Convergent enantioselective synthesis of the tricyclic core of phomactin A

Article abstract of DOI:10.1021/ol026159t

(Matrix Presented) The tricyclic core of phomactin A was synthesized from 6,6-dimethyl-2-cyclohexen-1-one. Key reactions include the addition of a cyclohexenyllithium reagent to an epoxyaldehyde and a regioselective intramolecular epoxide opening to insta

Full text of DOI:10.1021/ol026159t

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2413-2416
Convergent Enantioselective Synthesis
of the Tricyclic Core of Phomactin A
Peter J. Mohr and Randall L. Halcomb*
Department of Chemistry and Biochemistry, UniVersity of Colorado,
Boulder, Colorado 80309-0215
halcomb@colorado.edu
Received May 8, 2002
ABSTRACT
The tricyclic core of phomactin A was synthesized from 6,6-dimethyl-2-cyclohexen-1-one. Key reactions include the addition of a
cyclohexenyllithium reagent to an epoxyaldehyde and a regioselective intramolecular epoxide opening to install the oxadecalin core.
The phomactins are a novel class of platelet activating factor
(PAF) antagonists that were isolated from the marine fungus
Phoma sp. in the early 1990s.1 Of the seven phomactins
isolated, phomactin A (1) is the most structurally complex
and is the only phomactin to possess a tetracyclic structure
and a hydrated furan ring (Figure 1). Although a total
core. Recently, several reports5 have also addressed the
construction of the phomactin macrocycle using transition-
metal-mediated cyclizations and ring-closing metathesis. A
Suzuki macrocyclization has also been employed toward
phomactin D,6 the only phomactin that has been synthesized
to date.7
This letter describes the synthesis of 22, a simplified
oxadecalin-dihydrofuran system found within phomactin A,
starting from 6,6-dimethyl-2-cyclohexen-1-one.8 The syn-
thetic strategy is outlined in Scheme 1. Starting from enone
2, conversion to vinyl halide 3 (M ) halogen) should be
straightforward, and it is anticipated that addition of the
corresponding organometallic reagent (M ) metal) to ep-
oxyaldehyde 4 can be realized. Intramolecular epoxide
(2) Foote, K.; Hayes, C.; Pattenden, G. Tetrahedron Lett. 1996, 37,
275.
(3) (a) Chen, D.; Wang, J.; Totah, N. J. Org. Chem. 1999, 64, 1776. (b)
Seth, P.; Totah, N. J. Org. Chem. 1999, 64, 8750. (c) Seth, P.; Totah, N.
Org. Lett. 2000, 2, 2507. (d) Seth, P.; Chen, D.; Wang, J.; Gao, X.; Totah,
N. Tetrahedron 2000, 56, 10185.
Figure 1. Structures of representative phomactins.
(4) Chemler, S. R.; Iseloh, U.; Danishefsky, S. J. Org Lett. 2001, 3, 2949.
(5) (a) Mi, B.; Maleczka, R. Org. Lett. 2001, 3, 1491. (b) Foote, K.;
John, M.; Pattenden, G. Synlett. 2001, 365. (c) Chemler, S.; Danishefsky,
S. Org. Lett. 2000, 2, 2695. (d) Houghton, T. J.; Choi, S.; Rawal, V. H.
Org. Lett. 2001, 3, 3615.
(6) Kallan, N.; Halcomb, R. Org. Lett. 2000, 2, 2687.
(7) Miyaoka, H.; Saka, Y.; Miura, S.; Yamada, Y. Tetrahedron Lett. 1996,
37, 7107.
synthesis of phomactin A has not yet been reported, there
have been several reported approaches2-4 to the oxadecalin
(1) (a) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano,
H.; Hata, T.; Hanzawa, H. J. Am. Chem. Soc. 1991, 113, 5463. (b) Sugano,
M.; Sato, A.; Iijima, Y.; Furuya, K.; Haruyama, H.; Yoda, K.; Hata, T. J.
Org. Chem. 1994, 59, 564. (c) Sugano, M.; Sato, A.; Iijima, Y.; Oshima,
T.; Furuya, K.; Kuwano, H.; Hata, T. J. Antibiot. 1995, 48, 1188.
(8) Magnusson, G.; Thoren, S. J. Org. Chem. 1973, 38, 1380.
10.1021/ol026159t CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/13/2002

Scheme 1
opening of the addition product 5 would then give the pyran
exchange of [(methoxymethoxy)methyl]tributylstannane9 and
addition of the resulting anion to 6,6-dimethylcyclohex-2-
en-1-one 8 provided tertiary allylic alcohol 9. Oxidative
rearrangement with PCC10 gave 10, which was brominated
to provide 11. This bromination was carried out using
pyridinium tribromide, a mild alternative to Br2. Reaction
of 10 with Br2 led to decomposition, a problem that was
previously reported with a similar substrate.11 An enanti-
oselective reduction12 was then carried out with the (S)-CBS13
catalyst, and the resulting alcohol 12 was protected as the
tert-butyldimethylsilyl ether 13. At this point in the synthesis,
the protecting group on the primary alcohol was exchanged.
The MOM group introduced early in the synthesis could not
be successfully removed at an appropriate later stage.
Therefore, it was removed from 13 using magnesium
bromide,14 and the resulting free alcohol was reprotected as
a 3,4-dimethoxybenzyl (DMB) ether to give the fully
elaborated vinyl bromide 14. After considerable study, it was
determined that the DMB group was stable until the end of
the sequence and could also be removed successfully at a
suitable point.15
6. With the oxadecalin core in place, Suzuki macrocyclization
would provide 7. Global deprotection and hemiketal forma-
tion would then generate phomactin A (1).
The synthesis of vinyl bromide 14 (representing the
cyclohexenyl unit 3) is outlined in Scheme 2. Tin-lithium
Scheme 2a
The synthesis of epoxyaldehyde 18 (representing 4) is
outlined in Scheme 3. Alcohol 1516 was protected as the
benzyl ether, and subsequent desilylation gave allylic alco-
(9) Johnson, C.; Medich, J. J. Org. Chem. 1988, 53, 4131.
(10) Dauben, W.; Michno, D. J. Org. Chem. 1977, 42, 682.
(11) Dauben, W.; Warshawsky, A. Synth. Commun. 1988, 18, 1323.
(12) The enantiomeric excess and absolute configuration of compound
12 were determined according to the method of Mosher: Dale, J. A.;
Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(13) Corey, E. J.; Bakshi, R.; Shibata, S. J. Am. Chem. Soc. 1987, 109,
7925.
(14) Kim, S.; Kee, I.; Park, Y.; Park, J. Synlett 1991, 183.
(15) While a PMB ether was stable until the end of the sequence, it
could not be removed under standard deprotection conditions (DDQ or
CAN) to generate the desired dihydrofuran. Oxidation of the deprotected
primary allylic alcohol to the corresponding aldehyde was observed in both
cases.
(16) Watanabe, H.; Hatakeyyama, S.; Tazumi, K.; Takano, S.; Masuda,
S.; Okano, T.; Kobayashi, T.; Kubodera, N. Chem. Pharm. Bull. 1996, 44,
2281.
a Reagents and conditions: (a) n-BuLi, Bu3SnCH2OCH2OCH3,
THF, -78 °C (78%); (b) PCC, CH2Cl2, rt (90%); (c) pyridinium
tribromide, pyridine, CH2Cl2, rt to 40 °C (60%); (d) (S)-CBS,
BH3‚THF, THF, rt (92%, 80%ee); (e) TBS-Cl, imidazole, DMF, rt
(85%); (f) MgBr2‚Et2O, BuSH, Et2O, rt (70%); (g) NaH, DMB-
Br, THF, rt (95%).
2414
Org. Lett., Vol. 4, No. 14, 2002

Scheme 3a
Scheme 4a
a Reagents and conditions: (a) NaH, BnBr, THF, rt (95%); (b)
TBAF, THF, rt (90%); (c) TBHP, (-)-DIPT, Ti(O-i-Pr)4, 4 Å
sieves, CH2Cl2, -18 °C (92%, 84% ee); (d) Pyr‚SO3, Et3N, DMSO,
CH2Cl2, 0 °C (75%).
hol 16. A Sharpless asymmetric epoxidation17,18 provided
a Reagents and conditions: (a) t-BuLi, Et2O, -78 °C, then
TMEDA, 18 (60%); (b) Dess-Martin periodinane, NaHCO3,
CH2Cl2, rt (90%); (c) TBAF, THF, 0 °C (90%); (d) 1% HCl,
i-PrOH, 0 °C to rt (77%); (e) DDQ, 20:1 CH2Cl2/H2O, 0 °C to rt
(60%).
epoxide 17, which was oxidized19 to give epoxyaldehyde
18.
The coupling of the two components (14 + 18) is outlined
in Scheme 4. Lithium-halogen exchange of 14 was per-
formed in ether at -78 °C, and the addition of the resulting
vinyllithium reagent to aldehyde 18 was carried out in the
presence of TMEDA. In the absence of TMEDA, the yield
of addition product 19 was 15-20% lower. The resulting
alcohol 19 was isolated as a 10:1 mixture of diastereomers
at the newly formed carbinol center. This mixture was then
simultaneously oxidized20 without separation to give enone
20 as a single diastereomer. The silyl group was then
removed with fluoride, and the resulting alcohol under-
went an intramolecular epoxide opening under acidic con-
ditions to give bicyclic compound 21. None of the product
of 5-exo epoxide opening was observed.5a,21 With the
oxadecalin core now in place, the relative stereochemistry
was confirmed using coupling constant analysis and NOE
studies.22
was carried out in only 20 min at room temperature. Longer
reaction times led to the formation of other products,
primarily compound 23 (Scheme 5). The desired dihydro-
Scheme 5. Furan Formation
furan 22 was extremely unstable, even after purification, and
dehydrated readily1a,2,23 to provide the more stable furan 23.
Short reaction times and immediate purification of 22 were
both necessary to isolate the tricyclic core of phomactin A
in high yield.
The final conversion of 21 to 22 was carried out with DDQ
to successfully remove the DMB group and spontaneously
form the dihydrofuran, completing the synthesis of the
tricyclic core of phomactin A. This efficient deprotection
In summary, the tricyclic core of phomactin A was
synthesized. Key reactions include the addition of a cyclo-
hexenyllithium reagent to an epoxyaldehyde and an intramo-
lecular epoxide opening. The strategy employed here is
currently being adapted to an enantioselective total synthesis
of phomactin A.
(17) Gao, Y.; Hanson, R.; Klunder, J.; Ko, S.; Masamune, H.; Sharpless,
K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(18) Enantiomeric excess determined by the method of Mosher (see ref
12). For a Sharpless asymmetric epoxidation on a similar compound, see:
Evans, D. A.; Williams, J. M. Tetrahedron Lett. 1988, 29, 5065.
(19) Escudier, J.; Baltas, M.; Gorrichon, L. Tetrahedron 1993, 49,
5253.
(20) Dess, B.; Martin, J. J. Am. Chem. Soc. 1991, 113, 7277.
(21) Urano, M.; Kagawa, H.; Hrigaya, Y.; Li, S.; Onda, M. J. Heterocycl.
Chem. 1991, 28, 1845.
(22) See the Supporting Information for important NOE enhancements
on compound 21.
(23) Compound 22 was quantitatively converted to furan 23 on standing
in CDCl3 for 1 h. NMR analysis in C6D6 allowed for characterization of
22; however, the desired dihydrofuran still dehydrated within 24 h.
Org. Lett., Vol. 4, No. 14, 2002
2415

Acknowledgment. This research was supported by the
NIH (GM53496), Pfizer, and Novartis. R.L.H. also thanks
the National Science Foundation (Career Award) and the
Camille and Henry Dreyfus Foundation (Camille Dreyfus
Teacher-Scholar Award) for support. This work was great-
ly facilitated by a 500 MHz NMR spectrometer that
was purchased partly with funds from an NSF Shared
Instrumentation Grant (CHE-9523034). Bob Barkley
(University of Colorado) is thanked for obtaining mass
spectra.
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 9-14 and
16-23. This information is available free of charge via the
Internet at http://pubs.acs.org.
OL026159T
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Org. Lett., Vol. 4, No. 14, 2002