provide the alcohol 12 in good overall yield. Dehydration10
followed by selective deprotection of the TBS ether afforded
the hydroxy diene 8, which was converted into the hydroxy
triene 13 via sequential Wittig olefination and DIBAL-H
reduction. Katsuki-Sharpless asymmetric epoxidation,11
iodination of the resulting epoxy alcohol 14, and treatment
with zinc/AcOH produced the optically pure hydroxy triene
7 (R ) H) (>99% ee by the MTPA ester). The absolute
stereochemistry of the tertiary stereogenic center was con-
firmed to be S according to the modified Mosher method12
(Scheme 3).
Scheme 1. Diastereoselective Ring-Closing Metathesis
Grubbs’ ruthenium carbene complex 4, the cyclohexenes 3
with a quaternary stereogenic center were obtained via 1,4-
asymmetric induction in good chemical yield with up to 86%
de (in the case of R1 ) iPr, R2 ) TMS). In this communica-
tion, the application of our RCM methodology in an
enantiocontrolled total synthesis of (-)-aspidospermine (1)
is described.
Scheme 3a
(-)-Aspidospermine (1) can be obtained from optically
active lactam 5, which could be prepared from 6, according
to the procedure developed by Stork.2a We envisaged that a
pivotal construction of the quaternary carbon in 6 might be
realized diastereoselectively by RCM reaction of the triene
7, which in turn would be derived from the dienyl alcohol
8, as shown in Scheme 2.
Scheme 2. Retrosynthetic Analysis
a Reagents and conditions: (a) (i) TBSO(CH2)3Br, tBuLi, THF,
-78 °C f rt; (ii) (EtO)2P(O)CH2CO2Et, NaH, DME, reflux. (b)
(i) DIBAL-H, THF, 0 °C; (ii) EtOCHdCH2, Hg(OAc)2, reflux. (c)
iBu3Al, CH2Cl2, rt. (d) (i) o-Nitrophenyl selenocyanate, nBu3P, THF,
rt; (ii) H2O2, THF, rt; (iii) 1% HCl, EtOH, rt. (e) (i) (COCl)2,
DMSO, Et3N, CH2Cl2, rt; (ii) Ph3PdCHCO2Et, benzene, reflux;
(iii) DIBAL-H, THF, 0 °C. (f) L-(+)-DIPT, Ti(OiPr)4, TBHP, 4 Å
MS, CH2Cl2, 25 °C. (g) (i) I2, Ph3P, imidazole, benzene, rt; (ii) Zn,
AcOH, 50 °C.
The triene 7 (R ) H) was converted by conventional
means into the corresponding MOM, benzyl, and TMS ethers
and the benzoate ester. These compounds were treated with
10 mol % ruthenium carbene complex 4 in CH2Cl2 solution
(0.02 M) at room temperature for 48 h. The results are shown
in Table 1. The best result was obtained in the case of R )
TMS to afford the cyclohexenol 6 (R ) H) quantitatively
with 74% de (entry 5) after acidic hydrolysis. Fortunately,
since the two diastereomers could be easily separated by
chromatography, the optically pure 6 was obtained in 74%
yield (Table 1). Although the absolute configuration of the
newly generated quaternary stereogenic center could not be
determined at this stage, it was proposed to be R according
to our previous study. This was confirmed by its conversion
into the known lactam 5.
Preparation of the triene 7 (R ) H), the substrate of dia-
stereoselective RCM reaction, began with the reaction of the
amide 9, prepared from γ-butyrolactone,7 with 3-(tert-butyl-
dimethylsilyloxy)propyllithium8 followed by the Horner-
Emmons reaction to give the unsaturated ester 10. Reduction
with DIBAL-H followed by vinylation afforded the vinyl
ether 11, which was treated with triisobutylaluminum9 to
(4) For recent reviews, see: (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18-29. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39,
3012-3043. (c) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997,
36, 2036-2056. (d) Armstrong, S. K. J. J. Chem. Soc., Perkin Trans. 1
1998, 371-388. (e) Grubbs, R. H., Chang, S. Tetrahedron 1998, 54, 4413-
4450.
(5) Fukuda, Y.; Sasaki, H.; Shindo, M.; Shishido, K. Tetrahedon Lett.
2002, 43, 2047-2049.
(6) Schweb, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
(10) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
(7) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685-
1485-1486.
2688.
(11) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-
5976.
(8) Wilson, S. R.; Zucker, P. A. J. Org. Chem. 1988, 53, 4682-4693.
(9) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn.
1984, 57, 446-451.
(12) Ohtani, I.; Kusumi, T.; Kashmann, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096.
750
Org. Lett., Vol. 5, No. 5, 2003