Catalyzed asymmetric Diels-Alder reaction of benzoquinone. Total synthesis of (-)-ibogamine

Article abstract of DOI:10.1021/ol0001463

(equation presented) The Diels-Alder addition of diene 2 with benzoquinone catalyzed by (S)-BINOL-TiCl₂ produced cycloadduct 5 in >65% yield and 87% ee. The cycloadduct was transformed into (-)-ibogamine in nine steps (10% overall yield from be

Full text of DOI:10.1021/ol0001463

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2373-2376
Catalyzed Asymmetric Diels−Alder
Reaction of Benzoquinone. Total
Synthesis of (−)-Ibogamine†
James D. White* and Younggi Choi
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331-4003
james.white@orst.edu
Received June 5, 2000
ABSTRACT
The Diels−Alder addition of diene 2 with benzoquinone catalyzed by (S)-BINOL−TiCl2 produced cycloadduct 5 in >65% yield and 87% ee. The
cycloadduct was transformed into (−)-ibogamine in nine steps (10% overall yield from benzoquinone). A model for the transition state leading
to 5 is proposed.
The catalyzed asymmetric Diels-Alder reaction is among
the most powerful constructs for assembling a six-membered
ring in a stereocontrolled fashion.1 Many cycloadditions of
this class rely on two-point ligation of a chiral catalyst to
the dienophile, often a â-dicarbonyl system, so that only one
face of the dienophile is exposed to the diene partner. Single-
point ligation of an achiral dienophile to an asymmetric
catalyst will generally require a secondary interaction, either
electronic or steric, between the dienophile and catalyst for
good enantioselectivity. A few catalyzed asymmetric Diels-
Alder reactions of this latter type have been reported,2
including one involving naphthoquinone,3 but to our knowl-
edge none has involved benzoquinone as the dienophile. We
now describe a cycloaddition of benzoquinone to an achiral
diene which proceeds with high enantioselectivity in the
presence of a chiral catalyst, and we further demonstrate the
utility of this process in an asymmetric synthesis leading to
the indole alkaloid (-)-ibogamine (1).4,5
by Suzuki cross-coupling7 with bromo ether 3. Completion
of the uncatalyzed cycloaddition of benzoquinone to 2
required several hours at 80 °C, although the reaction was
cleanly endo selective. By contrast, the reaction of 2 with
benzoquinone in the presence of the (S)-BINOL complex 43
(30 mol %) was complete in 0.5 h at room temperature and
afforded the unstable endo adduct 5 in good yield. This
diketone was reduced under Luche conditions8 to give
hydroxy ketone 6 (65% from 2) which was converted to its
(4) Previous syntheses of (()-1: (a) Bu¨chi, G.; Coffen, D. L.; Kocsis,
K.; Sonnet, P. E.; Ziegler, F. E. J. Am. Chem. Soc. 1965, 87, 2073. (b)
Bu¨chi, G.; Coffen, D. L.; Kocsis, K.; Sonnet, P. E.; Ziegler, F. E. J. Am.
Chem. Soc. 1966, 88, 3099. (c) Sallay, S. I. J. Am. Chem. Soc. 1967, 89,
6762. (d) Nagata, W.; Hirai, S.; Okumura, T.; Kawata, K. J. Am. Chem.
Soc. 1968, 90, 1650. (e) Ikezaki, M.; Wakamatsu, T.; Ban, Y. J. Chem.
Soc., Chem. Commun. 1969, 88. (f) Rosenmund, P.; Haase, W. H.; Bauer,
J.; Frische, R. Chem. Ber. 1975, 108, 1871. (g) Atta-ur-Rahman; Beisler,
J. A.; Harley-Mason, J. Tetrahedron 1980, 36, 1063. (h) Imanishi, T.; Yagi,
N.; Hanaoka, M. Chem. Pharm. Bull. 1985, 33, 4202. (i) Huffman, J. W.;
Shanmugasundaram, G.; Sawdaye, R.; Raveendranath, P. C.; Desai, R. C.
J. Org. Chem. 1985, 50, 1460. (j) Kuehne, M. E.; Reider, P. J. J. Org.
Chem. 1985, 50, 1464. (k) Herdeis, C.; Hartke-Karger, C. Justus Liebigs
Ann. Chem. 1991, 99. (l) Henry, K. J., Jr.; Grieco, P. A.; Dubay, W. J.
Tetrahedron Lett. 1996, 37, 8289.
The diene 2 selected for this study was prepared from
1-butyne by hydroboration with catecholborane6 followed
† This paper is dedicated to the memory of Professor George Bu¨chi.
(1) For recent reviews, see: (a) Evans, D. A,; Johnson, J. S. Compr.
Asymm. Catal. 1999, 3, 1177. (b) Dias, L. C. J. Braz. Chem. Soc. 1997, 8,
289. (c) Kagan, H. B.; Riant, O. Chem. ReV. 1992, 92, 1007.
(2) Hawkins, J. M.; Loren, S. J. Am. Chem. Soc. 1991, 113, 7794.
(3) Mikami, K.; Motoyama, Y.; Terada, M. J. Am. Chem. Soc. 1994,
116, 2812.
(5) An asymmetric synthesis leading to an 80:20 mixture of enantiomers
of ibogamine favoring (+)-1 was accomplished by Trost (see Trost, B. M.;
Godleski, S. A.; Genet, J. P. J. Am. Chem. Soc. 1978, 100, 3930).
(6) (a) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1971, 93, 1816.
(b) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94, 4370.
(7) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(8) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454.
10.1021/ol0001463 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/29/2000

Mosher ester;9 the ee of 5 determined from both 1H and 19
F
conditions,8 followed by treatment of 9 with N-bromosuc-
NMR measurements on this ester was 87%. Decreasing the
reaction temperature of the Diels-Alder reaction to 0 °C
led to only a slight increase in yield and ee, but the protocol
used to obtain the chiral catalyst 4 had a profound effect on
the reaction. The catalyst prepared in situ by the method of
Mikami3 (BINOL + (i-PrO)2TiCl2) gave consistently good
yields and ee’s of 5, but an alternative method10 (BINOL +
(i-PrO)4Ti + SiCl4) for obtaining 4 resulted in significantly
lower yields and enantioselectivity. The catalyst TADDOL-
Ti11 also gave low ee values (26-58%) and yields (25-
41%) of 5 (Scheme 1).
cinimide (Scheme 2). This gave a 3:2 mixture of inseparable
Scheme 2a
Scheme 1a
bromo ethers 10 and 11 which was oxidized to enones 12
and 13. Ketone 12 crystallized from this mixture, and X-ray
analysis using anomalous dispersion confirmed its absolute
configuration as shown.13
Diol 9 was the pivotal substance in our plan for the
synthesis of natural (-)-ibogamine (1) which was patterned
after an earlier synthesis of the racemic alkaloid by Sallay.4c
Clean saturation of both olefinic bonds was accomplished
by hydrogenation over rhodium on alumina and resulted in
endo orientation of all four substituents on the cis-fused
decalin framework. Oxidation of the diol then gave diketone
14 (Scheme 3). Selective protection of the less hindered
ketone as its dimethyl ketal was accompanied by loss of the
tert-butyldimethylsilyl ether to yield 15, but this inadvertent
cleavage was turned into an advantage since it proved
necessary to blockade the primary alcohol with the more
robust triisopropylsilyl protecting group for a subsequent
Beckmann rearrangement.
The triisopropylsilyl ether of 15 was converted to anti
oxime 16 which underwent smooth Beckmann rearrangement
in the presence of p-toluenesulfonyl chloride to afford lactam
17.14 Elaboration of 17 into the azatricyclic core of 1 was
initially attempted through amino alcohol 18, obtained by
reduction of the lactam with Red-Al followed by cleavage
of the silyl ether. However, neither a Mitsunobu reaction15
nor any other method16 for effecting intramolecular displace-
The absolute configuration of 6, and hence 5, was
determined from the H NMR spectra of mandelates 7 and
1
8. The Mosher model as applied to mandelates by Trost12
predicts that Ha in (R)-mandelate 7 will be shielded by the
phenyl substituent relative to the corresponding proton in
the (S) diastereoisomer 8, and this is indeed the case (∆δ )
0.20 ppm). Further proof of the absolute configuration of 5
was obtained by its exhaustive reduction to 9 under Luche
(9) Dale, J. A.; Mosher, H. S.J. Am. Chem. Soc. 1973, 95, 512.
(10) Corey, E. J.; Matsumura, Y. Tetrahedron Lett. 1991, 32, 6289.
(11) Narasaka, K.; Iwasawa, N.; Inoue, M.; Yamada, T.; Nakashima,
M.; Sugimori, J. J. Am. Chem. Soc. 1989, 111, 5340.
(12) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S.
L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370.
(13) It is noteworthy that the absolute configuration of 5 corresponds to
that observed by Mikami (ref 3) for the Diels-Alder adduct obtained from
the reaction of 1-methoxybutadiene with naphthoquinone catalyzed by (S)-
4.
(14) For a contemporary view of the classical Beckmann rearrangement,
see: Nguyen, M. T.; Raspoet, G.; Vanquickenborne, L. G. J. Am. Chem.
Soc. 1997, 119, 2552.
2374
Org. Lett., Vol. 2, No. 15, 2000

Scheme 3a
Scheme 4a
(c 0.2, EtOH)] identical with a sample of the natural alkaloid
[mp 159-161 °C (lit.19 162-163 °C); [R]23 -45.0 (c 1.29,
EtOH) (lit.19 -36.4, CHCl3)] by comparison of IR and NMR
spectra. (-)-Ibogamine was obtained in 14 steps and 10%
overall yield from benzoquinone by this route.
A possible transition state for the enantioselective and
regioselective endo Diels-Alder addition leading to 5 is
shown in Figure 1. This model postulates a π-π interaction
ment of the hydroxyl substituent by the secondary amine
was successful, and it became clear from examination of a
molecular model that the conformation of 18 needed to
connect N and C1 creates a transannular steric repulsion
between the interior hydrogen of the CH2N moiety and the
endo OMe group of the dimethyl ketal. This analysis
suggested that lactam 17, in which the offending sp3 carbon
is replaced by a carbonyl, would be a more tractable substrate
for constructing the alicyclic framework of 1, and to this
end the TIPS ether 17 was advanced to tosylate 19 (Scheme
4). Exposure of the latter to sodium hydride resulted in clean
cyclization to furnish 20. After transketalization of 20 with
acetone, the resultant keto lactam was subjected to Fischer
indolization17 to yield 21. Reduction of this lactam proved
unexpectedly difficult and could not be accomplished with
conventional hydride reagents. Fortunately, 21 was reduced
efficiently with borane generated in situ18 and produced
crystalline (-)-ibogamine [mp 156-157 °C, [R]2D3 -45.8
Figure 1. Proposed (S)-Binol-TiCl2-benzoquinone complex in
which the top face of the more remote double bond of the quinone
is exposed for endo cycloaddition of 2, leading to 5.
between catalyst 4 and benzoquinone which allows exposure
of only one face of one of the two double bonds of the
quinone to the diene.20 Further studies, particularly with other
dienes, are needed to evaluate this model, but the superior
(15) (a) Mitsunobu, O. Synthesis 1981, 1. (b) For an application to
alkaloid synthesis, see: Simon, Cs.; Hosztafi, S.; Makleit, S. J. Heterocycl.
Chem. 1997, 34, 349.
(16) Shishido, Y.; Kibayashi, C. J. Org. Chem. 1992, 57, 2876.
(17) Robinson, B. The Fischer Indole Synthesis; J. Wiley & Sons: New
York. 1982.
(18) Sundberg, R. J.; Hong, J.; Smith, S. Q.; Sabat, M. Tetrahedron 1998,
54, 6259.
(19) Dickel, D. F.; Holden, C. L.; Maxfield, R. C.; Paszek, L. E.; Taylor,
W. I. J. Am. Chem. Soc. 1958, 80, 123.
Org. Lett., Vol. 2, No. 15, 2000
2375

asymmetric induction observed with 4 as catalyst indicates
that efficient enantioselective cycloaddition with a dienophile
such as benzoquinone is indeed possible.
Professor John Huffman, Clemson University, for a sample
of natural ibogamine. Financial support was provided by the
National Science Foundation (9711187-CHE).
Supporting Information Available: Characterization
data and procedures for preparation of 2, 5-17, 19-21, and
(-)-1; X-ray crystallographic data for 12. This material is
available free of charge via the Internet at http://pubs.acs.org
Acknowledgment. We are grateful to Dr. Alexandre F.
T. Yokochi for the X-ray crystal structure of 12 and to
(20) No evidence for a charge-transfer band was found in the UV-visible
spectrum of a mixture of 4 and benzoquinone. However, the solution
containing these compounds was an intense red-brown color.
OL0001463
2376
Org. Lett., Vol. 2, No. 15, 2000