Enantioselective addition of activated terminal alkynes to 1-acylpyridinium salts catalyzed by Cu-Bis(oxazoline) complexes

Article abstract of DOI:10.1021/ja0734849

CuI/bis(oxazoline)-catalyzed addition of propiolates and terminal ynones to 1-acylpyridinium salt (generated in situ from reaction of pyridine and methyl chloroformate) affords highly functionalized dihydropyridines with excellent enantioselectivity. It is found that the carbonyl group adjacent to the alkyne moiety is essential for the enantioselectivity of the addition. Short synthesis of indolizidines 167B and 223AB is achieved by employing two addition products. Copyright

Full text of DOI:10.1021/ja0734849

Published on Web 07/11/2007
Enantioselective Addition of Activated Terminal Alkynes to 1-Acylpyridinium
Salts Catalyzed by Cu-Bis(oxazoline) Complexes
Zhankui Sun, Shouyun Yu, Zuoding Ding, and Dawei Ma*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received May 16, 2007; E-mail: madw@mail.sioc.ac.cn
Piperidine units are frequently found in many natural pro-
Table 1. CuI-Catalyzed Addition of Ethyl Propiolate 2a to
1-Acylpyridinium Salts 1 in the Presence of Different Ligands and
Basesa
1
ducts and designed bioactive molecules. Their stereo-
1
-8
selective synthesis remains a great challenge.
Among existing
approaches for assembling these N-heterocycles,1
-8
asym-
metric attack of nucleophiles onto activated pyridines is very
attractive because it offers a direct access to dihydropyridines
that can be converted into substituted piperidines by different
transformations. Great progress has been achieved in this area due
3
to seminal contributions from the laboratories of Comins, Mara-
zano, Mangeney, Charette, Yamada, and Shibasaki. However,
most studies are focused on using chiral pyridine substrates,3-7
entry
R
ligand
baseb
solvent
yield (%)c
ee (%)d
4
5
6
7
8
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-Bu
Bn
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
L5
L5
L5
B1
B1
B1
B1
B1
B2
B3
B1
B1
B1
B1
B2
B2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
78
71
67
63
75
72
74
50
51
74
87
88
94
65
83
55
86
and only one example of a catalytic asymmetric reaction (addition
of TMSCN to N-acylpyridinium) was reported.8 Inspired by
recent progress on the direct, enantioselective addition of 1-alkynes
9
to imines and CuI-catalyzed three-component coupling of pyridine,
acid chlorides, and alkynes,10 we decided to develop a catalytic
asymmetric addition of terminal alkynes to 1-acylpyridinium
salts.
e
77
71
72
f
10
11
12
13
As summarized in Table 1, we selected the reaction of ethyl
propiolate 2a with 1-acylpyridinium salts 1 for model studies,
mainly because their addition products are valuable inter-
mediates for the elaboration of indolizidines. Initially, tridentate
bis(oxazolinyl)pyridine L1, the best ligand in Li’s direct addition
of terminal alkynes,9 was tested. We were pleased to find that,
under the induction of this ligand, CuI-catalyzed addition of 2a
to 1a (generated in situ from pyridine and methyl chloroformate)
afforded the desired addition product 3a in 78% yield and 50% ee
g
Me
Me
15
h
47
69
a
Reaction conditions: CuI (0.05 mmol), ligand (0.05 mmol), pyridine
(
0.5 mmol), ClCO2R (2.5 mmol), 2a (2.5 mmol), base (2.5 mmol), solvent
c
(
1 mL). b B1: i-Pr2NEt, B2: i-Pr2NPr-n, B3: i-Pr2NBu-n. Isolated yields.
a
d
e
Determined by HPLC on chiral stationary phase. Reaction was carried
out at -60 °C. No addition product was determined. 0.5 mmol of 2a,
ClCO2Me, and base were used. 5 mol % CuI and ligand were used.
f
g
h
(entry 1). Benzyl-substituted ligand L2 gave similar results (entry
2). The enantioselectivity increased to 74% when using bidentate
bis(oxazoline) L3 as a ligand. Further improvements were observed
when the two less bulky bis(oxazoline) ligands L4 and L5 were
used (entries 4 and 5). Switching the base from i-Pr
2
NEt to
i-Pr NPr-n provided the best enantioselectivity (entry 6), while i-Pr -
2
2
NBu-n gave 3a in only 65% ee (entry 7). The solvent has an
influence on the asymmetric induction, as well, chloroform gave a
slightly lower ee value, and the enantioselectivity dropped to 55%
when the reaction was performed in MeCN (compare entries 5
with 8 and 9). In addition, it was found that the N-substituents in
The optimized reaction conditions were then examined by
varying the 1-alkynes, and the results are summarized in Table 2.
Methyl propiolate led to almost identical yield and selectivity as
ethyl propiolate (entry 1). However, when benzyl propiolate was
employed, only 86% ee was observed (entry 2), indicating that
increasing the size of the propiolate remarkably decreases the
enantioselectivity. This trend was also seen when ynones were
applied under these reaction conditions. The highest ee value was
recorded using 1-pentyn-3-one (entry 4). With increasing chain
length of the ynones, the enantioselectivity gradually dropped
(compare entries 4-7). Benzoxy-substituted ynone also worked
well, affording dihydropyridine 3h in 73% yield and 77% ee (entry
7). Its additional functional group allows further conversion to more
complex molecules. It is noteworthy that in these cases no 1,4-
addition products of 1-acylpyridinium salt 1a were detected.
1
1
influence the reaction dramatically, and iso-butyl-substituted
b showed similar reactivity as 1a (entry 10), while benzyl
substituted 1c was inert under the current reaction conditions (entry
1). It is noteworthy that excess amounts of methyl chloroformate,
1
base, and ethyl propiolate are required to obtain satisfying results.
When equimolar amounts of these reagents were used, 3a was
isolated in poor yields (entry 12), presumably due to incomplete
formation of 1. Attempts to reduce the loading of the catalyst and
ligand to 5 mol % also resulted in low yield and enantioselectivity
(entry 13). Further optimization is needed to overcome these
drawbacks.
9300
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J. AM. CHEM. SOC. 2007, 129, 9300-9301
10.1021/ja0734849 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. CuI/L5-Catalyzed Addition of 1-Alkynes 2 to
for (5R,9R)-indolizidine 167B ([R]
Thus, we established that the absolute configuration of our addition
products is R. In the same manner, indolizidine 223AB 10 was
elaborated from 7f in 60% overall yield in four simple steps. To
date, our method represents the shortest synthesis of these two
alkaloids.
-111.3 (c 1.3, CH
D
2 2
Cl
)).13a
a
1-Acylpyridinium Salt 1a
1
4
In conclusion, we have developed the first catalytic asymmetric
addition of 1-alkynes to 1-acylpyridinium salts. It was found that
the carbonyl group in the 3 position of the 1-alkynes is important
for the enantioselectivity of the reaction. These findings may shed
light on other additions using 1-alkynes as substrates. The reaction
provides highly functionalized dihydropyridines with excellent
enantioselectivity, which are valuable building blocks for as-
sembling complex N-heterocycles. Further exploration of the scope
and limits of the synthetic application is in progress.
entry
R
product
time (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
CO2CH3
CO2Bn
COCH3
COCH2CH3
CO(CH2)3CH3
CO(CH2)4CH3
CO(CH2)3OBn
Ph
3b
3c
3d
3e
3f
3g
3h
3i
15
15
15
15
15
15
15
12
17
15
74
81
69
65
70
68
70
75
63
77
95
86
93
99
91
90
77
1
(CH2)3CH3
CH2OAc
3j
3k
11
3
10
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences and National Natural Science Foundation of
China (grant 20621062) for their financial support.
a
Reaction conditions: CuI (0.05 mmol), L5 (0.05 mmol), 2 (2.5 mmol),
pyridine (0.5 mmol), ClCO2Me (2.5 mmol), i-Pr2NPr-n (2.5 mmol), CH2Cl2
b
c
(
1 mL). Isolated yields. Determined by HPLC on chiral stationary phase.
Supporting Information Available: Experimental and spectral data
for all new compounds (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
Scheme 1. Synthesis of Indolizidines 167B and 223AB
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2
tion of dihydropyridines 3a and 3f was achieved (Pd/C, H , MeOH)
(
to afford tetrahydropyridines 6 (Scheme 1). Treatment of 6 with
allyl trimethylsilane in the presence of TFA12 produced 7a and 7f
as the only stereoisomer, respectively. Hydrogenation of 7a followed
(
by deprotection with TMSI and AlMe
3
-mediated cyclization af-
forded lactam 8, which was reduced with LAH to furnish indolizi-
dine 167B 9.13 The value of the optical rotation of synthetic 9 ([R]
27
D
-
102.7 (c 0.88, CH Cl )) was in close proximity to that reported
2
2
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