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. Author manuscript; available in PMC: 2008 Sep 17.
Published in final edited form as: J Am Chem Soc. 2006 Dec 20;128(50):15960–15961. doi: 10.1021/ja066663j

Total Synthesis of Amphidinolide E

Porino Va 1, William R Roush 1
PMCID: PMC2538580  NIHMSID: NIHMS60241  PMID: 17165709

Abstract

A convergent and highly stereocontrolled synthesis of amphidinolide E (1) has been accomplished. The synthesis features a highly diastereoselective (>20:1) BF3·Et2O promoted [3+2] annulation reaction between aldehyde 3 and allylsilane 4 to afford substituted tetrahydrofuran 2.

The amphidinolides are a family of over thirty biologically active macrolides isolated from the cultured symbiotic dinoflagellate Amphidinium sp.1 Many of the amphidinolides exhibit potent anti-tumor activity against murine lymphoma L1210 and human carcinoma KB cells.1 In addition, despite being isolated from a common dinoflagellate, the amphidinolides possess a high degree of structural diversity representing many very different molecular scaffolds. As a result of their complex structures, potent biological properties, and low availability from natural sources, the amphidinolides have attracted considerable attention as targets for synthesis and biological evaluation.2

As part of a program directed towards the synthesis of tetrahydrofuran-containing natural products,3 we have developed and report herein a convergent, highly stereocontrolled total synthesis of amphidinolide E (1).4–5

We envisaged that amphidinolide E could be accessed by elaboration of tetrahydrofuran 2, which in turn would be synthesized via a [3+2] annulation reaction6–8 of aldehyde 3 and allylsilane 4 (Figure 1). We anticipated that the cis-THF diastereomer 2 would predominate based on our prior studies of this reaction.8

Figure 1.

Figure 1

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Retrosynthetic analysis of amphidinolide E (1).

The synthesis of 1 commenced with the Swern oxidation of alcohol 5,9 which is available in five steps from commercially available isopropylidene dimethyl D-tartrate (Scheme 1). Treatment of the resulting aldehyde with vinyl magnesium bromide followed by a Johnson orthoester Claisen rearrangement10 of the mixture of diastereomeric allylic alcohols afforded methyl ester 6 in 60% overall yield. Reduction of 6 with DIBAL (−78 °C) yielded the targeted aldehyde 3.

Scheme 1.

Scheme 1

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Synthesis of Aldehyde 3

Allylsilane 4 was synthesized starting from homoallylic alcohol 7,11 which is available in high diastereoselectivity from the asymmetric crotylboration12 of L-glyceraldehyde pentylidene ketal13 (Scheme 2). Protection of 7 as the p-methoxybenzyl ether followed by hydroboration-oxidation of the vinyl group provided primary alcohol 8 (90% yield). Parik-Doering14 oxidation of 8 and subsequent Corey-Fuchs15 homologation of the aldehyde furnished alkyne 9 (88%). Acidic hydrolysis of the pentylidene ketal protecting group and oxidative cleavage of the resulting diol afforded aldehyde 10. Silylallylboration of 10 was accomplished with 9 : 1 selectivity (90% yield) by using (E)-γ-silylallylboronate (S,S)-11.16 Protection of the β-hydroxy allylsilane 12 as the triethylsilyl ether provided allylsilane coupling partner 4.

Scheme 2.

Scheme 2

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Synthesis of Allysilane 4

Treatment of aldehyde 3 and 2.5 equiv. of allylsilane 4 with 1 equiv. of BF3·Et2O in CH2C12 at −78 °C provided the cis-tetrahydrofuran 2 with >20 : 1 d.s. Excess allylsilane 4 can be recovered in excellent yield (the combined amounts of 2 and recovered 4 accounts for 92% of 4 used). The modest yield of 2 is due to the propensity of 3 to cyclotrimerize under the reaction conditions. Slow syringe pump addition of 3 into a −78 C solution of allylsilane 4 and BF3·Et2O failed to improve the yield. Furthermore, conducting the reaction at temperatures higher than −78°C resulted in significant Peterson elimination of 4.

Treatment of [3+2] adduct 2 with solid TBAF·3H2O in DMF at 90 °C effected smooth sp3 C-Si bond scission with concomitant removal of the triethylsilyl ether (Scheme 3).17 Reintroduction of the TES ether, and subsequent oxidative removal of the p-methoxybenzyl group gave alcohol 13a.

Scheme 3.

Scheme 3

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[3+2] Annulation Reaction of 3 and 4

Esterification of the C18 hydroxyl group of 13b and related intermediates with dienoic acid 14 proved to be astonishingly challenging (Scheme 4). Use of excess amounts (10–20 equiv.) of 14 and various coupling reagents invariably failed (see Supporting Information). Whereas in most cases the alcohol was recovered unscathed, the acid component was recovered as the fully conjugated, diene migrated species. No more than trace quantities of 16 could be isolated from these experiments. To remedy this problem, we reasoned that use of a “diene protected” analog of acid 14 might be effective. Gratifyingly, esterification of alcohol 13a using (CO)3Fe—complexed dienoic acid 15a18 (1.6 equiv) provided the targeted ester via the modified Yamaguchi method.19 Oxidative decomplexation of the (CO)3Fe—unit then provided polyene 16 in 94% yield for the two steps. Interestingly, use of the diastereomeric (CO)3Fe—protected dienoic acid 15b in the esterification-decomplexation sequence did not provide 16.20

Scheme 4.

Scheme 4

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Esterification of Alcohol 13

Formation of the C5-C6 olefin and closure of the 19-membered macrocycle was achieved by treating 16 with 20 mol % of Grubbs’ first generation olefin metathesis catalyst (Scheme 5). The (E,E)-diene 17 was isolated in 73% yield. In addition, an inseparable mixture of eneyne metathesis products was isolated in 10 % yield. Use of the more active Grubbs’ second generation or Grubbs-Hoveyda catalysts only resulted in decompostition of polyene 16. Stannylalumination-protonolysis21 of the alkyne unit of 17 gave vinylstannane 18 (58%) which was transformed into vinyl iodide 19 by treatment with MS (96% yield). Acidic hydrolysis of both the triethylsilyl and acetonide protecting groups afforded triol 20 (77% yield). Stille22 cross coupling of 20 with vinylstannane 215 under the Corey23 conditions completed the synthesis of (−)-amphidinolide E (59% yield). The spectroscopic properties of synthetic (−)-1 were in excellent agreement with the literature data reported by Kobayashi and co-workers. Because optical rotation data for natural 1 were unavailable, we repeated the tris-Mosher ester analysis of (−)-1 as described by Kobayashi.4b Our 1H NMR data were in perfect agreement with published NMR data for the tris-Mosher ester derivatives of 1,4b thereby confirming that synthetic (−)-1 is in fact the naturally occurring enantiomer of amphidinolide E.

Scheme 5.

Scheme 5

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Completion of Amphidinolide E Total Synthesis

In summary, a convergent and highly stereocontrolled synthesis of amphidinolide E has been accomplished. Key steps of this synthesis include a highly diastereoselective BF3·Et2O promoted [3+2] annulation reaction between aldehyde 3 and allylsilane 4 and a ring closing metathesis reaction of polyene 16. In addition, we have shown that the — Fe(CO)3 protecting group in 15 is vital to the successful esterification of the hindered hydroxyl group of 13.

Supplementary Material

SI1

Supporting Information Available: Experimental procedures and spectroscopic data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

SI2

Acknowledgments

This work is supported by a grant from the National Institutes of Health (GM38907 and GM38436). We thank Dr. Troy Ryba for assistance with hp1c purification of amphidinolide E, and Prof. Jun-ichi Kobayashi for providing comparative spectroscopic data for the natural product.

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

SI1

Supporting Information Available: Experimental procedures and spectroscopic data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

NIHMS60241-supplement-SI1.pdf (1.5MB, pdf)
SI2
NIHMS60241-supplement-SI2.pdf (2.7MB, pdf)

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