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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
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A chiral phosphoric acid-catalyzed intramolecular 1,3- structurally diverse synthesis of nitrogenous five-membered
dipolar cycloaddition of 4-(2-formylphenoxy)butenoates heterocycles with high optical purity.9 Recognizing the importance
with amino esters provides hexahydromeno[4,3-b]pyrrolidine of hexahydromeno[4,3-b]pyrrolidine derivatives and a paucity of
derivatives in high enantioselectivity (up to 94% ee). efficient approaches to access these molecules, we have great inter-
est in the development of an enantioselective intramolecular 1,3-
Hexahydromeno[4,3-b]pyrrolidine and its structural analogues dipolar cycloaddition of 4-(2-formylphenoxy)butenoates of type
have received considerable attention from synthetic and biological 1 with amino esters 2 using phosphoric acids as chiral catalysts10
chemists, because they constitute key subunits widely present in (Scheme 1). Herein, we will present our efforts on the discovery
biologically active and natural products, and serve as building of the first organocatalytic asymmetric intramolecular 1,3-dipolar
blocks in organic synthesis.1 For example, these compounds cycloaddition reaction for the synthesis of hexahydromeno[4,3-
have been non-competitive antagonists of the muscular nicotin b]pyrrolidine derivatives in high enantioselectivity.
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 Scheme 1 The phosphoric acid-catalyzed intramolecular 1,3-dipolar
cycloaddition.
for efficient synthetic methods, particularly those capable of
producing highly enantiomerically enriched hexahydromeno[4,3-
b]pyrrolidine derivatives. Although several transformations have An initial experiment of (E)-ethyl-4-(2-formylphenoxy)but-2-
been available for the construction of these skeletons, some enoate (1a) and methyl-2-amino-2-phenylacetate (2a) under the
protocols exploited metal-based chiral catalysts to control the influence of 10 mol% of a BINOL-derived phosphoric acid 4a in
stereoselectivity7 and the others merely gave racemic compounds the presence of 3 Å molecular sieves in chloroform was carried
under rigorous reaction conditions in the absence of catalysts.8 out. As we expected, the intramolecular [3+2] cycloaddition
Consequently, an enantioselective catalytic procedure for the facile reaction occurred to give the desired product 3a in 41% yield and
construction of polycyclic pyrrolidine skeletons in one-pot under 85 : 15 dr, but the enantioselectivity was low (33% ee, Table 1,
mild reaction conditions remains highly desirable with respect to entry 1). Encouraged by this preliminary result, a number of
synthetic efficiency and atom economy. 3,3¢-disubstituted binol-derived phosphoric acids 4 (Fig. 1) were
Most recently, we found that azomethines could be acti- evaluated to recruit the optimal catalyst (entries 2–9). As can be
vated by phosphoric acids by forming chiral azomethine ylide seen from Table 1, the reaction performance was highly dependent
dipoles capable of undergoing 1,3-dipolar cycloaddition reac- on the structure of phosphoric acids. The sterically bulky 3,3¢-
tions with electronically poor C=C double bonds and imines, substituents of phosphoric acids were seemingly deleterious to
leading to the emergence of several straightforward methods for the catalytic activity and stereoselectivity. For example, the use
of phosphoric acids bearing bulky 3,3¢-substituents as catalysts,
a which showed high stereoselectivity in many transformations,10a–c
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu, 610041 rendered an almost non-selective reaction (entries 2–4). 4g turned
b
Graduate School of Chinese Academy of Sciences, Beijing
c
Hefei National Laboratory for Physical Sciences at the Microscale and
Department of Chemistry, University of Science and Technology of China,
Hefei, 230026, China. E-mail: [email protected]; 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 obtained by performing the reaction at a higher concentration
(entry 10).
Having the optimal conditions, we first investigated the general-
Entry 4 Yield (%)b drc ee (%)d ity of the protocol for various a-arylglycine methyl esters (Table 3).
Both electronically rich and poor arylglycine methyl esters were
1 4a 41 85 : 15 33
2 4b 9 90 : 10 3 well tolerated and furnished the desired products in good yields
3 4c 34 83 : 17 3 and with high to excellent enantioselectivity. Generally, the
4 4d 37 87 : 13 1 electronically deficient a-arylglycine methyl esters provided higher
5 4e 11 74 : 26 25
enantioselectivity than the electronically rich derivatives (entries
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6 4f 38 93 : 7 32
7 4g 64 93 : 7 59 1–6 vs. 7). Specifically, methyl-2-amino-2-(2-fluorophenyl) acetate
8 4h 28 88 : 12 58
9 4i 15 83 : 17 2
a
The reaction was carried out at 0.1 mmol scale in chloroform (1 mL) Table 3 Scope of a-arylglycine methyl estersa
with 3 Å 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 1 H 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
1 2-ClC6 H4 (2b) 89 98 : 2 87
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- 2 3-ClC6 H4 (2c) 86 99 : 1 92
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,
3 4-ClC6 H4 (2d) 80 97 : 3 90
no reaction occurred in THF (entry 3). Variation of molecular
sieves from 3 to 4 and 5 Å suggested that 3 Å molecular sieves
turned out to be the best additive in terms of enantioselectivity

4 2-FC6 H4 (2e) 93 99 : 1 94
Table 2 Optimization of reaction conditionsa

5 3-FC6 H4 (2f) 82 99 : 1 90

Entry Solvent T/◦ C MS Yield (%)b drc ee (%)d

1 CH2 Cl2 25 3 Å 65 88 : 12 83
2 CHCl3 25 3 Å 64 93 : 7 59 6 4-FC6 H4 (2g) 84 97 : 3 91
3 THF 25 3 Å <5 — ND
4 Toluene 25 3 Å 81 99 : 1 90
5 Toluene 25 4 Å 95 99 : 1 84
6 Toluene 25 5 Å 48 90 : 10 59
7 Toluene 0 3 Å NR — ND 7 4-MeOC6 H4 (2h) 65 97 : 3 81
8 Toluene 10 3 Å 51 85 : 15 89
9 Toluene 40 3 Å 87 97 : 3 66
10 Toluene 25 3 Å 94 99 : 1 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 a
The reaction was carried out at 0.2 mmol scale in toluene (1 mL) with 3 Å
on 2a. c The dr refers to the ratio of 3a to its isomers and was determined MS (400 mg) at 25 ◦ C for 72 h and the ratio of 1a : 2 was 1.2 : 1. b Isolated
by 1 H NMR of crude product. d Determined by HPLC. e The reaction was yield based on 2. c The dr refers to the ratio of 3 to its isomers and was
performed in toluene (0.5 mL). determined by 1 H 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
Entry 1 (R1 , R2 ) 5 Yield (%)b drc ee (%)d asymmetric intramolecular 1,3-dipolar cycloaddition of alde-
hydes bearing dipolarophile functionalities with a-aryl amino
1 R1 = 5-Cl 60 98 : 2 53
R2 = Et esters. The phosphoric acid 4g enabled the reaction to give
(1b) 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-
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2 R1 = 5-OMe 56 94 : 6 68
R2 = Et lidine architectures, which hold great potential in the develop-
(1c) ment of related compounds as medicinal and pharmaceutical
agents.
3 R1 = 4-OMe 42 95 : 5 90
R2 = Et
(1d) Acknowledgements
We are grateful for financial support from NSFC (20732006),
4 R1 = 3-OMe 54 95 : 5 70 CAS, MOST (973 program 2010CB833300), and the Ministry of
R2 = Et
(1e)
Education.

5 R1 = 3-OEt 76 98 : 2 78 Notes and references

R2 = Et
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