11106
J. Am. Chem. SOC.1995,117, 11106-11112
Asymmetric Total Synthesis of the Stemona Alkaloid (-)-Stenine Peter Wipf,* Yuntae Kim, and David M. Goldstein Contribution from the Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 Received July 6, 1995@
Abstract: Stenine can be extracted from the roots of the Chinese medicinal plant Stemona tuberosa (Stemonaceae), and its structure and absolute configuration were derived by comparison to the major Stemona alkaloid tuberostemonine. We report the first enantioselective total synthesis of (-)-stenine by a strategy that takes advantage of a diastereoselective end-group-differentiatingcyclization in the oxidation of L-tyrosine. The resulting cis-fused indolone is converted to the trans-fused core of stenine upon reduction of a n-allylpalladium complex, and by stereoselective introduction of four additional stereocenters, a butyrolactone and an azepine ring are attached to this alkaloid building block.
Extracts of Stemona and Croomia species have been used in Chinese and Japanese folk medicine as insecticides, as drugs for the treatment of respiratory diseases such as bronchitis, pertussis, and tuberculosis, and as antihelmintics.' A large number of polycyclic alkaloids are found in the roots and rhizomes of Stemonaceae, and to date, the diverse structures of more than 20 polycyclic members of this class have been elucidated by a combination of crystallographic, spectroscopic, and degradative techniques.2 However, synthetic work has been quite limited, with total syntheses of racemic stenine reported by Hart and Chen3 and (+)-croomine and (-)-stemoamide by Williams4 and c o - ~ o r k e r s . ~ The efficient preparation of the novel and highly functionalized azepinoindole core of the major Stemona alkaloids stenine (1)6 and tuberostemonine (2)' offers an interesting synthetic problem. We envisioned a concise entry toward the perhydroindole ring system by means of bicycle 3, which is obtained enantio- and diastereomerically pure in a single step from L-tyrosine (4).* In this article, we document the potential for a general use of 3 in pyrrolidine alkaloid synthesis with a specific application for the first asymmetric synthesis of (-)-stenhe. A Abstract published in Advance ACS Abstracts, November 1, 1995. (1) (a) Gotz, M.; Strunz, G. M. Tuberostemonine and related compounds. Chemistry of the Stemona alkaloids. In Alkaloids; Wiesner, K., Ed.; MTP, International Review of Sciences, Organic Chemistry; Butterworths: London, 1973; Series 1, Vol. 9, pp 143-160. (b) Lee, H. M.; Chen, K. K. J. Am. Pharm. Assoc. 1940, 29, 391. ( 2 ) See, for example: (a) Dao, C. N.; Luger, P.; Ky, P. T.; Kim, V. N.; Dung, N. X. Acta Crystallogr. C 1994, C50, 1612. (b) Ye, Y.; Qin, G. W.; Xu, R. S. Phytochemistry 1994, 37, 1205, 1201. (c) Ye, Y.; Qin, G . W.; Xu, R. S. J. Nat. Prod. 1994, 57, 665. (d) Lin, W.; Ye, Y.; Xu, R. J. Nat. Prod. 1992,55,571. (e) Lin, W.; Xu, R.; Zhong, Q. Huaxue Xuebao 1991, 49, 927. (f) Lin, W.; Ye, Y.; Xu, R. Chin. Chem. Lett. 1991, 2, 369. (3) (a) Chen, C.-Y.; Hart, D. J. J. Org. Chem. 1993,58, 3840. (b) Chen, C.-Y.; Hart, D. J. J. Org. Chem. 1990, 55, 6236. (4) (a) Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc. 1989, I l l , 1923. (b) Williams, D. R.; Reddy, J. P.; Amato, G. S. Tetrahedron Lett. 1994, 35, 6417. (5) For other synthetic approaches toward Stemona alkaloids, see: (a) Xiang, L.; Kozikowski, A. P. Synlett 1990, 279. (b) Martin, S. F.; Corbett, J. W. Synthesis 1992,55. (c) Beddoes, R. L.; Davies, M. P. H.; Thomas, E. J. J. Chem. Soc., Chem. Commun. 1992, 538. (d) Morimoto, Y.; Nishida, K.; Hayashi, Y.; Shirahama, H. Tetrahedron Lett. 1993, 34, 5773. (6) (a) Uyeo, S.; Irie, H.; Harada, H. Chem. Pharm. Bull. 1967, 15, 768. (b) Harada, H.; Irie, H.; Masaki, N.;Osaki, K.; Uyeo, S. J. Chem. SOC., Chem. Commun. 1967, 460. (7) (a) Schild, H. Ber. Dtsch. Chem. Ges. 1936, 69, 74. (b) Goetz, M.; Boegri, T.; Gray, A. H.; Strunz, G. M. Tetrahedron 1968, 24, 2631. ( 8 ) Wipf, P.; Kim, Y. Tetrahedron Lett. 1992, 33, 5477.
- rN HO
/
COZH
L-Tyrosine (4)
Tuberostemonlne(2)
major challenge of this strategy, the conversion of the cishydroxyindole ring system in 3 to the trans-fused perhydroindole present in 1 and 2, was effectively solved by nallylpalladium chemistry.
Results and Discussion
@
The yield of the transformation of tyrosines 4 and 5 to bicycles 3 and 8 depends on the nature of the protective group R and the scale of the reaction (Scheme 1).8 With R = OBn, typical yields are 40-55% on a 1 g scale, whereas with R = OBu', yields as high as 60% can be ~ b t a i n e d . ~The high selectivity of this diastereotopic end-group-differentiatingIO cyclization is due to destabilizing steric interactions in conformers 7 , especially A's3-strain" between the amide oxygen and the methyl ester (E) substituent. Additionally, face-to-face interaction of the trans-amide and enone n-systems in the transition state for the cyclization positions the ester function in conformers 7 underneath the dienone in a sterically crowded environment. Traces of isomers 9 are only observed if the cyclization is performed at T > 100 "C in DMSO, and attempted further thermodynamic equilibrations of 8 (R = OBu') to 9 (R (9) The structural assignments of bicycles 3 and 8 are based on NOE and coupling constant analyses.* (10) (a) Schreiber, S. L.; Schreiber, T. S.;Smith, D. B. J. Am. Chem. SOC.1987, 109, 1525. (b) Hoye, T. R.; Peck, D. R.; Swanson, T. A. J. Am. Chem. SOC.1984, 106, 2738. (1 1) Hoffman, R. W. Chem Rev. 1989, 89, 1841.
0002-7863/95/1517-11106$09.00/00 1995 American Chemical Society
Asymmetric Total Synthesis of (-)-Renine
J. Am. Chem. SOC.,Vol. 117, No. 45, 1995 11107
Scheme 1
Scheme 2
fiH
NHC(0)R 3
R = OBn, OBu', alkyl, aryl
1. 2. BzZO, NaBH,,NE13
c
CeCl3*7H20 89%
Phl(OAc)z, NaHC03 MeOH, 2 1 4 0 OC
C02Me
Ho*.*-
Cbz
10
20-60% Pd,(dba),.CHCI,,
H h C 0 2 M e
q
B u ~ PHCOzHiNEt3 ,
H
I
Ho+.*
A''3-Stralnl
I
OH
-
,,,
w
YCb,"
+
11 (68%)
Ho""
Cbz
OH
12 (11%)
+
Cbz 13 (6%)
Table 1. Regioselective Reduction of Allylic Benzoate 10 isolated yields (%)
= OBu') failed under acidic and basic, as well as thermal, reaction conditions.l2,l3 Benzoylation of the tertiary allylic alcohol in the Cbzprotected bicycle 3 and reduction of the enone with N a B b in the presence of CeC13I4 gave the equatorial alcohol 10 in 89% yield as a single diastereomer (Scheme 2). Reduction of the n-allylpalladium complex derived from 10 at the more hindered tertiary carbon required considerable optimization of the reaction conditions. The use of catalytic tris(dibenzy1ideneacetone)dipalladium(0) chloroform complex (2.5 mol %), tributylphosphine (10 mol %), and triethylammonium formateI5 at 60 "C under strictly anaerobic conditions maximized the yield of the desired trans-hexahydroindole 11. Variations in the nature of the reducing agent and palladium ligands had a major impact on the product distribution in this reaction. In the presence of catalytic tricyclohexylphosphine, homoallylic alcohol 12 was formed in 65% as the major product, and in the absence of amines, the more acidic reaction conditions provided diene 13 as the sole product even in the presence of tributylphosphine. The use of sodium borohydride as the reducing agent resulted in a mixture of allylic alcohol 11 and (12) The 'HNMR spectrum of a mixture of bicyclic products obtained by the cyclization to 8 (R = OBu') in DMSO-& at 100 "C is shown in the supporting information. (13) The importance of the proposed allylic strain interactions in the highly diastereoselective formation of bicycles 3 and 8 is clearly illustrated by comparison to the results of Martin et al. in the cyclization of dienone amines i and iv, which lack the conformational rigidity of tyrosine carbamates and provide mixtures of hydroindoles: (a) Martin, S. F.; Davidsen, S. K.; Puckette, T. A. J. Org. Chem. 1987,52, 1962. (b) Martin, S. F.; Campbell, C. L. J. Org. Chem. 1988, 53, 3184.
? &
CHzCI,, 21 "C
/
0' I
HN '
90%
-
'
$oh
""N
0
I I H '
+ 1:1.5
entry
reaction conditions(solvent = THF)
11
12
13
1
Pd2(dbah*CHCh,BusP, HC02HINEt3,60 'C Pd2(dba)3CHC13,BU~P, HC02NH4,60 "C Pd2(dba)yCHCh,(C6H11)3P, HC02NH4,60 'C Pd2(dba)yCHCl,,Bu3P,HC02H,60 'C Pd2(dba)yCHC13,BusP, NaBH4,22 'C Pd(Ph3Ph Ph3P, NaBH4,22 "C
68 69
11 12 65
6 11 6 82
2 3 4
5 6
7
I 31
65 52
homoallylic alcohol 12 (Table 1). In contrast, attempted reduction of 0-protected derivatives of 10 was unsuccessful and starting material was recovered unchanged. The allylic alcohol probably assists in the complexation of Pd(0) from the sterically very hindered concave face of the bicycle (Figure 1). Subsequently, hydride transfer is proposed to occur from complexed formate to the more hindered terminus of the alkene in 15. Oxidation of the allylic alcohol 11 with tetrapropylammonium pemthenate (TPAP)I6regenerated the enone which was deprotonated with KHMDSA (Scheme 3). Due to the low reactivity of the resulting cross-conjugated dienolate and its instability at temperatures > - 10 "C (probably due to #?-eliminationof the carbamate), the subsequent alkylation had to be performed with pentenyl triflate. In contrast to the previously observed preferential equatorial alkylation from the #?-face of the cisbicycle 3,8the trans-fused dienolate derived from 11 underwent exclusive axial attack from the a-face to give the desired enone 16 in 34% yield (51% based on recovered starting material)." The moderate yield in this transformation is due to competitive 0-alkylation by the alkyl triflate, which we have yet been unable to suppress by variation of the dienolate counterion. 1,ZReduction of enone 16 to the equatorial alcohol with NaBH4/CeC13l4 set the stage for the introduction of the butyrolactone moiety (Scheme 3). Before the planned iodolactonization of the y,&unsaturated amide 17, obtained in 77% yield from enone 16 by an Eschenmoser-Claisen rearrangement,'8-3functional group manipulations at the terminal alkene and the pyrrolidine ring were performed. Selective cleavage
B&g N"'
/
\
0
111
ro
"d (14) Luche. J.-L.: Gemal. A. L. J. Am. Chem. SOC. 1979. 202. 5848. (15) Manda, T , Matsumoto, T.; Kawada, M.; TSUJ~, J. J. Org. Chem. 1992, 57, 1326.
(16) Griffith, W. P.; Ley, S. V . Aldrichimica Acta 1990, 23, 13. (17) The stereochemistry of 16 was assigned on the basis of the vicinal coupling constants:
A (18) Wick, A. E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta 1964, 47, 2425.
11108 J. Am. Chem. Soc., Vol. 117, No. 45, 1995
Wipf et al.
Scheme 4 1. LDA.HMPA Me1
18
I
2. Allyl-SnBu3,AlBN 77%
v
14
R'
bBU3
15
L
1. 12, pH 5.5
j
Cbz
Bu~P; HzOz 47%
Figure 1. TIPSO
Scheme 3
11
1 , TPAP, NMO 2. KHMDSA, -60°C;
HC=CH(CH2)30Tf
4. e(NO,)PhSeCN,
i
46%
H
C02Me
'
1 NaBH,, CeCl3.7H2O I
b
Cbz
1. HF, MeCN
2. H3CC(OMe)2NMe,, 130 "C 77%
18
c
2. Dess-Martin
perlodlnane;NaCIO,
Cbz 21
TIPSO Me2N
1. AD-mix B; NalO, 2. NaBH,
MezN
0
SJ
L
3. TIPS-CI, DMAP
76%
1. Pd(OH)2, H2 b
I8 TIPSO
1. LiOH, H20/THF 2. PhOPOC12, NEt; PhSeH
3. Bu3SnH,AIBN, 130 'C
70%
TIPSO
of the monosubstituted alkene over the cyclohexene ring was best performed with AD-mix-/3I9followed by sodium periodate cleavage of the resulting diol. These conditions provided a considerably improved selectivity over the standard JohnsonLemieux20protocol. Reduction of the aldehyde and silylation of the primary alcohol gave the triisopropylsilyl ether 18 in 76% overall yield from alkene 17. The tyrosine-derived methyl ester at C(2) of bicycle 18 provides a convenient handle for the introduction of the butyrolactone ring in tuberostemonine (2), but since this moiety is not present in stenine, the ester was reductively decarbonylated with the method of Ireland et aL2I to give 19 in 70% yield. During the iodolact~nization~ of the y,d-unsaturated amide 19, the pH of the reaction medium had to be adjusted to 5.5 to minimize silyl ether hydrolysis (Scheme 4). Subsequent Keck allylation22in neat allyltributylstannane gave 20 in 77% yield. Methylation of the lactone occurred selectively in 87% yield from the sterically more accessible face, and subsequent conversion of the allyl to a vinyl group by a Johnson-Lemieux oxidation,20reduction, and Grie~o-elimination~~ sequence provided tricycle 21 in 54% yield. (19)Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A,; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L.J. Org. Chem. 1992, 57, 2768. (20) Pappo, R.; Allen, D. S.; Lemieux, R. U.; Johnson, W. S. J. Org. Chem. 1956.21.478. Under these conditions, yields of
