Diastereospecific synthesis of enantiomerically pure polysubstituted azetidines from 1,3-amino alcohols with three chiral centers

Full text of DOI:10.1021/jo960494b

J . Org. Chem. 1996, 61, 5659-5662
5659
Sch em e 1
Dia ster eosp ecific Syn th esis of
En a n tiom er ica lly P u r e P olysu bstitu ted
Azetid in es fr om 1,3-Am in o Alcoh ols w ith
Th r ee Ch ir a l Cen ter s
J ose´ Barluenga,* Fe´lix Ferna´ndez-Mar´ı,
Argimiro L. Viado, Enrique Aguilar, and
Bernardo Olano
Instituto Universitario de Quı´mica Organometa´lica
“Enrique Moles”, Unidad Asociada al C.S.I.C., Universidad
de Oviedo, C/ J ulia´n Claverı´a, 8, 33071 Oviedo, Spain
Received March 13, 1996
In tr od u ction
Azetidines are an interesting class of four-membered
heterocyclic compounds with remarkable biological activ-
ity,1 which makes them important synthetic targets.2
Accordingly, development of effective general methods for
the synthesis of azetidines, especially in enantiomerically
pure form, is of significant value. In this context, the
preparation of optically active azetidines has mainly
relied on classical resolutions.3 However, some direct
entries to enantiomerically pure azetidines have been
described by reaction of 1,3-dihalo compounds or related
derivatives with primary amines,4 cyclization of 1,3-
amino alcohols,5 or reduction of azetidinones.6
Ta ble 1. 1,3-Am in o Alcoh ols 5 P r ep a r ed fr om â-Am in o
Keton es 4
4
R1
R3
5
yield (%)a mp (°C)
(()-anti-4a Ph
p-tolyl (()-syn,anti-5a
88b
93
106-7b
99-100
62-4
anti-4b
anti-4c
anti-4d
anti-4b
syn-4b
syn-4d
syn-4b
Ph
Ph
syn,anti-5b
syn,anti-5c
p-anisyl Ph
p-anisyl 2-furyl syn,anti-5d
Ph
Ph
p-anisyl 2-furyl syn,syn-5d
Ph Ph anti,syn-5b
91
91c
35
85-6c
Ph
Ph
anti,anti-5b
syn,syn-5b
91-3
72
100-3
syrupc
101-2 dec
87c
46
a
b
Isolated yield. Reference 7a. c Reference 9.
On the other hand, 1,3-amino alcohols with three chiral
centers have been in the focus of our efforts in the last
decade. Thus, we have described a diastereoselective
synthesis of these compounds by reduction of 4-amino-
1-azadienes and related systems.7 A diastereo- and
enantioselective preparation of 1,3-amino alcohols 5 was
carried out from 4-amino-1-azadienes 1 via the corre-
sponding dihydro- and tetrahydropyrimidines 2 and 3
using an aldehyde as chiral auxiliary (Scheme 1); â-amino
ketones 4 obtained from tetrahydropyrimidines 3 by
hydrolysis were submitted to reduction with complex
metal hydrides leading to 5.8 More recently, we reported
the synthesis of all isomers of the N-terminal amino acid
of the antibiotics nikkomycin B and Bx following the
synthetic plan outlined here.9
As part of our continuing interest in the chemistry of
1,3-amino alcohols we now report the synthesis of opti-
cally active 2,3,4-substituted azetidines from 1,3-amino
alcohols containing three chiral centers.
Resu lts a n d Discu ssion
P r ep a r a tion of 1,3-Am in o Alcoh ols 5 fr om â-Am i-
n o Keton es 4. 1,3-Amino alcohols 5 (R2 ) Me) were
synthesized by diastereoselective reduction of enantio-
merically pure â-amino ketones 4 (R2 ) Me) which can
be obtained as indicated in Scheme 1 by using (R)-O-
benzyllactic aldehyde as chiral auxiliary. Reduction of
anti-4 and syn-4 with Red-Al and DIBALH/ZnCl2 led to
syn,anti-5 and syn,syn-5, respectively, as the only dias-
tereoisomers (Scheme 2) according to reduction of the
carbonyl group through a rigid cyclic model.7a,d On the
other hand, reduction of anti-4 and syn-4 with N- and
K-selectride, respectively, took place mainly through an
open chain model7a to give anti,anti-5 and anti,syn-5 as
major components mixed with their respective epimers.
Compounds 5 used in the synthesis of azetidines were
obtained in diastereomerically pure form in moderate to
good yields following the procedure previously developed7d,9
(Table 1).
(1) (a) Testa, E.; Wittigens, A.; Maffii, G.; Bianchi, G. in Research
Progress in Organic, Biological and Medicinal Chemistry; Gallo, U.,
Santamaria, L., Eds.; North-Holland Publishing Co.; Amsterdam, 1964;
Vol 1, p 477. (b) Okutani, T.; Kaneko, T.; Masuda, K. Chem. Pharm.
Bull. 1974, 22, 1490. (c) Kobayashi, J .; Cheng, J .; Ishibashi, M.;
Wa¨lchli, M. P.; Yamamura, S.; Ohizumi, Y. J . Chem. Soc., Perkin
Trans. 1 1991, 1135. (d) Frigola, J .; Torrens, A.; Castrillo, J . A.; Mas,
J .; Van˜o´, D.; Berrocal, J . M.; Calvet, C.; Salgado, L.; Redondo, J .;
Garc´ıa-Granda, S.; Valent´ı, E.; Quintana, J . R. J . Med. Chem. 1994,
37, 4195 and references cited therein.
(2) For reviews see: (a) Cromwell, N. H.; Phillips, B. Chem. Rev.
1979, 79, 331. (b) Moore, J . A.; Ayers, R. S. In Small Ring Heterocycles;
Hassner, A., Ed.; Wiley; New York, 1983; Part 2, p 1. (c) Davies, D. E.;
Storr, R. C. In Comprehensive Heterocyclic Chemistry; Lwowski, W.,
Ed.; Pergamon; Oxford, 1984; Vol 7, p 237.
(3) (a) Rama Rao, A. V.; Gurjar, M. K.; Kaiwar, V. Tetrahedron:
Asymmetry 1992, 3, 859. (b) Kozikowski, A. P.; Tu¨ckmantel, W.; Liao,
Y.; Manev, H.; Ikonomovic, S.; Wroblewski, J . T. J . Med. Chem. 1993,
36, 2706. (c) Guanti, G.; Riva, R. Tetrahedron: Asymmetry 1995, 6,
2921.
(4) (a) Dure´ault, A.; Portal, M.; Carreaux, F.; Depezay, J . C.
Tetrahedron 1993, 49, 4201. (b) Hoshino, J .; Hiraoka, J .; Hata, Y.;
Sawada, S.; Yamamoto, Y. J . Chem. Soc., Perkin Trans. 1 1995, 693.
(5) (a) Poch, M.; Verdaguer, X.; Moyano, A.; Perica`s, M. A.; Riera,
A. Tetrahedron Lett. 1991, 32, 6935. (b) Hiraki, T.; Yamagiwa, Y.;
Kamikawa, T. Tetrahedron Lett. 1995, 36, 4841.
Syn th esis of 2,3,4-Su bstitu ted Azetid in es 6. Al-
though preparation of azetidines from 1,3-amino alcohols
is well documented, as indicated in the introduction,
synthesis of 2,3,4-substituted examples has been gener-
(6) (a) Yamashita, M.; Ojima, I. J . Am. Chem. Soc. 1983, 105, 6339.
(b) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K. J . Org. Chem. 1991,
56, 5263. (c) Shustov, G. V.; Rauk, A. J . Am. Chem. Soc. 1995, 117,
928.
(7) (a) Barluenga, J .; Olano, B.; Fustero, S. J . Org. Chem. 1985, 50,
4052. (b) Barluenga, J .; J oglar, J .; Gonza´lez, F. J .; Fustero, S.
Tetrahedron Lett. 1989, 30, 2001. (c) Barluenga, J .; Aguilar, E.; Olano,
B.; Fustero, S. Synlett 1990, 463. (d) Barluenga, J .; Aguilar, E.; Fustero,
S.; Olano, B.; Viado, A. L. J . Org. Chem. 1992, 57, 1219.
(8) Barluenga, J .; Olano, B.; Fustero, S.; Foces-Foces, M. C.; Cano,
F. H. J . Chem. Soc., Chem. Commun. 1988, 410.
(9) Barluenga, J .; Viado, A. L.; Aguilar, E.; Fustero, S.; Olano, B. J .
Org. Chem. 1993, 58, 5972.
S0022-3263(96)00494-X CCC: $12.00 © 1996 American Chemical Society

5660 J . Org. Chem., Vol. 61, No. 16, 1996
Notes
a
Sch em e 2
Ta ble 2. Azetid in es 6 a n d 7 Obta in ed fr om 1,3-Am in o Alcoh ols 5
entry
5
6
yield (%)a
mp (°C)b
7
yield (%)c
1
2
3
4
5
6
7
8
9
(()-syn,anti-5a
syn,anti-5b
syn,anti-5c
syn,anti-5d
anti,anti-5b
anti,anti-5b
syn,syn-5b
syn,syn-5d
anti,syn-5b
anti,syn-5b
(()-trans,trans-6a
trans,trans-6b
trans,trans-6c
trans,trans-6d
trans,trans-6b
cis,trans-6b
trans,cis-6b
trans,cis-6d
trans,cis-6b
cis,cis-6b
53
syrup
137-9
92-4
syrup
(()-trans,trans-7a
trans,trans-7b
trans,trans-7c
65
56
72
59 (54)d (47)e
55
33
41
39f
59
140-2
syrup
syrup
cis,trans-7b
76
10
35
10
13g (9)h
a
b
d
Isolated yield under the conditions indicated in Scheme 2. Recrystallized from hexane/CHCl3 (3:1). c Isolated yield from 6. Reaction
carried out in refluxing benzene. e Reaction carried out in refluxing THF. f A cis,trans-6b/trans,trans-6b mixture (ratio 96/4, 1H NMR
300 MHz) was observed in the crude product. trans,cis-6b was also isolated in 29% yield. Reaction performed in DMF at rt; trans,cis-
6b also isolated in 42% yield.
g
h
ally achieved by several methods with only low yields.5b,10
In this context, conversion of amino alcohols 5 to the
corresponding azetidines would constitute the systematic
synthesis of all possible diastereomers of the related
2,3,4-substituted azetidines. Transformation of 5 into
azetidines 6 was carried out with an excess of MsCl/Et3N
in different solvents overnight. When the reaction was
performed on amino alcohols with syn relative stereo-
chemistry at the carbinolic center, syn,anti-5 or syn,syn-
5, azetidines 6 with trans relative sterochemistry at this
carbon were obtained as the only diastereoisomers inde-
pendent of the solvent used in the reaction. The best
yields were obtained with CH2Cl2 (Table 2, entries 1-4,
7, and 8). However, when the reaction was carried out
with anti,anti-5b, trans,trans-6b was obtained as the
only diastereoisomer in CH2Cl2 (Table 2, entry 5), whereas
cis,trans-6b was obtained as the major diastereoisomer
mixed with its epimer in hexane/toluene (10:1) at room
temperature (Table 2, entry 6). On the other hand, no
azetidines were detected in CH2Cl2 starting from anti,-
syn-5b; by contrast, trans,cis-6b (equal to cis,trans-6b)
was formed as the only product in refluxing MeCN and
as the main productstogether with cis,cis-6bsin MeCN
at room temperature (Table 2, entries 9 and 10).
These results can be understood by taking into account
that although cyclization of 1,3-amino alcohols to aze-
tidines is basically a SN2 process, a SN1 mechanism does
usually compete and becomes even more favorable when
the leaving group is on a secondary carbon atom.11
Moreover, in our case the carbon bearing the leaving
group is benzylic; thus, whereas ring formation from syn-
3-aminopropanols takes place with inversion of configu-
(10) (a) Stevens, M. F.; Cromwell, N. H. J . Heterocyc. Chem. 1971,
8, 253. (b) Kurteva, V. B.; Lyapova, M. J .; Pojarlieff, I. G. J . Chem.
Res. (S) 1993, 270.
(11) For mechanistic considerations, see: Vaughan, W. R.; Klonows-
ki, R. S.; McElhinney, R. S.; Millward, B. B. J . Org. Chem. 1961, 26,
138.

Notes
J . Org. Chem., Vol. 61, No. 16, 1996 5661
Exp er im en ta l Section
Gen er a l. Solvents were dried according to established
protocols by distillation under nitrogen from an appropriate
drying agent. Thus, THF and benzene were distilled from
sodium/benzophenone ketyl. Dichloromethane and acetonitrile
were distilled from calcium hydride. DMF was distilled from
calcium hydride under reduced pressure (<20 mmHg), and
triethylamine was refluxed over KOH, distilled, and stored over
3 Å molecular sieves. Mesyl chloride was distilled from P2O5.
Solvents used in extractions were distilled prior to use.
Compounds were visualized on analytical thin-layer chro-
matograms (TLC) by UV light (254 nm) or by using ninhydrin
or potasium permanganate staining solutions. Silica gel (60 Å)
for flash chromatography was purchased from Scharlau or Merck
(200-450 mesh). GC-MS and HRMS were measured at 70 eV.
Reactions requiring an inert atmosphere were conducted
under dry nitrogen, and the glassware was oven dried (120 °C),
evacuated, and purged with nitrogen. Temperatures are re-
ported as bath temperatures. Melting points are reported
uncorrected. Fourier transform infrared (IR) spectra were
recorded on films. 1H NMR spectra were recorded with a 200
or a 300 MHz instrument, with tetramethylsilane as the internal
standard; 13C NMR spectra and DEPT experiments were deter-
mined at 50 or 75 MHz.
F igu r e 1.
ration to give trans-azetidines, the anti epimers, anti,-
anti-5b and anti,syn-5b, strongly tend to give also trans-
azetidines in a presumably SN1 process12 which occurs
with retention of configuration, leading through the most
accessible transition state to the most stable diastereoi-
somer. In this regard, formation of cis,trans-6b from
anti,anti-5b is favored by the use of a less polar solvent
and is presumably the result of a SN2 process,13 whereas
cis,cis-6b seems to be the most inaccessible azetidine due
perhaps to its hindered structure. Taking this into
account, it is not surprising that yields of azetidines 6
listed on Table 2 are low to moderate. Thus, although it
is quite common to find yields g70% in the synthesis of
azetidines from 1,3-amino alcohols with a primary carbin-
olic carbon,5a,14 rather lower yields are often obtained
from amino alcohols containing secondary carbinolic
carbons.5b,10b
Compounds (()-anti-4a ,16 anti-4d ,9 syn-4d ,9 (()-syn,anti-5a ,7a
syn,anti-5d ,9 and syn,syn-5d 9 have been previously reported and
were prepared as described. All other reagents were com-
mercially available and were used without any further purifica-
tion.
P r ep a r a tion of Azetid in es 6. Gen er a l P r oced u r e.
A
solution of amino alcohol 5 (2 mmol) in 150 mL of the corre-
sponding dry solvent (See Table 2, Scheme 2) was cooled to 0
°C, and Et3N (2.25 mL, 16 mmol) and MsCl (1.25 mL, 16 mmol)
were added dropwise via syringe. The resulting solution was
stirred overnight at the temperatures reported in Table 2 and
Scheme 2. The mixture was then cooled to 0 °C and treated
with 3 N NaOH (30 mL). The organic layer was extracted with
CH2Cl2 (2 × 25 mL), washed with saturated brine (25 mL), dried
over Na2SO4, and filtered. Solvents were removed under
reduced pressure, and the crude residue was chromatographed
on SiO2. Isolated yields of N-mesylazetidines 6 are reported in
Table 2.
The configurational assignment of azetidines 6 was
made from 1H NMR data on the basis of the coupling
constants J trans
and J cis
of the heterocycle which
H/H
H/H
are in the range of 5.8-7.9 and 8.4-8.9 Hz, respectively
(see Experimental Section), as expected for the azetidine
ring.15 The relative configuration was further confirmed
by NOE experiments as shown in Figure 1 for the
structures of trans,trans-6b and trans,cis-6d .
Azetidines 6, obtained as N-mesylated derivatives,
could be deprotected by reaction with Red-Al (Scheme
2). The reaction was carried out with trans,trans-6a -c
and cis,trans-6b to give the corresponding N-unsubsti-
tuted azetidines 7 in yields of 56-76% (Table 2, entries
1-3 and 6).
In conclusion, 1,3-amino alcohols 5, obtained through
diastereoselective reduction of â-amino ketones 4, were
cyclized to polysubstituted N-mesylazetidines 6 in low
to moderate yields. The synthesis allows one to obtain
all possible diastereoisomers of enantiomerically pure
azetidines 6 with three chiral centers in a diastereospe-
cific manner. Work is in progress in order to improve
the yields in the preparation of azetidines 6 and to study
the synthetic applications of N-unprotected azetidines 7
mainly as chiral auxiliaries.
(2R*,3S*,4S*)-1-Mesyl-3-m eth yl-2-p h en yl-4-(p-tolyl)a ze-
tid in e (tr a n s,tr a n s-6a ): colorless syrup; Rf ) 0.15 (Hex/AcOEt
1
5/1); H NMR (CDCl3, 300 MHz) δ 7.55-7.21 (9 H, m), 4.77 (1
H, d, J ) 7.7 Hz), 4.75 (1 H, d, J ) 7.7 Hz), 2.65 (3 H, s), 2.43
(1 H, ddq, J ) 6.7, 7.7, and 7.7 Hz), 2.37 (3 H, s), 1.28 (3 H, d,
J ) 6.7 Hz); 13C NMR (CDCl3, TMS, 75 MHz) δ 139.9 (C), 138.2
(C), 136.7 (C), 129.4 (CH), 128.7 (CH), 128.3 (CH), 126.7 (CH),
126.6 (CH), 68.1 (CH), 68.0 (CH), 45.1 (CH), 40.9 (CH3), 21.1
(CH3), 16.2 (CH3). Anal. Calcd for C18H21NO2S: C, 68.54; H,
6.71; N, 4.44. Found: C, 68.73; H, 6.68; N, 4.40.
(2R,3r ,4S)-1-Mesyl-3-m eth yl-2,4-diph en ylazetidin e (tr a n s,-
1
tr a n s-6b): IR ν (cm-1) 1454, 1322; H NMR (CDCl3, 200 MHz)
δ 7.59-7.32 (10 H, m), 4.83 (2 H, d, J ) 7.6 Hz), 2.69 (3 H, s),
2.47 (1 H, tq, J ) 6.7 and 7.6 Hz), 1.32 (3 H, d, J ) 6.7 Hz); 13
C
NMR (CDCl3, 75 MHz) δ 139.7 (C), 128.8 (CH), 128.3 (CH), 126.6
(CH), 68.1 (CH), 45.0 (CH), 40.8 (CH3), 16.3 (CH3); MS (m/ z)
301 (M+), 222, 184, 118; HRMS calcd for C17H19NO2S 301.1137,
found 301.1136
(2R,3R,4S)-2-(p-An isyl)-1-m esyl-3-m eth yl-4-p h en yla zeti-
d in e (tr a n s,tr a n s-6c): IR ν (cm-1) 1514, 1321; 1H NMR (CDCl3,
300 MHz) δ 7.56-7.33 (7 H, m), 6.96 (2 H, d, J ) 8.5 Hz), 4.77
(1 H, d, J ) 7.9 Hz), 4.73 (1 H, d, J ) 8.0 Hz), 3.84 (3 H, s), 2.65
(3 H, s), 2.46 (1 H, ddq, J ) 6.7, 7.9, and 8.0 Hz), 1.28 (3 H, d,
J ) 6.7 Hz); 13C NMR (CDCl3, 75 MHz) δ 159.6 (C), 139.9 (C),
131.2 (C), 128.7 (CH), 128.2 (CH), 126.5 (CH), 114.1 (CH), 67.9
(CH), 67.8 (CH), 55.2 (CH3), 45.1 (CH), 40.9 (CH3), 16.1 (CH3);
MS (m/ z) 331(M+), 214, 148, 118; HRMS calcd for C18H21NO3S
(12) This is in accordance with the observation of elimination and
fragmentation products in the reactions toward azetidines 6 described
in Scheme 2, which compete with ring closure especially in anti,anti-
5b and anti,syn-5b. The p-anisyl group in 5d favors SN1 processes even
more and increases rupture and elimination processes so much that
only 10% of trans,cis-6d or 33% of trans,trans-6d are obtained.
(13) The inversion of configuration detected in the cyclization of an
anti-amino alcohol is remarkable, despite formation of a hindered cis-
azetidine, which has also been observed in ref 5b. In our case, the
presence of an aryl group in the hydroxylic carbon would explain the
formation of a little amount of the trans-azetidine even in a very little
polar solvent (see Table 2, entry 6 and footnote f).
331.1242, found 331.1246. [R]28 ) - 3.9 (c 1.05, CHCl3).
D
(2R,3S,4S)-2-(p-An isyl)-4-(2-fu r yl)-1-m esyl-3-m eth yla ze-
tid in e (tr a n s,tr a n s-6d ): Colorless syrup; Rf ) 0.20 (Hex/AcOEt,
5/1); IR ν (cm-1) 1514, 1323; 1H NMR (CDCl3, 200 MHz) δ 7.49
(1 H, m), 7.50-6.94 (4 H, AB q, J ) 8.8 Hz), 6.45 (1 H, m), 6.40
(14) (a) Axenrod, T.; Watnick, C.; Yazdekhasti, H.; Dave, P. R.
Tetrahedron Lett. 1993, 34, 6677. (b) Huszthy, P.; Bradshaw, J . S.;
Krakowiak, K. E.; Wang, T.; Dalley, N. K. J . Heterocyc. Chem. 1993,
30, 1197.
(15) Batterham, T. J . NMR Spectra of Simple Heterocycles; Wiley;
New York, 1973; p 144.
(16) Barluenga, J .; Olano, B.; Fustero, S. J . Org. Chem. 1983, 48,
2255.

5662 J . Org. Chem., Vol. 61, No. 16, 1996
Notes
(1 H, m), 4.78 (1 H, d, J ) 7.8 Hz), 4.65 (1 H, d, J ) 7.6 Hz),
3.83 (3 H, s), 2.83 (1 H, ddq, J ) 6.8, 7.6, and 7.8 Hz), 2.61 (3 H,
s), 1.25 (3 H, d, J ) 6.8 Hz); 13C NMR (CDCl3,75 MHz) δ 159.7
(C), 152.1 (C), 143.2 (CH), 132.0 (C), 128.4 (CH), 114.0 (CH),
110.5 (CH), 109.3 (CH), 67.7 (CH), 60.1 (CH), 55.2 (CH3), 41.2
(CH), 41.1 (CH3), 16.2 (CH3); MS (m/ z) 321 (M+), 214, 148, 108.
d, J ) 6.6 Hz); 13C NMR (CDCl3, 75 MHz) δ 144.4 (C),141.3 (C),
136.6 (C), 128,9 (CH), 128.2 (CH), 127.0 (CH), 126.3 (CH), 64.7
(CH), 64.6 (CH), 50.1 (CH), 21.1 (CH3), 16.9 (CH3). Anal. Calcd
for C17H19N: C, 86.03; H, 8.07; N, 5.90. Found: C, 86.21; H,
8.00; N, 5.82.
( 2 R , 3 r , 4 S ) - 3 - M e t h y l - 2 , 4 - d i p h e n y l a z e t i d i n e
(tr a n s,tr a n s-7b): Colorless oil; Rf ) 0.41 (Hex/AcOEt/Et3N 100/
1/1); 1H NMR (CDCl3, 200 MHz) δ 7.63-7.28 (10 H, m), 4.46 (2
H, d, J ) 7.8 Hz), 2.54 (1 H, br s), 2.38 (1 H, tq, J ) 6.7 and 7.8
Hz), 1.33 (3 H, d, J ) 6.7 Hz); 13C NMR (CDCl3, 50 MHz) δ 144.4
(C), 128,2 (CH), 126.9 (CH), 126.3 (CH), 64.7 (CH), 50.1 (CH),
16.9 (CH3). Anal. Calcd for C16H17N: C, 86.06; H, 7.67; N, 6.27.
Found: C, 85.85; H, 7.70; N, 6.26.
HRMS calcd for C16H19NO4S 321.1035; found: 321.1035; [R]22
D
) + 5.0 (c 1.08, CHCl3).
(2S,4S)-1-Mesyl-3-m et h yl-2,4-d ip h en yla zet id in e (cis,-
1
tr a n s-6b): IR ν (cm-1) 1454, 1333; H NMR (CDCl3, 300 MHz)
δ 7.63-7.30 (10 H, m), 5.63 (1 H, d, J ) 8.7 Hz), 5.03 (1 H, d, J
) 5.8 Hz), 3.17 (1 H, ddq, J ) 5.8, 7.2, and 8.7 Hz), 2.43 (3 H, s),
0.85 (3 H, d, J ) 7.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 138.1
(C), 136.8 (C), 128.9 (CH), 128.8 (CH), 128.2 (CH), 127.9 (CH),
127.4 (CH), 73.2 (CH), 69.1 (CH), 41.3 (CH3), 38.9 (CH), 14.1
(CH3); MS (m/ z) 222 (M+ - 79), 149, 118, 44. Anal. Calcd for
(2R,3R,4S)-2-(p-An isyl)-3-m eth yl-4-ph en ylazetidin e (tr a n -
s,tr a n s-7c): colorless oil; Rf ) 0.35 (Hex/AcOEt/Et3N 20/1/1);
IR ν (cm-1) 3329, 1512, 1246. 1H NMR (CDCl3, 200 MHz) δ
7.59-7.28 (7 H, m), 6.95 (2 H, d, J ) 8.6 Hz), 4.41 (1 H, d, J )
7.3 Hz), 4.37 (1 H, d, J ) 7.6 Hz), 3.85 (3 H, s), 2.54 (1 H, NH,
br.s), 2.33 (1 H, ddq, J ) 6.7, 7.3, and 7.6 Hz), 1.28 (3 H, d, J )
6.7 Hz); 13C NMR (CDCl3, 50 MHz) δ 158.7 (C), 144.5 (C), 136.6
(C), 128,2 (CH), 127.5 (CH), 126.9 (CH), 126.2 (CH), 113.6 (CH),
64.6 (CH), 64.4 (CH), 55.2 (CH3), 50.3 (CH), 16.8 (CH3); MS (m/
z) 253 (M+), 148, 136, 118; HRMS calcd for C17H19NO 253.1467.
C
17H19NO2S: C, 67.81; H, 6.36; N, 4.65. Found: C, 67.69; H,
6.40; N, 4.59; [R]22 ) -129.3 (c 1.12, CHCl3).
D
(2S,3R,4S)-2-(p-An isyl)-4-(2-fu r yl)-1-m esyl-3-m eth yla ze-
tid in e (tr a n s,cis-6d ): Colorless syrup; Rf ) 0.14 (Hex/AcOEt
5/1); IR ν (cm-1) 1514, 1325; 1H NMR (CDCl3, 200 MHz) δ 7.55-
7.45 (3 H, m), 6.99-6.91 (2 H, m), 6.52-6.50 (1 H, m), 6.46-
6.43 (1 H, m), 5.35 (1 H, d, J ) 8.4 Hz), 5.16 (1 H, d, J ) 7.7
Hz), 3.83 (3 H, s), 3.10 (1 H, ddq, J ) 7.0, 7.7, and 8.4 Hz), 2.46
(3 H, s), 1.06 (3 H, d, J ) 7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ
159.8 (C), 150.5 (C), 142.7 (CH), 131.2 (C), 128.4 (CH), 114.0
(CH), 111.5 (CH), 110.8 (CH), 72.8 (CH), 61.8 (CH), 55.2 (CH3),
41.4 (CH), 39.9 (CH3), 12.6 (CH3); MS (m/ z) 321 (M+), 305, 265,
121; HRMS calcd for C16H19NO4S 321.10345, found: 321.1033;
found 253.1472; [R]23 ) + 4.8 (c 0.58, CHCl3).
D
(2S,4S)-3-Meth yl-2,4-diph en ylazetidin e (cis,tr a n s-7b); col-
1
orless syrup. Rf ) 0.23 (Hex/AcOEt 3/1); IR ν (cm-1) 3443; H
NMR (CDCl3, 300 MHz) δ 7.63-7.29 (10 H, m), 5.03 (1 H, d, J
) 8.6 Hz), 4.53 (1 H, d, J ) 6.7 Hz), 3.01 (1 H, ddq, J ) 6.7, 7.0,
and 8.6 Hz), 2.8-2.2 (1 H, br s, NH), 0.72 (3 H, d, J ) 7.0 Hz);
13C NMR (CDCl3, 75 MHz) δ 144.5 (C), 141.5 (C), 128.5 (CH),
128.2 (CH), 127.1 (CH), 126.8 (CH), 126.6 (CH), 125.8 (CH), 67.1
(CH), 62.0 (CH), 42.4 (CH), 15.1 (CH3). MS (m/ z) 223 (M+);
[R]22 ) -100.0 (c 0.27, CHCl3).
D
(2R,3s,4S)-1-Mesyl-3-m eth yl-2,4-d ip h en yla zetid in e (cis,-
cis-6b): colorless syrup; Rf ) 0.21 (Hex/AcOEt 3/1); 1H NMR
(CDCl3, 300 MHz) δ 7.59-7.32 (10 H, m), 5.58 (2 H, d, J ) 8.9
Hz), 3.22 (1 H, tq, J ) 7.3 and 8.9 Hz), 2.86 (3 H, s), 0.40 (3 H,
d, J ) 7.3 Hz); 13C NMR (CDCl3, 75 MHz) δ 136.7 (C), 128.3
(CH), 127.7 (CH), 126.9 (CH), 63.4 (CH), 40.2 (CH3), 34.0 (CH),
11.5 (CH3). Anal. Calcd for C17H19NO2S: C, 67.81; H, 6.36; N,
4.65. Found: C, 67.63; H, 6.39; N, 4.71.
[R]21 ) -185.0 (c 0.44, CHCl3). Anal. Calcd for C16H17N: C,
D
80.06; H, 7.67; N, 6.27. Found: C, 79.96; H, 7.61; N, 6.22.
Ack n ow led gm en t. We are thankful for the financial
support received from the Direccio´n General de Inves-
tigacio´n Cient´ıfica y Te´cnica (DGICYT, PB92-1005). A.
L. Viado and F. Ferna´ndez-Mar´ı are indebted to the
Ministerio de Educacio´n y Ciencia (Spain) for predoc-
toral fellowships. We are also grateful to Dr. Bernard
for measurement of the mass spectra.
P r ep a r a tion of Azetid in es 7. Gen er a l P r oced u r e.
A
solution of azetidine 6 (0.5 mmol) in dry benzene (15 mL) was
treated with an excess of Red-Al (2.0 mmol, 65 + wt % in toluene)
at room temperature. The resulting solution was refluxed until
TLC disappearance of starting material (∼3.5 h), and then cooled
to 0 °C, and 3 N NaOH (10 mL) was added dropwise. The
organic layer was extracted with AcOEt (3 × 15 mL), washed
with saturated brine (15 mL), dried over Na2SO4, and filtered.
Solvents were removed under reduced pressure, and the crude
residue was chromatographed on SiO2. Isolated yields of N-
unsubstituted azetidines 7 are given in Table 2.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and 1H and 13C NMR spectral data, as well as other
spectroscopic data for compounds anti-4b,c, syn-4b, syn,anti-
5b,c, anti,anti-5b, syn,syn-5b, and anti,syn-5b (4 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
(2R *,3S *,4S *)-3-Me t h yl-2-p h e n yl-4-(p -t olyl)a ze t id in e
(tr a n s,tr a n s-7a ): colorless oil; Rf ) 0.45 (Hex/AcOEt/Et3N 100/
1
1/1); H NMR (CDCl3, 300 MHz) δ 7.54-7.16 (9 H, m), 4.38 (1
H, d, J ) 7.3 Hz), 4.36 (1 H, d, J ) 7.3 Hz), 2.50 (1 H, NH, br s),
2.35 (3 H, s), 2.33 (1 H, ddq, J ) 6.6, 7.3, and 7.3 Hz), 1.25 (3 H,
J O960494B