Synthesis of chiral non-racemic azetidines by lipase-catalysed acetylations and their transformation into amino alcohols: Precursors of chiral catalysts

Article abstract of DOI:10.1016/S0957-4166(01)00077-5

Azetidinic mono-acetate 7, diol 6b and di-acetate 10a were prepared with high e.e. using PPL-catalysed acetylations. The absolute configurations of all new enantioenriched compounds were assigned by chemical correlation with known compounds. Mono-acetate 7 was then transformed into 30, an amino alcohol of noteworthy potential interest since it represents an interesting precursor for chiral catalysts, such as 32.

Full text of DOI:10.1016/S0957-4166(01)00077-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 605–618
Synthesis of chiral non-racemic azetidines by lipase-catalysed
acetylations and their transformation into amino alcohols:
precursors of chiral catalysts
Giuseppe Guanti* and Renata Riva*
Dipartimento di Chimica e Chimica Industriale and CNR,
Centro di Studio per la Chimica dei Composti Cicloalifatici ed Aromatici,† via Dodecaneso 31, I-16146 Genoa, Italy
Received 8 January 2001; accepted 15 February 2001
Abstract—Azetidinic mono-acetate 7, diol 6b and di-acetate 10a were prepared with high e.e. using PPL-catalysed acetylations.
The absolute configurations of all new enantioenriched compounds were assigned by chemical correlation with known
compounds. Mono-acetate 7 was then transformed into 30, an amino alcohol of noteworthy potential interest since it represents
an interesting precursor for chiral catalysts, such as 32. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
bered moiety have been isolated from some marine
sponges,1 the culture broth of Streptomyces cacaoi2 and
from the roots of barley.3 The syntheses of some aze-
tidine alkaloids,4–9 of differently N-substituted aze-
The occurrence of the azetidine nucleus in natural
products is uncommon; derivatives of this four-mem-
Scheme 1.
* Corresponding authors. E-mail: guanti@chimica.unige.it; riva@chimica.unige.it
†
Associated to the National Institute of the CNR for the Chemistry of Biological Systems.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00077-5

606
G. Guanti, R. Ri6a / Tetrahedron: Asymmetry 12 (2001) 605–618
Table 1. Asymmetrisation of diol 5 using S-PPL
Entry
mg enz./mg 5
Solvent
Time (min)
Conversiona (%)
5:7:8b
E.e.c (%)
1
2
3
4
5
6
7
8
2
2
2
2
2
1
1
1
VAd
VA
VA
VA
600
60
360
1440
2880
440
1390
1400
57.6
16.3
49.6
67.3
75.1
49.8
55.7
44.1
3.2:78.3:18.5
67.9:31.5:0.6
11.4:77.9:10.7
0.1:65.2:34.7
0.0:49.8:50.2
10.6:79.2:10.2
5.1:78.4:16.5
26.2:59.4:14.4
98.2
93.7
96.2
99.5
\99.5
95.5
VA
VA–i-Pr2O 1:1
VA–i-Pr2O 1:1
VA–hexane
98.0
94.6
a % of acetylated -OH groups versus initial -OH groups.
b Determined by GC–MS (SIM procedure); isolated yields of 5, 7, and 8 were in agreement with the gas chromatographic data.
c Determined by GLC using Cyclodex-B™ (J & W) column.
d VA, vinyl acetate.
tidine-2,4-dicarboxylic acids as precursors of rigid glu-
tamate analogues10 and of cyclic peptides derived from
sponding di-acetate 10a. The slower reacting enan-
tiomer remained unreacted as diol 6b.
L
-azetidine-2-carboxylic acid11 have been reported.
More recently, homochiral azetidines have been pre-
pared and used as ligands12–15 and catalysts16–18 for
asymmetric synthesis; however, the number of applica-
tions in this field appears limited.
The enzymatic reactions were performed on both diols
5 and 6 using first the microbial lipase from Pseu-
domonas cepacia (from Amano), which has been suc-
cessfully used on analogous pyrrolidine derivatives.22
However, since the outcome of the reaction was rather
modest, we abandoned this enzyme and turned our
attention to the mammalian lipase from porcine pan-
creas (PPL), immobilised on Celite, following our previ-
ously reported optimised procedure.23 Both diols
appeared to be good substrates for this enzyme and a
study on the factors affecting the reactivity was per-
formed in order to define the protocol of choice for
further synthetic applications. The reaction times, yields
and e.e.s for enzymatic reactions with 5 and 6 are
reported in Tables 1 and 2, respectively.
We have been active in the design and synthesis of new
chiral building blocks and in their utilisation as precur-
sors of polyfunctionalised natural products.19 Recently,
we reported some preliminary results on the prepara-
tion of optically active azetidines, following a chemoen-
zymatic route.20,‡
Herein, we describe in more detail the preparation of
azetidines 6b, 7 and 10a and establish their absolute
configuration. The azetidinic mono-protected diol 7
was transformed into the amino alcohol 30, which has
previously been used as a precursor of the oxazaboro-
lidine 32, a homogeneous catalyst for the enantioselec-
tive reduction of ketones in the presence of borane.
In the asymmetrisation of 5 (Table 1) the e.e. increased
with conversion, a result of kinetic resolution of the
minor enantiomer of 7 (entries 2–5). However, since
higher conversions caused a marked decrease in the
yield, we usually stopped the reaction at around 55%
conversion; at this point the e.e. is at least 98%. The
employment of di-iso-propyl ether as co-solvent with
vinyl acetate as acyl donor proved to be a useful
alternative set of reaction conditions (entries 6 and 7).
2. Results and discussion
The synthesis of diols 5 and 6 was performed as sum-
marised in Scheme 1, starting from commercially avail-
able glutaryl dichloride.
In the double kinetic resolution of 6 (Table 2), the best
results were obtained when a solubilising co-solvent was
added with vinyl acetate. Tetrahydrofuran was the best
solvent, giving rapid reaction and easier work-up,
although the presence of pyridine gave a higher enan-
tiomeric ratio (E) value.20 The optimised procedure
required the reaction to be stopped at a moderate
degree of conversion (entry 2). While acetate 10a has a
high e.e. of 98.5%, the moderate e.e. of the alcohol 6b
(85.6%) could be increased to up to 94.5% by a simple
recrystallisation from acetone.
Since diol 5 is a meso-form, it can be desymmetrised
and transformed into the mono-acetate 7. Diol 6, being
a racemic compound with C2 symmetry, can then be
subjected to a double sequential kinetic resolution, to
transform the faster reacting enantiomer into the corre-
‡ Only after our preliminary data were published20 was an enzymatic
resolution of azetidines described.21

G. Guanti, R. Ri6a / Tetrahedron: Asymmetry 12 (2001) 605–618
Table 2. Double sequential resolution of diol 6 using S-PPL
607
Entry
mg enz./mg 6
Solvent
Time (min)
Conversiona (%)
6:9:10b
E.e.c,d (%) 6, 9, 10
1
2
3
4
5
2.5
2.5
2.5
2.5
2.5
VA–THF 1:1
VA–THF 1:1
VA–Me2CO 1:1
VA–CH3CN 1:1
VA–Py 1:1
178
388
451
451
451
31.3
37.8
26.7
26.9
26.5
53.0:26.0:21.0
49.7:18.8:31.5
65.5:10.7:23.8
62.0:11.8:26.2
60.0:21.3:18.7
79.7, 82.2, 99.6
85.6,e 61.6, 98.5
43.0, 43.1, 98.7
45.0, 20.5, 97.3
61.3, 85.2, 99.4
a See Table 1, footnote a.
b See Table 1, footnote b.
c The major enantiomers were always 6b and 10a, while the prevailing mono-acetate was usually 9a.
d Determination of e.e. for 9 and 10: GLC, using Dmet.terBut.SBeta (persilylated b-cyclodextrin from MEGA); diol 6 was previously acetylated,
then analysed like 10.
e The e.e. can be increased by crystallisation: in this case the racemic diol precipitated out of solution while the almost optically pure enantiomer
remained in the mother liquor.
The absolute configuration of 6, 7, 9 and 10 was
established by chemical correlation with compounds of
known absolute stereochemistry. One of the few com-
mercially available azetidines in enantiomerically pure
variable yield, in the range 31–48%. A better yield
(59%) was obtained by performing the transformation
in two steps: Swern oxidation of 12 to the correspond-
ing aldehyde, and treatment with RuCl3–NaIO4 in
CCl4–CH3CN–H2O, maintaining the reaction pH at
higher values of 6–7 than the usual pH of 4. The
moderate yield is most likely due to double oxidation of
both the unprotected and protected hydroxymethyl
groups; actually, after treatment of the crude reaction
mixture with diazomethane, we also isolated 19 and 20.
It is known from the literature24 that methyl ethers can
be oxidised to the corresponding methyl esters by
Ru(VIII) but, in this case, since 20 was also identified,
it is unclear if the TBDMS group was hydrolysed
before or after oxidation of the methylene group.
form is -azetidine-2-carboxylic acid 16. For this reason
L
we transformed both 7 and 16 into a common deriva-
tive, alcohol 15, using a non-racemising strategy, in
order to compare the signs of their optical rotations
(Scheme 2).
The chemical elaboration of 7 thus required a demoli-
tion process in order to eliminate one of the two
hydroxymethyl groups. For this purpose we planned to
oxidise the hydroxyl group of 7 to the corresponding
carboxylic acid group for subsequent decarboxylation.
However, in practice, these transformations proved to
be more troublesome than expected and, after many
unsuccessful attempts to oxidise 7, we decided to
change the nitrogen protection from benzyl to t-
butoxycarbonyl. Moreover, during the conventional
hydrogenolysis of 710 simultaneous cleavage of the ace-
tyl group occurred and, for this reason, we had to
The decarboxylation step was performed using Barton’s
protocol,26,27 transforming 13 into the mixed anhydride
and then into the O-acylthiohydroxamate, which, by
treatment with t-BuSH/hw, gave 14. This intermediate
could not be purified completely because it was always
contaminated by the disulfide arising from radical cou-
’
’
pling of t-BuS and 2-Py-S . Deprotection of the silyl
ether with fluoride gave 15, which was easily purified by
silica chromatography.
protect the hydroxyl function of
7 as a tert-
butyldimethylsilyl ether before cleaving the benzyl pro-
tecting group. The absence of the benzyl chromophore
made the reaction difficult to follow and the debenzy-
lated derivative of 11 was volatile; however, we could
not use the more suitable tert-butyldiphenylsilyl group
since with this protecting group in place hydrogenolysis
was very sluggish, probably due to steric reasons.
The preparation of 15 from 16 was performed by
transforming commercial
L-azetidine-2-carboxylic acid
into 17 by conventional reactions; the ester function
was then chemoselectively reduced with NaBH4 to give
15.28,29,§ The optical rotation of 15 obtained from both
Finally, carbamate 12 was oxidised using Sharpless’
methodology,24,25 which has been successfully applied
previously on a similar piperidinic compound.25 How-
ever, the oxidation proceeded only in moderate and
§ This compound is volatile and the yield of 15 cannot be determined
very precisely since total solvent removal after chromatography also
causes a loss of product.

608
G. Guanti, R. Ri6a / Tetrahedron: Asymmetry 12 (2001) 605–618
Scheme 2.
7 and from 16 had a negative sign, thus allowing
assignment of (S)-configuration at C-(2) of 7. More-
over, since the two substituents in 7 have a cis-relation-
ship, the stereogenic centre bearing the acetoxymethyl
group must be (R)-configured. Finally, we demon-
strated that no racemisation occurred during both
transformations of 7 and 16 into 15 by converting
alcohol 15 into the corresponding diastereomeric cam-
phanoates 18 and by checking their enantiomeric purity
of the optical rotation of 24, compared with the
reported dibenzyl ether, confirmed the (2S,4S)-absolute
stereochemistry shown in Scheme 3, which is identical
to 6b. The opposite absolute configuration of di-acetate
10a was assigned by acetylation of 6b and comparing
the retention times by GLC analysis on a b-cyclodex-
trin based column. Finally, acetylation of the mono-
acetate 9a, which is present in small amounts,
confirmed that the mono-acetate has usually the same
absolute configuration as the di-acetate.20
1
using H NMR.
The absolute configuration of the trans-azetidines was
determined by transforming 6b into 24, using a proce-
dure developed by Yamamoto et al. on similar com-
pounds.12 The benzyl protecting group was removed
and substituted with a formyl group to give 22, which
was O-benzylated to give 23. Finally, base induced
cleavage of the formyl group gave the known com-
pound 24. The whole sequence was performed without
purification of intermediates, which were identified by
GC–MS analysis of crude reaction products. The sign
These results are in agreement with our previously
proposed model30 for the enzymatic hydrolysis of esters
or acetylations of alcohols catalysed by PPL: the pro-
(R)-hydroxyl group of 5 was acylated and, analogously,
in the double resolution, sequential acetylation of the
two pro-(R)-hydroxyl groups was observed.
As a possible synthetic application of these azetidines
we first chose an elaboration of cis-7, which, derived
from an asymmetrisation, can be obtained in virtually

G. Guanti, R. Ri6a / Tetrahedron: Asymmetry 12 (2001) 605–618
609
Scheme 3.
100% yield.¶ The mono-protected diol 7 is characterised
by the property of enantiodivergency30 and thus both
enantiomers of a given target can be obtained easily
using an appropriate protection–deprotection strategy
of the two oxygenated groups.
was mesylated and crude 25 was reduced by a one-pot
procedure to give 26. The formal substitution of Bn
with Boc, necessary to ensure good results in the fol-
lowing oxidation step, was realised in this case in just
one step, by hydrogenating 26 in the presence of both
Pd–C and Boc2O. It was not necessary to isolate the
intermediate secondary amine and the hydrogenolysis
could be carried out under atmospheric pressure giving
a clean and direct conversion of 26 to 27. The driving
force for this unusual one-pot transformation is proba-
bly removal of the secondary amine, which reacted as
soon as it formed. Since a high concentration of amine
results in partial deactivation of the catalyst, rapid
transformation into the carbamate lowers the overall
amine concentration during the reaction, allowing 27 to
form under very mild conditions.
We envisaged in 7 a possible precursor for chiral non-
racemic amino alcohols. These compounds are very
important in asymmetric synthesis since they are useful
precursors for chiral auxiliaries31,32 and catalysts.33–35
After a review of the literature, we aimed to prepare an
amino alcohol which, in principle, could be used to
prepare an oxazaborolidine, one of the most powerful
families of homogeneous catalysts, first of all for the
enantioselective reduction of prochiral carbonyl com-
pounds.34–37 At present, only two examples of ox-
azaborolidines bearing an azetidinic nucleus are
known.16,17 The homochiral amino alcohols were
obtained by resolution of a racemic azetidine using an
The Ru(VIII)-catalysed oxidation worked well in this
case, probably since no alkoxymethylene groups are
present as in 13. Methyl ester 28 was then treated with
an excess of PhMgCl in order to prepare tertiary alco-
hol 29. In 29 two phenyl groups were introduced
because the presence of the diphenylhydroxymethyl
group, which does not introduce an additional stereo-
genic centre, appears to play an essential (although as
yet unrationalised) role in determining the asymmetric
induction in many reactions.39
L
-tyrosine derivative16 or by formation of the azetidine
ring using (S)-1-phenylethylamine as reagent.17 Aziri-
dinic oxazaborolidines, derived from both enantiomers
of serine and threonine, are known.38
In our opinion, the preparation and use of amino
alcohol 30 would be advantageous because the above-
mentioned enantiodivergency means that both enan-
tiomers can be prepared from a common intermediate.
Additionally, this homochiral building block can be
obtained easily in an almost enantiopure form with a
simple chemoenzymatic procedure, avoiding tedious
and expensive resolution procedures. Moreover, in our
opinion, the presence of two stereogenic centres in the
azetidinic moiety should induce better enantioselectiv-
ity, since the steric difference of the two faces of the
amino alcohol would be enhanced (Scheme 4).
Finally, the Boc group was hydrolysed in near quantita-
tive yield by basic treatment. The e.e. of alcohol 30 was
tested by transformation into the Mosher amide 31,
which was analysed by HPLC, thus demonstrating that
no racemisation occurred during the transformation of
7 into 30.ꢀꢀ
We then studied the transformation of 30 into oxaza-
borolidine 32 (Scheme 5). We chose the oxazaboro-
lidine with a phenyl group bonded directly to boron
after careful evaluation of the literature data. Stone40
optimised the reduction of acetophenone using the
We then prepared an analogue of the threonine-derived
amino alcohol studied by Zwanenburg et al., bearing an
azetidine instead of an aziridine ring.38 Mono-acetate 7
¶ In this case, due to an incomplete substrate selectivity, the maximum
obtained yields are around 80%, depending also on the degree of
conversion.
ꢀꢀ Moreover, after crystallisation of 29 and/or 30, the e.e., being 98%,
can be increased up to 100%.

610
G. Guanti, R. Ri6a / Tetrahedron: Asymmetry 12 (2001) 605–618
Scheme 4.
useful oxazaborolidine through
a chemoenzymatic
route, although non-heterocyclic homochiral ligands for
hydrogenation have already been prepared by biocata-
lytic methods.41
4. Experimental
4.1. General
Scheme 5.
oxazaborolidine formed by condensation of phenyl-
boronic acid and (S)-diphenyl prolinol35 as catalyst in
the presence of BH3·1,4-oxathiane complex, working at
40°C. We employed a similar procedure for the prepa-
ration of 32 and then reduced acetophenone using
BH3·Me2S. Our preliminary results showed good cata-
lytic activity for (2R,4R)-32 and we isolated (S)-1-
phenylethanol in 83% yield. However, the e.e. was only
a mediocre 53%. Optimisation of this procedure is
currently under investigation in our laboratories since,
in this case, other reaction conditions or oxazaborolid-
ines bearing a different substituent at boron should give
better results. The reduction of other prochiral ketones
in the presence of borane should be investigated since
acetophenone is possibly a poor substrate for testing
the catalyst. The results of our further studies will be
reported in due course.
NMR spectra were taken, unless otherwise indicated, in
CDCl3 at 200 MHz (1H) and 50 MHz (13C). Chemical
shifts are reported in ppm (l scale) from TMS and
coupling constants are reported in hertz. Peak assign-
1
ment in H NMR spectra was also carried out with the
aid of double-resonance experiments. In ABX systems,
the proton A is considered downfield and B upfield.
Peak assignment in 13C spectra was made with the aid
of DEPT experiments. GC–MS were carried out on an
HP-5971A instrument, using an HP-1 column (12 m
long, 0.2 mm wide), electron impact at 70 eV, and a
mass temperature of about 170°C. Unless otherwise
indicated, analyses were performed with a constant He
flow of 0.9 mL/min, starting at 100°C for 2 min and
then raising the temperature by 20°C/min until 260°C;
the split ratio was about 100:1. Retention times are
measured in minutes from injection. Enantiomeric
excesses were determined by GLC analysis using an
HRGC 5300 instrument from Carlo Erba equipped
with: (a) Cyclodex-B™ (from J & W) column for
compound 7; (b) Dmet.terBut.SBeta (persilylated b-
cyclodextrin, from Mega) for compounds 9 and 10.
Diastereomeric ratios were determined with an HP
model 1090 liquid chromatograph equipped with a
Hypersil column. Values of [h]D were measured on a
Jasco DIP 181 instrument, usually as CHCl3 (contain-
3. Conclusions
In conclusion, we report here the synthesis and syn-
thetic elaboration of uncommon optically active N-con-
taining heterocycles to give a new class of 2-amino
alcohols, exemplified structurally by 30. To the best of
our knowledge, the synthesis of 30 represents the first
approach reported in the literature to a potentially

G. Guanti, R. Ri6a / Tetrahedron: Asymmetry 12 (2001) 605–618
611
ing 0.75% EtOH) solutions; concentrations of the sam-
ples are calculated in g/100 mL. IR spectra were mea-
sured with a Perkin–Elmer 881 instrument as CHCl3
solutions. TLC analyses were carried out on silica gel
plates, which were developed by these detection meth-
ods: (A) UV; (B) I2; (C) dipping into a ninhydrin
solution (900 mg in 300 mL nBuOH+9 mL AcOH) and
4.2.3. Characterisation of 1. Rf 0.58 (CH2Cl2–PE 6:4, B).
IR: wmax 2983, 1737, 1374, 1265, 1094, 1014 (for both 1
and 2). GC–MS: Rt 6.18; m/z 348 [M+ (81Br), 0.20]; 303
(12); 302 (51); 301 (27); 300 (100); 299 (13); 298 (51);
275 (14); 274 (14); 273 (28); 272 (25); 271 (14); 270 (12);
245 (18); 243 (11); 221 (22); 219 (24); 193 (50); 191 (48);
181 (20); 179 (19); 168 (75); 166 (82); 165 (57); 163 (61);
153 (11); 151 (12); 141 (15); 140 (40); 138 (39); 137 (18);
135 (22); 122 (22); 121 (10); 120 (24); 119 (11); 113 (18);
85 (27); 55 (17); 39 (14). 1H NMR: 1.32 [6 H, t,
CH3CH2O-, J=7.1]; 2.63 [1 H, dt, -CHBrCHHCHBr-,
J=14.8, 7.3]; 2.87 [1 H, dt, -CHBrCHHCHBr-, J=
14.8, 7.3]; 4.26 [4 H, q, CH3CH2O-, J=7.1]; 4.38 [2 H,
t, ꢀCHBr, J=7.4].
warming; (D) dipping into
a
solution of
(NH4)4MoO4·4H2O (21 g) and Ce(SO4)2·4H2O (1 g) in
H2SO4 (31 mL) and H2O (469 mL) and warming. Rf
values were measured after an elution of 7–9 cm.
Chromatography was carried out on 220–400 mesh
silica gel using the ‘flash’ methodology. Petroleum ether
(40–60°C) is abbreviated as PE. In extractive work-up,
aqueous solutions were always re-extracted thrice with
the appropriate organic solvent. Organic extracts were
dried over Na2SO4 and filtered, before evaporation of
the solvent under reduced pressure. All reactions
employing dry solvents were carried out under a nitro-
gen (or argon, where indicated) atmosphere. The purity
4.2.4. Characterisation of 2. Rf 0.51 (CH2Cl2–PE 6:4, B).
GC–MS: Rt 6.26; m/z 346 [M+ (79Br), 0.30]; 302 (53);
301 (27); 300 (100); 299 (14); 298 (51); 275 (13); 274
(13); 273 (28); 272 (24); 271 (14); 270 (11); 245 (19); 221
(20); 219 (20); 193 (45); 191 (42); 181 (19); 179 (19); 168
(68); 166 (78); 165 (57); 163 (56); 141 (13); 140 (37); 138
(37); 137 (17); 135 (21); 122 (22); 121 (11); 120 (21); 119
1
of all compounds was established by TLC, H NMR,
and (when possible) GC–MS. PPL was purchased from
Sigma and supported over Celite, as described in Ref.
23.
1
(11); 113 (16); 85 (28); 55 (20); 39 (16). H NMR: 1.32
[6 H, t, CH3CH2O-, J=7.2]; 2.66 [2 H, dd, -CHBr-
CH2CHBr-, J=7.8, 6.4]; 4.26 [4 H, q, CH3CH2O-,
J=7.2]; 4.51 [2 H, dd, ꢀCHBr, J=7.9, 6.5].
4.2. Diethyl (2R*,4S*)-2,4-dibromoglutarate 1 and
diethyl (2R*,4R*)-2,4-dibromoglutarate 2
4.3. Diethyl (2R*,4S*)- and (2R*,4R*)-1-benzylaze-
tidine-2,4-dicarboxylates 3 and 4
4.2.1. (2R*,4S*)- and (2S*,4S*)-2,4-dibromoglutaryl
dichloride. Commercial glutaryl dichloride (50 mL, 0.39
mmol) was placed in a two-necked flask, equipped with
a dropping funnel and an efficient reflux condenser, and
warmed in an oil bath to 85°C. A 300 W sun lamp was
positioned ca. 10 cm from the flask and turned on for
the duration of the reaction. Neat bromine (48.9 mL,
0.95 mol) was then added very slowly through a drop-
ping funnel over a period of 1.25 h, while maintaining
the temperature at 85°C. Effluent from the reflux con-
denser was vented to a scrubber system capable of
trapping bromine with 10% aqueous Na2S2O3 and
hydrogen bromide gas with soda lime. The dark mix-
ture was kept at the same temperature for an additional
4.25 h and then cooled to rt.
A 42:58 mixture of 1:2 (16.15 g, purity 93%, :43.41
mmol) was dissolved in benzene (160 mL) and treated
with benzylamine (15.6 mL, 143.28 mmol). The solu-
tion was refluxed under N2 for 24 h and the precipita-
tion of benzylammonium bromide began after 10–15
min. The mixture was diluted with water until all the
salts dissolved and extracted with Et2O. The combined
organic layers were washed with water and brine. Chro-
matography with PE–Et2O 9:1“6:4 gave pure 3 (4.05 g,
32%) and 4 (5.82 g, 46%) as yellow oils.
4.3.1. Characterisation of 3. Rf 0.36 (PE–Et2O 6:4, B).
IR: wmax 2980, 1731, 1443, 1370, 1202, 1180, 1027.
GC–MS: Rt 7.70; m/z 292 (M++1, 0.043); 219 (5.9); 218
(40); 191 (7.1); 174 (6.5); 117 (7.5); 92 (7.6); 91 (100); 65
4.2.2. Esterification. Absolute ethanol (200 mL) was
placed in a 1 L flask equipped with a dropping funnel.
The above prepared dichloride was transferred under
nitrogen into the funnel and dropped over a period of
15 min into the flask, which was previously cooled in an
ice bath. EtOH (3×25 mL) was used in order to transfer
the dichloride quantitatively. The orange–brown solu-
tion was stirred at rt for 18 h. After cooling the solution
to 0°C, solid NaHCO3 was added cautiously until CO2
evolution finished. Ice cold water and Et2O were added
and the mixture was transferred into a separatory fun-
nel. After extraction with Et2O, the combined organic
layers were washed with 10% Na2S2O3 solution and
brine. Solvent removal gave a crude product, which was
purified by distillation to give a pale yellow oil (138 g)
having a gas chromatographic purity of around 93%
and containing a 42:58 mixture of 1:2 in 95% overall
yield. Bp=117–118°C (5.5×10−2 torr).
1
(8.3). H NMR: 1.18 [6 H, t, CH3CH2O-, J=7.1]; 2.41
[2 H, centre of m, H3]; 3.59 [2 H, t, H2+H4, J=8.3];
3.88 [2 H, s, -CH2Ph]; 4.08 [4 H, centre of m,
CH3CH2O-]; 7.29–7.33 [5 H, m, aromatics]. 13C NMR:
14.09 [2 C, CH3CH2O-]; 24.69 [C3]; 59.39 [2 C, C2+C4];
60.19 [-CH2Ph]; 60.71 [2 C, CH3CH2O-]; 127.42 [CH
para of -CH2Ph]; 128.16 and 129.88 [4 C, CH ortho and
meta of -CH2Ph]; 135.59 [C ipso of -CH2Ph]; 171.58 [2
C, ꢀCO].
4.3.2. Characterisation of 4. Rf 0.50 (PE–Et2O 6:4, A,
B). IR: wmax 2979, 1726, 1446, 1372, 1344, 1181, 1025,
844. GC–MS: Rt 7.80; m/z 291 (M+, 0.18); 218 (44); 191
1
(5.2); 117 (8.8); 92 (7.6); 91 (100); 86 (5.7); 65 (8.2). H
NMR: 1.20 [6 H, t, CH3CH2O-, J=7.1]; 2.50 [2 H, t,
H3, J=6.8]; 3.88 [2 H, s, -CH2Ph]; 4.12 [4 H, q,
CH3CH2O-, J=7.1]; 4.20 [2 H, t, H2+H4, J=6.7]; 7.21–

612
G. Guanti, R. Ri6a / Tetrahedron: Asymmetry 12 (2001) 605–618
7.30 [5 H, m, aromatics]. 13C NMR: 14.16 [2 C,
CH3CH2O-]; 25.46 [C3]; 55.74 [-CH2Ph]; 60.61 [2 C,
CH3CH2O-]; 61.77 [2 C, C2+C4]; 127.14 [CH para of
-CH2Ph]; 128.15 and 128.91 [4 C, CH ortho and meta
of -CH2Ph]; 137.12 [C ipso of -CH2Ph]; 172.45 [2 C,
ꢀCO].
CH ortho and meta of -CH2Ph]; 140.72 [C ipso of
-CH2Ph].
4.5. General procedure for the enzymatic acetylations
(both asymmetrisation and double sequential kinetic
resolution)
4.4. (2R*,4S*)- and (2R*,4R*)-1-benzylazetidine-2,4-
Specific data, including quantity of enzyme, solvent,
reaction time, conversion, yield, and product e.e., are
reported in Tables 1 and 2; more data can be obtained
from Ref. 20. All reactions were performed at 0°C,
starting from 50 mg of 5 and 100 mg of 6. The diol was
dissolved in the appropriate solvent (VA as acylating
agent and solvent, with or without added co-solvent),
cooled to 0°C, and stirred for 15 min in the presence of
dimethanols 5 and 6
A suspension of LiAlH4 (3.37 g, 88.80 mmol) in dry
Et2O (50 mL) was cooled to 0°C. A solution of 3 or 4
(6.47 g, 22.21 mmol) in Et2O (50 mL) was added using
an addition funnel over a period of 15 min. The result-
ing slurry was stirred at 0°C for 1 h and then at rt for
an additional 3 h. The reaction flask was cooled again
to 0°C and aqueous NaOH (409 mg, 10.22 mmol in
13.3 mL of water, 738.9 mmol) was added very care-
fully. The resultant mixture was stirred until the alu-
minium salts became easily filtrable (preferably
overnight). After Buchner filtration the solid was
washed with warm acetone and, if necessary, the alumi-
nates were extracted in a Soxhlet with Et2O. The
organic layer was dried with Na2SO4 and the solvent
was evaporated.
,
powdered 3 A molecular sieves (10 mg/50 mg of diol).
Supported PPL was added and the mixture was stirred
again for the desired time. The enzyme was filtered and
washed with CH2Cl2 (cis-derivative) and acetone
(trans-derivative). The solvent was removed in vacuo to
give crude product, i.e. mixtures of 5, 7, 8 and 6b, 9a,
10a, respectively. Both enzymatic reactions were also
performed on a multigram scale and the results were
reproducible.
Racemic 7, 9, 10, necessary in order to set up the gas
chromatographic analysis, were prepared by treating a
solution of 5 or 6 in dry pyridine with a suitable
amount of acetic anhydride. Standard extractive work-
up with Et2O gave the desired products.
4.4.1. Purification and characterisation of 5. Gradient-
elution chromatography with Et2O, then AcOEt and,
finally, AcOEt:MeOH 9:1“7:3 gave a pale yellow solid
(3.68 g, 80%), which can be crystallised from CH2Cl2–i-
Pr2O to give a white solid. Mp=77.7–79.0°C (CH2Cl2–
i-Pr2O). Rf 0.40 (Me2CO–MeOH 9:1, A, B). IR: wmax
3432, 2919, 2869, 1452, 1399, 1330, 1157, 1089, 1011.
GC–MS (in this case initial temperature was 80°C): Rt
7.68; m/z 207 (M+, 0.17); 177 (6.3); 176 (51); 117 (3.7);
92 (7.5); 91 (100); 72 (3.5); 65 (7.6); 44 (2.2); 39 (2.9).
Anal. calcd for C12H17NO2 (207.27): C, 69.54; H, 8.27;
4.5.1. Purification of cis-series products and determina-
tion of conversion. Chromatography was performed
with AcOEt–PE 6:4“9:1, AcOEt, AcOEt–MeOH 9:1“
7:3 or PE–Me2CO 8:2“Me2CO (100%) solvent mix-
tures. Conversion was measured by GC–MS analysis
with SIM procedure (usual gas chromatographic condi-
tions, but a split ratio of 50:1 and an initial temp. of
80°C). Rt 7.63 5, 8.24 7, 8.89 8.
1
N, 6.76. Found: C, 68.56; H, 8.11; N, 6.83%. H NMR
(DMSO-d6): 1.72 [1 H, dt, H3, J=10.3, 8.1]; 2.12 [1 H,
dt, H3, J=10.5, 7.5]; 3.10–3.31 [6 H, m, -CH2OH+H2+
H4]; 3.76 [2 H, s, -CH2Ph]; 4.41 [2 H, broad s, -OH];
7.33–7.46 [5 H, m, aromatics]. 13C NMR (DMSO-d6):
23.73 [C3]; 61.21 [-CH2Ph]; 63.18 [2 C, C2+C4]; 64.65 [2
C, -CH2OH]; 126.87 [CH para of -CH2Ph]; 127.97 and
129.09 [4 C, CH ortho and meta of -CH2Ph]; 139.08 [C
ipso of -CH2Ph].
4.5.2. Purification of trans-series products and determi-
nation of conversion. Chromatography was performed
with PE–Me2CO 1:1“0:100, and CH2Cl2–MeOH–NH3
(50:50:2) as solvent mixtures. Conversion was measured
by GC–MS analysis with SIM procedure (usual gas
chromatographic conditions, but a split ratio of 50:1
and an initial temp. of 80°C). Rt 8.14 6b, 8.67 9a, 9.21
10a.
4.4.2. Purification and characterisation of 6. The crude
product was crystallised directly from acetone to give a
white solid (4.19 g, 91%). Mp=129.1–129.5°C
(Me2CO). Rf 0.15 (Me2CO–MeOH 9:1, A, B). IR: wmax
3431, 2911, 2874, 1402, 1310, 1190, 1093, 1023. GC–
MS (in this case initial temperature was 80°C): Rt 8.11;
m/z 207 (M+, 0.51); 177 (6.8); 176 (55); 117 (4.6); 92
(7.8); 91 (100); 72 (3.4); 65 (6.1). Anal. calcd for
C12H17NO2 (207.27): C, 69.54; H, 8.27; N, 6.76. Found:
C, 69.00; H, 8.12; N, 6.83%. 1H NMR (DMSO-d6): 2.04
[2 H, t, H3 J=6.3]; 3.50–3.67 [6 H, m, -CH2OH+H2+
H4]; 3.78 and 4.06 [2 H, AB syst., -CH2Ph, J=14.2];
4.58 [2 H, broad t, -OH; J=4.6]; 7.25–7.46 [5 H, m,
aromatics]. 13C NMR (DMSO-d6): 23.94 [C3]; 53.96
[-CH2Ph]; 62.21 [2 C, C2+C4]; 62.96 [2 C, -CH2OH];
126.36 [CH para of -CH2Ph]; 127.92 and 128.01 [4 C,
4.5.3. Characterisation of (2S,4R)-4-acetoxymethyl-1-
benzylazetidine-2-methanol 7 (pale yellow oil). Rf 0.50
(PE–Me2CO 6:4, A, B). [h]D=+14.8 (c 2.13, CHCl3,
determined on a sample with 99.5% e.e.). IR: wmax 3432,
2919, 2869, 1729, 1452, 1365, 1194, 1089, 1027. GC–
MS: Rt 7.28; m/z 249 (M+, 0.17); 219 (2.3); 218 (16);
177 (1.8); 176 (14); 159 (3.0); 158 (26); 92 (7.5); 91
(100); 65 (6.3); 43 (8.6). GLC [Cyclodex-B™ column;
He flow 3.1 mL/min (at rt), split ratio 50:1, inj. temp.
240°C, det. temp. 250°C, oven temp. 150°C): Rt 69.17
1
(2S,4R-7), 70.56 (2R,4S-7), h 1.023, RS 1.23. H NMR:
1.92–2.10 [2 H, m, H3]; 2.02 [3 H, s, CH3CO-]; 3.12 and
3.18 [2 H, AB part of ABX syst., -CH2OH, JAB=11.4;
JAX and JBX=3.2, 1.2]; 3.27–3.45 [2 H, m, H2+H4]; 3.62

G. Guanti, R. Ri6a / Tetrahedron: Asymmetry 12 (2001) 605–618
613
and 3.78 [2 H, AB syst., -CH2Ph, J=12.5]; 3.96 [2 H, d,
-CH2OAc, J=4.8]; 7.25–7.32 [5 H, m, aromatics]. 13C
NMR: 20.78 [-COCH3]; 21.07 [C3]; 60.04 [C4];
60.92 [-CH2Ph]; 62.01 [-CH2OH]; 62.90 [C2]; 66.73
[-CH2OAc]; 127.45 [CH para of -CH2Ph]; 128.39 and
128.94 [4 C, CH ortho and meta of -CH2Ph]; 137.88 [C
ipso of -CH2Ph]; 170.82 [ꢀCO].
(3.5); 158 (28); 92 (7.9); 91 (100); 65 (7.2); 43 (24); 41
(2.3); 39 (2.3). GLC [Dmet.terBut.SBeta column; the
same conditions used for 9a): Rt 47.30 [(2R,4R)-10a],
1
48.99 [(2S,4S)-10b], h 1.037, RS 2.30. H NMR: 1.99 [6
H, s, -CO2CH3]; 2.07 [2 H, t, H3, J=6.7]; 3.73 and 3.89
[2 H, AB syst., -CH2Ph, J=14.1]; 3.74–3.84 [2 H, m,
H2+H4]; 4.10 and 4.12 [4 H, AB part of ABX syst.,
-CH2OAc, JAB=11.7, JAX and JBX=8.4, 1.7]; 7.18–7.34
[5 H, m, aromatics]. 13C NMR: 20.77 [2 C, -COCH3];
23.60 [C3]; 54.44 [-CH2Ph]; 59.42 [2 C, C2+C4]; 65.59 [2
C, -CH2OAc]; 126.75 [CH para of -CH2Ph]; 127.87 and
128.16 [4 C, CH ortho and meta of -CH2Ph]; 139.16 [C
ipso of -CH2Ph]; 170.78 [ꢀCO].
4.5.4. Characterisation of (2R*,4S*)-2,4-bis(acetoxy-
methyl)-1-benzylazetidine 8 (pale yellow oil). Rf 0.72
(PE–Me2CO 6:4, A, B). IR: wmax 2998, 1729, 1365, 1194,
1027. GC–MS: Rt 7.92; m/z 291 (M+, 0.42); 231 (2.9);
219 (2.0); 218 (14); 159 (5.0); 158 (40); 92 (7.6); 91
(100); 65 (6.0); 43 (18). 1H NMR: 1.96 [6 H, s, CH3CO-];
1.69 [1 H, dt, H3, J=10.6, 8.4]; 2.16 [1 H, dt, H3,
J=10.7, 7.7]; 3.31 [2 H, centre of m, H2+H4]; 3.71 [2 H,
s, -CH2Ph]; 3.85 and 3.96 [4 H, AB part of ABX syst.,
-CH2OAc, JAB=11.4, JAB and JBX=5.8, 4.8]; 7.23–7.33
[5 H, m, aromatics]. 13C NMR: 20.76 [2 C, -COCH3];
23.68 [C3]; 60.06 [2 C, C2+C4]; 61.44 [-CH2Ph]; 67.40 [2
C, -CH2OAc]; 127.13 [CH para of -CH2Ph]; 128.14 and
129.09 [4 C, CH ortho and meta of -CH2Ph]; 138.17 [C
ipso of -CH2Ph]; 170.72 [2 C, ꢀCO].
4.6. (2R,4S)-1-Benzyl-4-{[(t-butyldimethyl)silyloxy]-
methyl}azetidine-2-methanol 11
4.6.1. (2R,4S)-2-(Acetoxymethyl)-1-benzyl-4-{[(t-butyldi-
methyl)silyloxy]methyl}azetidine. Mono-acetate 7 (1.25
g, 5.01 mmol) was dissolved in dry DMF (7 mL) and
treated with imidazole (854 mg, 12.54 mmol) and t-
BuMe2SiCl (97%, 937 mg, 6.03 mmol). After stirring
for 4 h at rt, the solution was diluted with water and
extracted with Et2O. Solvent removal gave the crude
product used directly in the saponification. Rf 0.46
(PE–Et2O 7:3, A, B). GC–MS (in this case the initial
temperature was 80°C): Rt 9.81; m/z 363 (M+, 0.012);
306 (2.4); 290 (3.4); 219 (4.2); 218 (29); 159 (8.6); 158
(71); 156 (2.6); 92 (7.6); 91 (100); 89 (7.5); 75 (5.8); 73
(9.2); 65 (4.4); 59 (5.1); 57 (2.8); 43 (14); 41 (4.1).
4.5.5. Characterisation of (2S,4S)-benzylazetidine-2,4-
dimethanol 6b. [h]D=−33.6 (c 1.47, Me2CO, determined
on a sample with 94.7% e.e). Spectroscopic data have
already been reported after the preparation of racemic
compound. GLC (Dmet.terBut.SBeta column): analyses
performed after acetylation in the conditions described
above for 9a.
4.5.6. Characterisation of (2R,4R)-4-acetoxymethyl-1-
benzylazetidine-2-methanol 9a. Rf 0.63 (AcOEt–MeOH
8:2, A, B). [h]D=+18.1 (c 2.28, CHCl3, determined on a
sample with 82.2% e.e.). IR: wmax 3432, 2919, 2869,
1729, 1452, 1365, 1194, 1089, 1027. GC–MS: Rt 7.66;
m/z 249 (M+, 0.41), 218 (15), 177 (2.1); 176 (16), 159
(2.8); 158 (24); 117 (2.0); 92 (7.3), 91 (100), 65 (5.8), 43
(7.3). GLC [Dmet.terBut.SBeta column; He flow 1.1
mL/min (at rt), split ratio 70:1, inj. temp. 200°C, det.
temp. 220°C, oven temp. 150°C“170°C, init. time 5
min, rate 2°C/min, final time 40 min): Rt 37.92
4.6.2. Saponification reaction. The crude product
obtained above was dissolved in absolute MeOH (7
mL) and cooled to 0°C. A 1 M solution of KOH in
MeOH (7.5 mL, 7.50 mmol) was added and stirring was
continued at the same temperature for 1 h. NH4H2PO4
(5% solution in water, 2 mL) was added and the
solution was concentrated under reduced pressure.
Standard extraction with AcOEt was performed, fol-
lowed by washing of the combined organic layers with
brine. After solvent removal, chromatography with PE–
AcOEt 3:7“AcOEt 100% gave pure 11 as a colourless
oil (1.40 g, 88%). Rf 0.39 (PE–AcOEt 8:2, A, B).
[h]D=−16.7 (c 2.11, CHCl3). IR: wmax 3440, 2954, 2927,
2858, 1194, 1125, 1076. GC–MS: Rt 8.39; m/z 321 (M+,
0.065); 291 (2.7); 290 (11); 264 (3.0); 190 (3.2); 177 (13);
176 (100); 158 (3.7); 142 (2.9); 117 (4.3); 92 (7.4); 91
(93); 89 (2.6); 75 (6.0); 73 (8.3); 72 (3.1); 65 (5.2); 59
1
[(2R,4R)-9a], 39.39 [(2S,4S)-9b], h 1.040, RS 2.56. H
NMR: 1.83 [1 H, centre of m, H3]; 2.00 [3 H, s,
CH3CO-]; 2.41 [1 H, dt, H3, J=11.0, 7.8]; 3.26 and 3.30
[2 H, AB part of ABX syst., -CH2OH, JAB=11.6, JAX
and JBX=3.1, 1.9]; 3.67 and 3.91 [2 H, AB system,
-CH2Ph, J=13.7]; 3.67–3.91 [2 H, m, H2+H4]; 4.23 and
4.39 [2 H, AB part of ABX syst., -CH2OAc, JAB=12.0,
JAX and JBX=6.4, 3.8]; 7.23–7.32 [5 H, m, aromatics].
13C NMR: 20.72 [-COCH3]; 21.52 [C3]; 53.71 [-CH2Ph];
58.42 [C4]; 61.47 [-CH2OH]; 63.72 [-CH2OAc]; 64.04
[C2]; 127.43 [CH para of -CH2Ph]; 128.35 and 128.44 [4
C, CH ortho and meta of -CH2Ph]; 136.98 [C ipso of
-CH2Ph]; 170.63 [ꢀCO].
1
(4.8); 57 (3.0); 45 (2.1); 41 (4.0). H NMR: 0.04 [6 H, s,
(CH3)2t-BuSi-]; 0.90 [9 H, s, Me2(CH3)3CSi-]; 1.99 [2 H,
t, H3, J=8.0]; 3.09 and 3.16 [2 H, AB part of ABX
syst., -CH2OH, JAB=11.3, JAX and JBX=3.1, 1.4];
3.18–3.32 [2 H, m, H2+H4]; 3.46 [2 H, d, -CH2OSiMe2t-
Bu, J=5.0]; 3.61 and 3.83 [2 H, AB syst., -CH2Ph,
J=12.6]; 7.23–7.34 [5 H, m, aromatics]. 13C NMR:
−5.34 and −5.31 [2 C, (CH3)2t-BuSi-]; 18.38 [(CH3)3C-];
20.76 [C3]; 25.96 [3 C, (CH3)3C-]; 61.21 [-CH2Ph]; 62.04
[-CH2OH]; 62.72 and 63.02 [2 C, C2+C4]; 66.47
[-CH2OSiMe2t-Bu]; 127.25 [CH para of -CH2Ph];
128.28 and 128.99 [4 C, CH ortho and meta of
-CH2Ph]; 138.38 [C ipso of -CH2Ph].
4.5.7. Characterisation of (2R,4R)-2,4-bis(acetoxy-
methyl)-1-benzylazetidine 10a. Rf 0.70 (PE–Et2O 3:7, A,
B). [h]D=+39.0 (c 2.56, CHCl3, determined on a sample
with 99.6% e.e.). IR: wmax 2946, 1724, 1367, 1248, 1027.
GC–MS: Rt 8.26; m/z 291 (M+, 0.28); 218 (7.7); 159

614
G. Guanti, R. Ri6a / Tetrahedron: Asymmetry 12 (2001) 605–618
4.7. (2R,4S)-1-(t-Butoxycarbonyl)-4-{[(t-butyldimethyl)-
4.8.2. Second oxidation step. The crude aldehyde was
dissolved in CCl4–CH3CN (6 mL, 1:1) and treated with
a previously prepared solution of NaIO4 (890 mg, 4.16
mmol) and RuCl3 (13 mg, 62.7 mmol) in water (4.5
mL). The pH was maintained at 7 by adding solid
NaHCO3. The biphasic system was vigorously stirred at
rt for 21 h. Since the reaction was incomplete, the pH
was adjusted to 3.8 by adding 1 M H2SO4 and addi-
tional RuCl3 (17 mg). After 1 h the reaction mixture
was saturated with NaCl and extracted with AcOEt.
The combined organic extracts were washed with 10%
aq. Na2SO3 and brine. After evaporation, chromatogra-
phy with PE–AcOEt 8:2“0:100 gave pure 13 as a
viscous colourless oil (192 mg, 59%). Rf 0.41 (PE–
AcOEt 1:1 with 1% AcOH, C). [h]D=+9.3 (c 0.92,
CHCl3). IR: wmax 3420, 3004, 1696, 1603, 1390, 1369,
silyloxy]methyl}azetidine-2-methanol 12
4.7.1. (2R,4S)-4-{[(t-Butyldimethyl)silyloxy]methyl}aze-
tidine-2-methanol. A solution of 11 (499 mg, 1.55 mmol)
was dissolved in MeOH (30 mL) and treated with
Pd(OH)2 over charcoal (20%, 250 mg). The mixture was
hydrogenated for 24 h under 5 atm hydrogen pressure.
The catalyst was filtered and the solvent evaporated to
give a colourless oil which was used ‘as is’ in the next
reaction. GC–MS: Rt 5.92; m/z 200 (M+−31, 6.1); 174
(7.7); 158 (8.3); 157 (20); 156 (19); 127 (6.8); 116 (27);
101 (14); 100 (6.3); 87 (5.4); 86 (100); 82 (6.1); 75 (34);
73 (25); 69 (22); 68 (24); 60 (8.3); 59 (11); 45 (5.0); 41
(11).
1
4.7.2. Protection reaction. The crude amine obtained
above was dissolved in a THF–H2O mixture (8 mL,
1:1) and cooled to 0°C. Di-tert-butyl dicarbonate (500
mL, 2.18 mmol) was added, followed by NaHCO3 (183
mg, 2.18 mmol) and aqueous NaOH (1N, 2 mL). The
mixture was then stirred at rt for 24 h, the aqueous
solution was saturated with NaCl and extracted with
AcOEt. The combined organic layers were washed with
brine and concentrated in vacuo. Chromatography with
PE–AcOEt 8:2“65:35 gave pure 12 as a colourless oil
(382 mg, 74%). Rf 0.50 (PE–AcOEt 7:3, C). [h]D=−39.0
(c 1.52, CHCl3). IR: wmax 3683, 3437, 2957, 2931, 2858,
1666, 1460, 1393, 1368, 1247, 1146. GC–MS: Rt 7.63;
m/z 275 (M+−57, 0.01); 220 (5.2); 219 (14); 218 (100);
200 (9.0); 160 (8.8); 158 (7.5); 157 (17); 156 (40); 142
(6.6); 127 (5.3); 116 (22); 115 (5.1); 101 (7.9); 100 (7.7);
89 (5.2); 86 (17); 82 (8.7); 75 (32); 73 (24); 68 (11); 59
(9.8); 58 (6.0); 57 (57); 55 (5.8); 41 (14). 1H NMR
(DMSO-d6, temp. 110°C): 0.07 [6 H, s, (CH3)2t-BuSi-];
0.91 [9 H, s, Me2(CH3)3CSi-]; 1.40 [9 H, s,
-CO2C(CH3)3]; 1.99 [1 H, dt, H3, J=11.0, 6.2]; 2.22 [1
H, dt, H3, J=11.0, 8.4]; 3.44–3.63 [2 H, m, H2+H4];
3.69 and 3.77 [2 H, AB part of ABX syst.,
-CH2OSiMe2t-Bu, JAB=10.6, JAX and JBX=5.7, 3.2];
3.97–4.11 [2 H, m, -CH2OH]; 4.27 [1 H, t, -OH, J=5.1].
13C NMR: −5.51 and −5.42 [2 C, (CH3)2t-BuSi-]; 18.41
[Me2C(CH3)3Si-]; 19.95 [C3]; 25.90 [3 C, Me2C(CH3)3-
Si-]; 28.33 [3 C, -CO2C(CH3)3]; 59.77 and 60.75 [2 C,
C2+C4]; 63.34 and 65.66 [2 C, -CH2O-]; 80.12
[-CO2C(CH3)3]; 157.05 [-CO2t-Bu].
1144. GC–MS: 13 is not suitable for this analysis. H
NMR: 0.01 [6 H, s, (CH3)2t-BuSi-]; 0.92 [9 H, s,
Me2C(CH3)3Si-]; 1.46 [9 H, s, -CO2C(CH3)3]; 1.35–1.75
[1 H, m, H3]; 2.50 [2 H, broad s, H3]; 3.56–4.40 [3 H, m,
-CH2OSiMe2t-Bu+H4]; 4.60 [1 H, broad t, H2, J=7.4].
13C NMR: −5.50 and −5.43 [2 C, (CH3)2t-BuSi-]; 18.39
[Me2C(CH3)3Si-]; 22.04 [C3]; 25.95 [3 C, Me2C(CH3)3Si-
]; 28.25 [3 C, -CO2C(CH3)3]; 57.88 and 61.22 [2 C,
C2+C4]; 65.31 [-CH2O-]; 81.20 [-CO2C(CH3)3]; 156.85
[-CO2t-Bu]; 173.57 [-CO2H].
4.9. (S)-1-(t-Butoxycarbonyl)-2-{[(t-butyldimethyl)-
silyloxy]methyl}azetidine 14
Acid 13 (144 mg, 417 mmol) was dissolved in dry THF
(4 mL) and cooled to −15°C. To this solution iso-butyl
chloroformate (54 mL, 417 mmol) and 4-methylmorpho-
line (46 mL, 417 mmol) were added and the mixture was
stirred for 5 min. A solution of N-hydroxy-2-thiopyri-
done (63.6 mg, 500 mmol) and Et3N (70 mL, 500 mmol)
in THF (10 mL) was added, while the reaction flask
was maintained in the dark. After 1 h t-BuSH (141 mL,
1.25 mmol) was added and the reaction was stirred at
15°C while irradiating with a 300 W sun lamp. After
1–2 min the solution, initially yellow, became colourless
and, after an additional 10 min, was extracted with
Et2O. After evaporation, the crude reaction mixture
was purified by chromatography with PE–Et2O 100:0“
1
85:15 to give 76.8 mg of product. H NMR analysis
revealed that this compound is a 65:35 (weight) mixture
of 14 and t-butyl-(2-pyridyl)disulfide. Thus, the esti-
mated yield is approx. 40%. Rf 0.28 (PE–Et2O 9:1, C).
GC–MS: Rt 6.41; m/z 228 (M+−73, 2.0); 189 (15); 188
(100); 100 (10); 75 (44); 73 (24); 71 (7.6); 70 (6.3); 59
4.8. (2R,4S)-1-(t-Butoxycarbonyl)-4-{[(t-butyldimethyl)-
silyloxy]methyl}azetidine-2-carboxylic acid 13
1
4.8.1. (2R,4S) - 1 - (t - Butoxycarbonyl) - 4 - {[(t - butyldi-
(8.7); 58 (7.6); 57 (50); 56 (27); 41 (16). H NMR: 0.03
methyl)silyloxy]methyl}azetidine-2-carbaldehyde.
Dry
and 0.06 [6 H, 2 s, (CH3)2t-BuSi-]; 0.91 [9 H, s,
Me2(CH3)3CSi-]; 1.43 [9 H, s, -CO2C(CH3)3]; 2.17 [2 H,
q, H3, J=7.4]; 3.65 and 3.92 [2 H, AB part of ABX
syst., -CH2OSiMe2t-Bu, JAB=10.8, JAX and JBX=3.8,
2.5]; 3.78 [2 H, t, H4, J=7.6]; 4.21 [1 H, centre of m,
H2].
DMSO (2.82 M in dry CH2Cl2, 1.34 mL, 3.76 mmol)
was cooled to −78°C and treated with oxalyl chloride
(2.41 M, in CH2Cl2, 976 mL, 2.35 mmol). After 10 min,
a solution of 12 (312 mg, 94.1 mmol) in dry CH2Cl2 (5
mL) was added and stirring continued for 10 min.
Finally, Et3N (918 mL, 6.59 mmol) was added and the
temperature was allowed to rise to −40°C. The reaction
was quenched with water and extracted with Et2O to
give, after solvent removal, crude aldehyde, which was
used directly in the next oxidation. Rf 0.46 (PE–AcOEt
8:2, B, C).
4.10. (S)-1-(t-Butoxycarbonyl)azetidine-2-methanol 15
4.10.1. From 14. A solution of 14 (74.7 mg, about 65%
pure) in dry THF (1 mL) cooled to 0°C was treated
with a 1 M solution of n-Bn4N+F− (331 mL, 331 mmol)

G. Guanti, R. Ri6a / Tetrahedron: Asymmetry 12 (2001) 605–618
615
and, after 10 min, the solution was stirred at rt for an
additional 15 min. Extraction with Et2O and solvent
removal under reduced pressure gave crude 15, which
was purified by chromatography using pentane–Et2O
4:6“100:0 as eluent. Alcohol 15 was obtained in 80–
85% yield (see text).
prepared from (2S)-15 and (1S)-camphanic chloride
and 0.54 (PE–Et2O 2:8, A, C) for 18 prepared from
(2S)-15 and (1R)-camphanic chloride.
4.13. (2S,4S)-Azetidine-2,4-dimethanol 21
Diol 6b (502 mg, 2.42 mmol) was dissolved in MeOH
(50 mL) and treated with Pd(OH)2–C (20%, 500 mg).
The suspension was stirred at rt and hydrogenated at 5
atm for 29 h. The catalyst was filtered out and the
solvent was removed from the filtrate in vacuo to give
crude 21. Rf 0.30 (Me2CO–MeOH 7:3, B). GC–MS (inj.
temp. 150°C, det. temp. 280°C, init. temp. 50°C, rate
20°C/min, final temp. 220°C, He constant flow 0.9
mL/min): Rt 5.87; m/z 117 (M+, 4.0); 87 (7.4); 86 (100);
69 (45); 68 (24); 60 (6.1); 58 (21); 57 (7.8); 56 (8.2); 55
(5.6); 54 (5.4); 44 (10); 43 (9.4); 42 (20); 41 (56); 40
(5.0); 39 (8.9); 32 (11); 31 (20).
4.10.2. From 17. Ester 17 (41.5 mg, 193 mmol) was
dissolved in MeOH (1 mL) and cooled to 0°C. NaBH4
(21.9 mg, 5.78 mmol) was then added and the mixture
was stirred at rt for 1 h. Quenching with saturated
aqueous NH4Cl, followed by extraction with Et2O,
gave crude alcohol, which was purified by chromatog-
raphy with pentane–Et2O 3:7“0:100 to give 15 as a
colourless oil with an overall yield ]74%. Rf 0.28
(PE–Et2O 2:8, C). [h]D=−20.3 (c 0.72, CHCl3). IR: wmax
3393, 2923, 2893, 1660, 1393, 1368, 1152. GC–MS: Rt
4.22; m/z 187 (M+, 0.40); 157 (8.7); 156 (28); 114 (17);
113 (5.7); 101 (6.7); 100 (45); 71 (11); 59 (7.2); 57 (100);
1
58 (5.6); 56 (90); 55 (6.0); 43 (10); 41 (25); 31 (6.3). H
4.14. (2S,4S)-2,4-Bis(hydroxymethyl)azetidine-1-carb-
aldehyde 22
NMR: 1.45 [9 H, s, -CO2C(CH3)3]; 1.71–2.27 [2 H, m,
H3]; 3.72–3.94 [4 H, m, H4+-CH2OH]; 4.45 [1 H, centre
of m, H2]. 13C NMR: 17.91 [C3]; 28.32 [3 C, -C(CH3)3];
46.65 [C4]; 63.64 [C2]; 66.76 [-CH2OH]; 80.30 [-
C(CH3)3]; 157.14 [-CO2t-Bu].
Crude 21 was suspended in MeOH–HCO2Me (10 mL,
1:1 mixture) and stirred at rt for 63 h and at 80°C for
1.75 h. The solvent was removed in vacuo to give crude
22. Rf 0.57 (Me2CO–MeOH 7:3, B). GC–MS (inj. temp.
150°C, det. temp. 280°C, init. temp. 50°C, rate 20°C/
min, final temp. 220°C, He constant flow 0.9 mL/min):
Rt 8.29; m/z 127 (M+−H2O, 5.5); 115 (33); 114 (95); 109
(6.8); 100 (6.9); 96 (14); 88 (12); 86 (48); 84 (8.5); 82
(5.1); 71 (9.2); 70 (10); 69 (100); 68 (85); 67 (6.2); 60
(12); 58 (35); 57 (13); 56 (12); 54 (10); 46 (7.5); 44 (7.2);
43 (18); 42 (25); 41 (98); 40 (6.1); 39 (17); 31 (34).
4.11. Methyl (S)-1-(t-butoxycarbonyl)azetidine-2-car-
boxylate 17
4.11.1. (S)-1-(t-Butoxycarbonyl)azetidine-2-carboxylic
acid. Commercial 16 (41 mg, 406 mmol) was N-pro-
tected following the same procedure described to pre-
pare 12. Rf 0.64 (n-PrOH–30% NH3 8:2, C).
4.11.2. Esterification. The crude acid prepared above
was dissolved in THF (5 mL) and treated with CH2N2
(1 M solution in Et2O, 5 mL). After a few minutes the
reaction was complete and the excess CH2N2 was
quenched by reaction with AcOH (:0.2 mL). After
solvent removal, crude 17 was purified directly by chro-
matography, using PE–Et2O 6:4“1:1 as eluent, to give
a colourless oil (80 mg, 92%). Rf 0.25 (PE–Et2O 6:4, C).
[h]D=−108.6 (c 1.06, CHCl3). IR: wmax 2897, 1742,
1695, 1394, 1368, 1145. GC–MS: Rt 4.71; m/z 215 (M+,
0.59); 160 (9.0); 159 (7.4); 156 (26); 142 (7.5); 114 (28);
4.15. (2S,4S)-2,4-Bis(benzyloxymethyl)azetidine-1-carb-
aldehyde 23
Crude 22 was dissolved in dry THF (20 mL) and cooled
to 0°C. Benzyl bromide (749 mL, 6.30 mmol) and NaH
(303 mg, 52% suspension in mineral oil) were added
cautiously. After a few minutes the mixture was stirred
at rt for 30 min and then heated under reflux for 3.25
h. After cooling to rt the reaction was diluted with
water and extracted with Et2O. The ethereal extract was
evaporated under reduced pressure and crude 23 was
used directly in the next reaction. Rf 0.41 (Et2O, A, B).
GC–MS (inj. temp. 150°C, det. temp. 280°C, init. temp.
50°C, rate 20°C/min, final temp. 220°C, He constant
flow 0.9 mL/min): Rt 14.20; m/z 217 (M+−117, 0.24);
128 (3.0); 126 (3.0); 113 (16); 111 (2.6); 100 (5.8); 98
(17); 96 (3.4); 92 (9.1); 91 (100); 72 (6.3); 71 (4.3); 70
(3.2); 68 (3.5); 65 (5.9).
1
100 (26); 59 (5.1); 57 (96); 56 (100); 55 (9.8); 41 (18). H
NMR: 1.43 [9 H, s, -C(CH3)3]; 2.09–2.25 [1 H, m, H3];
2.50 [1 H, centre of m, H3]; 3.78 [3 H, s, -CO2CH3];
3.83–4.10 [2 H, m, H4]; 4.62 [1 H, dd, H2, J=8.9, 5.4].
13C NMR: 20.23 [C3]; 28.28 [3 C, -C(CH3)3]; 47.54 [C4];
52.07 [-OCH3]; 60.46 [C1]; 79.98 [-C(CH3)3]; 155.34
[-CO2t-Bu]; 171.82 [-CO2Me].
4.12. (S)-1-(t-Butoxycarbonyl)-2-[(+)- or (−)-(camphan-
oyloxy)methyl]azetidine 18
4.16. (2S,4S)-2,4-Bis(benzyloxymethyl)azetidine 24
Crude 23 was dissolved in MeOH (25 mL) and treated
with 15% aqueous NaOH (2 mL). The mixture was
refluxed for 38 h wherein the biphasic system gradually
Alcohol 15 (6.0 mg, 32.04 mmol) was dissolved in dry
CH2Cl2 (500 mL) and treated with 4-N,N-dimethyl-
aminopyridine (23.5 mg, 192 mmol) and (1S)- or (1R)-
camphanic chloride (20.8 mg, 96.12 mmol). After 1 h
the solution was purified directly by preparative TLC,
using PE–Et2O 2:8 as eluent. Ester 18 was obtained in
71–82% yield. Rf 0.60 (PE–Et2O 2:8, A, C) for 18
became
a
homogeneous solution; 5% aqueous
NH4H2PO4 (3 mL) was added and the suspension was
concentrated in vacuo. Extraction with AcOEt, fol-
lowed by washing of the combined organic layers with
brine and solvent removal, gave crude 24. Chromatog-

616
G. Guanti, R. Ri6a / Tetrahedron: Asymmetry 12 (2001) 605–618
raphy with AcOEt–PE–Et3N 60:40:0“100:0:3 gave 24
as an oil (444 mg, 62% from 6b). Rf 0.25 (PE–AcOEt–
Et3N 40:60:2, A, B). [h]D=−6.5 (c 1.83, CHCl3). GC–
MS (inj. temp. 150°C, det. temp. 280°C, init. temp.
50°C, rate 20°C/min, final temp. 220°C, He constant
flow 0.9 mL/min): Rt 12.68, m/z 297 (M++1, 0.015); 176
(11); 150 (18); 92 (7.8); 91 (100); 70 (26); 68 (3.3); 65
0.39); 171 (8.4); 170 (29); 128 (11); 115 (8.5); 114 (87);
70 (99); 59 (7.4); 58 (6.1); 57 (100); 43 (11); 42 (8.2); 41
(22); 39 (5.3); 31 (6.2). H NMR: 1.34 [3 H, d, -CH3,
J=6.2]; 1.46 [9 H, s, -C(CH3)3]; 2.28 [1 H, dt, H3,
J=11.2, 8.2]; 2.31 [1 H, dt, H3, J=11.3, 8.2]; 3.75 and
3.77 [2 H, AB part of ABX syst., -CH2OH, JAB=11.5,
JAX and JBX=3.71, 3.69]; 4.09–4.34 [2 H, m, H2+H4].
13C NMR: 21.92 [ꢀCHCH3]; 26.25 [C3]; 28.37 [3 C,
-C(CH3)3]; 55.17 [C4]; 60.66 [C2]; 67.32 [-CH2OH];
80.19 [-C(CH3)]; 157.75 [-CO2t-Bu].
1
1
(5.8); 41 (2.1). H and 13C NMR data are in agreement
with reported data.12
4.17. (2R,4S)-2-(Acetoxymethyl)-1-benzyl-4-(methane-
sulfonyloxy)methylazetidine 25
4.20. Methyl (2R,4R)-1-(t-butoxycarbonyl)-4-methyl-
azetidine-2-carboxylate 28
A solution of 7 (2.85 g, 11.4 mmol) in dry CH2Cl2 (50
mL) was cooled to −30°C and treated with Et3N (1.91
mL, 13.7 mmol) and MsCl (973 mL, 12.6 mmol). After
3 h the mixture was diluted with aqueous saturated
NH4Cl solution (30 mL) and extracted with AcOEt.
The combined organic layers were washed with brine
and concentrated in vacuo. Mesylate 25 was used
directly in the following reaction. Rf 0.36 (Et2O–PE 8:2,
A, B). GC–MS (in this case initial temperature was
80°C): Rt 10.65; m/z 268 (M+−59, 0.90); 256 (2.7); 255
(6.1); 254 (42); 232 (2.8); 159 (5.8); 158 (49); 92 (7.7); 91
(100); 65 (5.6); 43 (6.1).
4.20.1. (2R,4R)-1-(t-Butoxycarbonyl)-4-methylazetidine-
2-carboxylic acid. A solution of 27 (1.24 g, 6.16 mmol)
in CCl4–CH3CN–H2O (21 mL, 2:2:3) was cooled to 0°C
and treated with NaIO4 (5.37 g, 25.1 mmol) and RuCl3
(28 mg, 135 mmol). The resulting dark mixture was
stirred at rt for 5 h and then diluted with 5% aqueous
NH4H2PO4. The resulting biphasic system was filtered
over a Celite pad, the extraction was performed with
AcOEt and the resulting combined organic layers were
washed with 10% aqueous Na2S2O3 and brine, before
the solvent was removed in vacuo. The crude acid was
esterified directly without further purification. Rf 0.20
(PE–Et2O 1:1 with 1% AcOH, C).
4.18. (2R,4R)-1-Benzyl-4-methylazetidine-2-methanol 26
The same procedure described for the reduction of
diesters 3 and 4 was followed, but performing the
reaction at 0°C. Chromatography with PE–Me2CO
1:1“0:100 gave 26 directly as a colourless oil (88%). Rf
0.40 (PE–Me2CO 6:4, A, B). [h]D=−15.9 (c 0.81,
CHCl3). IR: wmax 3007, 2957, 2922, 2863, 1601, 1384,
1236, 1084. GC–MS (in this case the initial temperature
was 80°C): Rt 6.22; m/z 191 (M+, 0.87); 161 (7.8); 160
(64); 117 (11); 92 (8.2); 91 (100); 90 (2.1); 65 (7.3); 56
4.20.2. Esterification. The crude acid was treated with
CH2N2, as described above for compound 17. After
solvent removal, direct chromatography with PE–Et2O
7:3“4:6 gave 28 as a colourless oil (1.11 g, 79%). Rf
0.66 (PE–Et2O 2:8, C). [h]D=+70.2 (c 1.72, CHCl3). IR:
wmax 3682, 3439, 2979, 2930, 1702, 1382, 1281, 1155,
1076, 1049, 1010. GC–MS: Rt 4.70; m/z 229 (M+, 2.2);
174 (8.8); 173 (7.0); 170 (45); 156 (15); 142 (6.4); 128
(22); 114 (76); 113 (14); 71 (5.1); 70 (100); 59 (8.7); 57
(78); 43 (5.3); 41 (14). 1H NMR: 1.43 [9 H, s, -C(CH3)3];
1.44 [3 H, d, CH3CH-, J=6.1]; 1.83 [1 H, dt, H3,
J=11.3, 6.3]; 2.60 [1 H, ddd, H3, J=11.3, 9.3, 8.1]; 3.77
[3 H, s, -CO2CH3]; 4.24 [1 H, centre of m, H4]; 4.52 [1
H, dd, H4, J=9.2, 6.3]. 13C NMR: 21.43 [ꢀCHCH3];
28.32 [4 C, C3+-C(CH3)3]; 52.10 [-CO2CH3]; 56.14 and
57.28 [2 C, C2+C4]; 79.84 [-C(CH3)]; 155.66 [-CO2t-Bu];
171.95 [-CO2Me].
1
(6.2); 44 (2.4); 39 (2.0). H NMR: 1.01 [3 H, d, -CH3,
J=6.0]; 1.74 [1 H, dt, H3, J=10.4, 8.1]; 2.08 [1 H, dt,
H3, J=10.5, 7.5]; 3.10–3.28 [4 H, m, H2+H4+-CH2OH];
3.57 and 3.68 [2 H, AB syst., -CH2Ph, J=12.5]; 7.19–
7.38 [5 H, m, aromatics]. 13C NMR: 21.64 [-CH3]; 26.52
[C3]; 58.49 [-CH2Ph]; 60.79 and 61.53 [2 C, C2+C4];
63.12 [-CH2OH]; 127.18 [CH para of -CH2Ph]; 128.22
and 129.02 [4 C, CH ortho and meta of -CH2Ph];
138.20 [C ipso of -CH2Ph].
4.21. (2R,4R)-1-(t-Butoxycarbonyl)-a,a-diphenyl-4-
methylazetidine-2-methanol 29
4.19. (2R,4R)-1-t-Butoxycarbonyl-4-methylazetidine-2-
methanol 27
To a THF solution of PhMgCl (2 M, 7.26 mL, 14.52
mmol), cooled to 0°C, was added a solution of 28 (1.11
g, 4.84 mmol) in dry THF (20 mL) via an addition
funnel over a 20 min period. The solution was allowed
to warm to rt. Since it was difficult for the reaction to
go to completion, additional PhMgBr solution was
added periodically, after cooling the mixture to 0°C (i.e.
a total of 24.25 mmol of Grignard reagent was used).
After 8 h aqueous saturated NH4Cl (20 mL) was added
and the extraction was performed with AcOEt. The
combined organic extracts were washed with 1N
NaOH, in order to extract the traces of phenol always
present, and then washed again with water until a
neutral pH was reached. After one treatment with
A suspension of 26 (1.55 g, 8.10 mmol) in MeOH (30
mL) was treated with di-tert-butyl dicarbonate (2.79
mL, 12.15 mmol) and Pd–C (10%, 500 mg). The mix-
ture was hydrogenated at 1 atm for 30 h. The catalyst
was filtered and the resulting solution concentrated.
After dilution with water the slurry was extracted with
Et2O and the combined organic extracts were washed
with brine. The solvent was then removed and the
crude product was chromatographed with PE–Et2O
6:4“1:9, Et2O (100%) to give 27 as a colourless oil
(1.24 g, 76%). Rf 0.33 (PE–Et2O 1:1, C). [h]D=−12.0 (c
2.02, CHCl3). IR: wmax 3376, 2978, 2929, 1664, 1368,
1345, 1155, 1070, 1041. GC–MS: Rt 4.27; m/z 201 (M+,

G. Guanti, R. Ri6a / Tetrahedron: Asymmetry 12 (2001) 605–618
617
brine, the solution was concentrated in vacuo and
chromatographed with PE–Et2O 8:2“65:25 to give 29
as a white solid (1.11 g, 65%), which was then recrys-
tallised from i-Pr2O–pentane. Mp=125.1–125.7°C (i-
Pr2O–pentane). Rf 0.30 (PE–Et2O 8:2, A, C).
[h]D=+261.5 (c 0.76, CHCl3). IR: wmax 3293, 2970,
2926, 1656, 1398, 1368, 1354, 1151. GC–MS: Rt 10.03;
m/z 280 (M+−73, 0.84); 184 (5.8); 183 (38); 171 (7.6);
170 (37); 115 (24); 114 (97); 105 (36); 77 (22); 71 (5.6);
70 (100); 57 (52); 43 (6.4); 41 (8.6). 1H NMR: 0.46 [3 H,
d, CH3CH-, J=6.3]; 1.46 [9 H, s, -C(CH3)3]; 1.73 [1 H,
dt, H3, J=11.6, 6.5]; 2.57 [1 H, dt, H3, J=11.6, 8.6];
4.04 [1 H, centre of m, H2]; 4.99 [1 H, dd, H4, J=8.5,
7.0]; 6.64 [1 H, broad s, -OH]; 7.29–7.33 [10 H, m,
aromatics]. 13C NMR: 19.50 [ꢀCHCH3]; 27.74 [C3];
28.36 [3 C, -C(CH3)3]; 55.24 [C4]; 66.57 [C2]; 79.91
[-C(CH3)]; 80.84 [Ph2COH-]; 126.77, 126.98, 128.08,
and 128.56 [8 C, C ortho and meta of Ph]; 126.92 and
127.21 [2 C, C para of Ph]; 143.82 and 144.75 [2 C, C
ipso of -Ph]; 158.46 [ꢀCO].
from (2R,4R)-30 with (S)-Mosher’s chloride. These
compounds were analysed using HPLC [Hypersil
column, flow 0.9 mL/min; hexane:Et2O 85:15; detector:
UV at 210 nm]. Rt 8.21 [31 from reaction of (2R,4R)-30
with (R)-Mosher’s chloride] and 14.62 [31 from reac-
tion of (2R,4R)-30 with (S)-Mosher’s chloride].
4.24. (5R,7R)-7-Methyl-2,4,4-triphenyl-3-oxa-1-aza-2-
borabicyclo[3.2.0]heptane 32
In a 50 mL flask, 30 (108 mg of 426 mmol) was
dissolved in dry toluene (10 mL), which was then
removed in vacuo. The resulting solid was dried at 0.9
mbar overnight and then dissolved in toluene (10 mL).
,
The solution was treated with powdered 4 A molecular
sieves (22 mg), previously activated at 250°C for 1 day,
and then with phenylboronic acid (57 mg, 468 mmol).
,
After refluxing for 3.5 h through a trap filled with 4 A
molecular sieves (beads placed between the flask and
the condenser), the solvent was removed and the crude
oxazaborolidine was dried for 2 h at 0.9 mbar. The pale
yellow solid was then dissolved in toluene to give a 0.21
M solution of 32, which was stored under nitrogen and
used directly in the following reduction.
4.22. (2R,4R)-a,a-Diphenyl-4-methylazetidine-2-
methanol 30
Compound 29 (587 mg, 16.61 mmol) was dissolved in a
solution of KOH in absolute ethanol (4 M, 11 mL) and
the resulting solution was stirred under reflux for 2.5 h.
The solution was concentrated under reduced pressure,
diluted with water and AcOEt and extracted with
AcOEt–MeOH 9:1. The combined organic extracts
were washed with brine and then with NH4H2PO4 (1
mL, 5% aqueous solution). The solvent was removed
under reduced pressure and crude 30 was purified by
chromatography with AcOEt–Et3N 100:0“98:2 to give
a white solid (400 mg, 95%). Compound 30 was then
crystallised from i-Pr2O–PE. Mp=97.7–98.2°C (i-
Pr2O–PE). Rf 0.37 (AcOEt with 2% of Et3N, A, C).
[h]D=+23.5 (c 0.78, CHCl3). IR: wmax 3347, 2998, 2956,
1598, 1486, 1445, 1379, 1307, 1167, 1135, 1106, 1059.
GC–MS: Rt 8.33; m/z 235 (M+−H2O, 0.097); 183 (2.0);
165 (2.2); 105 (10); 77 (10); 70 (100); 43 (5.8). 1H NMR:
1.16 [3 H, d, -CH3, J=6.1]; 1.87 [1 H, dt, H3, J=11.0,
8.3]; 2.09 [1 H, dt, H3, J=11.1, 7.4]; 2.17 [1 H, s, -OH];
3.85 [1 H, centre of m, H2]; 4.65 [1 H, t, H4, J=7.8];
5.12 [1 H, broad s, -NH]; 7.13–7.45 [10 H, m, aromat-
ics]. 13C NMR: 18.86 [ꢀCHCH3]; 26.88 [C3]; 51.72
[C4]; 60.51 [C2]; 76.38 [Ph2COH-]; 125.55, 125.86,
128.29 and 128.67 [8 C, C ortho and meta of Ph]; 127.44
and 127.82 [2 C, C para of Ph]; 141.31 and 142.49 [2 C,
C ipso of -CH2Ph].
4.25. Reduction of acetophenone to give (S)-1-phenyl-
ethanol in the presence of 32
A solution of 32 (0.21 M, 1 mL) was poured into a
two-necked flask equipped with an addition funnel. Dry
THF (2.5 mL) was added, followed by the addition of
a solution of BH3·Me2S in THF (2 M, 1.07 mL, 2.14
mmol). The mixture was stirred for 12 min at 40°C,
then acetophenone (249 mL, 2.14 mmol) in dry THF
(2.5 mL) was added over a period of 40 min. TLC at
the end of the addition showed that the reaction was
complete. The crude mixture was diluted with Et2O and
extracted with aqueous H2SO4 (1 M). After washing the
organic phase until neutral with 5% aqueous
NH4H2PO4 and brine, the solvent was removed. The
crude product was purified by chromatography with
PE–Et2O 7:3“3:7 to give pure (S)-1-phenylethanol
(217 mg, 83%). [h]D=−22.2 (c 3.46, CHCl3). E.e. 53%,
determined by chiral GLC [Dmet.terBut.SBeta
column].
Acknowledgements
The authors would like to thank the CNR, the
MURST (COFIN) and the University of Genova for
financial assistance, Amano for the generous gift of
lipase from Pseudomonas cepacia and Miss Domenica
Talia for her precious contribution to this project.
4.23. (2R,4R)-a,a-Diphenyl-1-{(+)- or (−)-[(methoxy)-
phenyl(trifluoromethyl)acetyl]}-4-methylazetidine-2-
methanol 31
Neat 30 (5.2 mg, 20.53 mmol) was treated with NaOH
(1N, 150 mL), THF (400 mL) and (1R)- or (1S)-Mosh-
er’s chloride. The mixture was stirred for 3 h at rt, then
diluted with water and extracted with Et2O. After chro-
matography on preparative TLC (PE–Et2O 1:1), amide
31 was obtained (73–76%). Rf 0.39 (PE–Et2O 1:1, A, D)
for 31 prepared from (2R,4R)-30 with (R)-Mosher’s
chloride and 0.53 (PE–Et2O 1:1, A, D) for 31 prepared
References
1. Kobayashi, J.; Cheng, J.; Ishibashi, M.; Wa¨lchli, M. R.;
Yamamura, S.; Ohizumi, Y. J. Chem. Soc., Perkin Trans.
1 1991, 1135–1137.

618
G. Guanti, R. Ri6a / Tetrahedron: Asymmetry 12 (2001) 605–618
21. Starmans, W. A. J.; Doppen, R. G.; Thijs, L.; Zwanen-
2. Isono, K.; Asahi, K.; Suzuki, S. J. Am. Chem. Soc. 1969,
burg, B. Tetrahedron: Asymmetry 1998, 9, 429–435.
22. Sibi, M. P.; Lu, J. L. Tetrahedron Lett. 1994, 35, 4915–
4918.
91, 7490–7505 and references cited therein.
3. Nomoto, K.; Mino, Y.; Ishida, T.; Yoshioka, H.; Ota,
N.; Inoue, M.; Takagi, S.; Takemoto, T. J. Chem. Soc.,
Chem. Commun. 1981, 338–339 and references cited
therein.
23. Banfi, L.; Guanti, G.; Riva, R. Tetrahedron: Asymmetry
1995, 6, 1345–1356.
24. Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless,
K. B. J. Org. Chem. 1981, 46, 3936–3938.
25. Clinch, K.; Vasella, A.; Schauer, R. Tetrahedron Lett.
1987, 28, 6425–6428.
4. Takikawa, H.; Maeda, T.; Seki, M.; Koshino, H.; Mori,
K. J. Chem. Soc., Perkin Trans. 1 1997, 97–111.
5. Yoda, H.; Oguchi, T.; Takabe, K. Tetrahedron Lett.
1997, 38, 3283–3284.
6. Knapp, S.; Dong, Y. Tetrahedron Lett. 1997, 38, 3813–
3816.
26. Barton, D. H. R.; Herve´, Y.; Potier, P.; Thierry, J.
Tetrahedron 1988, 44, 5479–5486.
27. Knight, D. W. In Encyclopaedia of Reagents in Organic
Synthesis (EROS); Paquette, L. A., Ed.; J. Wiley:
Chichester, UK, 1995; Vol. 4, pp. 2775–2778.
28. Baldwin, J. E.; Adlington, R. M.; Jones, R. H.; Schofield,
C. J.; Zarocostas, C.; Greengrass, C. W. Tetrahedron
1986, 42, 4879–4888.
7. Lin, G.-Q.; Liu, D.-G. Heterocycles 1998, 47, 337–348.
8. Liu, D.-G.; Lin, G.-Q. Tetrahedron Lett. 1999, 40, 337–
340.
9. Hamada, Y.; Shioiri, T. J. Org. Chem. 1986, 51, 5489–
5490.
10. Kozikowski, A. P.; Tu¨ckmantel, W.; Liao, Y.; Manev,
H.; Ikonomovic, S.; Wroblewski, J. T. J. Med. Chem.
1993, 36, 2706–2708 and references cited therein.
11. Boni, R.; Verdini, A. S.; Deber, C. M.; Blout, E. R.
Biopolymers 1978, 17, 2385–2399.
12. Hoshino, J.; Hiraoka, J.; Hata, Y.; Sawada, S.;
Yamamoto, Y. J. Chem. Soc., Perkin Trans. 1 1995,
693–697.
13. Starmans, W. A. J.; Walgers, R. W. A.; Thijs, L.; de
Gelder, R.; Smits, J. M. M.; Zwanenburg, B. Tetrahedron
1998, 54, 4991–5004.
14. Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 1999, 10,
1673–1679.
15. Marinetti, A.; Hubert, P.; Geneˆt, J.-P. Eur. J. Org. Chem.
2000, 1815–1820.
16. Rama Rao, A. V.; Gurjar, M. K.; Kaiwar, V. Tetra-
hedron: Asymmetry 1992, 3, 859–862.
29. Zarocostas, C.; Greengrass, C. W. J. Chem. Soc., Chem.
Commun. 1985, 42, 194–196.
30. Guanti, G.; Banfi, L.; Narisano, E. J. Org. Chem. 1992,
57, 1540–1554.
31. Studer, A. Synthesis 1996, 793–815.
32. Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996,
96, 835–875.
33. Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl.
1994, 33, 497–526.
34. Walbaum, S.; Martens, J. Tetrahedron: Asymmetry 1992,
3, 1475–1504.
35. Corey, E. J.; Helal, C. J. Angw. Chem., Int. Ed. Engl.
1998, 37, 1986–2012.
36. Singh, V. K. Synthesis 1992, 605–617.
37. Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763–784.
38. Willems, J. G. H.; Dommerholt, F. J.; Hammink, J. B.;
Vaarhorst, A. M.; Thijs, L.; Zwanenburg, B. Tetrahedron
Lett. 1995, 36, 603–606.
17. Starmans, W. A. J.; Thijs, L.; Zwanenburg, B. Tetra-
hedron 1998, 54, 629–636.
18. Wilken, J.; Erny, S.; Wassmann, S.; Martens, J. Tetra-
hedron: Asymmetry 2000, 11, 2143–2148.
19. Banfi, L.; Guanti, G. Eur. J. Org. Chem. 1998, 745–757
and references cited therein.
39. Brown, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 519–
522.
40. Stone, G. B. Tetrahedron: Asymmetry 1994, 5, 465–472.
41. Adger, B.; Berens, U.; Griffiths, M. J.; Kelly, M. J.;
McCague, R.; Miller, J. A.; Palmer, C. F.; Roberts, S.
M.; Selke, R.; Vitinius, U.; Ward, G. J. Chem. Soc.,
Chem. Commun. 1997, 1713–1714.
20. Guanti, G.; Riva, R. Tetrahedron: Asymmetry 1995, 6,
2921–2924.
.
.