Scheme 1
.
Organocatalytic Approach to Alkaloid Core
Structures
Scheme 2. Synthesis of 2,5-Disubstituted cis-Pyrrolidine 8
Table 1. Asymmetric Conjugate Addition of Glycine Ester 2a
with (S)-4a-c under Phase Transfer Conditionsa
which is susceptible to the acetal hydrolysis and reductively
aminated to furnish a hexahydropyrrolizine or octahydroin-
dolizine core structure 1 (n ) 1 or 2), respectively.
entry
catalyst
solvent
yield (%)b
ee (%)c
1
2
3
4
5
6
7
(S)-4a
(S)-4b
(S)-4c
(S)-4b
(S)-4b
(S)-4b
(S)-4b
CPME
CPME
CPME
THF
Et2O
dioxane
toluene
62
71
59
85
84
55
68
75
94
88
91
94
88
80
a Unless otherwise specified, the reaction was carried out at 0 °C for
6 h with glycine derivative 2a and 2 equiv of ethyl vinyl ketone in the
presence of 1 mol % of (S)-4a-c, 10 mol % of CsCl, and 5 equiv of K2CO3
under the given solvent and reaction conditions. b Isolated yield of 7.
c Enantiopurity of the conjugate adducts 7 was determined by HPLC analysis
using a chiral column [DAICEL Chiralcel AD-H] with hexane/isopropanol
as solvent.
Figure 1. Chiral phase transfer catalysts and Hantzsch ester.
Attempted reaction of glycine derivative 2a and ethyl vinyl
ketone with K2CO3 in the presence of 1 mol % of spiro-
type catalyst (S)-4a and 10 mol % of CsCl8 in cyclopentyl
methyl ether (CPME) at 0 °C gave conjugate adduct 7 in
62% yield with 75% ee (entry 1). Switching (S)-4a to a
sterically more hindered (S)-4b under similar conditions
improved the enantioselectivity to 94% ee (entry 2).9 On
the other hand, another sterically hindered (S)-4c, which is
found to be very effective in the asymmetric conjugate
additions of R-substituted R-cyanoacetates to acetylenic
esters,4 was not as effective as (S)-4b in terms of both
reactivity and selectivity (entry 3). Among other ethereal
solvents (THF, Et2O, and dioxane), Et2O was found to be
superior, giving 94% ee for 7 (entry 5). Use of toluene
slightly decreased enantioselectivity (entry 7). With the
optimal reaction condition for asymmetric conjugate addition
at hand, we carried out intramolecular reductive amination
of 7 with Hantzsch ester (2 equiv)6 and CF3CO2H (1 equiv)
in aqueous EtOH at 60 °C to furnish 2,5-disubstituted cis-
pyrrolidine 8 stereospecifically in 84% yield (Scheme 2).
We first examined asymmetric conjugate addition of
N-(diphenylmethylene)glycine di(tert-butyl)methyl ester 2a
and ethyl vinyl ketone under the influence of a chiral phase
transfer catalyst of type (S)-4 (Scheme 2 and Table 1).
(4) (a) Wang, X.; Kitamura, M.; Maruoka, K. J. Am. Chem. Soc. 2007,
129, 1038. (b) Lan, Q.; Wang, X.; Maruoka, K. Tetrahedron Lett. 2007,
48, 4675. See also: (c) Hashimoto, T.; Maruoka, K. Chem. ReV. 2007, 107,
5656.
(5) Tandem asymmetric conjugate addition-cyclization sequence: Shibu-
guchi, T.; Mihara, H.; Kuramochi, A.; Sakuraba, S.; Oshima, T.; Shibasaki,
M. Angew. Chem., Int. Ed. 2006, 45, 4635.
(6) Reviews: (a) Ouellet, S. G.; Walji, A. M.; Macmillan, D. W. C.
Acc. Chem. Res. 2007, 40, 1327. (b) You, S.-L. Chem. Asian J. 2007, 2,
820. See also (c) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. J. Am.
Chem. Soc. 2005, 127, 15036.
(7) (a) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 32. (b) Yang, J. W.; Hechavarria Fonseca, M. T.; Vignola,
N.; List, B. Angew. Chem., Int. Ed. 2005, 44, 108. (c) Rueping, M.; Sugiono,
E.; Azap, C.; Theissmann, T.; Bolte, M. Org. Lett. 2005, 7, 3781. (d)
Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed. 2005, 44,
7424. (e) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193. (f)
Tuttle, J. B.; Ouellet, S. G.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006,
128, 12662. (g) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128,
13368. (h) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2006, 128, 84. (i) Hoffmann, S.; Nicoletti, N.; List, B. J. Am.
Chem. Soc. 2006, 128, 13074. (j) Rueping, M.; Antonchick, A. P.;
Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683. (k) Rueping, M.;
Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 6751.
(l) Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 18.
(8) Without CsCl, no reaction was observed. See also our preceding
paper in this issue: Kano, T.; Kumano, T.; Maruoka, K. Org. Lett. 2009,
DOI: 10.1021/ol900476e.
(9) Replacement of a di(tert-butyl)methyl group of 2a with a tert-butyl
group, which is labile to CF3CO2H, resulted in a slight decrease in ee (from
94 to 92%).
2028
Org. Lett., Vol. 11, No. 9, 2009