The First Synthesis of a Daphnane Diterpene: The Enantiocontrolled Total Synthesis of (+)-Resiniferatoxin

Full text of DOI:10.1021/ja972279y

12976
J. Am. Chem. Soc. 1997, 119, 12976-12977
Scheme 1
The First Synthesis of a Daphnane Diterpene: The
Enantiocontrolled Total Synthesis of
(+)-Resiniferatoxin
Paul A. Wender,* Cynthia D. Jesudason, Hiroyuki Nakahira,
Norikazu Tamura, Anne Louise Tebbe, and Yoshihide Ueno
Department of Chemistry, Stanford UniVersity
Stanford, California 94305
ReceiVed July 9, 1997
Resiniferatoxin (RTX, 1) is a daphnane diterpene, identified
in the latex of Euphorbia resinifera on the basis of its
extraordinary irritant activity.1 While structurally related to the
potent tumor-promoting phorbol esters,2 RTX is not a tumor
promoter3 and does not compete for the phorbol ester binding
site on protein kinase C.4 It does, however, exhibit activity in
common with capsaicin (2), the major active constituent of red
peppers.5 In addition to its widely appreciated culinary use,
capsaicin is the active ingredient in several commercial analgesic
formulations and is also of interest as an antinociceptive agent
and antifeedant.6 Exhibiting potencies 103 to 105 times greater
than capsaicin in many assays, RTX itself is of special thera-
peutic interest as an analgesic agent, particularly for the treat-
ment of pain associated with diabetic polyneuropathy and
postherpetic neuralgia.7 In addition, RTX and its analogs serve
as key probes for biochemical investigations of the relatively
little studied vanilloid receptor.8 Notwithstanding the remark-
ably long (>2000 years) continuous therapeutic use of daphnane
extracts,5a the complexity and restricted availability of daphnanes
and their analogs have greatly limited studies on their molecular
mode of action.9,10
adduct was subsequently expected to protect the C9 hydroxyl
group and to bias conformationally the otherwise flexible B-ring
in order to control stereogenesis at C4 and C10 and attachment
of the A-ring (4 f 3). Introduction of the ortho ester and the
C20 homovanillyl chain was scheduled toward the end of the
synthesis in order to minimize handling of active intermediates
and to maximize flexibility with respect to analog preparation.
Absolute stereochemistry was controlled in the first step of
our synthesis (Scheme 2) through the known epoxidation12 of
7 (51%, 98% enantiomeric excess (ee)12b which gave after
protection (95%) epoxide 6. Opening of this epoxide with
LiCCOEt, followed by lactone formation, and methylation
yielded two lactones (87:13), of which trans-lactone 8 was the
major isolated diastereomer (66%, 3 steps).13 Reaction of 8
with lithiated tert-butyldimethylsilyl (TBS)-protected furfuryl
alcohol gave only the monoaddition product 9 (98%). Protection
of the C13 alcohol as acetate 10 (97%), reduction of the ketone
(∼100%), and oxidation of the furan nucleus with m-chlorop-
eroxybenzoic acid (m-CPBA) provided pyranone 11 (∼100%)
as an inconsequential mixture of stereoisomers. This mixture
was then converted to the acetates 5 (96%) which underwent
highly selective cycloaddition when heated with 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) in acetonitrile to yield only the
desired cycloadduct 4 (84%).14
We describe herein the asymmetric synthesis of RTX (1),
which marks the first synthesis of a daphnane, a family
consisting of over 120 members.11 Our synthesis was designed
around the use of an uniquely complex oxidopyrylium cycload-
dition (5 f 4) to set the daphnane BC-rings and relative
stereochemistry at C8 and C9. The oxygen bridge of the cyclo-
(1) (a) Hergenhahn, M.; Adolf, W.; Hecker, E. Tetrahedron Lett. 1975,
19, 1595. (b) Schmidt, R. J.; Evans, F. J. Phytochemistry 1976, 15, 1778.
(2) (a) Mechanisms of Tumor Promotion; Slaga, T. J., Ed.; CRC: Boca
Raton, FL, 1984; Vols. I-IV. (b) Naturally Ocurring Phorbol Esters; Evans,
F. J., Ed.; CRC: Boca Raton, FL, 1986.
(3) zur Hausen, H.; Bornkamm, G. W.; Schmidt, R.; Hecker, E. Proc.
Natl. Acad. Sci. U.S.A. 1979, 76, 782.
(4) (a) Driedger, P. E.; Blumberg, P. M. Proc. Natl. Acad. Sci. U.S.A.
1980, 77, 567. (b) Dimitrijevic, S. M.; Ryves, W. J.; Parker, P. J.; Evans,
F. J. Mol. Pharmacol. 1995, 48, 259.
(5) For lead references, see: (a) Appendino, G.; Szallasi, A. Life Sci.
1997, 60, 681. (b) Szallasi, A.; Blumberg, P. M. Pain 1996, 68, 195. (c)
Maggi, C. A.; Patacchini, R.; Tramontana, M.; Amann, R.; Giulianni, S.;
Santicioli, P. Neuroscience 1990, 37, 531. (d) Rouhi, A. M. Chem. Eng.
News 1996, 30.
(6) For recent reviews on the biological responses to capsaicin, see: (a)
Bevan, S.; Docherty, R. J. In Neurogical Inflammation; Geppetti, P., Holzer,
P., Eds.; CRC: Boca Raton, FL, 1996; p 53. (b) Winter, J.; Bevan, S.;
Campbell, E. A. Br. J. Anaesth. 1995, 75, 157. (c) Fuller, R. W. Arch. Int.
Pharmacodyn. 1990, 303, 147.
(7) (a) Geppetti, P. In Neurogical Inflammation; Geppetti, P., Holzer,
P., Eds.; CRC: Boca Raton, FL, 1996; p 289. (b) Watson, C. P. N.; Evans,
R. J.; Watt, V. R. Pain 1989, 38, 177. (c) Ross, D. R.; Varipapa, R. J. New
Engl. J. Med. 1989, 321, 474. (d) Cheshire, W. P.; Snyder, C. R. Pain
1990, 42, 307. (e) Tandan, R.; Lewis, G. A.; Badger, G. B.; Fries, T. J.
Diabetes Care 1992, 15, 8.
Attachment of the A-ring to 4 requires that appendages be
introduced at C4 and C10 in a trans-relationship. For this
purpose, cycloadduct 4 was converted to enone 13 through a
highly efficient five-step sequence (81% overall). Conjugate
(11) For representative synthetic efforts toward the daphnanes, tiglianes,
and ingenanes from this laboratory, see: (a) Wender, P. A.; Lee, H. Y.;
Wilhelm, R. S.; Williams, P. D. J. Am. Chem. Soc. 1989, 111, 8954. (b)
Wender, P. A.; Kogen, H.; Lee, H. Y.; Munger, J. D.; Wilhelm, R. S.;
Williams, P. D. J. Am. Chem. Soc. 1989, 111, 8957. (c) Wender, P. A.;
McDonald, F. M. J. Am. Chem. Soc. 1990, 112, 4956. (d) Wender, P. A.;
Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc. 1997, 119, 7897. For reviews
and lead references, see: (e) Kogen, H. J. Syn. Org. Chem. Jpn. 1990, 48,
724. (f) Rigby, J. H. Stud. Nat. Prod. Chem. 1993, 12, 233. (g) Tokunoh,
R.; Tomiyama, H.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett. 1996,
37, 2449. (h) Paquette, L. A.; Ross, R. J. J. Org. Chem. 1987, 52, 5497. (i)
Winkler, J. D.; Hong, B.; Buhador, A.; Kazanietz, M. G.; Blumberg, P. M.
J. Org. Chem. 1995, 60, 1381. (j) Funk, R. L.; Olmstead, J. A.; Parvez,
M.; Stallman, B. J. J. Org. Chem. 1993, 58, 5873. (k) Mehta, G.; Pathak,
V. J. J. Chem. Soc., Chem. Commun. 1987, 876. (l) Harwood, L. M.;
Ishikawa, T.; Philips, H.; Watkin, D. J. Chem. Soc., Chem. Commun. 1991,
527. (m) Bullman Page, P. C.; Jennens, D. C. J. Chem. Soc., Perkin Trans.
1 1992, 2587. (n) Rigby, J. H.; Claire, V. S.; Heeg, M. J. J. Org. Chem.
1996, 61, 1446. (o) McLoughlin, J. I.; Brahma, R.; Campopiano, O.; Little,
R. D. Tetrahedron Lett. 1990, 31, 1377. (p) Nakamura, T.; Matsui, T.;
Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032.
(8) (a) Caterina, M. J.; Schumacher, M. A.; Tominga, M.; Rosen, T. A.;
Levine, J. D.; Julius, D. Nature 1997, 389, 816. (b) Szallasi, A.; Nilsson,
S.; Farkas-Szallasi, T.; Blumberg, P. M.; Boekfelt, T.; Lundberg, J. M. Brain
Res. 1995, 703, 175.
(9) For lead references, see: (a) Walpole, C. S. J.; Wrigglesworth, R.;
Bevan, S.; Campbell, E. A.; Dray, A.; James, I. F.; Masdin, K. J.; Perkins,
M. N.; Winter, J. J. Med Chem. 1993, 36, 2381. (b) Szolcsanyi, J.; Jansco-
Gabor, A. Drug Res. 1976, 26, 33.
(10) (a) Walpole, C. S. J.; Bevan, S.; Bloomfield, G.; Breckenridge, R.;
James, I. F.; Ritchie, T.; Szallasi, A.; Winter, J.; Wrigglesworth, R. J. Med
Chem. 1996, 39, 2939. (b) Appendino, G.; Cravotto, G.; Palmisano, G.;
Annunziata, R.; Szallasi, A. J. Med. Chem. 1996, 39, 3123. (c) Lee, J.;
Acs, G.; Blumberg, P. M.; Marquez, V. E. Bioorg. Med. Chem. Lett. 1995,
5, 1331.
(12) (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. (b) Schreiber, S.
L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc. 1987, 109, 1525.
(13) This sequence is modeled after: (a) Askin, D.; Volante, R. P.;
Reamer, R. A.; Ryan, K. M.; Shinkai, I. Tetrahedron Lett. 1988, 29, 277.
(b) Schreiber, S. L.; Smith, D. B. J. Org. Chem. 1989, 54, 9. (c) Schreiber,
S. L.; Sammakia, T.; Uehling, D. E. J. Org. Chem. 1989, 54, 15.
(14) The stereochemistry of cycloadduct 4 follows from its conversion
to RTX and correlation with a derivative of an intermediate (compound 5
in ref 11c) in the synthesis of phorbol (see the Supporting Information).
S0002-7863(97)02279-8 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 52, 1997 12977
Scheme 2a
addition of vinyl cuprate to 13 followed by stereoelectronically
controlled R-face protonation, dictated by the oxygen bridge,
gave ketone 14 (96%). Addition of LiCCPh to the sterically
less-encumbered face of 14, followed by quenching of the
resulting alkoxide with MSTFA,15 afforded exclusively the
â-substituted silyl ether 15 (43%) and alcohol 16 (33%). The
latter can be converted to the former by independent silylation.
Zirconocene-mediated cyclization16 of 15, one of the most
complex examples of its kind, followed by oxidation of the
resulting C13 hydroxy group with tetrapropylammonium per-
ruthenate(VII) (TPAP) gave 17 in excellent yield (89%, 2 steps).
In a crucial test of stereocontrol, addition of isopropenyl-
magnesium bromide to 17 occurred as desired from the â-face
of the C13 carbonyl to give a single adduct 3 (75%), possessing
the complete daphnane framework. Ozonolysis of 3, deben-
zylation of the product, and carbonate formation gave 18 (62%,
3 steps). Selective removal of the C20 TBS group with 49%
aqueous HF (90%), conversion of the resulting alcohol to the
iodide (96%), and iodo ether elimination17 with activated zinc
afforded 19 (92%). Allylic oxidation of 19 with SeO2-t-BuO2H
in THF-HMPA (10:3) led to the formation of the desired C7
allylic alcohol 20 (61%) along with alcohol 21 (38%). Intro-
duction of the C20 oxygen was accomplished by treatment of
20 with thionyl chloride followed by nucleophilic displacement
by benzoate to give 22 (77%, 2 steps). Selective hydrolysis of
the carbonate with 0.5 M NaOH furnished the corresponding
diol (73%). Activation18 of phenylacetic acid, followed by
addtion to 4-(N,N-dimethylamino)pyridine (DMAP) and the diol
selectively provided the C14 ester 23 in 74% yield. Exposure
of 23 to mildly acidic conditions19 gave the ortho ester 24 in
46% yield.
The isopropenyl group was regenerated by a Peterson
olefination of the C15 ketone to provide 25.20 Benzoylation of
the C20 alcohol, C3 silyl enol ether formation, bromination,
and elimination of HBr afforded the enone 26 in 80% overall
yield.11b Finally, after the C4-TMS and C20 benzyl groups were
cleaved (96%, 2 steps), the C20 alcohol was esterified with
4-acetoxy-3-methoxyphenyl acetic acid19 and the acetate was
removed to afford RTX (1, 66%, 2 steps).21 Further synthetic,
structure-activity, receptor characterization, and mode of action
studies made possible through this effort are in progress.
Acknowledgment. This research was supported by a grant (CA31841)
from the National Institutes of Health and Research Associateships from
Sumitomo Pharmaceutical Co. (H.K. and Y.U.) and Takeda Chemical
Industries Ltd. (N.T.). Mass spectra were provided by the Mass
Spectrometry Facility, University of California-San Francisco.
Supporting Information Available: Experimental procedures and
characterization information (48 pages). See any current masthead page
for ordering and Interenet access instructions.
JA972279Y
(18) Inanaga, J.; Hirata, K.; Saeki, H.; Katuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(19) Adolf, W.; Sorg, B.; Hergenhahn, M.; Hecker, E. J. Nat. Prod. 1982,
45, 347.
(15) N-Methyl-N-(trimethylsilyl)trifluoroacetamide.
(20) (a) Peterson, D. J. J. Org. Chem. 1968, 33, 780. (b) Other (Tebbe,
Nysted, and Wittig) olefinations of the C15 carbonyl were unsuccessful.
(21) The synthetic material was characterized by comparison (1H NMR,
(16) (a) RajanBabu, T. V.; Nugent, W. A.; Taber, D. F.; Fagan, P. J. J.
Am. Chem. Soc. 1988, 110, 7128. (b) Negishi, E.; Holmes, S. J.; Tour, J.
M.; Miller, J. A.; Cederbaum, F. E.; Swanson, D. R.; Takahashi, T. J. Am.
Chem. Soc. 1989, 111, 3336.
13C NMR, Rf ) 0.40, hexane/EtOAc, 1/1; [synthetic [R]26 ) +67° (c )
D
0.5, CHCl3)], [natural [R]26D ) +69° (c ) 0.4, CHCl3)]) with natural RTX
(17) Bernet, B.; Vasella, A. HelV. Chim. Acta 1984, 67, 1328.
(from LC Laboratories).