70-3.77 (dd, 1H), 3.85-3.90 (d, 1H),
4.36 (t, 1H), 4.43-4.50 (m, 1H), 4.71 (s, 2H), 6.60-6.69 (d, 1H),
6.73-6.80 (dd, 1H), 6.88-7.00 (m, 3H), 7.16-7.24 (t, 1H), 7.35-7.48
(m, 6H), 7.61-7.68 (m, 4H).
[0065] Method 2. The procedure of Tome et al., Tetrahedron Letters,
Volume 37, pp 6951-6954 (1996), was followed. 1,3-Dichloroacetone
(8.0 g) and Ph.sub.3P (15.0 g) were stirred in THF (38 mL) at
reflux for 4 h. The cooled suspension was diluted with ether,
filtered and the solid was washed with ether and dried to give
(3-chloro-2-oxopropyl)triphenylphosph- onium chloride (20.86 g) as
a white solid. This material was dissolved in a mixture of water
(110 mL) and MeOH (110 mL) and treated with NaHCO.sub.3 (10.3 g).
The resulting white precipitate was collected by filtration, washed
with water and dried in vacuo to give
1-chloro-3-(triphenylphosphanylidene)-2-propanone (18.25 g). A
solution of this phosphorane (18.2 g) and 3-chlorophenol (7.28 g)
was stirred with K.sub.2CO.sub.3 (28.57 g) in DMSO (91 mL) at
62.degree. C. for 18 h, then diluted with water (2 L), extracted
with ether (3.times.1 L), dried (MgSO.sub.4), filtered and
concentrated to give 1-(3-chlorophenoxy)-3-(tr-
iphenylphosphanylidene)-2-propanone (21.7 g) as a tan solid.
.sup.1H NMR (CDCl.sub.3): .delta. 4.02 (s, 2H), 4.23-4.35 (d, 1H),
7.42-7.72 (m, 1 5H).
[0066] H.sub.5IO.sub.6 (3.15 g) was added to a stirred solution of
12 (5.3 g) in ether (100 mL). After 18 h, the mixture was eluted
through Celite with ether and concentrated. The residue was
dissolved in CH.sub.2Cl.sub.2 (53 mL). Molecular sieves (4A, 0.75
g) and 1-(3-chlorophenoxy)-3-(triphenylphosphanylidene)-2-propanone
(7.81 g) were added, and the mixture was stirred for 18 h., then
eluted through Florisil with 10% EtOAc-hexane. The crude product
obtained upon concentration was chromatographed on silica gel,
eluting with 18% EtOAc-hexane, to give 14 (5.77 g) as a colorless
oil.
[0067] Preparation of (2R (1E, 3R), 3R,
4R)-3-ITetrahydro-(2-(4-(3-chlorop-
henoxy)-3-hydroxy-1-butenyl)-4-(t-butyldiphenylsilyl)oxy)-3-furanyllpropan-
enitrile (15). A solution of 14 (172 g) in anhydrous THF (1.2 L)
was added at 10.degree. C. to a stirred solution of
(R)-2-methyl-CBS-oxazaborolidin- e (1 M in toluene, 30 mL),
BH.sub.3.multidot.THF (1 M in THF, 179 mL) and anhydrous THF (100
mL), keeping the reaction temperature at 10.degree. C. After
complete reaction, MeOH (300 mL) was carefully added and the
solution was concentrated. The residue (180 g) was chromatographed
on a Biotage Kiloprep 250 eluting with 30% EtOAc-hexane to give 90
g of material which was rechromatographed eluting with 6%
i-PrOH-hexane to give 15 (68 g) containing 6% of the 15-epimer and
9% of an unknown impurity. .sup.1H NMR (CDCl.sub.3): .delta. 1.09
(s, 9H), 1.70-1.75 (m, 1H), 1.81-1.86 (m, 1H), 2.03-2.26 (m, 3H),
2.40 (s, 1H), 3.78-3.81 (dd, 1H), 3.85-3.87 (d, 1H), 3.92-3.96 (m,
1H), 4.02-4.05 (dd, 1H), 4.33-4.36 (m, 1H), 4.40 (t, 1H), 4.62 (m,
1H), 5.90-5.97 (m, 2H), 6.83-6.87 (m, 1H), 6.95-7.01 (m, 2H), 7.25
(t, 1H), 7.42-7.68 (m, 6H), 7.66-7.72 (m, 4H).
[0068] Preparation of (2R (1E, 3R), 3R,
4R)-3-[Tetrahydro-(2-(4-(3-chlorop-
henoxy)-3-hydroxy-1-butenyl)-4-hydroxy)-3-furanyl]propanenitrile
(16). Neat 15 (26 g, 0.045 mol) was treated with tetrabutylammonium
fluoride (1M in THF, 225 mL). The solution was stirred for 1.5 h,
then quenched with water (1 L) and extracted with EtOAc
(4.times.600 mL). The organic extract was washed with brine (500
mL), dried (MgSO.sub.4), filtered and concentrated. The residue was
chromatographed on a Biotage Kiloprep 250 instrument with 20%
acetone-CH.sub.2Cl.sub.2. Fractions containing <1% of the
15-epimer by HPLC were combined and concentrated in vacuo to afford
16 (8.8 g) containing 0.9% of the 15-epimer. .sup.1H NMR
(CDCl.sub.3): .delta. 1.66-1.73 (m, 1H), 1.87-2.03 (m, 2H), 2.47
(t, 2H), 3.83-3.92 (m, 2H), 3.98-4.01 (dd, 1H), 4.11-4.16 (m, 2H),
4.45 (t, 1H), 4.55-4.57 (m, 1H), 5.86 (br s, 2H), 6.80-6.81 (d,
1H), 6.91-6.96 (m, 2H), 7.20 (t, 1H).
[0069] Preparation of (2R (1E, 3R), 3R,
4R)-3-[Tetrahydro-(2-(4-(3-chlorop-
henoxy)-3-(t-butyldimethylsilyl)oxy-1-butenyl)-4-(t-butyldimethylsilyl)oxy-
)-3-furanyl]propanenitrile (17). t-BuMe.sub.2SiCl (19.6 g) was
added to a stirred solution of 16 (8.8 g) and imidazole (18.2 g) in
DMF (100 mL). After 18h, water (400 mL) was added and the mixture
was extracted with ether (3.times.500 mL). The organic extract was
washed with brine (500 mL), dried (MgSO.sub.4), filtered and
concentrated. The residue was chromatographed on silica gel (hexane
to 20% EtOAc-hexane) to afford 17 (11.6 g). .sup.1H NMR
(CDCl.sub.3): .delta. 0.10 (s, 12 H), 0.91 (s, 18H), 1.45-1.70 (m,
1H), 1.73-2.01 (m, 2H), 2.32-2.43 (m, 2H), 3.71-3.77 (dd, 1H),
3.83-3.87 (d, 2H), 4.04-4.14 (m, 2H), 4.38 (t, 1H), 4.49-4.57 (m,
1H), 5.79-5.84 (m, 2H), 6.74-6.79 (ddd, 1H), 6.86-6.95 (m, 2H),
7.18 (t, 1H).
[0070] Preparation of (2R (1E, 3R), 3R,
4R)-3-[Tetrahydro-(2-(4-(3-chlorop-
henoxy)-3-(t-butyldimethylsilyl)oxy-1-butenyl)-4-(t-butyldimethylsilyl)oxy-
)-3-furanyl]propanal (18). Diisobutylaluminum hydride (1 M in
toluene, 131 mL) was added dropwise to a stirred solution of
solution of 17 (11.6 g) in toluene (230 mL), keeping the reaction
temperature below -65.degree. C. After 2.5 h, 5% HOAc in water (270
mL) was added and the mixture (pH 4) was allowed to warm to
0.degree. C., then extracted with ether (3.times.500 mL). The
organic extract was washed with water to pH 6, then with 2%
NaHCO.sub.3 (500 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated. The residue was chromatographed at once on silica gel
(hexane to 10% EtOAc-hexane) giving 18 (10.3 g) as a clear oil.
.sup.1H NMR (CDCl.sub.3): .delta. 0.11-0.13 (d, 12H), 0.83 (s,
18H), 1.50-1.89 (m, 3H), 2.33-2.44 (m, 2H), 3.65-3.69 (d, 1H),
3.76-3.79 (d, 2H), 3.93-4.08 (m, 2H), 4.25 (t, 1H), 4.42-4.49 (m,
1H), 5.71-5.75 (m, 2H), 6.66-6.71 (m, 2H), 7.15 (t, 1H), 9.64 (s,
1H).
[0071] Preparation of Isopropyl [2R (1E, 3R), 3R (4Z),
4R]-7-[tetrahydro-(2-(4-(3-chlorophenoxy)-3-(t-butyldimethylsilyl)oxy-1-b-
utenyl)-4-(t-butyldimethylsilyl)oxy)-3-furanyl]-4-heptenoate
(19).
[0072] A solution of 4-bromobutyric acid (50 g) in 2-propanol (200
mL) containing 1 mL of H.sub.2SO.sub.4 was refluxed for 3 h, then
cooled to ambient temperature, diluted with ether (500 mL), washed
with saturated NaHCO.sub.3 (3.times.300 mL), and brine (300 mL).
The organic extract was dried (MgSO.sub.4), filtered and
concentrated in vacuo to give isopropyl 4-bromo-butyrate (52 g) as
an oil. This ester was dissolved in MeCN (380 mL). Ph.sub.3P (100
g) was added and the solution was heated at reflux for 72 h, after
which TLC analysis (20% water/MeCN, C-18 RP TLC plates) showed
complete reaction. The mixture was cooled and concentrated and the
residue was slurried with toluene (400 mL) for 1 h. The solid was
collected by filtration and was washed with toluene (100 mL) and
then dried in vacuo at 50.degree. C. to provide
(3-(isopropoxycarbonyl)propyl)- triphenylphosphonium bromide (100.6
g). .sup.1H NMR (CDCl.sub.3): .delta. 1.19-1.22 (d, 6H), 1.85-1.97
(m, 2H), 2.85 (t, 2H), 3.95-4.10 (m, 2H), 4.89-5.03 (m, 1H),
7.65-7.94 (m, 15H).
[0073] NaN(SiMe.sub.3).sub.2 (1 M in THF, 36 mL) was added dropwise
to a stirred suspension of
(3-(isopropoxycarbonyl)propyl)triphenylphosphonium bromide (17.0 g)
in THF (95 mL) at -37.degree. C. After 20 min, a solution of 18
(10.3 g) in toluene (95 mL) was added dropwise over 30 min, keeping
the reaction temperature below -10.degree. C. After 10 min the
reaction was quenched with i-PrOH (40 mL), allowed to warm to
ambient temperature and then treated with saturated
KH.sub.2PO.sub.4 (750 mL). After stirring for 10 min, the mixture
was separated and the aqueous solution was extracted with ether
(2.times.600 mL). The combined organic extract was dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
chromatographed on silica gel eluting with a step gradient of
hexane to 30% EtOAc-hexane, to give 19 (9.5 g) as a clear oil.
.sup.1H NMR (CDCl.sub.3): .delta. 0.08 (s, 12H), 0.90 (br s, 18H),
1.21-1.24 (d, 6H), 1.22-1.27 (m, 1H), 1.62-1.68 (m, 2H), 2.07-2.10
(m, 2H), 2.29-2.34 (m, 4H), 3.73-3.75 (d, 1H), 3.83-3.85 (m, 2H),
3.99-4.02 (dd, 1H), 4.03-4.08 (m, 1H), 4.38 (t, 1H), 4.50-4.53 (q,
1H), 4.96-5.03 (m, 1H), 5.32-5.43 (m, 2H), 5.77-5.80 (m, 2H),
6.73-6.76 (dd, 1H), 6.86 (s, 1H), 6.89-6.91 (d, 1H), 7.16 (t,
1H).
[0074] Preparation of (2R (1E, 3R), 3R,
4R)-3-[Tetrahydro-(2-(4-(3-chlorop-
henoxy)-3-(t-butyldimethylsilyl)oxy-1-butenyl)-4-(t-butyldiphenylsilyl)oxy-
)-3-furanyl]propanenitrile (21). t-BuMe.sub.2SiCl (34.7 g) was
added to a stirred solution of 15 (66 g) and imidazole (32.2 g) in
DMF (760 mL). After 2.5 h the reaction was quenched with water (4
L) and extracted with ether (3.times.3 L). The organic extract was
washed with brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated. The residue was chromatographed on silica gel eluting
with EtOAc-hexane to give bis silyl ether 21 (72 g) as an oil.
.sup.1H NMR (CDCl.sub.3): .delta. 0.09 (s, 6H), 0.90 (s, 9H), 1.09
(s, 9H), 1.58-1.66 (m, 1H), 1.72-1.76 (m, 1H), 1.97-2.16 (m, 3H),
3.75-3.85 (m, 4H), 4.27 (t, 1H), 4.36 (t, 1H), 4.51-4.54 (q, 1H),
5.75-5.89 (m, 2H), 6.75-6.77 (dd, 1H), 6.87 (s, 1H), 6.91-6.93 (d,
1H), 7.18 (t, 1H), 7.38-7.49 (m, 6H), 7.62-7.65 (m, 4H).
[0075] Preparation of (2R (1E, 3R), 3R,
4R)-3-lTetrahydro-(2-(4-(3-chlorop-
henoxy)-3-(t-butyldimethylsilyl)oxy-1-butenyl)-4-(t-butyldiphenylsilyl)oxy-
)-3-furanyllpropanal (22). Diisobutylaluminum hydride (1 M in
toluene, 191 mL) was added to a stirred solution of 21 (72 g) in
toluene (1420 mL) keeping the reaction temperature below
-65.degree. C. After 2.5 h, 5% HOAc in water (1.4 L) was added and
the mixture (pH 4) was allowed to warm to 0.degree. C., then
extracted with ether (8 L). The organic extract was washed with
water and brine (to pH 6), dried (Na.sub.2SO.sub.4), filtered and
concentrated. The residue was chromatographed at once on silica gel
(hexane to 10% EtOAc-hexane) giving 22 (63.2 g) as a clear oil.
.sup.1H NMR (CDCl.sub.3): .delta. 0.07 (s, 6H), 0.88 (s, 9H), 1.08
(s, 9H), 1.53-1.68 (m, 1H), 1.84-1.99 (m, 1H), 2.22 (t, 2H),
3.71-3.73 (dd, 1H), 3.77-3.92 (d, 1H), 3.83-3.85 (d, 2H), 4.28 (t,
1H), 4.33 (t, 1H), 4.51-4.54 (q, 1H), 5.74-5.88 (m, 2H), 6.74-6.77
(dd, 1H), 6.86 (s, 1H), 6.90-6.91 (d, 1H), 7.17 (t, 1H), 7.37-7.44
(m, 6H), 7.63-7.66 (m, 4H), 9.58 (s, 1H).
[0076] Preparation of Isopropyl [2R (1E, 3R), 3R (4Z),
4R]-7-[tetrahydro-(2-(4-(3-chlorophenoxy)-3-(t-butyldimethylsilyl)oxy-1-b-
utenyl]-4-(t-butyldiphenylsilyl)oxy)-3-furanyl]-4-heptenoate (23).
NaN(SiMe.sub.3).sub.2 (1 M in THF, 181 mL) was added dropwise to a
stirred suspension of
(3-(isopropoxycarbonyl)propyl)triphenylphosphonium bromide (85 g)
in THF (620 mL) at -37.degree. C. After 20 min, a solution of 22
(62.5 g) in toluene (620 mL) was added dropwise over 30 min while
maintaining the reaction temperature below -10.degree. C. After 10
min the reaction was quenched with i-PrOH (192 mL), allowed to warm
to ambient temperature and then treated with saturated
KH.sub.2PO.sub.4 (3.6 L). After stirring for 10 min, the mixture
was separated and the aqueous solution was extracted with ether
(2.times.4 L). The combined organic extract was dried
(Na.sub.2SO.sub.4), filtered and concentrated. The residue was
chromatographed on silica gel eluting with a step gradient of
hexane to 30% EtOAc-hexane, to give 23 (61.5 g) as a clear oil.
.sup.1H NMR (CDCl.sub.3): .delta. 0.07 (s, 6H), 0.89 (s, 9H), 1.08
(s, 9H), 1.21-1.26 (d, 6H), 1.24-1.29 (m, 1H), 1.57-1.61 (m, 1H),
1.78-1.88 (s, 1H), 1.92-1.99 (m, 2H), 2.21-2.27 (m, 4H), 3.62-3.64
(d, 1H), 3.73-3.75 (d, 1H), 3.83-3.84 (d, 2H), 4.25-4.30 (t, 1H),
4.34 (t, 1H), 4.49-4.51 (m, 1H), 4.96-5.03 (m, 1H), 5.28-5.31 (m,
2H), 5.72-5.84 (m, 2H), 6.75-6.78 (d, 1H), 6.86 (s, 1H), 6.89-6.91
(d, 1H), 7.16 (t, 1H), 7.35-7.45 (m, 6H), 7.64-7.68 (m, 4H).
[0077] Preparation of Isopropyl [2R (1E, 3R), 3R (4Z),
4R]-7-[tetrahydro-(2-(4-(3-chlorophenoxy)-3-hydroxy-1-butenyl)-4-hydroxy)-
-3-furanyl]-4-heptenoate (20).
[0078] From 23. Tetrabutylammonium fluoride (1 M in THF, 750 mL)
was added to a stirred solution of 23 (60.5 g) in THF (250 mL).
After 3 h the reaction was quenched with water (2.5 L) and the
mixture was extracted with EtOAc (4.times.2 L). The organic
solution was dried (Na.sub.2SO.sub.4), filtered and concentrated
and the product was analyzed by HPLC which showed 20 (90%), the
15-epi-isomer (6%) and .DELTA..sup.4-trans isomer (4%). This
material was chromatographed on a Biotage Flash 75-L instrument,
eluting with 60% EtOAc-hexane. Product fractions were treated with
activated charcoal, filtered through Celite and concentrated in
vacuo to give 20 (35 g) as a clear oil. .sup.1H NMR (CDCl.sub.3):
.delta. 1.21-1.23 (d, 6H), 1.38-1.45 (m, 1H), 1.51-1.58 (m, 1H),
1.73-1.77 (m, 1H), 2.22-2.38 (m, 5H), 2.43-2.50 (m, 2H), 3.85-3.92
(m, 2H), 3.97-3.99 (dd, 1H), 4.06-4.13 (m, 2H), 4.41 (t, 1H),
4.55-4.56 (m, 1H), 4.96-5.00 (m, 1H), 5.32-5.44 (m, 2H), 5.81-5.90
(m, 2H), 6.77-6.82 (d, 1H), 6.91 (s, 1H), 6.93-6.95 (d, 1H), 7.19
(t, 1H).
[0079] From 19. Compound 19 (9.4 g, mol) was desilylated as
described immediately above to provide 6.5 g of crude 20.
Chromatography of this material on silica (70% EtOAc-hexane)
provided 6.2 g of semi-pure 20. This material was chromatographed
three times on a Biotage Flash 75 (60% EtOAc-hexane), pooling all
of the <1% epi and <5% trans fractions. The impure cuts were
chromatographed on a Waters DeltaPrep 4000 (1:1
MeOt--Bu-hexane+1.2% EtOH using both a 55-105.mu. PrepPak column
and a 10.mu. semi-prep column) and the clean cuts were combined
with the clean fractions from above and stripped of solvent.
Residual solvent was removed in vacuo on a Kugelrohr apparatus to
provide 20 (4.5 g) as a clear oil.
[0080] The invention has been described by reference to certain
preferred embodiments; however, it should be understood that it may
be embodied in other specific forms or variations thereof without
departing from its spirit or essential characteristics. The
embodiments described above are therefore considered to be
illustrative in all respects and not restrictive, the scope of the
invention being indicated by the appended claims rather than by the
foregoing description.
* * * * *