Synthesis of the C1–C15 fragment of elaiolide

Abstract

The synthesis of the C1–C15 fragment of elaiolide was achieved by successfully utilizing the desymmetrization strategy, zirconium catalyzed C–C bond formation and double stereodifferentiating aldol reactions.

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Elaiophylin (1), a glycosidic polyketide, was first isolated from the cultures of Streptomyces melanosporus by Arcamone et al.^1a and by Arai^1b from a related microorganism. Elaiophylin is a 16-membered macrolide which displays a wide range of bioactivities such as antimicrobial, cell cycle inhibition, apoptosis induction, immunosuppressive, anthelmintic, inhibition of K⁺-dependent adenosine triphosphatases, and plant growth inhibition.^2–4 The C2-symmetric structure of 1 including its absolute configuration was ascertained by chemical degradation,⁵ spectroscopic methods⁶ and X-ray crystallographic analysis.⁷ An impressive biological activity profile, structural intricacy, and the presence of acid and base sensitive hemiketal units enticed the synthetic community to attempt its total synthesis. Following the report on the synthesis of the tetramethyl derivative of elaiolide by Seebach and co-workers^8a and the first total synthesis of elaiophylin in 1986 by Kinoshita and co-workers,^8b notable synthetic studies have been carried out by several groups.^8c–m

As part of our ongoing programme to synthesize natural products comprised of polyketide units by a desymmetrization strategy,⁹ we aspired to demonstrate its versatility by synthesizing the C1–C15 unit 3 of elaiolide (1a), which is an aglycon of elaiophylin (1) (Fig. 1).

Fig. 1 Structure of elaiophylin and elaiolide.

Our retrosynthetic analysis of elaiolide 1a, as illustrated in Scheme 1, suggests a monomeric unit 2 that further led to the protecting group translocated tautomeric aldol adduct 3, which was anticipated to be derived from keto ester 4 and aldehyde 6, whose origins can be traced back to lactone 5¹⁰ and D-mannitol, respectively, with the former being synthesized earlier by us following the desymmetrization strategy developed in our laboratory.

Scheme 1 Retrosynthetic analysis.

Results and discussion

The synthesis of keto ester 3 started with the known Prelog-Djerassi type lactone 5,¹⁰ which on treatment with AlMe₃OMeNHMe·HCl at room temperature provided Weinreb amide 9 (98%).¹¹ Oxidative acetalization of alcohol 9 with DDQ¹² afforded acetal 10 (87%) (Scheme 2). Displacement of the amide functionality with 3.0 equiv. MeLi furnished methyl ketone 11 (99%).¹³ Treatment of keto-acetal 11 with 3.0 equiv. DIBAL-H led to the concomitant regioselective reductive opening ¹⁴ of the PMB acetal and reduction of the keto group to give 1,7-diol 12 (89%). 1,7-diol 12 was oxidized with IBX to furnish the keto aldehyde 13 (87%). Keto aldehyde 13 upon chemoselective HWE olefination¹⁵ with 2.5 equiv. crotyl phosphonate formed the aldol partner, keto ester 4 [>19 : 1 (E : Z), 85%].

Scheme 2 Synthesis of keto ester 4.

The synthesis of aldehyde 6a commenced with the known diol 8,¹⁶ whose primary and secondary alcohols were masked successively as a tosyl ester (NEt₃, nBu₂SnO and Ts–Cl) and silyl ether (ImH and TBDPS-Cl) to give 15 (86% over two steps). Attempted reductive elimination of the tosyl group in 15 using LiAlH₄ and superhydride for the synthesis of the carbo-metallation precursor resulted in the formation of a silyl deprotected, volatile and optically active methyl vinyl carbinol. This was circumvented by refluxing the tosyl ester 15 with NaBH₄ in DMSO¹⁷ at 80 °C for 3 h to afford allylic silyl ether 7a (77%).

An ethyl stereocenter was introduced into the olefin 7a by zirconium assisted carbomagnesation¹⁸ with Cp₂ZrCl₂–EtMgBr to provide the desired anti isomer 16 (70%) with a 9 : 1 ds ratio (from NMR). Treatment of primary alcohol 16 with Dess–Martin periodinane furnished aldehyde 6a (95%) (Scheme 3).

Scheme 3 Synthesis of aldehyde 6a.

Having both the fragments in hand, the aldol reaction performed between keto ester 4 and aldehyde 6a under TiCl₄–ⁱPr₂NEt enolating conditions gave a 6 : 4 mixture of aldol adducts. Treatment of the lithium enolate of keto ester 4 with aldehyde 6a at −78 °C led to only 5–10% of the aldol adduct after a prolonged time. Assuming that the sterically encumbered TBDPS silyl protecting group may be the cause for the formation of the aldol adduct in a poor diastereomeric ratio and yield, we planned to study the aldol reaction with the TBS version of aldehyde 6a. Following similar reaction conditions as demonstrated in Scheme 3 and starting from known diol 8, TBS protected aldehyde 6b was obtained in five steps with 46% overall yield. Making our assumption true, the aldol reaction¹⁹ performed between keto ester 4 and aldehyde 6b surprisingly gave a single diastereomer of 3 (Scheme 4, 85%), whose formation can be ascribed to the preferential facial bias exerted by the conjugated dienoate and the protecting groups at the C3 and C5 positions from the ketone during the Felkin-Anh mode of addition on the aldehyde in the transition state.²⁰

Scheme 4 Synthesis of the C1–C15 unit 3.

Conclusions

In conclusion, we have demonstrated the utilization of a desymmetrization strategy for the synthesis of intricate natural products comprised of polyketide domains by applying it to the C1–C15 unit of elaiolide approaching its total synthesis. Hoveyda's zirconium assisted carbometallation reaction has been promising to install the ethyl stereocenter at C14.

References

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, ¹H and ¹³C NMR spectra for all the new compounds are available. See DOI: 10.1039/c2ra22122e

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