Synthesis of the C6-C21 segment of amphidinolide E

Article abstract of DOI:10.1021/ol0523493

(Chemical Equation Presented) A convergent approach to a C6-C21 segment of the polyketide amphidinolide E has been developed through combination of three subunits by allenylindium bromide-aldehyde addition and Suzuki sp ²-sp³ couplin

Full text of DOI:10.1021/ol0523493

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5331-5333
Synthesis of the C6
Amphidinolide E
−C21 Segment of
James A. Marshall,* Gregory Schaaf, and Andrew Nolting
Department of Chemistry, UniVersity of Virginia, P.O. Box 400319,
CharlottesVille, Virginia 22904
jam5x@Virginia.edu
Received September 28, 2005
ABSTRACT
A convergent approach to a C6−C21 segment of the polyketide amphidinolide E has been developed through combination of three subunits
by allenylindium bromide-aldehyde addition and Suzuki sp2-sp3 coupling.
The amphidinolides are a family of macrocyclic lactones
isolated from the marine dinoflagellates Amphidinium sp.1
Though sharing a common biogenetic ancestry and origin
from acetate and propionate, the members of this family
display a wide array of structural variation in ring size and
carbon skeleton. Structural elements common to many of
the members include intraannular tetrahydrofuran, tetrahy-
dropyran, and epoxide rings and the presence of numerous
stereo centers. The combination of these diverse structural
features and the reported cytotoxicity of the amphidinolides
against human tumor cell lines render them attractive targets
for total synthesis.2 In this report we describe some initial
efforts directed at amphidinolide E, a member of the family
possessing a rare 19-membered lactone ring with an embed-
ded tetrahydrofuran moiety.3,4
In our synthetic plan we envisioned a disconnection into
four segments, A-D, which would be joined by Suzuki
coupling (A and C), chiral allenylmetal addition (A and B),
and Wittig condensation (C and D) (Figure 1). The final ring
Figure 1. Synthetic plan for amphidinolide E.
(1) Ishibashi, M.; Kobayashi, J. Heterocycles 1997, 44, 543. Kobayashi,
J.; Shimbo, K.; Kubota, T.; Tsuda, M. Pure Appl. Chem. 2003, 75, 337.
(2) For an overview of synthetic efforts toward the amphidinolide family,
see: A¨ıssi, C.; Riveiros, R.; Ragot, J.; Fu¨rstner, A. J. Am. Chem. Soc. 2003,
125, 15512.
(3) Kobayashi, J.; Ishibashi, M.; Murayama, T.; Takamatsu, M.; Iwamura,
M.; Ohizumi, Y.; Sasaki, T. J. Org. Chem. 1990, 55, 3421. Kubota, T.;
Tsuda, M.; Kobayashi, J. J. Org. Chem. 2002, 67, 1651.
(4) Synthesis of a C12-C29 segment: Gurjar, M. K.; Mohapatra, S.;
Phalgune, U. D.; Puranik, V. G.; Mohapatra, D. K. Tetrahedron Lett. 2004,
45, 7899.
closure would be effected by Yamaguchi lactonization. The
present report details our successful preparation of segments
A, B, and C and their incorporation into a C6-C21 segment
of amphidinolide E.
For the synthesis of a tetrahydrofuran precursor of A we
planned to add a chiral allystannane reagent to aldehyde E
to prepare a monoprotected syn-1,2-diol F, which upon base
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treatment would cyclize to tetrahydrofuran G by an internal
SN2 displacement (Scheme l).5
Scheme 3. Synthesis of Tetrahydrofuran 7
Scheme 1. Proposed Route to Segment A
The hydroxy ester 7 was protected as the MOM ether 8
and subjected to a two-step reduction-oxidation sequence
leading to aldehyde 10 (Scheme 4). Several allenylmetal
Our initial approach to aldehyde E employed the epoxide
1, prepared by Jacobsen kinetic resolution of the racemate
(Scheme 2).6 Treatment with a Normant allylcuprate reagent7
Scheme 4. Synthesis of Segment A and Coupling with B
Scheme 2. An Unexpected Dihydroxylation Outcome
afforded the unsaturated alcohol 2. However, an attempted
two-step dihydroxylation-diol cleavage8 of the unsaturated
mesylate 3 failed to produce aldehyde E owing to in situ
conversion of the presumed diol intermediate to the tetrahy-
drofuran 4. Although we could have finessed this unforeseen
event through use of a protecting group, the facile cyclization
of the diol intermediate suggested an alternative, more direct
route to the tetrahydrofuran unit in which a Sharpless
asymmetric dihydroxylation would introduce the contiguous
oxygenated stereocenters at C16 and C17.9
a Contaminated with tin byproducts.
protocols were examined for elaboration of this aldehyde to
the various anti adducts 12a-c. In the first of these, the (S)-
acetoxymethyl-substituted propargylic mesylate 11a, upon
conversion to the (M)-allenylzinc reagent and addition to
aldehyde 10 in situ, afforded the anti adduct 12a as the only
detectable stereoisomer, but in only 18% yield with recovery
of starting material.11 Extended reaction times failed to
increase the yield. Our second effort was more successful.
In this approach we employed the (S)-mesylate of 3-butyn-
2-ol (11b) to prepare the (M)-allenyltributyl tin reagent,
which upon treatment with InBr3 in the presence of aldehyde
13 afforded the adduct 12b in over 90% yield as a 95:5
mixture of diastereoisomers.12 Unfortunately, this product
was contaminated with tin byproducts that were difficult to
separate. Our third and overall preferred route to adduct 12
entailed in situ conversion of the (S)-TMS propargylic
An appropriate dihydroxylation precursor was conve-
niently prepared by cross-methathesis of alcohol 2 with ethyl
acrylate catalyzed by the Hoveyda ruthenium catalyst
(Scheme 3).10 Conversion of the resulting conjugated ester
alcohol 5 to the mesylate 6 and dihydroxylation with the
Sharpless AD-mix R reagent proceeded as expected with
concomitant cyclization to afford the tetrahydrofuran 7 as a
>90:10 mixture of separable diastereoisomers in 87% yield.
(5) Marshall, J. A.; Beaudoin, S.; Lewinski, K. J. Org. Chem. 1993, 58,
5876.
(6) Nielsen, L. P. C.; Stevenson, C. P.; Blackmond, D. G.; Jacobsen, E.
N. J. Am. Chem. Soc. 2004, 126, 1360.
(7) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
(8) Normant, J. F.; Bourgain, M. Tetrahedron Lett. 1971, 2583.
(9) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(10) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A.
H. J. Am. Chem. Soc. 1999, 121, 791-799. Chatterjee, A. K.; Choi, T.-L.;
Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360.
(11) Marshall, J. A.; Adams, N. D. J. Org. Chem. 2002, 67, 733.
(12) Marshall, J. A.; Palovich, M. J. Org. Chem. 1997, 62, 6001.
5332
Org. Lett., Vol. 7, No. 23, 2005

mesylate 11c to the (M)-allenylindium reagent, which reacted
with aldehyde 10 to afford the readily purified adduct 12c
in 83% yield.13
subjected to a Takai condensation with CHI3, Zn, and
catalytic CrCl3 to afford the (E)-vinyl iodide 25, representing
fragment C, in 73% yield from alcohol 23.16
It is worth noting that prior to the foregoing investigation
with the bis-TBS ether 23, considerable effort was expended
on various acetonide analogues with unsatisfactory results
owing to the instability of aldehyde intermediates related to
24. The corresponding TBS ether derivative, on the other
hand, proved quite tractable.
Alcohol 12c was protected as the pivalic ester 13, then
the PMB group was removed with DDQ in aqueous CH2-
Cl2, and the resulting primary alcohol 14 was converted to
the iodide 15 with iodine and Ph3P in the presence of
imidazole (Scheme 5).14
For completion of the A-B-C fragment synthesis we
planned to employ the Suzuki sp2-sp3 coupling reaction that
had served so well in our previous syntheses of discoder-
molide, callystatin A, and leptofuranin (Scheme 7).17 The
Scheme 5. Completion of the A-B Segment
Scheme 7. Coupling of Segments A-B and C
Segment C of our amphidinolide A-B-C array was
prepared from the PMB ether derivative 17 of (Z)-2-butene-
1,4-diol (Scheme 6). Oxidation with PCC proceeded with
Scheme 6. Synthesis of Segment C
present application proved no exception. In situ conversion
of iodide 15 to the boronate 26 with t-BuLi and 9-methoxy-
9-BBN followed by addition to a mixture of vinyl iodide
25, K2CO3, and Pd(dppf)Cl2 afforded the coupled product
27 in 82% yield.
The foregoing sequence provides a promising approach
to the synthesis of tetrahydrofuran-containing polyketides in
the amphidinolide family. Future work can now be directed
at the nontrivial elaboration and incorporation of segment
D and the polyene side chain (Figure 1).
Acknowledgment. Support for this work was provided
by research grant R01 CA090383 from the National Cancer
Institute.
isomerization of the double bond to afford the (E)-conjugated
aldehyde 18. This was reduced with DIBAL-H and protected
as the pivalic ester 20. Dihydroxylation with the Sharpless
AD-mix â reagent and subsequent silylation of the interme-
diate diol 21 led to the bis-TBS ether 22. Cleavage of the
PMB ether was effected with DDQ in aqueous CH2Cl2 to
afford alcohol 23, which was converted to aldehyde 24 with
the Dess-Martin periodinane reagent.15 Aldehyde 24 was
Supporting Information Available: Experimental pro-
1
cedures and H NMR spectra for all key compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0523493
(16) Takai, K.; Ichiguchi, T.; Hikasa, S. Synlett 1999, 8, 1268.
(17) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. Marshall, J.
A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885. Johnson, C. R.; Braun, M.
P. J. Am. Chem. Soc. 1993, 115, 11014. Marshall, J. A.; Bourbeau, M. P.
Org. Lett. 2002, 67, 2751. Marshall, J. A.; Schaaf, G. M. J. Org. Chem.
2003, 68, 7428.
(13) Marshall, J. A.;, Chobanian, H. R.; Yanik, M. M. Org. Lett. 2001,
3, 3369.
(14) Corey, E. J.; Pyne, S. H.; Su, W. Tetrahedron Lett. 1983, 24, 4883.
(15) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
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