First asymmetric synthesis of a Hasubanan alkaloid. Total synthesis of (+)-Cepharamine [8]

Full text of DOI:10.1021/ja981624w

J. Am. Chem. Soc. 1998, 120, 8259-8260
8259
Scheme 1a
First Asymmetric Synthesis of a Hasubanan Alkaloid.
Total Synthesis of (+)-Cepharamine
Arthur G. Schultz* and Aihua Wang
Department of Chemistry
Rensselaer Polytechnic Institute
Troy, New York 12180-3590
ReceiVed May 11, 1998
(-)-Cepharamine (1), isolated from Stephania cepharantha
Haijata, is a member of the hasubanan family of alkaloids.1 The
hasubanan alkaloids are of pharmacological interest because of
their structural resemblance to the morphine alkaloids; see
morphine (2).2 However, the absolute configuration at C(13) in
1 is opposite to that in morphine, resulting in an inversion of the
critical spatial relationship of the nitrogen atom to the aromatic
ring in 1 relative to 2. Thus, the natural enantiomers of
cepharamine and other hasubanan alkaloids are expected to be
ineffective analgesic agents.3 Although there has been substantial
interest in the synthesis of hasubanan alkaloids,4,5 an enantiose-
lective synthesis has not been reported. Herein we describe the
first asymmetric synthesis of (+)-cepharamine, the unnatural
enantiomer of 1, by a highly convergent strategy dependent upon
the asymmetric Birch reduction-alkylation protocol6 and a radical
cyclization reaction to fashion the critical C(9)-C(14) and C(12)-
C(13) bonds.
a Reaction conditions: (a) BF3‚OEt2, Bu4NF‚XH2O, CH2Cl2; (b)
NaBH4, THF; (c) PTSA, PhH, reflux; (d) CH3CO2CHO, pyridine, CH2Cl2;
(e) t-BuOOH, CuBr, PhH; (f) (TMSOCH2)2, TMSOTf; (g) AIBN,
Bu3SnH, PhH, reflux; (h) Na2CO3, MeOH, H2O, THF; (i) NaH, THF,
MOMCl, reflux; (j) NH3, THF, -33 °C to 25 °C; (k) MeOH, THF, -78
°C to reflux; (l) THF, reflux; (m) Et3N, CH2Cl2, -10 °C; (n) 18-crown-
6, DMF, 25 °C; (o) acetone, H2O, reflux.
Birch reduction of the chiral benzamide 37 with potassium in
NH3, THF, and tert-butyl alcohol (1 equiv) at -78 °C, followed
by addition of LiBr8 and then the alkylation reagent 49 gave the
1,4-cyclohexadiene 5 in 95% yield as a single diastereomer
(Scheme 1).10,11 Enol ether hydrolysis12 and reduction of the
resulting cyclohexenone derivative with NaBH4 gave a mixture
of diastereomerically related alcohols (∼1:1). As expected from
earlier model studies,13 both diastereomers gave the phenolic
lactone 6 on treatment with p-toluenesulfonic acid (PTSA) in
refluxing benzene solution. It is assumed that the syn-hydroxya-
mide converts to 6 by an acid-catalyzed transesterification and
the anti-hydroxyamide by an amide carbonyl assisted ionization
of the protonated alcohol.
(1) (a) Bentley, K. W. In The Alkaloids; Manske, R. H. F., Ed.; Academic
Press: New York, 1971; Vol. 13, pp 131-143. (b) Inubushi, Y.; Ibuka, T. In
The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1977;
Vol. 16, pp 393-430. (c) Matsui, M. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1988; Vol. 33, pp 307-347.
(2) For the pharmacology of the hasubanan alkaloids, see ref 1c.
(3) The unnatural enantiomers of codeine, morphine, and heroin showed
no antinociceptive activity on subcutaneous injection in mice; see: Iijima, I.;
Minamikawa, J.; Jacobson, A. E.; Brossi, A.; Rice, K. J. Org. Chem. 1978,
43, 1462-1463.
(4) For syntheses of racemic cepharamine, see: (a) Inubushi, Y.; Ibuka,
T.; Kitano, M. Tetrahedron Lett. 1969, 1611-1614. (b) Inubushi, Y.; Kitano,
M.; Ibuka, T. Chem. Pharm. Bull. 1971, 19, 1820-1841. (c) Kametani, T.;
Nemoto, H.; Kobari, T.; Shishido, K.; Fukumoto, K. Chem. Ind. (London)
1972, 538-540. (d) Kametani, T.; Kobari, T.; Fukumoto, K. J. Chem. Soc.,
Chem. Commun. 1972, 288-289. (e) Kametani, T.; Kobari, T.; Shishido, K.;
Fukumoto, K. Tetrahedron 1974, 30, 1059-1064. (f) Schwartz, M.; Wallace,
R. Tetrahedron Lett. 1979, 3257-3260.
Although it was found that 6 underwent radical cyclization (as
the unprotected phenol) to give the desired hydrophenanthrene
ring system,14 problems associated with the development of a
regiospecific construction of the 7-methoxy enone functionality
(5) For syntheses of some congeners of the hasubanan alkaloids, see (a)
Okuda, S.; Tsuda, K.; Yamaguchi, S. J. Org. Chem. 1962, 27, 4121-4122.
(b) Tomita, M.; Kitano, M.; Ibuka, T. Tetrahedron Lett. 1968, 3391-3393.
(c) Evans, D. A.; Bryan, C. A.; Wahl, G. M. J. Org. Chem. 1970, 35, 4122-
4127. (d) Keely, S. L., Jr.; Martinez, A. J.; Tahk, F. C. Tetrahedron 1970,
26, 4729-4742. (e) Evans, D. A.; Bryan, C. A.; Sims, C. L. J. Am. Chem.
Soc. 1972, 94, 2891-2892. (f) Monkovic, I.; Conway, T. T.; Wong, H.; Perron,
Y. G.; Pachter, I. J.; Belleau, B. J. Am. Chem. Soc. 1973, 95, 7910-7912. (h)
Monkovic, I.; Wong, H. Can. J. Chem. 1976, 54, 883-891.
(9) Alkylation reagent 4 was prepared in 5 steps (55% overall yield) from
isovanillin by modification of a literature procedure; see: Toth, J. E.; Hamann,
P. R.; Fuchs, P. L. J. Org. Chem. 1988, 53, 4694-4708.
(10) For the related highly diastereoselective alkylation of a chiral 2-alkyl
substituted benzamide, see: Schultz, A. G.; Kirincich, S. J. J. Org. Chem.
1996, 61, 5626-5630.
1
(11) All synthetic intermediates were characterized by H and 13C NMR,
IR and low resolution MS analyses. Compounds 3, 6, 9a, 12, 13, and 14 gave
satisfactory combustion analyses. All other compounds gave satisfactory high-
resolution MS analyses.
(6) (a) Schultz, A. G. Acc. Chem. Res. 1990, 23, 207-213. (b) Schultz, A.
G. J. Chin. Chem. Soc. (Taiwan) 1994, 41, 487-495.
(12) Gevorgyan, V.; Yamamoto, Y. Tetrahedron Lett. 1995, 36, 7765-
7766.
(13) Wang, A. Ph.D. Thesis, Rensselaer Polytechnic Institute, 1997.
(14) For a discussion of the importance of the lactone bridge in a substrate
related to 6 that undergoes radical cyclization by the 6-exo-trig pathway, see:
Schultz, A. G.; Wang, A. J. Org. Chem. 1996, 61, 4857-4859.
(7) Benzamide 3 was prepared in 5 steps (58% overall yield) from
commercially available 2-bromo-5-methoxybenzoic acid by way of a literature
procedure; see: Bruggink, A.; McKillop, A. Tetrahedron 1975, 31, 2607-
2619.
(8) LiBr is added to prevent elimination of HI from 4.
S0002-7863(98)01624-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/30/1998

8260 J. Am. Chem. Soc., Vol. 120, No. 32, 1998
Communications to the Editor
in cepharamine (Vide infra) required an earlier introduction of
the C(6) carbonyl group. Protection of the phenolic hydroxyl
group as the formate ester and allylic oxidation with tert-butyl
hydroperoxide and CuBr15 gave enone 7. Ketalization of 7 under
aprotic conditions16 provided 8, and radical cyclization of 8,
followed by basic hydrolysis of the formate ester gave 9a.
The phenol 9a was converted to a base-stable MOM derivative
9b, from which a very efficient Hofmann-type rearrangement gave
the cyclic carbamate 10. Formation of the cis-fused N-meth-
ylpyrrolidine ring was then effected in one experimental operation
by treatment of 10 with LiAlH4 in refluxing THF. This
remarkably efficient transformation of 10 to 11 evolved from a
careful study17 of the less efficient stepwise process involving
(1) cleavage of the aryl ether with CAN, (2) conversion of the
resulting alcohol to the mesylate, (3) intramolecular carbamate
N-alkylation, and (4) reduction of the cyclic carbamate with
LiAlH4.
Swern oxidation of 11 gave ketone 12, and alkylation of the
enolate of 12 under conditions that favor O-alkylation with MeI
afforded enol ether 13.18 It should be noted that this solution to
the challenge of construction of the C(6)-C(8) keto enol ether
in cepharamine is a considerable improvement with respect to
methodology involving oxidation to a 6,7-diketone derivative
followed by acid-catalyzed enol ether formation.19 Finally, acid-
catalyzed ketal and MOM ether hydrolysis proceeded without
disruption of the enol ether to give (+)-cepharamine (14) in 97%
yield: mp 184-185 °C (colorless prisms from ether); [R]26D +246
(c 2.8, CHCl3); lit. mp for (-)-cepharamine (1) 187-188 °C;
[R]22 -243 (c 0.88, CHCl3).20
D
In summary, the first asymmetric synthesis of a hasubanan
alkaloid, (+)-cepharamine (14), has been carried out with
complete regio- and stereocontrol. The synthesis of 14 required
16 steps from the chiral benzamide 3 and was carried out with
an overall yield of 12%. Important features of the synthesis are
the convergency of the asymmetric Birch reduction-alkylation
step 3 + 4 f 5, the efficient release of the chiral auxiliary by
the acid-catalyzed lactonization to give 6, the radical cyclization
that generates a quaternary center at C(13) by way of the 6-exo-
trig pathway, the efficient carboxyl to amino conversion 9b f
10 which very effectively extends the utility of the asymmetric
Birch reduction-alkylation protocol,21 and the development of a
potentially general solution to the introduction of C-ring func-
tionality in the hasubanan alkaloids. The opioid receptor
pharmacology of 14 and congeners is under investigation and will
be reported elsewhere when completed.
Acknowledgment. This work was supported by the National Institutes
of Health (GM 33061). This paper is dedicated to Professor Richard H.
Schlessinger, teacher and friend, who died on December 11, 1997.
Supporting Information Available: Experimental details and char-
acterization of isolated intermediates (14 pages, print/PDF). See any
current masthead page for ordering information and Web access
instructions.
(15) Salvador, J. A. R.; Sa´ e Melo, M. L.; Campos Neves, A. S. Tetrahedron
Lett. 1997, 38, 119-122.
(16) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21, 1357-
JA981624W
1358.
(17) Details of this study will be provided in the full account of this work.
(18) For an analogous O-alkylation of a ketone enolate flanked by two
quaternary centers, see: Schultz, A. G.; Kashdan, D. S. J. Org. Chem. 1973,
38, 3814-3815.
(19) For perspective, see the conversion of the keto lactam 65 to 68 (∼10%
yield) in ref 4b. In contrast to the reactivity of the lactam described in ref 4b,
the 6,7-diketone derived from 12 gave the regioisomeric keto enol ether. For
a related R-diketone O-alkylation developed in the context of cephalotaxine
construction, see: Burkholder, T. P.; Fuchs, P. L. J. Org. Chem. 1988, 110,
2341-2342.
(20) For a recent listing of physical and spectroscopic properties of (-)-
cepharamine, see: Kashiwaba, N.; Morooka, S.; Kimura, M.; Ono, M.; Toda,
J.; Suzuki, H.; Sano, T. J. Nat. Prod. 1996, 59, 476-480. IR, 1H and 13C
NMR spectra of (+)-cepharamine compared favorably to spectra of the natural
product. We thank Dr. Noriaki Kashiwaba and Professors Osamu Hoshino
and Toshiro Ibuka for the provision of key spectra of (-)-cepharamine.
(21) For a discussion of the strategic evolution of the asymmetric Birch
reduction-alkylation, see: Schultz, A. G.; Holoboski, M. A.; Smyth, M. S.
J. Am. Chem. Soc. 1996, 118, 6210-6219.