Total synthesis of (-)-dictyostatin

Article abstract of DOI:10.1021/ja0609708

A convergent total synthesis of dictyostatin is described. Key features of the synthesis include the use of titanium-mediated cyclizations of (silyloxy)enynes for the synthesis of stereotriads, a subunit coupling by metathesis, and macrocyclization by int

Full text of DOI:10.1021/ja0609708

Published on Web 04/01/2006
Total Synthesis of (-)-Dictyostatin
Gregory W. O’Neil and Andrew J. Phillips*
Department of Chemistry and Biochemistry, UniVersity of Colorado, Boulder, Colorado 80309-0215
Received February 9, 2006; E-mail: andrew.phillips@colorado.edu
Dictyostatin (1, Figure 1) is a marine-derived macrolide that
inhibits the growth of a variety of cancer cell lines (including Taxol-
resistant lines) at low nanomolar levels by a mechanism involving
tubulin polymerization.1 First isolated in small amounts by Pettit,2
and more recently by Wright,1 dictyostatin’s structure is defined
by a 22-membered macrolactone punctuated by 11 stereocenters,
two dienes, and a cis-1,2-disubstituted olefin.3 Its significant
therapeutic potential and relationship to discodermolide has resulted
in syntheses from the groups of Paterson4 and Curran,5 and in this
communication, we describe our synthesis of dictyostatin.
To maximize convergency, our strategy called for the union of
three subunits of similar complexity (compounds 2, 3, and 4) by
olefin metathesis at C10-C11, olefination at C17-C18, and a late
stage macrocyclization by an intramolecular Still-Gennari-modified
Horner-Wadsworth-Emmons reaction (Figure 1). This plan was
further underpinned by our interest in evaluating the utility of our
Figure 1. Synthesis strategy.
Scheme 1a
recently described (silyloxy)enyne cyclization in the context of
complex polyketide synthesis.6
The synthesis of the C18-C26 subunit 4 is shown in Scheme 1
and commences with known alcohol 5.7 Silylation with (propynyl)-
diisopropylbromosilane, followed by reduction to the primary
alcohol (LiBH4, 78%), and finally protection as the PMB ether
(PMBOC(dNH)CCl3, 82%) gave 6. Using our previously reported
conditions,6 (silyloxy)enyne 6 was cyclized to siloxane 7 in 65%
yield. Desilylation and acylation with acryloyl chloride led to 8 in
95% yield. Ring-closing metathesis with Grubbs’ second generation
catalyst8 gave the expected lactone and was followed by in situ
reduction to the lactol, then Wittig olefination to produce diene 9
in 85% yield for the three steps. Conversion of 9 to â-ketophos-
phonate 4 was achieved by a five-step sequence of straightforward
transformations: (i) oxidation of the PMB ether to the PMP acetal
(DDQ, 75%, 9 f 10), (ii) acetal cleavage to the PMB ether, (iii)
oxidation of the primary alcohol with Dess-Martin periodinane,
(iv) reaction with lithiodimethylphosphonate, and (v) oxidation with
Dess-Martin periodinane (60% from 10).
a Reagents and conditions: (1) (a) (propynyl)diisopropylbromosilane,
imidazole, DMF, 97%, (b) LiBH4, THF, 78%, (c) PMBOC(dNH)CCl3,
CSA, CH2Cl2, 82%; (2) ClTi(i-PrO)3, i-PrMgCl, 65%; (3) TBAF, DMF
then H2CdCHCOCl, i-Pr2NEt, CH2Cl2, 95%; (4) (a) 5 mol % of Grubbs
II, PhH, 60 °C then cool to -78 °C, DIBAL-H, (b) Ph3PCH3I, n-BuLi,
THF, 85% (from 8); (5) DDQ, CH2Cl2, 4 Å MS, 75%; (6) (a) DIBAL-H,
CH2Cl2, (b) Dess-Martin periodinane, CH2Cl2, (c) (MeO)2P(O)Me, n-BuLi,
THF, (d) Dess-Martin periodinane, CH2Cl2, 60% (from 10). Xc ) (R)-
benzyloxazolidinone.
The synthesis of 2 commenced with silylation of alcohol 119
with (ethynyl)diisopropylbromosilane to give 12 in 95% yield
(Scheme 2). Reductive (silyloxy)enyne cyclization with ClTi(i-
PrO)3-i-PrMgCl produced 13 in 73% yield and was followed by
removal of the siloxane to give 2 in 95% yield. Acylation of the
secondary alcohol with acid 310 under Yamaguchi11 conditions
yielded 14 (90%) and set the stage for the formation of the ∆10,11
olefin by ring-closing metathesis.12 Gratifyingly, treatment of a
toluene solution of 14 under reflux with a total of 15 mol % of
Grubbs’ second generation catalyst (in 5 mol % batches at 6 h
intervals) provided lactone 15 in 76% yield.
In advance of the introduction of the C18-C26 subunit, lactone
15 was converted to 16 in 73% yield by reduction to the hydroxy
aldehyde with DIBAL-H and olefination with (carboethoxy) meth-
ylenetriphenylphosphorane. Further reduction to the allylic alcohol,
diol silylation with TBSOTf, removal of the PMB ether (DDQ,
aqueous buffer), and finally oxidation with Dess-Martin periodi-
nane provided delicate aldehyde 17 (60% yield from 16). Reaction
with â-ketophosphonate 4 in the presence of Ba(OH)2 in aqueous
THF13 resulted in the smooth union of these two key fragments to
give enone 18 in 77% yield. After conjugate reduction of the C17-
C18 double bond with Stryker’s reagent14 and removal of the PMB
ether, 1-3-syn-reduction15 (Zn(BH4)2, dr > 20:1) provided diol 19
in 88% yield. Selective silylation of the C19 alcohol (TBSOTf,
89%), followed by acylation of the C21 alcohol under Yamaguchi
conditions11 gave phosphonate 20 in 93% yield. Careful removal
of the TBS ether from the allylic alcohol with aqueous acetic acid
(78%), followed by oxidation to the enal with Dess-Martin
periodinane provided the substrate for macrocyclization by an
intramolecular Still-Gennari-modified Horner-Wadsworth-Em-
mons reaction.16,17 To our delight, treatment with potassium
9
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J. AM. CHEM. SOC. 2006, 128, 5340-5341
10.1021/ja0609708 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2a
a Reagents and conditions: (1) (ethynyl)diisopropylbromosilane, imidazole, DMF, 95%; (2) ClTi(i-PrO)3, i-PrMgCl, 73%; (3) TBAF, DMF, 65 °C, 95%;
(4) 3, 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, PhMe, 90%; (5) 15 mol % of Grubbs II, PhMe, 110 °C, 76%; (6) DIBAL-H, CH2Cl2 then Ph3PCHCO2Et,
73%; (7) (a) DIBAL-H then TBSOTf, 2,6-lutidine, (b) DDQ, CH2Cl2, pH ) 7 buffer, (c) Dess-Martin periodinane, CH2Cl2 (60% from 16); (8) 4, Ba(OH)2,
THF-H2O, 80%; (9) (a) [Ph3P‚CuH]6, PhH, (b) DDQ, CH2Cl2-H2O, 0 °C, (82% over 2 steps), (c) Zn(BH4)2, Et2O, 88%; (10) (a) TBSOTf, CH2Cl2,
2,6-lutidine, 89%, (b) (CF3CH2O)2P(O)CH2CO2H, 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, PhMe, 93%; (11) (a) AcOH-THF-H2O, 78%, (b) Dess-
Martin periodinane, CH2Cl2, (c) K2CO3, 18-C-6, PhMe, rt, 85% (2 steps, 74% of desired diastereoisomer); (12) HF‚pyridine, THF, 40 h, 67%.
(4) Paterson, I.; Britton, R.; Delgado, O.; Meyer, A.; Poullennec, K. G. Angew.
carbonate and 18-crown-6 in toluene at room temperature resulted
in clean cyclization to form 21 in excellent yield and with good
Chem., Int. Ed. 2004, 43, 4629.
(5) Shin, Y.; Fournier, J.-H.; Fukui, Y.; Bruckner, A. M.; Curran, D. P. Angew.
diastereoselectivity (6.5:1 Z:E to E:E, 74% of desired over two
steps). Removal of the four TBS ethers with HF‚pyridine, followed
by chromatography, produced (-)-dictyostatin in 67% yield.
Synthetic dictyostatin was identical in all respects with physical
and spectroscopic data provided for the natural product.18
In summary, a convergent synthesis of (-)-dictyostatin has been
achieved in 26 steps via 11. As well as providing an avenue for
the preparation of larger amounts of the natural product, the
synthesis also offers an evaluation of the use of (silyloxy)enyne
cyclizations for the synthesis of syn-anti stereotriads in the context
of complex polyketide synthesis.
Chem., Int. Ed. 2004, 43, 4634.
(6) O’Neil, G. W.; Phillips, A. J. Tetrahedron Lett. 2004, 45, 4253.
(7) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem.
2001, 66, 894.
(8) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(9) Synthesized by a route analogous to that described in ref 6.
(10) For the synthesis of acid 3, see the Supporting Information.
(11) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989.
(12) Curran has recently described the cyclization of substrates related to 15
by RCM. See: Kangani, C. O.; Bruckner, A. M.; Curran, D. P. Org. Lett.
2005, 7, 379.
(13) (a) Sinisterra, J. V.; Mouloungui, Z.; Delmas, M.; Gaset, A. Synthesis
1985, 1097. (b) Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993,
774.
(14) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem. Soc.
1988, 110, 291.
(15) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338.
Acknowledgment. We thank Professor Dennis Curran for
copies of spectra for intermediates in their synthesis. Financial
support was provided by the NCI (CA110246).
(16) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
Supporting Information Available: Data and spectra for com-
pounds 1, 3-21. This material is available free of charge via the Internet
at http://pubs.acs.org.
(17) For other recent examples of macrolide synthesis by Z-selective intramo-
lecular Still-Gennari-modified Horner-Wadsworth-Emmons reaction,
see: (a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem.
Soc. 1998, 120, 5597. (b) Smith, A. B.; Verhoest, P. R.; Minbiole, K. P.;
Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942. (c) Williams, D. R.;
Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M. A.; Reeves, J. T.
Angew. Chem., Int. Ed. 2003, 42, 1258. (d) Gonza´lez, M. A.; Pattenden,
G. Angew. Chem., Int. Ed. 2003, 42, 1255. (e) Ghosh, A. K.; Wang, Y.
J. Am. Chem. Soc. 2000, 122, 11027.
References
(1) Isbrucker, R. A.; Cummins, J.; Pomponi, S. A.; Longley, R. E.; Wright,
A. E. Biochem. Pharmacol. 2003, 66, 75.
(2) (a) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Boyd, M. R.; Schmidt, J. M. J.
Chem. Soc., Chem. Commun. 1994, 1111. (b) Pettit, G. R.; Cichacz, Z.
A. WO 5430053, 1995; Chem. Abstr. 1995, 733500.
(3) Stereochemical assignment: Paterson, I.; Britton, R.; Delgado, O.; Wright,
A. E. Chem. Commun. 2004, 632.
(18) Synthetic [R]D ) -22.0 (c 0.05, MeOH); natural [R]D ) -20.0 (c 0.16,
MeOH).2 HRMS calculated for C32H52O6H+ 533.3836, found 533.3831.
For a comparison of NMR data, see the Supporting Information.
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