An organocatalytic approach to stereoselective synthesis of 2-hydroxyazetidines and 2-hydroxypyrrolidines

Article abstract of DOI:10.1016/j.tetlet.2013.04.013

A straightforward asymmetric synthesis of a new series of 2-hydroxyazetidines/2-hydroxypyrrolidines with excellent diastereoselectivity was developed via enamine catalysis using diphenylprolinol silyl ether. The Mannich-type reaction of chiral enamines with various aldimines/aziridines under mild conditions followed by intramolecular hemiaminalization affords the desired products 2-hydroxyazetidines and 2-hydroxypyrrolidines, respectively, in a one-pot operation. The scope and generality of the reaction was adequately investigated and the conditions were optimized extensively.

Full text of DOI:10.1016/j.tetlet.2013.04.013

Tetrahedron Letters 54 (2013) 3127–3131
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An organocatalytic approach to stereoselective synthesis
of 2-hydroxyazetidines and 2-hydroxypyrrolidines
⇑
Ankita Rai, Lal Dhar S. Yadav
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 December 2012
Revised 1 April 2013
Accepted 3 April 2013
Available online 10 April 2013
A straightforward asymmetric synthesis of a new series of 2-hydroxyazetidines/2-hydroxypyrrolidines
with excellent diastereoselectivity was developed via enamine catalysis using diphenylprolinol silyl
ether. The Mannich-type reaction of chiral enamines with various aldimines/aziridines under mild con-
ditions followed by intramolecular hemiaminalization affords the desired products 2-hydroxyazetidines
and 2-hydroxypyrrolidines, respectively, in a one-pot operation. The scope and generality of the reaction
was adequately investigated and the conditions were optimized extensively.
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
2-Hydroxyazetidines
2-Hydroxypyrrolidines
Organo-catalysis
Aziridine ring-opening
Stereoselective synthesis
Nitrogen heterocycles are of immense importance not only as
key components of a range of bioactive compounds, both naturally
occurring and synthetic, but also as synthetic precursors to a vari-
ety of pharmaceutically and industrially relevant nitrogen-contain-
ing compounds.1 In particular, azetidines1e and pyrrolidines2 are
ubiquitous in nature, and the search for new synthetic methodolo-
gies for their substituted and chiral ring systems would be of sig-
nificant value. Substituted azetidines are unique heterocycles
that have a wide range of synthetic applications,1,3,4 remarkable
biological activities1,3–6 and are prevalent in natural products.1,3–
their chemical and biological importance only a few and tedious
methods are available for their synthesis.12,13 Owing to the fast
growing chiral drug industry,15 currently interest is focussed on
stereoselective syntheses, especially those of heterocyclic sys-
tems.16–18 In this connection, we herein, report the first example
of the catalytic, stereoselective and efficient synthesis of 2-hydrox-
yazetidines (2-azetidinols) and 2-hydroxypyrrolidines (2-pyrrolid-
inols) as depicted in Scheme 1.
The present study is in continuation of our ongoing efforts to
develop synthetically useful organocatalytic processes,18 including
the synthesis of small ring heterocycles.17,19 The Mannich reaction
is a classic method for C–C bond forming strategies in organic syn-
thesis using asymmetric catalysis.20 Realizing the concept of
organocatalyzed addition of enamines formed in situ to imines as
acceptors, Hayashi et al.21a,b and others21c,d have already reported
the formation of b-amino compounds. Differing from those, our
synthetic approach relies on the asymmetric Mannich reaction
for the C–C bond formation followed by diastereoselective hem-
iaminalization and is applied to intramolecular cyclization of b-
amino compounds obtained from in situ generated enamines and
aldimines as well as aziridines. Thus, we have explored the scope
of enamine catalysis for the synthesis of 2-hydroxyazetidines and
2-hydroxypyrrolidines employing a pyrrolidine-based chiral cata-
lyst as the key point of the proposed strategy.
7
However, in contrast to the homologous small ring saturated
nitrogen heterocycles8 the synthetic approaches to enantioen-
riched azetidines are far less in number and generally involve mul-
tistep processes.1,9 Again, 3-azetidinols10 have been obtained by
the reduction of b-lactams, cyclization of 3-amino-1,2-diols and
nucleophilic substitution of L-threitol and 3-amino-1-chloroal-
kan-2-ols but 2-azetidinols are hitherto unknown compounds
although they might interest synthetic and medicinal chemists.
Similarly, the literature survey revealed that the hydroxy pyr-
rolidine ring system is present in many biologically active alka-
loids11 and these type of compounds were also exploited as
catalysts in asymmetric syntheses such as stereoselective reduc-
tion of ketones and Diels–Alder reaction.12 Apart from these, 2-
hydroxypyrrolidines are also used as intermediates for the synthe-
sis of various substituted pyrrolidines.13,14 Moreover, in spite of
With the aim of identifying a novel and efficient process to syn-
thesize 2-azetidinols, a model reaction of propionaldehyde with N-
tosylaldimine was investigated in detail. We began our studies by
examining the influence of a range of pyrrolidine based-catalysts
2a–e (Table 1) on the reaction. Among the catalysts tested, 2a
⇑
Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533.
E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.013

3128
A. Rai, Lal Dhar S. Yadav / Tetrahedron Letters 54 (2013) 3127–3131
R1
R2
OH
R3
R2
R4
N
R3
R5
N
Ph
OTMS
Ph
Ph
OTMS
Ph
5
4
N
N
H
O
single diastereomer
K2CO3
2
R1
H
THF, 5-7 h, rt
R1
THF, 30 min
R1
3
1
N
6
R4
OH
N
R5
7
single diastereomer
Scheme 1. Synthesis of 2-hydroxyazetidines 5 and 2-hydroxypyrrolidines 7.
Table 1
Table 2
Optimization of the reaction conditions for the synthesis of 2-azetidinol 5aa
Synthesis of 2-hydroxyazetidines 5a
O
R1
R2
OH
R3
O
Me
OH
(i) 2, rt, 30 min
(i) 2a, rt, 30 min
R2
N
R1
Ph
N
Me
R3
Ts
N
N
(ii) base, solvent, rt
4
(ii) K2CO3, THF, rt, 5-7 h
1
4
1
Ph
Ts
5
5
single diastereomer
single diastereomer
Ph
OH
Ph
2d
Ph
OTMS
Ph
Ph
OTES
Ph
Bn
O
N
N
N
H
N
N
H
N
H
N
H
N
Entry R1
R2
R3
Product Timeb
Yieldc,d
(%)
OH
2c
H
2e
2a
2b
(h)
1
2
3
4
5
6
7
8
Me
Ph
Ts
Ts
Ts
Ts
Ts
Ts
5a
5b
5c
5d
5e
5f
6
7
6
6
5
5
7
6
85
82
80
89
87
90
81
79
Entry
Catalyst 2
(mol %)
Base additive
(equiv)
Solvent
Yieldb (%)
Me
Me
Me
Et
4-MePh
4-MeOPh
4-ClPh
2-ClPh
4-NO2Ph
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
2a (15)
2a (20)
2a (25)
2a (20)
2a (20)
2a (20)
2a (20)
2a (20)
2a (20)
2a (20)
2a (20)
2a (20)
2a (20)
2a (20)
2b (20)
2c (20)
2d (20)
2e (20)
—
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.5)
K2CO3 (0.5)
Na2CO3 (1.0)
Pyridine (1.0)
NaHCO3 (1.0)
DABCO (1.0)
DBU (1.0)
THF
THF
THF
1,4-Dioxane
CH2Cl2
CH3CN
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
76
85
85
59
54
46
85
67
60
9
15
40
53
43
56
42
62
64
—
Me
PhCH2 2-MePh
PhCH2 2-MeOPh
PhSO2
4-MeOPhSO2
5g
5h
a
b
c
For the exprerimental procedure, see Ref. 26.
Time required for completion of step (ii).
Yield of isolated and purified product.
d
All compounds gave C, H and N analyses within 0.38% and satisfactory spectral
(IR, 1H NMR, 13C NMR and EIMS) data.
Et3N (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
K2CO3 (1.0)
—
Table 3
Synthesis of 2-hydroxypyrrolidines 7a
2a (20)
THF
—
a
R1
OH
For the experimental procedure, see Ref. 26.
Yield of isolated and purified product 5a.
b
R4
O
(i) 2a, rt, 30 min
(ii) K2CO3, THF, rt, 5-7 h
R1
N
R5
R4
N
1
6
R5
7
was found to be the best for triggering the reaction (Table 1, entries
2 and 15–18) through enamine catalysis. It neither interferes with
the reaction leading to side reactions nor forms any zwitterionic
entities. The reaction proceeds smoothly at ambient temperature
with optimum catalyst loading of 2a (20 mol %) to afford a single
diastereomer. The solvent effect was next examined, and THF
was found to be the best reaction medium in terms of the yield (Ta-
ble 1, entries 2 and 4–6).
Again, the presence of a base is a prerequisite for the success of
the hemiaminalization step. Several bases were examined, and it
was found that stronger bases such as DABCO, DBU and Et3N gave
moderate yields (Table 1, entries 12–14), whereas NaHCO3 and
pyridine gave poor yields (Table 2, entries 10 and 11). However,
K2CO3 (1.0 equiv) was found to be the best base additive (Table 1,
entry 2). In the same manner, we utilized these optimized reaction
conditions for the synthesis of 2-pyrrolidinols 7 using aldehyde 1
and aziridines 6, and to our delight, promising results were again
obtained in terms of yield and stereoselectivity. Only one diaste-
single diastereomer
Entry R1
R4
R5
Product Timeb
Yieldc,d
(%)
(h)
1
2
3
4
5
6
7
8
Me
Ph
Ts
Ts
Ts
Ts
7a
7b
7c
7d
7e
7f
5
5
7
6
7
7
6
5
84e
80
79
90
78
88
80
89
Me
Me
Me
Et
Me
Me
4-MePh
4-t-BuPh
4-ClPh
2-MePh
Ph
Ts
PhSO2
4-MeOPhSO2
PhSO2
Ph
7g
7h
PhCH2 Ph
a
b
c
For the experimental procedure, see Ref. 26.
Time required for completion of step (ii).
Yield of isolated and purified product.
d
All compounds gave C, H and N analyses within 0.38% and satisfactory spectral
(IR, 1H NMR, 13C NMR and EIMS) data.
e
Other conditions being the same as in Ref. 26 except the absence of 2a, the yield
for 7a was found to be 49%, whereas in the presence of 2a it was 84%.

A. Rai, Lal Dhar S. Yadav / Tetrahedron Letters 54 (2013) 3127–3131
3129
reomer of 5a was formed as determined by 1H NMR analysis of the
crude product.
high enantioselectivity is achieved. The TS models 8 and 10 are
similar to those originally proposed by Seebach and Golinski.23a,b
Moreover, the relative configuration of the products 2-azetidinols
5 and 2-pyrrolidinols 7 can be deduced from the mechanistic path-
way if we look at the TS as shown in A and B (cf. TS suggested by
Seebach et al.)23c because A bearing 1,2-diequatorial (trans) sub-
stituents and B having 1,3-equatorial, axial (cis) substituents are
stabler conformations due to minimum repulsive interactions in
the TS. Thus, A and B lead to 9 and 11, respectively. The reactions
were clean and all the synthesized products were characterized by
their IR, 1H NMR, 13C NMR and mass spectroscopic data. It was
gratifying that the formation of 2-azetidinols/2-pyrrolidinols was
entirely diastereoselective in favour of 2,4-cis/2,5-cis isomers,
respectively as determined by 1H NMR of crude products 5 and
7. The cis-stereochemistry of 2-azetidinols 5 was assigned and sup-
ported by comparison of JtransH/H values of 2-H and 3-H, 3-H and
4-H of the heterocycle, which are in the range of 6.5–7.7 Hz and
comparable with those reported in the literature.24 Similarly, 2,3-
Having established the optimal reaction conditions for forma-
tion of 5 and 7, we have surveyed the scope of reaction by using
various aldehydes 1 and aldimines 4/aziridines 6 and results are
summarized in Tables 2 and 3. It was found that the nature of a
substituent on the phenyl ring did not affect the
diastereoselectivity.
A plausible mechanism for the formation of 2-azetidinols 5 and
2-pyrrolidinols 7 is depicted in Scheme 2. In the first step, the cat-
alyst diphenylprolinol trimethylsilyl ether 2a activates aldehyde 1
by enamine formation which then stereoselectively adds to aldim-
ine 4. In the second step, the adduct undergoes intramolecular
cyclization promoted by K2CO3 leading to the product 2-azetidi-
nols 5. Similarly, when aziridines 6 are used, enamine reacts with
them followed by intramolecular cyclization to furnish 2-pyrrolid-
inols 7.
It may be mentioned here that the chiral carbon of aziridine 6 ap-
pears to be the main driving force for the formation of a single stereo-
isomer 7. However, in the presence of the catalyst 2a a significant
increase in the yield of 7 was observed (Table 3, footnote e).
In case of aziridines 6, the regioselective ring opening may follow
either electronic or steric control giving different compounds. Usu-
ally, the aziridine ring opening, takes place by a nucleophilic attack
on the benzylic carbon following the electronic control,22a,b but the
nucleophile prefers to attack the terminal carbon rather than the
benzylic carbon following the steric control.18c,22c–g Here, presum-
ably due to bulky nature of the attacking nucleophile, steric factor
predominates over electronic effect to afford products 7 and 11.
The C–C bond formation between the b-C-atom of enamine 3
and imino-carbon of 4 or CH2 of aziridine ring through the TS 8
and 10, respectively, is the enantiomeric-differentiating step
(Scheme 2). This takes place from the Si-face of the trans-enamine
because the bulky (Me3SiO)Ph2C group covers the Re-face, hence
trans-stereochemistry of 2-pyrrolidinols
7 was assigned and
supported by comparison of JtransH/H values of 2-H and 3-H of the
heterocycle, which are in the range of 6.0–6.9 Hz and are compara-
ble with those reported in the literature.25 The relative stereo-
chemistry of 5 and 7 are further established by NOE experiments
as shown in Figure 1. A strong NOE (7.9%) at 2-H/4-H was observed
in 2,4-cis-azetidinols 5. Similarly, in pyrrolidinols 7 2-H and 5-H are
located on the same face of the molecule as indicated by the observa-
tion of a strong NOE between (11.4%) them. Thus, 2-azetidinols 5 and
2-pyrrolidinols 7 have 2,4-cis and 2,5-cis configurations, respectively.
In summary, we have developed a novel one-pot procedure for
a highly stereoselective synthesis of 2-azetidinols and 2-pyrrolidi-
nols via a [2+2] annulation of aldehydes and aldimines, and [2+3]
annulation of aldehydes and aziridines, respectively. The synthetic
protocol presents the first chiral amine triggered synthesis of 2-
azetidinols and 2-pyrrolidinols via an anionic domino process,
O
R1
1
Ph
OTMS
2a
N
Ph
H
R4
Ph
OTMS
Ph
R2
N
N R5
R3
N
4
H
6
R1
3
R1
R5
R1
R3
CPh2OSMT
TMSOPh2C
N
CPh2OSMT
TMSOPh2C
N
N
N H
+
N
O
+
O N
R4
δ
H
δ
R2
H
H
S
Ar
S
Ar
δ-
H
N
N
H
H
R2
δ-
O
R5
10
R1
O
R1
R4
8
B
A
H2O
K2CO3
H2O
K2CO3
Ph
OTMS
Ph
Ph
OTMS
Ph
N
H
O
O
N
H
R1
R2
R1
H
N R5
H
9
N
11
R3
R4
R1
OH
R1
R2
OH
R3
R4
N
5
N
R5
7
Scheme 2. Plausible mechanism for the formation of 2-hydroxyazetidines 5 and 2-hydroxypyrrolidines 7.

3130
A. Rai, Lal Dhar S. Yadav / Tetrahedron Letters 54 (2013) 3127–3131
6. (a) Evans, G. B.; Furneaux, R. H.; Greatrex, B.; Murkin, A. S.; Schramm, V. L.;
11.4%
H
Tyler, P. C. J. Med. Chem. 2008, 51, 948; (b) Fuhshuku, K.-I.; Hongo, N.; Tashiro,
T.; Masuda, Y.; Nakagawa, R.; Seino, K.-I.; Taniguchi, M.; Mori, K. Bioorg. Med.
Chem. 2008, 16, 950; (c) Iserloh, U.; Wu, Y.; Cumming, J. N.; Pan, J.; Wang, L. Y.;
Stanford, A. W.; Kennedy, M. E.; Kuvelkar, R.; Chen, X.; Parker, E. M.; Strickland,
C.; Voigt, J. Bioorg. Med. Chem. Lett. 2008, 18, 414; (d) Ikee, Y.; Hashimoto, K.;
Nakashima, M.; Hayashi, K.; Sano, S.; Shiro, M.; Nagao, Y. Bioorg. Med. Chem.
Lett. 2007, 17, 942; (e) Slade, J.; Bajwa, J.; Liu, H.; Parker, D.; Vivelo, J.; Chen, G.
P.; Calienni, J.; Villhauer, E.; Prasad, K.; Repic, O.; Blacklock, T. J. Org. Process Res.
Dev. 2007, 11, 825; (f) Yeh, C. H.; Wu, S. J.; Tsai, Y. F.; Chen, H. Y.; Lin, C. Y. Plant
Sci. 2007, 172, 1124; (g) Kolocouris, N.; Zoidis, G.; Foscolos, G. B.; Fytas, G.;
Prathalingham, S. R.; Kelly, J. M.; Naesens, L.; De Clercq, E. Bioorg. Med. Chem.
Lett. 2007, 17, 4358; (h) Provins, L.; Christophe, B.; Danhaive, P.; Dulieu, J.;
Gillard, M.; Quere, L.; Stebbins, K. Bioorg. Med. Chem. Lett. 2007, 17, 3077; (i)
Zoidis, G.; Fytas, C.; Papanastasiou, I.; Foscolos, G. B.; Fytas, G.; Padalko, E.;
Clercq, E. D.; Naesens, L.; Neyts, J.; Kolocouris, N. Bioorg. Med. Chem. 2006, 14,
3341; (j) Bruner-Osborne, H.; Bunch, L.; Chopin, N.; Couty, F.; Evano, G.; Jensen,
A. A.; Kusk, M.; Nielsen, B.; Rabasso, N. Org. Biomol. Chem. 2005, 3, 3926.
7. (a) Rubenstein, E.; Zhou, H.; Krasinska, K. M.; Chien, A.; Becker, C. H.
Phytochemistry 2006, 67, 898; (b) Hamada, Y.; Shioiri, T. J. Org. Chem. 1986,
51, 5489; (c) Miyakoshi, K.; Oshita, J.; Kitahara, T. Tetrahedron 2001, 57, 3355;
(d) Aoyagi, Y. Phytochemistry. 2006, 67, 618; (e) Schummer, D.; Forche, E.;
Wray, V.; Domke, T.; Reichenbach, H.; Fle, G. H. Liebigs Ann. 1996, 971; (f) Isono,
K.; Asahi, K.; Suzuki, S. J. Am. Chem. Soc. 1969, 91, 7490; (g) Ohshita, K.;
Ishiyama, H.; Takahashi, Y.; Ito, J.; Mikami, Y.; Kobayashi, J. Bioorg. Med. Chem.
2007, 15, 4910; (h) Yoda, H.; Uemura, T.; Takabe, K. Tetrahedron Lett. 2003, 44,
977; (i) Kitajima, M.; Kogure, N.; Yamaguchi, K.; Takayama, H.; Aimi, N. Org.
Lett. 2003, 5, 2075; (j) Hayashi, H.; Takiuchi, K.; Murao, S.; Arai, M. Agric. Biol.
Chem. 1988, 52, 2131.
H
6.1%
H
H
Ha
Hb
CH3
N
CH3
OH
N
OH
Ts
H
H
H
Ts
7.9%
Figure 1. NOE for 2-hydroxyazetidines 5a and 2-hydroxypyrrolidines 7a.
thereby it also widens the scope of synthetic utility of organocatal-
ysis. No by-product formation, atom-economy, operational sim-
plicity, ambient temperature and high stereoselectivity are the
salient features of the present protocol, which would enhance
the scope of chemical and pharmaceutical applications of 2-azetid-
inol and 2-pyrrolidinol families of compounds.
Acknowledgments
8. (a) Cromwell, N. H.; Phillips, B. Chem. Rev. 1979, 79, 331; (b) Moore, J. A.; Ayers,
R. S. In Small Ring Heterocycles, Part 2; Hassner, A., Ed.; Wiley: New York, 1983;
p 1; (c) Davies, D. E.; Storr, R. C. In Comprehensive Heterocyclic Chemistry;
Lwowski, W., Ed.; Pergamon: Oxford, 1984; Vol. 7, p 237.
We sincerely thank the CSIR, Govt. of India, for financial support
(CSIR File No. 09/001/(0327)/2010/EMR-I) and the SAIF, Punjab
University, Chandigarh, for providing microanalyses and spectra.
.
9. (a)Asymmetric Synthesis of Nitrogen Heterocycles; Royer, J., Ed.; Wiley-VCH:
Weinheim, 2009; (b) Albrecht, L.; Jiang, H.; Dickmeiss, G.; Gschwend, B.;
Hansen, S. G.; Jørgensen, K. A. J. Am. Chem. Soc. 2010, 132, 9188; (c) Guo, S.; Xie,
Y.; Hu, X.; Xia, C.; Huang, H. Angew. Chem., Int. Ed. 2010, 49, 2728; (d) Hodgson,
D. M.; Kloesges, J. Angew. Chem., Int. Ed. 2010, 49, 2900; (e) Xu, Y.; Lu, G.;
Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, 3353; (f) Medjahdi,
M.; Go_nzlez-G_mez, J.; Foubelo, F.; Yus, M. J. Org. Chem. 2009, 74, 7859; (g)
Kawabata, T.; Moriyama, K.; Kawakami, S.; Tsubaki, K. J. Am. Chem. Soc. 2008,
130, 4153; (h) Moriyama, K.; Sakai, H.; Kawabata, T. Org. Lett. 2008, 10, 3883; (i)
Banide, E.; Lemau de Talanc, V.; Schmidt, G.; Lubin, H.; Comesse, S.; Dechoux,
L.; Hamon, L.; Kadouri-Puchot, C. Eur. J. Org. Chem. 2007, 4517; (j) De
Figueiredo, R. M.; Fr_hlich, R.; Christmann, M. J. Org. Chem. 2006, 71, 4147;
(k) Couty, F.; Evano, G.; Vargas-Sanchez, M.; Bouzas, G. J. Org. Chem. 2000, 70,
9028; (l) Pedrosa, R.; Andres, C.; Nieto, J.; del Pozo, S. J. Org. Chem. 2005, 70,
1408; (m) Lemau de Talanc, V.; Banide, E.; Bertin, B.; Comesse, S.; Kadouri-
Puchot, C. Tetrahedron Lett. 2005, 46, 8023; (n) Burtoloso, A. C. B.; Correia, C. R.
D. Tetrahedron Lett. 2004, 45, 3355; (o) Couty, F.; Evano, G.; Prim, D.; Marrot, J.
Eur. J. Org. Chem. 2004, 5, 3893; (p) Poch, M.; Verdaguer, X.; Moyano, A.; Perics,
M. A.; Riera, A. Tetrahedron Lett. 1991, 32, 6935; (q) Marinetti, A.; Hubert, P.;
Gent, J.-P. Eur. J. Org. Chem. 2000, 6, 1815.
10. (a) Gaertner, V. R. J. Org. Chem. 1967, 32, 2972; (b) Higgins, R. H.; Eaton, Q. L.;
Worth, L., Jr.; Peterson, M. V. J. Heterocycl. Chem. 1987, 24, 255; (c) Barluenga, J.;
Baragaña, B.; Concellon, J. M. J. Org. Chem. 1997, 62, 5974.
11. Srinivasa, A.; Mahadevan, K. M.; Hulikal, V. Synth. Commun. 2009, 39, 93.
12. Varma, P. P.; Mahadevan, K. M.; Khader, A.; Hulikal, V. Org. Commun. 2011, 4,
52.
13. Verma, S. K.; Atanes, M. N.; Busto, J. H.; Thai, D. L.; Rapoport, H. J. Org. Chem.
2002, 67, 1314.
14. Plehiers, M.; Hootele, C. Tetrahedron Lett. 1993, 34, 7569.
15. (a) Davies, N. M.; Teng, X. W. Adv. Pharm. 2003, 1, 242; (b) Briekner, S. J.;
Hutchinson, D. K.; Barbachyn, M. R.; Manninen, P. R.; Ulanourcz, D. A.; Garman,
S. A.; Grega, K. C.; Hendges, S. K.; Toops, D. S.; Ford, C. W.; Zurenko, G. E. J. Med.
Chem. 1996, 39, 673; (c) Corey, E. J.; Zhang, F.-Y. Angew. Chem., Int. Ed. 1999, 38,
1931; (d) Agranat, I.; Cancer, H.; Caldwell, J. Nat. Rev. Drug Disc. 2002, 1, 753.
16. (a) Chandrasekhar, S.; Mallikarjun, K.; Pavankumarreddy, G.; Rao, K. V.;
Jagadeesh, B. Chem. Commun. 2009, 4985; (b) Wang, Y.; Yu, D.-F.; Liu, Y.-Z.;
Wei, H.; Luo, Y.-C.; Dixon, D. J.; Xu, P.-F. Chem. Eur. J. 2010, 16, 3922; (c)
Urushima, T.; Sakamoto, D.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2010, 12, 4588;
(d) Tiecco, M.; Testafeeri, L.; Temperine, A.; Terlizzi, R.; Bagnoli, L.; Marini, F.;
Santi, C. Org. Biomol. Chem. 2007, 5, 3510; (e) Narhe, B. D.; Sriramurtghy, V.;
Yadav, V. K. Org. Biomol. Chem., http://dx.doi.org/10.1039/c2ob07140a.; (f)
Hoshino, J.; Hiraoka, J.; Hata, Y.; Sawada, S.; Yamamoto, Y. J. Chem. Soc., Perkin
Trans. 1 1995, 693.
17. (a) Rai, A.; Yadav, L. D. S. Org. Biomol. Chem. 2011, 9, 8058; (b) Rai, A.; Yadav, L.
D. S. Tetrahedron 2012, 68, 2459; (c) Rai, A.; Rai, V. K.; Singh, A. K.; Yadav, L. D. S.
Eur. J. Org. Chem. 2011, 4302.
18. (a) Yadav, L. D. S.; Singh, S.; Rai, V. K. Synlett 2010, 240; (b) Yadav, L. D. S.; Rai,
V. K.; Singh, S.; Singh, P. Tetrahedron Lett. 2010, 51, 1657; (c) Singh, S.; Rai, V. K.;
Singh, P. K.; Yadav, L. D. S. Synthesis 2010, 2, 2957; (d) Singh, A. K.; Chawla, R.;
Rai, A.; Yadav, L. D. S. Chem. Commun. 2012, 48, 3766.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
04.013.
References and notes
1. (a) Katrizky, A. L. In Advances in Heterocyclic Chemistry; Academic Press
(Science): Oxford, 2011; Vol. 104,; (b) Eguchi,
S Bioactive Heterocycles I;
Springer: Heidelberg, 2006; (c) Joule, J. A.; Mills, K. Heterocyclic Chemistry at a
Glance; Blackwell: Oxford, 2007; (d) Eicher, T.; Hauptmann, S. The Chemistry of
Heterocycles; Wiley-VCH: Weinheim, 2003; (e) Brandi, A.; Cicchi, S.; Cordero, F.
M. Chem. Rev. 2008, 108, 3988; (f) Couty, F.; Gwilherm, E. Synlett 2009, 3053.
2. (a) Franz´en, R. G. J. Comb. Chem. 2000, 2, 195; (b) Bellina, F.; Rossi, R.
Tetrahedron 2006, 62, 7213.
3. (a) Ghorai, M. K.; Kumar, A.; Tiwari, D. P. J. Org. Chem. 2010, 75, 137; (b)
Drouillat, B.; Couty, F.; Razafimahalo, V. Synlett 2009, 3182; (c) Drouillat, B.;
Couty, F.; David, O.; Evano, G.; Marrot, J. Synlett 2008, 1345; (d) Ghorai, M. K.;
Kumar, A.; Das, K. Org. Lett. 2007, 9, 5441; (e) Vargas-Sanchez, M.; Lakhdar, S.;
Couty, F.; Evano, G. Org. Lett. 2006, 8, 5501; (f) Van Brabandt, W.; Van
Landeghem, R.; De Kimpe, N. Org. Lett. 2006, 8, 1105; (g) Vargas-Sanchez, M.;
Couty, F.; Evano, G.; Prim, D.; Marrot, J. Org. Lett. 2005, 7, 5861; (h) Vanecko, J.
A.; West, F. G. Org. Lett. 2005, 7, 2949; (i) Yadav, V. K.; Sriramurthy, V. J. Am.
Chem. Soc. 2005, 127, 16366; (j) Prasad, B. A. B.; Bisai, A.; Singh, V. K. Org. Lett.
2004, 6, 4829; (k) Jiang, J.; Shah, H.; De Vita, R. J. Org. Lett. 2003, 5, 4101; (l)
Alcaide, B.; Almendros, P.; Aragoncillo, C.; Salgado, N. R. J. Org. Chem. 1999, 64,
9596.
4. (a) Singh, G. S.; D’Hooghe, M.; De Kimpe, N. In Comprehensive Heterocyclic
Chemistry III; Stevens, C. V., Ed.; Elsevier: Oxford, 2008; Vol. 2, pp 1–110; (b)
Couty, F. In Science of Synthesis; Schaumann, E., Enders, D., Eds.; Thieme:
Stuttgart, 2009; Vol. 40a, pp 773–816; (c) Zhang, Z.; Bai, X.; Liu, R.; Zi, G. Inorg.
Chim. Acta 2009, 362, 1687; (d) Couty, F.; Prim, D. Tetrahedron: Asymmetry
2002, 13, 2619; (e) Hermsen, P. J.; Cremers, J. G. O.; Thijs, L.; Zwanenburg, B.
Tetrahedron Lett. 2001, 42, 4243; (f) Guanti, G.; Riva, R. Tetrahedron: Asymmetry
2001, 12, 605; (g) Wilken, J.; Erny, S.; Wassmann, S.; Martens, J. Tetrahedron:
Asymmetry 2000, 11, 2143; (h) Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 1999,
10, 1673; (i) Starmans, W. A. J.; Walgers, R. W. A.; Thijs, L.; de Gelder, R.; Smits,
J. M. M.; Zwanenburg, B. Tetrahedron 1998, 54, 4991.
5. (a) Testa, E.; Wittigens, A.; Maffii, G.; Bianchi, G. In Research Progress in Organic,
Biological and Medicinal Chemistry; Gallo, U., Santamaria, L., Eds.; North-Holland
Publishing Co.: Amsterdam, 1964; Vol. 1, p 477; (b) Okutani, T.; Kaneko, T.;
Masuda, K. Chem. Pharm. Bull. 1974, 22, 1490; (c) Kobayashi, J.; Cheng, J.;
Ishibashi, M.; Wälchli, M. P.; Yamamura, S.; Ohizumi, Y. J. Chem. Soc., Perkin
Trans. 1 1991, 1135; (d) Frigola, J.; Torrens, A.; Castrillo, J. A.; Mas, J.; Vañó, D.;
Berrocal, J. M.; Calvet, C.; Salgado, L.; Redondo, J.; García-Granda, S.; Valentí, E.;
Quintana, J. R. J. Med. Chem. 1994, 37, 4195.
19. (a) Yadav, L. D. S.; Rai, A.; Rai, V. K.; Awasthi, C. Tetrahedron Lett. 2008, 49, 687;
(b) Yadav, L. D. S.; Patel, R.; Srivastava, V. P. Synlett 2008, 583; (c) Yadav, L. D. S.;

A. Rai, Lal Dhar S. Yadav / Tetrahedron Letters 54 (2013) 3127–3131
3131
Rai, A. Synlett 2009, 1067; (d) Yadav, L. D. S.; Kapoor, R. Garima Synlett 2009,
1055.
25. (a) Ghosh, A. K.; Kulkarni, S.; Xu, C.-X.; Fanwick, P. E. Org. Lett. 2006, 8, 4509;
(b) Reddy, J. S.; Rao, B. V. J. Org. Chem. 2007, 72, 2224.
20. (a) Cordova, A. Acc. Chem. Res. 2004, 37, 102; (b) Notz, W.; Tanaka, F.; Barbas, C.
F., III Acc. Chem. Res. 2004, 37, 580; (c) Mukherjee, S.; Yang, J. W.; Hoffman, S.;
List, B. Chem. Rev. 2007, 107, 5569.
26. General procedure for the synthesis of 2-hydroxyazetidines 5: A round-bottomed
flask was charged with a solution of aldehyde 1 (0.4 mmol) and the catalyst
diphenylprolinol trimethylsilyl ether 2a, (20 mol %) in THF (2 mL) previously
dried over 4 Å molecular sieves, and stirred for 30 min at rt. To this was added
aldimine 4 (0.4 mmol) followed by K2CO3 (0.4 mmol) in THF (2 mL) and stirred
at rt until complete consumption of aldimine 4 (5–7 h) as indicated by TLC.
Then, brine (2 mL) was added and the mixture was extracted with EtOAc
(3 Â 10 mL), dried over sodium sulfate, filtered and evaporated under reduced
pressure. The residue thus obtained was purified by flash column
chromatography (silica gel, 300–400 mesh; hexane/EtOAc, 95:5 as eluent) to
afford an analytically pure sample of 5 (Table 2).
21. (a) Hayashi, Y.; Okano, T.; Itoh, T.; Urushima, T.; Ishikawa, H.; Uchimaru, T.
Angew. Chem., Int. Ed. 2008, 47, 9053; (b) Urushima, T.; Ishikawa, H.; Hayashi, Y.
Chem. Eur. J. 2011, 17, 8273; (c) Marques, M. M. B. Angew. Chem., Int. Ed. 2006,
45, 348; (d) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5471.
22. (a) Dammacco, M.; Degennaro, L.; Florio, S.; Luisi, R.; Musio, B.; Altomare, A. J.
Org. Chem. 2009, 74, 6319; (b) Ghorai, M. K.; Das, K.; Shukla, D. J. Org. Chem.
2007, 72, 5859; (c) Wang, Z.; Cui, Y.-T.; Xu, Z.-B.; Qu, J. J. Org. Chem. 2008, 73,
2270; (d) Minakata, S.; Hotta, T.; Oderaotoshi, Y.; Komatsu, M. J. Org. Chem.
2006, 71, 7471; (e) Lu, P. Tetrahedron 2010, 66, 2549; (f) Srivastava Garima, V.
P.; Yadav, L. D. S. Green Chem. 2010, 12, 1460; (g) Minakata, S.; Kano, D.;
Oderaotoshi, Y.; Komatsu, M. Angew. Chem., Int. Ed. 2004, 43, 79.
23. (a) Seebach, D.; Golinski, J. Helv. Chim. Acta 1981, 64, 1413; (b) Seebachg, D.;
Beck, A. K.; Golinski, J.; Hay, J. N.; Laube, T. Helv. Chim. Acta 1985, 68, 162; (c)
Komisaraka, K.-P.; Benahoud, M.; Ishikawa, H.; Seebach, D.; Hayashi, Y. Helv.
Chim. Acta 2011, 94, 719.
General procedure for the synthesis of 2-hydroxypyrrolidines 7:
A round-
bottomed flask was charged with a solution of aldehyde 1 (0.4 mmol) and
the catalyst diphenylprolinol trimethylsilyl ether 2a, (20 mol %) in THF (2 mL)
previously dried over 4 Å molecular sieves, and stirred for 30 min at rt. To this
was added aziridine 6 (0.4 mmol) followed by K2CO3 (0.4 mmol) in THF (2 mL)
and stirred at rt until complete consumption of aziridine 6 (5–7 h) as indicated
by TLC. Then, brine (2 mL) was added and the mixture was extracted with
EtOAc (3 Â 10 mL), dried over sodium sulfate, filtered and evaporated under
reduced pressure. The residue thus obtained was purified by flash column
chromatography (silica gel, 300–400 mesh; hexane/EtOAc, 95:5 as eluent) to
afford an analytically pure sample of 7 (Table 3).
24. (a) Leung, H.-K.; Kulkarni, S. B.; Eagen, M. C.; Cromwell, N. H. J. Org. Chem. 1977,
42, 2094; (b) Durrat, F.; Sancher, M. V.; Couty, F.; Evano, G.; Marrot, J. Eur. J. Org.
Chem. 2008, 3286; (c) Kiss, L.; Mangelinckx, S.; Fülöp, F.; De Kimpe, N. Org. Lett.
2007, 9, 4399.