Synthesis of the C(18)-C(34) fragment of amphidinolide C and the C(18)-C(29) fragment of amphidinolide F

Article abstract of DOI:10.1021/ol102345v

A convergent synthesis of the C(18)-C(34) fragment of amphidinolide C and the C(18)-C(29) fragment of amphidinolide F is reported. The approach involves the synthesis of the common intermediate tetrahydrofuranyl-β- ketophosphonate via cross metathesis, Pd

Full text of DOI:10.1021/ol102345v

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5326-5329
Synthesis of the C(18)-C(34) Fragment
of Amphidinolide C and the C(18)-C(29)
Fragment of Amphidinolide F
Sudeshna Roy and Christopher D. Spilling*
Department of Chemistry and Biochemistry, UniVersity of MissourisSt. Louis,
One UniVersity BouleVard, St. Louis, Missouri 63121, United States
cspill@umsl.edu
Received September 28, 2010
ABSTRACT
A convergent synthesis of the C(18)-C(34) fragment of amphidinolide C and the C(18)-C(29) fragment of amphidinolide F is reported. The
approach involves the synthesis of the common intermediate tetrahydrofuranyl-ꢀ-ketophosphonate via cross metathesis, Pd(0)-catalyzed
cyclization, and hydroboration-oxidation. The ꢀ-ketophosphonate was coupled to three side chain aldehydes using a Horner-Wadsworth-Emmons
(HWE) olefination reaction to give dienones, which were reduced with L-selectride to give the fragments of amphidinolide C and F.
The amphidinolides are a structurally diverse group of natural
products isolated from symbiotic marine dinoflagellates
Amphidinium sp., found in Okinawan aceol flatworms.
Several members of the amphidinolide family possess high
levels of cytotoxicity against various cancer cell lines.1
played by the side chain C(26)-C(34) in determining the
biological activity of these molecules.
The unique structural features and potent cytotoxicity
render amphidinolide C (1), C2 (2), and F (3) very attractive
and challenging targets for total synthesis. The syntheses of
several fragments of these molecules have been reported,
but they have yet to succumb to total synthesis.3
Amphidinolide C (1) (Scheme 1), isolated from the three
strains (Y-56, Y-62, and Y-71) of the genus Amphidinium,
is one of the most cytotoxic members of the amphidinolide
family.2 Amphidinolide C exhibits cytotoxicity against
murine lymphoma L1210 (IC50 0.0058 µg/mL) and human
epidermoid carcinoma KB (IC50 0.0046 µg/mL) in vitro.
Interestingly, amphidinolide C2 (2) and F (3), which vary
only in the structure and length of the side chain, are
approximately 1000-fold less active, suggesting a crucial role
In our retrosynthetic analysis (Scheme 1), amphidinolides
C, C2, and F (1-3) are dissected into four fragments: the
northern C(18)-(25), the southern C(1)-C(9), and the
western C(10)-C(17) fragments and the side chains of
amphidinolideC,C(26)-(34),andamphidinolideF,C(26)-(29).
We have recently reported the synthesis of the C(1)-C(9)
(3) (a) Bates, R. H.; Shotwell, J. B.; Roush, W. R. Org. Lett. 2008, 10,
4343. (b) Shotwell, J. B.; Roush, W. R. Org. Lett. 2004, 6, 3865. (c) Kubota,
T.; Tsuda, M.; Kobayashi, J. Tetrahedron 2003, 59, 1613. (d) Armstrong,
A.; Pyrkotis, C. Tetrahedron Lett. 2009, 50, 3325. (e) Mohapatra, D. K.;
Dasari, P. K.; Rahaman, H.; Pal, R. Tetrahedron Lett. 2009, 50, 6276. (f)
Mohapatra, D. K.; Rahaman, H.; Chorghade, M. S.; Gurjar, M. K. Synlett
2007, 4, 567. (g) Mahapatra, S.; Carter, R. G. Org. Biomol. Chem. 2009, 7,
4582.
(1) (a) Kobayashi, J.; Ishibashi, M. Chem. ReV. 1993, 93, 1753. (b)
Tsuda, M.; Izui, N.; Shimbo, K.; Sato, M.; Fukushi, E.; Kobayashi, J. J.
Org. Chem. 2003, 68, 9109. (c) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep
2004, 21, 77.
(2) (a) Kobayashi, J.; Ishibashi, M.; Walchi, M. R.; Nakamura, H.;
Hirata, Y.; Sasaki, T.; Ohizumi, Y. J. Am. Chem. Soc. 1988, 110, 490. (b)
Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3, 1363.
10.1021/ol102345v  2010 American Chemical Society
Published on Web 10/28/2010

Scheme 1
.
Retrosynthetic Analysis of Amphidinolide C
Scheme 2. Synthesis of the 2,5-trans-Tetrahydrofuran 8
metathesis reaction between terminal alkenol 5 and the (S)-
carbonate 6 (>95% ee) using Grubbs second-generation
catalyst and CuI as a cocatalyst proceeded smoothly to give
the phosphonoallylic carbonate 7 as the major product in
78% yield8 as a g9:1 mixture of E- and Z-isomers, which
were inseparable by column chromatography. Palladium(0)-
catalyzed cyclization of 7 gave the 2,5-trans-tetrahydrofura-
nyl-(E)-vinylphosphonate 8 in 88% isolated yield together
with 5-8% of the undesired cis diastereomer.
The next challenge was to convert the vinylphosphonate
8 into ꢀ-ketophosphonate 11 (Scheme 3). Initially, Wacker
fragment of amphidninolide C (and F).4 In this report, we
describe the synthesis of the northern C(18)-C(25) fragment
and coupling to three side chain aldehydes to form the
C(18)-C(34) unit of amphidinolide C, the C(18)-C(29) unit
of amphidinolide F, and a synthetic analogue.
Scheme 3. Synthesis of the ꢀ-Ketophosphonate
The northern C(18)-C(25) fragment contains a 2,5-trans-
tetrahydrofuran ring. We recently reported a stereospecific
approach to cyclic ethers employing cross metathesis of an
alkenol and a phosphonoallylic carbonate (derived from
acrolein), followed by a Pd(0)-catalyzed cyclization reaction.5
The product vinylphosphonates can be oxidized to ꢀ-keto-
phosphonates, which can subsequently undergo Horner-
Wadsworth-Emmons (HWE) olefination reactions. This
approach appeared ideal for the synthesis of the C(18)-C(34)
fragment of amphidinolide C and the C(18)-C(29) fragment
of amphidinolide F. In general, it is quite flexible and allows
for the synthesis of a variety of side chain analogues for
structure-activity relationship studies.
The required alkenol 5 was prepared from PMB-protected
3-buten-1-ol (Scheme 2). Oxidation with mCPBA gave the
racemic epoxide (()-4. The racemic expoxide (()-4 was
subjected to hydrolytic kinectic resolution (HKR)6 to yield
the known (S)-epoxide (S)-47 in >95% enantiomeric excess.
Reaction of the (S)-epoxide (S)-4 with allylmagnesium
chloride and CuI furnished the alkenol 5.7a The cross
oxidation and various modifications were attempted.9 Un-
fortunately, the Wacker oxidation failed to yield the ꢀ-ke-
(7) The specific rotation value, [R]D, obtained for the nonracemic epoxide
(S)-4 contradicted the reported value by Marshall and co-workers but
matched that reported by Ley and co-workers (see Supporting Information).
(a) Marshall, J. A.; Sabatini, J. Org. Lett. 2005, 7, 5331. (b) Gaunt, M. J.;
Jessiman, A. S.; Orsini, P.; Tanner, H. R.; Hook, D. F.; Ley, S. V. Org.
Lett. 2003, 5, 4819.
(4) Paudyal, M. P.; Rath, N.P.; Spilling, C. D. Org. Lett. 2010, 12, 2954.
(5) He, A.; Sutivisedsak, N.; Spilling, C. D. Org. Lett. 2009, 11, 3124.
(6) (a) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science
1997, 227, 936. (b) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga,
M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am.
Chem. Soc. 2002, 124, 1307.
(8) (a) He, A.; Yan, B.; Thanavaro, A.; Spilling, C. D. J. Org. Chem.
2004, 69, 8643. (b) Rivard, M.; Blechert, S. Eur. J. Org. Chem. 2003, 2225.
Org. Lett., Vol. 12, No. 22, 2010
5327

tophosphonate 11. However, an alternative protocol employ-
ing a hydroboration-oxidation sequence was successful.
Hydroboration10 of the vinylphosphonate 8 using bis(pina-
colato)diboron (B2pin2), copper(I) iodide, and bis(2-diphe-
nylphosphinophenyl)ether (DPEPhos) as a ligand furnished
the desired ꢀ-borylated product 9 in quantitative yield as a
1:1 mixture of diastereomers. The formation of a 1:1
diastereomeric mixture was not a problem because of
eventual conversion to a ketone. The reproducibility of this
reaction proved to be highly dependent on the purity of the
reagents.11 Furthermore, the ꢀ-borylated product was found
to be unstable and underwent ꢀ-elimination on standing and
on exposure to silica gel. Similar eliminations of alkyl
boronates have been observed by others.12 Consequently, the
crude ꢀ-borylated product was subjected to sodium perborate
(NaBO3) oxidation without purification to obtain the ꢀ-hy-
droxyphosphonate 10 in 72% over 2 steps. Oxidation of the
alcohol was achieved using catalytic tetrapropylammonium
perruthenate (TPAP) and NMO to give the ꢀ-ketophospho-
nate 11 in 80% yield and completing the synthesis of the
northern C(18)-(25) fragment.
38% yield. In an effort to increase the yield, other Group I
carbonates and solvents were screened. Finally, a reaction
using anhydrous Cs2CO3 in dry isopropanol (i-PrOH) gave
dienone 12 in 93% yield (Scheme 4).16 Interestingly,
reactions using Cs2CO3 in CH3CN or CH2Cl2 were unsuc-
cesful. A Felkin-Anh controlled reduction of the dienone
12 at the C(24) position using L-selectride17 yielded the
alcohol 13 as a single diastereomer, concluding the synthesis
of the C(18)-C(29) unit of amphidinolide F. Other reducing
agents, such as NaBH4, resulted in diastereoisomeric mix-
tures.
Scheme 5
.
Synthesis of the Side Chain Aldehyde of
Amphidinolide C
Synthesis of the ꢀ-ketophosphonate (northern fragment)
11 sets the stage for Horner-Wadsworth-Emmons (HWE)
condensation reaction with a series of aldehydes. The HWE
reaction proved more troublesome than originally anticipated.
A number of bases and solvents [Ba(OH)2 in H2O and
THF;13 NaH in THF; NaHMDS in THF; t-BuOK and 18-
crown-6 in THF; LiCl and DBU in CH2Cl2,14 etc.) were
screened for the reaction of ꢀ-ketophosphonate 11 with
3-methyl-crotonaldehyde (Scheme 4). To our dismay, they
Scheme 4
.
Synthesis of the C(18)-C(29) Fragment of
Synthesis of the side chain aldehyde 19 (Scheme 5) of
amphidinolide C commenced with the PMB protection and
subsequent SeO2 oxidation of the commercially available
prenol, 14, to give the aldehyde 16 in moderate yield. Allylic
oxidations with SeO2 are often low yielding,18 and in this
case, 20-30% of the Z-isomer was also formed. A subse-
quent classic Nozaki-Hiyama-Kishi (NHK) coupling reac-
tion with the aldehyde 16 and 2-iodohexene furnished the
alkenol 17 in 75% yield. Further orchestration of the alkenol
17 by tert-butylmethylsilyl ether (TBS) protection, oxidative
cleavage of the PMB ether, and an allylic oxidation with
MnO2 gave the aldehyde 19. It should be noted that
compound 19 is racemic and will eventually yield C(29)
epimers of amphidinolide C. Although not important in this
demonstration of the application of the HWE reaction to the
synthesis of amphidinolide C and analogues, it should be
Amphidinolide F
all failed to yield the desired product. Eventually, optimized
reaction conditions using anhydrous K2CO3 and 18-crown-6
in toluene15 gave the desired dienone 12 in an unsatisfactory
(9) (a) Yan, B.; Spilling, C. D. J. Org. Chem. 2008, 73, 5385. (b) Poss,
A. J.; Smyth, M. S. Synth. Commun. 1987, 17, 1735. (c) Stutz, G.; Pondaven-
Raphalen, A. J. Chem. Res. Synop. 1980, 175. (d) Cornell, C. N.; Sigman,
M. S. J. Am. Chem. Soc. 2005, 127, 2796.
(15) Jackson, K. L.; Henderson, J. A.; Motoyoshi, H.; Phillips, A. Angew.
Chem., Int. Ed. 2009, 48, 2346.
(16) Uenishi, J.; Iwamoto, T.; Tanaka, J. Org. Lett. 2009, 11, 3262.
(17) (a) Mohapatra, D. K.; Nayak, S.; Mohapatra, S.; Chorghade, M. S.;
Gurjar, M. K. Tetrahedron Lett. 2007, 48, 5197. (b) Nicolaou, K. C.;
Brenzovich, W. E.; Bulger, P. G.; Francis, T. M. Org. Biomol. Chem. 2006,
4, 2119.
(10) Mun, S.; Lee, J.-E.; Yun, J. Org. Lett. 2006, 8, 4887.
(11) Bis(pinacolato)diboron proved to be the most unstable reagent. It
was stored in a glovebox and used up within 6 months.
(12) Maurer, K. W.; Armstrong, R. W. J. Org. Chem. 1996, 61, 3106.
(13) Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774.
(14) Blenchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(18) (a) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99,
5526. (b) Schomaker, J. M.; Geiser, A. R.; Huang, R.; Borhan, B. J. Am.
Chem. Soc. 2007, 129, 3794. (c) Maalouf, M. A.; Wiemer, A. J.; Kuder,
C. H.; Hohl, R. J.; Weimer, D. Bioorg. Med. Chem. 2007, 17, 1959.
5328
Org. Lett., Vol. 12, No. 22, 2010

possible to address the stereochemistry at C(29) using an
asymmetric NHK reaction.19
Again, reaction of the phosphonate 11 with aldehyde 19
using Cs2CO3 in i-PrOH yielded the dienone 20 in an
excellent 93% yield (Scheme 6). Similarly, reduction of the
Scheme 7. Synthesis of a Synthetic Analogue
Scheme 6
.
Synthesis of the C(18)-C(34) Fragment of
Amphidinolide C
In summary, we have accomplished the synthesis of the
C(18)-C(25) northern fragment 11 of amphidinolides C and
F via a cross metathesis, Pd(0)-catalyzed cyclization, and
hydroboration-oxidation sequence. The northern fragment
11 was coupled to three aldehydes using a HWE olefination
reactiontoform,afterstereoselectivereduction,theC(18)-C(29)
unit of amphidinolide F 13, the C(18)-C(34) unit of
amphidinolide C 21, and the synthetic analogue 25.
dienone with L-selectride delivered alcohol 21 with the
desired stereochemistry as the major diastereomer in 94%
yield, completing the synthesis of the C(18)-C(34) fragment
of amphidinolide C.
The significant difference in cytotoxicities (approximately
1000-fold) between amphidinolide C and F led us to apply
the HWE approach to a synthetic analogue. The preparation
of aldehyde 24 proceeded in four straightforward steps from
the commercially available oxocrotonate derivative 22
(Scheme 7). The aldehyde 22 was reduced to an alcohol
which was protected as a TBS ether 23. The ester was
reduced to an alcohol, which was reoxidized to give aldehyde
24. HWE olefination reaction of ꢀ-ketophosphonate 11 with
aldehyde 24 and subsequent reduction by L-selectride
furnished the synthetic analogue 25 as the major diastere-
omer.
Acknowledgment. This work was supported by grant
number R01-GM076192 from the National Institute of
General Medical studies. We thank Prof. R. K. Winter and
Mr. Joe Kramer of the Department of Chemistry and
Biochemistry, University of MissourisSt. Louis, for mass
spectra and Ms. Hillary Goode and Mr. Donnie Smith of
the Department of Chemistry and Biochemistry, University
of MissourisSt. Louis, for some preliminary experiments.
Supporting Information Available: Detailed experimen-
tal procedures and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) (a) Guo, H.; Dong, C.-G.; Kim, D.-S.; Urabe, D.; Wang, J.; Kim,
J. T.; Liu, X.; Sasaki, T.; Kishi, Y. J. Am. Chem. Soc. 2009, 131, 15387.
(b) Namba, K.; Wang, J.; Cui, S.; Kishi, Y. Org. Lett. 2005, 7, 5421. (c)
Namba, K.; Kishi, Y. Org. Lett. 2004, 6, 5031. (d) Choi, H.-W.; Nakajima,
K.; Demeke, D.; Kang, F.-A.; Jun, H.-S.; Wan, Z.-K.; Kishi, Y. Org. Lett.
2002, 4, 4435.
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