Asymmetric synthesis of 2-mono- and 2,3-trans-disubstituted azetidines

Article abstract of DOI:10.1002/ejoc.200400473

A versatile and efficient asymmetric synthesis of 2-mono-and 2,3-trans-disubstituted azetidines with excellent diastereomeric (de = 93 to ≥ 96%) and enantiomeric excesses (ee ≥ 96%) in good overall yields is described. Virtually stereoisomerically pure differently N,O-protected 3-amino-1-alkanols were prepared as intermediates. Key steps are a diastereoselective α-alkylation of aldehyde SAMP-hydrazones with benzyloxymethyl chloride as the electrophile, and a nucleophilic 1,2-addition of various organocerium reagents to the hydrazone CN double bond. An epimerisation-free reductive removal of the auxiliary gave O-benzyl-protected 3-amino-1-alkanols. After N-tosylation and hydrogenolytic cleavage of the benzylic protecting group, ring closure to the corresponding N-tosylazetidines was achieved in good yields under Mitsunobu conditions. Detosylation was easily accomplished employing sodium/naphthalene. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400473

FULL PAPER
Asymmetric Synthesis of 2-Mono- and 2,3-trans-Disubstituted Azetidines
Dieter Enders,*[a] Jörg Gries,[a] and Zin-Sig Kim[a]
Keywords: Azetidines / Amino alcohols / Asymmetric synthesis / Hydrazones / Cyclisation
A versatile and efficient asymmetric synthesis of 2-mono-
and 2,3-trans-disubstituted azetidines with excellent diaster-
eomeric (de = 93 to Ն 96%) and enantiomeric excesses (ee
the hydrazone CN double bond. An epimerisation-free re-
ductive removal of the auxiliary gave O-benzyl-protected 3-
amino-1-alkanols. After N-tosylation and hydrogenolytic
Ն 96%) in good overall yields is described. Virtually stereo- cleavage of the benzylic protecting group, ring closure to the
isomerically pure differently N,O-protected 3-amino-1-alk-
anols were prepared as intermediates. Key steps are a dias-
tereoselective α-alkylation of aldehyde SAMP-hydrazones
with benzyloxymethyl chloride as the electrophile, and a nu-
cleophilic 1,2-addition of various organocerium reagents to
corresponding N-tosylazetidines was achieved in good yields
under Mitsunobu conditions. Detosylation was easily ac-
complished employing sodium/naphthalene.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
duction of β-lactams,[11] double alkylation of primary am-
ines,[12] intramolecular C-alkylation or Michael addition,[13]
cyclisation of β-amino allenes,[14] carbene insertion into the
NH bond via α-amino diazo ketones[15] amongst others.[16]
One of the most reliable ways for the asymmetric synthesis
of substituted azetidines remains the synthesis of a straight
chain precursor, such as 3-amino-1-alkanols, with estab-
lished stereochemistry and subsequent ring closure by intra-
molecular N-alkylation.[17]
The synthesis of enantiomerically enriched 3-amino-1-al-
kanols has recently received much attention, as the direct
catalytic asymmetric Mannich reaction was reported as a
promising new method for their synthesis. The use of or-
ganometallic and amine catalysts in this reaction has re-
cently been reviewed.[18]
As part of our continuing interest in the asymmetric syn-
thesis of nitrogen heterocycles[19] we herein wish to report
an efficient and flexible synthesis of substituted azetidines.
Our synthetic strategy comprises the synthesis of virtually
enantiopure γ-amino alcohols as key intermediates em-
ploying the SAMP/RAMP-hydrazone methodology.[20]
Subsequent conversion into the azetidines is then carried
out by intramolecular nucleophilic substitution.
Azetidines have been less studied in the past than related
nitrogen heterocycles, although they show significant bio-
logical activities.[1] One explanation could be the small
number of natural products containing a four-membered
N-heterocycle in contrast to the large number of pyrrolidine
and piperidine compounds. The three-membered aziridines
also received significant attention as soon as convenient
methods for their asymmetric preparation and their appli-
cation as chiral building blocks in organic synthesis were at
hand.[2] Nevertheless, chiral azetidines have recently trig-
gered much interest as potential active pharmaceutical in-
gredients as indicated by the growing number of publi-
cations and patents emerging in this field.[3] One of the most
prominent biologically active azetidines is the non-opiate
analgesic agent ABT-594.[4]
Furthermore, ligands with an azetidine backbone have
been employed in various asymmetric catalytic processes
with convincing results, such as reductions,[5] diethylzinc ad-
ditions,[6] cycloadditions[7] and cyclopropanations.[8] En-
antiopure azetidines have also been used as substrates in
stereoselective ring enlargement reactions.[9] Despite these
promising developments in azetidine chemistry, the lack of
general diastereo- and enantioselective routes to these het-
erocycles is evident by the relatively low number of reports
on azetidines in the literature.[10]
Results and Discussion
The asymmetric synthesis of 2-mono- and 2,3-trans-dis-
ubstituted azetidines was achieved following the well estab-
lished protocols for the α-alkylation and 1,2-addition of al-
dehyde SAMP/RAMP-hydrazones with subsequent NϪN
bond cleavage, followed by ring closure as depicted in
Scheme 1.
Different approaches for the construction of nonracemic
azetidine ring systems have been reported, such as re-
[a]
Institut für Organische Chemie, Rheinisch-Westfälische
Technische Hochschule,
Professor-Pirlet-Str. 1, 52074 Aachen, Germany
Fax: (internat.) ϩ49-241-8092127
E-mail: enders@rwth-aachen.de
The SAMP-hydrazones 1 were obtained by condensation
of the chiral auxiliary with aldehydes.[21] For the synthesis
Eur. J. Org. Chem. 2004, 4471Ϫ4482
DOI: 10.1002/ejoc.200400473
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4471

D. Enders, J. Gries, Z.-S. Kim
FULL PAPER
Table 1. Diastereoselective α-alkylation of the hydrazones 1 with
benzyloxymethyl chloride
Product
R1
Yield [%]
de[a] [%]
(R,S)-2a
(R,S)-2b
(R,S)-2c
(R,S)-2d
Me
Et
nBu
Ph
70
69
79
81
Ն 96
Ն 96
Ն 96
Ն 96
[a]
1
Determined by H and 13C NMR spectroscopy.
The absolute configuration of the newly formed stereo-
genic centre of the hydrazones 2 was assigned according to
previous results obtained in α-alkylation reactions of alde-
hyde SAMP-hydrazones.[19a,20,23]
In the following step the second substituent was intro-
duced by the nucleophilic 1,2-addition of an organometallic
reagent to the hydrazone CN double bond.[24] Initial experi-
ments with alkyllithiums led to poor yields and the elimi-
nation of benzyl alcohol as a side reaction. The use of less
basic and more nucleophilic organocerium compounds,
which were freshly prepared from CeCl3 and organolithium
compounds following ImamotoЈs procedure,[25] gave the
corresponding hydrazines 3 in good yields (73Ϫ93%) and
high diastereoselectivities (de ϭ 94 to at least 96%)
(Table 2).
Scheme 1. Asymmetric synthesis of azetidines 6: a) LDA, benzyl-
oxymethyl chloride, THF; b) CeCl3, R2Li, THF; c) BH3·THF,
THF, then HCl; d) TsCl, K2CO3, NEt3, CH2Cl2; e) Pd/C, H2,
EtOAc; f) PPh3, iPrO2CNϭNCO2iPr, THF
of the 2,3-trans-disubstituted azetidines the SAMP-hydra-
zones 1 were first α-alkylated with benzyloxymethyl chlo-
ride corresponding effectively to a hydroxymethylation with
benzyl protection in a single step. Benzyloxymethyl chloride
had previously been successfully utilized for the alkylation
of hydrazones.[22] While 2d was obtained in good yield, we
achieved only moderate results with the aliphatic hydraz-
ones 2aϪc following the standard alkylation protocol. β-
Elimination of benzyl alcohol and oligomerisation of
benzyloxymethyl chloride were the side reactions as ob-
served by NMR spectroscopic analysis of the crude reaction
mixtures. They could be circumvented by using lower hy-
drazone concentrations, shorter reaction times and quench-
ing the reaction at low temperature. The use of other bases
Table 2. Diastereoselective nucleophilic addition of organocerium
reagent to the hydrazones 2
Product
R1
R2
Yield [%]
de[a] [%]
(R,R,S)-3a
(R,R,S)-3b
(R,R,S)-3c
(S,R,S)-3d
(R,R,S)-3e
(R,S)-3f
Me
Et
nBu
nBu
Ph
nBu
nBu
n-Hex
tBu
n-Hex
n-Hex
90
93
73
91
93
76
Ն 96
Ն 96
Ն 96
Ն 96
94 (91[b]
96
)
H
[a]
1
[b]
Determined by H and 13C NMR spectroscopy.
Before flash
column chromatography.
The preparation of monosubstituted azetidines started
like LTMP and LHMDS instead of LDA did not improve with the 1,2-addition to the unsubstituted hydrazone 2e
yields. Under optimised reaction conditions the hydrazones (R1 ϭ H), which was derived via condensation of 3-benzyl-
1aϪc were deprotonated with LDA at Ϫ5 °C over 2.5 h. A oxypropanal[26] and SAMP in 81% yield, without a preced-
significantly lower hydrazone concentration had to be used ing α-alkylation. 3f was obtained by the nucleophilic ad-
(9Ϫ12 mL THF/mmol hydrazone) than usually employed dition of the n-hexylcerium reagent to hydrazone 2e.
in the hydrazone alkylation protocols (typically 2Ϫ3 mL
The α-alkylation of hydrazone (S)-2e as an alternative
THF/mmol hydrazone). In order to achieve complete de- way for the preparation of stereoisomers of the hydrazones
protonation another 0.9 equivalents of nBuLi had to be ad- 2aϪd was not possible due to decomposition during the de-
ded to regenerate LDA and to complete the metalation of protonation.
the hydrazones. The aza-enolates thus obtained were alkyl-
It is important to note that an reverse addition of the
ated at Ϫ100 °C with benzyloxymethyl chloride. After 2Ϫ3 cerium reagent to the hydrazone solution was necessary in
h the reaction mixtures were subjected to an aqueous order to obtain high yields. Addition of the hydrazone solu-
workup and the crude products were purified by flash col- tion to the organocerium compound was only possible in
umn chromatography to give the alkylated, diastereomer- the cases of the less reactive tert-butyl reagent leading to the
ically pure hydrazones 2 (de Ն 96%) in 69Ϫ81% yield hydrazine 3d and the unsubstituted hydrazone 2e leading to
(Table 1).
the hydrazine 3f.
4472
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Eur. J. Org. Chem. 2004, 4471Ϫ4482

Asymmetric Synthesis of 2-Mono- and 2,3-trans-Disubstituted Azetidines
FULL PAPER
The absolute configuration of the newly generated stereo-
genic centre of the hydrazines 3 was assigned according to
the previously confirmed mechanism for 1,2-additions to
SAMP-hydrazones.[23b,27]
The O-benzyl-protected 3-amino-1-alkanols 4aϪf were
obtained after the NϪN bond cleavage of the correspond-
ing hydrazines 3. This was accomplished by heating the hy-
drazines with an excess of borane tetrahydrofuran complex
according to a standard procedure developed in our
group.[28] Purification by flash column chromatography af-
forded the pure amines 4 in good yields (64Ϫ92%) as shown
in Table 3.
Table 4. Protection of the amines 4 as tosyl amides 5
Product
R1
R2
Yield [%]
de[a] [%]
ee[b] [%]
(R,R)-5a
(R,R)-5b
(R,R)-5c
(S,R)-5d
(R,R)-5e
(R)-5f
Me
Et
nBu
nBu
Ph
nBu
nBu
n-Hex
tBu
n-Hex
n-Hex
89
92
99
76
Ն 96
98[c]
98[c]
Ն 96
Ն 96
Ϫ
Ն 96
Ն 96
Ն 96
Ն 96
97[d]
89
H
84 (2 steps)
Ն 96
[a] Determined by 1H and 13C NMR spectroscopy. [b] In correlation
with the de value of the corresponding hydrazine as determined by
1H and 13C NMR spectroscopy. The following steps are racemis-
ation-free. [c] Determined by gas chromatography. [d] Determined by
HPLC on a chiral stationary phase. Optical rotation of the RAMP
Table 3. Hydrazine cleavage with the borane tetrahydrofuran com-
plex
23
derived tosylamino alcohol (S,S)-5e: [α]D ϭ Ϫ20.7 (c ϭ 0.9,
CHCl3).
Product
R1
R2
Yield [%]
de[a] [%]
ee[b] [%]
(R,R)-4a
(R,R)-4b
(R,R)-4c
(S,R)-4d
(R,R)-4e
(R)-4f
Me
Et
nBu
nBu
Ph
nBu
nBu
n-Hex
tBu
n-Hex
n-Hex
92
83
78
64
88
Ϫ[c]
Ն 96
Ն 96
Ն 96
Ն 96
94
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Ϫ
Table 5. Hydrogenolytic cleavage of the O-benzyl ether 5 and ring
closure to the azetidines 6
Product R1
R2
Yield [%] (2 steps) de[a] [%] ee[b] [%]
H
Ϫ
(R,S)-6a Me nBu
(R,S)-6b Et nBu
(R,S)-6c nBu n-Hex 92
(S,S)-6d nBu tBu 93
97
92
93
96
95
Ն 96
Ն 96
Ն 96
Ն 96
96[d]
[a] Determined by 1H and 13C NMR spectroscopy. [b] In correlation
with the de value of the corresponding hydrazine as determined by
1H and 13C NMR spectroscopy and racemisation-free hydrazine
Ն 96[c]
Ն 96[c]
Ϫ
(R,S)-6e Ph
n-Hex 94
n-Hex 77
[c]
cleavage. Not isolated and directly converted into 5f.
(R)-6f
H
Ն 96
[a]
[b]
The tosyl group appeared to be the protecting group of
choice in this synthesis. Other protecting groups such as N-
benzyl and N-p-methoxybenzyl were tested in the course of
this work giving only poor yields during their introduction.
Alternatively, various carbamates gave undesired side
products during the ring closure by nucleophilic substi-
tution due to their ambident N- and O-nucleophilic charac-
ter. The NMR spectroscopic examination of the crude reac-
tion mixtures indicated the formation of oxazines by alky-
lation of the carbamate oxygen. This was in accordance
with observations made by Baldwin et al. during attempted
carbamate alkylations.[29]
Determined by gas chromatography.
In correlation with the
1
de value of the corresponding hydrazine as determined by H and
13C NMR spectroscopy. The following steps are racemisation-free.
[c]
1
[d]
Determined by H and 13C NMR spectroscopy.
Determined
by HPLC on a chiral stationary phase.
of (R,S)-6e, of which the enantiomer (S,R)-6e ([α]D22
ϭ
ϩ51.7 (c ϭ 1.0, CHCl3)) was also synthesized starting from
the RAMP-hydrazone (R)-1d. This enabled us to confirm
the ee values by HPLC on chiral stationary phases and to
confirm the racemisation-free course of the azetidine syn-
thesis.
The generation of the sulfonamides 5 was accomplished
in good yields (84Ϫ99%) by heating the amines with tosyl
chloride in the presence of K2CO3. For the preparation of
the tosylamine 5f with satisfactory yield triethylamine was
necessary as an additional base. In several cases the dia-
stereomeric excesses determined by 1H and 13C NMR could
be confirmed by GC (Table 4).
The O-benzyl ethers 5aϪf were cleaved by hydrogenolysis
in the presence of palladium on charcoal affording the cor-
responding protected amino alcohols. Finally, cyclisation to
the desired azetidines 6 was achieved in analogy to Mitsu-
nobu’s procedure for the alkylation of amines.[30] The 2,3-
disubstituted azetidines 6aϪe and the 2-monosubstituted
azetidine 6f were obtained in good yields (Table 5).
The trans-configuration of the disubstituted azetidines
6aϪe was proven by NOE-measurements on 6c as shown
in Figure 1. On radiation of one of the protons at C-4 a
strong nuclear Overhauser effect was observed with the pro-
ton at C-2 and with the protons of the alkyl substituent at
C-3. The other proton at C-4 showed strong interaction
with the proton at C-3. No enhancement was visible be-
tween the protons at C-2 and C-3, all this indicating their
relative trans-configuration.
The enantiomeric excesses given are based on the dia-
stereomeric excesses of the corresponding SAMP-hydraz-
ones and hydrazines. The following steps leading to the
azetidines were assumed to be racemisation-free. This was
Figure 1. NOE measurements on azetidine 6c, confirming the
indeed a valid assumption that could be proven in the case trans-configuration of the 2,3-disubstituted azetidines 6
Eur. J. Org. Chem. 2004, 4471Ϫ4482
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D. Enders, J. Gries, Z.-S. Kim
FULL PAPER
silica gel 60, 0.040Ϫ0.063 mm particle size. Optical rotation values
were measured on a PerkinϪElmer P 241 polarimeter with solvents
of Merck UVASOL quality. IR spectra: PerkinϪElmer FT/IR.
NMR spectra: Varian VXR 300, Varian Gemini 300 and Varian
Inova 400, using TMS as internal standard. Mass spectra: Varian
MAT 212 and Finnigan SSQ 7000. Microanalyses: Heraeus, CHN-
O-Rapid. Merck TLC plates with silica gel 60 F254 were used for
analytical TLC. Benzyloxymethyl chloride was prepared from for-
maldehyde and benzyl alcohol.[31] The SAMP/RAMP-hydrazones
were prepared from (S)- or (R)-proline according to the literature
The removal of the tosyl group was carried out in the
cases of the aliphatic azetidines 6c and the aromatic azetid-
ine 6e as depicted in Scheme 2. The cleavage of the tosyl
group proceeded cleanly with Na/naphthalene in dimeth-
oxyethane (DME) at Ϫ45 °C. The free azetidines were sub-
sequently protected as tert-butyl carbamates for easier iso-
lation and purification. No epimerisation was detected with
the aliphatic azetidine (R,S)-7a. Unfortunately, a slight
drop in the diastereomeric excess of the aromatic azetidine
1
(R,S)-7b from Ն 96% to 91% was detected by H NMR procedures.[21]
and HPLC. Nevertheless the ee value was confirmed to be
General Procedure for the α-Alkylation of SAMP-Hydrazones 1 with
96% by HPLC on a chiral stationary phase {(S,R)-7b:
Benzyloxymethyl Chloride (GP 1): LDA (1.1 equiv.) was freshly pre-
pared by addition of nBuLi (1.1 equiv.) to a solution of diisopro-
pylamine in dry THF (9Ϫ12 mL/mmol hydrazone) under argon at
Ϫ5 °C and stirring for 15 min. The SAMP-hydrazones 1 (1 equiv.)
were added drop wise to this solution. After stirring for 2 to 3 h
another portion of nBuLi (0.9 equiv.) was added. The mixture was
then cooled to Ϫ100 °C and benzyloxymethyl chloride (1.2 equiv.)
in dry THF (0.5 mL/mmol) was slowly added at this temperature.
This solution was warmed to Ϫ65 °C over 2 to 3 h. The reaction
mixture was quenched with water and after warming up pH-7
buffer solution was added. The mixture was extracted three times
with CH2Cl2 and the combined organic layers were washed with
brine, dried with Na2SO4 and concentrated in vacuo. The pure
products where obtained by flash column chromatography.
[α]2D3 ϭ ϩ5.8 (c ϭ 1.1, CHCl3)}.
Table 6. Reductive detosylation and Boc-protection of the chiral
azetidines 6
Product
R1
R2
Yield [%]
(2 steps)
de [%]
ee [%]
(R,S)-7a
(R,S)-7b
nBu
Ph
n-Hex
n-Hex
85
92
95[a]
91[c]
Ն 96[b]
96[d]
[a]
[b]
Determined by gas chromatography.
In correlation with the
de value of the corresponding hydrazine determined by 1H and 13
C
[c]
NMR spectroscopy. The following steps are racemisation-free.
Determined by H and 13C NMR spectroscopy. Determined by
1
[d]
(2R,2S)-(؊)-[3-Benzyloxy-2-methylpropylidene][2-(methoxymethyl)-
pyrrolidin-1-yl]amine [(R,S)-2a]: Hydrazone (S)-1a (3.41 g,
20.0 mmol) was alkylated according to GP 1. Purification by flash
column chromatography (pentane/Et2O, 6:1, 1% Et3N) gave (R,S)-
2a as a colourless oil (4.03 g, 70%). [α]2D3 ϭ Ϫ89.4 (c ϭ 1.0, CHCl3).
Rt ϭ 15.79 min (CP-Sil-8, 80Ϫ10Ϫ300). Rf ϭ 0.60 (pentane/Et2O,
1:1). IR (film): ν˜ ϭ 3063 (m), 3030 (m), 2875 (s), 2080 (w), 1952
(w), 1874 (w), 1811 (w), 1726 (w), 1602 (m), 1495 (m), 1455 (s),
1363 (m), 1304 (w), 1199 (s), 1103 (s), 1028 (w), 1000 (w), 973 (m),
HPLC on a chiral stationary phase.
Scheme 2. Tosyl cleavage and subsequent Boc protection: a) Na/
naphthalene, DME, Ϫ45 °C; b) (Boc)2O, TEA, DCM
903 (m), 878 (m), 740 (s), 700 (s), 611 (m) cmϪ1 1H NMR
.
(300 MHz, CDCl3): δ ϭ 1.12 (d, J ϭ 6.9 Hz, 3 H, CHCH3),
1.75Ϫ1.99 (m, 4 H, NCH2CH2CH2), 2.71 (m, 2 H, NϭCHCH,
NCHH), 3.36 (s, 3 H, OCH3), 3.30Ϫ3.60 (m, 6 H, NCHH,
CH2OCH2Ph, NCHCH2OCH3), 4.51 (s, 2 H, OCH2Ph), 6.56 (d,
J ϭ 5.9 Hz, 1 H, NϭCH), 7.26Ϫ7.33 (m, 5 H, CHarom.) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 15.8 (CH2CH3), 22.1 (NCH2CH2),
26.6 (NCH2CH2CH2), 37.5 (NϭCHCH), 50.1 (NCH2), 59.2
(OCH3), 63.4 (NCH), 72.9 (CH2OCH2Ph), 74.1 (OCH2Ph), 74.7
(CH2OCH3), 127.5, 127.6, 128.3 (Ar C), 138.6 (Ar Cq), 140.2 (Nϭ
CH) ppm. MS (EI, 70 eV): m/z (%) ϭ 290 (7) [Mϩ], 245 (100), 169
Conclusion
In summary, we have developed a versatile and efficient
asymmetric synthesis of 2-mono- and 2,3-trans-disubsti-
tuted azetidines starting from aldehyde-SAMP/RAMP-hy-
drazones including a short three-step asymmetric synthesis
of 3-amino-1-alkanols on the way. The amino alcohols and
azetidines were obtained in very good diastereomeric and (2), 123 (3), 91 (29), 70 (13). C17H26N2O2 (290.40): calcd. C 70.31,
H 9.02, N 9.65; found C 70.72, H 8.93, N 9.96.
enantiomeric purities. Furthermore, the removal of the to-
syl protecting group of the azetidines was shown for selec-
ted examples.
(2R,2S)-(؊)-[2-(Benzyloxymethyl)butylidene][2-(methoxymethyl)-
pyrrolidin-1-yl]amine [(R,S)-2b]: Hydrazone (S)-1b (2.76 g,
15.0 mmol) was alkylated according to GP 1. Purification by flash
column chromatography (pentane/Et2O, 5:1, 1% Et3N) gave (R,S)-
2b as a colourless oil (3.15 g, 69%). [α]2D4 ϭ Ϫ60.3 (c ϭ 1.2, CHCl3).
Rt ϭ 10.80 min (CP-Sil-8, 140Ϫ10Ϫ300). Rf ϭ 0.38 (pentane/Et2O,
2:1). IR (film): ν˜ ϭ 3063 (m), 3029 (m), 2961 (s), 2927 (s), 2873 (s),
1950 (w), 1874 (w), 1810 (w), 1726 (w), 1602 (m), 1456 (s), 1363
(m), 1341 (m), 1303 (m), 1199 (m), 1111 (s), 1028 (m), 973 (m), 905
(m), 737 (s), 699 (m), 612 (m) cmϪ1. 1H NMR (300 MHz, CDCl3):
δ ϭ 0.92 (t, J ϭ 7.5 Hz, 3 H, CH2CH3), 1.49 (m, 1 H, CHHCH3),
1.62 (m, 1 H, CHHCH3), 1.75Ϫ2.00 (m, 4 H, NCH2CH2CH2), 2.47
(m, 1 H, NϭCHCH), 2.74 (q, J ϭ 8.4 Hz, 1 H, NCHH), 3.32 (m, 1
H, NCHH), 3.36 (s, 3 H, OCH3), 3.39Ϫ3.60 (m, 5 H, CH2OCH2Ph,
Experimental Section
General Remarks: All solvents were dried and purified by conven-
tional methods prior to use. THF and dimethoxyethane were
freshly distilled from sodium/lead alloy and benzophenone under
argon. All moisture sensitive reactions were carried out under ar-
gon using standard Schlenk techniques. Diisopropylamine was dis-
tilled from CaH2 under argon and stored over molecular sieves.
Sodium metal was cleaned and rinsed with dry methanol before
use. Flash column chromatography was carried out with Merck
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Eur. J. Org. Chem. 2004, 4471Ϫ4482

Asymmetric Synthesis of 2-Mono- and 2,3-trans-Disubstituted Azetidines
NCHCH2OCH3), 4.48 (d, J ϭ 12.4 Hz, 1 H, OCHHPh), 4.53 (d, Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 352 (9) [Mϩ], 307 (100), 231
FULL PAPER
J ϭ 12.4 Hz, 1 H, OCHHPh), 6.54 (d, J ϭ 6.7 Hz, 1 H, NϭCH),
(17), 114 (5), 91 (52), 70 (11). C22H28N2O2 (352.47): calcd. C 74.97,
7.26Ϫ7.33 (m, 5 H, CHarom.) ppm. 13C NMR (75 MHz, CDCl3): H 8.01, N 7.95; found C 74.83, H 8.35, N 8.44.
δ ϭ 11.5 (CH2CH3), 22.1 (NCH2CH2), 23.4 (CH2CH3), 26.6
(2S)-(؊)-[3-(Benzyloxy)propylidene][2-(methoxymethyl)pyrrolidin-1-
(NCH2CH2CH2), 44.4 (NϭCHCH), 50.2 (NCH2), 59.2 (OCH3),
63.4 (NCH), 72.4 (CH2OCH2Ph), 72.9 (OCH2Ph), 74.7
(CH2OCH3), 127.4, 127.6, 128.3 (Ar C), 138.7 (Ar Cq), 139.8 (Nϭ
CH) ppm. MS (EI, 70 eV): m/z (%) ϭ 304 (6) [Mϩ], 259 (100), 183
(3), 91 (34), 70 (13). C18H28N2O2 (304.43): calcd. C 71.02, H 9.27,
N 9.20; found C 70.99, H 9.43, N 9.68.
yl]amine [(S)-2e]:[32] SAMP (6.11 g, 46.9 mmol) was added drop-
wise to benzyloxypropanal (7) (7.69 g, 46.9 mmol) at 0 °C. The
reaction mixture was warmed to room temperature over 16 h, di-
luted with diethyl ether (100 mL) and dried with MgSO4. The sol-
vent was removed under reduced pressure and hydrazone (S)-2e
(10.44 g, 81%) was obtained as a colourless oil after flash column
chromatography (pentane/EtO2, 4:1, 2% Et3N). [α]2D5 ϭ Ϫ94.7 (c ϭ
1.0, CHCl3). Rt ϭ 18.86 min (CP-Sil-8, 100Ϫ10Ϫ300). Rf ϭ 0.40
(pentane/Et2O, 2:1). IR (film): ν˜ ϭ 3087 (m), 3029 (m), 2954 (s),
2874 (s), 1603 (w), 1496 (w), 1454 (m), 1363(m), 1341(m), 1303(m),
1282 (m), 1198 (s), 1100 (s), 1029 (m), 972 (m), 909 (m), 874 (m),
735 (s), 699 (s) cmϪ1. 1H NMR (300 MHz, CDCl3): δ ϭ 1.74Ϫ1.98
(m, 4 H, NCH2CH2CH2), 2.54 (dt, J ϭ 5.5, 6.6 Hz, 2 H, Nϭ
CHCH2), 2.72 (m, 1 H, NCHH), 3.31Ϫ3.35 (m, 1 H, NCH), 3.36
(s, 3 H, OCH3), 3.40Ϫ3.45 (m, 2 H, NCHCH2), 3.55 (m, 1 H,
NCHH), 3.62 (t, J ϭ 6.6 Hz, 2 H, OCH2CH2), 4.51 (s, 2 H,
OCH2Ph), 6.65 (t, J ϭ 5.5 Hz, 1 H, HCϭN), 7.24Ϫ7.34 (m, 5 H,
Ph-CH) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 22.13 (NCH2CH2),
26.54 (NCH2CH2CH2), 33.54 (NϭCHCH2), 50.05 (NCH2), 59.08
(NCH), 63.23 (OCH3), 68.57 (CH2OCH2Ph), 72.75 (OCH2Ph),
74.67 (CH2OCH3), 127.32, 127.45, 128.12 (Ar CH), 134.74 (Ar Cq),
138.21 (NϭCH) ppm. MS (EI, 70 eV): m/z (%) ϭ 276 (9) [Mϩ],
231 (100), 91 (19), 70 (6). C16H24N2O2 (276.38): calcd. C 69.53, H
8.75, N 10.14; found C 69.44, H 8.44, N 10.28.
(2R,2S)-(؊)-[2-(Benzyloxymethyl)hexylidene][2-(methoxymethyl)-
pyrrolidin-1-yl]amine [(R,S)-2c]: Hydrazone (S)-1c (2.11 g,
9.9 mmol) was alkylated according to GP 1. Purification by flash
column chromatography (pentane/Et2O, 8:1 to 6:1, 1% Et3N) gave
(R,S)-2c as a colourless oil (2.61 g, 79%). [α]2D5 ϭ Ϫ81.7 (c ϭ 1.1,
CHCl3). Rt ϭ 14.19 min (CP-Sil-8, 120Ϫ10Ϫ300). Rf ϭ 0.48 (pen-
tane/Et2O, 2:1). IR (film): ν˜ ϭ 3062 (m), 3028 (m), 2927 (s), 2860
(s), 1956 (w), 1873 (w), 1809 (w), 1728 (w), 1601 (m), 1456 (s), 1361
(m), 1304 (w), 1199 (m), 1108 (s), 1026 (w), 972 (w), 902 (m), 739
(m), 699 (m), 612 (w) cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 0.88
(t, J ϭ 7.2 Hz, 3 H, CH2CH3), 1.31 (m, 4 H, CH2CH2CH3), 1.44
[m, 1 H, CHH(CH2)2CH3], 1.55 [m, 1 H, CHH(CH2)2CH3],
1.76Ϫ1.98 (m, 4 H, NCH2CH2CH2), 2.54 (m, 1 H, NϭCHCH),
2.72 (q, J ϭ 8.2 Hz, 1 H, NCHH), 3.32 (m, 1 H, NCHH), 3.36 (s,
3 H, OCH3), 3.50 (m, 5 H, CH2OCH2Ph, NCHCH2OCH3), 4.48
(d, J ϭ 12.2 Hz, 1 H, OCHHPh), 4.52 (d, J ϭ 12.2 Hz, 1 H,
OCHHPh), 6.53 (d, J ϭ 6.6 Hz, 1 H, NϭCH), 7.26Ϫ7.33 (m, 5 H,
CHarom.) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 14.0 (CH2CH3),
22.1 (NCH2CH2), 22.8 (CH2CH3), 26.5 (NCH2CH2CH2), 29.1
(CH2CH2CH3), 30.1 (CH2CH2CH2CH3), 42.9 (NϭCHCH), 50.1
(NCH2), 59.1 (OCH3), 63.3 (NCH), 72.7 (CH2OCH2Ph), 72.8
(OCH2Ph), 74.6 (CH2OCH3), 127.2, 127.4, 128.1 (Ar CH), 138.5
(Ar Cq), 139.9 (CHϭN) ppm. MS (EI, 70 eV): m/z (%) ϭ 332 (6)
[Mϩ], 287 (100), 211 (3), 91 (24), 70 (15). C20H32N2O2 (332.48):
calcd. C 72.25, H 9.70, N 8.43; found C 72.74, H 9.68, N 8.82.
General Procedure for the 1,2-Addition of Organocerium Reagents
to SAMP-Hydrazones 2 (GP 2): CeCl3·7 H2O (4.0 equiv.) was dehy-
drated for 2 h at 140 °C under reduced pressure (0.1 Torr) in a
Schlenk flask equipped with a magnetic stirrer. It was then sus-
pended in dry THF (15 mL/mmol) by sonification for 15 min and
additional stirring for 12 h. The suspension was cooled to Ϫ78 °C
and the organolithium reagent (4.0 equiv.) was added. The mixture
was stirred for 2 h at this temperature, giving a yellow or orange
coloured suspension. After the mixture had been cooled to Ϫ100
°C it was transferred through a double ended needle into a solution
of the hydrazone (1.0 equiv.) in dry THF (15 mL/mmol), that was
also cooled to Ϫ100 °C. The reaction mixture was warmed to Ϫ78
°C over approximately 2 h and then quenched with H2O. After a
saturated aqueous solution of NaHCO3 had been added the aque-
ous layer was extracted with CH2Cl2. The combined organic phases
were dried with Na2SO4 and concentrated in vacuo. The crude hy-
drazine was purified by flash column chromatography.
(2R,2S)-(؊)-[3-Benzyloxy-2-phenylpropylidene][2-(methoxymethyl)-
pyrrolidin-1-yl]amine [(R,S)-2d]: Hydrazone (S)-1d was alkylated
with
a slight variation of GP 1. SAMP-hydrazone (3.48 g,
15.0 mmol) was added dropwise to a solution of LDA (1.1 equiv.)
in dry THF (30 mL) at 0 °C. After stirring for 3 h at this tempera-
ture the mixture was cooled to Ϫ90 °C and a solution of benzyloxy-
methyl chloride (2.82 g, 18.0 mmol) dissolved in dry THF (6.0 mL)
was slowly added. After 45 min at this temperature the solution
was warmed to room temperature over 16 h. Purification by flash
column chromatography (pentane/Et2O, 10:1 to 4:1) gave (R,S)-2d
as a colourless oil (4.30 g, 81%). [α]2D4 ϭ Ϫ93.8 (c ϭ 0.9, CHCl3).
(1R,1ЈR,2S)-(؊)-[1-(2Ј-Benzyloxy-1Ј-methylethyl)pentyl][2-(meth-
Rt ϭ 18.86 min (CP-Sil-8, 100Ϫ10Ϫ300). Rf ϭ 0.76 (pentane/Et2O, oxymethyl)pyrrolidin-1-yl]amine [(R,R,S)-3a]: According to GP 2
1:1). IR (film): ν˜ ϭ 3060 (m), 3028 (m), 2874 (s), 1951 (w), 1877 CeCl3/nBuLi (4.0 equiv.) was reacted with hydrazone (R,S)-2a
(w), 1811 (w), 1745 (w), 1601 (m), 1494 (m), 1454 (s), 1359 (m), (1.74 g, 6.0 mmol). Compound (R,R,S)-3a (1.89 g, 90%) was ob-
1305 (m), 1199 (m), 1107 (s), 1027 (m), 971 (m), 902 (m), 742 (s), tained as a colourless oil after purification by flash column chro-
700 (s), 608 (w), 569 (w), 540 (w) cmϪ1
.
1H NMR (400 MHz,
matography (pentane/Et2O, 4:1, 1% Et3N). [α]2D7 ϭ Ϫ59.0 (c ϭ 1.0,
CDCl3): δ ϭ 1.74Ϫ1.97 (m, 4 H, NCH2CH2CH2), 2.76 (q, J ϭ CHCl3). Rt ϭ 15.88 min (CP-Sil-8, 100Ϫ10Ϫ300). Rf ϭ 0.29 (pen-
8.2 Hz, 1 H, NCHH), 3.28 (m, 1 H, NCHH), 3.33 (s, 3 H, OCH3), tane/Et2O, 2:1). IR (film): ν˜ ϭ 3063 (w), 3029 (m), 2957 (s), 2871
3.34Ϫ3.49 (m, 2 H, NCHCHHOCH3), 3.56 (dd, J ϭ 3.6, 9.1 Hz, (s), 1948 (w), 1807 (w), 1605 (w), 1457 (m), 1368 (m), 1199 (m),
1
H, NCHCHHOCH3), 3.75 (dd,
J
ϭ
6.6, 9.2 Hz,
1
H,
1100 (s), 917 (m), 738 (m), 699 (m), 610 (w) cmϪ1 1H NMR
.
CHHOCH2), 3.85 (m, 1 H, NϭCHCH), 3.92 (dd, J ϭ 6.8, 9.2 Hz, (300 MHz, CDCl3): δ ϭ 0.90 (t, J ϭ 6.6 Hz, 3 H, CH2CH3), 0.93
1 H, CHHOCH2), 4.50 (s, 2 H, OCH2Ph), 6.54 (d, J ϭ 5.8 Hz, 1 H, (d, J ϭ 6.9 Hz, 3 H, CHCH3), 1.23Ϫ1.44 [m, 6 H, (CH2)3CH3],
NϭCH), 7.19Ϫ7.33 (m, 10 H, CHarom.) ppm. 13C NMR (75 MHz, 1.52Ϫ2.16 (m, 5 H, NCH2CH2CH2, NCHCH), 2.18 (q, J ϭ 8.5 Hz,
CDCl3): δ ϭ 22.1 (NCH2CH2), 26.6 (NCH2CH2CH2), 49.1 (Nϭ
1 H, NCHH), 2.56 (m, 2 H, NCHCH2O, NH), 2.78 (m, 1 H,
CHCH), 49.8 (NCH2), 59.2 (OCH3), 63.2 (NCH), 72.8 NCHCH), 3.34 (s, 3 H, OCH3), 3.29Ϫ3.60 (m, 5 H, NCHH,
(CH2OCH2Ph), 72.8 (OCH2Ph), 74.7 (CH2OCH3), 126.6, 127.4, CH2OCH3, CH2OCH2Ph), 4.47 (d, J ϭ 12.1 Hz, 1 H, OCHHPh),
127.5, 128.2, 128.3, 128.4 (Ar C), 136.9 (NϭCH), 138.5, 140.9 (Ar 4.52 (d, J ϭ 12.1 Hz, 1 H, OCHHPh), 7.24Ϫ7.33 (m, 5 H, CHarom.
)
Eur. J. Org. Chem. 2004, 4471Ϫ4482
www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4475

D. Enders, J. Gries, Z.-S. Kim
FULL PAPER
ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 13.2, 14.2 (CH3), 21.0
(1S,2R,2ЈS)-(؊)-[2-(Benzyloxymethyl)-1-(tert-butyl)hexyl][2Ј-meth-
(CH2CH3), 23.3 (NCH2CH2), 26.4 (NCH2CH2CH2), 28.0 oxymethyl)pyrrolidin-1Ј-yl]amine [(S,R,S)-3d]:
(CH2CH2CH3), 29.5 (CH2CH2CH2CH3), 34.6 (NCHCH), 57.4 CeCl3/tBuLi (4.0 equiv.) in dry THF was prepared as described in
(NCH2), 59.0 (OCH3), 61.3 (NCHCH), 66.3 (NCHCH2O), 73.0 GP 2 and then cooled to Ϫ100 °C. A solution of hydrazone (R,S)-
A suspension of
(CH2OCH2Ph), 74.2 (CH2Ph), 75.4 (CH2OCH3), 127.5, 127.6, 2c (0.85 g, 2.5 mmol) in dry THF (5 mL) was slowly added to this
128.3 (Ar CH), 138.7 (Ar Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 348 orange coloured mixture. The solution was warmed to room tem-
(40) [Mϩ], 303 (100), 291 (11), 199 (37), 129 (17), 114 (8), 91 (34), perature over 16 h and worked up as described in GP 2. Compound
70 (18). C21H36N2O2 (348.52): calcd. C 72.37, H 10.41, N 8.04;
found C 72.29, H 10.51, N 8.41.
(S,R,S)-3d (0.89 g, 91%) was obtained as a colourless oil after puri-
fication by flash column chromatography (pentane/Et2O, 7:1).
[α]D24 ϭ Ϫ66.0 (c ϭ 1.0, CHCl3). Rt ϭ 14.85 min (CP-Sil-8,
120Ϫ10Ϫ300). Rf ϭ 0.39 (pentane/Et2O, 4:1). IR (film): ν˜ ϭ 3064
(w), 3030 (m), 2954 (s), 2868 (s), 1945 (w), 1806 (w), 1728 (w), 1604
(w), 1458 (m), 1391 (m), 1363 (m), 1250 (w), 1200 (m), 1100 (s),
(1R,1ЈR,2S)-(؊)-{1-[(1Ј-Benzyloxymethyl)propyl]pentyl}[2-(meth-
oxymethyl)pyrrolidin-1-yl]amine [(R,R,S)-3b]: According to GP 2
CeCl3/nBuLi (4.0 equiv.) was reacted with hydrazone (R,S)-2b
(0.63 g, 2.1 mmol). Compound (R,R,S)-3b (0.69 g, 93%) was ob-
tained as a colourless oil after purification by flash column chro-
matography (pentane/Et2O, 4:1). [α]2D3 ϭ Ϫ65.1 (c ϭ 2.0, CHCl3).
Rt ϭ 16.18 min (CP-Sil-8, 100Ϫ10Ϫ300). Rf ϭ 0.36 (pentane/Et2O,
2:1). IR (film): ν˜ ϭ 3087 (w), 3063 (w), 3030 (m), 2958 (s), 2929
(s), 2872 (s), 1954 (w), 1878 (w), 1807 (w), 1726 (w), 1623 (m), 1496
(m), 1455 (s), 1250 (s), 1098 (s), 914 (m), 734 (s), 698 (m), 646 (w)
1027 (w), 919 (w), 737 (m), 698 (m) cmϪ1 1H NMR (400 MHz,
.
CDCl3): δ ϭ 0.90 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 0.92 [s, 9 H,
C(CH3)3], 1.25Ϫ1.91 (m, 11 H, CHCH2CH2CH2, NCH2CH2CH2),
2.17 (q, J ϭ 8.4 Hz, 1 H, NCHH), 2.46 (m, 3 H, NCHCH2O,
NHCHCH), 3.33 (s, 3 H, OCH3), 3.15Ϫ3.67 (m, 5 H, NCHH,
CH2OCH3, CH2OCH2Ph), 4.44 (s, 2 H, OCH2Ph), 7.24Ϫ7.33 (m,
5 H, CHarom.) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 14.2
1
cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 0.90 (t, J ϭ 6.6 Hz, 3 H,
(CH2CH3),
20.9
(CH2CH3),
23.0
(NCH2CH2),
26.7
CH2CH3), 0.93 (t, J ϭ 6.5 Hz, 3 H, CH2CH3), 1.12Ϫ1.45 [m, 8
H, (CH2)3CH3, CHCH2CH3), 1.52Ϫ1.96 (m, 5 H, NCH2CH2CH2,
NCHCH), 2.14 (q, J ϭ 8.7 Hz, 1 H, NCHH), 2.46 (m, 2 H,
NCHCH2O, NH), 2.86 (m, 1 H, NCHCH), 3.33 (s, 3 H, OCH3),
3.29Ϫ3.58 (m, 5 H, NCHH, CH2OCH3, CH2OCH2Ph), 4.46 (d,
J ϭ 12.2 Hz, 1 H, OCHHPh), 4.51 (d, J ϭ 12.2 Hz, 1 H,
OCHHPh), 7.24Ϫ7.33 (m, 5 H, CHarom.) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 12.6, 14.4 (CH2CH3), 21.1, 21.2 (CH2CH3), 23.4
(NCH2CH2CH2), 27.9 [C(CH3)3], 30.3, 33.1 (CH2CH2CH2CH3),
35.5 [C(CH3)3], 39.0 (NCHCH), 56.5 (NCH2), 58.8 (OCH3), 66.1
(NCHCH2O), 67.5 (NCHCH), 72.0 (CH2OCH2Ph), 72.3 (CH2Ph),
75.3 (CH2OCH3), 127.1, 127.3, 128.0 (Ar CH), 138.6 (Ar Cq) ppm.
MS (EI, 70 eV): m/z (%) ϭ 390 (7) [Mϩ], 333 (100), 199 (9), 114
(8), 91 (19), 70 (8). C24H42N2O2 (390.60): calcd. C 73.80, H 10.84,
N 7.17; found C 73.45, H 10.92, N 7.57.
(NCH2CH2), 26.6 (NCH2CH2CH2), 28.5 (CH2CH2CH3), 30.5 (1R,1ЈR,2S)-(؊)-[1-(2Ј-Benzyloxy-1Ј-phenylethyl)heptyl][2-(meth-
(CH2CH2CH2CH3), 41.7 (NCHCH), 57.4 (NCH2), 59.2 (OCH3), oxymethyl)pyrrolidin-1-yl]amine [(R,R,S)-3e]: According to GP 2
60.0 (NCHCH), 66.3 (NCHCH2O), 71.6 (CH2OCH2Ph), 73.2 CeCl3/n-hexyllithium (4.0 equiv.) was reacted with hydrazone
(CH2Ph), 75.5 (CH2OCH3), 127.6, 127.7, 128.5 (Ar CH), 139.0 (Ar (R,S)-2d (1.41 g, 4.0 mmol). Compound (R,R,S)-3e (1.50 g, 93%)
Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 362 (36) [Mϩ], 317 (100), 305
was obtained as a colourless oil after purification by flash column
(12), 199 (63), 129 (20), 114 (9), 91 (38), 70 (19). C22H38N2O2 chromatography (pentane/Et2O, 6:1, Et3N 0.5%). [α]2D7 ϭ Ϫ60.1
(362.55): calcd. C 72.88, H 10.56, N 7.73; found C 72.47, H 10.78,
N 7.93.
(c ϭ 1.0, CHCl3). Rt ϭ 16.99 min (CP-Sil-8, 140Ϫ10Ϫ300). Rf ϭ
0.38 (pentane/Et2O, 2:1). IR (film): ν˜ ϭ 3062 (m), 3028 (m), 2926
(s), 2857 (s), 1948 (w), 1874 (w), 1808 (w), 1722 (w), 1602 (w), 1495
(m), 1455 (m), 1364 (m), 1198 (w), 1101 (s), 1028 (w), 917 (m), 754
(1R,1ЈR,2S)-(؊)-{1-[1Ј-(Benzyloxymethyl)pentyl]heptyl}[2-(meth-
oxymethyl)pyrrolidin-1-yl]amine [(R,R,S)-3c]: According to GP 2
CeCl3/n-hexyllithium (4.0 equiv.) was reacted with hydrazone
(R,S)-2c (1.00 g, 3.0 mmol). Compound (R,R,S)-3c (0.92 g, 73%)
was obtained as a colourless oil after purification by flash column
chromatography (pentane/Et2O, 6:1). [α]2D4 ϭ Ϫ48.9 (c ϭ 1.3,
CHCl3). Rt ϭ 16.65 min (CP-Sil-8, 120Ϫ10Ϫ300). Rf ϭ 0.44 (pen-
tane/Et2O, 4:1). IR (film): ν˜ ϭ 3062 (w), 3029 (m), 2926 (s), 2858
(s), 1946 (w), 1871 (w), 1807 (w), 1725 (w), 1604 (w), 1458 (s), 1363
(m), 1251(w), 1199 (m), 1101 (s), 1028 (w), 918 (w), 735 (m), 698
1
(s), 701 (s), 606 (w), 549 (w) cmϪ1. H NMR (400 MHz, CDCl3):
δ ϭ 0.83 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 1.12Ϫ1.30 [m, 8 H,
(CH2)4CH3], 1.31Ϫ1.91 (m, 6 H, NCH2CH2CH2, CH2(CH2)4CH3],
1.95 (q, J ϭ 8.5 Hz, 1 H, NCHH), 2.56 (m, 1 H, NCHCH2O), 2.85
(s, 1 H, NH), 3.11 (m, 2 H, NCHCH), 3.32 (s, 3 H, OCH3), 3.30
(m, 2 H, NCHH, CHHOCH3), 3.55 (dd, J ϭ 9.1, 3.9 Hz, 1 H,
CHHOCH3), 3.76 (m, 2 H, CH2OCH2Ph), 4.49 (s, 2 H, OCH2Ph),
7.17Ϫ7.34 (m, 10 H, CHarom.) ppm. 13C NMR (100 MHz, CDCl3):
δ
ϭ 14.1 (CH2CH3), 21.0, 22.6, 24.5, 26.4, 29.6, 31.0
1
(m), 609 (w) cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 0.89 (t, J ϭ
(NCH2CH2CH2, CH2CH2CH2CH2CH3), 33.8 (CH2(CH2)4CH3],
46.8 (NCHCH), 56.3 (NCH2), 58.9 (OCH3), 61.7 (NCHCH), 65.8
(NCHCH2O), 72.2 (CH2OCH2Ph), 73.0 (CH2Ph), 75.0
(CH2OCH3), 126.2, 127.3, 127.4, 128.0, 128.1, 128.3 (Ar CH),
138.0, 141.2 (Ar Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 438 (3) [Mϩ],
227 (100), 114 (8), 91 (12), 70 (10). HRMS calcd. for C28H42N2O2:
438.3246; found 438.3248.
7.1 Hz, 3 H, CH2CH3), 0.90 (t, J ϭ 6.5 Hz, 3 H, CH2CH3), 1.29
[m, 16 H, (CH2)5CH3, CH(CH2)3CH3], 1.52Ϫ1.89 (m, 5 H,
NCH2CH2CH2, NCHCH), 2.14 (q, J ϭ 8.6 Hz, 1 H, NCHH), 2.46
(m, 2 H, NCHCH2O, NH), 2.86 (m, 1 H, NCHCH), 3.33 (s, 3 H,
OCH3), 3.29Ϫ3.58 (m, 5 H, NCHH, CH2OCH3, CH2OCH2Ph),
4.44 (d, J ϭ 12.2 Hz, 1 H, OCHHPh), 4.50 (d, J ϭ 12.2 Hz, 1 H,
OCHHPh), 7.24Ϫ7.33 (m, 5 H, CHarom.) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 2 ϫ 14.3 (2 ϫ CH2CH3), 21.20 (CH2), 22.9
(1R,2S)-(؊)-[1-(2-Benzyloxyethyl)heptyl][2-(methoxymethyl)-
(NCH2CH2), 23.3, 26.3, 26.7, 28.0, 30.0, 30.4, 30.8, 32.2 (CH2), pyrrolidin-1-yl]amine [(R,S)-3f]: A suspension of CeCl3/n-hexyl-
40.0 (NCHCH), 57.5 (NCH2), 59.2 (OCH3), 60.2 (NCHCH), 66.3 lithium (4.0 equiv.) in dry THF was prepared as described in GP 2
(NCHCH2O), 71.8 (CH2OCH2Ph), 73.1 (CH2Ph), 75.5 and then cooled to Ϫ100 °C. A solution of hydrazone (S)-2e
(CH2OCH3), 127.6, 127.7, 128.5 (Ar CH), 139.0 (Ar Cq) ppm. MS (0.83 g, 3.0 mmol) in dry THF (45 mL) was slowly added to this
(EI, 70 eV): m/z (%) ϭ 418 (50) [Mϩ], 373 (100), 333 (15), 227 (88), yellow coloured mixture. The solution was warmed to room tem-
211 (7), 129 (17), 91 (28), 85 (7), 70 (13). C26H46N2O2 (418.66): perature over 16 h and worked up as described in GP 2. Compound
calcd. C 74.59, H 11.07, N 6.69; found C 74.26, H 10.92, N 7.12.
(R,S)-3f (0.82 g, 76%) was obtained as a colourless oil after purifi-
4476
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4471Ϫ4482

Asymmetric Synthesis of 2-Mono- and 2,3-trans-Disubstituted Azetidines
FULL PAPER
cation by flash column chromatography (pentane/Et2O, 2:1). by flash column chromatography (pentane/Et2O, 1:1, 2% Et3N).
[α]2D5 ϭ Ϫ77.3 (c ϭ 1.1, CHCl3). Rt ϭ 17.19 min (CP-Sil-8, Yield: 0.35 g (83%). [α]2D4 ϭ ϩ8.3 (c ϭ 1.6, CHCl3). Rt ϭ 10.92 min
100Ϫ10Ϫ300). Rf ϭ 0.11 (pentane/Et2O, 2:1). IR (film): ν˜ ϭ 3087 (CP-Sil-8, 100Ϫ10Ϫ300). Rf ϭ 0.46 (MeOH/CH2Cl2, 2:1). IR
(w), 3062 (w), 3030 (m), 2926 (s), 2856 (s), 1946 (w), 1873 (w), 1807 (film): ν˜ ϭ 3381 (w), 3064 (m), 3030 (m), 2958 (s), 2929 (s), 2871
(w), 1604 (w), 1494 (m), 1457 (s), 1363 (m), 1306 (w), 1198 (m),1102 (s), 1948 (w), 1872 (w), 1808 (w), 1606 (m), 1495 (m), 1456 (s,),
(s), 1027 (w), 919 (m), 859 (w), 812 (w), 738 (m), 698 (m), 610 (w) 1363 (m), 1204 (m), 1100 (s), 908 (w), 819 (w), 736 (m), 699 (m),
1
cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 0.89 (t, 3 H, J ϭ 6.9 Hz,
606 (w) cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ 0.91 [t, J ϭ
.
CH2CH3), 1.20Ϫ1.38 [m, 9 H, CHH(CH2)4CH3], 1.45Ϫ1.77 [m, 6 7.1 Hz, 3 H, (CH2CH3), 0.92 (t, J ϭ 7.4 Hz, 3 H, CH2CH3),
H, CH3(CH2)4CHH, NCHCH2CH2O, NCH2CH2CHH], 1.88 (m, 1.24Ϫ1.50 [m, 9 H, (CH2)3CH3, CHCH2CH3), 2.84 (m, 1 H,
1 H, NCH2CH2CHH), 2.12 (q, J ϭ 8.6 Hz, 1 H, NCHH), 2.55 (m, NCH), 3.51 (d, J ϭ 4.7 Hz, 2 H, CH2OCH2Ph), 4.47 (d, J ϭ
2 H, NH, NCHCH2O), 2.84 (m, 1 H, NCHCH2CH2O), 3.30Ϫ3.42 12.1 Hz, 1 H, OCHHPh), 4.49 (d, J ϭ 12.1 Hz, 1 H, OCHHPh),
(m, 2 H, NCHH, NCHCHHO), 3.35 (s, 3 H, OCH3) 3.44Ϫ3.63 7.25Ϫ7.34 (m, 5 H, CHarom.) ppm. 13C NMR (100 MHz, CDCl3):
(m, 3 H, CH2OCH2Ph, NCHCHHO), 4.50 (s, 2 H, OCH2Ph),
δ
ϭ
12.1 (CH3), 14.1 (CH3), 21.6, 22.8, 29.0, 35.0
7.26Ϫ7.37 (m, 5 H, CHarom.) ppm. 13C NMR (75 MHz, CDCl3):
(CH2CH2CH2CH3, CHCH2CH3), 45.6 (NCHCH), 52.3 (NCH),
δ
ϭ 14.1 (CH2CH3), 21.0, 22.7, 25.3, 26.2 (CH3CH2CH2, 70.2 (CH2OCH2Ph), 73.1 (CH2OCH2Ph), 127.3, 127.4, 128.1 (Ar
NCH2CH2CH2), 29.8, 32.0, 32.7 (NCHCH2CH2CH2), 33.9 CH), 138.4 (Ar Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 192 (7) [Mϩ
(NCHCH2CH2O), 57.2 (NCHCH2CH2O), 57.3 (NCH2), 59.0 Ϫ C4H9], 184 (5), 114 (17), 112 (12), 91 (36), 86 (100), 60 (10).
(OCH3), 65.9 (NCHCH2O), 68.9 (CH2OCH2Ph), 73.0 (OCH2Ph), C16H27NO (249.39): calcd. C 77.06, H 10.91, N 5.62; found C
75.1 (CH2OCH3), 127.5, 127.7, 128.3 (Ar CH), 138.5 (Ar Cq) ppm.
MS (EI, 70 eV): m/z (%) ϭ 362 (22) [Mϩ], 318 (23), 317 (100), 227
(6), 129 (13), 91 (23), 85 (5), 70 (8). C22H38N2O2 (362.56): calcd. C
72.88, H 10.56, N 7.73; found C 72.96, H 10.46, N 8.15.
76.68, H 10.88, N 6.00.
(5R,6R)-(؉)-5-(Benzyloxymethyl)dodecan-6-amine [(R,R)-4c]: Pre-
pared by NϪN cleavage of the corresponding hydrazine (R,R,S)-
3c (0.92 g, 2.2 mmol) with BH3·THF as described in GP 3. Com-
pound (R,R)-4c was obtained as a colourless oil after purification
by flash column chromatography (pentane/Et2O, 1:1, 3% Et3N).
General Procedure for the Preparation of O-Benzyl-Protected 3-
Amino-1-alkanols 4 by N؊N-Cleavage of the Hydrazines 3 (GP 3):
Hydrazines 3 were dissolved in dry THF (1.5 mL/mmol) in a
Schlenk flask under an argon. After a 1  solution of BH3·THF
in THF (10 equiv.) had been added, the mixture was heated to
reflux until complete conversion of the starting material was indi-
cated by TLC (4Ϫ6 h). The solution was then cooled to Ϫ5 °C and
a 1  aqueous HCl solution (10 mL/mmol hydrazine) was added.
After heating to reflux for 2 min the solvent was removed under
reduced pressure and the aqueous residue was neutralized with a
saturated NaHCO3 solution. Extraction with CH2Cl2 followed by
drying of the combined organic phases over Na2SO4 and sub-
sequent removal of the solvent in vacuo yielded the crude amines
4, which were purified by flash column chromatography.
Yield: 0.52 g (78%). [α]2D4 ϭ ϩ14.5 (c ϭ 1.0, CHCl3). Rt
ϭ
14.68 min (CP-Sil-8, 100Ϫ10Ϫ300). Rf ϭ 0.46 (MeOH/CH2Cl2,
1:10). IR (film): ν˜ ϭ 3389 (w), 3062 (m), 3030 (m), 2926 (s), 2857
(s), 1947 (w), 1875 (w), 1806 (w), 1607 (w), 1495 (w), 1457 (m),
1363 (m), 1205 (w), 1100 (m), 1027 (w), 736 (m), 698 (m), 608 (w)
1
cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 0.88 (t, J ϭ 6.9 Hz, 3 H,
CH3), 0.90 (t, J ϭ 6.9 Hz, 3 H, CH3), 1.17Ϫ1.46 [m, 16 H,
(CH2)5CH3, CH(CH2)3CH3], 1.53 (m, 1 H, NCHCH), 2.80 (m, 1
H, NCH), 3.47 (dd, J ϭ 5.4, 9.3 Hz, 1 H, CHHOCH2Ph), 3.50 (dd,
J ϭ 4.9, 9.3 Hz, 1 H, CHHOCH2Ph), 4.45 (d, J ϭ 12.1 Hz, 1 H,
OCHHPh), 4.49 (d, J ϭ 12.1 Hz, 1 H, OCHHPh), 7.25Ϫ7.34 (m,
5 H, CHarom.) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 2 ϫ 14.1
(2 ϫ CH3), 22.6, 23.0, 26.8, 28.5, 29.5, 29.9, 31.9 (CH2), 35.4
(NCHCH2), 44.0 (NCHCH), 52.6 (NCH), 70.5 (CH2OCH2Ph),
73.0 (CH2OCH2Ph), 127.2, 127.3, 128.1 (Ar CH), 138.5 (Ar Cq)
ppm. MS (CI, 100 eV): m/z (%) ϭ 306 (75) [MHϩ], 290 (7), 228
(5), 220 (20), 114 (100), 91 (17). C20H35NO (305.50): calcd. C 78.63,
H 11.55, N 4.58; found C 78.36, H 11.35, N 5.01.
(2R,3R)-(؉)-2-(Benzyloxymethyl)heptan-3-amine [(R,R)-4a]: Pre-
pared by NϪN cleavage of the corresponding hydrazine (R,R,S)-
3a (1.60 g, 4.6 mmol) with BH3·THF as described in GP 3. Com-
pound (R,R)-4a was obtained as a colourless oil after purification
by flash column chromatography (pentane/Et2O, 1:1, 2% Et3N).
Yield: 1.00 g (92%). [α]2D4 ϭ ϩ8.0 (c ϭ 1.0, CHCl3). Rt ϭ 10.41 min
(CP-Sil-8, 100Ϫ10Ϫ300). Rf ϭ 0.43 (MeOH/CH2Cl2, 2:1). IR
(film): ν˜ ϭ 3380 (w), 3062 (m), 3029 (m), 2929 (s), 2860 (s), 1948
(w), 1871 (w), 1808 (w), 1607 (m), 1525 (w), 1495 (m), 1456 (s,),
1365 (m), 1205 (m), 1100 (s), 1028 (w), 738 (s), 699 (m), 610 (w)
(3S,4R)-(؊)-4-(Benzyloxymethyl)-2,2-dimethyloctan-3-amine [(S,S)-
4d]: Prepared by NϪN cleavage of the corresponding hydrazine
(S,R,S)-3d (0.55 g, 1.4 mmol) with BH3·THF as described in GP 3.
Compound (S,R)-4d was obtained as a colourless oil after purifi-
cation by flash column chromatography (pentane/Et2O, 3:1, 1.5%
Et3N). Yield: 0.25 g (64%). [α]2D4 ϭ Ϫ10.0 (c ϭ 1.0, CHCl3). Rt ϭ
12.01 min (CP-Sil-8, 100Ϫ10Ϫ300). Rf ϭ 0.46 (MeOH/CH2Cl2,
1:10). IR (film): ν˜ ϭ 3398 (w), 3334 (w), 3064 (m), 3031 (m), 2955
(s), 2863 (s), 1948 (w), 1871 (w), 1806 (w), 1608 (m), 1460 (m), 1393
(m), 1363 (m), 1206 (w), 1098 (s), 1027 (w), 924 (w), 823 (w), 736
(s), 698 (m), 608 (w) cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 0.89
[t, J ϭ 7.0 Hz, 3 H, (CH2CH3), 0.90 [s, 9 H, C(CH3)3], 1.23Ϫ1.38
(m, 5 H, CHHCH2CH2CH3), 1.62 (m, 1 H, CHHCH2CH2CH3),
1.80 (m, 1 H, NCHCH), 2.44 (d, J ϭ 2.2 Hz, 1 H, NCH), 3.41 (dd,
J ϭ 5.9, 9.2 Hz, 1 H, CHHOCH2Ph), 3.59 (dd, J ϭ 4.3, 9.2 Hz, 1
H, CHHOCH2Ph), 4.44 (d, J ϭ 12.0 Hz, 1 H, OCHHPh), 4.48 (d,
1
cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 0.90 (t, J ϭ 7.0 Hz, 3 H,
CH2CH3), 0.92 (d, J ϭ 6.9 Hz, 3 H, CHCH3), 1.12Ϫ1.50 [m, 8 H,
(CH2)3CH3, NH2), 1.75 (m, 1 H, NCHCH), 2.71 (m, 1 H, NCH),
3.43 (m, 2 H, CH2OCH2Ph), 4.49 (s, 2 H, OCH2Ph), 7.25Ϫ7.34
(m, 5 H, CHarom.) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 14.1,
14.1
(CH2CH3,
CHCH3),
22.9
(CH2CH3),
28.7
(CH2CH2CH2CH3), 34.2 (NCHCH2), 39.4 (NCHCH), 53.7
(NCH), 73.1 (CH2OCH2Ph), 73.3 (CH2OCH2Ph), 127.4, 127.5,
128.3 (Ar CH), 138.7 (Ar Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 178
(8) [Mϩ Ϫ C4H9], 144 (6), 105 (9), 91 (30), 86 (100), 72 (11), 57
(5). C15H25NO (235.37): calcd. C 76.55, H 10.71, N 5.95; found C
76.49, H 10.33, N 6.34.
(3R,4R)-(؉)-3-(Benzyloxymethyl)octan-4-amine [(R,R)-4b]: Pre- J ϭ 12.0 Hz, 1 H, OCHHPh), 7.24Ϫ7.34 (m, 5 H, CHarom.) ppm.
pared by NϪN cleavage of the corresponding hydrazine (R,R,S)-
3b (0.42 g, 1.7 mmol) with BH3·THF as described in GP 3. Com-
13C NMR (100 MHz, CDCl3):
(CH2CH3), 27.1 [C(CH3)3], 30.0 (CH2CH2CH3), 33.2
δ ϭ 14.3 (CH2CH3), 23.4
pound (R,R)-4b was obtained as a colourless oil after purification (CH2CH2CH2CH3), 35.6 [C(CH3)3], 39.1 (NCHCH), 62.6 (NCH),
Eur. J. Org. Chem. 2004, 4471Ϫ4482
www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4477

D. Enders, J. Gries, Z.-S. Kim
FULL PAPER
71.5 (CH2OCH2Ph), 73.3 (OCH2Ph), 127.4, 127.5, 128.3 (Ar CH), with tosyl chloride in the presence of K2CO3. Tosylamine (R,R)-4b
138.7 (Ar Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 278 (4) [MHϩ], 262
was obtained as a colourless oil after flash column chromatography
(4), 220 (100), 114 (86), 91 (97), 86 (72). C18H31NO (277.44): calcd. (pentane/Et2O, 4:1). Yield: 0.52 g (92%); de ϭ 98% (GC, CP-Sil-8).
C 77.92, H 11.26, N 5.05; found C 77.54, H 11.41, N 5.47.
[α]2D2 ϭ ϩ7.8 (c ϭ 1.0, CHCl3). Rt ϭ 20.66 [major anti-isomer],
20.72 min [minor syn-isomer] (CP-Sil-8, 100Ϫ10Ϫ300). Rf ϭ 0.34
(pentane/Et2O, 4:1). IR (film): ν˜ ϭ 3286 (s), 3063 (m), 3031 (m),
2958 (s), 2870 (s), 1953 (w), 1918 (w), 1872 (w), 1810 (w), 1755 (w),
1598 (m), 1496 (m), 1456 (m), 1422 (m), 1326 (s), 1241 (w), 1209
(m), 1160 (s), 1095 (s), 1030 (m), 947 (m), 887 (w), 815 (s), 739 (s),
(2R,3R)-(؉)-1-Benzyloxy-2-phenylnonan-3-amine [(R,R)-4e]: Pre-
pared by NϪN cleavage of the corresponding hydrazine (R,R,S)-
3e (1.24 g, 2.8 mmol) with BH3·THF as described in GP 3. Com-
pound (R,R)-4e was obtained as a colourless oil after purification
by flash column chromatography (pentane/Et2O, 1:1, 3% Et3N).
Yield: 0.81 g (88%). [α]3D0 ϩ28.6 (c ϭ 1.0, CHCl3). Rt ϭ 13.22 min
(CP-Sil-8, 140Ϫ10Ϫ300). Rf ϭ 0.44 (MeOH/CH2Cl2, 1:10). IR
(film): ν˜ ϭ 3382 (w), 3061 (m), 3028 (m), 2926 (s), 2856 (s), 1950
(w), 1875 (w), 1808 (w), 1601 (m), 1494 (m), 1455 (s,), 1363 (m),
700 (s), 667 (s), 552 (m), 461 (w) cmϪ1
CDCl3): δ ϭ 0.74 (t, J ϭ 7.4 Hz, 3 H, CH2CH3), 0.78 (t, J ϭ
6.9 Hz, H, CH2CH3), 1.01Ϫ1.32 [m, H, (CH2)2CH3,
.
1H NMR (400 MHz,
3
6
CHCH2CH3], 1.43 (m, 2 H, NCHCH2), 1.51 (m, 1 H, NCHCH),
2.39 (s, 3 H, Ar Ϫ CH3), 3.35 (m, 2 H, CHHOCH2Ph, NCH), 3.55
(dd, J ϭ 3.3, 9.6 Hz, 1 H, CHHOCH2Ph), 4.41 (d, J ϭ 12.1 Hz, 1
H, OCHHPh), 4.47 (d, J ϭ 12.1 Hz, 1 H, OCHHPh), 5.52 (d, J ϭ
7.7 Hz, 1 H, NH), 7.22Ϫ7.38 (m, 7 H, CHarom.), 7.70 (d, J ϭ
8.0 Hz, 2 H, SO2CCHarom.) ppm. 13C NMR (100 MHz, CDCl3):
δ ϭ 11.8, 13.9 (CH2CH3), 21.4 (Ar Ϫ CH3), 21.7, 22.4,28.0
(CH2CH2CH3, CHCH2CH3), 33.5 (NCHCH2), 42.3 (NCHCH),
56.0 (NCH), 69.5 (CH2OCH2Ph), 73.2 (OCH2Ph), 126.7, 127.4,
127.6, 128.2, 129.1 (Ar CH), 137.7, 138.8, 142.4 (Ar Cq) ppm. MS
(EI, 70 eV): m/z (%) ϭ 403 (1) [Mϩ], 346 (8), 248 (10), 240 (100),
155 (18), 91 (53). C23H33NO3S (403.58): calcd. C 68.45, H 8.24, N
3.47; found C 68.06, H 8.55, N 3.86.
1205 (w), 1103 (s), 1028 (m), 909 (w), 826 (w), 738 (s), 701 (s) cmϪ1
.
1H NMR (400 MHz, CDCl3): δ ϭ 0.84 (t, J ϭ 6.9 Hz, 3 H, CH3),
1.08Ϫ1.42 [m, 10 H, (CH2)5CH3], 2.79 (dt, J ϭ 5.7, 7.3 Hz, 1 H,
NCHCH), 3.08 (m, 1 H, NCH), 3.82 (d, J ϭ 5.7 Hz, 2 H,
CH2OCH2Ph), 4.46 (d, J ϭ 12.1 Hz, 1 H, OCHHPh), 4.51 (d, J ϭ
12.1 Hz, 1 H, OCHHPh), 7.18Ϫ7.34 (m, 10 H, CHarom.) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 14.1 (CH3), 22.6 (CH2CH3), 26.1
(CH2CH2CH3), 29.3 (CH2(CH2)2CH3], 31.8 (CH2(CH2)3CH3], 35.4
(NCHCH2), 52.5 (NCHCH), 54.1 (NCH), 72.1 (CH2OCH2Ph),
73.1 (CH2OCH2Ph), 126.4, 127.5, 127.5, 128.3, 128.3, 128.5 (Ar
CH), 138.4, 142.0 (Ar Cq) ppm. MS (CI, 100 eV): m/z (%) ϭ 326
(100) [MHϩ], 310 (5), 248 (6), 240 (8), 218 (4), 114 (70), 91 (8).
C22H31NO (325.49): calcd. C 81.18, H 9.60, N 4.30; found C 80.88,
H 9.39, N 4.70.
(5R,6R)-(؉)-5-(Benzyloxymethyl)-N-tosyldodecan-6-amine [(R,R)-
5c]: According to GP 4 amine (R,R)-4c (0.37 g, 1.2 mmol) was
treated with tosyl chloride in the presence of K2CO3. Tosylamine
(R,R)-5c was obtained as a colourless solid after flash column chro-
General Procedure for the Tosylation of the Amines 4 (GP 4): The
amines 4 were dissolved in CH2Cl2 (10 mL/mmol). K2CO3 (10
equiv.) and tosyl chloride (1.5 equiv.) were added. The mixture was matography (pentane/Et2O, 5:1). Yield: 0.55 g (99%); de Ն 98%
heated to reflux for 2 h and stirred for 12 h at ambient temperature.
Filtration through a pad of SiO2 with CH2Cl2 and removal of the
solvent under reduced pressure gave the crude products, which were
further purified by flash column chromatgraphy.
(GC, CP-Sil-8); m.p. 54 °C. [α]2D4 ϭ ϩ5.9 (c ϭ 1.0, CHCl3). Rt ϭ
19.84 [major anti-isomer], 19.90 min [minor syn-isomer] (CP-Sil-8,
140Ϫ10Ϫ300). Rf ϭ 0.33 (pentane/Et2O, 4:1). IR (KBr): ν˜ ϭ 3315
(s), 3033 (w), 2932 (s), 2859 (s), 1952 (w), 1925 (w), 1814 (w), 1598
(m), 1497 (m), 1457 (m), 1428 (m), 1326 (s), 1256 (w), 1209 (w),
1158 (s), 1082 (s), 1025 (m), 1002 (m), 910 (m), 817 (m), 748 (m),
(2R,3R)-(؉)-2-(Benzyloxymethyl)-N-tosylheptan-3-amine [(R,R)-
5a]: According to GP 4 amine (R,R)-4a (0.81 g, 3.4 mmol) was
treated with tosyl chloride in the presence of K2CO3. Tosylamine
(R,R)-5a was obtained as a colourless oil after flash column chro-
matography (pentane/Et2O, 3:1). Yield: 1.20 g (89%); de Ն 96% (1H
NMR). [α]2D4 ϭ ϩ8.9 (c ϭ 0.6, CHCl3). Rt ϭ 20.34 min (CP-Sil-8,
100Ϫ10Ϫ300). Rf ϭ 0.64 (pentane/Et2O, 1:1). IR (film): ν˜ ϭ 3285
(s), 3063 (m), 3031 (m), 2957 (s), 2932 (s), 2864 (s), 1918 (w), 1809
(w), 1655 (w), 1599 (m), 1495 (m), 1455 (s), 1425 (m), 1326 (s),
1209 (w), 1160 (s), 1095 (s), 1029 (m), 947 (m), 875 (w), 816 (m),
702 (m), 669 (s), 583 (m), 540 (m) cmϪ1
CDCl3): δ ϭ 0.78 (t, J ϭ 7.1 Hz, 3 H, CH2CH3), 0.85 (t, J ϭ
7.0 Hz, H, CH2CH3), 0.99Ϫ1.25 [m, 14 H, (CH2)4CH3,
.
1H NMR (400 MHz,
3
CH(CH2)3CH3], 1.44 (m, 2 H, NCHCH2), 1.57 (m, 1 H, NCHCH),
2.39 (s, 3 H, ArϪCH3), 3.31 (m, 2 H, CHHOCH2Ph, NCH), 3.50
(dd, J ϭ 3.0, 9.7 Hz, 1 H, CHHOCH2Ph), 4.40 (d, J ϭ 12.1 Hz, 1
H, OCHHPh), 4.47 (d, J ϭ 12.1 Hz, 1 H, OCHHPh), 5.55 (d, J ϭ
8.0 Hz, 1 H, NH), 7.22Ϫ7.37 (m, 7 H, CHarom.), 7.70 (d, J ϭ
8.3 Hz, 2 H, SO2CCHarom.) ppm. 13C NMR (100 MHz, CDCl3):
δ ϭ 14.1 (CH2CH3), 14.3 (CH2CH3), 21.6 (ArϪCH3), 22.7, 22.9,
26.1, 28.7, 29.2, 29.7, 31.8 (CH2), 34.2 (NCHCH2), 40.8
(NCHCH), 56.6 (NCH), 69.9 (CH2OCH2Ph), 73.4 (OCH2Ph),
127.0, 127.5, 127.8, 128.5, 129.4 (ArϪCH), 137.9, 138.0, 142.6 (Ar
Cq) ppm. MS (EI, 70 eV): m/z (%) ϭ 459 (1) [Mϩ], 374 (8), 304
(9), 268 (100), 183 (6), 154 (15), 91 (34). C27H41NO3S (459.68):
calcd. C 70.55, H 8.99, N 3.05; found C 71.03, H 9.21, N 3.08.
739 (m), 700 (m), 667 (s), 584 (m), 552 (s) cmϪ1 1H NMR
.
(400 MHz, CDCl3): δ ϭ 0.76 (t, J ϭ 6.9 Hz, 3 H, CH2CH3), 0.80
(d, J ϭ 7.1 Hz, 3 H, CHCH3), 1.01Ϫ1.17 (m, 4 H, CH2CH2CH3),
1.37 (m, 2 H, NCHCH2), 1.88 (m, 1 H, NCHCH), 2.39 (s, 3 H,
ArϪCH3), 3.26 (m, 2 H, CHHOCH2Ph, NCH), 3.42 (dd, J ϭ 4.4,
9.6 Hz,
1 H, CHHOCH2Ph), 4.39 (d, J ϭ 11.8 Hz, 1 H,
COCHHPh), 4.44 (d, J ϭ 11.8 Hz, 1 H, OCHHPh), 5.34 (d, J ϭ
8.0 Hz, 1 H, NH), 7.21Ϫ7.37 (m, 7 H, CHarom.), 7.72 (d, J ϭ
8.2 Hz, 2 H, SO2CCHarom.) ppm. 13C NMR (100 MHz, CDCl3):
δ ϭ 14.1 (CH2CH3), 14.3 (CHCH3), 21.7 (ArϪCH3), 22.6, 27.8,
32.5 (CH2CH2CH2CH3), 36.0 (NCHCH), 57.2 (NCH), 72.4
(CH2OCH2Ph), 73.2 (OCH2Ph), 127.1, 127.6, 127.6, 128.4, 129.4
(Ar CH), 138.1, 138.7, 142.8 (Ar Cq) ppm. MS (EI, 70 eV): m/z
(%) ϭ 389 (1) [Mϩ], 332 (6), 240 (100), 226 (15), 155 (26), 91 (59).
C22H31NO3S (389.55): calcd. C 67.83, H 8.02, N 3.60; found C
67.40, H 8.08, N 4.05.
(3S,4R)-(؉)-4-(Benzyloxymethyl)-2,2-dimethyl-N-tosyloctan-3-
amine [(S,R)-5d]: According to GP 4 amine (S,R)-4d (0.24 g,
1.2 mmol) was treated with tosyl chloride in the presence of
K2CO3. Tosylamine (S,R)-5d was obtained as a colourless oil after
flash column chromatography (pentane/Et2O, 6:1). Yield: 0.27 g
(76%); de Ն 96% (NMR). [α]2D3 ϭ ϩ42.5 (c ϭ 1.0, CHCl3). Rt ϭ
17.09 min (CP-Sil-8, 140Ϫ10Ϫ300). Rf ϭ 0.32 (pentane/Et2O, 4:1).
IR (film): ν˜ ϭ 3309 (s), 3062 (m), 3032 (m), 2957 (s), 2868 (s), 1918
(3R,4R)-(؉)-3-(Benzyloxymethyl)-N-tosyloctan-4-amine [(R,R)-5b]: (w), 1808 (w), 1719 (w), 1599 (m), 1456 (s), 1367 (m), 1334 (s), 1209
According to GP 4 amine (R,R)-4b (0.35 g, 1.4 mmol) was treated (w), 1158 (s), 1094 (s), 1025 (m), 906 (m), 816 (m), 740 (m), 701
4478
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4471Ϫ4482

Asymmetric Synthesis of 2-Mono- and 2,3-trans-Disubstituted Azetidines
FULL PAPER
1
(m), 667 (s), 551 (s) cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 0.82
CHHOCH2Ph, NCH), 3.50 (dt, J ϭ 4.5, 8.9 Hz, 1 H,
[t, J ϭ 7.1 Hz, 3 H, CH2CH3], 0.84 [s, 9 H, C(CH3)3], 1.04Ϫ1.22 CHHOCH2Ph), 4.40 (s, 2 H, OCH2Ph), 5.13 (s, 1 H, NH),
[m, 6 H, (CH2)3CH3], 1.84 (m, 1 H, NCHCH), 2.39 (s, 3 H, 7.22Ϫ7.39 (m, 7 H, CHarom.), 7.32 (d, J ϭ 8.4 Hz, 2 H, SO2CCHarom.
ArϪCH3), 3.03 (dd, J ϭ 3.3, 9.6 Hz, 1 H, NCH), 3.20 (dd, J ϭ
ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 14.1 (CH2CH3), 21.5
)
8.0, 9.3 Hz, 1 H, CHHOCH2Ph), 3.47 (dd, J ϭ 4.0, 9.3 Hz, 1 H, (ArϪCH3), 22.5, 25.4, 29.0, 31.7 (CH3CH2CH2CH2CH2), 33.7
CHHOCH2Ph), 4.41 (d, J ϭ 11.8 Hz, 1 H, OCHHPh), 4.45 (d, J ϭ (NCHCH2CH2O), 35.0 (NCHCH2(CH2)4], 52.7 (NCH), 67.2
11.8 Hz, 1 H, OCHHPh), 5.67 (d, J ϭ 9.3 Hz, 1 H, NH), 7.18Ϫ7.40
(m, 5 H, CHarom.), 7.62 (d, J ϭ 8.2 Hz, 2 H, SO2CCHarom.) ppm. (Ar CH), 138.0, 138.4, 143.0 (Ar Cq) ppm. MS (EI, 70 eV): m/z
13C NMR (100 MHz, CDCl3): 13.9 (CH2CH3), 21.4 (%) ϭ 403 (1) [Mϩ], 318 (5), 268 (27), 248 (45), 212 (24), 171 (5),
(CH2OCH2Ph), 73.2 (OCH2Ph), 127.1, 127.6, 127.7, 128.4, 129.5
δ
ϭ
(ArϪCH3), 22.7 (CH2CH3), 27.0 [C(CH3)3], 29.8 (CH2CH2CH3), 154 (21), 142 (7), 114 (5), 91 (100), 65 (6). C23H33NO3S (403.59):
33.0 (CH2CH2CH2CH3), 36.0 [C(CH3)3], 38.3 (NCHCH), 66.3 calcd. C 68.45, H 8.24, N 3.47; found C 68.36, H 8.60, N 3.81.
(NCH), 71.5 (CH2OCH2Ph), 73.2 (CH2OCH2Ph), 126.7, 127.5,
General Procedure for the Hydrogenolytic Alcohol Deprotection and
the Ring Closure to Azetidines 6 (GP 5): A catalytic amount of Pd/C
(10 wt%, 54 wt% H2O) was added to a solution of the tosylamines 5
in EtOAc or MeOH. The reaction mixture was hydrogenated at
127.6, 128.3, 129.1 (Ar CH), 137.6, 139.2, 142.3 (Ar Cq) ppm. MS
(EI, 70 eV): m/z (%) ϭ 374 (34) [Mϩ Ϫ C4H9], 344 (6), 268 (48),
240 (121), 184 (14), 173 (8), 155 (15), 91 (100). C25H37NO3S
(431.63): calcd. C 69.57, H 8.64, N 3.25; found C 69.31, H 8.80,
atmospheric pressure until complete conversion of the starting ma-
N 3.63.
terial was indicated by TLC (2Ϫ3 h). After filtration through a pad
of Celite and removal of the solvent in vacuo, the resulting N-
(2R,3R)-(؉)-1-Benzyloxy-2-phenyl-N-tosylnonan-3-amine [(R,R)-
5e]: According to GP 4 amine (R,R)-4e (0.19 g, 0.6 mmol) was
tosylamino alcohols and PPh3 (1.5 equiv.) were dissolved in dry
THF (15 mL/mmol) under argon. Diisopropyl azodicarboxylate
treated with tosyl chloride in the presence of K2CO3. Tosylamine
(DIAD, 1.5 equiv.) was added dropwise at 0 °C with stirring. The
(R,R)-5e was obtained as a colourless solid after flash column chro-
solution was warmed to room temperature and stirred for 72 h.
The reaction mixture was then filtered through a pad of SiO2 and
concentrated in vacuo. The crude tosylazetidines 6 were purified
by flash column chromatography.
matography (pentane/Et2O, 4:1). Yield: 0.25 g (89%); de Ն 96% (1H
NMR); ee ϭ 97% (HPLC, Chiralpak AD 2); m.p. 125 °C. [α]2D4
ϭ
ϩ21.9 (c ϭ 0.9, CHCl3). Rt ϭ 24.81 min (CP-Sil-8, 140Ϫ10Ϫ300).
Rf ϭ 0.40 (pentane/Et2O, 2:1). IR (KBr): ν˜ ϭ 3319 (s), 3060 (m),
3031 (m), 2925 (s), 2859 (s), 1949 (w), 1877 (w), 1811 (w), 1599
(m), 1497 (m), 1453 (m), 1430 (m), 1329 (s), 1258 (w), 1208 (w),
1157 (s), 1090 (s), 1046 (m), 10245 (m), 1002 (m), 909 (m), 819 (m),
(2R,3S)-(؊)-2-Butyl-3-methyl-1-tosylazetidine [(R,S)-6a]: Accord-
ing to GP 5 compound (R,R)-5a (0.57 g, 1.5 mmol) was hydrogen-
ated in EtOAc (25 mL) in the presence of Pd/C (0.31 g). A mixture
of the crude amino alcohol and PPh3 in dry THF was then treated
with DIAD. After flash column chromatography (pentane/Et2O,
6:1) the tosylazetidine (R,S)-6a was obtained as a colourless solid.
Yield: 0.38 g (97%, 2 steps); de ϭ 93% (GC, CP-Sil-8); m.p. 62 °C.
[α]2D3 ϭ Ϫ87.5 (c ϭ 1.1, CHCl3). Rt ϭ 11.82 [major trans-isomer],
12.31 min [minor cis-isomer] (CP-Sil-8, 120Ϫ10Ϫ300). Rf ϭ 0.53
(pentane/Et2O, 2:1). IR (KBr): ν˜ ϭ 3100 (w), 3033 (m), 2965 (s),
2931 (s), 2863 (s), 1942 (w), 1833 (w), 1676 (w), 1597 (m), 1496 (w),
1459 (m), 1382 (m), 1341 (s), 1290 (m), 1161 (s), 1025 (s), 910 (m),
744 (m), 700 (s), 671 (s), 596 (m), 567 (m), 544 (m), 494 (m) cmϪ1
.
1H NMR (300 MHz, CDCl3): δ ϭ 0.81 (t, J ϭ 7.2 Hz, 3 H, CH3),
0.97Ϫ1.25 [m, 9 H, [CHH(CH2)4CH3], 1.42 (m, 1 H, CHH
(CH2)4CH3], 2.41 (s, 3 H, ArϪCH3), 3.02 (dt, J ϭ 4.7, 7.4 Hz, 1
H, NCHCH), 3.58 (dd, J ϭ 4.7, 9.6 Hz, 1 H, CHHOCH2Ph), 3.70
(m, 2 H, CHHOCH2Ph, NCH), 4.44 (d, J ϭ 12.1 Hz, 1 H,
CH2OCHHPh), 4.49 (d, J ϭ 12.1 Hz, 1 H, CH2OCHHPh), 5.00
(d, J ϭ 7.7 Hz, 1 H, NH), 7.06 (m, 2 H, CHarom.), 7.22Ϫ7.37 (m,
10 H, CHarom.), 7.70 (d, J ϭ 8.4 Hz, 2 H, SO2CCHarom.) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 14.0 (CH2CH3), 21.5 (ArϪCH3),
22.5, 24.7, 29.0, 31.6, 32.1 [(CH2)5CH3], 48.7 (NCHCH), 56.9
(NCH), 72.0 (CH2OCH2Ph), 73.2 (CH2OCH2Ph), 2 ϫ 127.1, 2 ϫ
127.8, 128.4, 128.5, 128.6, 129.5 (Ar CH), 137.8, 138.4, 139.2, 143.0
(Ar Cq) ppm. MS (CI, 100 eV): m/z (%) ϭ 480 (47) [MHϩ], 371
(30), 309 (8), 291 (30), 280 (26), 268 (100), 262 (61), 201 (21), 184
(8), 171 (7), 154 (16), 119 (13), 104 (76), 91 (59). C29H37NO3S
(479.67): calcd. C 72.61, H 7.77, N 2.92; found C 72.58, H 7.61,
N 2.85.
1
821 (s), 714 (m), 669 (s), 603 (s), 548 (s), 497 (m) cmϪ1. H NMR
(400 MHz, CDCl3): δ ϭ 0.81 (d, J ϭ 6.9 Hz, 3 H, CHCH3), 0.90
[t, J ϭ 6.9 Hz, 3 H, CH2CH3], 1.22Ϫ1.38 (m, 4 H, CH2CH2CH3),
1.68 (m, 1 H, NCHCHH), 1.84 (m, 1 H, NCHCHH), 2.24 (m, 1
H, CHCH3), 2.46 (s, 3 H, ArϪCH3), 3.08 (t, J ϭ 7.7 Hz, 1 H,
NCHH), 3.37 (m, 1 H, NCH), 3.81 (t, J ϭ 7.7 Hz, 1 H, NCHH),
7.36 (d, J ϭ 8.4 Hz, 2 H, CHarom.CCH3), 7.71 (d, J ϭ 8.4 Hz, 2
H, CHarom.CSO2) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 14.0
(CH2CH3), 18.5 (CHCH3), 21.6 (ArϪCH3), 22.6 (CH2CH3), 26.4
(CH2CH2CH3), 30.9 (NCHCH), 35.3 (NCHCH2), 54.8 (NCH2),
71.2 (NCH), 128.2 (Ar CHCSO2), 129.4 (Ar CHCCH3), 132.0 (Ar
CqSO2), 143.5 (Ar CqCH3) ppm. MS (EI, 70 eV): m/z (%) ϭ 281
(4) [Mϩ], 240 (6), 224 (30), 197 (12), 184 (23), 175 (10), 155 (100),
133 (42), 112(8), 106 (12), 98 (34), 91 (93), 84 (9), 70 (7), 65 (13).
C15H23NO2S (281.41): calcd. C 64.02, H 8.24, N 4.98; found C
63.77, H 8.55, N 5.00.
(R)-(؉)-1-Benzyloxy-N-tosylnonan-3-amine [(R)-5f]: The amine
(R)-4f was prepared by NϪN cleavage of the corresponding hydra-
zine (R,S)-3f (1.81 g, 5.0 mmol) with BH3·THF as described in GP
3 and then treated with tosyl chloride according to GP 4 in the
presence of K2CO3 and additional Et3N (1.51 g, 15.0 mmol). Tosyl-
amine (R)-5f was obtained as a colourless oil after flash column
chromatography (pentane/Et2O, 1:1). Yield: 1.24 g (84%, 2 steps).
[α]2D4 ϭ ϩ2.24 (c ϭ 1.0, CHCl3). Rt ϭ 21.99 min (CP-Sil-8,
100Ϫ10Ϫ300). Rf ϭ 0.27 (pentane/Et2O, 1:1). IR (KBr): ν˜ ϭ 3283
(2R,3S)-(؊)-2-Butyl-3-ethyl-1-tosylazetidine [(R,S)-6b]: According
to GP 5 compound (R,R)-5b (0.50 g, 1.2 mmol) was hydrogenated
(m), 3064 (m), 3031 (m), 2929 (s), 2859 (s), 1726 (w), 1599 (m), in EtOAc (25 mL) in the presence of Pd/C (0.30 g). A mixture of
1495 (m), 1454 (s), 1327 (s), 1208 (w), 1159 (s), 1096 (s), 1031 (m),
the crude amino alcohol and PPh3 in dry THF was then treated
with DIAD. After flash column chromatography (pentane/Et2O,
912 (m), 815 (m), 739 (s), 700 (m), 667 (s), 577 (m), 552 (s) cmϪ1
.
1H NMR (300 MHz, CDCl3): δ ϭ 0.85 (t, J ϭ 7.0 Hz, 3 H, 6:1) the tosylazetidine (R,S)-6b was obtained as a colourless oil.
CH2CH3), 1.04Ϫ1.26 [m, 8 H, (CH2)4CH3], 1.40 [m, 2 H,
NCHCH2(CH2)4], 1.56 (m, 1 H, NCHCHHCH2O), 1.68 (m, 1 H, Ϫ63.8 (c ϭ 1.1, CHCl3). Rt ϭ 10.67 [major trans-isomer], 11.15
NCHCHHCH2O), 2.41 (s, H, ArϪCH3), 3.38 (m, H, min [minor cis-isomer] (CP-Sil-8, 140Ϫ10Ϫ300). Rf ϭ 0.60 (pen-
Yield: 0.34 g (92%, 2 steps); de ϭ 96% (GC, CP-Sil-8). [α]2D2
ϭ
3
2
Eur. J. Org. Chem. 2004, 4471Ϫ4482
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4479

D. Enders, J. Gries, Z.-S. Kim
FULL PAPER
tane/Et2O, 2:1). IR (film): ν˜ ϭ 3030 (w), 2959 (s), 2932 (s), 2871
(400 MHz, CDCl3): δ ϭ 0.75 (t, J ϭ 7.2 Hz, 3 H, CH2CH3), 0.95
(s), 1924 (w), 1817 (w), 1671 (w), 1598 (m), 1495 (w), 1462 (m), [s, 9 H, C(CH3)3], 0.95Ϫ1.02 [m, 4 H, CH(CH2)2], 1.10 (m, 2 H,
1380 (m), 1345 (s), 1162 (s), 1091 (m), 1021 (w), 815 (m), 713 (m), CH2CH3), 2.06 (m, 1 H, NCHCH), 2.45 (s, 3 H, ArϪCH3), 3.25
668 (s), 603 (s), 551 (s), 498 (w) cmϪ1 1H NMR (400 MHz, (m, 2 H, NCHH, NCH), 3.81 (t, J ϭ 8.5 Hz, 1 H, NCHH), 7.36
.
CDCl3): δ ϭ 0.65 (t, J ϭ 7.4 Hz, 3 H, CH2CH3), 0.90 (t, J ϭ (d, J ϭ 8.2 Hz, 2 H, CHarom.CCH3), 7.73 (d, J ϭ 8.2 Hz, 2 H,
6.9 Hz, 3 H, CH2CH3), 1.03 (m, 1 H, CHCHHCH3), 1.17 (m, 1 CHarom.CSO2) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 13.8
H, CHCHHCH3) 1.26Ϫ1.35 [m, 4 H, (CH2)2CH3], 1.68 (m, 1 H,
NCHCHH), 1.82 (m, 1 H, NCHCHH), 2.08 (m, 1 H, NCHCH),
(CH2CH3), 21.5 (ArϪCH3), 22.4 (CH2CH3), 25.4 [C(CH3)3], 28.4
(CH2CH2CH3), 31.1 (NCHCH), 33.6, 33.7 (CHCH2, C(CH3)3],
2.46 (s, 3 H, ArϪCH3), 3.12 (t, J ϭ 7.8 Hz, 1 H, NCHH), 3.46 (m, 53.6 (NCH2), 78.8 (NCH), 128.1 (Ar CHCSO2), 129.3 (Ar
1 H, NCH), 3.79 (t, J ϭ 7.8 Hz, 1 H, NCHH), 7.36 (d, J ϭ 8.1 Hz, CHCCH3), 133.1 (Ar CqSO2), 143.4 (Ar CqCH3) ppm. MS (EI,
2 H, CHarom.CCH3), 7.70 (d, J ϭ 8.1 Hz, 2 H, CHarom.CSO2) ppm. 70 eV): m/z (%) ϭ 323 (3) [Mϩ], 266 (100), 155 (29), 139 (7), 110
13C NMR (100 MHz, CDCl3):
10.8 (CH2CH3), 14.0 (6), 91 (22). C18H29NO2S (323.49): calcd. C 66.83, H 9.04, N 4.33;
δ
ϭ
((CH2)3CH3], 21.5 (ArϪCH3), 22.6 (CH2CH3), 26.5 (CHCH2CH3), found C 66.54, H 8.96, N 4.27.
26.7 (CH2CH2CH3), 35.5 (NCHCH2), 37.2 (NCHCH), 53.1
(2R,3S)-(؊)-2-Hexyl-3-phenyl-1-tosylazetidine [(R,S)-6e]: Accord-
(NCH2), 69.5 (NCH), 128.1 (Ar CHCSO2), 129.4 (Ar CHCCH3),
132.1 (Ar CqSO2), 143.5 (Ar CqCH3) ppm. MS (EI, 70 eV): m/z
(%) ϭ 295 (9) [Mϩ], 266 (6), 240 (40), 238 (50), 197 (16), 189 (12),
183 (26), 155 (100), 146 (14), 140 (18), 133 (37), 126 (10), 98 (22),
91 (72), 84 (12), 65 (9). C16H25NO2S (295.44): calcd. C 65.05, H
8.53, N 4.74; found C 64.90, H 8.54, N 5.23.
ing to GP 5 compound (R,R)-5e (0.15 g, 0.3 mmol) was hydrogen-
ated in EtOAc (15 mL) in the presence of Pd/C (0.10 g). A mixture
of the crude amino alcohol and PPh3 in dry THF was then treated
with DIAD. After flash column chromatography (pentane/Et2O,
7:1) the tosylazetidine (R,S)-6e was obtained as a colourless solid.
Yield: 0.11 g (94%, 2 steps); de Ն 96% (NMR); ee ϭ 95.5% (HPLC,
(2R,3S)-(؊)-3-Butyl-2-hexyl-1-tosylazetidine [(R,S)-6c]: According OD.M); m.p. 69 °C. [α]2D3 ϭ Ϫ50.8 (c ϭ 1.0, CHCl3). Rt
ϭ
to GP 5 compound (R,R)-5c (0.48 g, 1.1 mmol) was hydrogenated
in EtOAc (50 mL) in the presence of Pd/C (0.26 g). A mixture of
the crude amino alcohol and PPh3 in dry THF was then treated
with DIAD. After flash column chromatography (pentane/Et2O,
7:1) the tosylazetidine (R,S)-6c was obtained as a colourless oil.
14.34 min (CP-Sil-8, 160Ϫ10Ϫ300). Rf ϭ 0.36 (pentane/Et2O, 6:1).
IR (KBr): ν˜ ϭ 3064 (w), 3025 (m), 2957 (m), 2931 (s), 2898 (m),
2861 (m), 1959 (w), 1879 (w), 1825 (w), 1596 (m), 1495 (m), 1462
(m), 1380 (m), 1343 (s), 1299 (m), 1165 (s), 1094 (s), 1023 (m), 978
(m), 822 (m), 757 (m), 706 (s), 664 (s), 612 (s), 551 (s), 527 (m), 496
Yield: 0.34 g (92%, 2 steps); de ϭ 95% (GC, CP-Sil-8). [α]2D2
ϭ
(w) cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 0.83 (t, J ϭ 6.3 Hz,
1
Ϫ53.9 (c ϭ 1.1, CHCl3). Rt ϭ 15.97 [major trans-isomer], 16.37 3 H, CH2CH3), 1.18Ϫ1.26 [m, 8 H, (CH2)4CH3], 1.80 (m, 1 H,
min [minor cis-isomer] (CP-Sil-8, 120Ϫ10Ϫ300). Rf ϭ 0.69 (pen-
tane/Et2O, 2:1). IR (film): ν˜ ϭ 2928 (s), 2858 (s), 1921 (w), 1670
NCHCHH), 1.92 (m, 1 H, NCHCHH), 2.51 (s, 3 H, ArϪCH3),
3.30 (q, J ϭ 8.2 Hz, 1 H, NCHCH), 3.57 (t, J ϭ 8.2 Hz, 1 H,
(w), 1598 (m), 1494 (w), 1463 (m), 1379 (m), 1346 (s), 1216 (w), NCHH), 3.88 (dt, J ϭ 8.2, 4.2 Hz, 1 H, NCH), 4.04 (t, J ϭ 8.2 Hz,
1163 (s), 1092 (m), 1036 (w), 816 (m), 712 (m), 670 (s), 606 (m), 1 H, NCHH), 6.69 (m, 2 H, CHarom.), 7.15 (m, 3 H, CHarom.), 7.36
1
551 (m), 504 (w) cmϪ1. H NMR (400 MHz, CDCl3): δ ϭ 0.78 (t,
(d, J ϭ 8.3 Hz, 2 H, CHarom.CCH3), 7.78 (d, J ϭ 8.3 Hz, 2 H,
J ϭ 7.1 Hz, 3 H, CH2CH3), 0.89 (t J ϭ 6.7 Hz, 3 H, CH2CH3), CHarom.CSO2) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 14.0
0.97 (m, 3 H, NCHCHCHH, CH2), 1.14 (m, 3 H, NCHCHCHH, (CH2CH3), 21.6 (ArϪCH3), 22.5, 24.1, 29.0, 31.5, 36.0
CH2) 1.25Ϫ1.33 (m, 8 H, CH2), 1.67 (m, 1 H, NCHCHH), 1.80 (CH2CH2CH2CH2CH2CH3), 40.9 (NCHCH), 54.9 (NCH2), 71.7
(m, 1 H, NCHCHH), 2.11 (m, 1 H, NCHCH), 2.45 (s, 3 H,
ArϪCH3), 3.13 (t, J ϭ 7.7 Hz, 1 H, NCHH), 3.46 (ddd, J ϭ 8.0, CqSO2), 139.9 (Ar CqCH), 143.8 (Ar CqCH3) ppm. MS (EI, 70 eV):
6.8, 5.0 Hz, 1 H, NCH), 3.79 (t, J ϭ 7.7 Hz, 1 H, NCHH), 7.36
m/z (%) ϭ 371 (1) [Mϩ], 155 (3), 117 (4), 104 (100), 91 (10).
(NCH), 126.9, 127.0, 128.4, 128.4, 129.6 (Ar CH), 131.8 (Ar
(d, J ϭ 8.1 Hz, 2 H, CHarom.CCH3), 7.71 (d, J ϭ 8.1 Hz, 2 H, C22H29NO2S (371.54): calcd. C 71.12, H 7.87, N 3.77 found; C
CHarom.CSO2) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 13.8, 14.1 70.66, H 7.81, N 3.60.
(CH2CH3), 21.5 (ArϪCH3), 22.4, 22.6, 24.5, 28.6, 29.2, 31.7, 33.2
(2R)-(؊)-2-Hexyl-1-tosylazetidine [(R)-6f]: According to GP 5 com-
pound (R)-5f (0.81 g, 2.0 mmol) was hydrogenated in MeOH
(30 mL) in the presence of Pd/C (0.40 g). A mixture of the crude
amino alcohol and PPh3 in dry THF was then treated with DIAD.
After flash column chromatography (pentane/Et2O, 4:1) the tosyla-
zetidine (R)-6f was obtained as a colourless oil. Yield: 0.46 g (77%,
2 steps). [α]2D5 ϭ Ϫ80.0 (c ϭ 1.8, CHCl3). Rt ϭ 15.57 min (CP-Sil-
8, 60Ϫ10Ϫ300). Rf ϭ 0.17 (pentane/Et2O, 4:1). IR (film): ν˜ ϭ 2928
(s), 2860 (m), 1922 (w), 1808 (m), 1770 (m), 1598 (m), 1495 (m),
(CH2), 35.6 (NCHCH), 35.8 (NCHCH2), 53.4 (NCH2), 69.7
(NCH), 128.1 (Ar CHCSO2), 129.4 (Ar CHCCH3), 132.2 (Ar
CqSO2), 143.5 (Ar CqCH3) ppm. MS (EI, 70 eV): m/z (%) ϭ 351
(4) [Mϩ], 294 (7), 284 (9), 268 (59), 266 (53), 217 (10), 202 (17),
196 (36), 184 (52), 155 (100), 133 (36), 126 (29), 112 (19), 91 (85).
C20H33NO2S (351.55): calcd. C 68.33, H 9.46, N 3.98; found C
68.34, H 9.11, N 4.43.
(2S,3S)-(؊)؊3-Butyl-2-tert-butyl-1-tosylazetidine [(S,S)-6d]: Ac-
cording to GP 5 compound (S,R)-5d (0.26 g, 0.6 mmol) was hydro- 1461 (m), 1404 (w), 1380 (w), 1345 (s), 1305 (m), 1161 (s), 1096 (s),
genated in EtOAc (15 mL) in the presence of Pd/C (0.19 g). A mix- 1020 (m), 946 (m), 818 (s), 770 (m), 714 (m), 670 (s), 608 (s), 553
ture of the crude amino alcohol and PPh3 in dry THF was then (s), 500 (m) cmϪ1. H NMR (300 MHz, CDCl3): δ ϭ 0.88 (t, J ϭ
treated with DIAD. After flash column chromatography (pentane/ 6.5 Hz, 3 H, CH2CH3), 1.18Ϫ1.30 [m, 8 H, (CH2)4CH3], 1.68 (m,
1
Et2O, 8:1) the tosylazetidine (S,S)-6d was obtained as a colourless 1 H, NCHCHH), 1.90 (m, 3 H, NCHCHH, NCH2CH2), 2.44 (s, 3
solid. Yield: 0.18 g (93%, 2 steps); de Ն 96% (NMR); m.p. 53 °C. H, ArϪCH3), 3.49 (m, 1 H, NCHH), 3.67 (m 1 H, NCHH), 3.84
[α]2D3 ϭ Ϫ28.1 (c ϭ 1.0, CHCl3). Rt ϭ 13.57 min (CP-Sil-8,
120Ϫ10Ϫ300). Rf ϭ 0.58 (pentane/Et2O, 4:1). IR (KBr): ν˜ ϭ 3063
(m, 1 H, NCH), 7.39 (d, J ϭ 8.2 Hz, 2 H, CHarom.CCH3), 7.71 (d,
J ϭ 8.2 Hz, 2 H, CHarom.CSO2) ppm. 13C NMR (75 MHz, CDCl3):
(w), 2964 (s), 2879 (s), 1934 (w), 1827 (w), 1626 (w), 1598 (m), 1494 δ ϭ 14.1 (CH2CH3), 21.6 (ArϪCH3), 22.2 (NCH2CH2), 22.65, 24.2,
(m), 1464 (m), 1387 (m), 1366 (m), 1342 (s), 1303 (m), 1214 (m), 29.1, 31.7, 36.1 (CH2CH2CH2CH2CH2CH3), 47.6 (NCH2), 64.2
1156 (s), 1094 (m), 1033 (m), 1010 (m), 983 (m), 848 (m), 823 (m), (NCH), 128.4 (Ar CHCSO2), 129.7 (Ar CHCCH3), 132.1 (Ar
713 (m), 673 (s), 620 (m), 574 (m), 546 (s) cmϪ1
.
1H NMR CqSO2), 143.8 (Ar CqCH) ppm. MS (EI, 70 eV): m/z (%) ϭ 295 (1)
4480
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Eur. J. Org. Chem. 2004, 4471Ϫ4482

Asymmetric Synthesis of 2-Mono- and 2,3-trans-Disubstituted Azetidines
FULL PAPER
[Mϩ], 238 (8), 210 (37), 184 (42), 155 (100), 140 (26), 91 (55), 65
(9). C16H25NO2S (295.44): calcd. C 65.05, H 8.53, N 4.74; found
C 64.60, H 8.34, N 4.96.
1 H, NCHCH), 3.87 (dd, J ϭ 8.7, 6.7 Hz, 1 H, NCHH), 4.18 (m,
2 H, NCH, NCHH), 7.20Ϫ7.37 (m, 5 H, CHarom.) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 14.1 (CH2CH3), 22.6 (CH2CH3), 24.5
(CH2CH2CH3), 28.5 [C(CH3)3], 29.3 (CH2(CH2)2CH3], 31.7
(CH2(CH2)3CH3], 35.4 (NCHCH2), 40.9 (NCHCH), 53.7 (br,
NCH2), 70.0 (NCH), 79.4 [C(CH3)3], 126.9, 127.0, 128.7 (Ar CH),
142.0 (Ar Cq), 156.8 (CϭO) ppm. MS (EI, 70 eV): m/z (%) ϭ 317
(3) [Mϩ], 261 (7), 217 (8), 170 (7), 104 (100), 91 (5), 57 (34).
C20H31NO2 (317.47): calcd. C 75.67, H 9.84, N 4.41 found C 75.45,
H 9.92, N 4.80.
General Procedure for the Reductive Detosylation and Boc-Protec-
tion of the Azetidines 6 (GP 6): Sodium metal (6.0 equiv.) was rinsed
with dry methanol and was put in a Schlenk flask together with
naphthalene (6.0 equiv.). After the flask had been evacuated and
filled with argon, the mixture was dissolved in dry dimethoxye-
thane (DME, 15 mL/mmol) at 0 °C and stirred for 2.5 h at this
temperature. The resulting dark green solution was then cooled to
Ϫ45 °C and the tosylazetidines 6 (1.0 equiv.) dissolved in DME
(9 mL/mmol) were slowly added at this temperature. After com-
plete conversion of the starting material had been indicated by TLC
the reaction was quenched by addition of a saturated aqueous
NaHCO3 solution. The mixture was then extracted with CH2Cl2
for several times. The combined organic layers were dried with
Na2SO4 and the solvent was removed in vacuo. The crude mixture
was then again dissolved in CH2Cl2 (10 mL/mmol) and stirred with
Et3N (1.2 equiv.) and (Boc)2O (1.2 equiv.) for 20 h at ambient tem-
perature. After addition of a saturated NaHCO3 solution the aque-
ous phase was extracted with CH2Cl2, dried with Na2SO4 and con-
centrated under reduced pressure. The pure N-Boc-azetidines 7
were obtained by flash column chromatography.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(Graduiertenkolleg 440, Sonderforschungsbereich 380) and the
Fonds der Chemischen Industrie. We would like to thank Degussa
AG, BASF AG, Bayer AG and Wacker Chemie for donations of
chemicals and Marc Lecour for his skilful experimental contri-
butions as an undergraduate student.
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[(R,S)-7a]: The tosylazetidine (R,S)-6c (0.10 g, 0.3 mmol) was
treated with sodium naphthalide in DME for 30 min at Ϫ45 °C
and converted into the corresponding Boc-protected azetidine as
described in GP 6. A pure product was obtained by flash column
chromatography (pentane/Et2O, 15:1) as a colourless oil. Yield:
0.07 g (85%, 2 steps); de ϭ 95% (GC, CP-Sil-8). [α]2D3 ϭ Ϫ22.6 (c ϭ
1.1, CHCl3). Rt ϭ 9.12 [major trans-isomer], 9.67 min [minor cis-
isomer] (CP-Sil-8, 120Ϫ10Ϫ300). Rf ϭ 0.60 (pentane/Et2O, 6:1).
IR (film): ν˜ ϭ 2928 (s), 2860 (s), 1704 (s), 1460 (m), 1394 (s), 1367
(s), 1254 (m), 1142 (s), 1069 (w), 903 (w), 876 (w), 769 (m), 731
(m), 655 (m), 622 (m), 509 (m), 464 (m) cmϪ1. 1H NMR (400 MHz,
CDCl3): δ ϭ 0.81 (t, J ϭ 6.9 Hz, 3 H, CH2CH3), 0.82 (t, J ϭ
7.3 Hz, 3 H, CH2CH3), 1.12Ϫ1.27 (m, 12 H, CH2), 1.37 [s, 9 H,
C(CH3)3] 1.38Ϫ1.55 (m, 3 H, NCHCHH, NCHCHCH2), 1.78 (m,
1 H, NCHCHH), 1.97 (m, 1 H, NCHCH), 3.32 (dd, J ϭ 8.3,
5.8 Hz, 1 H, NCHH), 3.46 (dt, J ϭ 7.0, 5.2 Hz, 1 H, NCH), 3.79
(t, J ϭ 8.3 Hz, 1 H, NCHH) ppm. 13C NMR (100 MHz, CDCl3):
δ ϭ 14.2 (2 ϫ CH2CH3), 2 ϫ 22.7, 24.8, 29.3, 29.5, 31.9 (CH2),
28.6 [C(CH3)3], 34.2 (NCHCHCH2), 35.0 (NCHCH2), 35.9
(NCHCH), 52.2 (br, NCH2), 68.0 (NCH), 79.0 [C(CH3)3], 156.6
(CϭO) ppm. MS (EI, 70 eV): m/z (%) ϭ 297 (11) [Mϩ], 241 (17),
224 (16), 184 (16), 170 (17), 156 (100), 140 (12), 126 (14), 112 (63),
74 (14), 57 (96). C18H35NO2 (297.48): calcd. C 72.68, H 11.86, N
4.71; found C 72.73, H 12.05, N 5.02.
[1e]
-Azetidine-2-carboxylic
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[(R,S)-7b]: The tosylazetidine (R,S)-6e (0.10 g, 0.3 mmol) was
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Eur. J. Org. Chem. 2004, 4471Ϫ4482
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4481

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Received July 5, 2004
4482
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