9074
J. Am. Chem. Soc. 1998, 120, 9074-9075
An asymmetric synthesis of chromans requires that the pal-
ladium-catalyzed allylic alkylation of phenols must be both
enantio- and regioselective.7 For example, our approach to the
preparation of the calanolide ring D chromanol requires a
palladium-catalyzed alkylation with tiglyl methyl carbonate
wherein attack of the phenol occurs at the more substituted
terminus of the π-allyl unit. However, previous work has shown
that phenols, especially ortho-substituted phenols, show a pro-
pensity for attack at the primary carbon of unsymmetrical
π-allylpalladium complexes.8 Therefore, our modular ligands (4-
6)9 must not only provide a mechanism for enantioselectivity but
A Catalytic Enantioselective Approach to Chromans
and Chromanols. A Total Synthesis of
(-)-Calanolides A and B and the Vitamin E Nucleus
Barry M. Trost* and F. Dean Toste
Department of Chemistry, Stanford UniVersity Stanford
California 94305-5080
ReceiVed April 6, 1998
Interest in calanolide A and B, isolated from several tropical
plants of the genus Calophyllum by Polonsky over 40 years ago,1
remained dormant until the mid-nineties. A flurry of synthetic
interest2 was spawned by the discovery that these coumarins were
HIV-1-specific reverse transcriptase inhibitors, with calanolide
A and B being the most potent.3 They are of special interest
because they are active against AZT-resistant strains of HIV-1.
Despite a number of synthetic efforts, only one asymmetric
synthesis of calanolides has been reported, and it required a
stoichiometric asymmetric reagent to create the chirality.2d
The key structural feature, both synthetically and biologically,
of the calanolides is the trisubstituted chroman ring.4 Its
stereochemistry, both relative and absolute, is the major challenge
in the synthesis of this biologically important class of molecules.
Furthermore, chiral chromans are prevalent in other natural
products, such as vitamin E, 3.5 We therefore sought a general
must also be able to reVerse the intrinsic regioselectiVity for attack
of phenols on these intermediates.10
We tested the feasibility to exercise regio- as well as enantio-
control by examining the palladium-catalyzed allylic alkylation
of 4-methoxyphenol 7a with crotyl methyl carbonate 8a (see Table
1 in Supporting Information). We were delighted to find that
using 3% ligand 4 with 1% Pd2dba3‚CHCl3 afforded the secondary
aryl ether 9a11 with excellent regioselectivity and 60-68% ee.
Lowering the temperature improved the enantioselectivity, but
as we have previously observed,7,12 there was an optimal
temperature below which the enantioselectivity deteriorates.
There was a clear influence of concentration on both the regio-
and enantioselectivity of the reaction. Slowing the rate of the
nucleophilic addition step by lowering the palladium catalyst
loading to 0.1% and the concentration of the reaction to 0.1 M
enabled us to isolate the secondary aryl ether 9a in a 94:6 ratio
and 83% ee. With this result in hand, we examined the palladium-
catalyzed reaction using tiglyl methyl carbonate 8b, the substrate
required for the calanolide synthesis. The palladium-catalyzed
reaction with 3,5-dimethoxyphenol 7b and the tiglyl carbonate
in the presence of ligand 4 afforded the secondary ether 9b in
90% ee but in slightly diminished regioselectivity (84:16).
Changing to the anthracene-based ligand 6 in THF improved the
route to the enantioselective preparation of chromans in which
the chirality was introduced in a catalytic reaction. We envisioned
an asymmetric O-alkylation of phenols followed by aromatic
substitution to close the ring.6 Besides the chromanol stereo-
chemistry, the synthesis of calanolides requires an efficient method
for the regioselective annulation of three rings onto a phloroglu-
cinol core, the chromanol (ring D), a chromene (ring C), and a
coumarin (ring B). Herein, we describe a new paradigm for the
enantioselective synthesis of chromans and chromanols which
culminates in a total synthesis of calanolides A and B and the
chroman nucleus of vitamin E.
(1) Polonsky, J. Bull. Chem. Soc. Fr. 1956, 914. Stout, G. H.; Hickernell,
G. K.; Sears, R. D. J. Org. Chem. 1968, 33, 3, 4191.
(2) For leading references see: (a) Deshpande, P. P.; Tagliferri, F.; Victory,
S. F.; Baker, D. C. J. Org. Chem. 1995, 60, 2964. (b) Rehder, K. S.; Kepler,
J. A. Synth. Commun. 1996, 26, 4005. (c) Khilevich, A.; Mar, A.; Flavin, M.
T.; Rizzo, J. D.; Lin, L.; Dzekhtser, S.; Brankovic, D.; Zhang, H.; Chen, W.;
Shuyuan, L.; Zembower, D. E.; Xu, Z.-Q. Tetrahedron: Asymmetry 1996, 7,
3315.
(7) We have previously reported on the use of 8a and 8b as substrates for
enantioselective allylations of sodium benzenesulfinate, a nucleophile which
shows a propensity for secondary attack even in the presence of achiral ligands.
Trost, B. M.; Krische, M. J.; Radinov, R.; Zanoni, G. J. Am. Chem. Soc. 1996,
118, 6257.
(3) Galinas, D. L.; Fuller, R. W.; McKee, T. C.; Cardellina, J. H., II;
Gulakowski, R. B.; McMahon, J. B.; Boyd, M. R. J. Med. Chem. 1996, 39,
4507 and references therein.
(4) For syntheses of ring D, see: Rama Rao, A. V.; Gaitonde, A. S.;
Prakash, K. R. C.; Prahlada Rao, S. A. Tetrahedron Lett. 1994, 35, 6347.
Ishikawa, T.; Oku, Y.; Ken-Ichiro, K.; Ishii, H. J. Org. Chem. 1996, 61, 6484.
(5) For some recent asymmetric approaches to vitamin E, see: Harada,
T.; Hayashiya, T.; Wada, I.; Iwa-ake, N.; Oku, A. J. Am. Chem. Soc. 1987,
109, 527. Inoue, S.; Ikeda, H.; Sato, S.; Horie, K.; Ota, T.; Miyamoto, O.;
Sato, K. J. Org. Chem. 1987, 52, 5497. Hubsher, J.; Barner, R. HelV. Chem.
Acta 1990, 73, 1068; Mizuguchi, S.; Suzuki, T.; Achiwa, K. Synlett 1996,
743. Tietze, L. F.; Go¨rlitzer, J. Synthesis 1997, 877.
(6) This approach is conceptually different from other chroman syntheses
in which the C-C bond is formed first, followed by C-O bond formation.
For a recent enantioselective example of this, see: Uozumi, Y.; Kato, K.;
Hayashi, T. J. Am. Chem. Soc. 1997, 119, 5063.
(8) (a) Takahashi, K.; Miyake, A.; Hata, G. Bull. Chem. Soc. Jpn. 1972,
45, 230. (b) Goux, C.; Lhoste, P.; Sinou, D. Synlett 1992, 725. (c) Goux, C.;
Massacret, M.; Lhoste, P.; Sinou, D. Organometallics 1995, 14, 4585.
(9) Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992,
114, 9327. Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089. For
a review, see: Trost, B. M. Acc. Chem. Res. 1994, 27, 4089.
(10) An alternative approach to the control of regioselectivity utilizes aryl
allyl carbonates as substrates; however, poor enantioselectivty (11%) was
obtained. Consiglio, G.; Scalone, M.; Franco, R. J. Mol. Catal. 1989, 50, L11.
(11) The absolute stereochemistry was determined by hydrogenating 9a
and comparing the saturated product to an authentic sample prepared by
Mitsonobu reaction of 7a with (R)-2-butanol.
(12) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 815.
S0002-7863(98)01142-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/21/1998