J. Am. Chem. Soc. 1997, 119, 9929-9930
9929
lation and afforded 8 as the exclusive product in 86% isolated
yield. 2-D H NMR studies (COSY-NOE) of the cyclization
Enantioselective Total Synthesis of the Potent
Anti-HIV Agent Neotripterifordin. Reassignment of
Stereochemistry at C(16)
1
product fully confirmed the structure 8. The efficiency of this
process may be associated with bidentate coordination of the
benzyloxy and oxirane oxygens with TiCl4 and concerted
oxirane C-O cleavage and cyclization, thus minimizing side
reactions such as pinacol-type rearrangement and elimination.
Replacement of the primary hydroxyl group of 8 by hydrogen
(oxidation9 and Wolff-Kishner reduction) followed by oxidative
cleavage of the vinyl group afforded the aldehyde 9 (78% overall
yield from 8) which by Pd-C-catalyzed hydrogenation in acidic
methanol provided the bridged ether 10 (98% yield). The
aromatic bridged ether 10 was transformed into the R,â-enone
11 by Birch reduction and subsequent acid treatment (75%).
Irradiation of the R,â-enone 11 (medium-pressure Hg lamp) in
the presence of allene in hexane solution at -30 °C for 30 min
afforded as major product the photoadduct 12 in 72% yield.10
Ozonolysis11 of 12 in methanol containing NaHCO3 at -78
°C for 10 min followed by treatment with Me2S and stirring at
23 °C for 15 h effected cleavage of the exocyclic methylene
group and methanolysis of the strained acylcyclobutanone unit
to form a keto ester (88% yield) which was reduced to the
corresponding hydroxy aldehyde 13 in 75% yield using di-
isobutylaluminum hydride (2 equiv, toluene, -78 °C, 3 h).
Aldehyde 13 was transformed into the hydroxy acetylene 14
(94%) by reaction with 2.5 equiv of CH3COC(N2)PO(OMe)2
and 3.4 equiv of K2CO3 in MeOH at 23 °C for 3 h.12 The
hydroxy acetylene 14 was converted to the corresponding
xanthate ester (92%) by sequential treatment with sodium
hydride (3.8 equiv)-imidazole (0.1 equiv) in THF at reflux for
3 h, then CS2 (excess, 0.5 h) and CH3I (excess, 0.5 h). Reaction
of this xanthate with n-Bu3SnH (2 equiv)-AIBN (cat.) in
toluene at reflux for 10 min effected radical formation13 and
cyclization to form pentacycle 15 in 95% yield. Transformation
of 15 to the target molecule 2 was accomplished by the
following sequence: (1) epoxidation (2.1 equiv of m-chlorop-
eroxybenzoic acid, 2.5 equiv of NaHCO3 in CH2Cl2 at 0 °C for
30 min, 85%); (2) oxirane reduction (with 4.5 equiv of LiAlH4
in ether, 23 °C, 30 min, 94%); (3) lactol ether cleavage (2:1 3
N HCl-THF, 40 °C, 2 h); and (4) Dess-Martin oxidation9 of
lactol to lactone at 23 °C for 4 h (80%). Synthetic 2 was
compared with authentic neotripterifordin14 by 1H and 13C NMR,
IR, and mass spectroscopies and by optical rotation and thin-
layer chromatography and was found to be identical.14 In
contrast, synthetic 1 (the C(16) diastereomer of 2) and neo-
tripterifordin were clearly distinguishable by each of the above
comparisons. Synthetic 1 was prepared from 15 by the
following sequence: (1) oxidative cleavage of the CdCH2 group
of 15 (O3, CH3OH, -78 °C, 10 min, 92%); (2) addition of
MeMgI to the resulting ketone (ether, 23 °C, 1 h, 94%); (3)
lactol ether cleavage (2:1 3 N HCl-THF, 40 °C, 2 h); and (4)
Dess-Martin oxidation of lactol to lactone (80%).15 Thus, it
E. J. Corey* and Kun Liu
Department of Chemistry and Chemical Biology
HarVard UniVersity, Cambridge, Massachusetts 02138
ReceiVed July 28, 1997
The Chinese medicinal plant Tripterygium wilfordii Hook
(Celastraceae) has provided extracts with antitumor, antiinflam-
matory, and immunosuppressive activities1,2 and a number of
bioactive compounds, including the antitumor diterpenoids
triptolide and tripdiolide3 and the potent inhibitor of HIV
replication, neotripterifordin (EC50 25 nM).4,5 Neotripterifordin,
which had previously been assigned structure 1,5 is also of
interest as a challenging target for synthesis because of the
combined complexity of pentacyclic topology, stereochemistry,
and functionality. In this paper, we describe an enantioselective
total synthesis of neotripterifordin which dictates revision of
structure from 1 to 2. The absolute stereochemistry of the
synthetic neotripterifordin was set in place by a combination
of enantioselective catalytic epoxidation and oxirane-initiated
cation-olefin polyannulation.
Wittig coupling of unsaturated ketone 3 with phosphonium
ylide 46 (1.1 equiv) in 20:1 THF-HMPA at -78 °C for 1 h
and then at 23 °C for 5 h produced the Z-olefin 5 stereospe-
cifically in 82% yield.7 Conversion of 5 to the triene 6 was
accomplished in 85% yield by the following sequence: (1) THP
(tetrahydropyranyl) cleavage (0.1 equiv of pyridinium tosylate
in ethanol at 55 °C for 4 h); (2) oxidation of the allylic alcohol
(MnO2 in hexane at 23 °C for 1 h); (3) Wittig methylenation
(Ph3PdCH2 in THF at 23 °C); and (4) desilylation (Bu4NF,
THF, 23 °C, 4 h). Katsuki-Sharpless epoxidation8 of the allylic
alcohol subunit of 6 (0.09 equiv of (-)-diethyl tartrate, 0.075
equiv of Ti(Oi-Pr)4, 3 equiv of t-BuOOH, 4 Å molecular sieves,
CH2Cl2, at -23 °C for 2 h and -12 °C for 15 h) gave the
corresponding (R)-R,â-epoxy carbinol of 96% ee in 94% yield
which was O-benzylated (1.15 equiv of NaH, 1.1 equiv of
benzyl bromide, 0.1 equiv of n-Bu4NI in THF at 23 °C for 6 h)
to form the chiral epoxy diene ether 7 in 94% yield. Treatment
of 7 with 1.2 equiv of TiCl4 in CH2Cl2 at -94 °C for 10 min
effected a remarkably clean and stereoselective double-annu-
(1) Kashiwada, Y.; Nishizawa, M.; Yamagishi, T.; Tanaka, T.; Nanaka,
G. L.; Cosentino, L. M.; Snider, J. V.; Lee, K. H. J. Nat. Prod. 1995, 58,
392.
(9) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(10) (a) Corey, E. J.; Bass, J. D.; Le Mahieu, R.; Mitra, R. B. J. Am.
Chem. Soc. 1964, 86, 5570. (b) Crimmins, M. T.; Reinhold: T. L. Org.
React. 1994, 44, 297. (c) In addition to 12, the allene photoaddition reaction
produced the diastereomeric R-cycloadduct in 24% yield.
(11) Schreiber, S. L.; Santini, C. J. Am. Chem. Soc. 1984, 106, 4038.
(12) (a) Muler, S.; Liepold, B.; Roth, G. T.; Bestmann, H. J. Synlett
1996, 521. (b) Ohira, S. Synth. Commun. 1989, 19, 561.
(2) Leigongteng Research Group of Giangsu. Ann. Acad. Med. Sinica
1982, 3.
(3) Kupchan, S. M.; Court, W. A.; Dailey, R. G.; Gilmore, J. C. J.; Bryan,
R. F J. Am. Chem. Soc. 1972, 94, 7194.
(4) Chen, K.; Shi, Q.; Fujioka, T.; Zhang, D. C.; Hu, C. Q.; Jin, J. Q.;
Kilkuskie, R. E.; Lee, K. H. J. Nat. Prod. 1992, 55, 88.
(5) Chen, K.; Shi, Q.; Fujioka, T.; Nakano, T.; Hu, C.-Q.; Jin, J.-Q;
Kilkuskie, R. E.; Lee, K.-H. Bioorg. Med. Chem. 1995, 3, 1345.
(6) The Wittig reaction components 3 and 4 were prepared by standard
methods using procedures described in the Supporting Information.
(7) For precedent, see: (a) Sreekumar, C.; Darst, K. P.; Still, W. C. J.
Org. Chem. 1980, 45, 4260. (b) Inoue, S.; Honda, K.; Iwase, N.; Sato, K.
Bull. Soc. Chem. Jpn. 1990, 63, 1629.
(13) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
(14) We are grateful to Dr. Khozirah Shaari of the Forest Products
Research Institute Malaysia (Kuala Lampur) and Drs. Ke Chen and K.-H.
Lee of the University of North Carolina for providing authentic samples of
neotripterifordin.
(15) Since it is clear that epoxidation of 15 must occur at the less sterically
shielded re face of C(16), the stereochemistry in 2 follows unambiguously;
a similar argument applies to the introduction of the C(16) stereocenter in
1. See: Carman, R. M. Aust. J. Chem. 1981, 34, 923.
(8) Gao, Y.; Hanson, R. M.; Klunder, J. M; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
S0002-7863(97)02549-3 CCC: $14.00 © 1997 American Chemical Society
Corey
