Synthesis of spirocyclopropyl γ-lactams by a highly stereoselective tandem intramolecular azetidine ring-opening/closing cascade reaction

Article abstract of DOI:10.1002/ejoc.201101278

A new tandem intramolecular azetidine ring-opening/closing cascade reaction affording spirocyclopropyl γ-lactams in high regio-and stereoselectivity is reported. The key step of the process is an S_N2-type ring-opening of TMSOTf-activated azetid

Full text of DOI:10.1002/ejoc.201101278

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101278
Synthesis of Spirocyclopropyl γ-Lactams by a Highly Stereoselective Tandem
Intramolecular Azetidine Ring-Opening/Closing Cascade Reaction
Pierre-Antoine Nocquet,[a] Damien Hazelard,[a] and Philippe Compain*[a,b]
Keywords: Domino reactions / Lactams / Cyclization / Small ring systems / Lewis acids
A new tandem intramolecular azetidine ring-opening/clos-
ing cascade reaction affording spirocyclopropyl γ-lactams in
high regio- and stereoselectivity is reported. The key step of
the process is an SN2-type ring-opening of TMSOTf-acti-
vated azetidine rings by silyl ketene acetals generated by
treatment with TMSOTf and triethylamine. This study is a
very rare example of nucleophilic ring opening of azetidines
that does not require formation of quaternary azetidinium
salts by N-alkylation or the use of N-electron-withdrawing
groups.
Introduction
Although less popular than aziridines, pyrrolidines, and
piperidines, azetidines constitute a class of attractive hetero-
cycles present in many natural products and pharmacologi-
cally relevant compounds.[1] Until recently, the reactivity of
azetidines was almost unexploited in comparison to that of
the widely used aziridines because of their lower synthetic
availability and reactivity.[2] For example, ring opening of
azetidines usually requires stronger activation including for-
mation of quaternary azetidinium salts by N-alkylation as
a consequence of reduced ring strain and electrophilicity.[3]
In a recent relevant study, azetidinium derivatives were in-
deed shown to be 17000 times less reactive than the corre-
sponding aziridinium analogs towards nucleophilic ring
opening.[3] Within the framework of a research program de-
voted to the design and biological evaluation of novel
classes of iminosugars,[4,5] our objective was to access
rapidly 2-azaspiro[3.3]heptane derivatives as precursors of
original bicyclic spiranic iminosugars 1 (Figure 1). For ex-
ample, compounds 2 may be viewed as a constrained analog
Figure 1. Iminosugars designed as pharmaceutical chaperones for
Gaucher disease.
tained in two steps from commercially available
4
(Scheme 1).[7] This was a short but challenging route, as for-
mation of four-membered cycles by such a process is disfa-
vored by ring strain and has almost no precedent.[8] First
attempts performed under classical conditions (NaH, THF)
failed to afford the desired 2-azaspiro[3.3]heptane derivative.
We then turned our attention to a cationic variant of the
Dieckmann reaction involving a silyl ketene acetal generated
by treatment of enolizable ester 5 with TMSOTf and triethyl-
amine (TEA).[9] In a first attempt, reaction of 5 following
Hoye’s protocol[9a] did not lead to the formation of the
Dieckmann product but to functionalized 5-azaspiro[2.4]-
heptane derivative 6a in 65% yield as a single diastereoiso-
mer (Scheme 1). The 5-azaspiro[2.4]heptane skeleton is a mo-
tif present in various biologically active molecules including
antibacterial and antiautoimmune agents.[10,11]
1
of α-1-C-Nonyl-DIX (3) having a blocked C4 conforma-
tion.
α-1-C-Nonyl-DIX (3) is a potent inhibitor of human β-
glucocerebrosidase and acts as a pharmacological chap-
erone of the N370S mutant of this enzyme for patients with
Gaucher disease.[6] The synthetic strategy we first envi-
sioned to access 2-azaspiro[3.3]heptane derivatives was
based on a Dieckmann reaction performed on diester 5 ob-
The structure of 6a and relative configuration of the two
asymmetric centers were determined by NMR spectroscopy
and further confirmed by X-ray crystallographic analysis of
primary alcohol 6b obtained after selective reduction of the
ester group (Figure 2).[12a] Access to the fully reduced pyr-
rolidine analog 6c was also easily performed from 6a by
using LAH.
In this paper, we wish to report our first exploration of
the synthetic scope of this novel tandem reaction and to
provide some insights into its mechanism for rationalizing
the unexpected formation of the azaspiro bicyclic products.
[a] Laboratoire de Synthèse Organique et Molécules Bioactives,
Université de Strasbourg/CNRS (UMR 7509), Ecole
Européenne de Chimie, Polymères et Matériaux,
25 rue Becquerel, 67087 Strasbourg, France
Fax: +33-3-68852754
E-mail: philippe.compain@unistra.fr
[b] Institut Universitaire de France,
103 Bd Saint-Michel, 75005 Paris, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101278.
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P.-A. Nocquet, D. Hazelard, P. Compain
Table 1. Reaction of 5 with Lewis acid and base.[a]
SHORT COMMUNICATION
Entry Lewis acid (equiv.)
Base (equiv.)
Temp.
Yield[b]
[%]
1
2
3
4
5
6
7
8
TMSOTf (2)
TMSOTf (1)
TMSOTf (2)
TMSOTf (3)
TMSOTf (2)
TMSOTf (2)
TMSOTf (2)
TMSOTf (2)
TMSOTf (2)
ZnOTf (2)
TEA (2.5)
TEA (2.5)
TEA (1)
TEA (2.5)
TEA (3)
TEA (2.5)
TEA (2.5)
TEA (2.5)
DIPEA (2.5)
TEA (2.5)
TEA (2.5)
TEA (2.5)
TEA (2.5)
TEA (2.5)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
Δ[d]
r.t.
r.t.
r.t.[f]
r.t.[f]
r.t.
r.t.
Δ
65
–
–
65
68
75[c]
70
[e]
–
9
38
–
10
11
12
13
14
ScOTf (2)
BF3·Et2O (2)
CuOTf (2)
–
Scheme 1. Reagents and conditions: (a) BnNH2 (1 equiv.), TEA
(3 equiv.), MeCN, Δ, 4 h; (b) LDA (1.1 equiv.), HMPA (6.3 equiv.),
methyl 3-bromopropionate (3 equiv.), THF, –78 °C to r.t.;
(c) TMSOTf (2 equiv.), TEA (2.5 equiv.), CH2Cl2, r.t. or Δ;
(d) LiBHEt3 (4 equiv.), THF, –78 to –65 °C; (e) lithium aluminum
hydride (LAH, 3.5 equiv.), THF, Δ.
[c]
–
–
[c]
TBDMSOTf (2)
25
[a] Reaction performed in DCM for 5 to 7 h. [b] Isolated yield.
[c] Reaction time: 24 h. [d] Reaction time: 3 h. [e] Reaction per-
formed in THF. [f] Room temperature for 24 h then reflux for 3 h.
No reaction took place in THF (Table 1, Entry 8), and
the yield was divided by almost a factor of 2 by using DI-
PEA instead of TEA as a base (Table 1, Entry 9). Screening
of various azaphilic and oxophilic Lewis acids[13] revealed
that the nature of the Lewis acid was crucial, as conversion
of the azetidine starting material was observed only with
TMSOTf (Table 1, Entries 10–13). The use of a more steri-
cally demanding trialkylsilyl triflate (TBDMSOTf) led to
low yields and modest conversion (Table 1, Entry 14). The
influence of diverse structural parameters in the outcome
of the spirocyclization reaction was then studied (Figure 3
and Scheme 2). Deactivation of the azetidine endocyclic ni-
trogen atom was found to be detrimental to the process, as
no spiranic product could be obtained from N-Tos or N-
Boc azetidines 7 and 8 (Figure 3).
Figure 2. Molecule structure (ORTEP)[12b] of compound 6b. Ther-
mal ellipsoid at 30% probability.
Results and Discussion
Figure 3. Test substrates for investigating the scope of the tandem
reaction.
Various experimental parameters were first examined
with the TMSOTf/TEA system in DCM to improve the
yield of the one-pot process. Decreasing the amount of
TMSOTf or TEA to one equivalent was found to be detri-
No desired product was obtained from lactam 9 either.[14]
mental, as no reaction took place (Table 1, Entries 2 and The reaction was found to be highly sensitive to the intro-
3), whereas the addition of more equivalents of Lewis acid duction of substituents in the α or β position to the primary
or base (Table 1, Entries 4 and 5) did not improve signifi- ester group; azetidines 10 and 11,[15] the methylated analogs
cantly the yield of the reaction. The best yields were ob- of 5, did not partake in the spirocyclization reaction. Not
tained by increasing the reaction time to 24 h or by increas- surprisingly, conversion of 12 provided the expected spiro-
ing the reaction temperature to reflux (Table 1, Entries 6 cyclopentane 14 as the increase of the alkyl chain length by
and 7).
one methylene unit favored the Dieckmann reaction
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Eur. J. Org. Chem. 2011, 6619–6623

Synthesis of Spirocyclopropyl γ-Lactams
(Scheme 2). Further increase in the alkyl chain length by am, the tertiary ester group was replaced by a hydrogen
two methylene units to favor azetidine ring opening (forma- atom, and the reaction was performed from azetidine 16.[18]
tion of a six-membered ring) over the Dieckmann reaction Treatment of 16 with TMSOTf and TEA afforded cyclo-
(formation of a disfavored seven-membered ring)[9a] led to propane 17 in 61% yield with 56%de in favor of the trans
substrate 13, which was not reactive under our typical cycli- product (Scheme 4). Disappointing results obtained with
zation conditions. The influence of steric effects on the cy- 10, 11, and azetidine 15 bearing a bulky tBu ester group
clization process was explored with tert-butyl ester 15, or with higher trialkylsilyl triflate (Table 1, Entry 14) are
which afforded the expected spiranic lactam in a much compatible with the fact that an SN2 process is a mecha-
lower yield than that of corresponding methyl ester analog nism known to be sensitive to steric hindrance.
5 (Scheme 2).
Scheme 4.
Conclusions
In conclusion, a novel, highly stereoselective tandem in-
tramolecular azetidine ring-opening/closing cascade reac-
tion is reported. In this one-step process, two cycles – a
cyclopropane and a γ-butyrolactam – and two asymmetric
centers are created. This study represents a very rare exam-
Scheme 2.
ple[19] of nucleophilic ring opening of azetidines without
formation of quaternary azetidinium salts by N-alkylation
or the use of N-electron-withdrawing groups.[20,21] Further
applications and mechanistic exploration of this methodol-
ogy are currently under investigation in our laboratory.
A tentative mechanism for the formation of spirocy-
clopropyl γ-lactam 6a is proposed in Scheme 3. We believe
that the key step of the process is an SN2-type ring open-
ing[2,16] of the TMSOTf-activated azetidine ring by the silyl
ketene acetal generated by treatment with TMSOTf and
TEA.[9a] Amino ester A, thus obtained, finally undergoes
an intramolecular cyclization to afford five-membered lact-
am 6a by reaction of the amine function with the ester
group in the γ position. This reaction proceeds in high re-
gioselectivity, as no formation of the six-membered lactam
was detected. Remarkably, in this process TMSOTf plays a
triple role by generating the reactive nucleophilic intermedi-
ate (the silyl ketene acetal), by activating the azetidinine for
the nucleophilic ring opening, and by activating the carb-
onyl group of the tertiary ester group for the final amide
bond formation.[17]
Experimental Section
General Methods: Tetrahydrofuran (THF) was dried by passage
through an activated alumina column under an atmosphere of ar-
gon. Dichloromethane (CH2Cl2) was distilled from CaH2 under an
atmosphere of argon. Triethylamine (TEA) was distilled from KOH
under an atmosphere of argon and stored over KOH. All reactions
were performed in standard glassware under an atmosphere of ar-
gon. Flash chromatography was performed on silica gel 60 (230–
400 mesh, 0.040–0.063 mm) purchased from E. Merck. Thin-layer
chromatography (TLC) was performed on aluminum sheets coated
with silica gel 60 F254 purchased from E. Merck. IR spectra were
recorded with a Perkin–Elmer Spectrum One Spectrophotometer.
NMR spectra were recorded with a Bruker AC 300 or AC 400 with
solvent peaks as reference. Carbon multiplicities were assigned by
distortionless enhancement by polarization transfer (DEPT) ex-
periments. The 1H signals were assigned by 2D experiments
(COSY). ESI-HRMS was carried out with a Bruker MicroTOF
spectrometer.
5-Benzyl-1-methoxycarbonyl-5-azaspiro[2.4]heptan-4-one (6a): To a
solution of azetidine 5 (80 mg, 0.28 mmol) in CH2Cl2 (1 mL) co-
oled to 0 °C was added TEA (96 μL, 0.69 mmol, 2.5 equiv.) and
TMSOTf (0.1 mL, 0.55 mmol, 2 equiv.). The solution was stirred
at room temperature for 24 h. Then, the reaction was quenched
with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3ϫ).
The combined organic layer was dried with Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was puri-
fied by flash chromatography (AcOEt/pentane, 1:5 to 1:1) to afford
Scheme 3. Proposed mechanism for the tandem reaction.
The proposed mechanism is supported by experimental
evidence and explains why azetidines 7, 8, and 9 are not
substrates of the cyclization reaction; the best activation of
the azetidine ring with TMSOTf is indeed expected for an
endocyclic amine. To isolate the aminocyclopropane inter-
mediate of type A by avoiding the formation of the β-lact- 6a (54 mg, 75%) as a yellow oil. TLC: Rf = 0.30 (silica gel; AcOEt/
Eur. J. Org. Chem. 2011, 6619–6623
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6621

P.-A. Nocquet, D. Hazelard, P. Compain
petroleum ether, 1:2). IR (film): ν = 1728, 1688 cm–1. 1H NMR authors are grateful to Dr. Michel Miesch for helpful discussions.
SHORT COMMUNICATION
˜
(300 MHz, CDCl3): δ = 7.38–7.21 (m, 5 H, Ph), 4.51 (d, J =
14.7 Hz, 1 H, CH2Ph), 4.45 (d, J = 14.7 Hz, 1 H, CH2Ph), 3.71 (s,
3 H, CO2Me), 3.32 (m, 2 H, 6-H), 2.28 (dd, J = 6.1, 8.8 Hz, 1 H,
1-H), 2.19 (dd, J = 8.3, 6.3 Hz, 2 H, 7-H), 1.58 (dd, J = 8.8, 4.0 Hz,
1 H, 2a-H), 1.35 (dd, J = 5.9, 4.1 Hz, 1 H, 2b-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 173.6 (CO), 172.0 (NCO), 136.3 (Cq-Ar),
128.8 (2 CH-Ar), 128.4 (2 CH-Ar), 127.8 (1 CH-Ar), 52.0 (OMe),
47.6 (CH2Ph), 44.2 (C-6), 31.6 (C-3), 25.3 (C-1), 22.9 (C-7), 19.3
(C-2) ppm. HRMS (ESI): calcd. for C15H17NO3Na [M + Na]+
282.110; found 282.110.
We further thank Michel Schmitt for NMR measurements.
[1]
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[4] a) P. Compain, O. R. Martin (Eds.), Iminosugars: from Synthe-
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[5] For recent examples, see: a) P. Compain, C. Decroocq, J. Iehl,
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[6] P. Compain, O. R. Martin, C. Boucheron, G. Godin, L. Yu, K.
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[8] To the best of our knowledge, only one example of the forma-
tion of cyclobutanes by way of a Dieckmann reaction has been
reported with no mention of the yield obtained: M. S. Chande,
V. Suryanarayan, Tetrahedron Lett. 2002, 43, 5173–5175.
[9] a) T. R. Hoye, V. Dvornikovs, E. Sizova, Org. Lett. 2006, 8,
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2807–2813.
[11] Spirocyclopropyl β-lactams were also found to display interest-
ing biological activities, see for example: V. P. Sandanayaka,
A. S. Prashad, Y. Yang, T. Williamson, Y. I. Lin, T. S. Mansour,
J. Med. Chem. 2003, 46, 2569–2571.
[12] a) CCDC-842061 contains the supplementary crystallographic
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; b) ORTEP-3 for Win-
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5-Benzyl-1-hydroxymethyl-5-azaspiro[2.4]heptan-4-one (6b): To a
solution of 6a (84 mg, 0.32 mmol) in THF (0.5 mL) cooled to
–78 °C was added LiBHEt3 (1 m in THF, 1.3 mL, 1.30 mmol,
4 equiv.). The solution was stirred for 1 h at –78 °C and 1.5 h at
–65 °C. Saturated aqueous NaHCO3 (0.4 mL) was added, and the
solution was warmed to 0 °C. H2O2 (35%, 90 μL) was added, and
the solution was stirred at 0 °C for 20 min. The solution was con-
centrated under reduced pressure. Water was added, and the solu-
tion was extracted with CH2Cl2 (3ϫ). The combined organic layer
was dried with Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography
(MeOH/CH2Cl2, 5:95) to afford 6b (67 mg, 89%) as a white pow-
der. TLC: R = 0.30 (silica gel; MeOH/CH Cl , 5:95). IR (film): ν
˜
f
2
2
= 3389, 1665 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.43–7.25 (m,
5 H, Ph), 4.60 (d, J = 14.6 Hz, 1 H, CH2Ph), 4.45 (d, J = 14.6 Hz,
1 H, CH2Ph), 3.89 (dd, J = 11.5, 5.7 Hz, 1 H, CH2OH), 3.46 (m,
1 H, CH2OH), 3.39 (m, 2 H, 6-H), 2.31 (m, 1 H, 1-H), 2.01 (m, 1
H, 7a-H), 1.77 (m, 1 H, 7b-H), 1.38 (dd, J = 9.1, 4.2 Hz, 1 H, 2a-
H), 0.64 (dd, J = 6.3, 4.4 Hz, 1 H, 2b-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 176.1 (NCO), 136.7 (Cq-Ar), 128.8 (2 CH-
Ar), 128.3 (2 CH-Ar), 127.7 (1 CH-Ar), 63.1 (CH2OH), 47.4
(CH2Ph), 44.5 (C-6), 27.2 (C-3), 25.1 (C-1), 22.4 (C-7), 17.6 (C-2)
ppm. HRMS (ESI): calcd. for C14H17NO2Na [M + Na]+ 254.115;
found 254.117.
5-Benzyl-1-hydroxymethyl-5-azaspiro[2.4]heptane
(6c):
LAH
(34 mg, 0.89 mmol, 3.5 equiv.) was added to a solution of 6a
(66.2 mg, 0.26 mmol) in THF (1.4 mL). The solution was stirred at
reflux for 3 h. After cooling, H2O (1 mL) followed by 10% NaOH
(2 mL) and H2O (3 mL) were added. The solution was filtered
through Celite and concentrated under reduced pressure to afford
6c (55 mg, quant.) as a yellow oil. IR (film): ν = 3342 cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 7.31–7.16 (m, 5 H, Ph), 4.12–3.88
(br. s, 1 H, OH), 3.64–3.51 (m, 3 H, CH2OH, CH2Ph), 3.25 (dd, J
= 11.1, 8.6 Hz, 1 H, CH2OH), 2.80 (m, 1 H, 5a-H), 2.61 (m, 1 H,
5b-H), 2.49 (d, J = 9.1 Hz, 1 H, 4a-H), 2.37 (d, J = 9.1 Hz, 1 H,
4b-H), 1.97 (m, 1 H, 7a-H), 1.62 (m, 1 H, 7b-H), 1.04 (m, 1 H, 1-
H), 0.68 (dd, J = 8.8, 4.9 Hz, 1 H, 2a-H), 0.27 (t, J = 5.2 Hz, 1 H,
2b-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.5 (Cq-Ar), 129.1
(2 CH-Ar), 128.4 (2 CH-Ar), 127.2 (CH-Ar), 63.9 (C-4 or
CH2OH), 63.7 (C-4 or CH2OH), 60.9 (CH2Ph), 50.0 (C-6), 28.8
(C-7), 25.25 (C-1), 25.2 (C-3), 17.0 (C-2) ppm. HRMS (ESI): calcd.
for C14H20NO [M + H]+ 218.154; found 218.153.
Supporting Information (see footnote on the first page of this arti-
1
1
cle): H NMR, H–1H NOESY NMR, and 13C NMR spectra for
compound 6a.
[14] a) M. Weigl, B. Wünsch, Tetrahedron 2002, 58, 1173–1183; b)
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[15] Diesters 10 and 11 were prepared by alkylation of methyl-1-
benzylazetidine-2-carboxylate with (R)-(+)-3-bromo-2-methyl-
propionate and methyl-3-bromobutanoate in 14 and 12% yield,
Acknowledgments
This work was supported by the Centre National de la Recherche
Scientifique (CNRS), the University of Strasbourg, and a doctoral
fellowship from the French Department of Research to P.-A.N. The
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6619–6623

Synthesis of Spirocyclopropyl γ-Lactams
respectively, by using the same alkylation conditions to those
described for the preparation of 5.
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[21]
Received: September 1, 2011
Published Online: October 14, 2011
[20] For examples of ring-opening reactions of azetidinium ions or
N-sulfonylazetidines with C-nucleophiles, see: a) F. Couty, O.
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