Formal synthesis of (+)-phorbol [8]

Full text of DOI:10.1021/ja010643u

5590
J. Am. Chem. Soc. 2001, 123, 5590-5591
Formal Synthesis of (+)-Phorbol1
Scheme 1
Kwangho Lee and Jin Kun Cha*
Department of Chemistry
UniVersity of Alabama
Tuscaloosa, Alabama 35487
ReceiVed March 12, 2001
The phorbol esters (e.g., 1b) have been identified to be among
the most potent tumor promoters.2 High tumor-promoting activity
of phorbol derivatives has been correlated to their activation of
protein kinase C (PKC) isozymes, which play a central role in
cellular signal transduction, and depends on optimal lipophilicities
of fatty acid side chains.3 Recent observations that other phorbol
derivatives and structurally related daphnane diterpenes apparently
lack tumor-promoting activity but exhibit antitumor, anti-HIV,
and analgesic properties have further heightened interest in this
important family of natural products. Efforts to elucidate the
structural basis for these interesting biological effects of phorbol
derivatives and ultimately design inhibitors with optimal specific-
ity for a PKC-signaling pathway have rendered phorbol (1a), a
tigliane diterpene, an attractive target for synthesis. Several
imaginative approaches notwithstanding, to date only the Wender
group has achieved a total synthesis by utilizing an elegant
application of the oxidopyrylium-olefin [5 + 2] cycloaddition.4
Herein we report a formal synthesis of (+)-phorbol by intersecting
with Wender’s advanced intermediate 2, which could also serve
as a pivotal precursor to prostratin and daphnane diterpenes.
As shown in Scheme 1, our synthetic plan was built upon a [4
+ 3] oxyallyl cycloaddition and subsequent intramolecular Heck
reaction for the stereocontrolled construction of the BC-ring
system of phorbol, followed by adaptation of Wender’s efficient
method for the A-ring construction.4,5 The utility of this key
strategy was previously demonstrated in the synthesis of the
tricycle 3, in racemic form, possessing the ABC-ring skeleton of
1a.6 The diastereoselective introduction of the C-11 methyl group,
which was required to complete a formal synthesis of 1a, was
deemed challenging. Therefore, we chose to incorporate the C-11
methyl group at an early stage in an enantioselective synthesis
of (+)-1a.
of the meso cycloadduct 9 was achieved by means of a lipase
from Candida rugosa to furnish the alcohol 10 in 90% yield and
80% ee [on the basis of H NMR studies with a chiral shift
1
reagent, Eu(hfc)3]. To set the stage for the A-ring annelation by
way of enyne cyclization, the two alkyl groups were introduced
onto the B-ring.10 Toward this end, 11 was prepared in 90%
overall yield in a straightforward manner. The regio- and
stereoselective introduction of the allyl group to nonracemic, yet
pseudosymmetric, 11 was realized in a 7:1 diastereoselectivity
by asymmetric deprotonation using Simpkins’ base 12 in the
presence of LiCl.11 Subsequent Mannich condensation and
elimination according to the Eschenmoser’s method afforded the
enone 13 in 70% overall yield. As a consequence of these two
asymmetric transformations, 13 was thus obtained in essentially
enantiomerically pure form (g97% ee). Conjugate addition of
vinyl cuprate to 13 and in situ protonation stereoselectively
afforded 14 (70%). Alternatively, 14 was prepared on a compa-
rable level of efficiency by means of radical allylation, followed
by base-induced equilibration of 15. The alkyne group was then
introduced by addition of phenylacetylide ceriate or lithium
phenylacetylide in the presence of lithium bromide from the
convex face of 14, followed by TMS protection, to provide 16.
After removal of the BOM-protecting group of 16 and
straightforward elaboration of 17 (Scheme 3), the C-11 methyl
group was next installed onto 18 diastereoselectively (>20:1) by
the powerful enantioselective conjugate addition procedure de-
veloped by Hruby to give 19.12 By standard methods involving
the Wittig olefination variant of Stork,13 the (Z)-vinyl iodide 4
was then prepared in 62% overall yield for the pivotal intra-
molecular Heck reaction:14 treatment of 4 with Pd(OAc)2 and
HCO2K yielded 20, as a single isomer, in 79% yield. Finally, the
Our synthesis began with the [4 + 3] cycloaddition of the
readily available furan 67 and the oxyallyl generated from 1,1,3-
trichloroacetone (7) under Fo¨hlisch’s conditions,8 followed by
reduction with zinc, to afford the cycloadduct 8 in 80-93% yield
(based on consumed starting material) (Scheme 2).9 After both
protecting groups were changed to the acetate, asymmetrization
* Author for correspondence. E-mail: jcha@bama.ua.edu.
(1) Part 14 in the series of synthetic studies on [4 + 3] cycloadditions of
oxyallyls. See also: (a) Part 13: Lee, J. C.; Cha, J. K. J. Am. Chem. Soc.
2001, 123, 3243. (b) Part 12: Lee, J. C.; Cha, J. K. Tetrahedron 2000, 56,
10175. (c) Part 11: Sung, M. J.; Lee, H. I.; Chong, Y.; Cha, J. K. Org. Lett.
1999, 1, 2017.
(2) (a) Naturally Occurring Phorbol Esters; Evans, F. J., Ed.; CRC Press:
Boca Raton, FL, 1986. (b) Hecker, E.; Schmidt, R. Fortschr. Chem. Org.
Naturst. 1974, 31, 377. (c) Evans, F. J.; Taylor, S. E. Fortschr. Chem. Org.
Naturst. 1983, 44, 1. (d) Fraga, B. M. Nat. Prod. Rep. 1992, 9, 217.
(3) (a) Nishizuka, Y. Nature 1984, 308, 693. (b) Nishizuka, Y. Nature 1988,
334, 661. (c) Protein Kinase C; Parker, P. J.; Dekker, L. V., Eds.; Landes:
Austin, TX, 1997. (d) Wang, Q. J.; Fang, T.-W.; Fenick, D.; Garfield, S.;
Bienfait, B.; Marquez, V. E.; Blumberg, P. M. J. Biol. Chem. 2000, 275, 12136.
(4) (a) Wender, P. A.; Kogen, H.; Lee, H. Y.; Munger, J. D., Jr.; Wilhelm,
R. S.; Williams, P. D. J. Am. Chem. Soc. 1989, 111, 8957. (b) Wender, P. A.;
McDonald, F. E. J. Am. Chem. Soc. 1990, 112, 4956. (c) Wender, P. A.;
Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc. 1997, 119, 7897. (d) Wender,
P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J.
Am. Chem. Soc. 1997, 119, 12976.
(9) For reviews on oxyallyls, see: (a) Noyori, R.; Hayakawa, Y. Org. React.
1983, 29, 163. (b) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1984,
23, 1. (c) Mann, J. Tetrahedron 1986, 42, 4611. (d) Rigby, J. H.; Pigge, F. C.
Org. React. 1997, 51, 351. (e) Harmata, M. Tetrahedron 1997, 53, 6235.
(10) Another synthesis of (+)-2a was successfully accomplished by
changing the reaction sequence in that the BC-ring annelation was first
performed prior to the related incorporation of the two alkyl groups necessary
for the A-ring construction: Lee, K.; Cha, J. K. unpublished results.
(11) For excellent reviews, see: (a) Simpkins, N. S. Chem. Soc. ReV. 1990,
19, 335. (b) Cox, P. J.; Simpkins, N. S. Tetrahedron: Asymmetry 1991, 2, 1.
(c) Koga, K.; Shindo, M. J. Synth. Org. Chem. Jpn. 1995, 53, 1021. (d)
O’Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439.
(5) Wender, P. A.; McDonald, F. E. Tetrahedron Lett. 1990, 31, 3691.
(6) Lee, K.; Cha, J. K. Org. Lett. 1999, 1, 523.
(7) Cf. Finan, P. A. J. Chem. Soc. 1963, 3917.
(8) Sendelbach, S.; Schwetzler-Raschke, R.; Radl, A.; Kaiser, R.; Henle,
G. H.; Korfant, H.; Reiner, S.; Fo¨hlisch, B. J. Org. Chem. 1999, 64, 3398
and references therein.
(12) (a) Nicola´s, E.; Russell, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58,
766. (b) Williams, D. R.; Kissel, W. S.; Li, J. J. Tetrahedron Lett. 1998, 39,
8593. (c) For an excellent review on enantioselective conjugate additions,
see: Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033.
(13) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173.
10.1021/ja010643u CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/16/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 23, 2001 5591
Scheme 2
Scheme 3
A-ring was constructed by adaptation of Wender’s method.4,5
Zirconocene-mediated cyclization of the enyne 20 under Negishi’s
conditions15 afforded an inseparable 4:1 mixture (81%) of the
ABC-ring tetracycle 21 and the C-2 epimer. On the other hand,
Sato’s enyne cyclization protocol16 gave 21 as the sole isomer
(83%).17
To intersect with Wender’s advanced intermediate 2, allylic
oxidation of 21 was next undertaken; CrO3-3,5-dimethylpyrazole
produced a 1:1 mixture of enone 22 and epoxide 23 in 85%
yield.18-20 Efficient deoxygenation of 23 by the procedure of
Ganem allowed recycling to 21.21 Finally, L-Selectride reduction
of 22 smoothly gave the key intermediate 2 in 93% yield. This
synthetic substance, [R]D ) -55° (c 0.47, CH2Cl2) {lit4c [R]D )
-54.7° (c 1.28, CH2Cl2)} was found to exhibit physical and
spectroscopic data identical to those reported by Wender.4
In summary, we have developed a formal synthesis of phorbol
(1a) and also a general strategy for the stereocontrolled construc-
tion of 6,7- or 5,7-fused bicyclic systems by means of a [4 + 3]
oxyallyl cycloaddition and subsequent intramolecular Heck reac-
tion.
(14) For recent reviews, see: (a) de Meijere, A.; Meyer, F. E. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2379. (b) Jeffery, T. In AdVances in Metal-
Organic Chemistry; Liebeskind, L. S., Ed.; JAI: Greenwich, 1996; Vol 5. (c)
Overman, L. E.; Link, J. T. In Metal-catalyzed Cross-coupling Reactions;
Diederich, F.; Stang, P. J., Eds.; VCH: New York, 1998.
(15) (a) Negishi, E.-i.; Holmes, S. J.; Tour, J. M.; Miller, J. A.; Cederbaum,
F. E.; Swanson, D. R.; Takahashi, T. J. Am. Chem. Soc. 1989, 111, 3336. (b)
RajanBabu, T. V.; Nugent, W. A.; Taber, D. F.; Fagan, P. J. J. Am. Chem.
Soc. 1988, 110, 7128.
Acknowledgment. We thank the National Institutes of Health
(GM35956) for generous financial support. We are indebted to Professor
Paul A. Wender for the 1H and 13C NMR spectra of 2, as well as helpful
discussions. We also thank Dr. Ken Belmore for the difference NOE
measurements.
(16) (a) Urabe, H.; Hata, T.; Sato, F. Tetrahedron Lett. 1995, 36, 4261.
(b) For an excellent review, see: Sato, F.; Urabe, H.; Okamoto, S. Synlett
2000, 753. Cf. (c) Montchamp, J.-L.; Negishi, E.-i. J. Am. Chem. Soc. 1998,
120, 5345. (d) Lee, J.; Cha, J. K. Tetrahedron Lett. 1996, 37, 3663.
(17) We believe that the C-2 methyl group of 21 has the R-configuration,
as shown in Scheme 3, on the basis of difference NOE measurements: when
the resonance of the -OTMS group was irradiated, a significant NOE was
observed for the methine hydrogen (δ 2.85 ppm) at C-2. Since the C-2
stereocenter is destined to become the olefin functionality, however, this
stereochemistry is inconsequential for the synthesis of 1a.
Supporting Information Available: Experimental procedures and
1
the H and 13C NMR spectra of key intermediates (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
JA010643U
(18) Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem. 1978, 43,
2057.
(20) A more expedient route to the incorporation of the alcohol functionality
at C-12 should be available by oxidatively trapping the enolate intermediate
in the conjugate addition of 18.
(19) The epoxide 23 was obtained as a single isomer, and the R-configu-
ration was tentatively assigned on the basis of difference NOE measurements.
(21) Martin, M. G.; Ganem, B. Tetrahedron Lett. 1984, 25, 251.