A straightforward synthesis of enantiopure bicyclic azetidines

Article abstract of DOI:10.1002/ejoc.200700616

Enantiomerically pure 1-azabicyclo[3.2.0]heptane derivatives were synthesized in a straightforward manner from readily available chiral sources, namely, enantiomerically pure epoxides and L-proline. The key step of this synthesis relied on a diastereosele

Full text of DOI:10.1002/ejoc.200700616

FULL PAPER
DOI: 10.1002/ejoc.200700616
A Straightforward Synthesis of Enantiopure Bicyclic Azetidines
Mangaleswaran Sivaprakasam,[a] François Couty,*[a] Olivier David,[a] Jérôme Marrot,[a]
Regati Sridhar,[b] Boga Srinivas,[b] and Kakulapati Rama Rao[b]
Keywords: Nitrogen heterocycles / Bicyclic compounds / Fused-ring systems / Strained molecules
Enantiomerically pure 1-azabicyclo[3.2.0]heptane deriva-
tives were synthesized in a straightforward manner from
readily available chiral sources, namely, enantiomerically
were found to be good precursors for the preparation of
azepanes, after transformation into the corresponding ammo-
nium trifluoromethanesulfonates followed by reaction with
nucleophiles.
pure epoxides and L-proline. The key step of this synthesis
relied on a diastereoselective intramolecular alkylation of a
proline enolate, which led to an azetidine ring fused to a five-
membered ring. These strained bicyclic nitrogen derivatives
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
reaction involving catalyst 2 was significantly enhanced rel-
ative to the same reaction catalyzed by pyrrolizidine 3.
However, difficulties encountered in the synthesis of 2 pre-
cluded further investigations. As part of our interest in the
chemistry of azetidines,[10] we wish to present herein, a
straightforward preparation of such bicyclic nitrogen het-
erocycles in a stereocontrolled way starting from readily
available synthons from the chiral pool. By following a
strategy developed in our group for the preparation of mo-
nocyclic azetidines, the key step in this synthesis relies on
diastereoselective alkylation of an enolate generated from a
proline derivative and involves the formation of the azetid-
ine ring by anionic cyclization. We also demonstrate that
these bicyclic nitrogen compounds are excellent precursors
for functionalized azepanes after transformation into their
ammonium trifluoromethanesulfonates followed by reac-
tion with a nucleophile, which induces the cleavage of the
endocyclic C–N bond.
Introduction
The azabicyclo[3.2.0]heptane (1) skeleton, to the best of
our knowledge, is not encountered in natural molecules,
and reports describing the preparation of such strained
heterocycles are also scarce. Synthetic strategies towards
this ring system include photoaddition of olefins to imin-
ium ions,[1] intramolecular carbolithiation of phenylthioalk-
enes with α-amino organolithium species,[2] direct ring clo-
sure of a four-membered ring by N-alkylation,[3] Pauson–
Khand reaction of suitably functionalized azetidines,[4] and
reduction of the corresponding thiolactams.[5] However, all
these approaches suffer from major drawbacks such as low
yield or a lack of generality, and straightforward access to
enantiomerically pure derivatives of this bicyclic nitrogen
heterocycle still needs to be discovered. Because of the
strain in these compounds, the strong pyramidization of the
amine moiety is expected to increase the accessibility of the
lone pair of electrons on the nitrogen atom, which would
thus enhance the nucleophilicity of the tertiary amine.
Therefore, enantiomerically pure derivatives of 1 would be
excellent candidates for organocatalytic processes involving
nucleophilic attack of a tertiary amine in the catalytic cycle,
such as ketene dimerization,[6] cyclopropanations mediated
by ammonium ylides,[7] Baylis–Hillman reaction,[8] or ki-
netic resolution of alcohols involving acylation with acyl
ammonium ions.[9] This idea was demonstrated by Barrett
et al.[5] who reported that kinetics of the Baylis–Hillman
Results
Synthesis of Azabicyclo[3.2.0]heptane Derivatives
Scheme 1 details our synthetic approach towards deriva-
tives of 1. Treatment of (R)-O-benzyl glycidol (4; 98% ee)
with proline in basic media induced the regioselective open-
ing of the epoxide ring to give an intermediate amino acid
that was later transformed into methyl ester 5. Chlorination
of this compound by using Appel’s reaction gave a mixture
of isomeric chlorides 6 and 7 in a 1:4 ratio. This inseparable
[a] Institut Lavoisier de Versailles, UMR 8081, Université de Ver-
sailles,
45, avenue des Etats-Unis, 78035 Versailles Cedex, France
Fax: +33-1-39254452
E-mail: couty@chimie.uvsq.fr
[b] Organic Chemistry Division-I, Indian Institute of Chemical
Technology,
Hyderabad 500007, India
5734
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5734–5739

A Straightforward Synthesis of Enantiopure Bicyclic Azetidines
mixture was immediately subjected to anionic cyclization by
treatment with LiHMDS in a mixture of THF/HMPA
(10:1) to give compound 8, which resulted from the intra-
molecular alkylation of the ester enolate by the primary
chloride in 7. This reaction did not consume secondary
chloride 6, which thus allowed facile purification of more
polar 8 that was isolated in 58% yield (72% based on unre-
acted 7). The enantiomeric purity of compound 8 was as-
sessed as follows: compound ent-8 was prepared following
Scheme 1 starting from ent-4 and -proline. Examination
of a mixture of 8 and ent-8 by 1H NMR spectroscopy in the
presence of (S)-α-(trifluoromethyl)benzyl alcohol[13] showed
resolved and separated signals for each enantiomer of the
methyl ester. Compound 8 was found to be optically pure
within the precision of the NMR (300 MHz) instrument.
Scheme 2. Synthesis of enantiomerically pure azabicyclo[3.2.0]hep-
tane derivative 13.
Figure 1. X-ray structure of compound 13.
for similar substrates.[14] It is therefore important to con-
duct the alkylation step on a freshly prepared mixture of
chlorides. As proven by the determination of the enantio-
meric purity of 8, it is considered that the formation of 7
or 11 involves a stereospecific SN2 reaction with no racemi-
zation during this chlorination.
Scheme 1. Synthesis of enantiomerically pure azabicyclo[3.2.0]hep-
tane 8.
In the case of O-aryl epoxides, nucleophilic opening by
-proline methyl ester could be efficiently promoted by β-
cyclodextrin by following our previously published method-
ology.[11] Thus, the 1:1 β-CD complex of epoxide 9 (98%
ee, with opposite absolute configuration to 4) was treated
with -proline methyl ester to give proline derivative 10 in
good yield. The same reaction sequence as in Scheme 1 was
applied to this alcohol to furnish bicyclic compound 13 in
46% overall yield and with total diastereoselectivity
(Scheme 2). The cis relative configuration of the substitu-
ents in this bicyclic azetidine was determined by X-ray
analysis, and the structure is depicted in Figure 1.[12]
Scheme 3. Chlorination of the β-amino alcohols proceeds via an
aziridinium ion.
The second point of discussion concerns the cyclization
step. The addition of HMPA as a cosolvent was found to
Two salient points of this efficient synthesis deserve com- be mandatory for the success of the ring-closing reaction,
ment. First, the formation of a mixture of chlorides is ex- which proceeds only at ca. –30 °C as judged by TLC con-
plained by the intervention of aziridinium ion 14, which is trol. The high cis diastereoselectivity is in accordance with
kinetically opened at the less-substituted side to give 7 (or our previous work on the synthesis of monocyclic azetid-
11) as the major chloride (Scheme 3, shown starting from ines through a similar strategy, and is quite easy to rational-
5). The chlorination conditions used in this work were cho- ize here.[14] In fact, examination of the two possible transi-
sen in such a way as to minimize the amount of secondary tion states A or B (Figure 2) leading to the formation of
chloride formed. Indeed, chlorination of 5 with the use of trans-15 or cis-13 reveals the clear-cut steric interactions
thionyl chloride in refluxing dichloromethane gave a signifi- that disfavor the formation of 15. In transition state A, the
cantly higher ratio of secondary chloride 6, and the mixture CH2OPh pendant group is directed into the endo face of the
of these chlorides was found to slowly evolve almost bicyclic nitrogen heterocycle, which generates severe steric
uniquely into the secondary chloride, which is the more interactions that could explain why this pathway is disfa-
thermodynamically stable isomer, as previously observed vored. It should be noted that the relative configuration in
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F. Couty et al.
FULL PAPER
the starting amino alcohol (compare 5 and 10) has no influ-
Most interestingly, these compounds were found to be
ence on (1) the ratio of the produced chloride (1:4 for each suitable precursors for the production of azepanes, a skel-
diastereoisomer) and (2) on the efficiency and diastereo- eton of continuous interest for the preparation of bioactive
selectivity of the alkylation step, which most probably in- compounds.[15] Thus, treatment of ent-8 with methyl trifluo-
volves a planar enolate as the reactive species. In conclu- romethanesulfonate gave almost quantitative yield of am-
sion, the three-step synthesis of functionalized enantiopure monium ion 18, which was obtained as a single dia-
azabicyclo[3.2.0]heptane derivatives from cheap and readily stereoisomer and whose presumed structure is depicted in
available chiral synthons is very efficient and should give Scheme 4 (alkylation is expected to occur on the exo face,
access to a large array of these heterocycles by varying the see X-ray structure of 13 in Figure 1). Reaction of this am-
nature of the proline and epoxide derivative.
monium salt with NaN3, KCN, or AcOCs in DMF gave
corresponding azepanes 19–21, which result from clean re-
gioselective nucleophilic opening by an SN2 reaction, as
judged by the stereochemical integrity of the produced
compounds.
Conclusion
We showed in this work that the azabicyclo[3.2.0]heptane
skeleton can be efficiently synthesized in a three-step se-
quence from commercially available chiral synthons. Exami-
nation of the catalytic activity of these nitrogen heterocycles
in organocatalyzed reactions is currently under study in our
group.
Figure 2. Examination of the possible transition states that may
explain the diastereoselectivity of the cyclization step.
Experimental Section
General Comments: H and 13C NMR spectra were recorded with
1
Reactivity of the Synthesized Azabicyclo[3.2.0]heptane
Derivatives
a Bruker Avance 300 spectrometer at 300 and 75 MHz, respectively;
chemical shifts are reported in ppm relative to TMS. Optical rota-
tions were determined with a Perkin–Elmer 141 instrument. All the
reactions were carried out under an atmosphere of argon. Column
chromatography was performed on silica gel 230–400 mesh by
using various mixtures of diethyl ether (Et2O), ethyl acetate (Ac-
OEt) petroleum ether (PE), and cyclohexane (CyH). TLC was run
on Merck Kieselgel 60F254 plates. THF and ether were distilled
from sodium/benzophenone ketyl. Dichloromethane was distilled
from calcium hydride. The mention of a “usual workup” means:
(1) decantation of the organic layer, (2) extraction of the aqueous
layer with ether, (3) drying the combined organic layers over
MgSO4, and (4) solvent evaporation under reduced pressure. Ste-
reoisomeric ratios were determined by NMR spectroscopic analysis
of the crude reaction mixtures before purification. Mass spectra
were recorded with a Hewlett–Packard MS Engin HP5989B
equipped with an ESI source Analytica Branford. HRMS spectra
were recorded by the “Service Central d’Analyses du CNRS”.
Next, some synthetic transformations of compound 8 de-
picted in Scheme 4 were studied. Functional group trans-
formations could be conducted successfully, and the hetero-
cycle survived LiAlH4 reduction of the ester moiety to give
primary alcohol 16. The ring system was also found to be
resistant to hydrogenolytic cleavage of the OBn group to
give alcohol 17. These experiments demonstrate that “tail-
oring” of the functional groups is possible, which is essen-
tial for optimization of these amines as organocatalysts.
(S)-Methyl 1-[(S)-3-(Benzyloxy)-2-hydroxypropyl]pyrrolidine-2-car-
boxylate (5): To a suspension of (S)-OBn glycidol (4; 2.95 g,
18 mmol) in ethanol (180 mL) was added -proline (4.14 g,
36 mmol) and triethylamine (36 mL). The resultant mixture was
stirred under an atmosphere of nitrogen at reflux overnight and
then evaporated. The crude residue was dissolved in methanol
(40 mL) and thionyl chloride (1.57 mL, 21.6 mmol) was added
dropwise at –15 °C. The resulting mixture was allowed to reach r.t.
and then heated at reflux for 1 h. After cooling to r.t., concentra-
tion under vacuo gave a crude residue that was dissolved in ethyl
acetate, and the organic layer was washed with a saturated aqueous
solution of NaHCO3. The organic layer was dried with sodium
sulphate and concentrated, and the crude residue was further puri-
fied by flash chromatography (SiO2, PE/AcOEt, 2:3) to give com-
pound 5 as a thick oil. Yield: 3.68 g (70%). Rf = 0.50 (PE/AcOEt,
Scheme 4. Synthetic transformations of azabicyclo[3.2.0]heptane
derivative 8.
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Eur. J. Org. Chem. 2007, 5734–5739

A Straightforward Synthesis of Enantiopure Bicyclic Azetidines
2:3). [α]2D0 = –31.5 (c = 0.23, CHCl3). 1H NMR (300 MHz, CDCl3,
25 °C): δ = 1.70–1.91 (m, 3 H, 4-H, 4Ј-H, 3-H), 2.00–2.17 (m, 1 H,
H, PhCH2O, major isomer), 4.50 (s, 2 H, PhCH2O, minor isomer),
7.13–7.31 (m, 5 H, PhH, mixture of isomers) ppm. 13C NMR
3Ј-H), 2.29–2.40 (m, 1 H, 5-H), 2.55–2.70 (m, 2 H, NCH2CHOH), (75 MHz, CDCl3, 25 °C, major isomer): δ = 23.6 (C-4), 29.7 (C-3),
3.14–3.24 (m, 1 H, 5Ј-H), 3.28 (dd, J = 9.1, 5.3 Hz, 1 H, 2-H), 3.38 43.3 (CH2Cl), 49.6 (C-5), 51.7 (OCH3), 60.8 (C-2), 62.4
(dd, J = 10.1, 4.9 Hz, 1 H, OCHHCHOH), 3.44 (dd, J = 10.1, (NCHCH2Cl) 69.4 (OCH2CHN), 73.3 (PhCH2O), 127.6, 128.4
4.9 Hz, 1 H, OCHHCHOH), 3.64 (s, 3 H, OCH3), 3.82 (quint, J = (CPh), 138.1 (ipso-CPh), 175.4 (CO) ppm. MS (ESI): m/z (%) =
4.7 Hz, 1 H, CHOH), 4.50 (s, 2 H, OCH2Ph), 7.15–7.31 (m, 5 H, 334 (100) [M + Na]+, 312 (30) [M + H]+, 276 (90), 142 (30). HRMS
PhH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 23.9 (C-4),
29.6 (C-3), 52.0 (OCH3), 53.6 (C-5), 58.2 (NCH2CHOH), 65.9 (C-
2), 68.2 (CHOH), 72.6 (OCH2CHOH), 73.5 (PhCH2O), 127.7,
127.8, 128.4 (CPh), 138.3 (ipso-CPh), 175.0 (CO) ppm. MS (CI):
m/z (%) = 294 (100) [M + H]+, 235 (5), 234 (30), 142 (10). HRMS
(ESI): calcd. for C16H24NO4 [M + H]+ 294.1705; found 294.1714.
(ESI): calcd. for C16H23ClNO3 [M + H]+ 312.1366; found 312.1367.
(S)-Methyl 1-[(R)-2-Chloro-3-phenoxypropyl]pyrrolidine-2-carboxyl-
ate (11) and (S)-Methyl 1-[(R)-1-Chloro-3-phenoxypropan-2-yl]pyr-
rolidine-2-carboxylate (12): Following the above procedure, a mix-
ture of chlorides 11 and 12 was obtained after flash chromatog-
raphy (SiO2, PE/AcOEt, 4:1) as a thick oil. Yield: 640 mg (85%).
Rf = 0.50 (PE/AcOEt, 4:1). [α]2D0 = – 23.1 (c = 0.61, CHCl3). 1H
NMR [300 MHz, CDCl3, 25 °C, mixture of regioisomers (primary
chloride/secondary chloride, 4:1)]: δ = 1.61–1.87 (m, 3 H, 4-H, 4Ј-
H, 3-H, mixture of isomers), 1.90–2.06 (m, 1 H, 3Ј-H, mixture of
isomers), 2.53 (appt q, J = 8.0 Hz, 1 H, 5-H, minor isomer), 2.79
(appt q, J = 8.0 Hz, 1 H, 5-H, major isomer), 2.97 (appt d, J =
6 Hz, 2 H, NCH2CHCl, minor isomer), 3.01–3.10 (m, 2 H, 5Ј-H,
mixture of isomers), 3.23–3.32 [m, 2 H, 2-H (minor isomer), 6-H
(major isomer)], 3.49 (s, 3 H, OCH3, major isomer), 3.51 (s, 3 H,
OCH3, minor isomer), 3.63–3.70 (appt d, J = 5.8 Hz, CH2Cl, 2 H,
major isomer), 3.72 (dd, J = 8.7, 3.1 Hz, 1 H, 2-H, major isomer),
3.98 (dd, J = 9.6, 5.6 Hz, 1 H, OCHHCH mixture of isomers),
4.04–4.18 (m, 2 H, OCHHCH of two isomers, NCHCl of minor
isomer), 6.70–6.90 (m, 3 H, PhH, mixture of isomers), 7.10–7.20
(m, 2 H, PhH, mixture of isomers) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C, major isomer): δ = 23.8 (C-4), 29.8 (C-3), 43.0
(CH2Cl), 49.5 (C-5), 51.8 (OCH3), 60.4 (C-2), 62.8 (NCHCH2Cl),
67.2 (PhOCH2), 114.6, 121.1, 129.5 (CPh), 158.4 (ipso-CPh), 175.3
(CO) ppm. MS (ESI): m/z (%) = 320 (50) [M + Na]+, 298 (15) [M
+ H]+, 262 (100), 142 (30). HRMS (ESI): calcd. for C15H21ClNO3
[M + H]+ 298.1210; found 298.1227.
(S)-Methyl 1-[(R)-3-(Phenoxy)-2-hydroxypropyl]pyrrolidine-2-car-
boxylate (10): Epoxide-β-CD complex (1 mmol) was placed in a
mortar and -proline methyl ester (1.1 mmol) dissolved in acetone
(1 mL) was added. The solid was ground vigorously for 6 h. The
completion of the reaction was confirmed by TLC. The complex
was transferred to a conical flask, ethyl acetate (20 mL) was added,
and the suspension was stirred for 20 min. This suspension was
filtered, and the filtrate was concentrated to afford the crude com-
pound, which was purified by column chromatography by using
silica gel treated with triethylamine (AcOEt/PE, 1:4) to give com-
pound 10 as a light yellow oil. Yield: 254 mg (91%). [α]2D0 = –62.4
1
(c = 0.01, CHCl3). H NMR (200 MHz, CDCl3, 25 °C): δ = 1.79–
2.02 (m, 3 H, 4-H, 4Ј-H, 3-H), 2.07–2.23 (m, 1 H, 3Ј-H), 2.42–2.56
(m, 1 H, 5-H), 2.68–2.87 (m, 2 H, NCH2CHOH), 3.26–3.41 (m, 2
H, 5-H, 2-H), 3.73 (s, 3 H, OMe), 3.80–3.91 (m, 1 H, CHOH),
3.94–4.09 (m, 2 H, CH2OPh), 6.83–6.94 (m, 3 H, ArH), 7.18–7.27
(m, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 23.7
(C-4), 29.8 (C-3), 52.0 (OCH3), 53.6 (C-5), 58.3 (NCH2CHOH),
66.0 (C-2), 67.6 (CHOH), 70.2 (OCH2CHOH), 114.6, 120.7, 129.3
(CPh), 158.8 (ipso-CPh), 174.9 (CO) ppm. IR (KBr): ν = 3444,
˜
2924, 1734, 1637, 1596, 1244, 1040, 755, 692 cm–1. HRMS: calcd.
for C15H22NO4 [M + H]+ 280.1548; found 280.1545.
General Procedure for the Synthesis of Bicyclic Azetidines 8 and 13:
To a solution of the chloride (1 mmol) in a mixture of THF (5 mL)
and HMPA (0.5 mL) was added dropwise at –90 °C a solution
of LiHMDS (1  in THF, 1.5 mL, 1.5 mmol). The reaction was
monitored by TLC and then quenched by the addition of an aque-
ous saturated solution of NH4Cl at 0 °C. Extraction of the reaction
mixture by using ether followed by the usual workup gave the crude
residue of bicyclic azetidine.
General Procedure for the Preparation of Chlorides 6, 7, 11, 12: A
solution of amino alcohol (1 mmol) in DCM (5 mL) was cooled to
0 °C under an atmosphere of argon. Carbon tetrachloride
(2.00 mmol) was added dropwise followed by triphenylphosphane
(2 mmol), and the resulting mixture was allowed to reach r.t. and
stirred for 5 h. After completion of the reaction, the mixture was
concentrated in vacuo at room temperature to minimize the forma-
tion of the aziridinium ion. The crude reaction mixture was puri-
fied by flash chromatography.
(5S,7R)-Methyl 7-[(Benzyloxy)methyl]-1-azabicyclo[3.2.0]heptane-5-
carboxylate (8): Following the above procedure, pure compound 8
was obtained after flash chromatography (SiO2, PE/AcOEt, 1:4) as
a colorless solid. Yield: 558 mg (58%). Rf = 0.20 (PE/AcOEt, 1:4).
M.p. 34–35 °C. [α]2D0 = –62.1 (c = 1.02, CHCl3). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 1.82–2.02 (m, 3 H, 4-H, 4Ј-H, 3-H),
2.05–2.22 (m, 2 H, 3Ј-H, 6-H), 2.40 (dd, J = 12.2, 6.7 Hz, 1 H, 6Ј-
H), 2.82 (dd, J = 9.3, 3.7 Hz, 2 H, 2-H, 2Ј-H), 3.05 (quint, J =
6.2 Hz, 1 H, 7-H), 3.43 (dd, J = 9.5, 6.2 Hz, 1 H, OCHHCH), 3.51
(dd, J = 9.6, 6.3 Hz, 1 H, OCHHCH), 3.65 (s, 3 H, OCH3), 4.47
(d, part of AB syst., J = 12.1 Hz, OCHHPh), 4.55 (d, part of AB
syst., J = 12.1 Hz, OCHHPh) 7.15–7.31 (m, 5 H, PhH) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 25.7 (C-4), 30.5 (C-6), 36.1
(C-3), 52.3 (OCH3), 55.9 (C-2), 58.3 (C-7), 70.8 (C-5), 73.4
(PhCH2O), 74.7 (OCH2CH), 127.6, 127.8, 128.3 (CH), 138.3 (ipso-
CPh), 176.2 (CO) ppm. MS (ESI): m/z (%) = 298 (100) [M +
Na]+, 276 (30) [M + H]+. HRMS (ESI): calcd. for C16H22NO3 [M
+ H]+ 276.1600; found 276.1590.
(S)-Methyl 1-[(S)-3-(Benzyloxy)-1-chloropropan-2-yl]pyrrolidine-2-
carboxylate (7) and (S)-Methyl 1-[(S)-3-(Benzyloxy)-2-chloropro-
pyl]pyrrolidine-2-carboxylate (6): Following the above procedure, a
mixture of chlorides 6 and 7 was obtained after flash chromatog-
raphy (SiO2, PE/AcOEt, 4:1) as a thick oil. Yield: 617 mg (60%).
Rf = 0.50 (PE/AcOEt, 4:1). [α]2D0 = –42.6 (c = 1.10, CHCl3). 1H
NMR [300 MHz, CDCl3, 25 °C, mixture of regioisomers (primary
chloride/secondary chloride, 4:1)]: δ = 1.65–1.91 (m, 3 H, 4-H, 4Ј-
H, 3-H, mixture of isomers), 1.93–2.10 (m, 1 H, 3Ј-H, mixture of
isomers), 2.51 (appt q, J = 8.1 Hz, 1 H, 5-H, minor isomer), 2.80
(appt q, J = 7.5 Hz, 1 H, 5-H, major isomer), 2.92 (appt d, J =
6.4 Hz, 2 H, NCH2CHCl, minor isomer), 2.98–3.10 (m, 2 H, 5Ј-H,
mixture of isomers), 3.11–3.20 (m, 1 H, NCHCH2Cl, major iso-
mer), 3.29 (dd, J = 8.7, 4.6 Hz, 1 H, 2-H, minor isomer), 3.57 (s, 3
H, OCH3, major isomer), 3.60 (s, 3 H, OCH3, minor isomer), 3.50–
3.70 [m, 6 H, OCH2CHN, CH2Cl (major isomer), OCH2CHCl
(minor isomer)], 3.76 (dd, J = 8.7, 4.6 Hz, 1 H, 2-H, major isomer),
4.04 [q, J = 5.7 Hz, 1 H, NCH2CHCl (minor isomer)], 4.43 (s, 2
(5R,7S)-Methyl
7-(Phenoxymethyl)-1-azabicyclo[3.2.0]heptane-5-
carboxylate (13): Following the above procedure, pure compound
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F. Couty et al.
FULL PAPER
13 was obtained after flash chromatography (SiO2, PE/AcOEt, 1:4)
reaction mixture was stirred at 0 °C for 1 h and was allowed to
reach r.t. (0.5 h). The reaction mixture was then concentrated under
reduced pressure, and the residue was triturated with small portions
of petroleum ether. Drying under vacuum gave 18 as a thick oil.
as a colorless solid. Yield: 412 mg (60%). Rf = 0.30 (PE/AcOEt,
20
1:4). M.p. 74–75 °C. [α]
= +50.9 (c = 0.16, CHCl3). 1H NMR
578
(300 MHz, CDCl3, 25 °C): δ = 1.86–2.01 (m, 3 H, 4-H, 4Ј-H, 3-H),
2.08–2.30 (m, 2 H, 3Ј-H, 6-H), 2.52 (dd, J = 9.3, 5.0 Hz, 1 H, 6Ј-
H), 2.87 (dd, J = 9.3, 5.0 Hz, 2 H, 2-H, 2Ј-H), 3.22 (quint, J =
Yield: 480 mg (quant.). [α]2D0 = –51.1 (c = 0.9, CHCl3). H NMR
1
(300 MHz, [D6]acetone): δ = 2.30–2.68 (m, 4 H, 3-H, 4-H or 6-H),
6.4 Hz, 1 H, 7-H), 3.69 (s, 3 H, OCH3), 3.94 (appt q, J = 9.5 Hz, 2.80–2.95 (m, 1 H, 3-H, 4-H or 6-H), 3.21 (dd, J = 11.9, 8.7 Hz, 1
2 H, PhOCH2CH), 6.80–6.98 (m, 3 H, PhH), 7.26 (t, J = 11.0 Hz,
H, 4-H or 6-H), 3.32 (s, 3 H, NMe), 3.54 (td, J = 11.5, 5.1 Hz, 1
H, 2-H), 3.78 (s, 1 H, OCH3), 3.95–4.18 (m, 3 H, 2Ј-H, CH2O),
2 H, PhH) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 25.7 (C-
3), 30.5 (C-6), 36.1 (C-4), 52.3 (OCH3), 55.9 (C-2), 57.6 (C-7), 70.8 4.62 (s, 2 H, PhCH2O), 4;65–4.79 (m, 1 H, 7-H), 7.20–7.45 (m, 5
(C-5), 71.8 (PhCH2O), 114.5, 120.7, 129.4 (CH), 158.8 (ipso-CPh), H, Ar) ppm. 13C NMR (75 MHz, [D6]acetone): δ = 24.8 (C-3, C-
176.1 (CO) ppm. MS (CI): m/z (%) = 284 (100) [M + Na]+, 300 4, or C-6), 25.9 (C-3, C-4, or C-6), 36.7 (C-3, C-4, or C-6), 42.8
(17). HRMS (ESI): calcd. for C15H20NO3 [M + H]+ 261.1443; (NCH3), 54.1 (OCH3), 66.8, 67.8 (CH2), 70.8 (C-7), 83.5 (CH2O),
found 262.1450.
83.6 (C-5), 128.7, 128.8, 129.3 (CHAr), 138.4 (ipso-CPh), 168.1
(C=O) ppm.
(5S,7R)
{7-[(Benzyloxy)methyl]-1-azabicyclo(3.2.0)heptan-5-yl}-
methanol (16): To a solution of methyl ester 8 (566 mg, 2.06 mmol)
in THF (10 mL) was added lithium aluminium hydride (118 mg,
Methyl (2S,4S)-4-Azido-2-benzyloxymethyl-1-methylazepane-4-car-
boxylate (19): To a solution of 18 (140 mg, 0.32 mmol) in DMF
3.10 mmol) portionwise at 0 °C. After stirring for few minutes at (4 mL) was added sodium azide (0.032 g, 0.48 mmol). The resulting
this temperature, the reaction mixture was refluxed for 3 h. After
the completion of reaction, the excess LAH was quenched by the
addition of 2  NaOH (5 mL) and the reaction mixture was filtered
off. The filtrate was concentrated and dried. The obtained product
was pure enough for further reactions. Yield: 458 mg (90%); Rf
suspension was stirred at r.t. for 2 h. The addition of water and
Et2O was then followed by the usual workup, and the residue was
purified by flash chromatography. Title compound 19 was obtained
as a clear oil. Yield: 93 mg (87%). Rf = 0.50 (AcOEt/MeOH, 9:1).
[α]2D0 = –15.2 (c = 2.1, CHCl3). 1H NMR (300 MHz, CDCl3, 25 °C):
= 0.30 (AcOEt/MeOH/NH4OH, 9:1:1). M.p. 71–73 °C. 1H NMR δ = 1.72–1.92 (m, 4 H, 5-H, 6-H), 2.00–2.17 (m, 2 H, 3-H), 2.41 (s,
(300 MHz, CD3OD, 25 °C): δ = 1. 45–2.14 (m, 6 H, 3-H, 3Ј-H, 4- 3 H, NMe), 2.85–3.01 (m, 3 H, 2-H, 6-H), 3.21 (dd, part of ABX
H, 4Ј-H, 6-H, 6Ј-H), 2.50–2.68 (m, 2 H, 2-H, 2Ј-H), 3.00 (quint, J syst., J = 7.1, 9.4 Hz, 1 H, NCHHCHO), 3.42 (dd, part of ABX
= 6.6 Hz, 1 H, 7-H), 3.26–3.50 (m, 4 H, OCH2CHN, NCqCH2OH), syst., J = 4.8, 9.4 Hz, 1 H, NCHHCHO), 3.85 (s, 3 H, OMe), 4.51
4.38 (d, part of AB syst, J = 11.8 Hz, 1 H, PhCHHO), 4.41 (d,
(s, 2 H, PhCH2O), 7.32–7.55 (m, 5 H, Ar) ppm. 13C NMR
part of AB syst, J = 11.8 Hz, 1 H, PhCHHO) 7.10–7.28 (m, 5 H, (75 MHz, CDCl3, 25 °C): δ = 19.9 (C-6), 35.1 (C-3), 35.9 (C-5),
PhH) ppm. 13C NMR (75 MHz, CD3OD, 25 °C): δ = 25.3 (C-3), 40.6 (NCH3), 52.9 (OCH3), 55.2 (C-7), 57.6 (C-2), 73.1 (C-4), 72.7
28.2 (C-4), 34.4 (C-6), 55.3 (C-2), 58.6 (C-7), 66.5 (NCqCH2OH), (OCH2CH), 73.2 (PhCH2O), 127.6, 127.7, 128.4 (CPh), 138.2 (ipso-
71.8 (C-5), 73.3 (PhCH2O), 74.4 (OCH2CH), 127.7, 127.8, 127.9 CPh), 173.7 (CO) ppm. IR (neat): ν = 2108, 1745 cm–1. MS (CI):
˜
(CH), 138.8 (ipso-CPh) ppm. CIMS: m/z (%) = 248 (100) [MH]+,
230 (7), 140 (15), 91 (90). HRMS (ESI): calcd. for C15H21NO2
[M+]: 247.1572; found 247.1570.
m/z (%) = 333.3 (100) [M + H]+.
(2S,4S)-Methyl 2-Benzyloxymethyl-4-cyano-1-methylazepane-4-car-
boxylate (20): To a solution of 18 (35 mg, 0.08 mmol) in DMF
(5S,7R)-Methyl 7-(Hydroxymethyl)-1-azabicyclo[3.2.0]heptane-5- (1 mL) was added sodium cyanide (16 mg, 0.24 mmol). The re-
carboxylate (17): To a mixture of azetidine (500 mg, 1.82 mmol) in
methanol (9 mL) and acetic acid (1 mL) was added 10% Pd on
charcoal (160 mg), and the suspension was hydrogenated at 15 atm
for 96 h. After completion of the reaction the mixture was filtered
through Celite, and the filtrate was concentrated and dried in
vacuo. The crude residue was then dissolved in aqueous NaHCO3
(1 mL), and the mixture was then extracted with DCM
(3ϫ10 mL). The organic layer was dried with MgSO4 and concen-
trated in vacuo to give the desired alcohol. The obtained amino
alcohol was pure enough for further reactions. Yield: 161 mg
sulting suspension was stirred at r.t. for 2 h. The addition of water
and Et2O was then followed by the usual workup, and the residue
was purified by flash chromatography. Title compound 20 was ob-
tained as a clear oil. Yield: 19 mg (74%). Rf = 0.50 (AcOEt/MeOH,
9:1). [α]2D0 = –2.3 (c = 1.6, CHCl3). 1H NMR (200 MHz, CDCl3,
25 °C): δ = 1.82–1.95 (m, 2 H, 5-H, 3-H or 6-H), 2.05–2.22 (m, 4
H, 5-H, 3-H or 6-H), 2.47 (s, 3 H, NMe), 2.85–3.05 (m, 2 H, 7-H),
3.02–3.15 (m, 1 H, 2-H), 3.37 (dd, part of ABX syst., J = 4.6,
9.4 Hz, 1 H, NCHHCHO), 3.45 (dd, part of ABX syst., J = 4.6,
9.4 Hz, 1 H, NCHHCHO), 3.75 (s, 3 H, OMe), 4.48 (s, 2 H,
PhCH2O), 7.20–7.32 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
(50%). Rf = 0.40 [AcOEt/MeOH/30% NH4OH, 9:1:1]. M.p. 183–
1
184 °C. H NMR (300 MHz, CDCl3, 25 °C): δ = 1. 86–2.03 (m, 3 CDCl3, 25 °C): δ = 31.8 (C-6), 30.1 (C-3), 36.7 (C-5), 41.6 (NCH3),
H, 3-H, 3Ј-H, 4-H), 2.04–2.25 (m, 2 H, 6-H, 4Ј-H), 2.47 (dd, J = 47.7 (C-4), 53.0 (OCH3), 53.7 (C-7), 59.7 (C-2), 73.1 (C-4), 71.7
12.2, 6.7 Hz 1 H, 6Ј-H), 2.75–2.85 (m, 2 H, 2-H, 2Ј-H), 3.02 (quint, (OCH2CH), 73.2 (PhCH2O), 118.8 (CN), 128.4, 128.6, 128.8
J = 4.5 Hz, 1 H, 7-H), 3.42 (dd, J = 11.6, 4.8 Hz, 1 H,
(CPh), 138.0 (ipso-CPh), 171.2 (CO) ppm. IR (neat): ν = 1730,
˜
CHCHHOH), 3.52 (dd, J = 11.6, 4.8 Hz, 1 H, CHCHHOH), 3.68 1206 cm–1. MS (CI): m/z (%) = 317.3 (100) [M + H]+.
(s, 3 H, OCH3), 4.20 (br. s, 1 H, OH) ppm. 13C NMR (75 MHz,
(2S,4S)-Methyl 4-Acetoxy-2-benzyloxymethyl-1-methylazepane-4-
CD3OD, 25 °C): δ = 25.6 (C-4), 28.7 (C-6), 35.9 (C-3), 52.3
carboxylate (21): To a solution of 18 (70 mg, 0.16 mmol) in DMF
(OCH3), 55.5 (C-2), 60.2 (C-7), 64.6 (CH2OH), 70.3 (C-5), 175.7
(2 mL) was added cesium acetate (92 mg, 0.48 mmol). The resulting
(CO) ppm. MS (ESI): m/z (%) = 208 (100) [M + Na]+, 186 (100)
suspension was stirred at r.t. for 2 h. The addition of water and
[M + H]+, 126 (90), 108 (40). HRMS (ESI): calcd. for C8H14NO3
Et2O was then followed by the usual workup, and the residue was
[M + H]+ (for the hydrolyzed ester) 172.0974; found 172.0981.
purified by flash chromatography. Title compound 21 was obtained
(1S,5R,7S)-7-Benzyloxymethyl-5-methoxycarbonyl-1-methyl-1-azo-
niabicyclo[3.2.0]heptane (18): To a solution of ent-8 (300 mg,
1.09 mmol) in dry dichloromethane (5 mL) was added dropwise at
0 °C methyl trifluoromethanesulfonate (0.250 mL, 2.2 mmol). The
as a clear oil. Yield: 33 mg (63%). Rf = 0.50 (AcOEt/MeOH, 9:1).
[α]2D0 = – 42.5 (c = 1.6, CHCl3). 1H NMR (200 MHz, CDCl3,
25 °C): δ = 1.30–1.45 (m, 1 H, 5-H, 3-H or 6-H), 1.52–1.70 (m, 1
H, 5-H, 3-H or 6-H), 2.01–2.22 (m, 3 H, 5-H, 3-H or 6-H), 2.08 (s,
5738
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 5734–5739

A Straightforward Synthesis of Enantiopure Bicyclic Azetidines
[7] V. K. Aggarwal, J. N. Harvey, R. Robiette, Angew. Chem. Int.
Ed. 2005, 44, 5471.
3H CH3CO), 2.39 (s, 3 H, NMe), 2.80–3.05 (m, 3 H, 2-H, 7-H),
3.27 (dd, part of ABX syst., J = 5.0, 9.2 Hz, 1 H, NCHHCHO),
3.38 (dd, part of ABX syst., J = 6.5, 9.2 Hz, 1 H, NCHHCHO),
3.65 (s, 3 H, OMe), 4.44 (s, 2 H, PhCH2O), 7.28–7.36 (m, 5 H, Ar)
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 20.0 (C-3, C-5, or
C-6), 21.2 (CH3CO), 34.3 (C-3, C-5, or C-6), 36.9 (C-3, C-5, or C-
6), 39.7 (NCH3), 53.6 (OCH3), 55.7 (C-7), 57.4 (C-2), 73.1 (C-4),
73.1 (OCH2CH), 73.2 (PhCH2O), 82.0 (C-4), 127.6, 128.6, 128.8
[8] J. E. Imbriglio, M. M. Vasbinder, S. J. Miller, Org. Lett. 2003,
5, 3741. See also ref.[5]
[9] S. J. Miller, Acc. Chem. Res. 2004, 37, 601.
[10] a) C. Agami, F. Couty, N. Rabasso, Tetrahedron Lett. 2002, 43,
4636; b) A. Carlin-Sinclair, F. Couty, N. Rabasso, Synlett 2003,
5, 729; c) F. Couty, G. Evano, N. Rabasso, Tetrahedron: Asym-
metry 2003, 14, 2412; d) F. Couty, G. Evano, D. Prim, J. Mar-
rot, Eur. J. Org. Chem. 2004, 3897; e) H. Braüner-Osborne, L.
Bunch, N. Chopin, F. Couty, G. Evano, A. A. Jensen, M. Kusk,
B. Nielsen, N. Rabasso, Org. Biomol. Chem. 2005, 3, 3936; f)
M. Vargas-Sanchez, F. Couty, G. Evano, D. Prim, J. Marrot,
Org. Lett. 2005, 7, 5861.
(CPh), 138.3 (ipso-CPh), 170.3, 172.6 (CO) ppm. IR (neat): ν =
˜
1730, 1213 cm–1. MS (CI): m/z (%) = 350.4 (100) [M + H]+.
Acknowledgments
[11] R. L. Rajender Reddy, N. N. Bhanumathi, K. Rama Rao,
Chem. Commun. 2000, 2321.
[12] CCDC-648991 (for 13) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
IFCPAR (Indo-French Centre for the Promotion of Advanced Re-
search) is gratefully acknowledged for financial support.
[13] W. H. Pirkle, M. S. Hoekstra, J. Am. Chem. Soc. 1976, 98,
[1]
a) P. S. Mariano, J. L. Stavinoha, J. Am. Chem. Soc. 1981, 103,
3136; b) P. S. Mariano, A. Leone-Bay, Tetrahedron Lett. 1980,
21, 4581.
N. J. Ashweek, I. Coldham, D. J. Snowden, G. P. Vennall,
Chem. Eur. J. 2002, 8, 195.
S. E. Denmark, J. I. Montgomery, L. A. Kramps, J. Am. Chem.
Soc. 2006, 128, 11620.
1832.
[14] S. Mangaleshwaran, F. Couty, G. Evano, B. Srinivas, R. Srid-
har, K. Rama Rao, Arkivoc 2007, x, 71.
[2]
[3]
[15] For some recent examples, see: a) A. Kamal, D. Rajasekhar
Reddy, P. S. Murali Mohan Reddy, Rajendar, Bioorg. Med.
Chem. Lett. 2006, 16, 1160; b) H. Li, Y. Blériot, J. M. Mallet,
E. Rodriguez-Garcia, P. Vogel, Y. Zhang, P. Sinaÿ, Tetrahedron:
Asymmetry 2005, 16, 313; c) L. Joong, P. Beak, J. Am. Chem.
Soc. 2006, 128, 2678; d) G. F. Painter, P. J. Eldridge, A. Fal-
shaw, Bioorg. Med. Chem. 2004, 12, 225.
[4] B. Alcaide, C. Polanco, M. A. Sierra, J. Org. Chem. 1998, 63,
6786.
[5] A. G. M. Barret, P. Dozzo, A. J. P. White, D. J. Williams, Tetra-
hedron 2002, 58, 7303.
[6] A. M. Calter, R. K. Orr, W. Song, Org. Lett. 2003, 5, 4745.
Received: July 4, 2007
Published Online: September 28, 2007
Eur. J. Org. Chem. 2007, 5734–5739
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5739