Stereoselective synthesis of azetidines and pyrrolidines from N-tert-butylsulfonyl(2-aminoalkyl)oxiranes

Article abstract of DOI:10.1021/jo9016666

(Chemical Equation Presented) Base-induced cyclization of enantiopure (2-aminoalkyl)oxiranes allowed the stereospecific formation of pyrrolidin-3-ols and/or 2-(hydroxymethyl)azetidines, depending on the reaction conditions. The oxidation of 2-(hydroxymeth

Full text of DOI:10.1021/jo9016666

pubs.acs.org/joc
Stereoselective Synthesis of Azetidines and Pyrrolidines from
N-tert-Butylsulfonyl(2-aminoalkyl)oxiranes†
ꢀ
Mohamed Medjahdi, Jose C. Gonzalez-Gomez, Francisco Foubelo,* and Miguel Yus*
ꢀ
ꢀ
´
ꢀ ꢀ
Departamento de Quımica Organica, Facultad de Ciencias and Instituto de Sıntesis Organica (ISO),
´
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
foubelo@ua.es, yus@ua.es
Received July 30, 2009
Base-induced cyclization of enantiopure (2-aminoalkyl)oxiranes allowed the stereospecific forma-
tion of pyrrolidin-3-ols and/or 2-(hydroxymethyl)azetidines, depending on the reaction conditions.
The oxidation of 2-(hydroxymethyl)azetidines led to azetidine-2-carboxylic acids in high yields.
Introduction
in pharmacy as highly biologically active compounds.5 How-
ever, five-membered pyrrolidines have well-known biologi-
cal activities and are widely represented in Nature. Proline
derivatives in particular have garnered much attention due to
their central role in organocatalysis.6 For all these reasons,
methodologies which allow access to enantiomerically pure
both azetidines and pyrrolidines are of great interest in the
context of discovering new drugs and more efficient organo-
catalysts. Many methodologies have been developed for the
preparation of nitrogen-containing heterocycles, with the
intramolecular nitrogen nucleophilic displacement of a leav-
ing group being one of the most commonly used. On the
Among small- and medium-size aza-heterocycles, azeti-
dines1 have attracted less attention than aziridines,2 pyrro-
lidines,3 and piperidines,4 mainly due to the lack of general
methods for their preparation. Recently, four-membered
nitrogen-containing heterocycles have found applicability
† Dedicated to Professor Peter Stanetty on occasion of his 60th birthday.
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2006, 181. (d) Pineschi, M. Eur. J. Org. Chem. 2006, 4979. (e) Olsen, C. A.;
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DOI: 10.1021/jo9016666
r
Published on Web 09/18/2009
J. Org. Chem. 2009, 74, 7859–7865 7859
2009 American Chemical Society

Medjahdi et al.
JOCArticle
other hand, one of the most direct and reliable methods for
the asymmetric synthesis of amine derivatives is the addition
of an organometallic reagent (mainly organomagnesium,7
organolithium,8 organozinc9 and organoindium10 derivatives)
to the CdN bond of enantiopure N-sulfinylimines. In this
context, N-tert-butylsulfinyl derivatives11 have found high
applicability in synthesis as electrophiles because both en-
antiomers are accessible in large-scale processes12 and be-
cause the chiral auxiliary is easily removed under acidic
conditions.8b In addition, practical processes for recycling
the tert-butylsulfinyl group upon deprotection of N-tert-
butylsulfinylamines have also been reported.13 We described
recently10a the stereoselective allylation of N-tert-butylsul-
finyl aldimines with allylindium species14 which can be
generated in the presence of the imine from allylic bromides
and indium metal under mild reaction conditions and exhibit
high tolerance to a wide range of functional groups in many
solvents.15 The resulting enantiopure N-tert-butylsulfinyl
homoallylamines were easily oxidized to give a diastereo-
meric mixture of the corresponding N-tert-butylsulfonyl(2-
aminoalkyl)oxiranes, which upon treatment under basic
conditions led to cis- and trans-pyrrolidin-3-ols.16 We report
here a full account of our studies of the base-induced
cyclization of (2-aminoalkyl)oxirane derivatives of type I
which, depending on the reaction conditions, could undergo
a 4-exo-tet or a 5-endo-tet ring closure, leading to the
corresponding 2-(hydroxymethyl)azetidine II or 3-hydroxy-
pyrrolidine derivatives III, respectively (Scheme 1). There
are only two examples in the literature of 4-exo-tet ring
closure in aminooxiranes of type I. One is the thermal
SCHEME 1. Base-Induced Cyclization Pathways of (2-Amino-
alkyl)oxirane Derivatives
decomposition of 5-aryl-2-methyl-5-methoxy-4-(cyclohexyl-
amino)-1,2-epoxypentan-3-one boron trifluoride complexes
leading to the corresponding azetidinone,17 and the other one
is the cyclization of N-tosyloxiraneethylamines, which upon
treatment with aqueous sodium hydroxide afforded either
2-(hydroxymethyl)azetidine or 3-hydroxylpyrrolidine deriva-
tives, depending on the location of a pentamethylene sub-
stitution in the chain connecting the nitrogen with the oxirane
ring.18
Results and Discussion
N-tert-Butylsulfinyl amines 2 were prepared with high
both chemical yields and diastereoselectivities by the reac-
tion of different N-tert-butylsulfinyl aldimines 1 with allyl
bromide and indium powder in THF at 60 °C (Table 1).10a
For (RS)-aldimines, the nucleophilic attack takes place
almost exclusively at the Si face of the imino group and,
logically, at the Re face for (SS)-enantiomers. The sense of
the stereoinduction has been explained by a chairlike model
in which the metal is chelated both by the oxygen and the
nitrogen of the imine moiety.10a In this way, homoallylamine
derivatives 2 are accessible in enantiomerically pure form
after column chromatography since the reaction products
of the indium-mediated allylation are diastereomers. The
oxidation of compounds 2 with 3 equiv of m-chloroperben-
zoic acid (m-CPBA) in dichloromethane at room tempera-
ture yielded N-tert-butylsulfonyl(2-aminoalkyl)oxiranes 3 in
almost quantitative yields (Table 1). The oxidation of
the sulfinyl group to the corresponding sulfonyl group
(t-BuSO2 or Bus) took place fairly rapidly. Subsequent
epoxidation under these reaction conditions occurred with-
out any stereoselection in spite of the presence of a stereo-
genic center in the molecule (a ca. 1:1 diastereomeric mixture
was always obtained). All attempts to separate diasteroi-
somers 3 (column chromatography, silica gel, hexane/ethyl
acetate) failed.16
We initially explored the base-induced cyclization of the
diastereomeric mixture of (2-aminoalkyl)oxiranes (2R*,20S)-
3d (derived from the aldimine of benzaldehyde and (RS)-N-
tert-butylsulfinyl amine). After some experimentation, we
found that the treatment of the crude reaction mixture of
(2R*,20S)-3d (without purification after the oxidation step,
that means that m-CPBA and m-CBA are present along with
the diastereomeric mixture of epoxides 3d) with potassium
carbonate in N,N-dimethylformamide (DMF) at 100 °C
for 24 h led, with total conversion, to a mixture of pyrroli-
din-3-ol derivatives (5S)-4d and (5S)-5d, which were easily
separated by column chromatography (Table 2, entry 1).16
The pyrrolidin-3-ols (5S)-4d (cis-isomer) and (5S)-5d (trans-
isomer) are formed through a disfavored 5-endo-tet ring
(8) (a) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268. (b)
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TABLE 1. Preparation of (2-Aminoalkyl)oxiranes 3 from Chiral Aldimines 1a
aReactions carried out using 1.0 mmol of aldimine 1, 1.2 mmol of allyl bromide, and 1.2 mmol of In in 5 mL of THF for the allylation step.
bDiastereoselectivities were determined by 1H NMR analysis of the crude reaction mixtures. cIsolated yields after column chromatography based on the
starting aldimine 1. dYields were always >95%.
TABLE 2. Optimization of the Base-Induced Cyclization of (2-Aminoalkyl)oxiranes (2R*,20S)-3da
reaction products (%)c
entry
reaction conditions
conversionb (%)
(5S)-4d
(5S)-5d
(4S)-6d
(4S)-7d
1d
2
3
4
5
6
7
8
K2CO3 (3 equiv), DMF (1 mL), 100 °C, 24 h
K2CO3 (3 equiv), DMF (1 mL), 100 °C, 24 h
K2CO3 (3 equiv), KI (1 equiv), DMF (1 mL), 100 °C, 24 h
K2CO3 (3 equiv), DMF (1 mL), 80 °C, 24 h
K2CO3 (3 equiv), DMF (1 mL), MW (65-70 W), 100 °C, 15 min
K2CO3 (1,1 equiv), DMF (1 mL), MW (5-15 W), 60 °C, 2 h
TfOH (1 mol %), THF (1 mL), 25 °C, 24 h
K2CO3 (1 g), no solvent, 100 °C, 48 h
100
100
100
100
72
53
23
51
33
43
72
53
18
19
32
47
38
49
31
25
12
38
14
13
20
24
12
17
19
11
19
13
6
51
100
100
100
92
0
63
9
36
35
22
32
33
26
9
K2CO3 (1 g), no solvent, 80 °C, 48 h
10
11
12
13
14
KHCO3 (1 g), no solvent, 80 °C, 48 h
K2CO3 (3 equiv), 1,4-dioxane (2 mL), 80 °C, 48 h
K2CO3 (3 equiv), 1,4-dioxane (2 mL), 100 °C, 48 h
K2CO3 (3 equiv), toluene (2 mL), 80 °C, 48 h
K2CO3 (3 equiv), toluene (2 mL), 100 °C, 48 h
69
37
14
19
9
7
0
91
26
18
aReactions carried out using 1 mmol of pure (2R*,20S)-3d. bDetermined by GC analysis. cYields reported were determined by GC analysis of the crude
reaction mixtures and are given in percent independently of the epoxide conversion. dStarting epoxide was used without purification after the oxidation step.
closure instead of a favored 4-exo-tet process according
to Baldwin’s rules.19 Surprisingly, when pure (2R*,20S)-
3d (m-CPBA and m-CBA were removed after column
chromatography) was treated under the same reaction
conditions a mixture of pyrrolidin-3-ols (5S)-4d, (5S)-5d,
2-(hydroxymethyl)azetidines (5S)-6d (cis-isomer), and (5S)-7d
(trans-isomer) were obtained (Table 2, entry 2). It seems that m-
CPBA or m-CBA present in the crude reaction mixture favored
the formation of the five-membered ring over the four-mem-
bered one, probably through an intermolecular nucleophilic
(19) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
J. Org. Chem. Vol. 74, No. 20, 2009 7861

Medjahdi et al.
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opening of the epoxide followed by intramolecular cyclization.
In order to confirm this hypothesis, the reaction was performed
with pure (2R*,20S)-3d in the presence of 1 equiv of potassium
iodide. As anticipated, the pyrrolidin-3-ols (5S)-4d and (5S)-5d
were the only reaction products (Table 2, entry 3). This is
proposed to occur via an iodohydrine intermediate that results
from iodide nucleophilic opening of the epoxide, which easily
would undergo intramolecular nitrogen nucleophilic displace-
ment leading to the pyrrolidines 4 and 5. In order to expand the
synthetic interest of (2-aminoalkyl)oxiranes 3 as precursors of
azetidines, experiments were carried out trying to favor the
4-exo-tet process. Temperature seems to have little influence in
the cyclization pathway since similar results were obtained
when the process was performed at 100 and 80 °C (Table 2,
entries 2 and 4, respectively). On the other hand, microwave
irradiation at different temperatures and reaction times
with potassium carbonate as a base led to poorer conversion,
with pyrrolidines being the major reaction products (Table 2,
entries 5 and 6). Acid-catalyzed cyclization with 1 mol % of
triflic acid in THF led almost exclusively to pyrrolidines (5S)-4d
and (5S)-5d (Table 2, entry 7). The best results for the forma-
tion of azetidines (5S)-6d and (5S)-7d were obtained when
the cyclization was performed at 100 or 80 °C without any
solvent and when the starting (2-aminoalkyl)oxiranes
(2R*,20S)-3d were supported on potassium carbonate. Under
these reaction conditions, pyrrolidines/azetidines were in a 1:2
ratio (Table 2, entries 8 and 9) and in a 1:1 ratio when the
cyclization was performed with potassium bicarbonate at 80 °C
(Table 2, entry 10). Cyclization in 1,4-dioxane or toluene took
place only at 100 °C (Table 2, entries 11-14), leading to
pyrrolidines (5S)-4d and (5S)-5d as the major reaction pro-
ducts.
SCHEME 2. Hydrolytic Kinetic Resolution of (2-Aminoalkyl)-
oxirane Derivatives 3
Conversion of diol 9 to epoxide 3 occurred through a
three-step process which involved (a) successive selective
acylation of the primary alcohol with pivaloyl chloride, (b)
mesylation of the secondary alcohol and (c) final basic
hydrolysis of the pivaloyl ester (Scheme 2).23 Yields of
epoxides 3 and diols 9 were over 40% in all cases (Table 3).
Regarding the influence of the stereogenic center present
in epoxides 3, slightly higher yields were obtained in the
HKR leading to syn-aminodiol derivatives 9 and the
corresponding epoxides 3 (Table 3; entries 1, 4, 6, 7, 10,
and 11). In this case, the catalyst and substrate seem to be a
match combination. Through this methodology, a diaster-
eomeric mixture of (2-aminoalkyl)oxiranes 3 was con-
verted into each diastereoisomer in approximately 70%
overall yield, depending on the configuration of the salen
cobalt complex 8 used in the HKR (Table 3; compare
entries 1-2, 3-4, etc.). The configuration of enantiopure
oxiranes 3 and diols 9 was thus assigned on the basis of the
known indium-promoted allylation step10a and Jacobsen
HKR.22,24
Access to enantiomerically pure (2-aminoalkyl)oxiranes
3 is of great synthetic utility because a single pyrrolidine or
azetidine stereoisomer could be prepared through this
methodology. As commented above, m-CPBA oxidation
of homoallylamine derivatives 2 gave an almost 1:1 mix-
ture of diastereomeric (2-aminoalkyl)oxirane derivatives 3
which could not be separated (Table 1). Better diastereo-
selectivity was obtained when the oxidation was performed
with a system consisting of 35% H2O2 and a catalytic
amount of methyltrioxorhenium(VII) (MTO, 2 mol %) in
the presence of pyridine (10 mol %) in CH2Cl2.20 For
instance, oxidation of (SC,RS)-2d gave a 2:1 mixture of
(2S,20S)-3d (Table 3, entry 10) and (2R,20S)-3d (Table 3,
entry 9), respectively, instead of an 1:1 diastereomeric
mixture. Sharpless asymmetric dihydroxylation21 of
homoallylamine derivatives 2 also provided an insepar-
able diastereomeric mixture of diols 9, which thus could
not be converted into enantiomerically pure epoxides 3.
We were pleased to find that Jacobsen hydrolytic kinetic
resolution (HKR)22 of a 1:1 diastereomeric mixture of (2-
aminoalkyl)oxiranes 3 (Table 1), using chiral cobalt com-
plex (R,R)-8 or its enantiomer, allowed the access to the
corresponding enantiomerically pure epoxide 3 and diol 9.
Base-induced cyclization of enantiomerically pure (2-
aminoalkyl)oxiranes 3 could be directed to the synthesis of
pyrrolidines (4 or 5) or azetidines (6 or 7), depending on
the reaction conditions (Table 2). Thus, the treatment
of enantiomerically pure oxiranes 3 with potassium carbo-
nate and potassium iodide in N,N-dimethylformamide
(DMF) at 100 °C for 24 h (method A) led to pyrrolidines 4
(cis-isomers) or 5 (trans-isomers) in high yield, depending
on the relative configuration of the starting oxirane
(Table 4). Surprisingly, when the cyclization was performed
at 80 °C and the chiral oxiranes 3 were supported on
potassium carbonate (method B), azetidines 6 (cis-isomers)
or 7 (trans-isomers) were the only isolated reaction products
in the case of oxiranes 3a-c (Table 4, entries 1-8). However,
in the case of oxiranes 3d, the corresponding pyrrolidines
were also formed (Table 2, entry 8, and Table 4, entries
9-12). The yields of these 4-exo-tet ring closures were
slightly higher in the case of cis-isomers 6 (Table 4, entries
1, 4, 6, and 7).
The configuration of the pyrrolidines 4 and 5 and the
azetidines 6 and 7 was assigned on the basis of the proposed
configuration of the starting oxiranes 3, assuming that
the intramolecular nucleophilic ring-opening of the epoxide
(20) Rudolph, J.; Reddy, K. L.; Chiang, J. P.; Sharpless, K. B. J. Am.
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(22) Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
124, 1307.
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(24) (a) Smit, M. S.; Labuschagne, M. Curr. Org. Chem. 2006, 10, 1145.
(b) Tokunaga, M.; Aoyama, H.; Kiyosu, J.; Shirogane, Y.; Iwasawa, T.;
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TABLE 3. Preparation of Enantiomerically Pure Oxiranes from a Mixture of Diastereoisomeric Oxiranes 3a
aReactions carried out starting from 1 mmol of a 1:1 diastereomeric mixture of oxiranes 3. bIsolated yields after column chromatography based on the
starting diastereomeric mixture of oxiranes 3 are given in parentheses. Isolated yield after column chromatography based on the starting diol 9.
c
dCombined yield of the enantiomerically pure oxirane 3 considering the HKR step and the cyclization of diol 9 based on the starting diastereomeric
mixture of oxiranes 3.
takes place through a SN2 mechanism with concomitant
inversion of the stereocenter involved in the case of azeti-
dines. This assumption was confirmed by crystal X-ray
analysis (see the Supporting Information) of the solid com-
pounds pyrrolidine (5S)-4c25 (Table 4, entry 7), and azeti-
dines (4R)-6c26 (Table 4, entry 6) and its diastereomer (4R)-
7c27 (Table 4, entry 5).
In order to explore the synthetic potential of 2-(hydroxy-
methyl)azetidine derivatives 6, we studied their oxidation with
a ruthenium trichloride-sodium periodate combination.28
(25) Crystal data (excluding structure factors) deposited at the
Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC 684401.
(26) Crystal data (excluding structure factors) deposited at the
Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC 741719.
(27) Crystal data (excluding structure factors) deposited at the
Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC 741869.
(28) Figadere, B.; Franck, X. Sci. Synth. 2006, 20a, 173.
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TABLE 4. Synthesis of Pyrrolidines 4 or 5 and Azetidines 6 or 7 from Enantiomerically Pure Oxiranes 3a
aReactions carried out starting from 0.5 mmol of enantiomerically pure oxirane 3. bIsolated yield after column chromatography based on the starting
oxirane 3. cPyrrolidine (5S)-5d was also isolated in 24% yield. dPyrrolidine (5S)-4d was also isolated in 26% yield. ePyrrolidine (5R)-4d was also isolated
in 20% yield. fPyrrolidine (5R)-5d was also isolated in 31% yield.
The corresponding 4-substituted azetidine-2-carboxylic acids
10, compounds homologous to proline, were obtained in
good yields, and it is worth mentioning that no epimeri-
zation occurred at the oxidation step and further workup
(Table 5).
TABLE 5. Synthesis of 4-Substituted Azetidine-2-carboxylic Acids 10a
Conclusions
In conclusion, enantiomerically pure pyrrolidin-3-ols 4 and
5 and/or 2-(hydroxymethyl)azetidines 6 and 7 are accessible
from N-tert-butylsulfonyl-(2-aminoalkyl)oxiranes 3 through
a base-catalyzed cyclization reaction by simply choosing
the appropriate reaction conditions. Since all these reactions
are stereospecific, the stereochemistry of the reaction products
4-7 is determined by the configurations of the starting aldimine
1 (allylation step) and the salen cobalt complex 8 (HKR).
Moreover, oxidation of 2-(hydroxymethyl)azetidines leads to
azetidine-2-carboxylic acids 10 in high yields.
aReactions carried out starting from 0.25 mmol of azetidines 6.
bIsolated yield after column chromatography based on the starting
azetidine 3 are given in parentheses.
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Experimental Section
128.2 (CH), 128.4 (CH), 140.9 (C); LRMS (EI) m/z 280 (M -
CH2OH), 191 (19), 190 (18), 161 (12), 160 (100), 117 (32), 91 (44), 86
(14), 57 (47); HRMS (EI) calcd for C15H22NSO2 (M - CH2OH)
280.1371, found 280.1370.
General Procedure for the Synthesis of Azetidine-2-carboxylic
Acids. To a solution of CH3CN (2.2 mL), CCl4 (0.8 mL) and
H2O (2.0 mL) were added successively at room temperature
General Procedure for the Synthesis of Pyrrolidin-3-ols
(Method A). A mixture of the corresponding N-tert-butyl-
sulfonyl(2-aminoalkyl)oxirane 3 (0.5 mmol), KI (0.5 mmol,
0.084 g), and K2CO3 (1.5 mmol, 0.208 g) in N,N-dimethylfor-
mamide (3 mL) was stirred for 24 h at 100 °C. Then, the resulting
mixture was hydrolyzed with water (5 mL), extracted with
EtOAc (3 ꢀ 15 mL), dried over anhydrous MgSO4, and con-
centrated under reduced pressure (15 Torr). The residue was
purified by column chromatography (silica gel, hexane/EtOAc)
to yield products 4 or 5.
(3R,5R)-N-tert-Butylsulfonyl-5-isopropylpyrrolidin-3-ol [(5R)-
4a]. Following the general procedure, but using 0.5 mmol of
starting oxirane (2R,20R)-3a, after workup, chromatography on
silica gel eluting firstwith5:1 and then 3:1 hexane/EtOAcafforded
119 mg (92% yield) of (5R)-4a as a white solid: [R]22D þ34 (c 0.79,
CH2Cl2); mp 92-93 °C (hexane/CH2Cl2); Rf 0.55 (hexane/
EtOAc: 1/1); IR ν (KBr) 3545-3497, 2960, 2873, 1465, 1389,
1311, 1124 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.86 (d, J = 6.9,
3H), 0.93 (d, J = 6.9, 3H), 1.37 (s, 9H), 1.56 (dt, J = 12.4, 9.0, 1H),
2.07-2.20 (m, 2H), 2.42 (br s, 1H), 2.80 (dd, J = 10.7, 9.1, 1H),
3.83 (dd, J = 10.2, 9.1, 1H), 4.15-4.34 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 15.2, 19.2, 24.4 (CH3), 30.8 (CH), 32.1, 56.5
(CH2), 60.4 (C), 62.9, 70.4 (C); LRMS (EI) m/z 249 (Mþ, 0.1),
86 (100), 68 (14), 57 (39); HRMS (EI) calcd for C8H16NSO3 (M -
i-Pr) 206.0851, found 206.0837.
General Procedure for the Synthesis of 2-(Hydroxymethyl)-
azetidines (Method B). To a solution of N-tert-butylsulfonyl(2-
aminoalkyl)oxirane 3 (0.5 mmol) in CH2Cl2 (1 mL) was added
K2CO3 (6.0 mmol, 1 g) and the mixture stirred at room
temperature for 15 min. After that, the solvent was removed
in a rotary evaporator (15 Torr), and the resulting solid residue
was heated at 80 °C for 48 h. It was then hydrolyzed with water
(15 mL), extracted with EtOAc (3 ꢀ 15 mL), dried over
anhydrous MgSO4, and evaporated (15 Torr). The residue was
purified by column chromatography (silica gel, hexane/EtOAc)
to yield products 6 or 7.
NaIO4 (0.120 g, 0.54 mmol) and RuCl3 3H2O (7.5 mg, 0.027
3
mmol). The resulting mixture was stirred for 30 min at the same
temperature and then added into a solution of the correspond-
ing 2-(hydromethyl)azetidine 6 (0.25 mmol) in CH3CN (4.5
mL). To the resulting dark solution was added an additional
lot of NaIO4 (0.060 g, 0.27 mmol), and the mixture was stirred
at room temperature for 30 min. The resulting salts were
removed by filtration through a Celite pad, washing thoroughly
with MeOH. The combined filtrate was concentrated under
reduced pressure (15 Torr) and the residue purified by column
chromatography (silica gel, EtOAc/MeOH, 3:1) to yield pro-
ducts 10.
(2R,4R)-N-(tert-Butylsulfonyl)-4-octylazetidine-2-carboxylic
Acid (10b). Following the general procedure, but using 0.25
mmol of starting 2-(hydroxymethyl)azetidine (4R)-6b, after
workup, chromatography on silica gel eluting with 3:1
EtOAc/MeOH afforded 73 mg (88% yield) of 10b as a colorless
oil: [R]20D þ19 (c 0.99, CH2Cl2); Rf 0.44 (hexane/EtOAc 1/3); IR
ν (film) 3560-3140, 2927, 2855, 1720, 1458, 1313, 1123 cm-1
;
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 7.0, 3H), 1.18-1.34
(m, 10H), 1.38 (s, 9H), 1.52-1.68 (m, 2H), 1.75-1.81 (m, 1H),
1.97-2.06 (m, 1H), 2.37-2.43 (m, 1H), 2.56-2.65 (m, 1H),
4.36-4.42 (m, 1H), 4.81 (dd, J = 9.2, 8.0, 1H); 13C NMR (100
MHz, CDCl3) δ 14.1 (CH3), 22.6 (CH2), 23.8 (CH2), 23.9 (CH3),
25.3 (CH2), 29.1 (CH2), 29.4 (CH2), 29.5 (CH2), 31.7 (CH2), 36.0
(CH2), 56.9 (CH), 59.2 (C), 60.5 (CH), 175.6 (C); LRMS (EI) m/
z 333 (Mþ, 0.2), 288 (4), 254 (6), 168 (100), 99 (30), 74 (20), 57
(56); HRMS (EI) calcd for C15H30NSO2 (M - CO2H) 288.1997,
found 288.2001.
Acknowledgment. This work was generously supported
ꢀ
Consolider Ingenio 2010-CSD2007-00006 and CTQ-2007-
65218). J.C.G.-G. thanks the Spanish MEC for a Juan de la
Cierva contract.
(2R,4R)-N-tert-Butylsulfonyl-2-hydroxymethyl-4-(2-phenylethyl)-
azetidine [(4R)-6c]. Following the general procedure, but using 0.5
mmol of starting oxirane (2S,20R)-3c, after workup, chromatogra-
phy on silica gel eluting first with 5:1 and then 3:1 hexane/EtOAc
afforded 140 mg (90% yield) of (4R)-6c as a white solid: [R]22D -25
(c 1.62, CH2Cl2); mp 57-59 °C (hexane/CH2Cl2); Rf 0.27 (hexane/
EtOAc 2/1); IR ν (KBr) 3500-3235, 3068, 3025, 2970, 2868, 1474,
1360, 1294, 1125 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.36 (s, 9H),
1.78-1.88 (m, 1H), 2.04-2.27 (m, 3H), 2.54-2.60 (m, 2H), 3.56-
3.69 (m, 2H), 4.29-4.39 (m, 1H), 7.15-7.21 (m, 3H), 7.26-7.30;
13C NMR (100 MHz, CDCl3) δ22.5(CH2),24.0(CH3), 30.7 (CH2),
37.8 (CH2), 58.4 (C), 59.6 (CH), 60.7 (CH), 64.0 (CH2), 126.0 (CH),
by the Spanish Ministerio de Educacion y Ciencia (MEC;
Supporting Information Available: Experimental proce-
dures, full characterization and copies of 1H and 13C NMR
spectra of all compounds, and X-ray crystal data for compounds
(5S)-4c, (4R)-6c and (4R)-7c. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 20, 2009 7865