10948
J. Am. Chem. SOC. 1994,116, 10948-10954
Asymmetric Tandem Claisen-Ene Strategy for Convergent Synthesis of (+)-9( 11)-Dehydroestrone Methyl Ether: Stereochemical Studies on the Ene Cyclization and Cyclic Enol Ether Claisen Rearrangement for Steroid Total Synthesis Koichi Mikami; Kazuhiko Takahashi, Takeshi Nakai, and Tadafumi Uchimaru? Contribution from the Department of Chemical Technology, Tokyo Institute of Technology, Meguro-ku, Tokyo 152, Japan, and National Institute of Materials and Chemical Research, AIST, MITI, Tsukuba, Science City 305, Japan Received April 18, 1994@
Abstract: An asymmetric synthesis of (+)-9(1l)-dehydroestrone methyl ether (l), a key intermediate for estrogen analogs, is described using a new strategy of consecutive carbocyclizations for the D and C rings of the steroid skeleton based on an asymmetric tandem Claisen-ene sequence. Studies of the stereochemical features of the cyclic enol ether Claisen rearrangement and intramolecular ene reaction are also reported. In the model study of the ene cyclizations, high trans diastereofacial selectivity is found for the a-alkylcrotyl and the a&-dialkylcrotyl ether systems with a methoxycarbonyl group at the acetylenic terminus, which remarkably facilitates the ene cyclization. The Claisen rearrangements of the enol ethers of cyclic ketones were found to exhibit a high level of either anti or syn diastereoselectivity along with high E olefinic stereoselectivity by making judicious use of either 2,6-dimethylphenol or PdC12(RCN)2 as the catalyst.
Steroids have played vital roles as target molecules in the development of new synthetic strategies, because of their welldefined structures which provide an opportunity to test new methodologies and explore their stereochemistry.’S2 The concept of “tandem reaction ~ e q u e n c e ”has ~ been used for shortening of the synthetic sequence and for relaying of stereochemical control in a multistep synthesis of complex natural products. Herein we report the asymmetric tandem Claisen rearrangement and ene reaction sequence as an efficient strategy for the asymmetric synthesis of (+)-9( 11)-dehydroestronemethyl ether (l),a key intermediate for estrogen^.^,^ The key transformation is the convergent combination of the A,B and C,D ring synthons by the asymmetric Claisen-ene sequence (I I1 In), which
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* Address correspondenceto this author at Tokyo Institute of Technology. National Institute of Materials and Chemical Research. @Abstractpublished in Advance ACS Abstracts, November 1, 1994. (1) Reviews: (a) Groen, M. B.; Zeelen, F. J. Recl. Trav. Chim. PaysBas 1986,105,465.(b) Taub, D. In The Total Synthesis of Natural Products; ApSimon, J., Ed.; John Wiley: New York, 1984; Vol. 6. (c) Blickenstaff, R. T.; Ghosh, A. C.; Wolf, G. C. Total Synthesis of Steroids; Academic Press: New York, 1974. (d) Fieser, L. F.; Fieser, M. Steroids; Reinhold: New York, 1959. (2) Recent examples: (a) Horiguchi, Y.; Nakamura, E.; Kuwajima, I. J. Am. Chem. SOC. 1989, 11I , 6257. (b) Takahashi, T.; Shimizu, K.; Doi, T.; Tsuji, J. J. Am. Chem. SOC. 1988, 110, 2674. (c) Stork, G.; Saccomano, N. A. Tetrahedron Lett. 1987, 28, 2087. (d) Johnson, W. S.; Lindell, S. D.; Steele, J. J. Am. Chem. SOC. 1987, 109, 5852. (e) Ziegler, F. E.; Wang, T. F. J. Am. Chem. SOC.1984, 106, 718. (3) Reviews: (a) Ziegler, F. E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 6, p 875. (b) Mikami, K.; Nakai, T. Synthesis 1991,594 Nakai, T.; Mikami, K. Kagaku no Ryoiki 1982, 36, 661; Chem. Abstr. 1982, 96, 16001. For a recent example of the tandem Claisen-ene reaction, see: Mandai, T.; Matsumoto, S.; Kohama, M.; Kawada, M.; Tsuji, J. J. Org. Chem. 1990, 55, 5671. (4) (a) Posner, G. H.; Switzer, C. J. Am. Chem. SOC. 1986, 108, 1239. (b) Ziegler, F. E.; Lim, H. J. Org. Chem. 1982, 47, 5230. (c) Posner, G. H.; Mallamo, J. P.; Black, A. Y. Tetrahedron 1981,37,3921.(d) Quinckert, G.; Weber, W. D.; Schwartz, U.; Duemer, G. Angew. Chem., Int. Ed. Engl. 1980, 19, 1027; Quinckert, G.; Schwartz, U.; Stark, H.; Weber, W. D.; Baier, H.; Adam, F.; Duemer, G. Angew. Chem., Int. Ed. Engl. 1980, 19, 1029. (5) A preliminary report of this work Mikami, K.; Takahashi, K.; Nakai, T. J. Am. Chem. SOC. 1990, 112, 4035.
is theorized to proceed with high stereochemical control (Scheme 1). Thus, this tandem strategy investigates two stereochemical questions: (1) diastereoselectivity induced on C-8 and (2-14 (steroid numbering) of I1 in the Claisen rearrangements with the cyclic enol ether of steroid A,B-ring component 4, which should proceed with a high level of 1,3chirality transfer from C-12 to C-14 in compound I,6 (2) diastereofacial selectivity of the quaternary carbon C-13 (In) in the intramolecular ene reaction7 of substrate I1 having the chiral center C-14 on the ene component rather than the enophile.
Results and Discussion Diastereofacial Selectivity in Intramolecular Ene Reactions. Our total synthesis was preceded by the investigation of the diastereofacial selectivity of the intramolecular ene reaction of type 5-(3,4)s to construct the steroid D ring. The main point of interest was the stereocontrol over the newly created quaternary carbons, which had not been previously explored?x8 Furthermore, asymmetric ene cyclizations, hithertoreported, have used chiral enophiles9 rather than chiral ene components to induce diastereofacial selectivity. Allylic propargyl ethers 7 with a variety of substituents were prepared as model ene systems [X = O]loaby standard methods using phase transfer techniques. Methoxycarbonylation (n(6) Excellent review on the chirality transfer via sigmatropic rearrangements: Hill, R. K. In Asymmetric Synthesis; Momson, J. D, Ed.; Academic Press: New York, 1984; Vol. 3. (7)Reviews on intramolecular ene reactions: (a) Snider, B. B. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: London, 1991; Vols. 2 and 5. (b) Taber, D. F. Intramolecular DielsAlder and Alder Ene Reactions; Springer-Verlag: Berlin, 1984. (c) +poker, W.; Snieckus, V. Angew. Chem., Int. Ed. Engl. 1978, 17, 476. (8) In an intramolecular ene reaction, the carbon numbers, where the tether connects the ene and enophile components constituting the [1,5]hydrogen shift system, are exemplified in (m,n) fashion. The numerical prefut 1 stands for the f o d n g ring size. Thus, the present mode of fivemembered ring cyclization can be referred to as 5-(3,4), which corresponds to the five-membered ring cyclization via Oppolzer’s type I ene reaction. For the notation of l-(m,n), see a comprehensive review on ene reactions: Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021.
0002-786319411516-10948$04.50/0 0 1994 American Chemical Society
Synthesis of (+)-9(11)-Dehydroestrone Methyl Ether
J. Am. Chem. SOC.,Vol. 116, No. 24, 1994 10949
Scheme 1
Cleis
2
6
5
1
BuLUClC02CH3, THF, -78 OC)12 of the propargyl ethers 7 gave the ester derivatives 7'. The ene cyclizations of the propargyl ethers 7 and 7' were run on heating in sealed tubes. The trans configuration of the major diastereomer was assigned through comparison of its 13C NMR spectrum with that of the minor diastereomer; the configuration of the isomer in which C-a resonates at a lower field was assigned as trans.13 Table 1 summarizes the products 8 and their relative stereochemistry, which reveals the following significant features of those ene cyclizations.
7
8
(1) The ene cyclization is markedly enhanced by the (9) (a) Townsend, C. A.; Scholl, T.; Arigoni, D. J. Chem. Soc., Chem. Commun. 1975,921. (b)Nakatani, Y.; Kawashima, K. Synthesis 1978, 147. (c) Oppolzer, W.; Robbiani, C.; Battig, K. Helv. Chim. Acta 1980,63, 2015; Tetrahedron 1984, 40, 1391. (d) Tietze, L.-F.; Kiedrowski, G. V . Tetrahedron Lett. 1982, 22, 219. (e) Oppolzer, W.; Thirring, K. J. Am. Chem. SOC. 1982, 104, 4978. (f) Smith, A. B. lit Fukui, M. J. Am. Chem. SOC. 1987, 109, 1269. (8) Funakoshi, K.; Sakai, K.; Hata, T.; Tamura, C. Tetrahedron Lett. 1989, 30, 4849 and references cited therein. (10) (a) Mikami, K.; Takahashi, K.; Nakai, T. Chem. Lett. 1987, 2347. A few reports have appeared on similar 5-(3,4) ene cyclizations of related substrates: (b) [X = NR] Oppolzer, W.; Pfenninger, E.; Keller, K. Helv. Chim. Acta 1973,56, 1807. (c) [X = CHz] Reference 9a. (d) Snider, B. B.; Killinger, T. A. J. Org. Chem. 1978, 43, 2161. (e) [X = C(CN)OSiRs)] Stork, G.; Kraus, G. J. Am. Chem. SOC. 1976, 98, 6747. (11) Mikami, K.; Azuma, K.; Nakai, T. Tetrahedron 1984, 46, 2303. (12) Taschener, M. J.; Rosen, T.; Heathcock, C. H. Org. Synth. 1985, 64, 108. (13) Eliel, E. L.; Rao, V. S.; Dietrusiewicz, K. M. Org. Magn. Reson. 1979, 12, 461.
Table 1. Thermal Ene Cyclization entry ether R'
R2
R3
temp ("C)/ % time (h) product yield"
trans:
cisb ~
1 2 3 4 5 6 7
7
a
H 7'b H 7'c Me 7'd i-Pr 7'e Ph 7'f i-Pr 7'g Ph
H
H H COzMe H C02Me H COzMe H C02Me Me COzMe Me C02Me
250/6 200/1 130/24 130124 130/24 130/24 130/24
Sa
8b 8c 8d 8e 8f Sg
95 98 90 90 97 93 88
86:14 '95:'s 93:7 90:lO 92:8
Isolated yield after column chromatography. Determined by %C (Zorbax SIL, hexane/ethyl acetate) and/or 'H NMR.
introduction of an electron-withdrawing ester group at the acetylenic terminus (e.g., entry 1 vs 2).lod (2) Relatively high levels of 1,2-asymmetric induction, i.e., trans diastereofacial selection, were observed (entries 3-7). Particularly noteworthy is that the remarkably high selectivity is obtained with the substrates bearing the bulky a-substituents (entries 4-7). (3) It should be noted here that quaternary carbons can be generated with high levels of trans diastereofacial selectivity as observed with the B-methylcrotyl ether systems (entries 6 and 7 ) . The high trans diastereofacial selectivity is desired in the stereoselective construction of the steroid D ring and hence is of mechanistic importance. The trans diastereofacial selectivity may be reasonably explained in terms of ab initio MM2 transition state models A and B.14 Of the two transition states A and B, transition state A leading to the trans configuration is sterically less congested than transition state B leading to the (14) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y. D.; Brown, F. K.; Spellmeyer, D. C.; Mew, J. T.; Li, Y.;Loncharich, R. Science 1986, 231, 1108.
10950 J. Am. Chem. SOC., Vol. 116, No. 24, 1994
Mikami et al.
Table 2. Cyclic Enol Ether Claisen Rearrangements enol ether
alcohol
entry
1 2 3 4
(E)-9a (R = H)'
5 6 7 8 9 1Oh 11 12 13
(Z)-9a (R = H)d
catalyst Hg(OAch
4
DMP PdClz(PhCN)Z DMP PdClZ(PhCN)z DMP PdClZ(PhCN)z DMP PdC12(MeCN)2 DMP DMP DMP
(E)-9b(R = i-Buy (E)-9a (R = H)'
10
(Z)-9a (R = H)d (E)-9c(R = Me)' (Z)-9c (R = Me)'
temp (OC)/time(h) 140/10 100/17 100117 rt/3 100117 rt/24 100/10 rt/l 120/14 rt/lO 120114 120114 120114
product lla
llbs 12a 1243
% yield"
antilsynb
95 91 94 95 95 4@ 95 95 95 78 95 95 95
61:39 77:23 94:6 13:87 1585 21:79 >95:
