Stereoselective synthesis of chiral 4-(1-Chloroalkyl)-β-lactams starting from amino acids and their transformation into functionalized chiral azetidines and pyrrolidines

Article abstract of DOI:10.1021/jo101220q

Chiral short-chain α-chloroaldehydes were prepared starting from enantiomerically pure amino acids in a three-step approach, thus providing a practical synthetic alternative for known organocatalytic α-chlorination procedures. The latter aldehydes proved

Full text of DOI:10.1021/jo101220q

pubs.acs.org/joc
Stereoselective Synthesis of Chiral 4-(1-Chloroalkyl)-β-Lactams Starting
from Amino Acids and Their Transformation into Functionalized Chiral
Azetidines and Pyrrolidines
†
‡
,†
Stijn Dekeukeleire,†,§ Matthias D’hooghe, Karl W. Tornroos, and Norbert De Kimpe*
€
†Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653,
B-9000 Ghent, Belgium, and ‡Department of Chemistry, University of Bergen, Alleꢀgt. 41, 5007 Bergen,
Norway. §Aspirant of the Fund for Scientific Research Flanders (FWO-Vlaanderen).
norbert.dekimpe@UGent.be
Received June 29, 2010
Chiral short-chain R-chloroaldehydes were prepared starting from enantiomerically pure amino
acids in a three-step approach, thus providing a practical synthetic alternative for known organo-
catalytic R-chlorination procedures. The latter aldehydes proved to be useful starting materials for
the stereoselective Staudinger synthesis of (3S,4S)-4-[(1S)-1-chloroalkyl]azetidin-2-ones in high dia-
stereomeric ratios and good overall yields, which were used as chiral building blocks for the pre-
paration of a number of azetidines and pyrrolidines.
Introduction
The application of chiral R-haloaldehydes, however, has not
been evaluated until recently, when (2S)-2-chloropropanal,
prepared via oxidation of commercially available (2S)-2-
chloropropanol, was used as a substrate for the synthesis
of chiral 4-(1-chloroethyl)-β-lactams in our preliminary
work.4 To date, the enantioselective R-halogenation of alde-
hydes has been studied to a limited extent.5,6 In particular,
only three major approaches toward chiral R-chloroalde-
hydes are reported in the literature, all of them based on
asymmetric catalysis. The first method involves a proline-
catalyzed R-chlorination of aldehydes using N-chlorosucci-
nimide as the chlorine source.7 The other two approaches
comprise the use of a chiral imidazolidinone as the asym-
metric catalyst,8 with the chlorinating agent being either
As the concept of chirality has become an important issue
and challenge in organic and medicinal chemistry, many
efforts are devoted to the development of chiral approaches
(often catalytic methodologies) toward β-lactams nowa-
days.1,2 The Staudinger reaction, utilizing either a chiral
ketene or a chiral imine, is generally acknowledged as the
method of choice for the asymmetric synthesis of β-lactams.
In that context, the use of chiral R-oxy- and R-amino-
substituted aldehydes for the stereoselective synthesis of
azetidin-2-ones has already been proven to be successful.3
(1) (a) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578.
(b) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III;
Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831. (c) Taggi, A. E.; Hafez, A. M.;
Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc. 2002, 124,
6626.
(2) (a) Palomo, C.; Aizpurua, J. M.; Inaki, G.; Oiarbide, M. Eur. J. Org.
Chem. 1999, 3223. (b) France, S.; Weatherwax, A.; Taggi, A. E.; Lectka, T.
Acc. Chem. Res. 2004, 37, 592. (c) Cossio, F. P.; Arrieta, A.; Sierra, M. A.
Acc. Chem. Res. 2008, 41, 925.
(3) For a few examples, see: (a) Wagle, D. R.; Garai, G.; Chiang, J.;
Monteleone, M. G.; Kurys, B. E.; Strohmeyer, T. W.; Hedge, V. R.; Manhas,
M. S.; Bose, A. K. J. Org. Chem. 1988, 53, 4227. (b) Brown, A. D.; Colvin,
E. W. Tetrahedron Lett. 1991, 32, 5187. (c) Jayaraman, M.; Deshmukh, A. R.
A. S.; Bhawal, B. M. Tetrahedron 1996, 52, 8989. (d) Palomo, C.; Cossio,
F. P.; Cuevas, C.; Lecea, B.; Mielgo, A.; Roman, P.; Luque, A.; Martinez-
Ripoll, M. J. Am. Chem. Soc. 1992, 114, 9360.
(4) D’hooghe, M.; Van Brabandt, W.; Dekeukeleire, S.; Dejaegher, Y.;
De Kimpe, N. Chem.;Eur. J. 2008, 14, 6336.
(5) Fluorination: (a) Steiner, D. D.; Mase, N.; Barbas, C. F., III. Angew.
€
Chem., Int. Ed. 2005, 44, 3706. (b) Enders, D.; Huttl, M. R. M. Synlett 2005,
991. (c) Beeson, T. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
8826. (d) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjoersgaard, A.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703.
(6) Bromination and iodination: (a) Bertelsen, S.; Halland, N.; Bach-
mann, S.; Marigo, M.; Braunton, A.; Jørgensen, K. A. Chem. Commun. 2005,
4821. (b) Kano, T.; Ueda, M.; Maruoka, K. J. Am. Chem. Soc. 2008, 130,
3728.
(7) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen,
K. A. J. Am. Chem. Soc. 2004, 126, 4790.
5934 J. Org. Chem. 2010, 75, 5934–5940
Published on Web 08/12/2010
DOI: 10.1021/jo101220q
r
2010 American Chemical Society

Dekeukeleire et al.
JOCArticle
SCHEME 1
hexachlorocyclohexadienone8a or sodium/lithium chloride
(used in combination with copper(II) triflate).8b Despite their
synthetic potential, minor drawbacks are sometimes encoun-
tered applying these methods, especially in terms of substrate
scope (e.g., short-chain aldehydes), workup procedures (toil-
some removal of hexachlorocyclohexadienone), and cost-price
(expensive catalyst (2R,5R)-diphenylpyrrolidine).
In order to provide an alternative for the oxidation of
commercially available (2S)-chloro-1-propanol toward
(2S)-2-chloropropanal,4 a novel synthetic approach toward
chiral nonracemic short-chain R-chloroaldehydes is disclosed
in the present report. As the synthesis evolves from enantio-
merically pure R-amino acids, the presented route can be
considered as the first convenient noncatalytic entry into chiral
R-chloroaldehydes. This approach provides a valuable and
interesting synthetic alternative for the known catalytic R-
chlorination procedures. With the intention to demonstrate
their synthetic potential, the latter chiral aldehydes were used
as powerful chiral inductors in the synthesis of a series of
new 4-(1-chloroalkyl)-β-lactams which in turn were shown
to be eligible substrates for further elaboration toward a
variety of azaheterocyclic compounds such as azetidines
and pyrrolidines (“β-lactam synthon method”).9
anhydrous dichloromethane for 15 h, affording the envi-
saged (2S)-2-chloroalkanals 2a-d in 44-50% overall yield
(Scheme 1). The formation of (2S)-2-chloroalkanals 2 start-
ing from S-amino acids 1 implies anchimeric assistance of the
carboxyl group during replacement of the amino group by
chloride, thus resulting in a double Walden inversion at the
asymmetric carbon atom. The proof that indeed the S-enan-
tiomers were obtained was provided by measurement of the
optical rotation of (2S)-2-chloro-3-phenylpropanal 2a, as
the observed RD value for this compound (R20D = -7.1, c =
1.0, CHCl3) was in accordance with literature data (R20
=
D
-8.8, c = 1.0, CHCl3).8a This synthetic route comprises the
first convenient noncatalytic entry toward chiral nonracemic
R-chloroaldehydes and can provide a useful alternative for
known organocatalytic R-chlorination procedures in terms
of substrate scope, synthetic procedures, and economical
considerations.
To check if any racemization had occurred during the
conversion of amino acids 1 into chiral nonracemic R-chlo-
roaldehydes 2, chiral GC analysis was performed on (2S)-2-
chloro-3-methylbutanal 2b, pointing to an enantiomeric ratio
1
of 97.5/2.5. An additional proof was provided by H NMR
analysis of (2S,3S)-2-chloro-3-methylpentanal 2d. The obser-
vation of two diastereoisomers in a 95/5 ratio in the 1H NMR
spectrum of the latter aldehyde 2d can be rationalized con-
sidering the presence of two stereogenic centers, of which only
one is susceptible to racemization (at the 2-position). Conse-
quently, the appearance of a second diastereoisomer in the 1H
NMR spectrum can be attributed to (2R,3S)-2-chloro-3-
methylpentanal. From these observations, it can be concluded
that racemization only takes place to a very limited extent
(e5%), affording chiral nonracemic R-chloroaldehydes 2 in
high enantiomeric excess.
Results and Discussion
With the intention to provide a novel and practical
synthetic approach toward chiral short-chain R-chloroalde-
hydes, a three-step procedure starting from R-amino acids
was devised involving (i) initial conversion into R-chloro
acids, followed by (ii) reduction to β-chloroalkanols and (iii)
oxidation to the corresponding R-chloroaldehydes. Despite
their availability and synthetic potential, chiral R-amino
acids have not been employed as substrates for the prepara-
tion of chiral R-chloroaldehydes until now.
As (2S)-2-chloropropanal has previously been shown to be
a powerful inductor for the stereoselective synthesis of
4-(1-chloroethyl)azetidin-2-ones,4 a series of R-chloroimines
were prepared via imination of R-chloroaldehydes 2 in dichlor-
omethane in the presence of MgSO4 and Et3N utilizing 1 equiv
of different primary amines, which were used immediately and
as such for the Staudinger synthesis of β-lactams upon treatment
with 1.3 equiv of phenoxy-, methoxy- or benzyloxyacetyl chlor-
ide in the presence of triethylamine in benzene, affording the
corresponding novel (3S,4S)-4-[(1S)-1-chloroalkyl]azetidin-2-
ones 3a-g in good overall yields (60-72%) and high diastere-
omeric ratios (95-83/5-17) (Scheme 1, Table 1). These ob-
servations clearly point to a strong and general inducing effect of
the R-chloro atom, enabling the stereoselective synthesis of 4-(1-
chloroalkyl)-β-lactams in a convenient way. It should be noted
that the reported yields are yields obtained after purification by
column chromatography on silica gel.
In order to replace the amino group of R-amino acids by
a chloro atom, enantiomerically pure amino acids 1 (i.e.,
L-phenylalanine, L-valine, L-leucine, and L-isoleucine) were
treated with 1.6 equiv of sodium nitrite in a 6 M solution of
hydrochloric acid for 4 h at 0 °C.10 Reduction of the resulting
(2S)-2-chloroalkanoic acids using 2 molar equiv of lithium
aluminum hydride in diethyl ether under reflux for 15 min led
to the formation of the corresponding alcohols,11 which were
subsequently subjected to an oxidation step involving treat-
ment with 3 equiv of pyridinium chlorochromate (PCC) in
(8) (a) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2004, 126, 4108. (b) Amatore, M.; Beeson, T. D.; Brown, S. P.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2009, 48, 5121.
(9) Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997, 377.
(10) Fu, S.-C.; Birnbaum, S. M.; Greenstein, J. P. J. Am. Chem. Soc. 1954,
76, 6054.
(11) Koppenhoefer, B.; Weber, R.; Schurig, V. Synthesis 1982, 316.
J. Org. Chem. Vol. 75, No. 17, 2010 5935

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TABLE 1. Synthesis of (3S,4S)-4-[(1S)-1-Chloroalkyl]azetidin-2-ones
3a-g
lactams have already been proven to be excellent starting
materials for the preparation of a large variety of novel azah-
eterocyclic compounds.15 To demonstrate the high synthetic
potential of chiral 4-(1-chloroalkyl)azetidin-2-ones 3a-g,
the preparation of a series of novel chiral 3-chloropyrroli-
dines was envisaged, as pyrrolidines comprise an important
class of azaheterocycles because of their presence in many
biologically interesting compounds.16 From a synthetic point
of view, 2-(1-haloalkyl)azetidines, mainly 2-(1-chloro-1-
methylethyl)azetidines, are known to be suitable substrates for
rearrangements toward pyrrolidines.17 Furthermore, one exam-
ple of a rearrangement of two racemic 4-(1-chloroethyl)-4-
methyl-β-lactams to the corresponding 4-benzyloxy-3-chloro-
2,3-dimethylpyrrolidines has been reported, in which the benzy-
loxy group, the chloro atom, and the 2-methyl group reside at
the same side (all-cis, previously erroneously described as the cis-
2,3-dimethyl isomer).4 In that respect, (3S,4S)-4-[(1S)-1-chlor-
oalkyl]azetidin-2-ones 3a-g, obtained as single diastereoisomers
after column chromatography, were treated first with 4 equiv of
monochloroalane (AlH2Cl) in diethyl ether under reflux for 4 h,
affording novel (2S,3S)-2-[(1S)-1-chloroalkyl]azetidines 4a-g
in moderate to good yields after purification by column chro-
matography (Scheme 2, Table 2). Subsequently, the latter aze-
tidines 4 underwent rearrangement via intermediate bicyclic
azetidinium ions 6 toward a series of new, chiral (2R,3S,4R)-2-
alkyl-3-chloropyrrolidines 5a-g upon reflux in acetonitrile for
18-96 h (Scheme 2, Table 2) in analogy with the previously re-
ported transformation of 2-(1-chloro-1-methylethyl)azetidines
into the corresponding 3-chloropyrrolidines.15c Sterical hin-
drance due to the presence of an extra methyl group in the
azetidine side chain (R1 = iPr and (S)-sBu) accounts for longer
reaction times in the case of 2-alkyl-3-chloropyrrolidines 5c, 5f,
and 5g.
isolated
yielda(%)
diastereomeric
ratiob
compound
R1
Bn
Bn
iPr
iBu
iBu
(S)-sBu
(S)-sBu
R2
R3
3a
3b
3c
3d
3e
3f
cHex
iPr
iPr
allyl
nBu
Bn
Bn
Ph
Bn
Me
Bn
Me
Ph
63
60
68
72
62
64
64
94/6
95/5
87/13
91/9
89/11
87/13
83/17
3g
nPr
aAfter purification by column chromatography on silica gel. bBased
on GC analysis of the crude reaction mixtures.
The relative stereochemistry of β-lactams 3 with regard to
the protons at C3 and C4 was assigned as cis based on the
coupling constants between these protons in 1H NMR
(4.9-5.1 Hz, CDCl3), in accordance with literature data.12
The full configuration of β-lactams 3 was established by
X-ray analysis of azetidin-2-one 3a, providing the irrefutable
proof for the formation of (3S,4S)-4-[(1S)-1-chloroalk-
yl]azetidin-2-ones 3 as the major stereoisomers, which is in
accordance with theoretical considerations in the literature.
Indeed, the origin of the asymmetric induction in the Stau-
dinger synthesis of 4-(1-oxy- or 1-aminoalkyl)-β-lactams has
been rationalized on the basis of the magnitude of the
stereoelectronic effect exerted by the σ*(C-X) orbital
(with X = OH or NH2 and C a stereogenic carbon atom)
over the HOMO in the transition states.4,13 Furthermore,
according to a theoretical study on the hyperconjugative
acceptor ability of σ bonds, the σ*(C-X) acceptor abilities
increase by at least 30% when X is a halogen atom in
comparison with X being an oxygen or a nitrogen atom,14
which was thus acknowledged experimentally in this work.
In order to determine the enantiomeric ratio of azetidin-2-
ones 3, which can be influenced by the stability of the
intermediate R-chloroimines toward racemization upon imi-
ne-enamine tautomerism, β-lactams 3a and 3b were treated
with either 4 or 2.5 equiv of (R)-(-)-2,2,2-trifluoro-1-(9-
Furthermore, hydrogenolysis of the benzyloxy group
within pyrrolidine 5e was performed applying 5 bar H2 in
the presence of 10% Pd/C and 2 equiv of HClconc in MeOH at
room temperature for 15 h, affording pyrrolidine 7 bearing a
free hydroxyl group as a useful template for further deriva-
tization (Scheme 3).
1
anthryl)ethanol (Pirkle alcohol) prior to H NMR analysis
(CDCl3). In the case of (3S,4S)-3-benzyloxy-4-[(1S)-1-
chloro-2-phenylethyl]-1-cyclohexylazetidin-2-one 3a, an en-
antiomeric ratio of 82/18 was observed (using 4 equiv of
Pirkle alcohol), whereas for (3S,4S)-4-[(1S)-1-chloro-2-
phenylethyl]-1-isopropyl-3-phenoxyazetidin-2-one 3b, an
enantiomeric ratio of 83/17 was found (using 2.5 equiv of
Pirkle alcohol). Thus, it can be concluded that epimerization
occurs only to a limited extent during imination and/or
Staudinger reaction starting from R-chloroaldehydes 2, which is
in accordance with previous findings.4
The relative configuration of 2-alkyl-3-chloropyrrolidines
5 (all-cis) is a direct consequence of the reaction mechanism
since the formation of pyrrolidines 5 as single diastereomers
can only be attributed to a SN2-based pathway via inter-
mediate bicyclic azetidinium salts 6.17c Furthermore, this
relative configuration was confirmed by qualitative NOESY
experiments performed on (2R,3S,4R)-4-benzyloxy-1-butyl-
3-chloro-2-(2-methylpropyl)pyrrolidine 5e.
In order to establish its enantiomeric ratio, esterification
of 4-hydroxypyrrolidine 7 was performed utilizing 1 equiv of
(1S)-(-)-camphanic chloride in CH2Cl2 at room tempera-
ture for 15 h in the presence of 0.1 equiv of DMAP and
2 equiv of Et3N, pointing to a diastereomeric ratio of 86/14
(based on GC/MS analysis). Consequently, an enantiomeric
ratio of 86/14 can be assigned to the starting pyrrolidine 5e.
Because of the combination of a strained four-membered
ring system, a nucleophilic nitrogen lone pair and an electro-
philic center in the side chain, racemic 4-(1-haloalkyl)-β-
(12) (a) Barrow, K. D.; Spotswood, T. M. Tetrahedron Lett. 1965, 37,
3325. (b) Decazes, J.; Luche, J. L.; Kagan, H. B. Tetrahedron Lett. 1970, 42,
3361.
(13) Palomo, C.; Cossio, F. P.; Cuevas, C.; Lecea, B.; Mielgo, A.; Roman,
P.; Luque, A.; Martinez-Ripoll, M. J. Am. Chem. Soc. 1992, 114, 9360.
(14) Alabugin, I. V.; Zeidan, T. A. J. Am. Chem. Soc. 2002, 124, 3175.
(15) For a few examples, see: (a) Dekeukeleire, S.; D’hooghe, M.; De
Kimpe, N. J. Org. Chem. 2009, 74, 1644. (b) Leemans, E.; D’hooghe, M.;
(16) (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435. (b) Felpin, F.;
Lebreton, J. Eur. J. Org. Chem. 2003, 3693. (c) Pearson, W. H.; Stoy, P.
ꢁ
Synlett 2003, 7, 903. (d) Pichon, M.; Figadere, B. Tetrahedron: Asymmetry
1996, 4, 927.
€
Dejaegher, Y.; Tornroos, K. W.; De Kimpe, N. J. Org. Chem. 2008, 73, 1425.
(17) (a) Couty, F.; Durrat, F.; Prim, D. Tetrahedron Lett. 2003, 44, 5209.
(b) Outurquin, F.; Pannecoucke, X.; Berthe, B. Eur. J. Org. Chem. 2002,
1007. (c) Van Brabandt, W.; Van Landeghem, R.; De Kimpe, N. Org. Lett.
2006, 8, 1105. (d) Durrat, F.; Vargas Sanchez, M.; Couty, F.; Evano, G.;
Marrot, J. Eur. J. Org. Chem. 2008, 3286.
(c) Van Brabandt, W.; Dejaegher, Y.; Van Landeghem, R.; De Kimpe, N.
Org. Lett. 2006, 8, 1101. (d) Van Brabandt, W.; De Kimpe, N. J. Org. Chem.
2005, 70, 3369. (e) D’hooghe, M.; Dekeukeleire, S.; Leemans, E.; De Kimpe,
N. Pure Appl. Chem. 2010, 81, 1749.
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SCHEME 2
TABLE 2. Synthesis of (2R,3S,4R)-2-Alkyl-3-chloropyrrolidines 5a-g
transformation of 2-(1-chloroalkyl)azetidines with retention
of enantiomeric purity.
isolated
yielda(%)
enantiomeric
ratio
compound
R1
R2
R3
5a
5b
5c
5d
5e
5f
Bn
Bn
iPr
iBu
iBu
cHex
iPr
iPr
allyl
nBu
Bn
Bn
Ph
Bn
Me
Bn
Me
Ph
71
75
74
52
75
68
67
82/18
87/13
94/6
81/19
86/14
100/0b
100/0b
Experimental Section
Synthesis of (2S)-2-Chloroalkanals 2. As a representative
example, the synthesis of (2S)-2-chloro-3-phenylpropanal 2a
starting from L-phenylalanine 1a is described.
(S)-sBu
(S)-sBu
To a stirred solution of 8.26 g of L-phenylalanine 1a (50
mmol) in 6 M HCl (250 mL) at 0 °C was added 5.52 g of NaNO2
(80 mmol, 1.6 equiv) in small portions. After stirring for 4 h at
0 °C, the reaction mixture was extracted with Et2O (3 ꢀ 125 mL).
The combined organic fractions were dried overnight over
calcium chloride dihydrate, and after removal of the drying
agent through filtration and evaporation of the solvent in vacuo,
crude (2S)-2-chloro-3-phenylpropionic acid was obtained. Sub-
sequently, 2.88 g of LiAlH4 (76 mmol, 2 molar equiv based on
the estimated quantitative yield of the crude (2S)-2-chloro-3-
phenylpropionic acid) was added in small portions to a solution
of (2S)-2-chloro-3-phenylpropionic acid in anhydrous Et2O
(150 mL) at 0 °C. After heating under reflux for 15 min, water
(20 mL) was added to neutralize the residual hydride. After
decantation of the solvent, the residue was washed with Et2O
(3 ꢀ 75 mL). After drying (MgSO4) of the combined organic
fractions and filtration, the solvent was evaporated under
reduced pressure, affording crude (2S)-2-chloro-3-phenylpro-
pan-1-ol. Then, 19.18 g of pyridinium chlorochromate (89
mmol, 3 equiv based on the estimated quantitative yield of the
crude (2S)-2-chloro-3-phenylpropan-1-ol) was added to a solu-
tion of (2S)-2-chloro-3-phenylpropan-1-ol (30 mmol) in dry
CH2Cl2 (150 mL). After stirring for 15 h at room temperature,
the reaction mixture was filtered over silica gel and the filter cake
was washed with CH2Cl2 (2 ꢀ 50 mL). After evaporation of the
solvent under reduced pressure, the crude (2S)-2-chloro-3-phe-
nylpropanal 2a was obtained in 48% overall yield with regard to
amino acid 1a (purity >90% based on 1H NMR, CDCl3). The
spectral data of compound 2a were in accordance with those
reported in the literature.8a
5g
nPr
aAfter purification by column chromatography on silica gel. bThese
compounds were isolated as single diastereomers due to the presence of
an additional chiral center [R1 = (S)-sBu].
SCHEME 3
When (2R,3S,4R)-1-allyl-3-chloro-4-methoxy-2-(2-methyl-
propyl)pyrrolidine 5d was treated with 1 equiv of L-tartaric
acid in THF at room temperature for 15 h, a diastereomeric
ratio of 81/19 was found for the resulting salt (based on 1H
NMR analysis, CD3OD), which points to an enantiomeric
ratio of 81/19 for pyrrolidine 5d.
In addition, when pyrrolidines 5a-c were treated with 3
(for pyrrolidines 5a and 5b) or 1 (in the case of pyrrolidine 5c)
equiv of Pirkle alcohol prior to 1H NMR analysis (CDCl3),
enantiomeric ratios of 82/18, 87/13, and 94/6, respectively,
were observed.
These observations confirm the high enantiomeric purity
of pyrrolidines 5 and corroborate the significance of amino
acids as synthons for the convenient preparation of chiral
pyrrolidines in a straightforward way.
Due to their instability, (2S)-2-chloroalkanals 2 were not
subjected to further purification and were used immediately
and as such in the next reaction step.
Synthesis of (3S,4S)-4-[(1S)-1-Chloroalkyl]azetidin-2-ones
3a-g. As a representative example, the synthesis of (3S,4S)-3-
benzyloxy-4-[(1S)-1-chloro-2-phenylethyl]-1-cyclohexylazetidin-
2-one 3a is described.
To a solution of 1.69 g of (2S)-2-chloro-3-phenylpropanal 2a
(10 mmol) in dry CH2Cl2 (50 mL) were added 2.41 g of MgSO4
(20 mmol, 2 equiv) and 0.99 g of cyclohexylamine (10 mmol, 1
equiv). After stirring for 1.5 h at room temperature, the drying
agent was removed through filtration and the solvent was eva-
porated under reduced pressure. Then, benzene (50 mL) was
added, and after evaporation of the residual dichloromethane
In conclusion, a convenient and straightforward noncata-
lytic protocol for the synthesis of chiral short-chain R-
chloroaldehydes is disclosed, providing a useful synthetic
alternative for known organocatalytic R-chlorination proce-
dures. Furthermore, the latter (2S)-2-chloroalkanals were
shown to be suitable starting materials for the synthesis of
novel chiral (3S,4S)-4-[(1S)-1-chloroalkyl]azetidin-2-ones
in high diastereomeric and enantiomeric ratios. The latter
β-lactams were subsequently elaborated toward a series
of chiral nonracemic 2-alkyl-3-chloropyrrolidines via ring
J. Org. Chem. Vol. 75, No. 17, 2010 5937

Dekeukeleire et al.
JOCArticle
under vacuo, 3.04 g of Et3N (30 mmol, 3 equiv) was added, after
which the reaction mixture was heated to reflux temperature.
Subsequently, a solution of 2.40 g of benzyloxyacetyl chloride
(13 mmol, 1.3 equiv) in benzene (10 mL) was added dropwise to
the boiling solution in benzene. After complete addition, the
reaction mixture was stirred overnight (15 h) at room tempera-
ture. Subsequently, the reaction mixture was washed with water
(50 mL), and the aqueous phase was extracted with CH2Cl2 (3 ꢀ
20 mL). After drying (MgSO4) and evaporation of the solvent,
the crude reaction mixture was purified by column chromatog-
raphy on silica gel (hexane/EtOAc 4/1), affording pure (3S,4S)-
3-benzyloxy-4-[(1S)-1-chloro-2-phenylethyl]-1-cyclohexylazeti-
din-2-one 3a in 63% yield.
(3S,4S)-3-Benzyloxy-4-[(1S)-1-chloro-2-phenylethyl]-1-cyclo-
hexylazetidin-2-one 3a: White crystals; mp 113.7 °C; Rf = 0.38
(hexane/EtOAc 4/1), yield 63%; [R]D= -10 (c = 0.06, CH2Cl2),
1H NMR (300 MHz, CDCl3) δ 1.17-1.25 and 1.57-2.02 (3H
and 7H, 2m), 2.84 (1H, dd, J = 14.0, 9.4 Hz), 3.36 (1H, dd, J =
14.0, 2.1 Hz), 3.36-3.47 (1H, m), 3.85 (1H, dd, J = 9.4, 5.0 Hz),
4.28 (1H, ddd, J = 9.4, 9.4, 2.1 Hz), 4.67 (1H, d, J = 5.0 Hz),
4.77 and 5.03 (2 ꢀ 1H, 2d, J = 11.3 Hz), 7.13-7.15, 7.24-7.26
and 7.28-7.42 (10H, 3m); 13C NMR (75 MHz, CDCl3) δ 25.3,
25.4, 25.7, 30.8, and 31.1 (5 ꢀ CH2), 40.7 (CH2), 54.9 (CH), 61.3
(CH), 64.3 (CH), 73.2 (CH2), 80.4 (CH), 126.9, 128.3, 128.4,
128.6, and 129.7 (10 ꢀ CH), 136.9 and 137.2 (2 ꢀ C), 167.4 (C);
IR (KBr, cm-1) νCdO = 1724; νmax = 2928, 1151, 1058, 988,
751, 698; MS (70 eV) m/z (%) 398/400 (Mþ þ 1, 100). Anal.
Calcd for C24H28ClNO2: C, 72.44; H, 7.09; N, 3.52. Found: C,
72.46; H, 7.23; N, 3.51.
(3S,4S)-4-[(1S)-1-Chloro-2-phenylethyl]-1-isopropyl-3-pheno-
xyazetidin-2-one 3b: White crystals; mp 98.7 °C; Rf = 0.13
(hexane/EtOAc 9/1); yield 60%; [R]D =-49 (c = 0.12, CH2Cl2);
1H NMR (300 MHz, CDCl3) δ 1.37 and 1.46 (2 ꢀ 3H, 2d, J =
6.8 Hz), 2.91 (1H, dd, J = 14.3, 9.4 Hz), 3.47 (1H, dd, J = 14.3,
2.2 Hz), 3.93 (1H, sept, J = 6.8 Hz), 4.03 (1H, dd, J = 9.5, 4.9
Hz), 4.49 (1H, ddd, J = 9.5, 9.4, 2.2 Hz), 5.27 (1H, d, J = 4.9
Hz), 7.03-7.08, 7.17-7.21 and 7.25-7.39 (10H, 3m); 13C NMR
(75 MHz, CDCl3) δ 20.83 and 20.88 (2 ꢀ CH3), 41.0 (CH2), 47.4
(CH), 61.5 (CH), 63.9 (CH), 80.3 (CH), 116.1 (2 ꢀ CH), 122.8
(CH), 127.2, 128.6, 129.6, and 129.8 (7 ꢀ CH), 136.9 (C), 157.6
(C), 165.9 (C); IR (KBr, cm-1) νCdO = 1741; νmax = 2971, 1494,
1230, 748, 696, 688; MS (70 eV) m/z (%) 344/6 (Mþ þ 1, 100).
Anal. Calcd for C20H22ClNO2: C, 69.86; H, 6.45; N, 4.07.
Found: C, 69.93; H, 6.22; N, 3.82.
ν
CdO =1755;νmax=2957, 1353, 1215, 1031, 929; MS(70eV) m/z
(%) 246/8 (Mþ þ 1, 100). Anal. Calcd for C12H20ClNO2: C,
58.65; H, 8.20; N, 5.70. Found: C, 58.73; H, 8.46; N, 5.52.
(3S,4S)-3-Benzyloxy-1-butyl-4-[(1S)-1-chloro-3-methylbutyl]-
azetidin-2-one 3e: Light-yellow oil; Rf = 0.31 (hexane/EtOAc 6/
1); yield 62%; [R]D = -56 (c = 0.22, CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 0.81 and 0.92 (2 ꢀ 3H, 2d, J = 6.6 Hz), 0.92 (3H,
t, J = 7.3 Hz), 1.30 (2H, sext, J = 7.3 Hz), 1.45-1.70 (4H, m),
1.88-1.99 (1H, m), 3.32 (1H, ddd, J = 13.8, 8.3, 5.5 Hz), 3.54
(1H, ddd, J = 13.8, 8.0, 8.0 Hz), 3.78 (1H, dd, J = 9.9, 5.0 Hz),
4.18-4.26 (1H, m), 4.61 (1H, d, J = 5.0 Hz), 4.67 and 4.95 (2 ꢀ
1H, 2d, J = 11.6 Hz), 7.27-7.38 (5H, m); 13C NMR (75 MHz,
CDCl3) δ 13.8, 20.5, and 23.8 (3 ꢀ CH3), 20.2 (CH2), 24.5 (CH),
29.5 (CH2), 41.4 (CH2), 43.3 (CH2), 62.3 (2 ꢀ CH), 73.0 (CH2),
80.8 (CH), 128.03, 128.09, and 128.5 (5 ꢀ CH), 137.0 (C), 168.0
(C); IR (NaCl, cm-1) νCdO = 1754; νmax = 2957, 1455, 1115,
736, 697; MS (70 eV) m/z (%) 338/40 (Mþ þ 1, 40), 304 (Mþþ1-
Cl, 100). Anal. Calcd for C19H28ClNO2: C, 67.54; H, 8.35; N,
4.15. Found: C, 67.32; H, 8.48; N, 4.23.
(3S,4S)-1-Benzyl-4-[(1S,2S)-1-chloro-2-methylbutyl]-3-meth-
oxyazetidin-2-one 3f: Colorless oil; Rf = 0.19 (hexane/EtOAc 6/
1); yield 64%; [R]D = -11 (c = 0.32, CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 0.86 (3H, t, J = 7.4 Hz), 0.99 (3H, d, J = 6.6
Hz), 1.14-1.29 and 1.31-1.46 (2 ꢀ 1H, 2m), 1.83-1.94 (1H, m),
3.58 (3H, s), 3.83 (1H, dd, J = 10.0, 5.1 Hz), 4.21 (1H, dd, J =
10.0, 2.5 Hz), 4.37 (1H, d, J = 14.6 Hz), 4.40 (1H, d, J = 5.1 Hz),
4.86 (1H, d, J = 14.6 Hz), 7.29-7.37 (5H, m); 13C NMR (75
MHz, CDCl3) δ 11.9 (CH3), 17.2 (CH3), 22.9 (CH2), 36.9 (CH),
45.5 (CH2), 59.3 (CH, and CH3), 70.2 (CH), 83.6 (CH), 127.8,
128.7, and 128.8 (5 ꢀ CH), 135.9 (C), 168.1 (C); IR (NaCl, cm-1
)
ν
c=o = 1755; νmax = 2964, 1454, 1350, 1216, 1075, 1033, 721,
700; MS (70 eV) m/z (%) 296/8 (Mþ þ 1, 100). Anal. Calcd for
C16H22ClNO2: C, 64.97; H, 7.50; N, 4.74. Found: C, 65.12; H,
7.88; N, 4.57.
(3S,4S)-4-[(1S,2S)-1-Chloro-2-methylbutyl]-3-phenoxy-1-pro-
pylazetidin-2-one 3g: Light-yellow oil; Rf = 0.25 (hexane/EtOAc
7/1); yield 64%; [R]D = -140 (c = 0.46, CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 0.89 and 0.93 (2 ꢀ 3H, 2t, J = 7.4 Hz), 1.09 (3H,
d, J = 6.6 Hz), 1.22-1.84 (4H, m), 2.01-2.09 (1H, m), 3.36 (1H,
ddd, J = 13.8, 8.3, 5.5 Hz), 3.54 (1H, ddd, J = 13.8, 7.8, 7.8 Hz),
4.18 (1H, dd, J = 9.8, 5.1 Hz), 4.36 (1H, dd, J = 9.8, 2.2 Hz),
5.22 (1H, d, J = 5.1 Hz), 7.01-7.11 and 7.29-7.35 (5H, 2m); 13
C
NMR (75 MHz, CDCl3) δ 11.5 and 12.0 (2 ꢀ CH3), 17.2 (CH3),
20.8 and 23.1 (2 ꢀ CH2), 37.0 (CH), 43.9 (CH2), 60.1 (CH), 69.9
(CH), 80.5 (CH), 116.0 (2 ꢀ CH), 122.6 (CH), 129.8 (2 ꢀ CH),
(3S,4S)-3-Benzyloxy-4-[(1S)-1-chloro-2-methylpropyl]-1-iso-
propylazetidin-2-one 3c: Light-yellow oil; Rf = 0.24 (hexane/
157.6 (C), 166.5 (C); IR (NaCl, cm-1) νCdO = 1758, νmax
=
1
EtOAc 6/1); yield 68%; [R]D = -47 (c = 0.23, CH2Cl2); H
2964, 1598, 1495, 1232, 752, 690; MS (70 eV) m/z (%) 310/2 (Mþ
þ 1, 100). Anal. Calcd for C17H24ClNO2: C, 65.90; H, 7.81; N,
4.52. Found: C, 66.12; H, 8.14; N, 4.33.
NMR (300 MHz, CDCl3) δ 0.91 and 1.00 (2 ꢀ 3H, 2d, J = 6.8
Hz), 1.29 and 1.42 (2 ꢀ 3H, 2d, J = 7.2 Hz), 2.17 (1H, sept ꢀ d,
J = 6.8, 2.2 Hz), 3.81-3.88 (2H, m), 4.18 (1H, dd, J = 9.9, 2.2
Hz), 4.53 (1H, d, J = 5.0 Hz), 4.68 and 4.93 (2 ꢀ 1H, 2d, J = 11.8
Hz), 7.28-7.36 (5H, m); 13C NMR (75 MHz, CDCl3) δ 15.5,
20.7, 20.87, and 20.94 (4 ꢀ CH3), 29.7 (CH), 47.3 (CH), 60.5
(CH), 70.1 (CH), 72.8 (CH2), 80.4 (CH), 127.7, 128.0, and 128.6
(5 ꢀ CH), 137.2 (C), 167.5 (C); IR (NaCl, cm-1) νCdO = 1747;
νmax = 2969, 1335, 1052, 731, 697; MS (70 eV) m/z (%) 310/2
(Mþ þ 1, 100). Anal. Calcd for C17H24ClNO2: C, 65.90; H, 7.81;
N, 4.52. Found: C, 66.07; H, 8.10; N, 4.29.
Synthesis of (2S,3S)-2-[(1S)-1-chloroalkyl]azetidines 4a-g.
As a representative example, the synthesis of (2S,3S)-3-benzy-
loxy-2-[(1S)-1-chloro-2-phenylethyl]-1-cyclohexylazetidine 4a is
described.
To an ice-cooled solution of 2.40 g of aluminum(III) chloride
(18 mmol, 3 equiv) in dry Et2O (40 mL) was added 0.68 g of
LiAlH4 (18 mmol, 3 equiv) in small portions. The reaction mix-
ture was stirred for 30 min at room temperature, after which a
solution of 2.40 g of (3S,4S)-3-benzyloxy-4-[(1S)-1-chloro-2-
phenylethyl]-1-cyclohexylazetidin-2-one 3a (6 mmol, 1 equiv) in
dry Et2O (10 mL) was added dropwise. After 4 h at reflux
temperature, water (20 mL) was added carefully to neutralize
the residual hydride. After decantation of the solvent, the residue
was extracted with Et2O (3 ꢀ 20 mL) and the combined organic
fractions were dried (MgSO4). After filtration of the drying agent
and evaporation of the solvent, the crude reaction mixture was
purified by column chromatography on silica gel (hexane/EtOAc
6/1), providing pure (2S,3S)-3-benzyloxy-2-[(1S)-1-chloro-2-phe-
nylethyl]-1-cyclohexylazetidine 4a in 76% yield.
(3S,4S)-1-Allyl-4-[(1S)-1-chloro-3-methylbutyl]-3-methoxya-
zetidin-2-one 3d: Light-yellow oil;Rf = 0.12 (hexane/EtOAc 6/1);
yield 72%; [R]D = -58 (c = 0.48, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 0.90 and 0.95 (2 ꢀ 3H, 2d, J = 6.9 Hz), 1.52-1.57 (2H,
m), 1.89-2.03 (1H, m), 3.58 (3H, s), 3.81 (1H, dd, J = 9.4, 5.0
Hz), 3.91 (1H, dd, J = 15.4, 7.2 Hz), 4.14-4.24 (2H, m), 4.45 (1H,
d, J = 5.0 Hz), 5.21-5.27 (2H, m), 5.72-5.85 (1H, m); 13C NMR
(75 MHz, CDCl3) δ 20.5 and 23.7 (2 ꢀ CH3), 24.5 (CH), 43.3
(CH2), 44.1 (CH2), 59.3 (CH3), 62.01 and 62.07 (2 ꢀ CH),
83.4 (CH), 119.1 (CH2), 131.5 (CH), 167.8 (C); IR (NaCl, cm-1
)
5938 J. Org. Chem. Vol. 75, No. 17, 2010

Dekeukeleire et al.
JOCArticle
(2S,3S)-3-Benzyloxy-2-[(1S)-1-chloro-2-phenylethyl]-1-cyclo-
hexylazetidine 4a: Colorless oil; Rf = 0.36 (hexane/EtOAc 6/1);
yield 76%; [R]D = -11 (c = 0.08, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 1.03-1.30 and 1.43-1.89 (2 ꢀ 5H, 2m), 2.53-2.70
(1H, m), 2.95 (1H, dd, J = 14.6, 10.2 Hz), 3.24 (1H, dd, J = 8.8,
6.6 Hz), 3.46 (1H, dd, J = 14.6, 1.9 Hz), 3.47-3.56 (1H, m), 3.75
(1H, dd, J = 7.4, 7.4 Hz), 4.28 (1H, ddd, J = 7.4, 6.6, 2.4 Hz),
4.43 (1H, d, J = 11.6 Hz), 4.51-4.57 (1H, m), 4.64 (1H, d, J =
11.6 Hz), 7.18-7.39 (10H, m); 13C NMR (75 MHz, CDCl3) δ
24.9, 25.3, 26.0, 26.9, and 31.2 (5 ꢀ CH2), 40.5 (CH2), 52.8
(CH2), 62.0 (CH), 68.7 (2 ꢀ CH), 70.7 (CH), 71.3 (CH2), 126.6,
127.94, 127.99, 128.4, 128.5, and 129.5 (10 ꢀ CH), 137.8 and
138.6 (2 ꢀ C); IR (NaCl, cm-1) νmax = 2927, 1453, 1112, 909,
730, 697; MS (70 eV) m/z (%) 384/6 (Mþ þ 1, 100). Anal. Calcd
for C24H30ClNO: C, 75.08; H, 7.88; N, 3.65. Found: C, 74.93; H,
8.02; N, 3.49.
(2S,3S)-2-[(1S)-1-Chloro-2-phenylethyl]-1-isopropyl-3-pheno-
xyazetidine 4b: Colorless oil; Rf = 0.22 (hexane/EtOAc 9/1);
yield 56%; [R]D = -52 (c = 0.15, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 1.01 and 1.02 (2 ꢀ 3H, 2d, J = 6.3 Hz), 2.90 (1H, dd,
J = 14.3, 9.8 Hz), 3.20 (1H, sept, J = 6.3 Hz), 3.32-3.44 (3H,
m), 3.79 (1H, dd, J = 8.8, 6.6 Hz), 4.68 (1H, ddd, J = 9.8, 9.8,
2.0 Hz), 4.86 (1H, ddd, J = 6.6, 6.6, 2.2 Hz), 6.79-6.89,
6.95-7.00 and 7.15-7.31 (10H, 3m); 13C NMR (75 MHz,
CDCl3) δ 15.3 and 21.0 (2 ꢀ CH3), 40.7 (CH2), 50.8 (CH2),
52.0 (CH), 64.4 (CH), 67.7 (CH), 69.1 (CH), 115.0 (2 ꢀ CH),
121.5 (CH), 126.8, 128.4, 129.5, 129.7, and 129.8 (7 ꢀ CH), 138.2
(C), 157.0 (C); IR (NaCl, cm-1) νmax = 2964, 1599, 1494, 1237,
750, 698, 691; MS (70 eV) m/z (%) 330/2 (Mþ þ 1, 100). Anal.
Calcd for C20H24ClNO: C, 72.82; H, 7.33; N, 4.25. Found: C,
73.01; H, 7.51; N, 3.96.
(2S,3S)-3-Benzyloxy-2-[(1S)-1-chloro-2-methylpropyl]-1-iso-
propylazetidine 4c: Light-yellow oil; Rf = 0.22 (hexane/EtOAc
4/1); yield 73%; [R]D = -85 (c = 0.51, CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 0.90 and 0.95 (2 ꢀ 3H, 2d, J = 6.6 Hz), 1.01 and
1.02 (2 ꢀ 3H, 2d, J = 6.9 Hz), 2.17 (1H, sept ꢀ d, J = 6.6, 2.3
Hz), 3.13 (1H, dd, J = 8.5, 6.1 Hz), 3.22 (1H, d, J = 8.5 Hz), 3.27
(1H, sept, J = 6.9 Hz), 3.62 (1H, dd, J = 10.3, 6.6 Hz), 4.08 (1H,
ddd, J = 6.6, 6.1, 1.8 Hz), 4.32 (1H, d, J = 12.1 Hz), 4.45 (1H,
dd, J = 10.3, 2.3 Hz), 4.61 (d, J = 12.1 Hz), 7.25-7.36 (5H, m);
13C NMR (75 MHz, CDCl3) δ 13.8, 16.0, 20.8, and 20.9 (4 ꢀ
CH3), 30.1 (CH2), 48.6 (CH), 50.4 (CH), 65.8 (CH), 70.6 and
70.7 (2 ꢀ CH and CH2), 127.5, 127.7, and 128.4 (5 ꢀ CH), 138.00
(C); IR (NaCl, cm-1) νmax = 2964, 1454, 1200, 1107, 734, 697;
MS (70 eV) m/z (%) 296/8 (Mþ þ 1, 100). Anal. Calcd for
C17H26ClNO: C, 69.02; H, 8.86; N, 4.73. Found: C, 69.29; H,
9.11; N, 4.40.
4.37 (1H, d, J = 12.1 Hz), 4.52-4.60 (1H, m), 4.68 (1H, d, J =
12.1 Hz), 7.33-7.40 (5H, m); 13C NMR (75 MHz, CDCl3) δ 14.2
(CH3), 20.7 (CH2 and CH3), 23.9 (CH3), 24.6 (CH), 29.6 (CH2),
43.2 (CH2), 56.9 (CH2), 59.3 (CH2), 62.5 (CH), 70.6 (CH2), 71.0
(CH), 73.7 (CH), 127.7, 127.8, and 128.3 (5 ꢀ CH), 137.9 (C); IR
(NaCl, cm-1) νmax = 2925, 1447, 1110, 732, 697; MS (70 eV) m/z
(%) 324/6 (Mþ þ 1, 100). Anal. Calcd for C19H30ClNO: C,
70.45; H, 9.34; N, 4.32. Found: C, 70.32; H, 9.59; N, 4.13.
(2S,3S)-1-Benzyl-2-[(1S,2S)-1-chloro-2-methylbutyl]-3-meth-
oxyazetidine 4f: White crystals; mp 54.6 °C; Rf = 0.27 (hexane/
1
EtOAc 7/1); yield 80%; [R]D = -123 (c = 1.15, CH2Cl2); H
NMR (300 MHz, CDCl3) δ 0.92 (3H, t, J = 7.4 Hz), 1.02 (3H, d,
J = 6.6 Hz), 1.21-1.34 and 1.45-1.60 (2 ꢀ 1H, 2m), 1.75-1.88
(1H, m), 2.77 (1H, dd, J = 8.9, 5.5 Hz), 3.22 (3H, s), 3.27 (1H, d,
J = 8.9 Hz), 3.39 (1H, d, J = 12.7 Hz), 3.49 (1H, dd, J = 10.2,
6.1 Hz), 3.90 (1H, ddd, J = 6.1, 5.5, 1.1 Hz), 4.40 (1H, d, J =
12.7 Hz), 4.47 (1H, dd, J = 10.2, 2.8 Hz), 7.22-7.35 (5H, m); 13
C
NMR (75 MHz, CDCl3) δ 12.0 (CH3), 17.0 (CH3), 23.6 (CH2),
37.6 (CH), 55.5 (CH2), 56.1 (CH3), 62.7 (CH2), 69.9 and 70.2 (2
ꢀ CH), 73.6 (CH), 127.1, 128.3, and 129.3 (5 ꢀ CH), 137.7 (C);
IR (KBr, cm-1) νmax = 2935, 1452, 1357, 1185, 1105, 1045, 732,
695; MS (70 eV) m/z (%) 282/4 (Mþ þ 1, 100). Anal. Calcd for
C16H24ClNO: C, 68.19; H, 8.58; N, 4.97. Found: C, 68.33; H,
8.81; N, 4.71.
(2S,3S)-2-[(1S,2S)-1-Chloro-2-methylbutyl]-3-phenoxy-1-pro-
pylazetidine 4g: Light-yellow oil; Rf = 0.41 (hexane/EtOAc 7/1);
yield 79%; [R]D = -85 (c = 0.56, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 0.88 and 0.89 (2 ꢀ 3H, 2t, J = 7.4, 7.2 Hz), 1.04 (3H, d,
J = 6.6 Hz), 1.21-1.59 (4H, m), 1.78-1.88 (1H, m), 2.23 (1H,
ddd, J = 11.0, 9.6, 5.2 Hz), 3.02 (1H, dd, J = 9.4, 5.5 Hz), 3.21
(1H, ddd, J = 11.0, 10.2, 6.3 Hz), 3.51-3.56 (2H, m), 4.65 (1H,
dd, J = 10.5, 2.8 Hz), 4.78 (1H, ddd, J = 5.5, 5.5, 1.5 Hz),
6.71-6.76, 6.83-6.99 and 7.21-7.30 (5H, 3m); 13C NMR (75
MHz, CDCl3) δ 11.9 (2 ꢀ CH3), 17.0 (CH3), 20.5 and 23.6 (2 ꢀ
CH2), 37.4 (CH), 57.4 (CH2), 61.5 (CH2), 69.1 (CH), 69.8 and
70.6 (2 ꢀ CH), 115.0 (2 ꢀ CH), 121.4 (CH), 129.7 (2 ꢀ CH),
156.7 (C); IR (NaCl, cm-1) νmax = 2961, 1599, 1494, 1238, 751,
690; MS (70 eV) m/z (%) 296/8 (Mþ þ 1, 100). Anal. Calcd for
C17H26ClNO: C, 69.02; H, 8.86; N, 4.73. Found: C, 69.22; H,
9.08; N, 4.42.
Synthesis of (2R,3S,4R)-2-Alkyl-3-chloropyrrolidines 5a-g.
As a representative example, the synthesis of (2R,3S,4R)-2-
benzyl-4-benzyloxy-3-chloro-1-cyclohexylpyrrolidine 5a is de-
scribed.
A solution of 1.54 g of (2S,3S)-3-benzyloxy-2-[(1S)-1-chloro-
2-phenylethyl]-1-cyclohexylazetidine 4a (4 mmol) in acetonitrile
(25 mL) was stirred for 18 h at reflux temperature. After
evaporation of the solvent, the crude reaction mixture was
purified by column chromatography on silica gel (hexane/
EtOAc 7/1), affording pure (2R,3S,4R)-2-benzyl-4-benzyloxy-
3-chloro-1-cyclohexylpyrrolidine 5a in 71% yield.
(2R,3S,4R)-2-Benzyl-4-benzyloxy-3-chloro-1-cyclohexylpyr-
rolidine 5a: Light-yellow oil; Rf = 0.35 (hexane/EtOAc 7/1);
yield 71%; [R]D = -18 (c = 1.30, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 1.06-1.25 and 1.63-1.84 (2 ꢀ 5H, 2m), 2.57-2.70
(1H, m), 2.92 (1H, dd, J = 13.2, 4.4 Hz), 2.96-3.12 (3H, m),
3.39-3.42 (1H, m), 3.94 (1H, ddd, J = 8.4, 8.4, 4.2 Hz),
4.21-4.26 (1H, m), 4.35 and 4.61 (2 ꢀ 1H, 2d, J = 11.6 Hz),
7.19-7.34 (10H, m); 13C NMR (75 MHz, CDCl3) δ 23.7, 25.6,
26.4, 26.5, and 33.1 (5 ꢀ CH2), 36.1 (CH2), 48.5 (CH2), 56.8
(CH), 63.7 (CH), 64.2 (CH), 71.4 (CH2), 77.4 (CH), 126.4, 127.9,
128.6, and 129.5 (10 ꢀ CH), 137.6 and 139.0 (2 ꢀ C); IR (NaCl,
cm-1) νmax = 2925, 1452, 1139, 738, 698; MS (70 eV) m/z (%)
384/6 (Mþ þ 1, 100). Anal. Calcd for C24H30ClNO: C, 75.08; H,
7.88; N, 3.65. Found: C, 74.84; H, 8.05; N, 3.36.
(2S,3S)-1-Allyl-2-[(1S)-1-chloro-3-methylbutyl]-3-methoxya-
zetidine 4d: Colorless oil; Rf = 0.28 (hexane/EtOAc 6/1); yield
1
66%; [R]D = -112 (c = 0.24, CH2Cl2); H NMR (300 MHz,
CDCl3) δ 0.83 and 0.86 (2 ꢀ 3H, 2d, J = 6.9 Hz), 1.33-1.41 (2H,
m), 1.81-1.94 (1H, m), 2.71 (1H, dd, J = 9.2, 5.5 Hz), 2.80 (1H,
dd, J = 13.1, 8.0 Hz), 3.12 (1H, dd, J = 9.6, 6.3 Hz), 3.18 (3H, s),
3.34 (1H, d, J = 9.2 Hz), 3.80 (1H, dd ꢀ t, J = 13.1, 5.0, 1.7 Hz),
3.88 (1H, ddd, J = 6.3, 5.5, 1.1 Hz), 4.30-4.38 (1H, m),
5.01-5.13 (2H, m), 5.70-5.83 (1H, m); 13C NMR (75 MHz,
CDCl3) δ 20.7 and 23.8 (2 ꢀ CH3), 24.6 (CH), 43.1 (CH2), 55.6
(CH2), 56.2 (CH3), 61.7 (CH2), 62.3 (CH), 73.0 and 73.2 (2 ꢀ
CH), 117.6 (CH2), 134.4 (CH); IR (NaCl, cm-1) νmax = 2956,
1465, 1366, 1190, 1111, 920, 689; MS (70 eV) m/z (%) 232/4 (Mþ
þ 1, 100). Anal. Calcd for C12H22ClNO: C, 62.19; H, 9.57; N,
6.04. Found: C, 61.95; H, 9.76; N, 5.84.
(2S,3S)-3-Benzyloxy-1-butyl-2-[(1S)-1-chloro-3-methylbutyl]-
azetidine 4e: Colorless oil; Rf = 0.40 (hexane/EtOAc 6/1); yield
1
74%; [R]D = -96 (c = 0.27, CH2Cl2); H NMR (300 MHz,
CDCl3) δ 0.94-0.99 (9H, m), 1.33-1.55 (6H, m), 1.99-2.12
(1H, m), 2.24-2.32 (1H, m), 2.84 (1H, dd, J = 9.0, 5.2 Hz),
3.18-3.32 (2H, m), 3.60 (1H, d, J = 9.0 Hz), 4.19-4.24 (1H, m),
(2R,3S,4R)-2-Benzyl-3-chloro-1-isopropyl-4-phenoxypyrroli-
dine 5b: Light-yellow oil; Rf = 0.37 (hexane/EtOAc 7/1); yield
1
75%; [R]D = -22 (c = 0.56, CH2Cl2); H NMR (300 MHz,
J. Org. Chem. Vol. 75, No. 17, 2010 5939

Dekeukeleire et al.
JOCArticle
CDCl3) δ 1.00 and 1.17 (2 ꢀ 3H, 2d, J = 6.3 Hz), 2.96 (1H, dd,
J = 13.2, 4.4 Hz), 3.03 -3.25 (3H, m), 3.21 (1H, d, J = 8.0 Hz),
3.32-3.42 (1H, m), 4.33 (1H, dd, J = 4.4, 4.4 Hz), 4.65 (1H, ddd,
7.22-7.39 (5H, m); 13C NMR (75 MHz, CDCl3) δ 11.7 (CH3),
16.3 (CH3), 26.3 (CH2), 37.6 (CH), 54.4 (CH2), 57.4 (CH3), 61.6
(CH2), 64.1 (CH), 71.2 (CH), 79.0 (CH), 127.1, 128.3, and 128.5
(5 ꢀ CH), 139.9 (C); IR (NaCl, cm-1) νmax = 2961, 1452, 1374,
1221, 1125, 729, 694; MS (70 eV) m/z (%) 282/4 (Mþ þ 1, 100).
Anal. Calcd for C16H24ClNO: C, 68.19; H, 8.58; N, 4.97. Found:
C, 68.52; H, 8.91; N, 4.67.
(2R,3S,4R)-3-Chloro-2-{(1S)-1-methylpropyl)}-4-phenoxy-1-
propylpyrrolidine 5g: Light-yellow oil; Rf = 0.31 (hexane/
EtOAc 7/1); yield 67%; [R]D = þ4 (c = 0.63, CH2Cl2); 1H
NMR (300 MHz, CDCl3) δ 0.94 (2 ꢀ 3H, 2t, J = 7.4 Hz), 1.07
(3H, d, J = 7.2 Hz), 1.11-1.21 and 1.53-1.69 (1H and 3H, 2m),
1.90-1.98 (1H, m), 2.39-2.48 and 2.57-2.67 (2 ꢀ 1H, 2m), 2.83
(1H, dd, J = 8.3, 3.9 Hz), 3.02 (1H, dd, J = 10.9, 7.4 Hz), 3.41
(1H, dd, J = 10.9, 9.4 Hz), 4.70-4.74 (1H, m), 4.77-4.84 (1H,
m), 6.98-7.05 and 7.30-7.35 (5H, 2m); 13C NMR (75 MHz,
CDCl3) δ 11.7 and 11.8 (2 ꢀ CH3), 16.2 (CH3), 22.7 and 26.2 (2
ꢀ CH2), 37.3 (CH), 54.9 (CH2), 60.2 (CH2), 63.7 (CH), 71.8
(CH), 75.6 (CH), 116.2 (2 ꢀ CH), 121.9 (CH), 129.7 (2 ꢀ CH),
157.6 (C); IR (NaCl, cm-1) νmax = 2961, 1599, 1493, 1237, 752,
735, 690; MS (70 eV) m/z (%) 296/8 (Mþ þ 1, 100). Anal. Calcd
for C17H26ClNO: C, 69.02; H, 8.86; N, 4.73. Found: C, 69.33; H,
9.11; N, 4.41.
Synthesis of (2R,3S,4R)-1-Butyl-3-chloro-4-hydroxy-2-(2-met-
hylpropyl)pyrrolidine 7. Palladium on activated carbon (0.019 g,
10% Pd) was added to a solution of 0.19 g of (2R,3S,4R)-4-
benzyloxy-1-butyl-3-chloro-2-(2-methylpropyl)pyrrolidine 5e
(0.6 mmol, 1 equiv) and HClconc (1.2 mmol, 2 equiv) in methanol
(5 mL), and the resulting mixture was placed in a Parr appara-
tus. The inside of the Parr apparatus was then degassed and
filled with hydrogen gas, after which the mixture was stirred at
room temperature for 16 h while applying 5 bar of hydrogen gas.
After filtration of the heterogeneous mixture through Celite and
evaporation of the solvent in vacuo, the crude reaction product
was purified by column chromatography on silica gel (hexane/
EtOAc 4/1), affording pure (2R,3S,4R)-1-butyl-3-chloro-4-hy-
droxy-2-(2-methylpropyl)pyrrolidine 7 in 90% yield.
J = 8.0, 8.0, 4.4 Hz), 6.85-6.98 and 7.18-7.30 (10H, 2m); 13
C
NMR (75 MHz, CDCl3) δ 13.5 and 22.4 (2 ꢀ CH3), 35.9 (CH2),
47.4 (CH2), 48.1 (CH), 63.2 (CH), 65.3 (CH), 76.2 (CH), 116.1 (2
ꢀ CH), 122.0 (CH), 126.6, 128.7, 129.5, 129.7 (7 ꢀ CH), 138.7
(C), 157.5 (C); IR (NaCl, cm-1) νmax = 2964, 1597, 1493, 1238,
750, 691; MS (70 eV) m/z (%) 330/2 (Mþ þ 1, 100). Anal. Calcd
for C20H24ClNO: C, 72.82; H, 7.33; N, 4.25. Found: C, 73.06; H,
7.56; N, 3.87.
(2R,3S,4R)-4-Benzyloxy-3-chloro-1,2-diisopropylpyrrolidine
5c: White crystals; mp 45.1 °C; Rf = 0.11 (hexane/EtOAc 4/1);
yield 74%; [R]D = -37 (c = 1.56, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 0.88 and 1.06 (2 ꢀ 3H, 2d, J = 6.8 Hz), 1.32 and 1.39 (2
ꢀ 3H, 2d, J = 6.3 Hz), 2.27 (1H, sept ꢀ d, J = 6.8, 2.2 Hz),
3.61-3.72 (1H, m), 3.79-3.91 (1H, m), 4.04-4.14 (1H, m),
4.28-4.39 (2H, m), 4.44 and 4.70 (2 ꢀ 1H, 2d, J = 12.1 Hz), 5.22
(1H, dd, J = 10.2, 2.2 Hz), 7.29-7.37 (5H, m); 13C NMR (75
MHz, CDCl3) δ 15.3, 15.7, 18.2, and 20.5 (4 ꢀ CH3), 29.4 (CH),
51.0 (CH2), 54.1 (CH), 63.2 (CH), 68.5 and 70.3 (2 ꢀ CH), 71.6
(CH2), 127.9, 128.3, and 128.7 (5 ꢀ CH), 136.4 (C); IR (KBr,
cm-1) νmax = 2966, 1454, 1140, 734, 695; MS (70 eV) m/z (%)
296/8 (Mþ þ 1, 100). Anal. Calcd for C17H26ClNO: C, 69.02; H,
8.86; N, 4.73. Found: C, 69.36; H, 9.09; N, 4.44.
(2R,3S,4R)-1-Allyl-3-chloro-4-methoxy-2-(2-methylpropyl)-
pyrrolidine 5d: Colorless oil; Rf = 0.27 (hexane/EtOAc 4/1);
yield 52%; [R]D = -7 (c = 0.22, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ 0.85 and 0.92 (2 ꢀ 3H, 2d, J = 6.9 Hz), 1.21-1.43 (1H,
m), 1.56-1.76 (2H, m), 2.82 (1H, dd, J = 10.6, 8.8 Hz),
2.89-2.96 (2H, m), 3.04 (1H, dd, J = 10.6, 8.0 Hz), 3.36 (3H,
s), 3.34-3.44 (1H, m), 3.93 (1H, ddd, J = 8.8, 8.0, 4.0 Hz), 4.44
(1H, dd, J = 4.0, 3.6 Hz), 5.10-5.19 (2H, m), 5.77-5.90 (1H,
m); 13C NMR (75 MHz, CDCl3) δ 22.1 and 24.1 (2 ꢀ CH3), 25.4
(CH), 38.6 (CH2), 54.0 (CH2), 56.3 (CH2), 57.4 (CH3), 63.36 and
63.40 (2 ꢀ CH), 79.5 (CH), 118.0 (CH2), 134.6 (CH); IR (NaCl,
cm-1) νmax = 2955, 1466, 1367, 1216, 1144, 992, 919; MS (70 eV)
m/z (%) 232/4 (Mþ þ 1, 100). Anal. Calcd for C12H22ClNO: C,
62.19; H, 9.57; N, 6.04. Found: C, 61.89; H, 9.73; N, 5.76.
(2R,3S,4R)-4-Benzyloxy-1-butyl-3-chloro-2-(2-methylpropyl)-
pyrrolidine 5e: Colorless oil; Rf = 0.31 (hexane/EtOAc 6/1); yield
(2R,3S,4R)-1-Butyl-3-chloro-4-hydroxy-2-(2-methylpropyl)-
pyrrolidine 7: Light-brown crystals; mp 82.3 °C; Rf = 0.11
(hexane/EtOAc 4/1); yield 75%; H NMR (300 MHz, CDCl3)
1
δ 0.90 and 0.96 (2 ꢀ 3H, 2d, J = 6.1 Hz), 0.91 (3H, t, J = 6.6 Hz),
1.26-1.49 and 1.64-1.73 (5H and 2H, 2m), 2.15-2.24 (2H, m),
2.64-2.77 (1H, m), 2.74 (1H, dd, J = 10.5, 8.3 Hz), 2.83 (1H,
ddd, J = 9.4, 4.3, 4.3 Hz), 3.00 (1H, dd, J = 10.5, 6.6 Hz),
4.35-4.41 (1H, m), 4.47 (1H, dd, J = 4.3, 4.3 Hz); 13C NMR (75
MHz, CDCl3) δ 14.1, 22.1, and 24.1 (3 ꢀ CH3), 20.7, 25.4, 30.5,
and 39.2 (3 ꢀ CH2 and CH), 53.9 (CH2), 58.1 (CH2), 64.5 (CH),
1
75%; [R]D = -13 (c = 0.58, CH2Cl2); H NMR (300 MHz,
CDCl3) δ 0.89 and 0.96 (2 ꢀ 3H, 2d, J = 6.3 Hz), 0.90 (3H, t, J =
6.6 Hz), 1.22-1.51 and 1.60-1.82 (4H and 3H, 2m), 2.10-2.27
(1H, m), 2.64-2.88 (3H, m), 3.19 (1H, dd, J = 10.2, 8.0 Hz),
4.10-4.22 (1H, m), 4.44-4.47 (1H, m), 4.45 and 4.70 (2 ꢀ 1H, 2d,
J = 11.6 Hz), 7.28-7.42 (5H, m); 13C NMR (75 MHz, CDCl3) δ
14.1, 22.1, and 24.1 (3 ꢀ CH3), 20.6, 25.4, 30.1, and 38.3 (3 ꢀ CH2
and CH), 53.9 (CH2), 55.0 (CH2), 63.4 (CH), 64.7 (CH), 71.6
(CH2), 76.8 (CH), 128.0 and 128.6 (5 ꢀ CH), 137.6 (C); IR (NaCl,
cm-1) νmax = 2954, 1455, 1366, 1142, 734, 696; MS (70 eV) m/z
(%) 324/6 (Mþ þ 1, 100). Anal. Calcd for C19H30ClNO: C, 70.45;
H, 9.34; N, 4.32. Found: C, 70.22; H, 9.66; N, 4.15.
68.1 (CH), 70.8 (CH); IR (NaCl, cm-1) νOH = 3040; νmax
=
2955, 1462, 1139, 918, 726; MS (70 eV) m/z (%) 234/6 (Mþ þ 1,
100). Anal. Calcd for C12H24ClNO: C, 61.65; H, 10.35; N, 5.99.
Found: C, 61.88; H, 10.56; N, 5.73.
Acknowledgment. The authors are indebted to Ghent
University (GOA) and the Fund for Scientific Research
(FWO-Flanders) for financial support.
(2R,3S,4R)-1-Benzyl-3-chloro-2-{(1S)-1-methylpropyl)}-4-
methoxypyrrolidine 5f: Colorless oil; Rf = 0.32 (hexane/EtOAc
6/1); yield 68%; [R]D = þ10 (c = 1.13, CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 0.93 (3H, t, J = 7.4 Hz), 1.10 (3H, d, J = 7.2
Hz), 1.15-1.25 and 1.64-1.75 (2 ꢀ 1H, 2m), 1.96-2.03 (1H, m),
2.74 (1H, dd, J = 10.6, 7.4 Hz), 2.85-2.95 (1H, m), 3.05 (1H, dd,
J = 10.6, 10.6 Hz), 3.37 (3H, s), 3.53 and 3.93 (2 ꢀ 1H, 2d, J =
14.0 Hz), 3.87-4.00 (1H, m), 4.65 (1H, dd, J = 4.2, 4.2 Hz),
Supporting Information Available: Crystallographic data of
compound 3a and spectroscopic data of compounds 3b-g,
4b-g, and 5b-g. This material is available free of charge via
the Internet at http://pubs.acs.org.
5940 J. Org. Chem. Vol. 75, No. 17, 2010