Stereoselective syntheses of the C(1)-C(9) fragment of amphidinolide C

Article abstract of DOI:10.1021/ol801852j

(Chemical Equation Presented) Stereoselective syntheses of the C(1)-C(9) fragments 18 and 28 of amphidinolide C have been developed. The first-generation sequence involves a diastereoselective chelate-controlled [3 + 2]-annulation reaction of 6 and 7, while the second-generation synthesis involves an intramolecular hetero-Michael cyclization of 8.

Full text of DOI:10.1021/ol801852j

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4343-4346
Stereoselective Syntheses of the
C(1)-C(9) Fragment of Amphidinolide C
Robert H. Bates,† J. Brad Shotwell,‡ and William R. Roush*,†,‡
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458, and
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 41809
roush@scripps.edu
Received August 8, 2008
ABSTRACT
Stereoselective syntheses of the C(1)-C(9) fragments 18 and 28 of amphidinolide C have been developed. The first-generation sequence
involves a diastereoselective chelate-controlled [3 + 2]-annulation reaction of 6 and 7, while the second-generation synthesis involves an
intramolecular hetero-Michael cyclization of 8.
The amphidinolides are a structurally diverse group of natural
products isolated from the symbiotic marine dinoflagellate
Amphidinium sp. Kobayashi and co-workers have character-
ized more than 30 members of this family since 1986, many
of which exhibit potent cytotoxicity against human cancer
cell lines.1 Not surprisingly, the amphidinolides have at-
tracted considerable interest from the synthetic community.
Total syntheses of many members of this class have been
reported, with several resulting in stereochemical reassig-
ments.2
0.0058 and 0.0046 µg/mL against murine lymphoma L1210
and epidermoid carcinoma KB cells, respectively. Interest-
ingly, the structurally related amphidinolides C24 (2) and
F5 (3) display significantly reduced activities against these
cell lines (0.8 and 3 µg/mL, respectively, for 2; 1.5 and 3.2
µg/mL, respectively for 3), suggesting that the C(25)-C(34)
side chain plays an important role in the bioactivity of
amphidinolides C, C2, and F. As such, amphidinolide C is
an important target for synthesis and exploration as a lead
compound for drug development. Several efforts on the
synthesis of 1-3 have appeared, including a report from our
laboratory on the synthesis of the C(11)-C(29) fragment of
amphidinolide F.3b,6
Amphidinolide C3 (1) is one of the most cytotoxic
members of this family, exhibiting in vitro cytotoxicities of
† Scripps Florida.
A retrosynthetic analysis of 1-3 is presented in Figure 1.
We envisage that these targets can be assembled from the
major fragments 4 and 5 via a late-stage cross-coupling and
macrolactonization sequence (or esterification followed by
‡ University of Michigan.
(1) For recent reviews, see: (a) Kobayashi, J.; Ishibashi, M. Chem. ReV.
1993, 93, 1753. (b) Chakraborty, T.; Das, S. Curr. Med. Chem.: Anti-Cancer
Agents 2001, 1, 131. (c) Kobayashi, J.; Shimbo, K.; Kubota, T.; Tsuda, M.
Pure Appl. Chem. 2003, 75, 337. (d) Kobayashi, J.; Tsuda, M. Nat. Prod.
Rep. 2004, 21, 77.
(2) An up-to-date list of references for total syntheses of members of
the amphidinolide family is provided in the Supporting Information.
(3) (a) Kobayashi, J.; Ishibashi, M.; Wa¨lchli, M.; Nakamura, H.; Hirata,
Y.; Sasaki, T.; Ohizumi, Y. J. Am. Chem. Soc. 1988, 110, 490. (b) Ishiyama,
H.; Ishibashi, M.; Kobayashi, J. Chem. Pharm. Bull. 1996, 44, 1819. (c)
Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3, 1363. (d) Kubota,
T.; Tsuda, M.; Kobayashi, J. Tetrahedron 2003, 59, 1613.
(4) Kubota, T.; Sakuma, Y.; Tsuda, M.; Kobayashi, J. Marine Drugs
2004, 2, 83.
(5) Kobayashi, J.; Tsuda, M.; Ishibashi, M.; Shigemori, H.; Yamasu,
T.; Hirota, H.; Sasaki, T. J. Antibiot. 1991, 44, 1259.
(6) (a) Shotwell, J. B.; Roush, W. R. Org. Lett. 2004, 6, 3865. (b)
Mohapatra, D. K.; Rahaman, H.; Chorghabe, M. S.; Gurjar, M. K. Synlett
2007, 567
.
10.1021/ol801852j CCC: $40.75
Published on Web 09/11/2008
2008 American Chemical Society

Scheme 1. Synthesis of Tetrahydrofuran 13 via [3 +
2]-Annulation Reaction of 6 and 7
Figure 1. Amphidinolide C: retrosynthetic analysis.
macrocyclization via intramolecular cross-coupling). Both
fragments 4 and 5 possess trans-tetrahydrofuran ring systems
that appeared to be excellent targets for synthesis via chelate-
controlled [3 + 2]-annulation7 reactions of aldehydes and
allylsilanes.8 We have previously reported the synthesis of
an advanced precursor to 4 via a [3 + 2]-annulation
sequence.6a At the outset, we envisaged that the C(1)-C(9)
fragment 5 could be assembled efficiently via the chelate-
controlled [3 + 2]-annulation reaction of crotylsilane 69 and
an appropriate aldehyde coupling partner. In practice, a first-
generation synthesis of 5a (X ) H) was developed that
proceeds via the [3 + 2]-annulation reaction of 6 and 7.
Owing to the length of this first generation synthesis, we
also developed a second-generation sequence culminating
in the synthesis of 5b (X ) H) via the intramolecular hetero-
Michael addition of 8. Both syntheses are presented herein.
Allylsilane 6 was prepared in 75-91% ee by the known
enantioselective Rh(II)-catalyzed insertion of the diazoester
derived from 9 into the Si-H bond of phenyldimethylsilane
(Scheme 1).9 We initially targeted aldehydes 11 for use in
chelate-controlled [3 + 2]-annulation reactions with 6, since
this would introduce the correct number of carbon atoms in
the C(3) substituent of tetrahydrofuran 12. The dithiane unit
in 12a and the benzyl ether in 12b would also be sufficiently
robust to survive the Hudrlik conditions10 that we initially
contemplated using for protiodesilylation of 12 (a milder
protocol for protiodesilylation was subsequently devel-
oped).11 However, all attempts to effect the chelate-controlled
[3 + 2]-annulation reactions of 6 with either 11a or 11b
and a variety of chelating Lewis acids (SnCl4, TiCl4, etc.)
failed to provide more than trace amounts of the 2,5-trans-
tetrahydrofurans 12; rather, the 2,5-cis-tetrahydrofuran isomer
(not shown) was obtained preferentially, indicating that the
dithiane and benzyl ether units of 11a,b were incapable of
forming a kinetically competent concentration of ꢀ-chelate
with the aldehyde.12
The required 2,5-trans-THF stereochemistry was success-
fully accessed via the SnCl4-promoted [3 + 2]-annulation
reaction of crotylsilane 6 and ethyl glyoxalate (7) (Scheme
1). This reaction provided 13 in 82% yield with >20:1
diastereoselectivity. Further elaboration of 13 to the C(1)-C(9)
fragment of amphidinolide C is summarized in Scheme 2.
Reduction of 13 with DIBAL followed by conversion of
the primary alcohol to the mesylate and then to the
corresponding iodide set the stage for a one-carbon homolo-
gation via alkylation with 2-lithio-1,3-dithiane.13 This four-
step sequence provided the 2,5-trans-THF 12a in 74% overall
yield. Protiodesilylation of 12a using modified8a Hudrlik
conditions (TBAF, KOtBu, DMSO, H2O, 18-crown-6)10
effected simultaneous deprotection of the primary TBS ether.
Subsequent oxidation (SO3-pyridine, DMSO)14 of the
(7) (a) Panek, J.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868. (b)
Panek, J.; Beresis, R. J. Org. Chem. 1993, 58, 809. (c) Micalizio, G.; Roush,
W. Org. Lett. 2000, 2, 461.
(8) (a) Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949. (b)
Tinsley, J. M.; Roush, W. R. J. Am. Chem. Soc. 2005, 127, 10818. (c)
Tinsley, J. M.; Mertz, E.; Chong, P. Y.; Rarig, R.-A., F.; Roush, W. R.
Org. Lett. 2005, 7, 4245. (d) Mertz, E.; Tinsley, J. M.; Roush, W. R. J.
Org. Chem. 2005, 70, 8035. (e) Va, P.; Roush, W. R. J. Am. Chem. Soc.
2006, 128, 15960. (f) Va, P.; Roush, W. R. Tetrahedron 2007, 63, 5768.
(g) Huh, C. W.; Roush, W. R. Org. Lett. 2008, 10, 3371.
(10) (a) Hudrlik, P.; Hudrlik, A.; Kulkarni, A. J. Am. Chem. Soc. 1982,
104, 6809. (b) Hudrlik, P.; Holmes, P.; Hudrlik, A. Tetrahedron Lett. 1988,
29, 6395. (c) Hudrlik, P.; Gebreselassie, P.; Tafesse, L.; Hudrlik, A.
Tetrahedron Lett. 2003, 44, 3409.
(11) Heitzman, C. L.; Lambert, W. T.; Mertz, E.; Shotwell, J. B.; Tinsley,
J. M.; Va, P.; Roush, W. R. Org. Lett. 2005, 7, 2405.
(12) (a) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191. (b) Reetz,
M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556.
(9) (a) Davies, H.; Hansen, T.; Rutberg, J.; Bruzinski, P. Tetrahedron
Lett. 1997, 38, 1741. (b) Bulugahapitiya, P.; Landais, Y.; Parra-Rapado,
L.; Planchenault, D.; Weber, V. J. Org. Chem. 1997, 62, 1630.
(13) Seebach, D.; Wilka, E. M. Synthesis 1976, 476.
(14) Parikh, J.; Doering, W. J. Am. Chem. Soc. 1967, 89, 5505.
4344
Org. Lett., Vol. 10, No. 19, 2008

Scheme 2
.
First-Generation Synthesis of the C(1)-C(9)
Fragment 18 of Amphidinolide C
Scheme 3. Synthesis of Cyclization Substrate 8
ous in situ lactonization of the γ-hydroxy ester, followed by
diastereoselective hydrogenation of the butenolide double
bond20 and protection of the primary alcohol, gave lactone
21 with 20:1 diastereoselectivity. DIBAL reduction of 21
gave the corresponding lactol, which was converted to 8 by
treatment with the stabilized ylide Ph3PdCHCO2Me.
Treatment of 8 with TBAF in THF effected the intramo-
lecular Michael cyclization with simultaneous deprotection
of the TBS ether and provided tetrahydrofuran 22 with 9:1
diastereoselectivity in 84% yield (Scheme 4). An analogous
cyclization was reported by Kobayashi and co-workers during
their stereochemical assignment work on amphidinolide C.3c
This transformation evidently proceeds under kinetic control,
as treatment of the minor tetrahydrofuran diastereomer 23
with TBAF in THF at ambient temperature did not provide
any 22. The diastereoselectivity of the kinetically controlled
primary alcohol gave aldehyde 14. Treatment of this
intermediate with Brown’s γ-borylallylborane 1515 then gave
anti-diol 16 in 47% yield with ca. 5:1 diastereoselectivity.
Protection of the diol as a bis-TBS ether set the stage for
dithiane deprotection (MeI, KHCO3, MeCN).16 Chlorite
oxidation17 of the C(1)-carboxaldehyde and esterification of
the resulting carboxylic acid provided ester 17 (same as 5a,
X ) H) in 34% yield for the four steps. Finally, ozonolysis
of 17 provided the amphidinolide C C(1)-C(9) aldehyde
18 in 76% yield.
This synthesis of 18 proceeds in 13 steps from crotylsilane
6 in ca. 7% overall yield (17 steps from commercial
precursors, including the synthesis of 6). This synthesis of
18 was too lengthy for an intermediate of such modest
complexity, with seven steps devoted to elaboration of the
methoxycarbonyl group of tetrahydrofuran 13. Thus, our
inability to effect the chelate-controlled [3 + 2]-annulation
reaction of 6 and 11a or 11b proved to be quite costly. We
therefore decided to pursue a second generation approach,
in which the trans-THF unit is assembled via the intramo-
lecular hetero-Michael cyclization of 8 (see Scheme 3).
The second-generation sequence began with the Horner-
Wadsworth-Emmons olefination of glyceraldehyde isopen-
tylidene ketal 1918 using the Still-Genari reagent.19 This
provided Z-enoate 20 with >96:4 Z/E selectivity. Acid-
catalyzed deprotection of the pentylidene ketal and spontane-
Scheme 4. TBAF-Promoted Cyclization of 8
(15) Brown, H. C.; Narla, G. J. Org. Chem. 1995, 60, 4686.
(16) Takano, S.; Hatakeyama, S.; Ogasawara, K. J. Chem. Soc., Chem.
Commun. 1977, 68.
(17) Kende, A. S.; Johnson, S.; Sanfilippo, P.; Hodges, J. C.; Jungheim,
L. N. J. Am. Chem. Soc. 1986, 108, 3513.
(18) Schmid, C. R.; Bradley, D. A. Synthesis 1992, 587.
(19) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
Org. Lett., Vol. 10, No. 19, 2008
4345

as 5b, X ) H). Ozonolysis of 27 then gave aldehyde 28,
which differs from aldehyde 18 (Scheme 2) only with respect
to the ethyl versus a methyl ester. This second-generation
synthesis of 28 was completed in 11 steps from aldehyde
19 (13 from commercial materials) in 21% overall yield.
Scheme 5. Completion of the Second-Generation Synthesis of
the C(1)-C(9) Fragment 26 of Amphidinolide C
In summary, we have developed two syntheses of the
C(1)-C(9) fragment of amphidinolide C. The first-generation
synthesis involving the chelation-controlled [3 + 2]-annu-
lation reaction of 6 and glyoxylate 7 provided 2,5-trans-
tetrahydrofuran 13 that was elaborated to the C(1)-C(9)
fragment 18 by an 11-step sequence (Scheme 2). However,
this effort was compromised by the inability to effect chelate-
controlled [3 + 2]-annulations with aldehydes 11a or 11b,
which would have led to a much shorter synthesis of 18 if
successfully implemented. Consequently, a more efficient
second-generation synthesis of the C(1)-C(9) fragment 28
was developed that proceeds via the kinetically controlled
Michael cyclization of 8 (Scheme 5). The latter sequence is
the one that we now use for bringing up material in onging
efforts to complete total syntheses of amphidinolides C, C2,
and F. Studies along these lines will be reported in due
course.
cyclization of 8 can be rationalized by minimization of A1,3-
strain in transition state A.21
Acknowledgment. This work was supported by the
National Institutes of Health (GM38436 and GM038907).
J.B.S. gratefully acknowledges the National Cancer Institute
for a postdoctoral fellowship (CA103339).
Tetrahydrofuran 22 was elaborated to the amphidinolide
C C(1)-C(9) fragment 28 as summarized in Scheme 5.
Oxidation of 22 with DMSO-pyridine under Parikh-Doering
conditions13 gave aldehyde 24. Allylboration of 24 with the
second-genaration γ-borylallylborane 25 developed in our
laboratory22 provided diol 26 with 92:8 diastereoselectivity.
Diol 26 was then protected as the bis-TBS ether 27 (same
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Herdeis, C.; Lu¨tsch, K. Tetrahedron: Asymmetry 1993, 4, 121.
(21) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
(22) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644.
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