Stereocontrolled synthesis of substituted N-arenesulfonyl azetidines from γ-(phenylseleno)alkyl arylsulfonamides

Article abstract of DOI:10.1039/b712861d

Different synthetic methodologies for the stereocontrolled synthesis of substituted azetidines are reported. The approach utilizes an optimized oxidation reaction of γ-(phenylseleno)alkyl arylsulfonamides, followed by the intramolecular substitution of th

Full text of DOI:10.1039/b712861d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereocontrolled synthesis of substituted N-arenesulfonyl azetidines from
c-(phenylseleno)alkyl arylsulfonamides
Marcello Tiecco,* Lorenzo Testaferri, Andrea Temperini,* Raffaella Terlizzi, Luana Bagnoli, Francesca Marini
and Claudio Santi
Received 21st August 2007, Accepted 5th September 2007
First published as an Advance Article on the web 21st September 2007
DOI: 10.1039/b712861d
Different synthetic methodologies for the stereocontrolled synthesis of substituted azetidines are
reported. The approach utilizes an optimized oxidation reaction of c-(phenylseleno)alkyl
arylsulfonamides, followed by the intramolecular substitution of the resulting phenylselenonyl group by
the nitrogen atom.
Introduction
Azetidines are an interesting and important class of four-
membered heterocyclic compounds because of their reactivity1
and biological activity.2 The formation of the azetidine ring
from acyclic precursors is a disfavoured process compared to the
analogous construction of six-, five- and even three-membered
rings. Only a few stereospecific methods are available for their
synthesis, especially in enantiomerically pure form. Optically
Scheme 1 Synthesis of N-benzoyl-oxazolidin-2-ones from b-hydroxyalkyl
phenyl selenides.
active azetidines, which can find application in enantioselective
catalysis,3 are generally obtained from racemic mixtures using
stoichiometric amounts of enantiomerically pure auxiliaries to
closure reaction which occurs by a stereospecific intramolecular
form diastereoisomeric pairs.4 Enzymatic resolutions have also
nucleophilic substitution of the selenonyl group by the nitrogen
been explored.5 Some enantioselective syntheses of azetidines have
atom of the carbamate.
A similar reaction sequence is now described for a new and
convenient stereospecific synthesis of substituted N-arenesulfonyl
azetidines 6 starting from substituted c-phenylseleno arylsulfon-
also been reported. Interesting examples are the intermolecular
reaction of chiral non-racemic 1,3-dihalo or 1,3-diol derivatives
with primary amines,6 the intramolecular cyclization of optically
active 1,3-amino alcohols or 3-amino-1,2-diols,7 the reduction of
amides 4 which are oxidized to the selenones 5 and then cyclized
enantiomerically pure b-lactams8 and the intramolecular alkyla-
(Scheme 2).
tion of an a-amino stabilized carbanion obtained from optically
pure b-amino alcohols.9 Another approach is based on a two-
step methodology involving an internal alkylation of a chiral
non-racemic haloaminohydrin10 followed by debenzylation of the
resulting azetidinium salt. Enantiomerically pure 3-oxo-azetidines
can be then prepared by diazoketones, derived from N-protected
a-amino acids, through insertion of carbenoid species into the
N–H bond.11
As part of our ongoing interest in the chemistry of organose-
lenium compounds we have recently observed that the se-
lenonyl group can be easily intramolecularly displaced by ni-
Scheme 2 Synthesis of azetidines 6 by intramolecular substitution of the
trogen nucleophiles thus affording nitrogen containing hetero-
cyclic compounds.12 Thus, starting from chiral non-racemic b-
hydroxyalkyl phenyl selenides 1 we effected the stereospecific
synthesis of various substituted optically active 1,3-oxazolidin-2-
ones 3. As indicated in Scheme 1, compounds 1 were transformed
into the corresponding N-benzoyl carbamate derivatives which
were oxidized to selenones 2.13 These, in the presence of a base, gave
the desired compounds 3. The key step of the process is a new ring
selenonyl group by a nitrogen atom.
To our knowledge a similar intramolecular substitution has
been reported only in one case, for the preparation of the
unsubstituted N-tosyl azetidine (Scheme 2: R1 = R2 = H, Ar = p-
Tol).14 After this report no other examples have been described
in the literature. One important step of our procedure is the
preparation of the starting sulfonamides 4, whose syntheses have
not been reported in the literature so far. In the present paper we
therefore describe some simple stereocontrolled methods to effect
the synthesis of these interesting compounds.
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica
Organica, Universita` di Perugia, I-06123, Perugia, Italy. E-mail: Tiecco@
unipg.it; Fax: +39-075-5855116; Tel: +39-075-5855101
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hydroxyselenide 10c was directly prepared from the commer-
cially available enantiomerically enriched epoxide 9c (98% ee).
After deprotection of 10a–c and reprotection of the amino
group as 2-nitrobenzenesulfonyl (nosyl) derivatives, the interme-
diate alcohols were directly converted into the corresponding
tetrahydropyranyl derivatives of substituted c-[N-(phenylseleno)
alkyl]arylsulfonamides 4a–c (Scheme 3).
Results and discussion
The required phenylseleno sulfonamides 4 were prepared by differ-
ent synthetic approaches starting from commercially available chi-
ral building blocks such as epoxides, lactones and esters or through
enantioselective processes starting from achiral compounds.
Method 1: Preparation of c-[N-(phenylseleno)alkyl]-
arylsulfonamides 4a–c from a-amino epoxides
Cyclizations of c-[N-(phenylseleno)alkyl]arylsulfonamides 4a–c to
azetidines 6a–c
The first method uses as starting materials enantiomerically pure
a-amino acids which were transformed into the corresponding
a-amino epoxides. As depicted in Scheme 3 (S)-a-amino acids 7
were efficiently converted into the corresponding enantiopure N-
Boc a-amino aldehydes 8 according to the procedures described
in the literature.15,16 These were treated with dimethyl sulfoxonium
methylide, according to the procedure described by Ashton et al.,17
to afford the epoxides 9a,b as 4 : 1 syn–anti mixtures (as deter-
The oxidations of selenides 4a–c into the selenones 5a–c were
carried out in THF at room temperature with an excess of m-
chloroperoxybenzoic acid and in the presence of potassium hydro-
genphosphate according to our previously reported method.12 The
selenone intermediates19,20 were not isolated but directly cyclized to
the azetidines 6a–c by addition of powdered potassium hydroxide.
After the usual workup, evaporation of the solvent afforded the
crude N-nosyl azetidines 6a–c which were finally deprotected to
give the N-nosyl-3-azetidinols 11a–c in satisfactory overall yields
(Scheme 3 and Table 1).
1
mined by H NMR15,16,18) of two diastereoisomers which could
not be separated. Regiospecific opening of these mixtures with
phenylselenolate anions12 provided the corresponding mixtures
of the two b-hydroxyselenides 10a,b in good yields. The b-
Scheme 3 Reagents and conditions: (i) see ref. 16; (ii) Me3SO+I− (1.2 equiv.), NaH (1.1 equiv.), DMSO, 25 ◦C, 4 h; (iii) PhSeSePh (0.5 equiv.), NaBH4
(1.0 equiv.), EtOH, 40 ◦C, 5 h; (iv) H2SO4 (10.0 equiv.), dioxane, 25 ◦C, 1 h; (v) NsCl (1.4 equiv.), Et3N (1.4 equiv.), CH2Cl2, 0 ◦C → 25 ◦C, 14 h, then DHP
(1.2 equiv.), TsOH·H2O (0.01 equiv.), CH2Cl2, 25 ◦C, 20 h; (vi) MCPBA (4 equiv.), K2HPO4 (5 equiv.), THF, 25 ◦C, 3 h, then KOH (7.5 equiv.), 25 ◦C,
6 h; (vii) TsOH·H2O (0.05 equiv.), MeOH, 25 ◦C, 16 h. Ns = 2-nitrobenzenesulfonyl; DHP = 3,4-dihydro-2H-pyran; MCPBA = 3-chloroperoxybenzoic
acid; Ts = 4-toluenesulfonyl.
Table 1 Preparation of azetidine alcohols 11a–c from a-amino epoxides 9
Entrya
a
Epoxy amide 9
N-Arylsulfonyl selenides 4
Yields (%)b
74
Azetidines 11
Yields (%)c
61
b
c
86
71
56
50
a The products reported in entries a and b are 4 : 1 mixtures of two diastereoisomers. Only the major diastereoisomer is indicated. b Yields calculated from
the starting hydroxy selenides 10. c Yields of the overall oxidation–cyclization–deprotection process.
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Obviously the azetidine alcohols 11a and 11b were obtained as
4 : 1 mixtures of two diastereoisomers which could not be separated
by column chromatography. Compound 11c was instead obtained
as a single enantiomer (98% ee). The nosyl group can be easily
removed,21 which increases the importance of the present method
for the synthesis of optically active azetidines.
4e, synthesized from 4d by reduction of the ester group, the
known azetidine alcohol 6e23 was obtained in better yield (62%)
(Scheme 4).
The simple c-lactone 15 also can be employed as a precursor
for a stereoselective synthesis of azetidines. Alkylation of 15
afforded the racemic a-benzyl-c-lactone 16 (Scheme 5). The
lithium enolate of 16 was enantioselectively protonated26 with
the chiral proton source R-pantolactone at −78 ◦C in THF. The
optically active lactone 16 was obtained in a 61 : 39 enantiomeric
ratio as determined by HPLC on a chiral stationary phase. The
predominant R configuration was indicated by the sign of the
specific optical rotation.26 Compound 16 was then subjected to
ring opening by phenylselenolate anion in DMF22 to afford the
acid 17.
Through the simple steps described below, the acid 17 was trans-
formed into the required c-[N-(phenylseleno) alkyl]arylsulfona-
mide 4f. Thus, the treatment of acid 17 with oxalyl chlo-
ride gave the crude acyl chloride which, with trimethylsily-
lazide in dichloromethane at 40 ◦C, afforded the corresponding
isocyanate.27 This was directly converted in good yield into the free
amine 18. Protection with 2-nitrobenzenesulfonyl chloride gave 4f
in good overall yield. The chiral non-racemic substituted N-nosyl-
azetidine 6f was then obtained in excellent yield after the usual
oxidation–cyclization procedure. HPLC analysis on the chiral sta-
tionary phase of 6f showed a 55 : 45 enantiomeric ratio indicating
that a decrease in the enantiomeric ratio has occurred, probably
during the Curtius rearrangement as previously observed.28
Method 2: Preparation of c-[N-(phenylseleno) alkyl]arylsulfona-
mides 4d-f from c-lactones and cyclization to azetidines 6d–f
The second synthetic approach to obtain the other sulfonamides
necessary for the present investigation is indicated in Schemes 4
and 5.
Enantiomerically enriched (98% ee) homoserine lactone hy-
drobromide 12 was protected as N-tosyl derivative 13 and then
subjected to ring opening byphenylselenolate anion inDMF.22 The
resulting acid was directly treated with diazomethane to give the
sulfonamide 4d. After the oxidation–cyclization procedure shown
above, the azetidine ester 6d was obtained in moderate yield (44%).
The physical properties of this compound were identical to those
already described in the literature.23 Compound 6d is the precursor
of L-azetidine-2-carboxylic acid (L-Aze) which, because of its
constrained a-amino acid structure, has found many applications
in pharmaceutical24 and in synthetic chemistry.25 The low yield
of 6d is probably due to the hydrolysis of the ester group by the
hydroxide ion employed in the cyclization step. In fact, when the
cyclization was performed on the tetrahydropyranyl derivative
Scheme 4 Reagents and conditions: (i) TsCl (1.2 equiv.), Et3N (2.2 equiv.), CH2Cl2, 0 ◦C → 25 ◦C, 7 h, 78%; (ii) PhSeSePh (0.5 equiv.), NaBH4 (1.0 equiv.),
DMF, 100 ◦C, 6 h; (iii) CH2N2, Et2O, 25 ◦C, 5 min, 83% (two steps); (iv) MCPBA (4 equiv.), K2HPO4 (5 equiv.), THF, 25 ◦C, 2 h, then KOH (7.5 equiv.),
25 ◦C, 3 h, 44%; (v) LiAlH4 (2.2 equiv.), THF, 0 ◦C, 2 h, 73%; (vi) DHP (2.0 equiv.), TsOH·H2O (0.1 equiv.), CH2Cl2, 25 ◦C, 18 h, 80%; (vii) TsOH·H2O
(0.05 equiv.), MeOH, 25 ◦C, 8 h, 62% (two steps). Ts = 4-toluenesulfonyl; MCPBA = 3-chloroperoxybenzoic acid; DHP = 3,4-dihydro-2H-pyran.
Scheme 5 Reagents and conditions: (i) LDA (1.1 equiv.), THF, then BnBr (1.2 equiv.), −78 ◦C, 1 h, 70%; (ii) LDA (1.1 equiv.), THF, −78 ◦C, then
(R)-(−)-pantolactone (2.0 equiv.), −78 ◦C, 10 min, 92%; (iii) PhSeSePh (0.5 equiv.), NaBH4 (1 equiv.), DMF, 100 ◦C, 5 h, 75% (two steps); (iv) (COCl)2
(1.5 equiv.), 25 ◦C, 5 h, then TMSN3 (1.2 equiv.), CH2Cl2, 40 ◦C, 5 h; (v) 1 M aq. NaOH (1.1 equiv.), THF, 100 ◦C, 4 h; (vi) NsCl (1.3 equiv.), Et3N
(1.3 equiv.), CH2Cl2, 0 ◦C → 25 ◦C, 5 h, 55% (four steps); (vii) MCPBA (4 equiv.), K2HPO4 (5 equiv.), THF, 25 ◦C, 2 h, then KOH (7.5 equiv.), 25 ◦C,
15 h, 80%. TMSN3 = trimethylsilylazide; Ns = 2-nitrobenzenesulfonyl; MCPBA = 3-chloroperoxybenzoic acid.
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Method 3: Preparation of c-[N-(phenylseleno) alkyl]arylsulfona-
mides 4g and 4h from c-hydroxy selenides and cyclization to
azetidines 6g and 6h
with low enantioselectivity. The enantiomerically enriched alcohol
23 was then converted into the arylsulfonamide 4h through its
corresponding phthalimide, as described above for the alcohol 20.
Finally oxidation of the selenium atom followed by addition of
potassium hydroxide afforded the desired azetidine 6h (70% yield)
in 56 : 44 enantiomeric ratio as demonstrated by HPLC analysis.
A simple substrate-controlled stereospecific synthesis of azetidines
starting from easily available enantiomerically pure b-hydroxy es-
ters is illustrated in Scheme 6. Thus commercial (S)-3-hydroxy es-
ter 19 (98% ee) was easily converted in four steps (without isolation
of the intermediates) into the c-hydroxyselenide 20 in 71% overall
yield. By reaction with phthalimide, under Mitsunobu conditions,
20 was converted into the corresponding phthalimido derivative. It
is well known that the Mitsunobu reaction occurs with complete
inversion of configuration at the stereogenic center.29 Nitrogen
deprotection of the crude phthalimide gave the corresponding
free amine which was reacted with 2-nitrobenzenesulfonyl chloride
to give the corresponding arylsulfonamide 4g (71% yield). After
the usual oxidation–cyclization procedure the optically active N-
nosyl azetidine 6g was obtained in good yield (59%). No loss of
the enantiomeric purity occurred during all these conversions as
demonstrated by the enantiomeric ratio of 6g (>99 : 1), measured
by HPLC analysis on the chiral stationary phase.
A different synthetic strategy for the preparation of optically
active c-hydroxyselenides is depicted in Scheme 7. Thus, the con-
jugate addition of benzeneselenol to the a,b-unsaturated ketone 21
gave the b-phenylseleno ketone 22 in excellent yield.30 Asymmetric
reduction with the reagent prepared from (S)-(−)-2-amino-3-
methyl-1,1-diphenylbutan-1-ol and borane31 in THF produced
the optically active c-hydroxyselenide 23 in excellent yield but
Conclusions
A new and convenient synthesis of substituted azetidines is pre-
sented. Different synthetic approaches to the c-(phenylseleno)alkyl
arylsulfonamides required as starting materials have also been
developed. The key step in the formation of azetidines is the ring
closure reaction which occurs by a stereospecific intramolecular
nucleophilic substitution of the selenonyl group by the nitrogen
atom of the arylsulfonamides. This reaction confirms the extremely
good leaving ability of the selenonyl group. The present procedure
favourably compares with other previously described methods.
Preliminary results indicate that the procedure described here can
also be applied to the synthesis of five- and six-membered ring
heterocyclic compounds.
Experimental
1H NMR and 13C NMR spectra were recorded on a Bruker
Avance DR 200 at 200 and 50.3 MHz, respectively; unless
otherwise specified, CDCl3 was used as solvent. Chemical shifts
Scheme 6 Reagents and conditions: (i) DHP (1.2 equiv.), TsOH·H2O (0.1 equiv.), Et2O, 25 ◦C, 48 h; (ii) LiAlH4 (2.2 equiv.), THF, 0 ◦C, 5 h; (iii) PhSeCN
(1.2 equiv.), PBu3 (1.2 equiv.), THF, 25 ◦C, 8 h; (iv) TsOH·H2O (0.1 equiv.), MeOH, 25 ◦C, 18 h, 71% (four steps); (v) PPh3 (1.4 equiv.), PhthNH
(1.4 equiv.), DIAD (1.3 equiv.), THF, 0 ◦C → 25 ◦C, 7 h; (vi) H2N–NH2 (1.1 equiv.), EtOH, 110 ◦C, 2 h, then NsCl (1.4 equiv.), Et3N (1.4 equiv.),
CH2Cl2, 0 ◦C → 25 ◦C, 15 h, 71% (three steps); (vii) MCPBA (4 equiv.), K2HPO4 (5 equiv.), THF, 25 ◦C, 2 h, then KOH (7.5 equiv.), 6 h, 59%. DHP =
3,4-dihydro-2H-pyran; Ts = 4-toluenesulfonyl; PhthNH = phthalimide; DIAD = diisopropyl azodicarboxylate; Ns = 2-nitrobenzenesulfonyl; MCPBA =
3-chloroperoxybenzoic acid.
Scheme 7 Reagents and conditions: (i) PhSeSePh (0.6 equiv.), NaBH4 (1.3 equiv.), EtOH, 25 ◦C, 3 h, 86%; (ii) 1 M BH3 in THF (2.0 equiv.),
(S)-(−)-2-amino-3-methyl-1,1-diphenylbutan-1-ol (1.0 equiv.), 25 ◦C, 48 h, 87%; (iii) PPh3 (1.4 equiv.), PhthNH (1.4 equiv.), DIAD (1.3 equiv.), THF,
0
◦C → 25 ◦C, 14 h; (iv) H2N–NH2 (1.1 equiv.), EtOH, 110 ◦C, 3 h; (v) NsCl (1.4 equiv.), Et3N (1.4 equiv.), CH2Cl2, 0 ◦C → 25 ◦C, 12 h, 66% (three
steps); (vi) MCPBA (4 equiv.), K2HPO4 (5 equiv.), THF, 25 ◦C, 2 h, then KOH (7.5 equiv.), 5 h, 70%. PhthNH = phthalimide; DIAD = diisopropyl
azodicarboxylate; Ns = 2-nitrobenzenesulfonyl; MCPBA = 3-chloroperoxybenzoic acid.
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(d) are reported in parts per million (ppm) and are referenced
to tetramethylsilane (Me4Si) for H NMR or to the appropriate
(1S,2S) (distinct signals): dH 4.64 (1 H, d, J 8.5, NH), 3.42–3.23
(1 H, m, CHO) and 0.98 (3 H, t, J 7.5, CH3); dC 155.5, 53.8, 45.9
and 9.9; m/z (E/I) 172 (13, M − CH3CH2), 158 (9%), 102 (16), 72
(36), 59 (23) and 57 (100).
1
solvent peak (13C NMR). Coupling constants (J) are quoted in
Hertz (Hz) to the nearest 0.1 Hz. FT-IR spectra were recorded with
a Jasco model 410 spectrometer on a Diffuse Reflectance sampling
cell. Only significant absorption maxima (mmax) are reported, and
all absorptions are reported in wavenumbers (cm−1). GC-MS
analyses were obtained with a HP-6890 gas chromatograph (HP-
5MS capillary column; 30 m × 0.25 mm i.d., film 0.25 lm)
equipped with a HP-5973 mass selective detector at an ionizing
voltage of 70 eV. For the ions containing selenium only the
peaks arising from the selenium-80 isotope are given. HPLC was
carried out using a HP 1100 system equipped with a UV/Vis
detector with the columns and solvents specified. Melting points
are uncorrected. Optical rotations were measured in a 50 mm
cell with a Jasco DIP-1000 digital polarimeter using the D-line
of sodium at the given temperature. [a]D values are given in
10−1 deg cm2 g−1; concentrations (c) are quoted in g 100 mL−1.
Elemental analyses were carried out on a Carlo Erba 1106
elemental analyzer. Commercial grade Et2O and CH2Cl2 were
used without purification. DMF, MeOH and EtOH were dried by
using standard procedures. Reactions were monitored by thin layer
chromatography (TLC) carried out on aluminium foil sheets pre-
coated with silica (Merck silica gel 60 F254), which were visualized
by the quenching of UV fluorescence (kmax254 nm) and/or by
staining with 5% w/v phosphomolybdic acid in EtOH followed
by heating. Column chromatography was performed on Merck
silica gel 60 (70–230 mesh).
Preparation of b-hydroxyalkyl phenyl selenides 10a–c
The b-hydroxyalkyl phenyl selenides 10a–c were prepared by the
regiospecific ring opening of the corresponding epoxides with
sodium phenyl selenolate in ethanol as reported in the literature.12
Yields, physical and spectral data are reported below.
tert-Butyl (1S,2R) and (1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-
3-(phenylseleno)propylcarbamate (10a),12. (1.6 g, 19% global
yield starting from the corresponding amino acids). 82 : 18 mixture
of syn–anti diastereoisomers as determined by 1H NMR analysis.
tert-Butyl (1S,2R) and (1S,2S)-1-ethyl-2-hydroxy-3-(phenyl-
seleno)propylcarbamate (10b). (3.5 g, 97%). Yellow oil (found:
C, 53.3; H, 7.3; N, 4.3. Calc. for C16H25NO3Se: C, 53.6; H, 7.0; N,
3.9%); mixture of diastereoisomers syn–anti (83 : 17). syn Isomer:
dH(200 MHz, CDCl3, Me4Si) 7.60–7.42 (2 H, m, ArH), 7.32–7.20
(3 H, m, ArH), 4.75 (1 H, d, J 9.3, NH), 3.74–3.35 (2 H, m, CHO
and CHN), 3.12 (1 H, dd, J 12.9 and 3.8, CH2SeAr), 2.93 (1 H,
dd, J 12.9, 9.5, CH2SeAr), 2.84 (1 H, d, J 2.9, OH), 1.70–1.45
(2 H, m, CH2CH3), 1.43 (9 H, s, 3 × CH3) and 0.91 (3 H, t, J 6.9,
CH2CH3); dC(50.3 MHz, CDCl3) 156.3, 132.8 (2 C), 129.0 (2 C),
128.9, 127.1, 79.1, 70.7, 55.2, 34.4, 28.2 (3 C), 25.9 and 10.6; anti
isomer (distinct signals): dH 4.69 (1 H, d, J 9.3, NH), 2.73 (1 H, d,
J 3.0, OH) and 0.93 (3 H, t, J 7.1, CH2); dC 72.9, 56.2, 34.8, 22.6
and 10.4.
The optically active epoxide 9c, the amino c-lactone 12 and the
b-hydroxy ester 19, used as starting materials, were commercially
available and have enantiomeric excesses equal to or greater than
98%. The analytical data for compounds 10a,12 13,32 6d,23 6e,23
16,33 and 2034 were in agreement with those already reported in
the literature.
tert-Butyl (1S,2S)-1-benzyl-2-hydroxy-3-(phenylseleno)propyl-
carbamate (10c). (1.5 g, 98%). Pale yellow solid, mp 139–141 ◦C;
[a]2D0 −11.8 (c 1.96 in CHCl3); found: C, 59.8; H, 6.95; N, 3.0. Calc.
for C21H27NO3Se: C, 60.0; H, 6.5; N, 3.3%; dH(200 MHz, CDCl3,
Me4Si) 7.63–7.50 (2 H, m, ArH), 7.36–7.12 (8 H, m, ArH), 4.62
(1 H, d, J 7.8, NH), 4.04–3.68 (2 H, m, CHO and CHN), 3.30–
3.12 (1 H, m, CH2SeAr), 3.10 (1 H, br s, OH), 3.09–2.75 (3 H, m,
CH2SeAr and CH2Ar) and 1.35 (9 H, s, 3 × CH3); dC(50.3 MHz,
CDCl3) 155.8, 137.8, 134.2, 133.1 (2 C), 129.4, 129.3, 128.4 (2 C),
127.4, 126.4 (2 C), 123.5, 79.7, 72.2, 55.7, 35.8, 33.5 and 28.2 (3 C).
Caution
Because of their potentially explosive properties, all reactions
involving azides were carried out with the appropriate protection
under a well-ventilated hood.
Preparation of the epoxides 9a and 9b
Preparation of O-protected c-[N-(phenylseleno)alkyl]-2-
nitrobenzenesulfonamides 4a–c. General procedure
The a-amino aldehydes 8a and 8b were obtained from the
corresponding L-amino acids as reported by Luly et al.16 and
directly transformed into the epoxides 9a and 9b according to
the procedure reported in the literature.17 Epoxide 9a was not
isolated but it was directly transformed into the corresponding
b-hydroxyalkyl phenyl selenide 10a.
A solution of b-hydroxyalkyl phenyl selenide 10c (1.50 g,
3.56 mmol) in 12 : 1 dioxane–H2SO4 (26 mL) was stirred at
room temperature for 1 h. The reaction was then quenched by
careful addition of powdered sodium hydroxide (5.80 g, 145 mmol)
and 8 mL of H2O. The reaction mixture was then extracted
with diethyl ether (3 × 10 mL) and the combined organic layers
were dried over sodium sulfate and then evaporated. The crude
residue was dissolved in dry CH2Cl2 (30 mL) at 0 ◦C. To this
solution were added triethyl amine (0.69 mL, 4.98 mmol) and 2-
nitrobenzenesulfonyl chloride (1.10 g, 4.98 mmol). The mixture
was warmed to room temperature and stirred for 14 h. A 7%
solution of hydrochloric acid (50 mL) and CH2Cl2 (30 mL) was
then added. The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (2 × 20 mL). The combined organic
layers were dried over sodium sulfate, filtered and concentrated
tert-Butyl (1S)-1-[(2R)-oxiran-2-yl]propylcarbamate and tert-
butyl (1S)-1-[(2S)-oxiran-2-yl]propylcarbamate (9b). (1.8 g,
61%). Pale yellow oil (found: C, 59.3; H, 9.75; N, 6.6. Calc. for
C10H19NO3: C, 59.6; H, 9.5; N, 6.9%); mixture of diastereoisomers
syn–anti (83 : 17). syn Isomer (1S,2R): dH(200 MHz, CDCl3,
Me4Si) 4.52 (1 H, d, J 8.5, NH), 3.88–3.70 (1 H, m, CHO), 3.07–
2.98 (1 H, m, CH2O), 2.92–2.69 (m, 1 H, CH2O), 2.64–2.55 (1 H,
m, CHN), 1.80–1.48 (2 H, m, CH2), 1.46 (3 H, s, CH3), 1.44 (6 H,
s, 2 × CH3) and 1.02 (3 H, t, J 7.5, CH3); dC(50.3 MHz, CDCl3)
155.7, 79.2, 53.2, 49.5, 44.0, 28.2 (3 C), 26.3, and 10.2; anti isomer
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in vacuo. The crude residue was dissolved in dry Et2O (30 mL)
and 3,4-dihydro-2H-pyran (0.40 mL, 4.2 mmol) was added. p-
Toluenesulfonic acid monohydrate (190 mg, 1 mmol) was added
to this solution which was then stirred at room temperature for
21 h. The mixture was concentrated under reduced pressure and
the residue was purified by column chromatography on silica gel
(Et2O 40% in light petroleum) to give 4c. By the same procedure
4a and 4b were prepared. Yields, as well as physical and spectral
data are reported below.
(1 H, dd, J 14.0 and 4.4, CH2Ar), 2.72 (1 H, dd, J 14.0 and 10.0,
CH2Ar) and 1.95–1.46 (6 H, m, 3 × CH2); dC(50.3 MHz, CDCl3)
146.6, 137.5, 135.1, 132.5, 132.4 (2 C), 132.1, 130.0, 129.6, 129.2
(2 C), 129.1, 129.0, 128.8, 127.7, 126.7, 126.1, 124.5, 102.3, 84.7,
65.1, 59.5, 35.2, 30.9, 30.4, 24.5, and 21.3.
Typical procedure for the conversion of c-[N-(phenylseleno)alkyl]-
arylsulfonamides into N-aryl-azetidines
Commercial m-chloroperoxybenzoic acid (0.40 g, 2.36 mmol) was
added to a mixture of 4c (0.35 g, 0.59 mmol) and powdered
potassium hydrogenphosphate (0.51 g, 2.95 mmol) in tetrahy-
drofuran (15 mL) at room temperature. The resulting mixture
was stirred and the progress of the reaction was monitored by
TLC. When the selenide was completely consumed (3 h) powdered
potassium hydroxide (0.24 g, 4.42 mmol) was added and stirring
was continued until the selenone was consumed (6 h). The mixture
was then diluted with water (30 mL) and extracted with diethyl
ether (3 × 20 mL). The combined organic layers were dried over
sodium sulfate and evaporated. The crude product was dissolved
in MeOH (20 mL) and p-toluenesulfonic acid monohydrate
(19 mg, 0.10 mmol) was added. This solution was then stirred
at room temperature for 16 h. This final deprotection treatment
was effected only to obtain products 11a–c. The mixture was
concentrated under reduced pressure and the residue was purified
by column chromatography on silica gel using a mixture of Et2O–
light petroleum (70 : 30) as eluant to give 11c. Yields, physical and
spectral data of the new compounds are reported below.
N-{(1S,2R) and (1S,2S) 1-(Cyclohexylmethyl)-3-(phenylseleno)-
2-[(2R*)-tetrahydro-2H-pyran-2-yloxy]propyl}-2-nitrobenzene-
sulfonamide (4a). (1.4 g, 74%). Colourless oil (found: C, 54.9;
H, 5.7; N, 5.1. Calc. for C27H36N2O6SSe: C, 54.45; H, 6.1; N,
4.7%); 4 : 1 mixture of four stereoisomers. Only the signals of the
syn isomer are indicated below. syn Isomer: 1 : 1 mixture of two
diastereoisomers. dH(200 MHz, CDCl3, Me4Si) 8.30–8.20 (2 H, m,
ArH), 7.95–7.80 (4 H, m, ArH), 7.78–7.63 (2 H, m, ArH), 7.50–
7.32 (4 H, m, ArH), 7.30–7.15 (6 H, m, ArH), 5.67 (1 H, d, J 9.2,
NH), 5.61 (1 H, d, J 8.8, NH), 4.62–4.48 (2 H, m, 2 × OCHO),
4.21–3.67 (4 H, m, 2 × CHO and 2 × CHN), 3.62–3.28 (4 H,
m, 2 × CH2O), 3.07–2.64 (4 H, m, 2 × CH2SeAr) and 1.95–0.60
(38 H, m, 2 × CH and 18 × CH2); dC(50.3 MHz, CDCl3) 147.4
(2 C), 136.6 (2 C), 135.0, 134.8, 133.3, 132.9, 132.7, 132.4, 132.2,
132.1, 131.4 (2 C), 130.3, 130.2, 129.5 (2 C), 129.0 (2 C), 126.9,
126.6, 125.1, 125.0, 101.1, 97.5, 79.9, 75.7, 63.0, 62.9, 53.9, 53.1,
40.8, 39.9, 33.7, 33.5, 33.1, 33.0, 32.9, 32.8, 31.0, 30.7, 27.9, 27.7,
26.1, 25.8 (2 C), 25.3, 25.2, 25.0, 19.6, 19.5 and 19.4 (2 C).
N-{(1S,2R) and (1S,2S) 1-Ethyl-3-(phenylseleno)-2-[(2R*)-
tetrahydro-2H -pyran-2yloxy]propyl}-2-nitrobenzenesulfonamide
(4b). (1.6 g, 86%). Colourless oil (found: C, 50.3; H, 5.2; N, 5.0.
Calc. for C22H28N2O6SSe: C, 50.1; H, 5.35; N, 5.3%); 4 : 1 mixture
of four stereoisomers. Only the signals of the syn isomer are
indicated below. syn Isomer: 1 : 1 mixture of two diastereoisomers.
dH(200 MHz, CDCl3, Me4Si) 8.22–8.10 (2 H, m, ArH), 7.88–7.76
(2 H, m, ArH), 7.74–7.61 (4 H, m, ArH), 7.50–7.32 (4 H, m,
ArH), 7.28–7.15 (6 H, m, ArH), 5.78 (1 H, d, J 8.2, NH), 5.75
(1 H, d, J 9.1, NH), 4.60–4.50 (2 H, m, 2 × OCHO), 3.99–3.56
(6 H, m, 2 × CHO, 2 × CHN and CH2O), 3.52–3.35 (2 H, m,
CH2O), 3.31 (1 H, dd, J 12.8 and 3.7, CH2SeAr), 2.97 (1 H, dd, J
12.8 and 5.3, CH2SeAr), 2.73 (1 H, dd, J 12.7 and 8.0, CH2SeAr),
2.62 (1 H, dd, J 12.7 and 10.1, CH2SeAr), 1.89–1.32 (16 H, m,
8 × CH2), 0.81 (3 H, t, J 7.5, CH2CH3) and 0.80 (3 H, t, J 7.3,
CH2CH3); dC(50.3 MHz, CDCl3) 151.2, 150.1, 135.5, 135.3, 133.2,
133.1, 132.9, 132.8 (2 C), 132.4, 132.3, 131.4, 130.4, 130.3, 129.7,
129.6, 129.2 (2 C), 129.1, 127.1, 126.7, 125.1(2 C), 124.8, 101.4,
97.7, 79.1, 75.2, 63.6, 63.0, 58.4, 57.5, 30.8, 30.7, 28.0 (2 C), 26.8,
26.1, 25.1(2 C), 20.0, 19.6, 10.6 and 10.3.
(2S,3S*)-2-(Cyclohexylmethyl)-1-[(2nitrophenyl)sulfonyl] aze-
tidine-3-ol (11a). (0.26 g, 61%). Colourless oil (found: C, 54.5;
H, 6.6; N, 7.6. Calc. for C16H22N2O5S: C, 54.2; H, 6.25; N, 7.9%);
mmax/cm−1 3528, 2923, 1558, 1371 and 1167; 82 : 18 mixture of
two diastereoisomers. Major isomer: dH(200 MHz, CDCl3, Me4Si)
8.06–7.92 (1 H, m, ArH), 7.80–7.60 (3 H, m, ArH), 4.65–4.45 (1 H,
m, CHO), 4.33 (1 H, dd, J 9.5 and 6.5, CH2N), 3.73 (1 H, dd, J 9.5
and 2.8, CH2N), 3.45–3.33 (1 H, m, CHN), 2.22 (1 H, s, OH) and
1.85–0.75 (13 H, m, CH and CH2); dC(50.3 MHz, CDCl3) 148.3,
133.8, 131.8, 131.6, 130.6, 124.1, 68.4, 63.4, 58.8, 35.6, 34.2, 33.2,
33.0 and 25.6 (3 C); minor isomer (distinct signals): dC(50.3 MHz,
CDCl3) 133.3, 132.9, 130.8, 125.2, 73.2, 66.7, 58.2, 33.9 and 32.6;
m/z (E/I) 311 (47, M − 43), 215 (20%), 186 (100), 109 (18), 83
(19) and 55 (11).
(2S,3S*)-3-Ethyl-1-[(2-nitrophenyl)sulfonyl]azetidine-3-ol (11b).
(0.2 g, 56%). White solid, mp 118–121 ◦C (found: C, 46.0; H,
5.35; N, 9.5. Calc. for C11H14N2O5S: C, 46.15; H, 4.9; N, 9.8%);
mmax/cm−1 3431, 2963, 1547, 1352 and 1164; 83 : 17 mixture of
diastereoisomers. Major isomer: dH(200 MHz, CD3OD, Me4Si)
8.08–7.97 (1 H, m, ArH), 7.88–7.79 (3 H, m, ArH), 4.38 (1 H,
dd, J 6.8 and 3.3, CHO), 4.34–4.22 (1 H, m, CHN), 4.24 (1 H,
dd, J 9.2 and 6.8, CH2N), 3.73 (1 H, dd, J 9.2 and 3.3, CH2N),
2.09–1.64 (2 H, m, CH2CH3) and 0.90 (3 H, t, J 7.5, CH2CH3);
dC(50.3 MHz, CD3OD) 149.6, 135.0, 132.6, 131.5, 131.0, 125.0,
72.4, 62.9, 59.3, 22.5 and 9.8; minor isomer (distinct signals):
dH(200 MHz, CD3OD, Me4Si) 4.16–3.97 (2 H, m, CHO and
CH2N), 3.70–3.62 (1 H, m, CH2N) and 0.95 (3 H, t, J 7.5,
CH2CH3); dC(50.3 MHz, CD3OD) 148.2, 131.7, 76.4, 65.6, 58.8,
26.9 and 8.5.
N-{(1S,2S)-1-Benzyl-3-(phenylseleno)-2-[(2R*)-tetrahydro-2H-
pyran-2-yloxy]-propyl}-2-nitrobenzenesulfonamide (4c). (1.5 g,
71%). Pale yellow oil (found: C, 55.3; H, 4.6; N, 4.5. Calc.
for C27H30N2O6SSe: C, 55.0; H, 5.1; N, 4.75%); mixture of
diastereoisomers (95 : 5). Major isomer: dH(200 MHz, CDCl3,
Me4Si) 7.75–7.64 (2 H, m, ArH), 7.60–7.12 (8 H, m, ArH),
7.02–6.82 (4 H, m, ArH), 4.63–4.44 (1 H, m, OCHO), 4.30–3.40
(5 H, m, NH, CHO, CHN and CH2O), 3.13 (1 H, dd, J 12.70
and 8.3, CH2SeAr), 2.96 (1 H, dd, J 12.7 and 5.7, CH2SeAr), 2.89
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(2S,3R)-2-Benzyl-1-[(2-nitrophenyl)sulfonyl]azetidin-3-ol (11c).
(0.1 g, 50%). Pale yellow oil (found: C, 54.8; H, 4.9; N, 7.6. Calc.
for C16H16N2O5S: C, 55.2; H, 4.6; N, 8.0%); [a]2D7 118.5 (c 1.31 in
CHCl3); mmax/cm−1 3470, 2894, 1540, 1349 and 1162; dH(200 MHz,
CDCl3, Me4Si) 7.95–7.85 (1 H, m, ArH), 7.78–7.61 (3 H, m, ArH),
7.35–7.17 (5 H, m, ArH), 4.42 (1 H, dt, J 8.8 and 5.2, CHN), 4.24
(1 H, dt, J 6.7 and 5.2, CHO), 4.06 (1 H, dd, J 8.1 and 6.7, CH2N),
3.72 (1 H, dd, J 8.1 and 5.2, CH2N), 3.21 (1 H, dd, J 13.8 and
5.2, CH2Ar), 2.96 (1 H, dd, J 13.8 and 8.8, CH2Ar) and 2.05 (1 H,
br s, OH); dC(50.3 MHz, CDCl3) 148.6, 135.6, 134.1, 131.8, 130.9,
129.7, 129.4 (2 C), 128.5 (2 C), 126.7, 124.1, 74.1, 65.1, 58.0 and
39.3.
21.5; m/z (E/I): 399 (M+, 18%) 242 (13), 197 (47), 171 (19), 155
(61), 91 (100), 77 (12) and 56 (29).
4-Methyl-N-((1S)-3-(phenylseleno)-1-{[(2S*)-tetrahydro-2H-
pyran-2-yloxy]methyl}propyl)benzenesulfonamide (4e). The alco-
hol 14 (0.30 g, 0.75 mmol) was dissolved in dry CH2Cl2
(10 mL) and 3,4-dihydro-2H-pyran (0.14 mL, 1.50 mmol) and p-
toluenesulfonic acid monohydrate (19 mg, 0.1 mmol) were added.
The resulting mixture was stirred at room temperature for 18 h
and then concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel using a mixture
of Et2O–light petroleum (40 : 60) as eluant to give 4e (0.3 g,
80%) as a colourless oil (found: C, 54.55; H, 6.3; N, 2.7. Calc.
for C22H29NO4SSe: C, 54.8; H, 6.1; N, 2.9%); 1 : 1 mixture of two
diastereoisomers. dH(200 MHz, CDCl3, Me4Si) 7.80–7.69 (4 H, m,
ArH), 7.48–7.37 (4 H, m, ArH), 7.32–7.14 (10 H, m, ArH), 5.58
(1 H, d, J 8.0, NH), 5.20 (1 H, d, J 8.1, NH), 4.92–4.84 (1 H, m,
OCHO), 4.61–4.50 (1 H, m, OCHO), 4.36–4.25 (2 H, m, CHN),
4.08–3.60 (3 H, m, 2 × CH2O), 3.59–3.29 (5 H, m, 2 × CH2O),
3.22–3.10 (1 H, m, ArSeCH2), 3.01–2.72 (3 H, m, 2 × ArSeCH2)
2.40 (6 H, s, CH3), 1.99–1.28 (12 H, m, 6 × CH2) and 0.94–0.76
(4 H, m, 2 × CH2); dC(50.3 MHz, CDCl3) 143.2, 143.1, 138.0,
137.9, 132.5 (2 C), 132.4 (2 C), 129.5 (6 C), 128.9 (4 C), 127.0
(4 C), 126.8, 126.7, 100.0, 99.0, 70.2, 68.5, 63.1, 62.4, 53.4, 53.3,
33.0 (2 C), 30.4, 30.3, 25.1, 25.0, 23.7, 23.6, 21.4 (2 C), 19.8 and
19.3.
Methyl (S)-2-{[(4-methylphenyl)sulfonyl]amino}-4-(phenyl-
seleno)butanoate (4d). Compound 13 was prepared in 78% yield
by standard acylation procedure32 from commercially available
(S)-(−)-a-amino-c-butyrolactone hydrobromide 12. Ester 4d
was synthesized by cleavage of the corresponding lactone 13
with sodium phenyl selenolate in refluxing DMF22 followed
by treatment of the crude acid with an ethereal solution of
diazomethane. Purification by column chromatography on silica
gel using a mixture of Et2O–light petroleum (60 : 40) a◦s eluant
gave 4d (2.8 g, 83%) as a pale yellow solid, mp 66–67 C; [a]D26
4.1 (c 1.65 in CHCl3); (found: C, 50.5; H, 5.2; N, 3.0. Calc. for
C18H21NO4SSe: C, 50.7; H, 4.9; N, 3.3%); dH(200 MHz, CDCl3,
Me4Si) 7.76–7.67 (2 H, m, ArH), 7.48–7.36 (2 H, m, ArH),
7.34–7.21 (5 H, m, ArH), 5.31 (1 H, d, J 9.0, NH), 4.06 (1 H,
ddd, J 9.0, 8.3 and 4.8, CHN), 3.49 (3 H, s, OCH3), 3.01–2.73
(2 H, m, ArSeCH2), 2.42 (3 H, s, CH3) and 2.17–1.84 (2 H, m,
CH2); dC(50.3 MHz, CDCl3) 171.5, 143.6, 136.3, 132.7 (2 C),
129.5 (2 C), 129.0, 128.9 (2 C), 127.1 (2 C), 127.0, 55.3, 52.4,
33.5, 22.7 and 21.4; m/z (E/I) 427 (M+, 11%), 272 (29), 210
(13), 185 (14), 157 (33), 155 (60), 114 (73), 91 (100), 65 (15) and
56 (24).
The oxidation–cyclization reaction of 4e was effected as re-
ported for 4a–c and afforded, after purification by column
chromatography on silica gel (gradient: 80–100% Et2O in light
petroleum), the optically active azetidine alcohol (S)-6e (0.1 g,
62%).
3-Benzyldihydrofuran-2(3H)-one (16). To a round-bottom
flask equipped with
a dropping funnel, diisopropylamine
(0.57 mL, 4.40 mmol) in 30 mL of THF was added at −78 ◦C
and the solution was treated with the equivalent amount of n-
butyllithium (2.75 mL, 1.6 M in hexane, 4.40 mmol). To this
solution the c-butyrolactone 15 (0.31 mL, 4.0 mmol) was added
followed by addition of benzyl bromide (0.57 mL, 4.80 mmol) in
5 ml of THF after 20 minutes. Stirring was continued at −78 ◦C
for 1 h and the reaction was then quenched with saturated aq.
NH4Cl solution, extracted with Et2O (2 × 30 mL), dried over
sodium sulfate, filtered and evaporated. Purification by column
chromatography on silica gel (gradient: 50–70% Et2O in light
petroleum) gave the a-benzyl lactone 16 (0.5 g, 70%) as a pale
yellow oil; m/z (E/I): 176 (M+, 85%), 147 (100), 104 (44), 91 (99),
77 (12) and 65 (21).
The oxidation–cyclization reaction of 4d was effected as re-
ported above for 4a–c. After purification by column chromatog-
raphy on silica gel (CH2Cl2 as eluant), the azetidine ester (S)-6d
(0.1 g, 44%) was obtained.
N-[(1S)-1-(Hydroxymethyl)-3-(phenylseleno)propyl]-4-methyl-
benzenesulfonamide (14). To a solution of the ester 4d (1.30 g,
3.04 mmol) in THF (30 mL), lithium aluminium hydride (6.7 mL,
1.0 M in THF, 6.70 mmol) was added dropwise at 0 ◦C. After
2 h the reaction was quenched by addition of water (5 mL). The
mixture was partitioned between saturated aq. NH4Cl (30 mL)
and Et2O (40 mL), and the layers were separated. The aqueous
layer was extracted with Et2O (2 × 20 mL), and the combined
organic layers were washed with brine, dried over sodium sulfate,
filtered and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (gradient: 3–20% MeOH in
(2R)-2-Benzyl-4-(phenylseleno)butanoic acid (17)
The lithium enolate of 22 (generated with LDA in THF at −78 ◦C)
was protonated with a chiral proton source (R-pantolactone) as
reported in the literature26 to give (R)-16 in 92% yield; [a]2D2 −12.6
(c 2.42 in CHCl3); HPLC analysis (Chiracel OD-H column, 250 ×
4.6 mm, Daicel, 4% 2-propanol in hexane, flow rate 1 mL min−1,
UV detection at 220 nm) showed an er of 61 : 39 (tr: 27.1 min for
the minor enantiomer; tr: 28.5 min for the major enantiomer). The
c-lactone (R)-16 (0.64 g, 3.64 mmol) by treatment with sodium
phenyl selenolate in refluxing DMF22 for 5 h and after quenching
by careful addition of hydrochloric acid (20% in water, 20 mL)
◦
CH2Cl2) to give 14 (0.9 g, 73%) as a white solid, mp 92 C; [a]D27
−1.15 (c 1.50 in CHCl3); (found: C, 51.0; H, 5.5; N, 3.2. Calc. for
C17H21NO3SSe: C, 51.25; H, 5.3; N, 3.5%); mmax/cm−1 3318, 2935,
1435, 1322 and 1155; dH(200 MHz, CDCl3, Me4Si) 7.82–7.70 (2 H,
m, ArH), 7.40–7.27 (7 H, m, ArH), 5.39 (1 H, d, J 8.0, NH), 3.63–
3.32 (3 H, m, CHN and CH2OH), 2.85–2.53 (2 H, m, ArSeCH2)
2.48 (1 H, br s, OH) 2.40 (3 H, s, CH3) and 1.85–1.70 (2 H, m,
CH2); dC(50.3 MHz, CDCl3) 143.6, 137.5, 132.5 (2 C), 129.8 (2 C),
129.6, 129.0 (2 C), 127.0 (2 C), 126.9, 64.5, 55.2, 31.9, 23.5 and
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gave the corresponding acid 17. The mixture was extracted with
EtOAc (2 × 30 mL) and the combined organic layers were washed
with brine, dried over sodium sulfate, filtered and concentrated
in vacuo. The residue was purified by column chromatography on
silica gel using a mixture of Et2O–light petroleum (50 : 50) as
eluant to give the acid 17 (1.2 g, 75%) as a pale yellow oil (found:
C, 61.0; H 5.8. Calc. for C17H18O2Se: C 61.3; H 5.4%); mmax/cm−1
3026, 1704, 1437 and 1235; dH(200 MHz, CDCl3, Me4Si) 9.92 (1 H,
br s, COOH), 7.48–7.07 (10 H, m, ArH), 3.10–2.68 (5 H, m, CH2
and CH) and 2.19–1.75 (2 H, m, CH2); dC(50.3 MHz, CDCl3)
181.1, 138.3, 132.6, 129.4, 128.9 (3 C), 128.7 (2 C), 128.3 (2 C),
126.8, 126.4, 46.9, 37.5, 31.4 and 24.9.
8% 2-propanol in hexane, flow rate 1 mL min−1, UV detection
at 230 nm) showed an er of 55 : 45; tr: 30.6 min for the minor
enantiomer; tr: 41.1 min for the major enantiomer; dH(200 MHz,
CDCl3, Me4Si) 7.90–7.78 (1 H, m, ArH), 7.70–7.53 (3 H, m,
ArH), 7.28–7.04 (5 H, m, ArH), 4.60 (1 H, ddt, J 8.9, 4.7 and 8.1,
CHN), 3.90 (1 H, dt, J 8.5 and 8.4, CH2N), 3.81–3.69 (1 H, m,
CH2N), 3.11 (1 H, dd, J 13.6 and 4.7, ArCH2), 2.88 (1 H, dd, J
13.6 and 8.9, ArCH2) and 2.09–1.92 (2 H, m, CH2); dC(50.3 MHz,
CDCl3) 148.6, 136.0, 133.7, 131.7, 130.7, 130.4, 129.2 (2 C), 128.3
(2 C), 126.5, 124.0, 64.9, 48.4, 41.9 and 21.4; m/z (E/I): 176
(56, M − 156), 147 (80), 131 (17), 117 (16), 104 (30), 91 (100) and
65 (15%).
N-[(1R)-1-Benzyl-3-(phenylseleno)propyl]-2-nitrobenzenesulfo-
namide (4f). Acid 17 (0.92 g, 2.75 mmol) was reacted with oxalyl
chloride (0.40 mL, 4.12 mmol) at room temperature for 5 h. The
solution was evaporated under reduced pressure. The residue was
dissolved in dry CH2Cl2 (5 mL), the solvent was removed and the
residue immediately dissolved in dry CH2Cl2 (4 mL) and used for
the next reaction. Freshly distilled TMSN3 (1.42 mL, 3.30 mmol)
was added to this solution and the mixture was refluxed for 5 h
and then cooled to room temperature. The solvent was evaporated
under reduced pressure and the residue was dissolved in THF
(6 mL). To the stirred solution of the isocyanate, 1 N NaOH
(3 mL) was added dropwise. The mixture was heated at reflux for
4 h. After addition of Et2O (20 mL), the two phases were separated
and the aqueous layer was extracted with Et2O (2 × 10 mL). The
combined organic phases were dried (Na2SO4). Evaporation of the
solvent under reduced pressure afforded the crude amine 18 which
was acylated in the next step. The amine 18 (0.64 g, 2.1 mmol)
was dissolved in dry CH2Cl2 (20 mL) at 0 ◦C. To this solution
triethyl amine (0.36 mL, 2.6 mmol) and 2-nitrobenzenesulfonyl
chloride (0.58 g, 2.6 mmol) were added. The mixture was warmed
to room temperature and stirred for 5 h before being partitioned
between saturated aq. NH4Cl (30 mL) and CH2Cl2 (30 mL). The
two layers were separated, and the aqueous phase was extracted
with CH2Cl2 (2 × 10 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated in vacuo. The
residue was purified by column chromatography on silica gel using
a mixture of EtOAc–light petroleum (20 : 80) as eluant to give the c-
[N-(phenylseleno)alkyl]arylsulfonamide 4f (0.7 g, 55%), colourless
oil (found: C, 53.6; H; 4.8; N, 5.5. Calc. for C22H22N2O4SSe: C,
53.9; H, 4.5; N, 5.7%); [a]2D5 −2.3 (c 1.25 in CHCl3); dH(200 MHz,
CDCl3, Me4Si) 8.02–7.92 (1 H, m, ArH), 7.80–7.70 (1 H, m, ArH),
7.68–7.58 (2 H, m, ArH), 7.47–7.33 (2 H, m, ArH), 7.33–7.18 (3 H,
m, ArH), 7.13–6.82 (5 H, m, ArH), 5.41 (1 H, d, J 8.2, NH), 4.04–
3.83 (1 H, m, CHN), 3.09–2.65 (4 H, m, ArCH2 and ArSeCH2)
and 2.01–1.86 (2 H, m, CH2); dC(50.3 MHz, CDCl3) 136.6, 134.5,
133.0, 132.9, 132.8 (2 C), 130.2, 129.2, 129.1 (3 C), 129.0 (2 C),
128.2 (2 C), 126.9, 126.7, 125.3, 55.8, 41.6, 35.6 and 23.6.
(2S)-4-(Phenylseleno)butan-2-ol (20). To a stirred solution of
ethyl (S)-3-hydroxybutyrate 19 (1 mL, 7.65 mmol) and 3,4-
dihydro-2H-pyran (0.84 mL, 9.20 mmol) in Et2O (70 mL),
TsOH·H2O (190 mg, 1 mmol) was added in one portion at room
temperature. After 48 h the mixture was chilled to 0 ◦C and lithium
aluminium hydride (16.5 mL, 1.0 M in THF, 16.50 mmol) was
added dropwise. After 5 h the reaction was quenched by careful
addition of water (10 mL). The mixture was partitioned between
saturated aq. NH4Cl (30 mL) and Et2O (40 mL), and the two
layers were separated. The aqueous layer was extracted with Et2O
(2 × 40 mL), and the combined organic layers were washed
with brine, dried over sodium sulfate, filtered and concentrated
in vacuo. The crude product was dissolved in THF (50 mL).
Phenyl selenocyanate (1.09 mL, 8.96 mmol) and tributylphosphine
(2.2 mL, 8.96 mmol) were added at room temperature. The
resulting mixture was stirred and the progress of the reaction was
monitored by TLC. When the alcohol was completely consumed
(8 h) the reaction mixture was concentrated in vacuo. The residue
was then diluted with MeOH (50 mL) and p-toluenesulfonic acid
monohydrate (190 mg, 1 mmol) was added to the solution, which
was then stirred at room temperature for 18 h. The mixture
was concentrated under reduced pressure. Purification by column
chromatography on silica gel (gradient: 40–60% Et2O in light
petroleum) gave the optically pure c-hydroxyselenide 2034 (1.2 g,
71%) as a colourless oil; [a]2D2 40.6 (c 2.19 in CHCl3).
N-[(1R)-1-Methyl-3-(phenylseleno)propyl]-2-nitrobenzenesulfo-
namide (4g). To a stirred solution of the alcohol 20 (1.80 g,
7.83 mmol) and phthalimide (1.61, 10.90 mmol) in THF (30 mL),
triphenylphosphine (2.80 g, 10.9 mmol) was added. DIAD
(1.96 mL, 10.10 mmol) was subsequently added dropwise at
0 ◦C. After 7 h the reaction mixture was concentrated in vacuo, the
residue dissolved in a mixture of Et2O–light petroleum (50 : 50) and
passed through a silica gel pad. The filtrate was concentrated and
the crude phthalimide derivative was employed in the following
step. The phthalimide was dissolved in ethanol (100 mL) and
immediately treated with hydrazine hydrate (0.5 mL, 10.14 mmol).
After stirring for 2 h at 110 ◦C, the reaction mixture was allowed
to slowly reach room temperature and concentrated. After the
addition of CH2Cl2 (50 mL) the suspension was filtered. The
filtrate was dried over sodium sulfate and evaporated. The crude
amine was dissolved in dry CH2Cl2 (80 mL) at 0 ◦C. To this solution
triethyl amine (1.41 mL, 10.91 mmol) and 2-nitrobenzenesulfonyl
chloride (2.408 g, 10.91 mmol) were added. The mixture was
warmed to room temperature and stirred for 15 h before being
partitioned between aq. HCl (7%, 30 mL) and CH2Cl2 (50 mL).
The layers were separated, and the aqueous layer was extracted
(2R)-2-Benzyl-1-[(2-nitrophenyl)sulfonyl]azetidine (6f). The
oxidation–cyclization reaction of 4f was carried out as reported
above for compound 4d and gave, after purification by column
chromatography on silica gel using a mixture of Et2O–light
petroleum (50 : 50) as eluant, the optically active azetidine (R)-6f
(0.2 g, 80%) as a white solid, mp 100 ◦C (found: C, 57.6; H, 5.0; N,
8.3. Calc. for C16H16N2O4S: C, 57.8; H, 4.85; N, 8.4%); [a]2D2 −34.2
(c 2.46 in CHCl3); mmax/cm−1 2893, 1717, 1539, 1369 and 1162;
HPLC analysis (Chiracel OD-H column, 250 × 4.6 mm, Daicel,
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with CH2Cl2 (2 × 30 mL). The combined organic layers were
dried over sodium sulfate, filtered and concentrated in vacuo. The
residue was purified by column chromatography on silica gel using
CH2Cl2 as eluant and 4g (2.3 g, 71%) was obtained as a pale
(1 H, m, ArH), 7.90–7.78 (1 H, m, ArH), 7.76–7.64 (2 H, m, ArH),
7.47–7.36 (2 H, m, ArH), 7.32–7.20 (3 H, m, ArH), 5.17 (1 H, d,
J 8.6, NH), 3.75–3.55 (1 H, m, CHN), 2.99–2.71 (2 H, m, CH2),
1.90–1.72 (2 H, m, CH2), 1.50–1.06 (4 H, m, CH2) and 0.79 (3 H,
t, J 7.1, CH3); dC(50.3 MHz, CDCl3) 147.3, 134.5, 133.4, 132.7,
132.2 (2 C), 130.3, 129.6 (2 C), 128.9, 126.7, 125.0, 54.8, 37.0, 35.4,
32.3, 18.3 and 13.5; m/z (E/I): 412 (71, M − CH3CH2), 256 (54%),
227 (86), 210 (78), 173 (10), 156 (90), 108 (36), 92 (100), 72 (30)
and 56 (19).
◦
yellow solid, mp 87–89 C (found: C, 46.7; H, 4.6; N, 6.4. Calc.
for C16H18N2O4SSe: C, 46.5; H, 4.4; N 6.8%); [a]2D2 −45.3 (c 1.83 in
CHCl3); dH(200 MHz, CDCl3, Me4Si) 8.18–8.10 (1 H, m, ArH),
7.86–7.79 (1 H, m, ArH), 7.75–7.65 (2 H, m, ArH), 7.45–7.35
(2 H, m, ArH), 7.31–7.19 (3 H, m, ArH), 5.18 (1 H, d, J 7.3, NH),
3.74–3.63 (1 H, m, CHN), 2.92 (1 H, ddd, J 12.4, 8.2 and 6.0,
ArSeCH2), 2.82 (1 H, ddd, J 12.4, 8.3 and 7.2, ArSeCH2), 1.90–
1.72 (2 H, m, CH2) and 1.09 (3 H, t, J 5.2, CH3); dC(50.3 MHz,
CDCl3) 147.6, 134.5, 133.4, 132.9. 132.5 (2 C), 130.6, 129.5, 129.0
(2 C), 126.9, 125.2, 50.9, 37.4, 23.1 and 21.5.
1-[(2-Nitrophenyl)sulfonyl]-2-propylazetidine (6h). The oxi-
dation–cyclization reaction of 4h was effected as reported above for
4g and gave, after purification by column chromatography on silica
gel using a mixture of Et2O–light petroleum (40 : 60) as eluant, the
optically active azetidine 6h (0.1 g, 70%) as a colourless oil (found:
C, 50.3; H, 5.9; N, 9.7. Calc. for C12H16N2O4S: C, 50.7; H, 5.7; N,
9.85%); [a]2D1 10.1 (c 0.88 in CHCl3); mmax/cm−1 2961, 1723, 1546,
1341 and 1166; HPLC analysis (Chiracel OD-H column, 250 ×
4.6 mm, Daicel, 1% 2-propanol in hexane, flow rate 1 mL min−1,
UV detection at 230 nm) showed an er of 56 : 44; tr: 66.8 min
for the minor enantiomer; tr: 71.1 min for the major enantiomer;
dH(200 MHz, CDCl3, Me4Si) 8.08–7.91 (1 H, m, ArH), 7.78–7.55
(3 H, m, ArH), 4.42 (1 H, ddt, J 8.2, 4.6 and 4.4, CHN), 3.99
(1 H, dt, J 8.8 and 8.4, CH2N), 3.81 (1 H, ddd, J 8.8, 8.1 and 4.1,
CH2N), 2.25–1.50 (4 H, m, 2 × CH2), 1.38–1.08 (2 H, m, CH2)
and 0.89 (3 H, t, J 7.3, CH3); dC(50.3 MHz, CDCl3) 148.5, 133.8,
131.7, 130.7, 130.6, 124.0, 64.9, 48.5, 37.8, 21.8, 17.3 and 13.7;
m/z (E/I): 241 (81, M − CH3CH2CH2), 186 (100%), 98 (18) and
77 (13).
(2R)-2-Methyl-1-[(2-nitrophenyl)sulfonyl]azetidine (6g). The
oxidation–cyclization reaction of 4g was effected as reported above
for 4d and gave, after purification by column chromatography on
silica gel using a mixture of Et2O–light petroleum (40 : 60) as
eluant, the enantiomerically pure azetidine 6g (0.2 g, 59%) as a
white solid, mp 42 ◦C (found: C, 46.5; H, 5.0; N, 10.6. Calc.
for C10H12N2O4S: C, 46.9; H, 4.7; N, 10.9%); [a]2D1 −115.2 (c 1.09
in CHCl3); mmax/cm−1 3090, 2980, 1541, 1333 and 1158; HPLC
analysis (R,R-Whelk O1 column, 250 × 4.6 mm, Merck KGaA,
4% 2-propanol in hexane, flow rate 2 mL min−1, UV detection at
250 nm) showed an er > 99 : 1; tr: 18.7 min; dH(200 MHz, CDCl3,
Me4Si) 8.05–7.92 (1 H, m, ArH), 7.77–7.61 (3 H, m, ArH), 4.53
(1 H, tq, J 8.2 and 6.3, CHN), 3.98 (1 H, dt, J 9.1 and 7.9, CH2N),
3.85 (1 H, ddd, J 9.1, 7.9 and 3.8, CH2N), 2.22 (1 H, dddd, J 10.8,
8.2, 7.9 and 3.8, CH2), 1.96 (1 H, ddt, J 10.8, 8.2 and 7.9, CH2),
and 1.42 (3 H, d, J 6.3, CH3); dC(50.3 MHz, CDCl3) 148.7, 133.7,
131.6, 131.1, 130.7, 124.0, 61.4, 48.4, 23.7 and 22.1; m/z (E/I):
241 (9, M − CH3), 239 (17%), 186 (100), 107 (6), 92 (6) and
56 (19).
Acknowledgements
Financial support from MIUR, National Projects PRIN2003,
PRIN2005 and FIRB2001, Consorzio CINMPIS, Bari and Uni-
versity of Perugia is gratefully acknowledged.
1-(Phenylseleno)hexan-3-ol (23)
Notes and references
1-(Phenylseleno)hexan-3-one 22 was prepared as reported in the
literature.30 The asymmetric reduction of 22 was carried out under
the conditions employed by Itsuno and Ito.31 The crude alcohol
was purified by column chromatography on silica gel using a
mixture of Et2O–light petroleum (30 : 70) as eluant and the
optically active b-hydroxyselenide 23 (0.4 g, 87%) was obtained
as a colourless oil (found: C, 55.9; H, 7.3. Calc. for C12H18OSe: C,
56.0; H, 7.05%); [a]2D1 −1.8 (c 1.24 in CHCl3); dH(200 MHz, CDCl3,
Me4Si) 7.58–7.40 (2 H, m, ArH), 7.35–7.13 (3 H, m, ArH), 3.82–
3.60 (1 H, m, CHO), 3.12–2.89 (2 H, m, CH2), 1.90–1.72 (2 H,
m, CH2), 1.65 (1 H, br s, OH), 1.55–1.16 (4 H, m, CH2) and 0.91
(3 H, t, J 6.9, CH3); dC(50.3 MHz, CDCl3) 132.2 (2 C), 130.1,
128.9 (2 C), 126.5, 70.9, 39.3, 37.2, 23.9, 18.6 and 13.9; m/z (E/I):
258 (M+, 100%), 185 (21), 171 (15), 157 (54), 100 (24), 72 (74) and
55 (54).
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©