Intramolecular pyridine activation - dearomatization reaction highly stereoselective synthesis of polysubstituted indolizidines and quinolizidines

Article abstract of DOI:10.1021/ol901264f

An unprecedented intramolecular pyridine activation-asymmetric dearomatization reaction is described. This process produces 5-substituted indolizidines and 6-substituted quinolizidines in excellent yields and in a highly regio- and diastereoselective fash

Full text of DOI:10.1021/ol901264f

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3398-3401
Intramolecular Pyridine
Activation-Dearomatization Reaction:
Highly Stereoselective Synthesis of
Polysubstituted Indolizidines and
Quinolizidines
Guillaume Barbe, Guillaume Pelletier, and Andre´ B. Charette*
De´partement de chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received June 5, 2009
ABSTRACT
An unprecedented intramolecular pyridine activation-asymmetric dearomatization reaction is described. This process produces 5-substituted
indolizidines and 6-substituted quinolizidines in excellent yields and in a highly regio- and diastereoselective fashion. Formal syntheses of
trans-indolizidine alkaloids are presented along with some preliminary results in the formation of C-5 quaternary centers.
Extracts from the skin of amphibians provide a large array
of structurally unique1 and pharmacologically active alka-
loids.2 Particularly, indolizidine and quinolizidine alkaloids
represent privileged motifs, and accordingly, their chemical
syntheses have benefited from a worldwide interest.3
Despite immense efforts, a more general and expedient
approach to synthetically flexible polysubstituted indoliz-
idines and quinolizidines remains highly desirable.4 Herein,
we report on the stereoselective synthesis of 5(6)-substituted
indolizidines (quinolizidines) through an unprecedented
intramolecular pyridine activation-asymmetric dearomati-
zation reaction.
Over the past decades, pyridine dearomatization has
emerged as an attractive and cost-effective approach to the
asymmetric synthesis of polysubstituted piperidines.5,6 Rec-
ognizing the unique directing ability of nitrogen-containing
(5) For chiral auxiliary-based strategies, see: (a) Mehmandoust, M.;
Marazano, C.; Das, B. C. J. Chem. Soc., Chem. Commun. 1989, 1185. (b)
Comins, D. L.; Goehring, R. R.; Sajan, J. P.; O’Connor, S. J. Org. Chem.
1990, 55, 2574. (c) Comins, D. L.; Hong, H. J. Am. Chem. Soc. 1991, 113,
6672. (d) Sreith, J.; Boiron, A.; Sifferlen, T.; Strehler, C.; Tschamber, T.
Tetrahedron Lett. 1994, 35, 3927. (e) Comins, D. L.; Josef, S. P.; Goehring,
R. R. J. Am. Chem. Soc. 1994, 116, 4719. (f) Charette, A. B.; Grenon, M.;
Lemire, A.; Pourashraf, M.; Martel, J. J. Am. Chem. Soc. 2001, 123, 11829.
(g) Hoesl, C. E.; Pabel, J.; Polborn, K.; Wanner, K. T. Heterocycles 2002,
58, 383. (h) Legault, C.; Charette, A. B. J. Am. Chem. Soc. 2003, 125,
(1) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68,
1556.
(2) For a review of the biological significance of indolizidine alkaloids,
see: Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical
and Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon: New York,
1999; Vol. 13, pp 1-161.
6360. (i) Comins, D. L.; Sahn, J. J. Org. Lett. 2005, 7, 5227
.
(3) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139. and other reviews in
these series.
(6) For catalysis-based strategies, see: (a) Ichikawa, E.; Suzuki, M.;
Yabu, K.; Albert, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004,
126, 11808. (b) Legault, C.; Charette, A. B. J. Am. Chem. Soc. 2005, 127,
8966. (c) Sun, Z.; Yu, S.; Ding, Z.; Ma, D. J. Am. Chem. Soc. 2007, 129,
9300. (d) Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2007,
46, 4562. (e) Black, D. A.; Beveridge, R. E.; Arndtsen, B. A. J. Org. Chem.
(4) For recent approaches, see: (a) Yu, R. T.; Lee, E. E.; Malik, G.;
Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2379. (b) Liu, P.; Hong, S.;
Weinreb, S. M. J. Am. Chem. Soc. 2008, 130, 7562. (c) Yu, R. T.; Rovis,
T. J. Am. Chem. Soc. 2006, 128, 12370. (d) Turunen, B. J.; Georg, G. I.
J. Am. Chem. Soc. 2006, 128, 8702.
2008, 73, 1906
.
10.1021/ol901264f CCC: $40.75
Published on Web 07/10/2009
 2009 American Chemical Society

functionalities,7 our group disclosed a highly regio- and
stereoselective dearomatization of unsubstituted pyridine.5f
In an effort to find a general entry into the indolizidine and
quinolizidine scaffold, we hypothesized that treating a chiral-
auxiliary derived pyridinium salt such as A with Grignard
reagents could undergo an amidine-directed addition (B) at
the 5(6)-position selectively (Scheme 1).8 In the event,
Table 1. Pyridine Activation-Grignard Addition Optimization
entry
additive
none
K2CO3
MgO
Et3N
DIPEA
pyridine
2,6-lutidine
2-chloropyridine
2-chloropyridine
2-chloropyridine
2-chloropyridine
2-chloropyridine
1
equiv
[1a] (M)
yielda (%)
Scheme 1. Intramolecular Pyridine Activation Strategy
1
2
3
4
5
6
7
8
2.00
2.00
2.00
2.00
2.00
2.00
2.00
2.00
1.50
1.25
1.50
1.50
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.10
0.01
39
44
53
0
0
11
60
78
92
84
89
87
9
10
11
12
a
Determined by H NMR vs Ph3CH as an internal standard.
the formation of the unsaturated indolizidine 2aa in 92%
NMR yield as a single regio- and diastereomer (entry 9).
The stereoinduction is believed to originate from a
precomplexation of the E-imidate lone pair to the Grignard
reagent, thereby directing the nucleophilic addition at the
proximal 5(6)-position of the pyridinium ring (intermediate
diastereoenriched unsaturated compounds 2 would be gener-
ated, allowing for further derivatization along the rings.
Pyridinium salt A would in return come from a new
intramolecular pyridine activation reaction. More precisely,
we reasoned that treating amides 1 with trifluoromethane-
sulfonic anhydride (Tf2O) would result in the formation of
a highly reactive iminium species9 capable of triggering a
base-mediated cyclization with the pyridine ring.10
Table 2. Synthesis of Polysubstituted Indolizidines and
Quinolizidinesa
To begin our study, we developed short multigram scale
syntheses of 1 and elected to use 1a for reaction develop-
ment.11 After extensive optimization, we found that treating
pyridine 1a with Tf2O in the presence of 2-chloropyridine
(2-ClPyr) smoothly produced pyridinium salt A as a transient
intermediate (Table 1, entry 9).12 The use of 2-ClPyr as a
non-nucleophilic and slightly basic additive was found crucial
for efficient intramolecular pyridine activation.13
Most importantly, it ensured the stability of the base-
sensitive pyridinium A (entries 4-6). These results led us
to anticipate deprotonation issues when treating A with
strongly basic Grignard reagents. Gratifyingly, addition of
MeMgBr to pyridinium salt A at -78 °C cleanly resulted in
entry
n
R1:R2
RMgX
2
yield (%)b
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
1
2
2
2
1
1
H:H MeMgBr
2aa
2ab
2ac
2ad
2ae
2af
94
91
89
89
83
85
84
86
84
85
83
86
88
87
93
H:H n-pentylMgCl
H:H i-PrMgClc
H:H c-hexylMgBr
H:H t-BuMgClc
H:H vinylMgBr
H:H 2-furylMgBrd
H:H 2-thiophenylMgBre
2ag
2ah
9
H:H N-Me-2-indolylMgBrd 2ai
10
11
12
13
14
15
H:H 1-hexynylMgBrf
H:H vinylMgBr
2aj
(7) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(8) For examples of amidine-directed transformations, see: (a) Shawe,
T. T.; Meyers, A. I. J. Org. Chem. 1991, 56, 2751. (b) Pastine, S. J.; Gribkov,
D. V.; Sames, D. J. Am. Chem. Soc. 2006, 128, 14220.
(9) Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 18, and
references cited therein.
2bf
2bh
2bj
2ca
2da
H:H 2-thiophenylMgBre
H:H 1-hexynylMgBrf
H:Me MeMgBrc
Me:H MeMgBrc
(10) Charette, A. B.; Grenon, M. Can. J. Chem. 2001, 79, 1694.
(11) See Supporting Information for more details.
a All reactions performed on 1 mmol of 1. b Isolated yield of a single
regio- and diastereomer. c Grignard addition at -20 °C. d Prepared from
the heteroaryl, n-BuLi, and MgBr2-Et2O. e Prepared from 2-bromothiophene
and Mg turnings. f Prepared from the terminal alkyne and EtMgBr.
(12) Myers, A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.; Madar,
D. J. J. Am. Chem. Soc. 1997, 119, 6072.
(13) (a) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128,
14254. (b) Medley, J. W.; Movassaghi, M. J. Org. Chem. 2009, 74, 1341,
and references cited therein.
Org. Lett., Vol. 11, No. 15, 2009
3399

Scheme 2. Stereoselective Synthesis of trans-Indolizidines
B, Scheme 1). Coordination to the magnesium by the ether
functionality ensures a high degree of organization at the
transition state. By minimizing the 1,3-allylic strain with the
chiral auxiliary, this chelation shifts the Grignard reagent
toward the ꢀ-face of the pyridinium ring resulting in the
observed diastereomer.14
With our optimal conditions in hand, we evaluated the
scope of the reaction. As shown in Table 2, sp3 (entries 1-5),
sp2 (entries 6-9, 11, and 12), and sp (entries 10 and 13)
hybridized carbon nucleophiles react smoothly with the
pyridinium intermediates A, producing indolizidines 2a and
quinolizidines 2b with excellent yields, regio-, and diaste-
reoselectivities.15
(entry 14) and 5,6-disubstituted indolizidines (entry 15),
respectively.
These results contrast with literature precedents5h,17 and
prompted us to further explore the directing ability of the
auxiliary for the formation of quaternary centers. To our
delight, using 1e and PhMgBr as reagents, the C-5 quaternary
center was formed as a single regio- and diastereomer.15
After hydrogenation of the remaining alkenes, a good yield
of the 5,5-disubstituted indolizidine 4em was obtained (eq
1, Scheme 3).18 To our knowledge, this represents the first
Scheme 3. Quaternary Center Formation
A demonstration of the synthetic relevance of this meth-
odology is shown in Scheme 2. Starting from 10 mmol of
the amide 1a, our standard conditions using n-PrMgCl and
n-HexMgBr as nucleophiles afforded dihydropyridines 2ak
and 2al, respectively. Subsequently, diastereoselective hy-
drogenation of the alkenes using Pd/C in acetone gave the
corresponding saturated cycles. These amidines were then
regioselectively hydrolyzed via the formation of an ami-
dinium salt using MeI as the alkylating reagent followed by
a basic treatment of the amidinium salt in aqueous NaOH.
This two-step process led to the isolation of the correspond-
ing trans-indolizidinones 3ak and 3al in over 75% yield
overall for the four steps. These trans-indolizidinones are
known in the literature16 to be intermediates in the asym-
metric syntheses of indolizidines trans-167B,16a trans-
209D,16b and 5E,9Z-223AB,16c and they allowed us to
confirm the absolute configuration of indolizidines 2a.
Finally, we evaluated the effect of pyridine substitution
on the outcome of the activation-dearomatization process.
By substituting positions 3 and 5, the excellent yields, regio-
and diastereoselectivities were maintained producing 5,8-
asymmetric quaternary center formation via a pyridine
dearomatization reaction. In addition, this features unusually
mild conditions for the activation of 2,6-disubstituted pyri-
dine.
In conclusion, a highly stereoselective synthesis of 5(6)-
substituted indolizidines (quinolizidines) has been described.
(16) (a) Toyooka, N.; Nemoto, H. Heterocycles 2005, 66, 549. (b)
Alegret, C.; Riera, A. J. Org. Chem. 2008, 73, 8661. (c) Hart, D. J.; Tsai,
Y. J. Org. Chem. 1982, 47, 4403
.
(17) (a) Comins, D. L.; Abdullah, A. H. J. Org. Chem. 1982, 47, 4315.
(b) Yamaguchi, R.; Nakazono, Y.; Kawanisi, M. Tetrahedron Lett. 1983,
24, 1801. (c) Lemire, A.; Grenon, M.; Pourashraf, M.; Charette, A. B. Org.
Lett. 2004, 6, 3517, and references cited therein
.
(18) Hydrogenation of the diene was found necessary to ensure complete
stability of the indolizidine. Although still under investigation, evidence
points toward the formation of ring-opened products resulting from a 6π-
electron electrocyclic ring-opening process. For recent calculations, see:
Walker, M. J.; Hietbrink, B. N.; Thomas IV, B. E.; Nakamura, K.; Kallel,
E. A.; Houk, K. N. J. Org. Chem. 2001, 66, 6669.
(14) This is supported by NOE experiments performed on compound
2aa. See Supporting Information for more details.
(15) All entries in this paper showed >20:1 rr and >20:1 dr by 1H NMR
of the crude mixture, with the exception of t-Bu (entry 5, Table 2) which
showed a ratio of 14:1 rr and >20:1 dr.
3400
Org. Lett., Vol. 11, No. 15, 2009

This strategy highlights an unprecedented intramolecular
pyridine activation-asymmetric dearomatization reaction.
Applications of this methodology to the total synthesis of
natural products along with a complete survey of the
quaternary center formation are under investigation. The
results will be reported in due course.
Chair Program, and the Universite´ de Montre´al. G.B. thanks
NSERC and Boehringer Ingelheim for postgraduate fellow-
ships. G.P. thanks FQRNT and NSERC for postgraduate
fellowships.
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by NSERC
(Canada), Merck Frosst Canada, Boehringer Ingelheim, the
Canada Foundation for Innovation, the Canada Research
OL901264F
Org. Lett., Vol. 11, No. 15, 2009
3401