Synthesis of the C(17)-C(27) fragment of the 20-deoxybryostatins

Article abstract of DOI:10.1016/S0040-4039(00)01697-X

A synthesis of the C(17)-C(27) fragment of the 20-deoxybryostatins is described in which the key step is a palladium(0) catalysed coupling of a tributyltin enolate with a vinylic bromide. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01697-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9565–9568
Synthesis of the C(17)–C(27) fragment of the
20-deoxybryostatins
Pedro Almendros, Alastair Rae and Eric J. Thomas*
Department of Chemistry, The University of Manchester, Manchester M13 9PL, UK
Received 11 September 2000; revised 19 September 2000; accepted 21 September 2000
Abstract
A synthesis of the C(17)–C(27) fragment of the 20-deoxybryostatins is described in which the key step
is a palladium(0) catalysed coupling of a tributyltin enolate with a vinylic bromide. © 2000 Elsevier
Science Ltd. All rights reserved.
The bryostatins are a group of complex marine macrolides isolated from Bugula neritina
(Linaeus) which exhibit anti-tumour activity against the murine P388 lymphocytic leukemia and
which are presently undergoing both phase I and phase II clinical trials.1 The synthesis of the
bryostatins is of considerable interest at present because of their biological activities and limited
availability from natural sources. As well as many partial syntheses,2 total syntheses of
bryostatin 7 and 2, 1 and 2, were first described by Masamune3 and Evans4 and biologically
active macrocyclic analogues have been prepared by Wender.5 No total synthesis of a 20-deoxy-
bryostatin, e.g. bryostatin 11 3, has been published to date although two approaches to the
C(17)–C(27) fragment of bryostatin 11 have been reported.6
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01697-X

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We here describe a stereoselective synthesis of the protected hydroxyketone 4 which is
synthetically equivalent to the C(17)–C(27) fragment of bryostatin 11.7 Our synthesis is based on
the stereospecific palladium(0) catalysed coupling of a tributyltin enolate with the vinylic
bromide 14, a reaction first reported by Migita and coworkers.8,9
The synthesis of the vinylic bromide 14 is outlined in Scheme 1. The tert-butyldimethylsilyl
ether 6 of (E)-pent-3-enol was prepared from the methyl ester 4 by reduction and protection.
Asymmetric hydroxylation using ADmix-b gave the vicinal diol 7,10 estimated to have an ee of
85 ( 5)%,11 which was protected as its acetonide, desilylated and oxidized to give the aldehyde
8. Chelation controlled addition of allenylzinc bromide gave the (4S)-alcohol 9 together with its
4-epimer, ratio 80:20. The configuration assigned to the alcohol 9 is consistent with literature
1
examples3 and was confirmed by comparison of the H NMR spectra of its acetyl mandelates.12
After chromatographic separation, the alcohol 9 was protected as its p-methoxybenzyl ether 10
which was taken through to the methyl ester 11 by alkyne deprotonation and acylation using
methyl chloroformate. Stereoselective conjugate addition of a tri-n-butyltin cuprate13 gave the
(E)-ab-unsaturated ester 12, which was reduced and protected to give the tert-butyldiphenylsilyl
ether 13. Treatment with freshly recrystallized N-bromosuccinimide gave the vinylic bromide 14.
Scheme 1. Reagents and conditions: (i) DIBAL-H, −78–20°C (80%); (ii) t-BuMe2SiCl, imid. (90%); (iii) ADmix-b, 0°C
(81%; 85% ee); (iv) 2,2-dimethoxypropane, PPTS (97%); (v) TBAF (80%); (vi) DMSO, (COCl)2, then 4 equiv. Et3N,
−78°C (95%); (vii) HCCCH2Br, zinc (50%); (viii) NaH, PMBCl; (ix) n-BuLi, MeO2CCl (61% from 9); (x) (Bu3Sn)2,
n-BuLi, CuBr·DMS (68%); (xi) DIBAL-H, −78–20°C; (xii) t-BuPh2SiCl, imid. (77% from 12); (xiii) NBS (93%)
The enol acetate 16 was prepared from the ketone 159 by treatment with lithium hexamethyl-
disilazide and acetic anhydride. Coupling the vinylic bromide 14 with the enol acetate was
accomplished by heating in a degassed solution in toluene in the presence of tributyltin
methoxide and freshly prepared PdCl2(o-tolyl3P)2 at 100°C for 1 h to give the bg-unsaturated
ketone 4 in 73% yield free from any of its geometrical isomer (1H NMR14). The structure of the
product 4 was assigned on the basis of spectroscopic data and by analogy with previous work.

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Scheme 2. Reagents and conditions: (i) LiN(SiMe3)2, LiCl, Ac2O, −78°C (65%); (ii) 14, Pd(o-tolyl3P)2Cl2, Bu3SnOMe,
PhCH3, 100°C (73%)
In particular, the trisubstituted double-bond was shown to have retained its geometry and not
to have migrated into conjugation with the ketone (Scheme 2).9,14
Ketone 4 corresponds to the C(17)–C(27) fragment of a 20-deoxybryostatin, e.g. 3. Further
elaboration for incorporation into a synthesis of a bryostatin would include protection of the
ketone, perhaps as a cyclic acetal, and oxidation of the sulfide to a sulfone for coupling with a
C(16)-aldehyde, e.g. via a Julia coupling. As preliminary studies for this work, the sulfide 4 was
oxidized to the sulfone 17, deprotected to give the alcohol 18 and reduced to the epimeric
mixture of alcohols 19 which were protected as their triethylsilyl ethers 20. Present work is
concerned with the conversion of these intermediates into a cyclic acetal and incorporation into
a synthesis of a bryostatin (Scheme 3).
Scheme 3. Reagents and conditions: (i) MCPBA (74%); (ii) DDQ (54%); (iii) lithium triethylborohydride (50:50; 75%);
(iv) Et3SiOTf, Et3N (75%)
Acknowledgements
We thank the EU for a fellowship (to P.A.) and Elsevier Science for support (for A.R.).
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1
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.