Stereoselective synthesis of the C1-C13 fragment of (+)-discodermolide using asymmetric allyltitanations

Article abstract of DOI:10.1021/ol034958l

(Matrix presented) The synthesis of the C1-C13 fragment of (+)-discodermolide has been achieved. The configurations of the stereogenic centers have been controlled by enantioselective allyl- and crotyltitanations of aldehydes, and the Z configuration of t

Full text of DOI:10.1021/ol034958l

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3029-3031
Stereoselective Synthesis of the C1−C13
Fragment of (+)-Discodermolide Using
Asymmetric Allyltitanations
Samir BouzBouz* and Janine Cossy*
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin
75231, Paris Cedex 05, France
janine.cossy@espci.fr; samir.bouzbouz@espci.fr
Received May 30, 2003
ABSTRACT
The synthesis of the C1−C13 fragment of (+)-discodermolide has been achieved. The configurations of the stereogenic centers have been
controlled by enantioselective allyl- and crotyltitanations of aldehydes, and the Z configuration of the olefin at C8−C9 was controlled by a
ring-closing metathesis.
Discodermolide was isolated by Gunasekera and co-workers
at the Harbor Branch Oceanographic Institute in 1990 from
the deep-water marine sponge Discodermia dissoluta.1 This
compound has a unique polyketide structure bearing 13
stereogenic centers, and the absolute configuration of these
stereogenic centers was established by Schreiber et al. during
their initial synthesis of both (+)- and (-)-discodermolide.
(+)-Discodermolide is both a potent immunosuppressive
and anticancer agent as well as an antifungal agent.2,3 It
inhibits T-cell proliferation with an IC50 of 9 nM and graft-
versus-host disease in transplanted mice.
agents. Due to the potential therapeutic applications and the
extreme scarcity of (+)-discodermolide (0.002% w/w) from
frozen marine sponge, there has been considerable synthetic
effort toward discodermolide, culminating in several total
syntheses3,5 and numerous fragment syntheses.6 Herein, we
report the results of our synthetic studies concerning an ap-
proach toward the C1-C13 subunit 18 which sets the stage
for a convergent synthesis of (+)-discodermolide (Scheme 1).
According to our retrosynthetic analysis, the C14-C15
bond could be formed by using a sp2-sp3-type pallad-
ium(0)-mediated cross-coupling reaction between a vinyl
Furthermore, startling cytotoxity causing cell cycle arrest
in the G2/M phase in a variety of human and marine cell
lines.4 Discodermolide stabilizes microtubules and has been
recognized as one of the most potent tubulin polymerizing
(4) (a) Ter Haar, E.; Kowalski, R. J.; Hamel, E.; Lin, C. M.; Longley,
R. E.; Gunasekera, S. P.; Rosenkranz, H. S.; Day, B. W. Biochemistry 1996,
35, 5, 243. (b) Hung, D. J.; Chen, J.; Schreiber, S. L. Chem. Biol. 1996, 3,
287.
(5) Total synthesis: (a) Smith, A. B., III; Qiu, Y.; Jones, D. R.;
Kobayashi, K. J. Am. Chem. Soc. 1995, 117, 12011. (b) Smith, A. B., III;
Kaufman, M. D.; Beauchamp, T. J.; LaMarche, M. J.; Arimoto, H. Org.
Lett. 1999, 1, 1823. (c) Haried, S. S.; Yang, G.; Strawn, M. A.; Myles D.
C. J. Org. Chem. 1997, 62, 6098. (d) Marshall, J. A.; Lu, Z.-H.; Johns, B.
A. J. Org. Chem. 1998, 63, 7885. (e) Paterson, I.; Florence, G. J.; Gerlach,
K.; Scott, J. P. Angew. Chem., Int. Ed. 2000, 39, 2, 377. (f) Paterson, I.;
Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc.
2001, 123, 9535. (g) Halstead, D. P. Ph.D. Thesis, Harvard University,
Cambridge, MA, 1998. (h) Formal synthesis: Francavila, C.; Chen, W.;
Kinder, F. R., Jr. Org. Lett. 2003, 5, 1233.
(1) (a) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E. J. Org. Chem.
1990, 55, 4912; additions and corrections: J. Org. Chem. 1991, 56, 1346.
(b) Gunasekera, S. P.; Pomponi, S. A.; Longley, R. E. U.S. Patent No.
US5840750, Nov 24, 1998.
(2) (a) Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasekera, M.;
Gunasekera, S. P. Transplantation 1991, 52, 650. In vivo studies were also
performed: (b) Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasekera,
M.; Gunasekera, S. P. Transplantation 1991, 52, 656. (c) Gunasekera, S.
P.; Granik, S.; Longley, R. E. J. Nat. Prod. 1989, 52, 757.
(3) (a) Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber S. L.
J. Am. Chem. Soc. 1993, 115, 12621. (b) Hung, D. T.; Nerenberg, J. B.;
Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054.
(6) References for synthetic approaches to discodermolide, see: Arefolov,
A.; Panek J. S. Org. Lett. 2002, 4, 2397.
10.1021/ol034958l CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/25/2003

the double bond at C8-C9, compound 2 was transformed
to lactone 4 in two steps. Compound 2 was first converted
to the unsaturated ester 3 in 89% yield by treatment with
acryloyl chloride in the presence of i-Pr2NEt (CH2Cl2,
-78 °C). Subsequent ring-closing metathesis using Grubbs’
catalyst III10 in refluxing CH2Cl2 afforded lactone 4 (85%
yield). This lactone was transformed to the allylic alcohol 5
in 72% yield by reduction with Dibal-H at -78 °C followed
by reduction of the subsequent lactol by NaBH4 in MeOH
at 0 °C. It is worth noting that the ring-closing metathesis
of an unsaturated ester followed by reduction of the lactone
resulted in the exclusive formation of the (Z)-allylic alcohol
5. Protection of this allylic alcohol as a pivaloyl ester (PivCl,
pyridine, 25 °C) followed by protection of the secondary
alcohol as a MOM ether (MOMCl, i-Pr2NEt, CH2Cl2, 25 °C)
led to compound 6 in 81% yield. To transform 6 to aldehyde
8, compound 6 was first reduced with Dibal-H (CH2Cl2,
-78 °C) to the corresponding alcohol 7 and then transformed
to aldehyde 8 with a Swern oxidation (90% yield) (Scheme
2).
Scheme 1
Scheme 2 a
iodide (C1-C14 fragment), which could be synthesized from
compound 18 (C1-C13 fragment), and iodide 20 (C15-
C24 fragment), which could be obtained from stereopentad
19.7 Compound 18 could be synthesized from the unsaturated
aldehyde 8. We projected that the transformation of 8 to 18,
which implies the control of stereogenic centers C2, C4, C5,
and C7, could be realized using the high face selective and
stereoselective chiral allyltitanium complex (R,R)-I and the
(E)-crotyltitanium complexes (R,R)-II and (S,S)-II.8 Alde-
hyde 8 will be synthesized from the commercially available
(S)-2-methyl-3-silyloxypropanal 1 using the (E)-crotyltita-
nium complex (R,R)-II to set the C10 and C11 stereogenic
centers. A ring-closing metathesis (RCM) reaction will
control the Z double bond present at C8-C9 (Scheme 1).
The synthesis of the C1-C13 fragment of (+)-discoder-
molide began with the addition of the cyclopentadienyl-
alkoxycrotyltitanium complex (R,R)-II to (S)-2-methyl-3-
silyloxypropanal 1. This addition afforded a 96/4 mixture
of two separable diastereomers from which compound 2 was
isolated in 91% yield. By analogy with previous results, the
(S)-configuration can be attributed to the C11 and C10
stereogenic centers.9 To control the (Z) stereochemistry of
a Key: (a) (R,R-II, ether, -78 °C, 91%; (b) acryloyl chloride,
iPr2NEt, CH2Cl2, -78 °C, 89%; (c) Grubbs’ catalyst III, CH2Cl2,
reflux, 85%; (d) (i) Dibal-H, CH2Cl2, -78 °C, (ii) NaBH4, MeOH,
i
0 °C, 72%; (e) (i) PivCl, pyridine, 25 °C, (ii) MOMCl, Pr2NEt,
CH2Cl2, 25 °C, 81%; (f) Dibal-H, CH2Cl2, -78 °C, 93%; (g)
(COCl)2, DMSO, -78 °C, Et3N, CH2Cl2, 90%.
The elaboration of a suitable precursor to the C1-C13
fragment of (+)-discodermolide from 8 required the instal-
lation of the C7 stereogenic center with the (S)-configuration
and, thus, the use of the allyltitanium complex (R,R)-I in
ether at -78 °C. The homoallylic alcohol 9 was obtained in
(9) The structure of 2 was determined by comparaison with the analytical
data reported in the literature see: Roush, W. R.; Palkowitz, A. D.; Ando,
K. J. Am. Chem. Soc. 1990, 112, 6348.
(10) Grubbs, R. H.; Scholl, M.; Ding, S.; Lee, C. W. Org. Lett. 1999, 1,
953.
(7) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 3995.
(8) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, J.; Rothe-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
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Org. Lett., Vol. 5, No. 17, 2003

high diastereoselectivity (dr ) 96/4) and in 90% yield by
treatment of 8 with the (R,R)-I complex. The choice of a
hindered protecting group for the hydroxy group is of
significant importance for the progress of the synthesis
because it will protect the disubstituted double bond at
C8-C9 during the oxidation of the terminal olefin.11 Thus,
the homoallylic alcohol 9 was subjected to TBDPSCl
(imidazole, CH2Cl2) and transformed to the silyl ether 10 in
93% yield. As anticipated, the oxidation of 10 with OsO4/
NMO/NaIO4 (acetone/H2O) was selective and gave exclu-
sively aldehyde 11 in high yield (89%). Therefore, the
presence of the aldehyde was appropriate for the introduction
of the C4 and C5 stereogenic centers which were controlled
by using the (S,S)-II complex at -78 °C. After treatment of
11 with the (S,S)-II complex, compound 12 was obtained in
high diastereoselectivity (dr ) 95/5) and in good yield (91%).
Protection of the hydroxy group at C5 with TBSOTf (2,6-
lutidine, -78 °C) afforded compound 13 in 85% yield. The
last two stereogenic centers at C2 and C3 were introduced
in a three-step sequence from compound 13 (Scheme 3). The
yield of 78%, with the anti relative stereochemistry between
the groups at C2 and C3. Inversion of the hydroxy group at
C3 was achieved by using a Swern oxidation followed by a
diastereoselective reduction of the obtained ketone by
Dibal-H in toluene at -80 °C.12 This two-step process led
to compound 15 in an overall yield of 81% (syn/anti >
25/1) (Scheme 3).
To establish the relative stereochemistry at C3, C4, and
C5, 15 was transformed to acetonide 16 in three steps. After
removal of the three silyl protecting groups, the allylic
alcohol at C7 was protected selectively with TBDPSCl
(imidazole, CH2Cl2), and the obtained product was treated
with dimethoxypropane in acetone in the presence of CSA
to produce acetonide 1613 in 60% overall yield. The relative
syn configuration of the hydroxy groups at C3 and C5 was
confirmed by the analysis of the 13C NMR (δ ) 19.5, 30.0
for Me2C) (Scheme 3). The transformation of 15 to ester
18, which corresponds to the C1-C13 fragment of disco-
dermolide, was achieved in five steps. The protection of the
hydroxy group at C8 as a TBS ether led to 17 in 84% yield.
After selective cleavage of the terminal double bond (OsO4/
NMO/NaIO4), the aldehyde was oxidized to the carboxylic
acid upon treatment with buffered NaClO2. The methyl ester
was produced by esterification of the acid (TMSCHN2,
MeOH, benzene, 65% yield) and selectively deprotected to
give alcohol 18 in 82% yield upon treatment with NH4F in
refluxing MeOH (Scheme 4).
Scheme 3 a
Scheme 4 a
a Key: (a) TBSOTf, 2,6-lutidine, -20 °C, 84%; (b) (i) OsO4,
NMO, NaIO4, acetone/H2O, 25 °C, (ii) NaClO2, NaH2PO4, H2O,
t-BuOH/H2O, (iii) TMSCHN2, MeOH, benzene, 65%; (c) NH4F,
MeOH, 65 °C, 82%.
a Key: (a) (R,R)-I, ether, -78 °C, 90%; (b) ClSitBuPh2,
imidazole, CH2Cl2, 93%; (c) OsO4/NMO/NaIO4, acetone/H2O, 89%;
(d) (S,S)-II, ether, -78 °C, 91%; (e) TBSOTf, 2,6-lutidine, -78
°C, 85%; (f) (i) OsO4/NMO/NaIO4, acetone/H2O, (ii) (R,R)-II, ether,
-78 °C, 78%; (g) (i) (COCI)2, DMSO, -78 °C, Et3N, CH2Cl2, (ii)
Dibal-H, toluene, -80 °C, 81%; (h) (i) TBAF, THF, 25 °C, 24 h,
(ii) ClSi-t-BuPh2, imidazole, CH2Cl2, (iii) DMP, acetone, CSA, 25
°C, 60%.
In conclusion, the synthesis of the fully elaborated
C1-C13 fragment of (+)-discodermolide, compound 8, was
completed by using high face selective chiral allyl- and
crotyltitanations. Progress toward the total synthesis of
(+)-discodermolide continues and will be reported in due
course.
Supporting Information Available: 1H NMR and 13C
NMR spectra for compounds 5, 10, 16, and 18. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL034958L
terminal double bond present in 13 was selectively oxidized
to the corresponding aldehyde (OsO4/NMO/NaIO4), which
was then treated directly with the (R,R)-II complex (ether,
-78 °C) to produce the homoallylic alcohol 14 in an overall
(12) Boger, D. L.; Curran, T. T. J. Org. Chem. 1992, 57, 2235.
(13) Rychnovsky, S. D.; Rogers, B. N.; Richardson, R. I. Acc. Chem.
Res. 1998, 31, 9.
(11) Andrus, M. B.; Lepore, S. D.; Sclafani, J. A. Tetrahedron Lett. 1997,
38, 4043.
Org. Lett., Vol. 5, No. 17, 2003
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