U.S. patent application number 09/922055 was filed with the patent office on 2002-12-26 for process for preparing discodermolide and analogues thereof.
Invention is credited to Kinder, Frederick R. JR..
Application Number | 20020198389 09/922055 |
Document ID | / |
Family ID | 26985090 |
Filed Date | 2002-12-26 |
United States Patent
Application |
20020198389 |
Kind Code |
A1 |
Kinder, Frederick R. JR. |
December 26, 2002 |
PROCESS FOR PREPARING DISCODERMOLIDE AND ANALOGUES THEREOF
Abstract
A more practical synthesis for preparing discodermolide and
structurally related analogues, novel compounds useful in the
process and novel compounds prepared by the process.
Inventors: |
Kinder, Frederick R. JR.;
(Morristown, NJ) |
Correspondence
Address: |
THOMAS HOXIE
NOVARTIS CORPORATION
PATENT AND TRADEMARK DEPT
564 MORRIS AVENUE
SUMMIT
NJ
079011027
|
Family ID: |
26985090 |
Appl. No.: |
09/922055 |
Filed: |
August 3, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60325767 |
Aug 7, 2000 |
|
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Current U.S.
Class: |
549/292 |
Current CPC
Class: |
C07D 309/30 20130101;
C07F 7/1804 20130101 |
Class at
Publication: |
549/292 |
International
Class: |
C07D 309/30 |
Claims
What is claimed is:
1. A process for preparing a compound of formula V 13which
comprises, in a first step, coupling a ketone compound of formula I
14with an aldehyde compound of formula II 15in the presence of a
dialkyl boron halide or triflate, an amine base, and a polar
organic solvent to obtain a .beta.-hydroxyketone of formula III
16in a second step, reducing the ketone compound obtained in the
first step by treating it with a borohydride reagent in a polar
organic solvent and a protic solvent to obtain a 1,3-diol of
formula IV 17and, in a third step, lactonizing and deprotecting the
acid labile hydroxyl protecting groups of the 1,3 diol obtained in
the second step by treating it with a hydrogen halide dissolved in
a polar solvent or mixture of solvents to obtain the desired
compound of formula V, where R.sub.1 is (C.sub.1-6) alkyl, benzyl
or an acid labile hydroxyl protecting group; R.sub.2 is (C.sub.1-6)
alkyl or benzyl; R.sub.3 is hydrogen, (C.sub.1-6) alkyl, benzyl,
C(O)(C.sub.1-12) alkyl, C(O)Ph, C(O)O(C.sub.1-12) alkyl, C(O)OPh,
C(O)NH(C.sub.1-12) alkyl, C(O)NHPh or an acid labile hydroxyl
protecting group; R.sub.3" is an acid labile hydroxyl protecting
group; R.sub.4 is hydrogen or methyl; and X is O, NH, NCH.sub.3, S
or CH.sub.2, with the proviso that when X is O and R.sub.3 is an
acid labile hydroxyl protecting group in the compound of formula I,
the "--X--R.sub.3" moiety in the compound of formula V is --OH.
2. A process according to claim 1 wherein the coupling step is
carried out in the presence of
.beta.-chlorodiisopinocamphenylborane, triethylamine and diethyl
ether, at a temperature of between -78.degree. C. and -20.degree.
C.
3. A process according to claim 1 wherein the reduction step is
carried out in the presence of tetramethylammonium
triacetoxyborohydride, acetonitrile and acetic acid, at a
temperature of between -40.degree. C. and -10.degree. C.
4. A process according to claim 1 wherein the lactonization and
deprotection of the acid labile hydroxyl protecting groups step is
carried out in the presence of aqueous hydrogen chloride, methanol
and tetrahydrofuran, at a temperature of between -20.degree. C. and
40.degree. C.
5. A compound of formula I: 18where R.sub.1 is (C.sub.1-6) alkyl,
benzyl, or an acid labile hydroxyl protecting group; R.sub.2 is
(C.sub.1-6) alkyl, or benzyl; R.sub.3 is hydrogen, (C.sub.1-6)
alkyl, benzyl, C(O)(C.sub.1-12) alkyl, C(O)Ph,
C(O)O(C.sub.1-12)alkyl, C(O)OPh, C(O)NH(C.sub.1-12)alkyl, C(O)NHPh,
or an acid labile hydroxyl protecting group; R.sub.4 is hydrogen or
methyl; and X is O, NH, NCH.sub.3, S or CH.sub.2.
6. A compound according to claim 5 of formula Ia: 19where each of
R.sub.1' and R.sub.2' is (C.sub.1-6) alkyl; X' is O, or CH.sub.2;
and R.sub.3 and R.sub.4 are as defined in claim 5.
7. A compound according to claim 6 of formula Ib: 20where R.sub.3'
is (C.sub.1-6)alkyl, C(O)(C.sub.1-12)alkyl, benzyl,
C(O)O(C.sub.1-12)alkyl, or an acid labile hydroxyl protecting
group; and R.sub.1' and R.sub.2' are as defined in claim 6.
8. A compound according to claim 7 of formula Ic: 21where R.sub.3"
is an acid labile hydroxyl protecting group.
9. A compound according to claim 8 which is
(2R,3S,4R)-3-[[(1,1-dimethylet-
hyl)dimethylsilyl]oxy]-N-methoxy-N,2,4-trimethyl-5-oxo-hexanamide
having the formula 22
10. A process for preparing a compound of formula I according to
claim 5 which comprises, in a first step, addition of a methyl or
ethyl organometallic reagent to an aldehyde of formula VI 23in the
presence of a polar organic solvent to obtain an alcohol of formula
VII 24and, in a second step, oxidizing the alcohol compound
prepared in the first step by treating it with an oxidant and a
base in a polar organic solvent to obtain the desired compound of
formula I, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and X are as
defined in claim 5.
11. A process according to claim 10 wherein the addition step is
carried out in the presence of methylmagnesium bromide and diethyl
ether, at a temperature of between -78.degree. C. and 40.degree.
C.
12. A process according to claim 10 wherein the oxidation step is
carried out in the presence of sulfur trioxide-pyridine complex,
triethylamine and dichloromethane, at a temperature of between
-78.degree. C. and 40.degree. C.
13. A compound of formula III: 25where R.sub.1 is (C.sub.1-6)
alkyl, benzyl, or an acid labile hydroxyl protecting group; R.sub.2
is (C.sub.1-6) alkyl, or benzyl; R.sub.3 is hydrogen, (C.sub.1-6)
alkyl, benzyl, C(O)(C.sub.1-12) alkyl, C(O)Ph,
C(O)O(Cl.sub.12)alkyl, C(O)OPh, C(O)NH(C.sub.1-12)alkyl, C(O)NHPh,
or an acid labile hydroxyl protecting group; R.sub.4 is hydrogen or
methyl; X is O, NH, NCH.sub.3, S or CH.sub.2; and each R.sub.3" is
an acid labile hydroxyl protecting group.
14. A compound according to claim 13 which is
(2R,3S,4R,7S,8Z,10S,11S,12S,- 13Z, 16S,17R,18R,19S,20S,21
E)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[(1,1--
dimethylethyl)-dimethylsilyl]oxy]-7-hydroxy-N-methoxy-N,2,4,10,12,14,16,18-
,20-nonamethyl-5-oxo-8,13,21,23-tetracosatetraenamide having the
formula 26
15. A compound of formula IV: 27where R.sub.1 is (C.sub.1-6) alkyl,
benzyl, or an acid labile hydroxyl protecting group; R.sub.2 is
(C.sub.1-6) alkyl, or benzyl; R.sub.3 is hydrogen,
(C.sub.1-6)alkyl, benzyl, C(O)(C.sub.1-12) alkyl, C(O)Ph,
C(O)O(C.sub.1-12)alkyl, C(O)OPh, C(O)NH(C.sub.1-12)alkyl, C(O)NHPh,
or an acid labile hydroxyl protecting group; R.sub.4 is hydrogen or
methyl; X is O, NH, NCH.sub.3, S or CH.sub.2; and each R.sub.3" is
an acid labile hydroxyl protecting group.
16. A compound according to claim 15 which is
(2R,3S,4S,5S,7S,8Z,10S,11S,1-
2S,13Z,16S,17R,18R,19S,20S,21E)-19-[(aminocarbonyl)oxy]-3,11,17-tris[[(1,1-
-dimethylethyl)dimethylsilyl]oxy]-5,7-dihydroxy-N-methoxy-N,2,4,10,12,14,1-
6,18,20-nonamethyl-8,13,21,23-tetracosatetraenamide having the
formula 28
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/xxx,xxx, filed Aug. 7, 2000, which was converted
from U.S. application Ser. No. 09/633,753, and which is
incorporated herein by reference.
[0002] The invention relates to a process for preparing
discodermolide and analogues thereof, to novel compounds utilized
in the process and to novel compounds prepared by the process.
FIELD OF INVENTION
[0003] The present invention relates to the area of synthetic
methodology and, more particularly, to a process for preparing
discodermolide and analogues thereof.
BACKGROUND OF THE INVENTION
[0004] 1
[0005] (+)-Discodermolide is a novel polyketide natural product
that was isolated from extracts of the marine sponge Discodermolide
dissoluta by researchers at the Harbor Branch Oceanographic
Institution (HBOI) (Gunasekera S P, Gunasekera M, Longley R E,
Schulte G K. Discodermolide: a new bioactive polyhydroxylated
lactone from the marine sponge Discodermia dissolute. [published
erratum appears in J. Org. Chem. 1991;56:1346]. J. Org. Chem.
1990;55:4912-15.). Discodermolide lacks obvious structural
resemblance to paclitaxel, yet it shares with paclitaxel (the
active substance in the drug Taxol) the ability to stabilize
microtubules. In mechanism-based assays, discodermolide is more
effective than paclitaxel. In fact, of the handful of compounds
known to induce polymerization of purified tubulin, discodermolide
is the most potent. However, microtubules, a major structural
component in cells, are not simple equlibrium polymers of tubulin.
They exist as regulated GTP-driven dynamic assemblies of
heterodimers of .alpha. and .beta. tubulin. Although the dynamics
are relatively slow in interphase cells, upon entering mitosis, the
rate of growing and shortening increases 20 to 100-fold--the
average microtubule turns over half the tubulin subunits every ten
seconds. This change in rate allows the cytoskeletal microtubule
network to dismantle and a bipolar spindle-shaped array of
microtubules to assemble. The spindle attaches to chromosomes and
moves them apart. The response to complete suppression of
microtubule dynamics in cells is death. However, mitotic cells are
more sensitive and the tolerance threshold appears to be cell-type
specific. Molecules like paclitaxel that bind with high affinity to
microtubules disrupt the dynamics process in tumor cells with
lethal results even when the ratio of bound drug to tubulin is very
low. Discodermolide binds to tubulin competitively with paclitaxel.
Since paclitaxel has proven to be useful in treating some cancers,
other compounds of the same mechanistic class may have utility
against hyperproliferative disorders.
[0006] Future development of discodermolide or structurally related
analogues is hindered by the lack of a reliable natural source of
the compound or a feasible synthetic route. Naturally occurring
discodermolide is scarce and harvesting the producing organism
presents logistical problems. Accordingly, there is an ever-growing
need for improved syntheses which enable the preparation of
commercially acceptable quantities of discodermolide and
structurally related analogues.
Description of the Prior Art
[0007] WO 00/04865 discloses the preparation of intermediates for
the synthesis of discodermolide and their polyhydroxy dienyl
lactone derivatives for pharmaceutical use.
[0008] Agnew. Chem., Vol. 39, No. 2, pgs. 377-380 (2000) discloses
the total synthesis of the antimicrotubule agent (+)-discodermolide
using boron-mediated aldol reactions of chiral ketones.
[0009] Org. Lett., Vol. 1, No. 11, pgs. 1823-1826 (1999) discloses
the gram-scale synthesis of (+)-discodermolide.
[0010] Diss. Abstr. Int., Vol. 60, No. 3, pg. 1087 (1999) discloses
the total synthesis of (+)-miyakolide, (-)-discodermolide and
(+)-discodermolide.
[0011] Tetrahedron Lett., Vol. 40, No. 30, pgs 5449-5453 (1999)
discloses the synthesis of C1-C8 and C9-C24 fragments of
(-)-discodermolide.
[0012] Diss. Abstr. Int., Vol. 59, No. 11, pg. 5854 (1999)
discloses a total synthesis of (-)-discodermolide.
[0013] J. Org. Chem., Vol. 63, No. 22, pgs. 7885-7892 (1998)
discloses the total synthesis of (+)-discodermolide.
[0014] WO 98/24429 discloses synthetic techniques and intermediates
for polyhydroxy, dienyllactones and mimics thereof.
[0015] J. Am. Chem. Soc., Vol. 118, No. 45, pgs. 11054-11080 (1996)
discloses the syntheses of discodermolides useful for investigating
microtubule binding and stabilization.
[0016] J. Am. Chem. Soc., Vol. 117, No. 48, pgs. 12011-12012 (1995)
discloses the total synthesis of (-)-discodermolide.
[0017] British Patent Application 2,280,677 discloses the total
synthesis of discodermolide.
SUMMARY OF THE INVENTION
[0018] The present invention relates to a more practical synthesis
of discodermolide and analogues thereof. In another embodiment, the
instant invention relates to novel compounds useful in the
preparation of discodermolide and analogues thereof. In a further
embodiment, the instant invention relates to novel compounds which
are prepared by the process of the instant invention.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The essence of the instant invention is the discovery of a
more practical synthesis for discodermolide and analogues thereof.
More particularly, it has been discovered that discodermolide and
analogues thereof can be prepared by a three-step reaction as
follows: 2
[0020] where R.sub.1 is (C.sub.1-6) alkyl, benzyl or an acid labile
hydroxyl protecting group; R.sub.2 is (C.sub.1-6) alkyl or benzyl;
R.sub.3 is hydrogen, (C.sub.1-6) alkyl, benzyl, C(O)(C.sub.1-12)
alkyl, C(O)Ph, C(O)O(C.sub.1-12) alkyl, C(O)OPh, C(O)NH(C.sub.1-12)
alkyl, C(O)NHPh or an acid labile hydroxyl protecting group;
R.sub.3" is an acid labile hydroxyl protecting group; R.sub.4 is
hydrogen or methyl; and X is O, NH, NCH.sub.3, S or CH.sub.2, with
the proviso that when X is O and R.sub.3 is an acid labile hydroxyl
protecting group in the compound of formula I, the "--X--R.sub.3"
moiety in the compound of formula V is --OH.
[0021] As to the individual steps, Step 1 involves the coupling of
a ketone compound of formula I with an aldehyde compound of formula
II via an aldol reaction to obtain a .beta.-hydroxyketone compound
of formula III. The coupling is conveniently carried out with
between 1 and 20, preferably between 5 and 15, equivalents of the
ketone compound of formula I relative to the aldehyde compound of
formula II. The coupling is conducted in the presence of: 1) a
dialkylboron halide or triflate, preferably a chiral boron chloride
or triflate, more preferably .beta.-chlorodiisopinocamphenylborane;
2) a base, preferably an amine, more preferably triethylamine; and
3) a polar organic solvent, preferably an ether, more preferably
diethyl ether, at a temperature of between -100.degree. C. and
20.degree. C., preferably between -78.degree. C. and -20.degree.
C., for a period of between 2 and 72 hours, preferably for 16
hours.
[0022] Step 2 concerns the reduction of the .beta.-hydroxyketone
compound of formula III and, more particularly, the ketone group
common to such compounds, to obtain a 1,3-diol compound of formula
IV. The reduction is conducted in the presence of: 1) a ketone
reducing agent, preferably a borohydride such as
tetramethylammonium triacetoxyborohydride; 2) a polar organic
solvent, preferably acetonitrile; and 3) a protic solvent,
preferably a carboxylic acid, such as acetic acid, at a temperature
of between -78.degree. C. and 20.degree. C., preferably between
-40.degree. C. and 10.degree. C., for a period of between 2 and 72
hours, preferably for 16 hours.
[0023] As to Step 3, it involves the lactonization and deprotection
of the acid labile hydroxyl protecting groups of a compound of
formula IV to obtain a compound of formula V. The lactonization and
deprotection reaction is conducted in the presence of: 1) a protic
acid, preferably an aqueous protic acid solution, preferably an
aqueous hydrogen halide solution, such as aqueous hydrogen
chloride; and 2) a polar organic solvent, preferably a mixture of
polar organic solvents, more preferably a mixture of an aliphatic
alcohol and an ether, such as methanol and tetrahydrofuran, at a
temperature of between -20.degree. C. and 40.degree. C., preferably
between 20.degree. C. and 25.degree. C., for a period of 8 hours
and 7 days, preferably between 16 and 72 hours, more preferably
between 24 and 48 hours.
[0024] In another embodiment, the instant invention relates to the
novel ketone compounds of formula I: 3
[0025] where
[0026] R.sub.1 is (C.sub.1-6) alkyl, benzyl, or an acid labile
hydroxyl protecting group;
[0027] R.sub.2 is (C.sub.1-6) alkyl, or benzyl;
[0028] R.sub.3 is hydrogen, (C.sub.1-6) alkyl, benzyl,
C(O)(C.sub.1-12) alkyl, C(O)Ph, C(O)O(C.sub.1-12)alkyl, C(O)OPh,
C(O)NH(C.sub.1-12)alkyl, C(O)NHPh, or an acid labile hydroxyl
protecting group;
[0029] R.sub.4 is hydrogen or methyl; and
[0030] X is O, NH, NCH.sub.3, S or CH.sub.2.
[0031] Preferred compounds are those of formula Ia: 4
[0032] where
[0033] each of R.sub.1' and R.sub.2' is (C.sub.1-6) alkyl;
[0034] X is O, or CH.sub.2; and
[0035] R.sub.3 and R.sub.4 are as defined above.
[0036] More preferred compounds are those of formula Ib: 5
[0037] where
[0038] R.sub.3' is (C.sub.1-6)alkyl, C(O)(C.sub.1-12)alkyl, benzyl,
C(O)O(C.sub.1-12)alkyl, or an acid labile hydroxyl chain group
protecting group; and
[0039] R.sub.1' and R.sub.2' are as defined above.
[0040] Even more preferred compound are those of formula Ic: 6
[0041] where R.sub.3" is an acid labile hydroxyl protecting
group.
[0042] In the above definitions: the term "(C.sub.1-6) alkyl" as
used herein refers to a straight or branched chain group consisting
solely of carbon and hydrogen and having from 1 to 6 carbon atoms,
whereas the term "(C.sub.1-12) alkyl" as used herein refers to a
straight or branched chain group consisting solely of carbon and
hydrogen and having from 1 to 12 carbon atoms. Examples of "alkyl"
groups include methyl, ethyl, propyl, butyl, pentyl,
3-methylpentyl, etc.
[0043] The term "acid labile hydroxyl protecting groups" as used
herein refers to any oxygen bound group that can be removed upon
exposure to an acid. Numerous examples of these groups are known by
those skilled in the art and can be found in Greene and Wuts,
Protective Groups in Organic Synthesis, 2d edition, John Wiley
& Sons, New York, 1991. Specific examples include, but are not
limited to, t-butyldimethylsilyl, triethylsilyl,
t-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, and
tetrahydropyranyl.
[0044] In a further embodiment, the instant invention relates to a
process for preparing the novel compounds of formula I. More
particularly, the compounds of formula I may be prepared as
depicted below: 7
[0045] where R.sub.1, R.sub.2, R.sub.3, R.sub.4 and X are as
defined above.
[0046] As to the individual steps, Step A involves the addition of
a methyl or ethyl group to an aldehyde compound of formula VI to
obtain an alcohol compound of formula VII. The addition is carried
out in the presence of: 1) an organometallic reagent, preferably an
alkyllithium or alkylmagnesium halide such as methylmagnesium
bromide; and 2) a polar organic solvent, preferably an ether such
as diethyl ether, at a temperature of between -78.degree. C. and
40.degree. C., preferably at -78.degree. C. and 0.degree. C., more
preferably at about -40.degree. C., for a period of between 5
minutes and 24 hours, preferably between 30 minutes and 2 hours,
more preferably for about 1 hour.
[0047] Step B involves the oxidation of an alcohol compound of
formula VII to obtain the desired ketone compound of formula I. The
oxidation is carried out in the presence of: 1) an oxidant,
preferably a combination of dimethylsulfoxide and an activating
agent, more preferably a combination of dimethylsulfoxide and
sulfur trioxide complex with pyridine; 2) a base, preferably an
organic base, more preferably a trialkylamine such as
triethylamine; and 3) a polar organic solvent, preferably a
chlorinated hydrocarbon such as dichloromethane. The oxidation is
suitably carried out a temperature of between -78.degree. C. and
40.degree. C., preferably between 50.degree. C. and 20.degree. C.,
for a period of between 5 minutes and 24 hours, preferably between
1 hour and 12 hours, more preferably between 4 and 6 hours.
[0048] The aldehyde compounds of formulae II and VI are either
known or may be prepared analogous to processes set forth in the
literature for other structurally similar aldehydes.
[0049] In still another embodiment, the instant invention relates
to the novel .beta.-hydroxyketone compounds of formula III and the
novel 1,3-diol compounds of formula IV.
[0050] Although the product of each reaction described above may,
if desired, be purified by conventional techniques such as
chromatography or recrystallization (if a solid), the crude product
of one reaction is advantageously employed in the following
reaction without purification.
[0051] As is evident to those skilled in the art, compounds of
formulae I and III-V contain asymmetric carbon atoms and,
therefore, it should be understood that the individual
stereoisomers are contemplated as being included within the scope
of this invention.
[0052] The following examples are for purposes of illustration only
and are not intended to limit in any way the scope of the instant
invention.
EXAMPLE 1
[0053] Preparation of
(2R,3S,4R)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-
-N-methoxy-N,2,4-trimethyl-5-oxo-hexanamide 8
a) Preparation of
(2R,3S,4S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-5-h-
ydroxy-N-methoxy-N,2,4-trimethyl-hexanamide
[0054] 9
[0055] To a solution of 6.9 g (21.8 mmol) of
(2R,3S,4R)-3-[[(1,1-dimethyle-
thyl)dimethylsilyl]oxy]-N-methoxy-N,2,4-trimethyl-5-oxo-pentanamide
in 50 mL of ether is added 10.2 mL (30.5 mmol) of a 3M solution of
methylmagnesium bromide in ether, dropwise, at -40.degree. C.,
after which the mixture is stirred at -20.degree. C. for 1 hour.
The reaction mixture is then diluted with 200 mL of ether and the
reaction is quenched by adding the reaction mixture to 20 g of
crushed ice at 0.degree. C. The mixture is then washed with 100 mL
of 1M sodium hydrogen sulfate solution and partitioned with two 150
mL portions of ether. The organic layers are then combined and
dried over sodium sulfate. The crude product mixture is then
chromatographed employing an eluent mixture of 20% ethyl acetate in
hexane initially and then an eluent mixture of 40% ethyl acetate in
hexane to yield two diastereomers as light yellow oils which are
used in the next step without further purification.
[0056] Diastereomer 1: .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.4.08 (dd, J=9.8, 6.8 Hz, 2H), 3.64 (s, 3H), (d, J=2.6Hz, 2H
), 3.08 (s, 3H), 3.00 (m, 2H), 1.48 (m, 2H), 1.07 (d, J=6.8 Hz,
3H), 1.05 (d, J=6.4 Hz, 3H), 0.81 (s, 9H), 0.76 (d, J=7.2 Hz, 2H),
0.01 (d, J=3.8 Hz, 6H).
[0057] Diastereomer 2: .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta.4.19 (dd, J=12.1, 6.0 Hz, 2H), 3.86 (dd, J=9.0, 1.51 Hz,
2H), 3.56 (s, 3H), 3.18 (m, 2H), 3.01 (s, 3H), 1.28 (m, :2H), 1.06
(d, J=6.8 Hz, 3H), 0.94 (d, 6.4 Hz, 3H), 0.88 (d, 7.2 Hz, 3H), 0.78
(s, 9H), 0.01 (d, 1.3Hz, 6H).
b) Preparation of the Title Compound
[0058] To a solution of 13.1 g (39.5 mmol) of the diastereomeric
mixture prepared in a) above in a mixture comprising 150 mL of
methylene chloride, 50 mL of dimethylsulfoxide and 25 mL of
triethylamine is added, dropwise via an addition funnel, 19.0 g
(120 mmol) of sulfur trioxide pyridine complex in 150 mL of
dimethylsulfoxide at 0.degree. C. The resultant solution is then
stirred for 11/2 hours at 0.degree. C., after which time the
reaction mixture is concentrated via a rotary evaporator in a
cooling both at <10.degree. C. The solution is then diluted with
200 mL of ether, and then extracted successively with 200 mL of a
1M sodium hydrogen sulfate solution and 200 mL of brine. The
organic layer is then dried over sodium sulfate and the crude
product mixture is purified by flash chromatography employing
hexane as the eluent initially and then an eluent mixture of 5%
ethyl acetate in hexane to yield the desired compound as a clear
oil.
[0059] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.4.23 (dd, J=7.5,
4.2 Hz, 2H), 3.61 (s, 3H), 3.01 (s, 3H), 2.92 (m, 2H), 2.64 (m,
2H), 2.08 (s, 3H), 1.03 (d, J=6.8 Hz, 3H), 0.98 (d, J=7.2 Hz, 3H),
0.81 (s, 9H), 0.00 (s, 6H).
EXAMPLE 2
[0060] Preparation of (+)-discodermolide 10
a) Preparation of
(2R,3S,4R,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,21E)-
-19-[(aminocarbonyl)oxyl]-3,11,17-tris[[(1,1-dimethylethyl)dimethylsilyl]o-
xy]-7-hydroxy-N-methoxy-N,2,4,10,12,14,16,18,20-nonamethyl-5-oxo-8,13,21,2-
3-tetracosatetraenamide
[0061] 11
[0062] To a stirred solution of 2.18 g (6.79 mmol, 10 equiv.) of
(+)-.beta.-chlorodiisopinocamphenylborane in 4 mL of diethyl ether
at 0.degree. C. is added 1.04 mL (11 equiv., distilled over calcium
hydride) of triethylamine and then a solution of 2.25 g (6.79 mmol,
10 equiv.) of the compound of Example 1 in 3 mL of diethylether.
After stirring for 2 hours at 0.degree. C., the mixture is cooled
to -78.degree. C., after which time a pre-cooled (-78.degree. C.)
solution of 450 mg (0.679 mmol) of
(2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15E)-13-[(amino-carbonyl)oxyl]-5,1-
1-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,6,8,10,12,14-hexamethyl-2,7-
,15,17-octadecatetraenal in 4 mL of diethylether is added via
cannula. After the resultant mixture is maintained at a temperature
of -78.degree. C. for 3 hours, it is transferred to a freezer
(-27.degree. C.) for 16 hours. The reaction is then quenched with 8
mL of methanol (the pH of which is adjusted to 7 with 12 mL of
buffer solution) and 4 mL of 50% hydrogen peroxide solution at
0.degree. C. After stirring for 2 hours at 25.degree. C., the
organic layers are separated. The aqueous layer is then extracted
five times with 25 mL portions of dichloromethane. The combined
organic layers are then dried over magnesium sulfate, concentrated
using a rotary evaporator and chromatographed (Biotage, silica gel,
gradient 10-30% ethyl acetate/hexane) to yield the desired compound
as a colorless, highly viscous oil.
[0063] [.alpha.].sub.D+12.56.degree. (c=1.0, CH.sub.2Cl.sub.2); IR
(CH.sub.2Cl.sub.2) 3547 (m, OH), 3359 (m, CONH2), 2958 (vs), 2990
(vs), 1729 (vs, C.dbd.O), 1664 (m), 1462 (s), 1385 (s), 1254(s),
1037 (s), 1037 (s), 1004 (s), 835 (vs); .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta.6.61 (1H, ddd, J=17.1, 10.5, 10.5 Hz, H.sub.23),
6.03 (1H, dd, J=11.0, 11.0 Hz, H.sub.22), 5.50 (1H, dd, J=10.6,
10.6 Hz, H.sub.9), 5.37 (1H, dd, J=10.6, 10.5 Hz, H.sub.21), 5.35
(1H, dd, J=10.8, 8.5 Hz, H.sub.8), 5.23 (1H, dd, J=15.3, 2.1 Hz,
H.sub.24A), 5.13 (1H, d, J=10.2 Hz, H.sub.24B), 5.05 (1H, d, J=10.0
Hz, H.sub.13), 4.79 (1H, t, J=8.0 Hz, H.sub.7), 4.72 (1H, t, J=5.9
Hz, H.sub.19), 4.60-4.50 (2H, br, CONH.sub.2), 4.33 (1H, dd, J=6.9,
4.3 Hz, H.sub.3), 3.74 (3H, s, NOCH.sub.3), 3.43 (1H, dd, J=5.0,
4.1 Hz, H.sub.17), 3.31 (1H, dd, J=5.2, 5.1 Hz, H.sub.11), 3.13
(3H, s, NCH.sub.3), 3.08 (1H, br, OH), 3.00 (1H, m, H.sub.20),
2.78-2.69 (2H, m, H4+H.sub.6A), 2.70-2.62 (1H, m, H.sub.10),
2.66-2.54 (2H, m, H.sub.2+H.sub.6B), 2.49-2.45 (1H, m, H.sub.12),
2.12(1H, dd, J=12.4, 12.3 Hz, H.sub.15A), 1.93-1.86 (2H, m,
H.sub.16+H.sub.18), 1.76-1.65 (1H, m, H15B), 1.62 (3H, s,
Me.sub.14), 1.14 (3H, d, J=7.0 Hz, Me.sub.2), 1.11(3H, d, J=7.0 Hz,
Me.sub.4), 1.00 (3H, d, J=3.1 Hz, Me.sub.20), 0.99 (3H, d, J=3.3
Hz, Me.sub.10), 0.96-0.90 (21H, m, Me.sub.18+2.times.SiC(CH-
.sub.3).sub.3), 0.88 (3H, d, J=6.6 Hz, Me.sub.12), 0.83 (9H, s,
SiC(CH.sub.3).sub.3), 0.73 (3H, d, J=6.7 Hz, Me.sub.16), 0.10 &
0.08 & 0.04 & 0.03 & 0.03 & 0.01 (6.times.3H,
3.times.Si(CH.sub.3).sub.2); .sup.13C NMR (100.6 MHz, CDCl.sub.3)
.delta.212.9, 175.9, 156.9, 136.0, 133.7, 132.1, 131.9, 131.3,
129.8, 129.6, 117.9, 80.6, 78.7, 76.8, 73.6, 64.9, 62.1, 61.3,
54.7, 53.1, 51.7, 49.0, 45.1, 44.9, 37.9, 37.1, 36.2, 35.9, 35.0,
34.4, 30.0, 29.1, 26.26, 26.24, 25.97, 23.0, 18.51, 18.5, 18.43,
18.14, 17.43, 16.44, 13.5, 10.99, 10.1, -3.29, -3.4, -3.5, -3.9,
-4.1, -4.4; m/z (ESI+) 1017 (100 (MNa.sup.+)).
b) Preparation of
(2R,3S,4S,5S,7S,8Z,10S,11S,12S,13Z,16S,17R,18R,19S,20S,2-
1E)-19-[(aminocarbonyl)oxyl]-3,11,17-tris[[(1,1-dimethylethyl)dimethylsily-
l]oxy]-5,7-dihydroxy-N-methoxy-N,2,4,10,12,14,16,18,20-nonamethyl-8,13,21,-
23-tetracosatetraenamide
[0064] 12
[0065] To a solution of 1.02 g (3.9 mmol) of tetramethylammonium
triacetoxyborohydride in 2.2 mL of anhydrous acetonitrile is added
2.2 mL of anhydrous acetic acid and the mixture is stirred at
ambient temperature for 30 min. The mixture is then cooled to
-29.degree. C. and to the cooled mixture is added a solution of 450
mg (0.453 mmol) of the compound prepared in a) above in 1 mL of
anhydrous acetonitrile. The resultant mixture is then stirred at
-29.degree. C. for 18 hours, after which time the reaction is
quenched with 2 mL of 0.5N aqueous sodium potassium tartrate. The
mixture is then allowed to warm slowly to ambient temperature,
after which it is diluted with methylene chloride and washed with
saturated sodium bicarbonate. The aqueous layer is then extracted
four times with methylene chloride. The combined organic layers are
then washed with brine, dried with sodium sulfate and concentrated
in vacuo. The resultant residue is then purified by flash
chromatography (Biotage, silica gel, gradient 10-30% ethyl
acetate/hexane) to yield the desired compound as a white solid.
[0066] [.alpha.]+29.75 degree (c=0.87, CH.sub.2Cl.sub.2); .sup.1H
NMR (499.87 MHz, CDCl.sub.3) .delta.6.60 (1H, ddd, J=16.8, 10.5,
10.5 Hz, H.sub.23), 6.02 (1H, t, J=11.0, H.sub.22), 5.48 (1H, dd,
J=10.0, 9.8 Hz, H.sub.9), 5.37 (1H, dd, J=10.6, 11.2 Hz, H.sub.21),
5.35 (1H, dd, J=10.8, 8.5 Hz, H.sub.8), 5.22 (1H, d, J=15.8 Hz,
H.sub.24A), 5.12 (1H, d, J=10.2 Hz, H.sub.24B), 4.98 (1H, d, J=10.1
Hz, H.sub.13), 4.79 (1H, t, J=6.3 Hz, H.sub.7), 4.65 (1H, t, J=5.9
Hz, H.sub.19), 4.60-4.50 (2H, br, CONH.sub.2), 4.20 (1H, dd, J=7.7,
2.3 Hz, H.sub.3), 3.92, (1H, m, H.sub.5), 3.73 (3H, s, NOCH.sub.3),
3.45 (1H, br, OH-5), 3.41 (1H, dd, J=10.9, 4.7 Hz, H.sub.17), 3.31
(1H, dd, J=5.2, 5.1 Hz, H.sub.11), 3.18 (3H, s, NCH.sub.3), 3.08
(1H, br, OH), 2.99 (1H, m, H.sub.20), 267 (1H, m, H.sub.10),
2.43-2.41 (2H, m, 2.11 (1H, t, J=12.3 Hz), 1.90-1.87 (2H, m),
1.76-1.58 (10H, m), 1.25 (3H, t, Me), 1.17 (3H, d, J=7.1 Hz, Me),
0.99 (3H, d, J=6.4 Hz, Me), 0.97 (3H, d, J=6.5 Hz, Me), 0.93-0.83
(30H, m, Me+3.times.SiC(CH.sub.3).sub.3), 0.71 (3H, d, J=6.8 Hz,
Me), 0.10 & 0.08 & 0.04 & 0.03 & 0.03 & 0.03
& 0.01 (6.times.3H, 3.times.Si(CH.sub.3).sub.2). .sup.13C NMR
(100.6MHz, CDCl.sub.3) .delta.156.88, 140.02, 134.19, 133.66,
132.10, 131.88, 131.40, 131.30, 131.11, 130.06, 129.79, 117.91,
115.44, 80.79, 80.69, 78.61, 78.32, 74.31, 70.68, 65.55, 61.66,
45.69, 40.38, 38.36, 37.92, 37.83, 37.29, 36.29, 35.07, 34.91,
34.45, 32.36, 29.68, 26.21, 26.12, 26.03, 25.95, 22.95, 18.52,
18.43, 18.12, 17.41, 17.07, 16.57, 13.44, 12.29, 10.32, 10.14,
-3.20, -3.43, -3.96, -4.16, -4.48. m/z (ESI+) 1019 (100
(MNa.sup.+)).
c) Preparation of the Title Compound
[0067] To a solution of 450 mg (0.452 mmol) of the compound
prepared in b) above in 56 mL of tetrahydrofuran is added 56 mL of
an aqueous solution of 4N hydrochloric acid. The resultant solution
is then stirred at room temperature for 24 hours, 10 ml of methanol
is then added, and this solution is then stirred for an additional
24 hours at room temperature. To the solution is then added 50 mL
of ethyl acetate, followed by the addition of sodium bicarbonate at
0.degree. C. to a pH of 8. The organic solution is then washed with
brine. The aqueous layer is then extracted three times with 30 mL
portions of ethyl acetate, and the combined extracts are dried over
sodium sulfate. Filtration and concentration followed by flash
chromatography employing an eluent mixture of 50% methylene
chloride in ethyl acetate initially and then 100% ethyl acetate
yields the desired compound, m.p. 122.degree.-124.degree. C.
[0068] [.alpha.]+22.0.degree. (c=1.41, MeOH) .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta.6.68 (1H, ddd, J=16.7, 10.9, 10.5 Hz, H.sub.23),
6.08 (1H, t, J=11.0, Hz, H.sub.22), 5.62 (1H, t, J=10.1 Hz,
H.sub.9), 5.48 (1H, t, J=10.7, H.sub.21), 5.39 (1H, dd, J=10.7, 8.8
Hz, H.sub.8), 5.28 (1H, d, J=16.9, Hz, H.sub.24A), 5.17 (1H, d,
J=10.2 Hz, H.sub.24B), 4.96 (1H, d, J=10.1 Hz, H.sub.13), 4.86 (2H,
br, CONH.sub.2), 4.60 (1H, t, J=10.4 Hz, H.sub.7), 4.58 (1H, t,
J=9.7 Hz, H.sub.19), 3.66 (1H, t, 3.9), 3.22 (1H, dd, J=7.9, 3.3
Hz), 3.15 (1H, m), 3.12 (1H, dd, J=8.5, 3.0 Hz), 2.68 (1H, m,
H.sub.10), 2.64 (1H, m, H.sub.2), 2.33 (1H, m, H.sub.12), 1.90 (5H,
m), 1.63 (1H, m), 1.62 (3H, s, Me), 1.55-1.50 (1H, m), 1.26 (3H, d,
J=7.4 Hz, Me), 1.07(6H, d, J=6.8 Hz, 2Me), 1.01 (3H, d, J=6.8 Hz,
Me), 0.94 (3H, d, J=6.6 Hz, Me), 0.89 (3H, d, J=6.8 Hz, Me), 0.79
(3H, d, J=6.3 Hz, Me). .sup.13C NMR (100.6 MHz, CDCl.sub.3)
.delta.176.8, 160.33, 134.17. 133.92, 133.88, 133.59, 133.28,
131.59, 131.00, 118.80, 80.66, 80.22, 78.48, 76.48, 73.66, 63.70,
44.56, 42.60, 38.79, 37.71, 36.92, 36.77, 36.69, 34.97, 34.62,
23.45, 19.73, 18.25, 18.11, 16.05, 15.84, 13.27, 9.44. m/z (ESI+)
594 (100 (M+1.sup.+)).
* * * * *