Synthesis of 3-azabicyclo [4.1.0]heptane-1-carboxylic acid

Article abstract of DOI:10.1016/j.tet.2010.05.006

A full study on the synthesis of 3-azabicyclo[4.1.0]heptane-1-carboxylic acid is described.Three different approaches were investigated in order to achieve an efficient synthesis of this unnatural aminoacid.The optimized synthetic route relies upon three key steps: (i) diazomalonate insertion on 4-phtalimido 1-butene, (ii) intramolecular cyclization and (iii) chemoselective reduction of the resulting lactam.Due to its bicyclic nature and conformational constraints, this aminoacid may be an useful building block in medicinal chemistry.

Full text of DOI:10.1016/j.tet.2010.05.006

Tetrahedron 66 (2010) 5492e5497
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 3-azabicyclo[4.1.0]heptane-1-carboxylic acid
,
,
b,
Carmela Napolitano a, Manuela Borriello b y, Francesca Cardullo b , Daniele Donati z, Alfredo Paio b,
*
,
Stefano Manfredini a
*
a Department of Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara, 17-19, I-44100 Ferrara, Italy
b GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Medicine Research Centre, via Fleming, 4, I-37135 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 July 2009
Received in revised form 19 April 2010
Accepted 4 May 2010
Available online 8 May 2010
A full study on the synthesis of 3-azabicyclo[4.1.0]heptane-1-carboxylic acid is described. Three different
approaches were investigated in order to achieve an efficient synthesis of this unnatural aminoacid. The
optimized synthetic route relies upon three key steps: (i) diazomalonate insertion on 4-phtalimido 1-
butene, (ii) intramolecular cyclization and (iii) chemoselective reduction of the resulting lactam. Due to
its bicyclic nature and conformational constraints, this aminoacid may be an useful building block in
medicinal chemistry.
Ó 2010 Published by Elsevier Ltd.
1. Introduction
ring at the C-1/C-6 positions, might find wide application in the
lead optimization phase of different molecular structures: i.e.,
One of the strategies adopted in our lead optimization pro-
grammes is the introduction of conformational constraint in the de-
sign of new inhibitor structures. The goal is tighter and/or more
selective binding of the inhibitor to its target.1 Reducing the entropic
costs of binding can produce the desired effect, but only if enthalpi-
cally important contacts are not lost as a result of the structural
constraint. The most common tactic toward these ends involves the
construction of cyclic isosteres of acyclic structures.1a,b The further
constraint of cyclic structures can be achieved through the in-
troduction of unsaturation, through fusion to a second ring, or by
conversion of a (mono)cyclic system into a bicyclic one.1c,d,2 Here we
glycomimetics, peptidomimetics, and secondary-structure in-
ducing elements.
COOH
COOH
COOH
HN
HN
HN
Nipecotic acid
Guvacine
1
Figure 1.
report the synthesis of a constrained bicyclic
ample of the latter approach.
b-amino acid as an ex-
2. Results and discussion
The interest in cyclic
b-amino acids has increased exponen-
At the beginning of this project, a careful survey of the literature
revealed only one approach to the synthesis of 3-azabicyclo[4.1.0]
heptane-1-carboxylic systems involving the cyclopropanation of
the 3-hydroxymethyl tetrahydropyridine. The preparation was ac-
complished with samarium/mercury amalgam and chloroiodo-
methane followed by alcohol oxidation (Scheme 1).11
tially in the past few years and they have become a hot topic in
synthetic and medicinal chemistry.3e8 Among these, nipecotic
acid and guvacine, which may be considered as conformationally
restricted
g
-aminobutyric acid (GABA) analogues,9 have been
used as the basis for the design of some lipophilic and highly
potent GABA uptake inhibitors (Fig. 1).10 As part of our efforts to
identify novel building blocks for the preparation of modified
analogues of biologically active compounds, we became in-
terested in the synthesis of 3-azabicyclo[4.1.0]heptane-1-carbox-
1. Hg-Sm, CH2ICl, THF
Cbz
COOH
Cbz
2. CrO3, aq. H2SO4, Acetone
OH
N
N
ylic acid (1). This
derive from nipecotic acid through the fusion of a cyclopropyl
b-amino acid, which can be envisioned to
Scheme 1. Brighty’s synthesis of Cbz-protected aminoacid 1.
In a preliminary effort, similarly to the approach used in Scheme
1, arecoline (2a) and its simple analogues (2b, 2c) were identified as
key precursors (Scheme 2). In order to avoid the use of highly toxic
reagents, such as Hg and CrO3, we focused our attention on direct
* Corresponding authors. E-mail address: mv9@unife.it (S. Manfredini).
y
Present address: Rothpharma, via Valosa di Sopra, 9, I-20052 Monza (MI), Italy.
Present address: Nerviano Medical Sciences, viale Pasteur, 10, I-20014, Nerviano
z
(MI), Italy.
0040-4020/$ e see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.05.006

C. Napolitano et al. / Tetrahedron 66 (2010) 5492e5497
5493
cyclopropanation approaches encouraged by the success previously
achieved on substrates which are close analogues of the amines
2aec (structures not reported).
O
O
Ref [23]
Boc
COOMe
O
HN
N
Pg
R
Pg
R
N
N
8
9
-
S+CH2
N
2a Pg=Me, R=COOMe
2b Pg= Boc, R=COOMe
2c Pg=PMB, R=CH2OH
3a Pg=Me, R=COOMe
3b Pg= Boc, R=COOMe
3c Pg=PMB, R=CH2OH
NaH, DMSO, 15%
COOMe
Scheme 2. Direct cyclopropanation.
O
Boc
Unfortunately, all our attempts to cyclopropanate those sub-
strates were unsuccessful. In a first effort, we tested Simmons/
Smith reaction conditions12,13 on arecoline (2aec). Despite the
coordinative potential of the neighboring amino group, arecoline
could not be directly applied to the Simmons/Smith reaction due to
its propensity to undergo N-ylide formation.14 In order to avoid the
supposed formation of ammonium ylides, the methyl amino group
was exchanged for the non-nucleophilic tert-butylcarbamate
group. Cyclopropanation of 2b using Simmons/Smith conditions
and Denmark’s activated IZnCH2Cl reagent15 afforded only traces of
the desired product. Several other reaction conditions (diazo-
methane,16 TMSCHN2,17 Corey’s ylide as carbene sources18) were
then explored without satisfactory results. Hypothesizing that the
low reactivity of 2b under Simmons/Smith conditions was due to
the absence of a zinc chelating group19 (OH or OR), alcohol 2c was
chosen as testing ground for the reaction.
The functional group exchange did not induce an increase in the
ring reactivity, suggesting that the methyl ester group and the
hydroxymethylene group may be interfering with the cyclo-
propanation reaction either directly through unfavourable steric
interactions or indirectly by altering the conformation of the pi-
peridine ring. In order to verify this hypothesis, the reactivity of two
different substrates, in which planar characteristics had been in-
cluded, was evaluated.
In a first effort, the ester group of 2b was exchanged for a cyano
group. Conversion of the methyl ester into the corresponding amide 5,
followed by dehydration with trichloroacetyl chloride/TEA20 afforded
nitrile 6 in satisfactory overall good yield. The use of Corey’s condi-
tions21 was necessary for cyclopropanation success, even if 7 was iso-
lated only in very low yield (3%). Interestingly, implementation of
reaction conditions using dimethylamino-phenylsulfoxonium meth-
ylide22 as the carbene source led to a slight improvement inyield (11%).
Treatment of 7 with concd HCl under microwave irradiation allowed
a one-pot nitrile hydrolysis and Boc group cleavage to give 1 as the
hydrochloride salt in almost quantitative yield (Scheme 3).
N
10
Scheme 4. Route 2. Synthesis of intermediate lactam 10.
Next we explored the chemoselective reduction of lactam 10. In
an improved protocol,24 10 was reduced with lithium
triethylborohydride to a diastereomeric mixture of N-Boc aminals
11.25 Further reduction with triethylsilane and BF3$Et2O followed
by acidic work-up gave 12 in 50% overall yield starting from 10.
Next ester hydrolysis followed by Boc group cleavage afforded 1 in
excellent yield (Scheme 5).
OH
BF3*Et2O,
Superhydride,
THF, 64%
Boc
COOMe
Et3SiH, CH2Cl2, 78%
N
10
11
1. LiOH,
H2O/MeOH/THF, 86%
(to give acid 13)
Boc
COOMe
2. TFA, CH2Cl2, 90%
COOH
N
HN
12
1
Scheme 5. Route 2. Chemoselective reduction and full deprotection.
Critically evaluating our findings, we realized that the cyclo-
propanation of the six-membered ring was the weak point of our
approaches, precluding the access to 1 on multigram scale. In order
to avoid the low yielding cyclopropanation step and find a more
favorable approach to 1, we decided to optimize route 2 in-
vestigating a de novo synthesis for the key intermediate.
O
1. LiOH, H2O/MeOH
(to give acid 4)
S+ CH2
N
-
HCl conc.,
2. HMDS, TBTU,
100 °C mw,
DIPEA, CH2Cl2,
48% over 2 steps
Cl3CCOCl, TEA,
DMF, 98%
Boc
CONH2
Boc
CN
Boc
CN
quantitative
NaH, DMSO, 11%
N
N
N
2b
1
5
6
7
Scheme 3. Route 1. Synthesis via 3-Boc-3-azabicyclo[4.1.0]heptane-1-carbonitrile intermediate (7).
In the second approach the arecoline core was exchanged for
To this end, a rapid and efficient procedure was planned, in-
volving the cyclopropanation of an appropriate amino olefin fol-
lowed by intramolecular lactamization (Scheme 6). Since the amino
group required eventual protection, 4-phthalimido 1-butene (14)26
was employed as starting material.
a piperidone-like moiety. The preparation of amido ester 9 starting
from Boc protected d
-valerolactam (8) is well precedented.23
To our regret, according with the previous findings the cyclo-
propanation of piperidone 9 was found poor yielding. Classical
Corey’s cyclopropanation afforded 10 in 5% yield, while the use of
dimethylamino-phenylsulfoxonium methylide led again to a slight,
but not satisfactory improvement in yield (15%, Scheme 4).
The copper-promoted reaction of dimethyl dibromomalonate27
with 4-phthalimido 1-butene (14) at 75 ꢀC28 led only to the for-
mation of a small amount of 15. Unsatisfactory yields (29e31%)

5494
C. Napolitano et al. / Tetrahedron 66 (2010) 5492e5497
O
amine 16 (64% yield). Upon standing in neat form, partial lactamiza-
O
COOMe
COOMe
tion to 17 was observed by 1H NMR spectroscopic analysis (15e30%).
Initial attempts to promote intramolecular cyclization of 16
were unsuccessful, affording multiple products attributed to de-
composition of starting material. Optimization efforts included the
evaluation of the effect of basic and acidic catalysis in combination
with temperature and solvent screening. The most significant im-
provements were realized employing excess N2H4$H2O (5 equiv)
and running the reaction in MeOH at reflux; under these condi-
tions, efficient intramolecular cyclization was observed together
with undesired hydrolysis of the ester group and carboxylic acid 18
was isolated in good yield (80%). Intrigued by this finding, we next
directed our efforts on the achievement of the complete conversion
of phthaloylamine 15 into lactam 17. Vigorous hydrazinolysis con-
ditions (2.5 equiv N2H4$H2O, reflux, 18 h) provided ester 17 in
satisfactory yield (69%) after crystallization (Scheme 7).
Boc
COOMe
N
N
O
10
15
O
N
O
14
Scheme 6. Retrosynthetic approach to 10.
Br
Br
MeOOC
Cu (3 eq.), I2 (0.033 eq.),
DMSO, rfx, 2h, 31%
COOMe
O
O
COOMe
COOMe
N2H4*H2O (1.1 eq.),
MeOH, rt, 64%
COOMe
COOMe
N
N
N2
H2N
O
O
MeOOC
COOMe
14
15
16
Rh2(OAc)4 (5%), PhCl,
rfx, 1h, 64%
N2H4*H2O (2.5 eq.),
MeOH, rfx, 69%
N2H4*H2O (5 eq.),
MeOH, rfx, 80%
spontaneous upon
neat form (slow)
O
O
Boc2O, DMAP,
Toluene/CH2Cl2, 90%
COOMe
COOH
HN
HN
10
17
18
Scheme 7. De novo synthesis of 10.
were also obtained under stronger thermal and microwave assisted
conditions (150e175 ꢀC). Best results were gained replacing
dibromomalonate with dimethyl diazomalonate as the carbene
source. Indeed Rh(II)-catalysed insertion of diazomalonate29 on 14
Finally, N-protection as a tert-butylcarbamate, necessary for the
two-step chemoselective reduction to 12, followed by full depro-
tection gave access to 1 in good yield (16% overall yield starting from
14) (Scheme 8).
N2
MeOOC
COOMe
Rh2(OAc)4 (5%), PhCl,
O
O
COOMe
COOMe
O
N2H4*H2O (2.5 eq.),
MeOH, rfx, 69%
rfx, 1h, 64%
COOMe
N
N
HN
O
O
14
15
17
1. Boc2O, DMAP, Toluene/CH2Cl2, 90%
2. Superhydride, THF, 64%
1. LiOH, H2O/MeOH/THF, 86%
2. TFA, CH2Cl2, 90%
Boc
COOMe
COOH
3. BF3*Et2O, Et3SiH, CH2Cl2, 78%
N
HN
12
Scheme 8. Total synthesis of 3-azabicyclo[4.1.0]heptane-1-carboxylic acid (1).
1
required lower reaction temperatures (70 ꢀC) and afforded 15 in
satisfactory yield (64%).30 For the closure to the six-membered ring,
we were encouraged by a Danishefsky and Dynak communication31
of the spontaneous lactamization of amino diester 15 after
N-deprotection. Classical dephthaloylation conditions (1.1 equiv
N2H4$H2O, MeOH, room temperature) gave access to the deprotected
In summary, a straightforward approach to 3-azabicyclo-[4.1.0]
heptane-1-carboxylic acid (1) has been herein reported
(Scheme 8). The synthesis involved three key steps: (i) cyclo-
propanation of 4-phthalimido 1-butene, (ii) intramolecular cycli-
zation, and (iii) chemoselective reduction of a lactam. Due to its
bicyclic nature and conformational constraints, we foresee that 1

C. Napolitano et al. / Tetrahedron 66 (2010) 5492e5497
5495
might find application as a building block for the synthesis of
glycomimetics, peptidomimetics, and secondary-structure in-
ducing elements.
0.67 min. Anal. Calcd for C12H19NO4: C, 59.73; H, 7.94; N, 5.81; O,
26.52. Found: C, 60.04; H, 8.30; N, 5.77; O, 25.89.
3.1.2. 5,6-Dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl es-
ter (4). To a solution of monohydrate LiOH (1.19 g, 28.2 mmol) in
H2O (10 mL) was added ester 2b (3.42 g, 14.2 mmol) diluted in
a 10:1 mixture of MeOH/THF (11 mL). The mixture was stirred at
room temperature for 4 h, acidified with 1 N HCl (15 mL) and
extracted three times with CH2Cl2 (3ꢂ30 mL). The combined or-
ganics were dried (Na2SO4), filtered, and the solvent evaporated
under diminished pressure to afford acid 5 (3.20 g, quantitative),
which did not need any purification. IR (neat) 1725, 1702, 1646,
1445, 1435, 1382, 1366, 1299, 1243. 1H NMR (400 MHz, CD3OD)
3. Experimental section
3.1. General
All moisture-sensitive reactions were performed under a nitro-
gen atmosphere. All solvents and reagents were used as supplied,
unless noted otherwise. Reactions were monitored by TLC (pre-
coated silica gel plates F254, Merck). Purifications were performed
using Vac Master systems. SPE-Si cartridges are silica solid phase
extraction columns supplied by Varian. Mass spectra (MS) were
taken on a Micromass ZMD 2000 Mass Spectrometer, operating in
ES (þ) ionization mode. Total ion current (TIC) and DAD UV chro-
matographic traces together with MS and UV spectra associated
with the peaks were taken on a UPLC/MS AcquityÔ system
equipped with 2996 PDA detector and coupled to a Waters
Micromass ZQÔ mass spectrometer operating in positive or nega-
tive electrospray ionization mode. [LC/MSdES (þ/ꢁ): analyses
performed using an AcquityÔ UPLC BEH C18 column (50ꢂ2.1 mm,
d
7.40 (br s, 1H, CH]C), 4.18 (br s, 4H, NCH2C, NCH2CH2), 2.34 (br s,
2H, NCH2CH2), 1.58 (s, 9H, C(CH3)3). 13C NMR (100 MHz, CD3OD)
d
169.6, 155.4, 142.1, 129.6, 80.3, 42.4, 42.1, 28.3, 22.4. UPLC/MS
(ESþ), m/z: found 228 [MHþ], C11H17NO4 requires 227. tR: 0.62 min.
Anal. Calcd for C11H17NO4: C, 58.14; H, 7.54; N, 6.16; O, 28.16. Found
C, 58.31; H, 7.51; N, 6.09; O, 28.09.
3.1.3. 5-Carbamoyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-
butyl ester (5). Carboxylic acid 4 (0.550 g, 2.42 mmol), DIPEA
(1.86 mL, 10.65 mmol), and TBTU (1.71 g, 5.32 mmol) were dis-
solved in DMF (12 mL) and the solution was stirred at room tem-
perature for 1 h. HMDS (0.86 g, 5.32 mmol) was added and stirring
was prolonged for further 18 h. The mixture was diluted with EtOAc
(30 mL) and washed with saturated aq NH4Cl (2ꢂ20 mL). The
aqueous layers were backextracted twice with EtOAc (3ꢂ20 mL).
The combined organics were dried (Na2SO4), filtered, and the sol-
vent evaporated under diminished pressure. Purification of the
crude residue by chromatography over SPE-Si column (25 g, grad.
1.7 m
m particle size), column temperature 40 ꢀC, mobile phase:
Adwaterþ0.1% HCOOH/BdCH3CNþ0.06% HCOOH, flow rate:
1.0 mL/min, run time¼1.5 min, gradient: t¼0 min 3% B, t¼0.05 min
6% B, t¼0.57 min 70% B, t¼1.06 min 99% B, t¼1.449 min 99% B,
t¼1.45 min 3% B, stop time 1.5 min. Positive ES 100e1000, Negative
ES 100e800, UV detection DAD 210e350 nm. The use of this
methodology is indicated by ‘UPLC/MS’ in the analytic character-
ization of the described compounds. Melting points are determined
with a capillary apparatus. IR spectra were recorded on a Perkin-
Elmer Spectrum 100 FT-IR spectrophotometer (crystals: diamond/
ZnSe 14,031). 1H and 13C NMR spectra were recorded on Bruker
Advance 400 spectrometer; solvent CDCl3 unless otherwise speci-
fied. Wherever necessary, two-dimensional HeH COSY experi-
ments were carried out for complete signal assignments.
Combustion analysis was performed using CHNSeO analyzer.
hexane/acetone¼95:5 to hexane/acetone¼50:50) afforded
(0.26 g, 48%) as a colorless oil. IR (neat) 3365, 3179,1724,1642,1623,
1438, 1439, 1385, 1366, 1180. 1H NMR (400 MHz, CDCl3)
6.70 (br s,
5
d
1H, CH]C), 5.48 (br s, 2H,CONH2), 4.15e4.18 (m, 2H, NCH2C), 3.51 (t,
2H, J 9.4 Hz, NCH2CH2), 2.27e2.36 (m, 2H, NCH2CH2), 1.50 (s, 9H, C
(CH3)3). 13C NMR (100 MHz, CDCl3)
d 168.6, 153.3, 136.8, 127.0, 80.5,
41.4, 41.1, 28.4, 22.7. UPLC/MS (ESþ), m/z: found 227 [MHþ],
C11H18N2O3 requires 226. tR: 0.54 min. Anal. Calcd for C11H18N2O2:
C, 58.39; H, 8.02; N, 12.38; O, 21.21. Found C, 58.31; H, 8.04; N,
12.29; O, 21.36.
3.1.1. 5,6-Dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl es-
ter 3-methyl ester (2b). K2CO3 (18.3 g, 133.0 mmol) was added to
a solution of arecoline hydrobromide (25.0 g, 106.0 mmol) in H2O
(60 mL). After 30 min, the mixture was extracted three times with
Et2O (3ꢂ60 mL), the combined organic layers were dried (Na2SO4),
filtered, and the solvent evaporated under diminished pressure.
The resulting oil was dissolved in toluene (120 mL) and ACEeCl
(14.0 mL, 128 mmol) was added slowly. The reaction was heated to
reflux for 16 h. HCl (0.1 N, 100 mL) was added and the mixture was
extracted three times with Et2O (3ꢂ100 mL). The combined or-
ganics were dried (Na2SO4), filtered, and the solvent evaporated
under diminished pressure. The resulting carbamate was dissolved
in MeOH (100 mL) and heated to reflux. After 2 h, solvent was
removed under reduced pressure. The resulting amine was dis-
solved in CH2Cl2 (150 mL) and cooled to 0 ꢀC. TEA (16.5 mL,
118 mmol) and Boc2O (31.7 g, 145 mmol) were added. After 24 h,
1 M HCl (100 mL) was added, the layers separated and organic
phase extracted twice with CH2Cl2 (2ꢂ150 mL). The combined
organics were washed with saturated NaHCO3, dried (Na2SO4),
filtered, and the solvent evaporated under diminished pressure.
Flash chromatography of the crude residue (PE/EtOAc¼90:10) gave
2b (20.0 g, 78%) as a white solid: mp 29e31 ꢀC. IR (neat) 1724,
1712, 1652, 1439, 1430, 1390, 1368, 1265, 1221. 1H NMR (400 MHz,
3.1.4. 5-Cyano-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl
ester (6). Trichloroacetyl chloride (0.974 g, 5.36 mmol) dissolved in
dry CH2Cl2 (3 mL) was added dropwise to a stirred mixture of 5
(1.10 g, 4.87 mmol) and TEA (1.35 mL, 9.74 mmol) in dry CH2Cl2
(8 mL), which had been pre-cooled to 0 ꢀC. After the addition was
finished, the mixture was treated with ice-cooled water (10 mL), 5%
NaOH (10 mL), 5% HCl (10 mL), and finally with H2O (10 mL). The
organic layer was dried (Na2SO4), filtered, and the solvent evapo-
rated under diminished pressure to afford nitrile 6 (1.0 g, 98%) as
a pale yellow oil. IR (neat) 2223, 1724, 1648, 1439, 1389, 1365, 1225.
1H NMR (400 MHz, CDCl3)
NCH2C), 3.53 (t, 2H, J 9.4 Hz, NCH2CH2), 2.33 (br s, 2H, NCH2CH2),
d 6.77 (br s, 1H, CH]C), 4.06 (br s, 2H,
1.49 (s, 9H, C(CH3)3). 13C NMR (100 MHz, CDCl3)
d 154.2,143.5,119.6,
117.3, 80.9, 42.5, 41.2, 29.0, 25.6. UPLC/MS (ESþ), m/z: found 209
[MHþ], C11H16N2O2 requires 208. tR: 0.70 min. Anal. Calcd for
C11H17NO4: C, 63.44; H, 7.74; N, 13.45; O, 15.36. Found C, 63.54; H,
7.78; N, 13.41; O, 15.27.
3.1.5. 1-Cyano-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-
butyl ester (7). NaH (0.017 g, 0.720 mmol, 60% oil dispersion) was
added to a solution of dimethylamino-phenylsulfoxonium meth-
ylide (0.13 g, 0.480 mmol) in DMSO (2 mL). After 20 min a solution
of 6 (0.10 g, 0.480 mmol) in DMSO (2 mL) was added and the
mixture was stirred at room temperature for 18 h. Brine (10 mL)
CDCl3)
d 7.02e7.10 (m, 1H, CH]C), 4.08e4.14 (m, 2H, NCH2C), 3.76
(s, 3H, OCH3), 3.48 (dd, 2H, J 10.7, 5.5 Hz NCH2CH2), 2.26e2.36 (m,
2H, NCH2CH2), 1.48 (s, 9H, C(CH3)3). 13C NMR (100 MHz, CDCl3)
d
165.8, 154.8, 137.9, 128.1, 80.0, 51.7, 42.6, 39.5, 28.4, 25.5. UPLC/
MS (ESþ), m/z: found 242 [MHþ], C12H19NO4 requires 241. tR:

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C. Napolitano et al. / Tetrahedron 66 (2010) 5492e5497
was added and the reaction extracted four times with a 50:50
mixture hexane/EtOAc (4ꢂ10 mL). The combined organics were
dried (Na2SO4), filtered, and the solvent evaporated under di-
minished pressure. Purification of the crude residue by chroma-
tography over SPE-Si column (2 g, grad. hexane to hexane/
acetone¼95:5) gave 7 (12.7 mg, 11%) as a pale yellow oil. IR (neat)
2236, 1723, 1452, 1439, 1390, 1365, 1220. 1H NMR (400 MHz, CDCl3)
extracted three times with EtOAc (3ꢂ10 mL). The combined or-
ganics were dried (Na2SO4), filtered, and the solvent evaporated
under diminished pressure. Purification of the crude residue by
chromatography over SPE-Si column (2 g, grad. hexane to hexane/
EtOAc¼95:5) afforded 10 (0.19 g, 15%) as a pale yellow oil. Method B
(starting from 17): to a solution of lactam 17 (0.40 g, 2.36 mmol) in
a 2:1 mixture toluene/CH2Cl2 (15 mL) was added DMAP (0.43 g,
3.55 mmol) followed by Boc2O (0.659 mL, 2.84 mmol). The result-
ing mixture was heated to reflux for 2 h, then diluted with CH2Cl2
(15 mL) and washed with brine (30 mL). The organic layer was
dried (Na2SO4), filtered, and the solvent evaporated under di-
minished pressure. Purification of the crude residue by chroma-
tography over SPE-Si column (10 g, CH2Cl2) afforded 10 (0.57 g,
90%) as a pale yellow oil. IR (neat) 1764, 1718, 1439, 1390, 1368,
d
3.97e4.30 (m, 1H, NCHaHbC), 3.45e3.70 (m, 2H, NCHaHbC,
NCHaHbCH2), 2.88e3.03 (m, 1H, NCHaHbCH2), 1.99e2.13 (m, 1H,
NCH2CHbHaCH), 1.67e1.84 (m, 2H, CH2CHCH2, NCH2CHbHaCH), 1.57
(s, 9H, C(CH3)3), 1.47 (dd, 1H, J 11.6, 7.8 Hz, N^CCCHaHbCH), 0.83 (t,
1H, J 8.5 Hz, N^CCCHaHbCH). 13C NMR (100 MHz, CDCl3) d 156.1,
115.0, 80.5, 52.5, 43.9, 28.2, 26.2, 23.8, 19.8, 19.4. UPLC/MS (ESþ),
m/z: found 223 [MHþ], C12H18N2O2 requires 222. tR: 0.70 min. Anal.
Calcd for C12H18N2O2: C, 64.84; H, 8.16; N, 12.60; O, 14.40. Found C,
64.81; H, 8.17; N, 12.63; O, 14.42.
1295, 1141. 1H NMR (400 MHz, CDCl3)
d 3.76e3.85 (m, 4H, OCH3,
NCHbHaCH2), 3.45e3.54 (m, 1H, NCHbHaCH2), 2.15e2.32 (m, 1H,
NCH2CHaHb), 1.98e2.08 (m, 1H, CH2CHCH2), 1.86e1.97 (m, 2H,
NCH2CHaHb, CHCHaHbC), 1.52e1.57 (m, 9H, C(CH3)3), 1.47e1.50 (m,
3.1.6. 2-[2-(1,3-Dihydro-isoindol-2-yl)-ethyl]-cyclopropane-1,1-di-
carboxylic acid dimethyl ester (15). Rhodium(II) acetate dimer
(0.580 g, 1.31 mmol) was added to a mixture of 14 (5.28 g,
26.2 mmol) in chlorobenzene (50 mL). The suspension was warmed
to an internal temperature of þ60 ꢀC and dimethyl diazomalonate
(6.64 g, 42.0 mmol) was added dropwise keeping the Ti below
þ70 ꢀC. After 1 h, further dimethyl diazomalonate (6.64 g,
42.0 mmol) was added dropwise keeping the Ti below þ70 ꢀC and
the reaction mixture was stirred for 1 h. The suspension was cooled
to room temperature, diluted with CH2Cl2 (50 mL), and filtered
from the catalyst. Solvent was partially removed under reduced
pressure; the crude material was purified by chromatography over
SPE-Si column (50 g, cyclohexane/EtOAc¼60:40) to afford 15
(5.55 g, 64%) as an off-white solid: mp¼124e126 ꢀC; IR (neat) 1769,
1H, CHCHaHbC). 13C NMR (100 MHz, CDCl3)
d 170.2, 167.1, 152.8,
83.5, 52.8, 42.7, 31.2, 28.0, 25.5, 22.6, 19.0. UPLC/MS (ESþ), m/z:
found 270 [MHþ], C13H19NO5 requires 269. tR: 0.63 min. Anal. Calcd
for C13H19NO5: C, 57.98; H, 7.11; N, 5.20; O, 29.71. Found C, 58.03; H,
7.04; N, 5.37; O, 29.56.
3.1.9. 3-Aza-bicyclo[4.1.0]heptane-1,3-dicarboxylic acid 3-tert-butyl
ester 1-methyl ester (12). A solution of Superhydride (1.0 M) in THF
(2.49 mL, 2.49 mmol) was added over 30 min to a solution of lac-
tam 10 (0.56 g, 2.08 mmol) in dry THF (5 mL), which had been pre-
cooled to ꢁ10 ꢀC. After 2 h at 0 ꢀC, further superhydride solution
(0.50 mL) was added and the solution was allowed to stir at room
temperature for 2 h. The reaction mixture was quenched with
water (15 mL) and extracted three times with EtOAc (3ꢂ20 mL).
The combined organics were dried (Na2SO4), filtered, and the sol-
vent evaporated under diminished pressure. Purification of the
crude residue by chromatography over SPE-Si column (5 g, cyclo-
hexane/EtOAc¼60:40) afforded 11 (0.36 g, 64%) as unseparable
mixture of diastereoisomeric aminals. A solution of aminals 11
(0.25 g, 0.92 mmol) and triethylsilane (0.15 mL, 0.921 mmol) in
CH2Cl2 (8 mL) was cooled to ꢁ78 ꢀC and BF3$OEt2 (0.12 mL,
0.921 mmol) was added dropwise. After 30 min, further trie-
thylsilane (0.15 mL, 0.921 mmol) and BF3$OEt2 (0.12 mL,
0.921 mmol) were added. The resulting mixture was stirred 1.5 h at
ꢁ78 ꢀC, then warmed to room temperature, diluted with CH2Cl2
(15 mL), and washed with H2O (2ꢂ20 mL). The organic layer was
dried (Na2SO4), filtered, and the solvent evaporated under di-
minished pressure. Purification of the crude residue by chroma-
tography over SPE-Si column (5 g, cyclohexane/EtOAc¼95:5)
afforded 12 (0.26 g, 50% over two steps) as a pale yellow oil. IR
(neat) 1705, 1691, 1477, 1439, 1388, 1365, 1248, 1164. 1H NMR
1734,1702, 1436, 1292, 1207. 1H NMR (400 MHz, CDCl3)
d 7.82e7.89
(m, 2H, Ph), 7.69e7.76 (m, 2H, Ph), 3.76e3.87 (m, 5H, NCH2CH2,
OCH3), 3.73 (s, 3H, OCH3), 1.90e2.01 (m, 1H, CH2CHCH2), 1.63e1.86
(m, 2H, NCH2CH2), 1.37e1.48 (m, 2H, CHCH2C). 13C NMR (100 MHz,
CDCl3) d 170.4, 168.3, 168.2, 134.0, 132.1, 123.2, 52.7, 52.6, 37.0, 33.7,
27.8, 25.9, 20.5. UPLC/MS (ESþ), m/z: found 332 [MHþ], C17H17NO6:
requires 331. tR: 0.68 min. Anal. Calcd for C17H17NO6: C, 61.63; H,
5.17; N, 4.23; O, 28.97. Found C, 61.78; H, 5.01; N, 3.98; O, 29.23.
3.1.7. 2-Oxo-3-aza-bicyclo[4.1.0]heptane-1-carboxylic acid methyl
ester (17). N2H4$H2O (0.257 mL, 8.19 mmol) was added to a solution
of diester 15 (1.08 g, 3.27 mmol) in MeOH (40 mL) and the mixture
was heated to reflux. After 18 h the mixture was cooled to room
temperature and solvent was partially evaporated under reduced
pressure. The residue was dissolved in CH2Cl2 (20 mL); precipitate
was filtered off and the solvent evaporated under reduced pressure.
Recrystallization of the crude residue from Et2O/MeOH¼95:5
afforded 17 (0.353 g, 69%) as an off-white solid: mp¼133e135 ꢀC; IR
(neat) 3275, 1720, 1660, 1628, 1437, 1280. 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3)
d 3.82e4.12 (m, 2H, NCH2C), 3.71 (s, 3H, OCH3),
d
6.58 (br s, 1H, NH), 3.77 (s, 3H, OCH3), 3.23e3.32 (m, 1H,
3.51 (br s, 1H, NCHaHbCH2), 2.87e3.03 (m, 1H, NCHaHbCH2),
1.94e2.08 (m, 1H, NCH2CHaHb), 1.66e1.86 (m, 2H, NCH2CHaHb,
CH2CHCH2), 1.44e1.53 (m, 9H, C(CH3)3), 1.41 (dd, 1H, J 9.8, 8.4 Hz
CHCHaHbC), 0.75 (dd, 1H J 10.5, 11.2 Hz, CHCHaHbC). 13C NMR
NCHbHaCH2), 3.04e3.15 (m, 1H, NCHaHbCH2), 2.09e2.21 (m, 1H,
NCH2CHaHb), 1.91e2.00 (m, 2H, NCH2CHaHb, CH2CHCH2), 1.88e1.94
(m, 1H, CHCHaHbC), 1.46 (t, 1H, J 10.7 Hz, CHCHaHbC). 13C NMR
(100 MHz, CDCl3)
d
170.5, 168.6, 52.7, 38.0, 28.0, 24.7, 20.3, 16.4.
(100 MHz, CDCl3) d 174.4, 154.9, 79.7, 52.0, 43.1, 38.3, 28.4, 26.5,
UPLC/MS (ESþ), m/z: found 170 [MHþ], C8H11NO3 requires 169. tR:
0.37 min. Anal. Calcd for C8H11NO3: C, 56.80; H, 6.55; N, 8.28; O,
28.37. Found C, 56.48; H, 6.03; N, 7.62; O, 29.87.
22.2, 19.9, 19.1. UPLC/MS (ESþ), m/z: found 256 [MHþ], C13H21NO4
requires 255. tR: 0.67 min. Anal. Calcd for C13H21NO4: C, 61.16; H,
8.29; N, 5.49; O, 25.07. Found C, 61.23; H, 8.37; N, 5.35; O, 25.05.
3.1.8. 2-Oxo-3-aza-bicyclo[4.1.0]heptane-1,3-dicarboxylic acid 3-
tert-butyl ester 1-methyl ester (10): method A (starting from 9). NaH
(0.028 g, 1.185 mmol, 60% oil dispersion) was added portionwise to
a solution of dimethylamino-phenylsulfoxonium methylide (0.19 g,
0.711 mmol) in DMSO (3 mL). After 20 min a solution of 9 (0.12 g,
0.474 mmol) in DMSO (3 mL) was added and the stirring was pro-
longed for further 3 h. Brine (3 mL) was added and the reaction
3.1.10. 3-Aza-bicyclo[4.1.0]heptane-1,3-dicarboxylic acid 3-tert-butyl
ester (13). To a solution of LiOH (0.034 g, 1.41 mmol) in H2O (2 mL)
was added ester 12 (0.180 g, 0.705 mmol) diluted in a 10:1 mixture
MeOH/THF (2.2 mL). The resulting mixture was stirred at room
temperature for 3 h, then acidified with 1 M HCl (2 mL), diluted
with H2O (5 mL), and extracted three times with CH2Cl2 (3ꢂ10 mL).
The organic layer was dried (Na2SO4), filtered, and the solvent

C. Napolitano et al. / Tetrahedron 66 (2010) 5492e5497
5497
evaporated under diminished pressure to afford 13 (0.15 g, 86%)
as a colorless oil. IR (neat) 1725, 1705, 1452, 1435, 1384, 1366,
1243. 1H NMR (400 MHz, CDCl3)
3.94 (br s, 2H, NCH2C),
References and notes
1. For recent examples, see: (a) Hanessian, S.; MacKay, D. B.; Moitessier. J. Med.
Chem. 2001, 44, 3074; (b) Dutta, A. K.; Davis, M. C.; Reith, M. E. A. Bioorg. Med.
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2002, 43, 177; (d) Kolhatkar, R.; Cook, C. D.; Ghorai, S. K.; Deschamps, J.;
Beardsley, P. M.; Reith, M. E. A.; Dutta, A. K. J. Med. Chem. 2004, 47, 5101.
2. Renslo, A. R.; Gao, H.; Jaishankar, P.; Venkatachalam, R.; Gordeev, M. Org. Lett.
2005, 7, 2627.
d
3.35e3.54 (m, 1H, NCHbHaCH2), 2.94e3.04 (m, 1H, NCHaHbCH2),
1.96e2.10 (m, 1H, NCH2CHbHa), 1.72e1.85 (m, 2H, NCH2CHaHb,
CH2CHCH2), 1.42e1.54 (m, 10H, C(CH3)3, CCHbHaCH), 0.83 (t, 1H, J
9.3 Hz CCHaHbCH). 13C NMR (100 MHz, CDCl3)
d 179.8, 156.0, 79.9,
44.7, 38.5, 28.0, 26.7, 22.0, 20.9, 19.8. UPLC/MS (ESþ), m/z: found
243 [MHþ], C12H19NO4 requires 242. tR: 0.62 min. Anal. Calcd for
C12H19NO4: C, 59.73; H, 7.94; N, 5.80; O, 26.52. Found C, 59.95; H,
8.06; N, 5.49; O, 26.50.
3. Juaristi, E.; Soloshonok, V. A. Enantioselective Synthesis of b-Amino Acids; Wiley-
Interscience: New York, NY, 2005.
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5. Miller, J. A.; Nguyen, S. T. Mini-Rev. Org. Chem. 2005, 2, 39.
6. Ortuno, R. M.; Moglioni, A. G.; Moltrasio, G. Y. Curr. Org. Chem. 2005, 9, 237.
7. Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833.
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8. Fülop, F.; Martinek, T. A.; Tóth, G. K. Chem. Soc. Rev. 2006, 35, 323.
3.1.11. 3-Azabicyclo[4.1.0]heptane-1-carboxylic acid (1): method A
(starting from 7). In a 5 mL microwave vial was added 7 (0.03 g,
0.135 mmol) dissolved in 37% aq HCl (1 mL). The mixture was
heated to 150 ꢀC for 10 min under mw irradiation. Volatiles were
evaporated under diminished pressure to afford 1 as hydrochlo-
ride salt (0.019 g, quantitative). Method B (starting from 13):
compound 13 (0.10 g, 0.415 mmol) was dissolved in a 3:1 mixture
CH2Cl2/TFA (4 mL). The solution was stirred at 0 ꢀC for 45 min;
volatiles were evaporated under reduced pressure to give com-
pound 1 (0.095 g, 90%) as trifluoroacetic salt, which did not need
any purification. IR (neat) 1674, 1665, 1611, 1517, 1459, 1217. 1H
9. Johnston, G. A. R.; Alla, R. D.; Kennedy, S. M. G.; Twitchin, B. In GABA-
Neurotransmitters: Pharmaco-chemical Biochemical and Pharmacological As-
pects; Krogsgaard-Larsen, P., Scheel-Krüger, J., Kofoed, H., Eds.; Munksgaard:
Copenhagen, 1978; pp 147e164.
10. Hoesl, C. E.; Hofner, G.; Wanner, K. T. Tetrahedron 2004, 60, 307.
11. Brighty, K.E.; Conn, G. U.S. Patent 5,164,402, 1992.
12. Simmons, H. E.; Cairns, T. L.; Vladuchick, S. A.; Hoiness, C. M. Org. React. 1973,
20, 1.
13. Takakis, I. M.; Rhodes, Y. E. J. Org. Chem. 1978, 43, 3496.
14. (a) Aggarwal, V. K.; Fang, G. Y.; Charmant, J. P. H.; Meek, G. Org. Lett. 2003, 5,1757;
(b) Aggarwal, V. K.; Fang, G. Y.; Charmant, J. P. H.; Meek, G. Org. Lett. 2003, 5, 4417.
15. Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974.
16. Manecke, G.; Kautz, J. Tetrahedron Lett. 1975, 13, 629.
17. Aoyama, T.; Iwamoto, Y.; Nishigaki, S.; Shioiri, T. Chem. Bull. Pharm. 1989, 37, 253.
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19. Zhuo, J.; Burns, D. M.; Zhang, C.; Xu, M.; Weng, l.; Qian, D.-Q.; He, C.; Lin, Q.; Li,
Y.-L.; Shi, E.; Agrios, C.; Metcalf, B.; Yao, W. Synlett 2007, 460.
20. Moltzen, E. K.; Pedersen, H.; Bøgesø, K. P.; Meier, E.; Frederiksen, K.; Sanchez,
C.; Løve Lembøl, H. J. Med. Chem. 1994, 37, 4085.
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22. Johnson, C. R.; Haake, M.; Schroeck, C. J. Am. Chem. Soc. 1970, 92, 6594.
23. For the synthesis of 9 see: (a) Ecija, M.; Diez, A.; Rubiralta, M.; Casamitjana, N.;
Kogan, M. J.; Giralt, E. J. Org. Chem. 2003, 68, 9541; (b) Cossy, J.; Mirguet, O.;
Pardo, D. G.; Desurs, J.-R. New J. Chem. 2003, 27, 475.
NMR (400 MHz, D2O)
d 4.27 (d, 1H, J 14.4 Hz, NCHbHaC), 3.11e3.19
(m, 1H, NCHbHaCH2), 3.04 (d, 1H, J 14.4 Hz, 1H, NCHaHbC), 2.70 (td,
1H, J 12.3, 4.4 Hz, NCHaHbCH2), 2.02 (dd, 1H, J 14.9, 4.6 Hz,
CH2CHbHaCH), 1.98 (dt, 1H, J 14.9, 6.2 Hz, CH2CHaHbCH), 1.85e1.92
(m, 1H, CH2CH2CH), 1.66 (dd, 1H, J 9.6, 5.4 Hz, CH2CHCHbHa), 1.07
(dd, 1H, J 7.0, 5.4 Hz, CH2CHCHaHb). 13C NMR (100 MHz, D2O)
d
176.6, 43.1, 38.1, 30.3, 21.2, 19.9, 18.6. UPLC/MS (ESþ), m/z: found
142 [MHþ], C7H11NO2 requires 141. tR: 0.21 min. Anal. Calcd for
C7H11NO2: C, 59.56; H, 7.85; N, 9.92; O, 22.67. Found C, 59.64; H,
8.01; N, 10.03; O, 22.32.
24. Maligres, P. E.; Chartrain, M. M.; Upadhyay, V.; Cohen, D.; Reamer, R. A.; Askin,
D.; Volante, R. P.; Reider, P. J. Org. Chem. 1998, 63, 9548.
25. Upon NMR analysis this intermediate revealed to be an inseparable mixture of
diastereomeric compounds whose molar ratio could not to be exactly de-
termined. Indeed the spectra is complicated by the presence of more isomers
due to the presence of the BOC group and of two diastereoisomers.
26. Compound 11 was prepared according to Harding, K. E.; Nam, D. Tetrahedron
Lett. 1988, 29, 3793.
Acknowledgements
The authors would like to thank Dr. Silvia Davalli and her
spectroscopic group for careful assistance in NMR spectroscopy
experiments and structure assignments and Dr. Elisa Durini
and Dr. Silvia Vertuani for careful assistance in manuscript
revision.
27. Meketa, M. L.; Mahajan, Y. R.; Weinreb, S. M. Tetrahedron Lett. 2005, 46, 4749.
28. Kawabata, N.; Tanimoto, M. Tetrahedron 1980, 36, 3517.
29. Dimethyl diazomalonate was prepared according to Tullis, J. S.; Helquist, P. Org.
Synth. 1998, 9, 155.
30. The yield does not include recovered 14 in the 10e15% range.
31. Danishefsky, S.; Dynak, J. J. Org. Chem. 1974, 39, 1979.