Total synthesis of potential antitumor agent, (-)-dictyostatin

Article abstract of DOI:10.1021/ol062737k

(Chemical Equation Presented) The potential antitumor agent (-)-dictyostatin has been synthesized utilizing Brown crotylboration to achieve eight of the eleven chiral centers. The yield for the 26-step longest sequence is ～4%. The C9-C10 coupling is achie

Full text of DOI:10.1021/ol062737k

ORGANIC
LETTERS
2007
Vol. 9, No. 1
157-160
Total Synthesis of Potential Antitumor
Agent, ( )-Dictyostatin
−
P. Veeraraghavan Ramachandran,* Amit Srivastava, and Debasis Hazra
Herbert C. Brown Center for Borane Research, Department of Chemistry,
Purdue UniVersity, 560 OVal DriVe, West Lafayette, Indiana 47907-2084
chandran@purdue.edu
Received November 8, 2006
ABSTRACT
The potential antitumor agent (
−)-dictyostatin has been synthesized utilizing Brown crotylboration to achieve eight of the eleven chiral centers.
The yield for the 26-step longest sequence is
∼
4%. The C9 C10 coupling is achieved via a stereoselective vinylzincate addition.
−
The clinically successful microtubule stabilizing cancer
chemotherapeutic agent paclitaxel (Taxol) suffers from
limitations, such as low solubility in water, multiple mech-
anisms of drug resistance, and toxicity.1 This has led to the
search for novel natural and synthetic mitotic spindle poisons.
Structurally related dictyostatin2 and discodermolide,3 iso-
lated from different species of marine sponges, are examples
of such molecules possessing cytotoxicity at low nanomolar
levels. Like epothilones,4 they do not bind to P-glycoprotein,
a principal mediator of taxane resistance.5
(-)-Dictyostatin (1) is a 22-membered macrolactone with
11 stereocenters, a Z-alkene, and two dienes,6 whereas (+)-
discodermolide is an open-chain carbamate with 13 stereo-
centers and a δ-lactone moiety. Paterson and Curran simul-
taneously reported the first two total syntheses of 1.7 A third
total synthesis, via a titanium-mediated silyloxy enyne
cyclization, has been recently published by Phillips.8 Curran
has also reported the synthesis and biological evaluation of
several analogues of 1.9
As part of our ongoing projects involving the synthesis
of medicinally important natural products via boranes,10 we
were interested in the synthesis of (-)-dictyostatin. Herein,
we report a borane-mediated convergent synthesis of 1. The
yield for the 26-step longest sequence, starting from methyl
(2S)-3-hydroxy-2-methylpropionate (Roche ester), is ∼4%.11
Figure 1 illustrates the retrosynthetic analysis. Eight of the
(7) (a) Paterson, I.; Britton, R.; Delgado, O.; Meyer, A.; Poullennec, K.
G. Angew. Chem., Int. Ed. 2004, 43, 4629. (b) Shin, Y.; Fournier, J.; Fukui,
Y.; Bruckner, A. M.; Curran, D. P. Angew. Chem., Int. Ed. 2004, 43, 4633.
(8) O’Neil, G. W.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 5340.
(9) (a) Shin, Y.; Choy, N.; Balachandran, R.; Madiraju, C.; Day, B. W.;
Curran, D. P. Org. Lett. 2002, 4, 4443. (b) Shin, Y.; Fournier, J.;
Balachandran, R.; Madiraju, C.; Raccor, B. S.; Zhu, G.; Edler, M. C.; Hamel,
E.; Day, B. W.; Curran, D. P. Org. Lett. 2005, 7, 2873. (c) Fukui, Y.;
Bruckner, A. M.; Shin, Y.; Balachandran, R.; Day, B. W.; Curran, D. P.
Org. Lett. 2006, 8, 301.
(1) Taxane Anticancer Agents; Georg, G. I., Chen, T. T., Ojima, I., Vyas,
D. M., Eds.; ACS Symposium Series 583, American Chemical Society:
Washington, D.C., 1995.
(2) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Boyd, M. R.; Schmidt, J. M.
J. Chem. Soc., Chem. Commun. 1994, 1111.
(3) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K.
J. Org. Chem. 1990, 55, 4912.
(4) Altmann, K.-H. In Medicinal Chemistry of BioactiVe Natural
Products; Liang, X.-T., Fang, W.-S., Eds.; John Wiley: New York, 2006;
Chapter 1.
(5) Madiraju, C.; Edler, M. C.; Hamel, E.; Raccor, B. S.; Balachandran,
R.; Zhu, G.; Giuliano, K. A.; Vogt, A.; Shin, Y.; Fournier, J.; Fukui, Y.;
Bruckner, A. M.; Curran, D. P.; Day, B. W. Biochemistry 2005, 44, 15033.
(6) Paterson, I.; Britton, R.; Delgado, O.; Wright, A. Chem. Commun.
2004, 632.
(10) (a) Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C.
Tetrahedron Lett. 2000, 41, 583. (b) Ramachandran, P. V.; Reddy, M. V.
R.; Yucel, A. J. J. Org. Chem. 2001, 66, 2512. (c) Ramachandran, P. V.;
Reddy, M. V. R.; Rearick, J. P.; Hoch, N. Org. Lett. 2001, 3, 19. (d)
Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C. J. Organomet. Chem.
2001, 624, 239. (e) Ramachandran, P. V.; Chandra, J. S.; Reddy, M. V. R.
J. Org. Chem. 2002, 67, 7547. (f) Ramachandran, P. V.; Prabhudas, B.;
Chandra, J. S.; Reddy, M. V. R. J. Org. Chem. 2004, 69, 6294. (g)
Ramachandran, P. V.; Chandra, J. S.; Prabhudas, B.; Pratihar, D.; Reddy,
M. V. R. Org. Biomol. Chem. 2005, 3, 3812.
10.1021/ol062737k CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/09/2006

Scheme 2. Synthesis of C11-C17 Subunit 3
Figure 1. Retrosynthetic analysis for the preparation of 1.
11 stereocenters were created via four pinane-mediated
crotylborations,12 and the Roche ester and Myers’ alkylation13
provided two more stereocenters. The three subunits were
assembled via Julia olefination14 and a substrate-controlled
vinylzincate addition, which provided the remaining stereo-
center.
The synthesis of 2 (Scheme 1) began with a pinane-based
E-crotylboration of 5 to provide the homoallylic alcohol 6
as a single diastereomer,15 which was protected as a TBS
ether and converted to the aldehyde 7. This was then con-
verted to the alkyne 8 by a Corey-Fuchs reaction16 and to
the boronic acid 9 via hydroboration with diisopinocampheyl-
borane, followed by elimination of R-pinene.17 Suzuki cou-
pling18 with the Z-vinyl iodide 1019 resulted in the diene ester
11.20 Selective deprotection of the TBS ether of the 1°-ol
and Des-Martin periodinane (DMP) oxidation provided 2.
The Roche ester was converted to aldehyde 12 in three
steps and 75% yield to initiate the preparation of sulfone 3
(Scheme 2). Crotylboration with (+)-B-(Z)-crotyldiisopino-
campheylborane,12 followed by protection of the 2°-ol as the
Scheme 1. Synthesis of C1-C9 Subunit 2
Scheme 3. Synthesis of C18-C23 Subunit 4
158
Org. Lett., Vol. 9, No. 1, 2007

Scheme 4. Assembly of Subunits of 1
TBS ether, gave 13. The olefin was converted to the aldehyde
diisopinocampheylborane,12 periodate cleavage, and reduction
sequences gave the 1,3-diol 17, which was converted to the
PMP acetal 18. Regioselective deprotection of the acetal and
reprotection of the 1°-ol as the benzyl ether provided 19.
Selective deprotection of the TBS ether of the 1°-ol at the
other end, followed by DMP oxidation, gave the aldehyde 4
(Scheme 3).
using a periodate cleavage and then converted to the iodide
14 via the alcohol. This was then transformed to the chiral
amide 15 using Myers’ protocol13 to stereoselectively intro-
duce the methyl group at the C-16 position of dictyostatin.
A similar sequence was utilized by Paterson and Curran also
in their total syntheses of 1.7 The amide was reduced to the
1°-ol using a lithium aminoborohydride reagent,13,21 and
finally, the subunit 3 was realized via a Mitsunobu reac-
tion22-oxidation sequence.
Aldehyde 16 was prepared from commercially available
ethyl glyoxylate via a pinane-based Z-crotylboration,12 reduc-
tion, TBS protection, and periodate cleavage sequences in
62% yield. A second crotylboration with (-)-B-(E)-crotyl-
With the three required subunits in hand, we focused on
their assembly (Scheme 4). Julia coupling14 of the sulfone 3
and aldehyde 4 provided the alkene 20. The hydrogenation
of the alkene and the benzyl ether was achieved at high
pressure (500 psi) at the expense of the PMB ether, which
was reintroduced using the same protocol as that for the
conversion from 17 to 19, and the resulting 1°-ol was
oxidized to the aldehyde. The terminal diene of 21 was
introduced via a standard protocol utilized in the synthesis
of discodermolide23 and the prior syntheses of 1.7 The TBS
ether of the 1°-ol was selectively removed, oxidized, and
treated with the Wittig salt to obtain the Z-vinyl iodide 22.
A lithium-halide exchange, followed by transmetalation
with dimethylzinc, provided the Z-vinylzincate,24 which was
added to 2 to provide, fortuitously, only the desired epimer
of 23. This was established by analyzing the 13C NMR
spectrum, as described by Rychnovsky.25 For this purpose,
23 was converted to the 1,3-diol and the acetonide using
TBAF and 2,2-dimethoxypropane/pTSA, respectively. The
tertiary carbon of the acetonide was observed at δ 100.51
ppm, and the methyl carbons were observed at δ 24.45 ppm
in the 13C spectrum. Selective deprotection of the TBS ether
(11) In comparison, Paterson’s synthesis of 1 involved 27 steps for the
longest linear sequence in 3.8% yield (ref 7a). Curran’s 34 steps afforded
1% yield (ref 7b), and the 26-step longest sequence by Phillips yielded
∼1% (ref 8).
(12) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293.
(13) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D.
J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(14) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett.
1991, 32, 1175.
(15) None of the peaks corresponding to the other diastereomers were
observed in the 1H NMR of the crude samples for all of the crotylboration
reactions during our synthesis. For crotylboration of chiral aldehydes, see:
Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1987, 52, 3701.
(16) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
(17) (a) Mikhailov, B. M.; Bubnov, Yu. N.; Kiselev, V. G. J. Gen. Chem.
USSR 1966, 36, 65. (b) Brown, H. C.; Jadhav, P. K.; Desai, M. C. J. Org.
Chem. 1982, 47, 4583. (c) Martinez-Fresneda, P.; Vaultier, M. Tetrahedron
Lett. 1989, 30, 2929. (d) Kamabuchi, A.; Moriya, T.; Miyaura, N.; Suzuki,
A. Synth. Commun. 1993, 23, 2851.
(18) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(19) Ma, S.; Lu, X.; Li, Z. J. Org. Chem. 1992, 57, 709.
(20) The diene ester 11 was prepared via a Negishi coupling also in
70% yield. 8 was treated with Schwartz’s reagent, followed by transmeta-
lation with ZnCl2, and coupled with 10 in the presence of (PPh3)4Pd. For
an update on Negishi coupling, see: Negishi, E.; Hu, Q.; Huang, Z.; Qian,
M.; Wang, G. Aldrichimica Acta 2005, 38, 71.
(21) For a review on recent advances in the chemistry of lithium
aminoborohydrides, see: Pasumansky, L.; Singaram, B.; Goralski, C. T.
Aldrichimica Acta 2005, 38, 61.
(22) Mitsunobu, O.; Wada, M.; Sano, T. J. Am. Chem. Soc. 1972, 94,
679.
(23) (a) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew.
Chem., Int. Ed. 2000, 39, 377. (b) Paterson, I.; Schlapbach, A. Synlett 1995,
498.
(24) Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198.
(25) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. L. Acc. Chem.
Res. 1998, 31, 9.
Org. Lett., Vol. 9, No. 1, 2007
159

at C7 was possible because it has a neighboring carbon with
an anti-methyl group, whereas the TBS ethers at C13 and
C19 have syn-methyl groups on adjacent carbons. We are
examining this reaction in detail to understand the stereo-
selectivity.
Conversion of 23 to 1 was achieved via the following
sequence of reactions: TBS protection, PMB deprotection,
hydrolysis, Yamaguchi macrolactonization,26 and global
deprotection of the TBS ethers.7b,27
simple. We are currently preparing analogues of 1 via
modified crotylborane reagents.28 We are also collaboratively
examining the folate-mediated delivery of 1.29
Acknowledgment. We thank the Herbert C. Brown
Center for Borane Research for financial support. We also
thank Prof. Dennis P. Curran (University of Pittsburgh) for
helpful discussions.
In summary, we have achieved a convergent synthesis of
naturally occurring (-)-dictyostatin. This protocol is ame-
nable to scale-up. The availability of both antipodes of
R-pinene makes the synthesis of diastereomers of 1 relatively
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL062737K
(26) Inanage, J.; Kuniko, H.; Hiroko, S.; Katsuki, T. J.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(28) For a review on pinane-based versatile “allyl” borane reagents,
see: Ramachandran, P. V. Aldrichimica Acta 2002, 35, 23.
1
(27) The H and 13C NMR of our sample (1.5 mg) matched with those
reported in the literature (refs 7 and 8).
(29) Hilgenbrink, A. R.; Low, P. S. J. Pharm. Sci. 2005, 94, 2.
160
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