Organocatalytic asymmetric intramolecular [3+2] cycloaddition: A straightforward approach to access multiply substituted hexahydrochromeno[4,3-b] pyrrolidine derivatives in high optical purity

Article abstract of DOI:10.1039/c002369h

A chiral phosphoric acid-catalyzed intramolecular 1,3-dipolar cycloaddition of 4-(2-formylphenoxy)butenoates with amino esters provides hexahydromeno[4,3-b]pyrrolidine derivatives in high enantioselectivity (up to 94% ee).

Full text of DOI:10.1039/c002369h

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Organocatalytic asymmetric intramolecular [3+2] cycloaddition: A
straightforward approach to access multiply substituted
hexahydrochromeno[4,3-b]pyrrolidine derivatives in high optical purity†
Nan Li,a,b Jin Song,c Xi-Feng Tu,c Bin Liu,c Xiao-Hua Chenc and Liu-Zhu Gong*a,c
Received 4th February 2010, Accepted 12th March 2010
First published as an Advance Article on the web 23rd March 2010
DOI: 10.1039/c002369h
A
chiral phosphoric acid-catalyzed intramolecular 1,3-
structurally diverse synthesis of nitrogenous five-membered
heterocycles with high optical purity.9 Recognizing the importance
of hexahydromeno[4,3-b]pyrrolidine derivatives and a paucity of
efficient approaches to access these molecules, we have great inter-
est in the development of an enantioselective intramolecular 1,3-
dipolar cycloaddition of 4-(2-formylphenoxy)butenoates of type
1 with amino esters 2 using phosphoric acids as chiral catalysts10
(Scheme 1). Herein, we will present our efforts on the discovery
of the first organocatalytic asymmetric intramolecular 1,3-dipolar
cycloaddition reaction for the synthesis of hexahydromeno[4,3-
b]pyrrolidine derivatives in high enantioselectivity.
dipolar cycloaddition of 4-(2-formylphenoxy)butenoates
with amino esters provides hexahydromeno[4,3-b]pyrrolidine
derivatives in high enantioselectivity (up to 94% ee).
Hexahydromeno[4,3-b]pyrrolidine and its structural analogues
have received considerable attention from synthetic and biological
chemists, because they constitute key subunits widely present in
biologically active and natural products, and serve as building
blocks in organic synthesis.1 For example, these compounds
have been non-competitive antagonists of the muscular nicotin
receptor.2 Moreover, they have been used as conformationally
restricted nicotine or rivastigmine analogues,3 and, therefore, hold
great potential to be acetylcholinesterase inhibitors.4 In addition,
similar structural scaffolds widely occur in a large number of
natural compounds, as exemplified by martinelline5 and sceletium
alkaloid A4.6 The significance of this heterocyclic skeleton in
organic and medicinal chemistry has led to a great demand
for efficient synthetic methods, particularly those capable of
producing highly enantiomerically enriched hexahydromeno[4,3-
b]pyrrolidine derivatives. Although several transformations have
been available for the construction of these skeletons, some
protocols exploited metal-based chiral catalysts to control the
stereoselectivity7 and the others merely gave racemic compounds
under rigorous reaction conditions in the absence of catalysts.8
Consequently, an enantioselective catalytic procedure for the facile
construction of polycyclic pyrrolidine skeletons in one-pot under
mild reaction conditions remains highly desirable with respect to
synthetic efficiency and atom economy.
Scheme 1 The phosphoric acid-catalyzed intramolecular 1,3-dipolar
cycloaddition.
An initial experiment of (E)-ethyl-4-(2-formylphenoxy)but-2-
enoate (1a) and methyl-2-amino-2-phenylacetate (2a) under the
influence of 10 mol% of a BINOL-derived phosphoric acid 4a in
˚
the presence of 3 A molecular sieves in chloroform was carried
out. As we expected, the intramolecular [3+2] cycloaddition
reaction occurred to give the desired product 3a in 41% yield and
85 : 15 dr, but the enantioselectivity was low (33% ee, Table 1,
entry 1). Encouraged by this preliminary result, a number of
3,3¢-disubstituted binol-derived phosphoric acids 4 (Fig. 1) were
evaluated to recruit the optimal catalyst (entries 2–9). As can be
seen from Table 1, the reaction performance was highly dependent
on the structure of phosphoric acids. The sterically bulky 3,3¢-
substituents of phosphoric acids were seemingly deleterious to
the catalytic activity and stereoselectivity. For example, the use
of phosphoric acids bearing bulky 3,3¢-substituents as catalysts,
which showed high stereoselectivity in many transformations,10a–c
rendered an almost non-selective reaction (entries 2–4). 4g turned
Most recently, we found that azomethines could be acti-
vated by phosphoric acids by forming chiral azomethine ylide
dipoles capable of undergoing 1,3-dipolar cycloaddition reac-
tions with electronically poor C C double bonds and imines,
leading to the emergence of several straightforward methods for
=
aChengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu, 610041
bGraduate School of Chinese Academy of Sciences, Beijing
cHefei National Laboratory for Physical Sciences at the Microscale and
Department of Chemistry, University of Science and Technology of China,
Hefei, 230026, China. E-mail: gonglz@ustc.edu.cn; Fax: (+) 86-(0)551-
3606266; Tel: (+)86-(0)551-3600671
† Electronic supplementary information (ESI) available: Experimental
details and characterization data for the new compounds. CCDC reference
number 759560. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c002369h
Fig. 1 Catalysts evaluated in this study.
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Table 1 Screening of chiral phosphoric acidsa
(entries 4–6). Either lowering or elevating the temperature afforded
unsatisfactory results (entries 8–9). Particularly, the reaction did
not work upon being conducted at 0 ◦C (entry 7). The best results
were obtainedby performing the reaction at a higher concentration
(entry 10).
Having the optimal conditions, we first investigated the general-
ity of the protocol for various a-arylglycine methyl esters (Table 3).
Both electronically rich and poor arylglycine methyl esters were
well tolerated and furnished the desired products in good yields
and with high to excellent enantioselectivity. Generally, the
electronically deficient a-arylglycine methyl esters provided higher
enantioselectivity than the electronically rich derivatives (entries
1–6 vs. 7). Specifically, methyl-2-amino-2-(2-fluorophenyl) acetate
Entry
4
Yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
41
9
85 : 15
90 : 10
83 : 17
87 : 13
74 : 26
93 : 7
93 : 7
88 : 12
83 : 17
33
3
3
34
37
11
38
64
28
15
1
25
32
59
58
2
Table 3 Scope of a-arylglycine methyl estersa
a The reaction was carried out at 0.1 mmol scale in chloroform (1 mL)
with 3 A MS (200 mg) at 25 ◦C for 72 h and the ratio of 1a : 2a was
˚
1.2 : 1. b Isolated yield based on 2a. c The dr refers to the ratio of 3a to its
isomers and was determined by 1H NMR of crude product. d Determined
by HPLC.
Entry 2 (Ar)
3
Yield (%)b drc
ee (%)d
out to be the optimal catalyst and gave the highest levels
of stereochemical outcome (entries 5–8). Surprisingly, bisphos-
phoric acid 4i, which gave excellent enantioselectivity for 1,3-
dipolar cycloaddition,9a,c also delivered an almost racemic product
(entry 9).
With the optimal organocatalyst in hand, the reaction param-
eters including solvents, molecular sieves and temperature were
investigated and the results are summarized in Table 2. Screening
of solvents found that toluene was the best media for the reaction in
terms of conversion and stereoselectivity (entries 1–4). However,
no reaction occurred in THF (entry 3). Variation of molecular
1
2
3
4
2-ClC6H4 (2b)
89
86
80
93
98 : 2 87
3-ClC6H4 (2c)
4-ClC6H4 (2d)
2-FC6H4 (2e)
99 : 1 92
97 : 3 90
99 : 1 94
˚
˚
sieves from 3 to 4 and 5 A suggested that 3 A molecular sieves
turned out to be the best additive in terms of enantioselectivity
Table 2 Optimization of reaction conditionsa
5
6
7
a
3-FC6H4 (2f)
82
84
65
99 : 1 90
97 : 3 91
97 : 3 81
Entry
Solvent
T/◦C
MS
Yield (%)b
drc
ee (%)d
˚
1
2
3
4
5
6
7
8
9
CH2Cl2
CHCl3
THF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
25
25
25
25
25
25
0
10
40
25
3 A
65
64
<5
81
95
48
NR
51
87
94
88 : 12
93 : 7
—
99 : 1
99 : 1
90 : 10
—
85 : 15
97 : 3
99 : 1
83
59
ND
90
84
59
ND
89
4-FC6H4 (2g)
4-MeOC6H4 (2h)
˚
3 A
˚
3 A
˚
3 A
˚
4 A
˚
5 A
˚
3 A
˚
3 A
˚
3 A
66
10
3 A
91e
˚
a The reaction was carried out at 0.1 mmol scale in solvent (1 mL) with MS
(200 mg) for 72 h and the ratio of 1a : 2a was 1.2 : 1. b Isolated yield based
on 2a. c The dr refers to the ratio of 3a to its isomers and was determined
by 1H NMR of crude product. d Determined by HPLC. e The reaction was
performed in toluene (0.5 mL).
˚
The reaction was carried out at 0.2 mmol scale in toluene (1 mL) with 3 A
MS (400 mg) at 25 ◦C for 72 h and the ratio of 1a : 2 was 1.2 : 1. b Isolated
yield based on 2. c The dr refers to the ratio of 3 to its isomers and was
determined by 1H NMR of crude product. d Determined by HPLC.
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Table 4 Scope of aldehydesa
donating substituent at C4 proceeded in a moderate yield, but
with excellent enantioselectivity (entry 3). The replacement of the
(E)-ethyl-4-(2-formylphenoxy)but-2-enoate (1a) with (E)-methyl-
4-(2-formylphenoxy)but-2-enoate (1h) was also able to provide
good yield and enantioselectivity (entry 7).
In summary, we have disclosed a Brønsted acid-catalyzed
asymmetric intramolecular 1,3-dipolar cycloaddition of alde-
hydes bearing dipolarophile functionalities with a-aryl amino
esters. The phosphoric acid 4g enabled the reaction to give
hexahydromeno[4,3-b]pyrrolidine derivatives in high yield and
enantioselectivity (up to 94% yield, 94% ee). This reaction
provided a straightforward entry to privileged polycyclic pyrro-
lidine architectures, which hold great potential in the develop-
ment of related compounds as medicinal and pharmaceutical
agents.
Entry 1 (R1, R2)
5
Yield (%)b drc
ee (%)d
1
2
3
4
5
6
7
R1 = 5-Cl
R2 = Et
(1b)
60
56
42
54
76
63
84
98 : 2 53
R1 = 5-OMe
R2 = Et
(1c)
94 : 6 68
R1 = 4-OMe
R2 = Et
(1d)
95 : 5 90
95 : 5 70
98 : 2 78
97 : 3 68
99 : 1 74
Acknowledgements
We are grateful for financial support from NSFC (20732006),
CAS, MOST (973 program 2010CB833300), and the Ministry of
Education.
R1 = 3-OMe
R2 = Et
(1e)
R1 = 3-OEt
R2 = Et
(1f)
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R1 = 3-F
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(1h)e
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˚
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(2e) was the most suitable substrate to undergo the cycloaddition
reaction in 93% yield and 94% ee (entry 4). These outcomes
are actually particularly significant in view of formidable chal-
lenges present in the construction of enantioenriched polycyclic
pyrrolidine compounds bearing quaternary stereogenic centers.11
The relative and absolute stereochemistry was assigned by X-ray
crystallography (see ESI†), and other products were assigned by
analogy.
Further exploration was focused on the generality of the
protocol for different aldehydes (Table 4). Variation of the
electronic properties of the substituent at either C3 or C5
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good yields ranging from 54 to 76% and moderate to good
enantioselectivities ranging from 53 to 78% ee (entries 1–2
and 4–6). Notably, the cycloaddition reaction with (E)-ethyl-
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