Organocatalytic approach to enantioselective one-pot synthesis of pyrrolidine, hexahydropyrrolizine, and octahydroindolizine core structures

Article abstract of DOI:10.1021/ol900477x

An enantioselective organocatalytic, one-pot synthesis of pyrrolidine, hexahydropyrrolizine, and octahydroindolizine core structures was realized starting from readily available glycine esters by combination with several different organocatalytic reaction

Full text of DOI:10.1021/ol900477x

ORGANIC
LETTERS
2009
Vol. 11, No. 9
2027-2029
Organocatalytic Approach to
Enantioselective One-Pot Synthesis of
Pyrrolidine, Hexahydropyrrolizine, and
Octahydroindolizine Core Structures
Yong-Gang Wang, Takeshi Kumano, Taichi Kano, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto
606-8502, Japan
maruoka@kuchem.kyoto-u.ac.jp
Received March 7, 2009
ABSTRACT
An enantioselective organocatalytic, one-pot synthesis of pyrrolidine, hexahydropyrrolizine, and octahydroindolizine core structures was realized
starting from readily available glycine esters by combination with several different organocatalytic reactions.
Enantioselective organocatalysis has emerged as a powerful
and promising synthetic field which is complementary to
metal-catalyzed transformations and has accelerated the
development of new methodologies to synthesize diverse
chiral molecules.1 The operational simplicity, ready avail-
ability of catalysts, and low toxicity associated with orga-
nocatalysis provide a highly attractive method to synthesize
complex organic structures. In particular, the development
of fully organocatalytic approaches to certain core structures
for preparing natural products or physiologically active
compounds is quite attractive and challenging in terms of
the environmental consciousness. Here we wish to report our
case study on this subject, targeting an enantioselective
organocatalytic, one-pot synthesis of hexahydropyrrolizine
and octahydroindolizine core structures2 1 starting from
readily available glycine esters3 2 in combination with several
different organocatalytic reactions (Scheme 1).
Our key strategy is based on the development of asym-
metric conjugate addition of N-(diphenylmethylene)glycine
ester 2 and R,ꢀ-enones 3 (n ) 1 or 2) by using a chiral phase
transfer catalyst of type (S)-4 (Figure 1).4,5 Organocatalytic
intramolecular reductive amination of conjugate adduct 5
with Hantzsch ester6,7 would proceed in a stereoselective
manner to give pyrrolidine derivative 6 as an intermediate,
(2) (a) Rizk, A.-F. M., Ed. Pyrrolizidine Alkaloids; CRC Press: Boston,
1991; World Health Organization: Geneva, 1988. (b) Hartmann, T.; Witte,
L. In Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W.,
Ed.; Elsevier Science, Ltd.: Oxford, 1995; Vol. 9, Cahpter 4. (c) Liddell,
J. R. Nat. Prod. Rep. 2002, 19, 773. (d) Michael, J. P. Alkaloids 2001, 55,
91. (e) Pyne, S. G.; Davis, A. S.; Gates, N. J.; Hartley, J. P.; Lindsay, K. B.;
Machan, T.; Tang, M. Synlett 2004, 15, 2670. (f) Cheng, Y.; Huang, Z.-T.;
Wang, M.-X. Curr. Org. Chem. 2004, 8, 325. (g) Michael, J. P. Nat. Prod.
Rep. 2004, 21, 625.
(1) Reviews: (a) List, B. Acc. Chem. Res. 2004, 37, 548. (b) Notz, W.;
Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. (c) Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (d) Berkessel, A.;
Gro¨ger, H. Asymmetric Organocatalysis: From Biomimetic Concepts to
Application in Asymmetric Synthesis; Wiley-VCH: Weinheim, Germany,
2005. (e) EnantioselectiVe Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH:
Weinheim, Germany, 2007. (f) List, B. Chem. Commun. 2006, 819. (g)
Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007, 107,
5471.
(3) Maruoka, K.; Ooi, T.; Kano, T. Chem. Commun. 2007, 1487.
10.1021/ol900477x CCC: $40.75
Published on Web 04/06/2009
 2009 American Chemical Society

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%).
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Org. Lett., Vol. 11, No. 9, 2009

Scheme 3
.
Synthesis of Octahydroindolizine 1a
Scheme 4. Synthesis of Hexahydropyrrolizine 1b
combination with several different organocatalytic reactions.
This approach allows the facile synthesis of a natural alkaloid
such as (+)-Monomorine.
This information led us to develop a facile synthesis of
octahydroindolizine core structure 1a (Scheme 3). Accord-
ingly, we carried out asymmetric conjugate addition of
glycine ester 2a with R,ꢀ-enone 3a (2.0 equiv) and K2CO3
(5 equiv) under the influence of chiral phase transfer catalyst
(S)-4b and CsCl in Et2O at 0 °C for 15 h to give conjugate
adduct 5a in 88% yield with 94% ee. Intramolecular
reductive amination of adduct 5a and subsequent acetal
hydrolysis followed by reductive amination was effected with
Hantzsch ester (5 equiv) and CF3CO2H in aqueous EtOH at
60 °C for 48 h to furnish octahydroindolizine core structure
1a in 70% yield without loss of enantioselectivity. The
absolute configuration of 1a was unambiguously confirmed
by X-ray crystallographic analysis after reduction and
subsequent p-bromobenzoate formation. The one-pot reaction
of the whole reaction sequence was also realized without
any difficulty by sequentially adding several different
reagents to afford 1a in 48% overall yield.
Scheme 5. Synthesis of (+)-Monomorine
Asymmetric conjugate addition of glycine ester 2b with
R,ꢀ-enone 3b (2.0 equiv) and K2CO3 (5 equiv) in the
presence of chiral phase transfer catalyst (S)-4b and CsCl
in Et2O at 0 °C for 16 h afforded conjugate adduct 5b in
85% yield with 90% ee (Scheme 4). It should be noted that
the enantioselectivity was slightly decreased by switching
the cyclic acetal moiely of 3b to 1,3-dioxolane (78% yield,
86% ee). Treatment of the adduct 5b with Hantzsch ester (5
equiv) and CF3CO2H in aqueous EtOH at 60 °C for 48 h
produced hexahydropyrrolizine core structure 1b in 55%
yield. The one-pot reaction of the entire sequence was again
realized to afford 1b in 31% overall yield.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research on Priority Areas
“Advanced Molecular Transformation of Carbon Resources”
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. Y.W. thanks to the Japan Society for
the Promotion of Science for Postdoctoral Fellowship for
Foreign Researchers.
Supporting Information Available: Experimental details
1
and H and 13C NMR spectra of all new compounds. This
Our approach was highlighted by the short synthesis of
physiologically active (+)-Monomorine in a highly stereo-
selective manner as shown in Scheme 5.10,11
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we were successfully able to develop an
enantioselective organocatalytic, one-pot synthesis of pyr-
rolidine, hexahydropyrrolizine, and octahydroindolizine core
structures starting from readily available glycine esters by
OL900477X
(11) (a) Riesinger, S. W.; Lo¨fstedt, J.; Petersson-Fasth, H.; Ba¨ckvall,
J.-E. Eur. J. Org. Chem. 1999, 3277. (b) Momose, T.; Toshima, M.; Seki,
S.; Koike, Y.; Toyooka, N.; Hirai, Y. J. Chem. Soc., Perkin Trans. 1 1997,
1315. (c) Higashiyama, K.; Nakahata, K.; Takahashi, H. J. Chem. Soc.,
Perkin Trans. 1 1994, 351. (d) Munchhof, M. J.; Meyers, A. I. J. Am. Chem.
Soc. 1995, 117, 5399, and references cited therein. (e) Randl, S.; Blechert,
S. J. Org. Chem. 2003, 68, 8879.
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Stein, F. Experientia 1973, 29, 530. (b) Garraffo, H. M.; Spande, T. F.;
Daly, J. W.; Baldessari, A.; Gros, E. G. J. Nat. Prod. 1993, 56, 357
.
Org. Lett., Vol. 11, No. 9, 2009
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