Total synthesis of amphidinolide E

Article abstract of DOI:10.1021/ja066663j

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 allylsilan

Full text of DOI:10.1021/ja066663j

Published on Web 11/30/2006
Total Synthesis of Amphidinolide E
Porino Va and William R. Roush*
Departments of Chemistry and Biochemistry, Scripps Florida, Jupiter, Florida 33458†
Received September 14, 2006; E-mail: roush@scripps.edu
The amphidinolides are a family of over thirty biologically active
macrolides isolated from a cultured symbiotic dinoflagellate Am-
phidinium species.1 Many of the amphidinolides exhibit potent
antitumor 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 amphi-
dinolides have attracted considerable attention as targets for
synthesis and biological evaluation.2
Figure 1. Retrosynthetic analysis of amphidinolide E (1).
Scheme 1. Synthesis of Aldehyde 3
As part of a program directed toward the synthesis of tetrahy-
drofuran-containing natural products,3 we have developed and report
herein a convergent, highly stereocontrolled total synthesis of
amphidinolide E (1).4,5
Scheme 2. Synthesis of Allysilane 4
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 on the basis of our prior studies of this reaction.8
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 3. [3+2] Annulation Reaction of 3 and 4
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 â-hydroxy allylsilane 12 as the
triethylsilyl ether provided allylsilane coupling partner 4.
Treatment of aldehyde 3 and 2.5 equiv of allylsilane 4 with 1
equiv of BF3‚Et2O in CH2Cl2 at -78 °C provided the cis-
tetrahydrofuran 2 with >20:1 ds. 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. The 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.
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 conju-
gated, diene migrated species. No more than trace quantities of 16
could be isolated from these experiments. To remedy this problem,
† This work was initiated at the University of Michigan, Ann Arbor, MI, 48109.
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10.1021/ja066663j CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Esterification of Alcohol 13
Acknowledgment. This work is supported by the National
Institutes of Health (Grants GM38907 and GM38436). We thank
Dr. Troy Ryba for assistance with HPLC purification of amphidi-
nolide E and Prof. Jun-ichi Kobayashi for providing comparative
spectroscopic data for the natural product.
Note Added after ASAP Publication. After this paper was
published ASAP on November 30, 2006, Scheme 4 was revised to
show the correct stereochemistry of 15a,b. The Supporting Infor-
mation has also been updated with corrected structures. The
corrected version was published ASAP on December 6, 2006.
Scheme 5. Completion of Amphidinolide E Total Synthesis
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.
References
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Tetrahedron Lett. 2004, 45, 7899. (b) Marshall, J. A.; Schaaf, G.; Nolting,
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was undergoing review, Kim and coworkers reported a total synthesis
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S. K.; Jung, S. K.; Lee, E. Angew. Chem. Int. Ed. 2006, 45, DOI:
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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-decom-
plexation sequence did not provide 16.20
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 NIS (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.
(18) For synthesis of 15 see the SI and (a) Donaldson, W. A.; Craig, R.;
Spanton, S. Tetrahedron Lett. 1992, 33, 3967. (b) Wasicak, J. T.; Craig,
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(20) Details of the divergent behavior of 15a and 15b in the esterification of
13 will be published separately: Va, P.; Roush, W. R. Submitted for
publication.
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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.
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