A second generation pyranose-based approach to the F ring (C38-C45) of altohyrtin A

Article abstract of DOI:10.1016/S0957-4166(99)00011-7

A second generation approach to the F ring, fragment C38-C45, of altohyrtin A (1) is described herein. The C43-C44 C-glycosidic linkage was prepared and subsequently functionalised with a thioketal moiety.

Full text of DOI:10.1016/S0957-4166(99)00011-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 217–219
A second generation pyranose-based approach to the F ring
(C38–C45) of altohyrtin A
Pierre D. Kary and Stanley M. Roberts ∗
Department of Chemistry, Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, UK
Received 19 November 1998; accepted 7 January 1999
Abstract
A second generation approach to the F ring, fragment C38–C45, of altohyrtin A (1) is described herein. The
C43–C44 C-glycosidic linkage was prepared and subsequently functionalised with a thioketal moiety. © 1999
Elsevier Science Ltd. All rights reserved.
Altohyrtin A 1 (spongistatin 1), isolated from the marine sponge Hyrtios altum, has been shown to
display potent cytotoxic activity against a variety of human cancer cell lines.1 The recent synthetic
interest2 is testament to its appeal. In a recent report,3 we described the first pyranose-based approach
to the F ring (C38–C43) of altohyrtin A 1. This strategy aimed to create the β-C-glycoside at C44 by
utilising a Horner–Emmons coupling to the lactol 3 (Scheme 1).4
Scheme 1.
∗
Corresponding author.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00011-7

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P. D. Kary, S. M. Roberts / Tetrahedron: Asymmetry 10 (1999) 217–219
We describe a second generation approach with a disconnection which creates a C38–C45 fragment 4
and allows for more facile homologation of the exocyclic diene chain.
The epoxy alcohol 6 was protected as its benzyl ether 7 (Scheme 2) under standard conditions. The
epoxide was opened using the lower order cuprate (CH3)2CuMgI, providing 8 in 73% yield. After
benzylation to furnish 9, attempts were made to hydrolyse the 1,6-anhydrobridge under the conditions
developed in our labs previously.3
Scheme 2. Reagents and conditions: (i) THF, DMF, NaH, BnBr, tetrabutylammonium iodide, 0°C to rt, 3.5 h, 80%; (ii) THF,
CuI, CH3MgCl, 2 h, −42°C, rt, 14 h, 73%; (iii) as (i), 16 h, 83%; (iv) Ac2O, −78°C, TES-OTf, −78°C to −5°C, 30 min, 83%
However, the acetal group of compound 9 was stable to acetic anhydride and triethylsilyl triflate until
the temperature of the reaction was raised to −5°C. At this temperature, the 2-O-benzyl ether, which is
thought to have stabilised the 1,6-acetal, was concomitantly hydrolysed along with the 1,5-acetal ring
to yield the triester 10. This observation is consistent with that of Wong who reported the hydrolysis
of a primary benzyl ether under similar conditions (trimethylallylsilane, TMS-OTf).5 These acetolysis
conditions conveniently provided the required differential protection of the C40 and C41 hydroxyl
groups. Differential protection of these alcohols is of critical importance for later stage couplings to
C1 of althohyrtin A and was attained with much greater difficulty in our previous efforts.3
The triester 10 was treated with allyltrimethylsilane and BF3·OEt2 at 0°C for 41 h to yield the allyl
α-C-glycoside 12 (Scheme 3) in high yield.6 Ozonolysis of the olefin in sodium methoxide7 provided the
ester 13 as a 7:4 mixture favouring the α-anomer. After protective group manipulation to give compound
14 and subsequent functional group interchange, the thioketal 15 was isolated in 12% overall yield from
compound 10.
Studies investigating the further elaboration of compound 15 will be reported in due course.
Acknowledgements
We wish to thank BBSRC for a ROPA award to PDK. We also wish to thank Professor S. V. Ley for
fruitful discussions.
References
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P. D. Kary, S. M. Roberts / Tetrahedron: Asymmetry 10 (1999) 217–219
219
Scheme 3. Reagents and conditions: (i) allyl-TMS, BF3·OEt2, CH3CN, 0°C, 41 h, 90% yield; (ii) DCM, −78°C, 2.5 M NaOMe,
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