Synthetic studies toward amphidinolide B1: Synthesis of the C9-C26 fragment

Article abstract of DOI:10.1021/ol051544e

(Chemical Equation Presented) The synthesis of the C₉-C ₂₆ portion of amphidinolide B₁ is described. A Fleming allylation followed by elimination was employed for the construction of the C₁₃-C₁₅ diene portion. Sharpless asymmetric dihydroxylation was utilized for regioselective functionalization of a styrene-derived alkene, in the presence of the C₁₃-C₁₅ diene functionality. A highly diastereoselective aldol reaction was developed to establish the C₁₈ stereochemistry.

Full text of DOI:10.1021/ol051544e

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4209-4212
Synthetic Studies toward Amphidinolide
B1: Synthesis of the C9−C26 Fragment
Wei Zhang and Rich G. Carter*
Department of Chemistry, 153 Gilbert Hall, Oregon State UniVersity,
CorVallis, Oregon 97331
rich.carter@oregonstate.edu
Received June 30, 2005
ABSTRACT
The synthesis of the C9−C26 portion of amphidinolide B1 is described. A Fleming allylation followed by elimination was employed for the
construction of the C13 C15 diene portion. Sharpless asymmetric dihydroxylation was utilized for regioselective functionalization of a styrene-
−
derived alkene, in the presence of the C13−C15 diene functionality. A highly diastereoselective aldol reaction was developed to establish the
C18 stereochemistry.
Amphidinolide B1 (1) was first observed in the dinoflagellate
Amphidinium sp., isolated from the Okinawan flatworm
Amphiscolops sp. (Scheme 1).1 The relative stereochemistry
of 1 was determined by X-ray crystal analysis,2 and the
absolute stereochemistry was established by degradation.3
Macrolide 1 is a member of a diverse family of natural
products4 that are potent cytotoxic agents with impressive
IC50 activity in a series of screens: L1210 murine leukemia
cell line (0.14 ng/mL), human colon tumor HCT 116 cell
line (0.12 µg/mL), and KB cancer cell line (4.2 ng/mL).1,2,4,5
The biological activity and complex structural architecture
of 1 has led to considerable synthetic interest;6,7 yet, the total
synthesis of 1 remains an elusive target.8
Scheme 1. Retrosynthetic Strategy for Amphidinolide B1
Our initial retrosynthetic strategy, as outlined in Scheme
1, involves a Mitsunobu macrolactonization of seco acid 2.
(1) Ishibashi, M.; Ohizumi, Y.; Hamashima, M.; Nakamura, H.; Hirata,
Y.; Sasaki, T.; Kobayashi, J. J. Chem. Soc., Chem. Commun. 1987, 1127-
29.
(2) Bauer, I.; Maranda, L.; Shimizu, Y.; Peterson, R. W.; Cornell, L.;
Steiner, J. R.; Clardy, J. J. Am. Chem. Soc. 1994, 116, 2657-58.
(3) Ishibashi, M.; Ishiyama, H.; Kobayashi, J. Tetrahedron Lett. 1994,
35, 8241-42.
(4) For a recent review: Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004,
21, 77-93.
(5) Kobayashi, J.; Ishibashi, M.; Nakamura, H.; Ohizumi, Y.; Hirata,
Y.; Sasaki, T.; Ohta, T.; Nozoe, S. J. Nat. Prod. 1989, 52, 1036-41.
Compound 2 could, in turn, be available from Wadsworth-
Emmons reaction of a C9 aldehyde with the phosphonate 4.
A diastereoselective aldol reaction between methyl ketone
10.1021/ol051544e CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/19/2005

Scheme 2
6 and aldehyde 5 would be used to form the C18,19 linkage.
mide provided the tertiary alkoxy function in 91% yield and
greater than 20:1 dr. Subsequent treatment with MeLi and
silylation yielded the protected methyl ketone 9. Combination
with the readily available allyl silane 12 using freshly distilled
TiCl4 yielded the C14,15-coupled material 13 in 65-70% yield
as 6:1 ratio of diastereomers at C15. Next, elimination of the
homoallylic alcohol 13 using SOCl2 and pyridine in toluene
provided the C13-C15 diene 14 as a single stereoisomer at
C14-C15. The desired product was contaminated with the
unconjugated diene 15 in a 2.2:1 ratio (14/15). While
compounds 14 and 15 could be separated by HPLC,
Finally, the 1,3-diene fragment present in 5 is particularly
challenging as it appears that the C16-alkoxy moiety renders
a palladium- or copper-mediated strategy problematic for its
formation.7a,9 For this reason, an alternate method for its
construction needed to be developed.
The synthesis of aldehyde 5 began with the commercially
available (S)-lactic acid (7) (Scheme 2). After acetalization
with pivaldehyde, Seebach alkylation10 with cinnamyl bro-
(6) (a) Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J. Org. Chem. 2004,
69, 2569-72. (b) Carter, R. G.; Zhang, W. 227th ACS National Meeting,
Mar 28-Apr 2, 2004, Anaheim, CA; American Chemical Society: Wash-
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(8) For total syntheses of other members of the amphidinolides: (a)
Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198-99.
(b) Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945-48. (c)
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J. Am. Chem. Soc. 2002, 124, 12420-21. (g) Ghosh, A. K.; Liu, C. J. Am.
Chem. Soc. 2003, 125, 2374-75. (h) A¨ıssa, C.; Riveiros, R.; Ragot, J.;
Frustner, A. J. Am. Chem. Soc. 2003, 125, 15512-20. (i) Ghosh, A. K.;
Gong, G. J. Am. Chem. Soc. 2004, 126, 3704-05. (j) Trost, B. M.;
Harrington, P. E. J. Am. Chem. Soc. 2004, 126, 5028-29. (k) Trost, B. M.;
Papillon, J. P. N. J. Am. Chem. Soc. 2004, 126, 13618-19. (l) Lepage, O.;
Kattnig, E.; Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 15970-71. (m)
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Lee, D.-H.; Rho, M.-D. Tetrahedron Lett. 2000, 41, 2573-76. (c) Ohi, K.;
Nishiyama, S. Synlett 1999, 571-72. (d) Ohi, K.; Nishiyama, S. Synlett
1999, 573-75. (e) Eng, H. M.; Myles, D. C. Tetrahedron Lett. 1999, 40,
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82. (g) Chakraborty, T. K.; Thippewamy, D. Synlett 1999, 150-52. (h)
Ishiyama, H.; Takemura, T.; Tsuda, M.; Kobayashi, J. J. Chem. Soc., Perkin
Trans. 1 1999, 1163-66. (i) Chakraborty, T. K.; Thippewamy, D.; Suresh,
V. R.; Jayaprakash, S. Chem. Lett. 1997, 563-64. (j) Chakraborty, T. K.;
Suresh, V. R. Chem. Lett. 1997, 565-66. (k) Lee, D. H.; Lee, S.-W.
Tetrahedron Lett. 1997, 38, 7909-10. (l) Ohi, K.; Shima, K.; Hamada, K.;
Saito, Y.; Yamada, N.; Ohba, S.; Nishiyama, S. Bull. Chem. Soc. Jpn. 1998,
71, 2433-40. (m) Ndubaku, C. O.; Jamison, T. F. 227th ACS National
Meeting, Mar 28-Apr 2, 2004, Anaheim, CA; American Chemical
Society: Washington, DC, 2004; ORGN-392. (n) Schneekloth, J. S., Jr.;
Mandal, A.; Crews, C. M. 228th ACS National Meeting, Aug 22-27, 2004,
Philadelphia; American Chemical Society: WAshington, DC, 2004; MEDI-
172. (o) Nelson, S. G.; Gopalarathnam, A.; Kassick, A. J. 229th ACS
National Meeting, Mar 13-18, 2005, San Diego; American Chemical
Society: Washington, DC, 2005; ORGN-413. (p) Mandal, A. K.; Schneek-
loth, J. S., Jr.; Crews, C. M. Org. Lett. 2005, 7, 3645-48.
(9) Chakraborty7g has shown that the C13-C14 palladium coupling can
be affected on substrates containing an sp2-hybridized center at C16. Also,
Nelson and co-workers quite recently have disclosed the apparent ability
access the C13-C15 diene via a Suzuki coupling.7o
(10) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40, 1313-
24.
4210
Org. Lett., Vol. 7, No. 19, 2005

purification of the desilylated compounds 16 and 17 proved
logistically easier as they were separable by standard
chromatographic methods. Subsequent Mitsunobu-type in-
corporation of the C9 cyanide11 and protection yielded 18.
Next, Sharpless asymmetric dihydroxylation of 18 using AD
mix â*12 provided the C18,19 diol as an inconsequential 6:1
mixture of diastereomers. The selectivity for the C18,19 alkene
over the C13-C15 diene was attributed to, in part, a beneficial
π-stacking interaction between the neighboring aromatic ring
and the corresponding Sharpless ligand.13 Dihydroxylation
under standard OsO4, NMO conditions provided a complex
mixture of products. AD mix R* also proved to be a poor
reagent for this transformation. Interestingly, dihydroxylation
of the unconjugated diene 20 with AD mix â* was again
regioselective for the C18,19 alkene; however, no diastereo-
selectvity was observed in the dihydroxylation. Finally,
cleavage of the diol 19 yielded the necessary aldehyde 5.
An analogous procedure with the unconjugated diene series
provided the aldehyde 22.
Scheme 4
The synthesis of the eastern subunit 6 commenced with
the previously prepared aldehyde 246a (Scheme 3). Boron-
Scheme 3
Chelation-controlled aldol condensation of lithium enolate
derived from the methyl ketone 6 with the aldehyde 5
provided the coupled material 27 in 69% yield as a single
diastereomer. This result is in contrast to work by Pattenden’s
and Kobayashi’s laboratories in which poor selectivity
(approximately 3:2 dr) was observed using enolates derived
from LDA, NaHMDS, or KHMDS.7a,h In both cases, non-
chelating silyl protecting groups15 were employed on C21 of
the enolate. We attribute part of the improved selectivity at
C18 to the use of the R-chelating PMB group on the enolate,
as shown in the model 26. It should be noted, however, that
when the analogous aldol reaction with the unconjugated
diene-containing aldehyde 22 was preformed, diminished
selectivity (approximately 2:1 dr) was observed. The C18
stereochemistry of 27 was confirmed by Mosher ester
analysis.16 Finally, silyl protection under specific conditions17
mediated aldol reaction of aldehyde 24 with the oxazolidi-
none 2314 gave the desired C21-C23 syn,syn adduct 25 in
good yield. The minor diastereomer in the aldol appeared to
be the anti aldol adduct (JH21,H22 ) 9.0 Hz). Subsequent
silylation at C22 followed by conversion to the thioester and
cuprate addition yielded the desired methyl ketone 6.
With the methyl ketone subunit 6 and the diene fragment
5 constructed, focus shifted toward their union (Scheme 4).
(15) (a) Keck, G. A.; Castellino, S. Tetrahedron. Lett. 1987, 28, 281-
84. (b) Frye, S. V.; Eliel, E. Tetrahedron Lett. 1986, 27, 3223-26. It should
be noted that there have been selected examples reported to the contrary:
(c) Willard, P. G.; Hintze, M. J. J. Am. Chem. Soc. 1987, 109, 5539-41.
(d) Evans, D. A.; Allison, B. D.; Yang, M. G. Tetrahedron Lett. 1999, 40,
4457-60. (e) Evans, D. A.; Halstead, D. P.; Allison, B. D. Tetrahedron
Lett. 1999, 40, 4461-64.
(11) Andrus, M. B.; Meredith, E. L.; Hicken, E. J.; Simmons, B. L.;
Glancey, R. R.; Ma, W. J. Org. Chem. 2003, 68, 8162-69.
(12) AD mix â* ) (DHQD)2PHAL (15.2 mg), K2OsO4‚2H2O (2.55 mg),
K2CO3 (293.6 mg), K3Fe(CN)6 (699.6 mg). Commercially available AD
mix â proved to be slow and inefficient.
(13) (a) Kolb, H. C.; Andersson, P. G.; Sharpless, K. B. J. Am. Chem.
Soc. 1994, 116, 1278-91. (b) Corey, E. J.; Guzman-Perez, A.; Noe, M. C.
J. Am. Chem. Soc. 1995, 117, 10805-16. (c) Mander, L. N.; Morris, J. C.
J. Org. Chem. 1997, 62, 7497-99. (d) Carter, R. G.; Weldon, D. J. Org.
Lett. 2000, 2, 3913-16.
(14) Evans, D. A.; Gage, J. R.; Leighton, J. L.; Kim, A. S. J. Org. Chem.
1992, 57, 1961-63.
(16) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-96. (b) Dale, J. A.; Mosher, H. S. J. Am. Chem.
Soc. 1973, 95, 512-19. (c) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J.
Org. Chem. 1973, 38, 2143-47. (d) For a recent review: Seco, J. M.;
Quinoa, E.; Riguera, R. Chem. ReV. 2004, 104, 17-118.
(17) Magnus, P.; Carter, R.; Davies, M.; Elliott, J.; Pitterna, T.
Tetrahedron 1996, 52, 6283-306.
Org. Lett., Vol. 7, No. 19, 2005
4211

[TBSOTf (1.2 equiv), Et3N/CH2Cl2 (1:1)] provided silyl ether
27. If more traditional silylation conditions were employed
[e.g., TBSOTf (1.2 equiv), 2,6-lutidine (1.5 equiv)], migration
of the 1,1-disubstituted alkene at C13 into the C12-C13
trisubstituted position appeared to be observed.
In summary, an efficient approach to the C9-C26 portion
of amphidinolide B1 is disclosed. Key steps in the approach
include a novel method for the construction of the C13-C15
diene, regioselective dihydroxylation of a styrene derivative
using Sharpless AD mix and a highly diastereoselective aldol
reaction to form the C18 stereocenter. While much has been
accomplished toward the total synthesis of 1, significant
challenges remain including the incorporation of the C6-C9
epoxy alkene moiety and the nontrivial Mitsunobu macro-
cyclization of an R,â-unsaturated seco acid.
in part by a grant from the NIH - National Institute of
Environmental Health Sciences (P30 ES00210). We thank
Professor Max Deinzer (Mass Spectrometry Facility, Envi-
ronmental Health Sciences Center, Oregon State University)
and Dr. Jeff Morre´ (Mass Spectrometry Facility, Environ-
mental Health Sciences Center, Oregon State University) for
mass spectral data, Rodger Kohnert (Oregon State Univer-
sity) for NMR assistance, and Dr. Roger Hanselmann (Rib-X
Pharmaceuticals) for his helpful discussions.
Note Added after ASAP Publication. There was an error
in Scheme 2 in the version published ASAP August 19, 2005;
the corrected version was published September 2, 2005.
Supporting Information Available: Complete experi-
mental procedures are provided, including 1H and 13C spectra,
of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support was provided by the
National Institutes of Health (NIH) (GM63723) and Oregon
State University. This publication was also made possible
OL051544E
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