Formal synthesis of (+)-discodermolide.

Article abstract of DOI:10.1021/ol034186t

[structure: see text] Herein we report the formal total synthesis of (+)-discodermolide in 21 steps (longest linear sequence) from commercially available Roche ester. This synthesis features the assembly of C(9-18) and C(19-24) fragments via a metal-chelated aldol coupling reaction.

Full text of DOI:10.1021/ol034186t

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1233-1236
Formal Synthesis of (+)-Discodermolide
Charles Francavilla, Weichun Chen, and Frederick R. Kinder, Jr.*
NoVartis Pharmaceuticals Corporation, Oncology Research, 556 Morris AVenue,
Summit, New Jersey 07901
frederick.kinder@pharma.noVartis.com
Received February 3, 2003
ABSTRACT
Herein we report the formal total synthesis of (+)-discodermolide in 21 steps (longest linear sequence) from commercially available Roche
ester. This synthesis features the assembly of C9-18 and C19-24 fragments via a metal-chelated aldol coupling reaction.
(+)-Discodermolide (1) is a potent microtubule stabilizing
agent isolated from the Caribbean sponge Discodermia
dissoluta.1 Discodermolide is a potent inhibitor of tumor cell
growth in vitro and is not cross-resistant with paclitaxel or
epothilone-resistant cells.2 Discodermolide also demonstrates
significant human tumor growth inhibition in hollow fiber
and xenograft mouse models (including paclitaxel-resistant
tumors).3 Discodermolide is currently undergoing Phase 1
clinical trials. Drug supply needs have been met using total
synthesis.4 To address the drug supply needs of advanced
clinical trials, further synthesis refinements are necessary.
Herein we describe a hybrid of several reported syntheses
that features a novel assembly of C9-18 and C19-24 fragments
via a metal-chelated aldol coupling reaction.5
Scheme 1
(1) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K.
J. Org. Chem. 1990, 55, 4912. Additions and corrections: Gunasekera, S.
P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K. J. Org. Chem. 1991,
56, 1346.
(2) (a) Jordan, M. A. Curr. Med. Chem.: Anti-Cancer Agents 2002, 2, 1.
(b) Altmann, K. H. Curr. Opin. Chem. Chem. Biol. 2001, 5, 424. (c) He,
L. F.; Orr, G. A.; Horwitz, S. B. Drug DiscoVery Today 2001, 6, 1153. (d)
He, L.; Chia-Ping, H. Y.; Horwitz, S. B. Mol. Cancer Ther. 2001, 1, 3. (e)
Kowalsky, R. J.; Giannakakou, P.; Gunasekera, S. P.; Longley, R. E.; Day,
B. W.; Hamel, E. Mol. Pharmacol. 1997, 52, 613.
(3) Kinder, F. R., Jr.; Bair, K. W.; Chen, W.; Florence, G.; Francavilla,
C.; Geng, P.; Gunasekera, S.; Guo, Q.; Lassota, P. T.; Longley, R. E.;
Palermo, M. G.; Paterson, I.; Pomponi, S.; Ramsey, T. M.; Rogers, L.;
Sabio, M.; Sereinig, N.; Sorensen, E.; Wang, R. M.; Wright, A. Abstracts
of Papers, 224th National Meeting of the American Chemical Society,
Boston, MA, August 18-22, 2002; American Chemical Society: Wash-
ington, DC, 2002; MEDI-236.
(4) Detailed account of the synthesis of the Phase 1 batch of discoder-
molide by the Novartis Pharma Chemical and Analytical Development group
will be reported elsewhere.
Key synthesis disconnections as outlined in the retrosyn-
thetic analysis of 1 (Scheme 1) include formation of the bond
(5) For a review, see: Kaleese, M. ChemBioChem 2000, 1, 171.
10.1021/ol034186t CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/21/2003

onate,7 was subjected to a one-pot combination8 of Nozaki-
Hiyama9 and Peterson-type syn elimination10 reactions, which
gave only the (Z)-diene 8. This was followed by deprotection
to provide alcohol 9 and a Dess-Martin oxidation11 to give
5.
Scheme 2a
Aldehyde 6 (Scheme 3), obtained from methyl (S)-3-
hydroxy-2-methylpropionate, was subjected to crotyl-bora-
tion12 to give 11 (via Roush chiral auxiliary13 10). Silylation
of the alcohol 11 and oxidative cleavage of the alkene 12
provided aldehyde 13. Utilizing the chemistry developed by
Zhao and co-workers,14 13 and an R-iodoalkyl ylide gave
the 2-iodo-2-alkene 14. The high Z:E ratio was attributed to
the removal of the iodo-betaine intermediate, which would
ultimately form the (E)-olefin, through formation of an
epoxide via a Darzan reaction.15 A Negishi cross-coupling
of the Riecke organozinc compound16 and 14 gave the methyl
ester 15.
Originally, the ethyl ketone 4 was synthesized in a two-
step procedure by formation of the Weinreb amide17 16,
followed by nucleophilic attack by EtMgBr. Later, it was
found that this two-step procedure could be easily done in
one pot18 using 6-10 equiv of EtMgBr and N,O-dimethyl-
hydroxylamine hydrochloride.
a Reaction conditions: (a) CrCl2, (1-bromo-2-propenyl)trimeth-
ylsilane, THF, 0 °C f rt, 18 h; then 6 M KOH, methanol, 25 °C,
1 h, 57%. (b) DDQ, water, rt, 1 h, 81%. (c) Dess-Martin
periodinane, DCM, rt, 4 h, 73%.
at C6-7 via chiral boron-mediated aldol reaction with the
corresponding aldehyde prepared from 2 and ketone 3 as
described by Paterson.6 Intermediate 2 was prepared by
elaboration of the metal-chelated aldol (vide infra) product
from ketone 4 and aldehyde 5. Both intermediates 3 and 4
were prepared from aldehyde 6 via common stereotriad
intermediate 13 (see Scheme 3). The remarkably stable
aldehyde 5 was prepared in three steps from aldehyde 7.
Scheme 3a
Scheme 4a
a Reaction conditions: (a) 10, toluene, 4 Å molecular sieves,
-78 °C, 18 h. (b) TBSOTf, 2,6-lutidine, THF, 0 °C, 1.5 h, 95%.
(c) (i) MNO, OsO4, acetone, t-BuOH, water, rt, 18 h; (ii) NaIO4,
water, THF, rt, 2 h, 71%. (d) Ph3PEtI, BuLi, 0 °C, 10 min; then
0.1 M I2 in THF, -78 °C, 15 min; then NaHMDS, THF, -23 °C,
10 min; then 13, -33 °C, 30 min, 36%. (e) (R)-(+)-3-Methoxy-
2-methyl-3-oxopropylzinc bromide, Pd(PPh3)4, THF, rt, 18 h, 87%.
(f) N,O-Dimethylhydroxylamine hydrochloride, toluene, 2.0 M
AlMe3 in hexanes, 0 °C, 30 min; then 15 in toluene, 80 °C, 2 h,
91%. (g) EtMgBr, THF, 0 °C, 1 h, 75%. (h) N,O-Dimethylhy-
droxylamine hydrochloride, EtMgBr, THF, -10 °C f rt, 2 h, 90%.
a Reaction conditions: (a) LDA, THF, -78 °C, 2 h; then 5, -78
f -19 °C, 19 h, 77% (based on 73% recovered starting material).
(b) DIBAL-H, THF, -100 °C, 4 h, 88%. (c) 2,2-Dimethoxypropane,
CSA, rt, 5 h, 69%.
An aldol coupling with ethyl ketone 4 (Scheme 4) and
aldehyde 5 formed a lithium-chelated six-membered ring
intermediate to give the undesired stereochemistry in 17. The
(6) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J.
Am. Chem. Soc. 2001, 123, 9535.
(7) Smith, A. B., III; Qiu, Y.; Kaufman, M.; Arimoto, H.; Jones, D. R.;
Kobayashi, K. U.S. Patent 6 031 133, 2000.
Aldehyde 7 (Scheme 2), which was obtained from a three-
step procedure from methyl (R)-3-hydroxy-2-methylpropi-
1234
Org. Lett., Vol. 5, No. 8, 2003

opposite stereogenic center at C18 was suspected due to the
sluggishness of the aldol reaction, which required an unusu-
ally high temperature and long reaction time. We speculate
that equilibration of the (Z)-enolate to the (E)-enolate would
give the anti-configuration. To investigate, we performed
reactions that would help identify which stereocenters were
obtained at C18 and C19 for compound 17.
Scheme 6a
To determine if the anti-relationship was present, the acetal
19 was synthesized (Scheme 4). Through a C19-hydroxy-
directed reduction, the carbonyl was stereoselectively reduced
to diol 18. The acetal was formed by treatment of the diol
with 2,2-dimethoxypropane and CSA.
The suspected relationship was determined upon measure-
ment of the coupling constants as well as performing a NOE
experiment. One methyl of the acetal had a NOE with the
C17 hydrogen, C19 hydrogen, and C18 methyl hydrogens.
Additionally, the other acetal methyl had a NOE with the
C18 hydrogen.
To determine the absolute stereochemistry, both (R)- and
(S)-Mosher esters19 were synthesized (Scheme 5). Subtraction
of the chemical shifts for each 1H NMR signal in compound
20 from that of compound 21 gave a value for each in hertz.
These values provided evidence to deduce the stereochem-
istry of compound 17.
Scheme 5a
a Reaction conditions: (a) LDA, THF, -78 °C, 1.5 h; then
MgBr2, 5, -78°C, 18 h, 35% (based on 74% recovered starting
material). (b) Trichloroacetyl isocyanate, DCM, rt, 1 h; then neutral
alumina, rt, 4 h, 93%. (c) Li(t-BuO)3AlH, THF, -78 °C, 1 h, 91%.
(d) 2,6-lutidine, TBSOTf, DCM, rt, 1 h, 93%. (e) DDQ, water,
DCM, rt, 1 h, 92%. (f) TEMPO, BAIB, rt, 2 h, 97%. (g)
(CF3CH2O)2P(O)CH2C(O)OCH3, K2CO3, 18-crown-6, -20 °C f
0 °C, 2 h, 83%.
rate and hindered the equilibration to the (E)-enolate.
Analysis of the new diastereomer by synthesis of the (R)-
and (S)-Mosher esters and the acetal derivatives showed that
the desired stereochemistry was obtained.
a Reaction conditions: (a) (R)-(-)-R-Methoxy-R-(trifluorometh-
yl)phenylacetyl chloride, DMAP, pyridine, DCM, rt, 24 h, 86%.
(b) (S)-(-)-R-Methoxy-R-(trifluoromethyl)phenylacetyl chloride,
DMAP, pyridine, DCM, rt, 24 h, 86%.
The reason for the significant amount of recovered starting
material was most likely due to the presence of water in the
aldehyde. This was seen in the NMR spectrum of 5. In
addition, we observed that an increase in the number of
equivalents of 5 resulted in increased recovery of starting
material (4). The diastereoselectivity of this reaction was 11:
1:0:0, albeit in low overall yield.
The alcohol 22 was converted to the carbamate 23. Using
the carbamate as a directing group20 allowed stereoselective
reduction of the carbonyl to the corresponding alcohol 24
An aldol coupling, using magnesium as the chelation metal
(Scheme 6), proved to be effective at increasing the reaction
(8) Paterson, I.; Schlapbach, A. Synlett 1995, 498.
(9) Cintas, P. Synthesis 1992, 248.
(10) Hudrlik, P. F.; Peterson, D. J. Am. Chem. Soc. 1975, 97, 1464.
(11) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(12) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990,
112, 6348.
(13) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339.
(14) Chen, J.; Wnag, T.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827.
(15) Arimoto, H.; Kaufman, M. D.; Kobayashi, K.; Qiu, Y.; Smith, A.
B., III. Synlett 1998, 765.
(16) Available through Aldrich, catalog no. 49,949-8.
(17) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(18) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
(19) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092. (b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc.
1973, 95, 512. (c) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem.
1973, 38, 2143.
(20) Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc.
1996, 118, 11054.
Org. Lett., Vol. 5, No. 8, 2003
1235

to carboxylic acid 28, followed by an amide coupling reaction
to obtain the corresponding Weinreb amide 29. The conver-
sion of 29 to 3 has been reported.23 Completion of the total
synthesis of 1 using intermediates 2 and 3 has been reported
elsewhere.3,4,23
Scheme 7a
In conclusion, we have described a 21-step linear synthesis
(34 total steps) of discodermolide that features a magnesium-
chelated aldol coupling reaction of two major fragments to
establish the carbon-carbon bond at C18-19. Furthermore,
key components of several previously published discoder-
molide syntheses were utilized in the present synthesis.6,20,24-26
a Reaction conditions: (a) NaClO2, NaH2PO4, t-BuOH, 2,3-
dimethyl-2-butene, rt, 1 h, 91%. (b) 2-Chloro-4,6-dimethoxy-1,3,5-
triazine, NMM, THF, 0 °C, 1 h; then N,O-dimethylhydroxylamine
hydrochloride, NMM, 0 °C f rt, 19 h, 87%.
Supporting Information Available: Experimental pro-
cedures and spectral data for the preparation of all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
to be accomplished with a 30:1 selectivity. The C17 alcohol
was silylated to provide 25. Subsequent oxidative deprotec-
tion of the C7 alcohol provided 26. Alcohol 26 was oxidized21
to aldehyde 27, followed by Still-Gennari olefination22 to
give the (Z)-olefin 2.
OL034186T
(23) Process for preparing discodermolide and analogues thereof.
Kinder, F. R. (Novartis A.-G., Switz.; Novartis-Erfindungen Verwaltungs-
gesellschaft m.b.H.). PCT Int. Appl. 22 pp. CODEN: PIXXD2 WO 0212220
A2 20020214, 2002.
(24) Smith, A. B., III; Beauchamp, T. J.; LaMarche, M. J.; Kaufman,
M. D.; Qui, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem.
Soc. 2000, 122, 8654.
To complete the synthesis of 1, ketone 3 was prepared
from aldehyde 13 (Scheme 7). Aldehyde 13 was oxidized
(21) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974.
(22) Still, W. C.; Gennari, C. Tetrahedron 1983, 24, 4405.
(25) Filla, S. A.; Song, J. J.; Chen, L.; Masamune, S. Tetrahedron Lett.
1999, 40, 5449.
(26) Yang, G.; Myles, D. C. Tetrahedron Lett. 1994, 35, 2503.
1236
Org. Lett., Vol. 5, No. 8, 2003