Synthesis of racemic and enantiopure 3,4-methanonipecotic acid

Article abstract of DOI:10.1016/j.tetasy.2015.09.015

The synthesis of both racemic and enantiomerically pure (1R,6S)-3,4-methanonipecotic acid, a cyclopropane-containing β-amino acid, which is a valuable building block for drug discovery, is described. The synthetic scheme commences from natural (S)-malic acid and allows for the preparation of the title compound in 12 steps in 28% overall yield. A novel approach to the racemic 3,4-methanonipecotic acid, which relies on a Simmons-Smith cyclopropanation as the key step, was also developed. In this case, the product was obtained in 8 steps and 38% total yield.

Full text of DOI:10.1016/j.tetasy.2015.09.015

Tetrahedron: Asymmetry 26 (2015) 1268–1272
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of racemic and enantiopure 3,4-methanonipecotic acid
Andriy V. Tymtsunik a,b, Yevhen M. Ivon a,b, Igor V. Komarov a,b, Oleksandr O. Grygorenko a,
⇑
a National Taras Shevchenko University of Kyiv, Volodymyrska Street, 64, Kyiv 01601, Ukraine
b Enamine Ltd, Alexandra Matrosova Street, 23, Kyiv 01103, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of both racemic and enantiomerically pure (1R,6S)-3,4-methanonipecotic acid, a cyclo-
propane-containing b-amino acid, which is a valuable building block for drug discovery, is described.
The synthetic scheme commences from natural (S)-malic acid and allows for the preparation of the title
compound in 12 steps in 28% overall yield. A novel approach to the racemic 3,4-methanonipecotic acid,
which relies on a Simmons–Smith cyclopropanation as the key step, was also developed. In this case, the
product was obtained in 8 steps and 38% total yield.
Received 4 September 2015
Accepted 23 September 2015
Available online 21 October 2015
Ó 2015 Published by Elsevier Ltd.
1. Introduction
The idea of bicyclic cyclopropane amino acids has previously
been applied to the design of tailor-made
a- and c-amino acids,
Natural products provide us a boundless pool of ideas for design;
many examples of the successful application of this concept can be
found in the literature.1 Non-proteinogenic amino acids exhibit a
class of natural products that are rarely found in higher organisms
but are widespread in bacteria and plants. The functions of these
amino acids vary significantly, and in many cases are yet to be
established. Cyclopropane amino acids represent a special subtype
of non-proteinogenic natural amino acids that are embodied in
coronamic acid 1 (Pseudomonas corona-facience), carnosadine 2
that is, proline analogues 94 and 105 and 3,4-methanoisonipecotic
acid 11 (Fig. 2).6 This concept was also used in the synthesis of
b-proline analogues 12,7 13,8 and 14.9 b-Amino acids have been
shown to exhibit an intrinsic conformational behavior when
incorporated into b-peptides; on the other hand, b-amino acid
derivatives are often characterized by potent biological activity.10
In particular, nipecotic acid 15 reveals GABA reuptake inhibitor
activity;11 the oligomers of 15 appear to adopt a regular secondary
structure which is not stabilized by hydrogen bonds.12
(Grateloupia carmosa), cleonine
3
(Streptomyces verticillus),
trans-3,4-methanoglutamic acid 4 (Blighia unuugata) and 3,4-
methanoproline 5 (Aesculus parviflora) (Fig. 1).2 The latter com-
pound is an example of bicyclic cyclopropane-containing amino
acids which are also incorporated (as a part of polycyclic systems)
into the molecules of lenticellarines 6–8 (Dysoxylum lenticellare).3
COOH
COO-
COO-
COO-
N
N
+
+
H2
H2
N
+
H2
11
9
10
COO-
+
NH2
COO-
+
H
N
MeOOC
MeOOC
NH3
COO-
H2N
COO-
N
+
NH2
N
N
N
H2
+
2
+
H2
1
H2
MeO
OH
HOOC
12
13
14
- and
COO-
+
COO-
+
R
COO-
Figure 2. Synthetic bicyclic cyclopropane
a
c-amino acids.
6, R = H
N
NH3
+
NH3
7
, R = OH
H2
8, R = OMe
3
4
5
If the concept described above is applied to the molecule of
amino acid 15, structures 16–19 are generated (Fig. 3). Recently,
the synthesis of the racemic compound 17 was described
(Scheme 1).13 The key step of this seven-step reaction sequence
Figure 1. Naturally occurring cyclopropane amino acids and their derivatives.
⇑
Corresponding author. Tel.: +380 44 239 33 15; fax: +380 44 502 48 32.
E-mail address: gregor@univ.kiev.ua (O.O. Grygorenko).
http://dx.doi.org/10.1016/j.tetasy.2015.09.015
0957-4166/Ó 2015 Published by Elsevier Ltd.

A. V. Tymtsunik et al. / Tetrahedron: Asymmetry 26 (2015) 1268–1272
1269
OH
PhCH2Br
100%
NaBH4
87%
OH
OH
COO-
Na+
+H2N
N+
N
COO-
N
Br-
N
N
25
15
Ph
53%
Ph
24
COO-
COO-
Et2Zn (4 mol)
CH2I2 (4 mol)
N
O
N
+
H2
+
H2
16
COO-
F
O
N
17
Dess-Martin
periodinane
H2, Pd-C
OH
OH
CF3
COO-
Boc2O
91%
N
N
N
Boc
Boc
27
26
N
Ph
N
+
CF3
NaClO2, NaH2PO4
2-methyl-2-butene
+
H2
73% (per
2 steps)
H2
18
19
23
O
Figure 3. Nipecotic acid 15, its cyclopropane-containing methanologues and
biologically active derivative of 17.
CO2H
HCl
OH
96%
N
N
Cl-
17.HCl
+
Boc
H2
28
H2N
Scheme 2. Our synthesis of racemic amino acid 17.
MeO2C
O
O
N2
22
N2H4.xH2O
O
N
MeO2C
N
O
protecting group, alcohol 27 was subjected to
a two-step
Rh2(OAc)4
64%
O
oxidation sequence (first with Dess–Martin periodinane, then
using Pinnick reaction) to give the Boc derivative 28. Removal
of the protecting group in the molecule of 28 using a modified
known procedure13 allowed amino acid 17 to be obtained as
the hydrochloride.
O
O
O
MeO2C
CO2Me
20
69%
For the preparation of enantiomerically pure amino acid 17,
we used a strategy similar to that described for the preparation
of racemic 17.13 However, for the preparation of enantiomeri-
cally pure amino ester 20, the known enantiopure chloride 29
was taken, which was previously used in the syntheses of
cyclopropane-containing amino acids, such as 2,3-methanopro-
line 9.16 Compound 29 can be prepared from natural (S)-malic
acid 30 in three steps (Scheme 3). The reaction of 29 with
diethyl malonate and NaH gave the cyclopropane derivative
31. In turn, the reaction of 29 with NaN3 in CH3CN led to the
formation of azide 31. Catalytic hydrogenation of 31 was
accompanied by partial cyclization, to give a mixture of (S)-20
and (1R,6S)-21. To complete the cyclization of (R)-20, this mix-
ture was refluxed in methanol. Finally, the bicyclic lactone
(1R,6S)-21 was transformed into enantiomerically pure
(1R,6S)-17 (as the hydrochloride) in five steps analogous to
those shown in Scheme 1 for the racemate. It should be noted
that in our hands, the reduction of lactam 33 with LiBHEt3
under the reaction conditions described for the racemate13 did
not give reproducible results. An alternative procedure involv-
ing the use of DIBAL as the reducing agent17 was employed
instead, which gave excellent results.
CO2Me
CO2Me
OH
CO2Me
LiBHEt3
64%
Boc2O
DMAP
90%
N
O
N
N
H
O
21
Boc
Boc
Et3SiH
78%
BF3.Et2O
O
CO2Me
CO2H
TFA
90%
LiOH
86%
O-
N
N
N
+
Boc
Boc
H2
17
28
Scheme 1. Literature synthesis of racemic compound 17.
included intramolecular cyclization of the in situ generated amino
ester 20 to give bicyclic lactone 21. This method involved the use of
explosive and shock sensitive diazomalonate 22 in refluxing
chlorobenzene in the first step, which might limit scaling up of
the synthesis.
It was found that a derivative of amino acid 17, compound 23,
was found to be a subnanomolar neurokinin NK1 receptor antago-
nist (pKi = 9.8) (Fig. 3).14 This result demonstrates the utility of
compound 17 as a building block for medicinal chemistry. Herein
we report a novel approach to racemic amino acid 17, as well as
synthesis of its enantiomerically pure (1R,6S)-isomer.
To prove the enantiomeric purity of the product, ester 34 was
reduced with LiBH4 to give alcohol (1R,6S)-27 (Scheme 4). Both
racemic and enantiopure samples of 27 were analyzed by chiral
stationary phase HPLC; the enantiomeric excess of (1R,6S)-27
was found to be 91.5%.
2. Results and discussion
3. Conclusion
Our approach to the synthesis of racemic 17 relied on a
Simmons–Smith cyclopropanation of the known amino alcohol
24, prepared in two steps from the readily available 3-pyridinyl-
methanol 25 (Scheme 2).15 It should be noted that previous
work stated that the cyclopropanation of analogues of 24 under
various conditions was unsuccessful.13 We have found that reac-
tion of 24 with a 4-fold excess of diethylzinc–diiodomethane
system gave the expected product 26 in 53% yield. This reaction
was performed successfully on a 100 g scale. After changing the
A novel approach to racemic 3,4-methanonipecotic acid was
developed. An eight-step reaction sequence involving
a
Simmons–Smith cyclopropanation as the key step allowed the title
compound to be obtained in 38% overall yield. An approach to
enantiomerically pure (1R,6S)-3,4-methanonipecotic acid has also
been described. In this case, the target product was obtained in
12 steps and 28% overall yield from natural (S)-malic acid.

1270
A. V. Tymtsunik et al. / Tetrahedron: Asymmetry 26 (2015) 1268–1272
O
O
4.2. (3-Benzyl-3-azabicyclo[4.1.0]heptan-1-yl)methanol 26
OH
OH
OH
BH3.Me2S
98%
S
SOCl2
O
O
HO
O
O
OH
A solution of CH2I2 (536 g, 2.00 mol) in CH2Cl2 (500 mL) was
added dropwise to a solution of Et2Zn (1 M in Hexanes, 2 L,
2.00 mol) in CH2Cl2 (500 mL) at 0 °C. The resulting mixture was
stirred at 0 °C for 1 h, after which a solution of alcohol 24
(101.6 g, 0.500 mol) in CH2Cl2 (1 L) was added dropwise at À10
to 0 °C. The resulting mixture was stirred at 0 °C for 2 h then
warmed to rt overnight with stirring and cooled again to 0 °C. Next,
2 M aq HCl (1.5 L) was added dropwise with external cooling and
stirring (CAUTION! Highly exothermic reaction and violent gas
evolution). The organic phase was separated and extracted with
2 M aq HCl (2 Â 300 mL). The combined aqueous phases were
made alkaline (pH = 12–14) with 40% aq KOH upon external cool-
ing. The product was extracted with CH2Cl2 (4 Â 450 mL). The
combined organic extracts were dried over Na2SO4, and evaporated
to dryness to give the product 26. 57.6 g (53%). Colorless oil. Anal.
Calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.17; H,
9.06; N, 6.29. MS (CI): 218 (MH+). 1H NMR (500 MHz, CDCl3)
d 7.39–7.15 (m, 5H), 3.49 (d, J = 13.3 Hz, 1H), 3.43 (d, J = 13.3 Hz,
1H), 3.40 (s, 2H), 2.76 (d, J = 11.2 Hz, 1H), 2.72 (br s, 1H), 2.68 (d,
J = 11.2 Hz, 1H), 2.27–2.18 (m, 1H), 2.16–2.09 (m, 1H), 2.02–1.93
(m, 1H), 1.82–1.68 (m, 1H), 0.89 (dd, J = 13.4, 7.9 Hz, 1H),
0.65–0.58 (m, 1H), 0.53 (dd, J = 9.1, 4.0 Hz, 1H). 13C NMR
(126 MHz, CDCl3) d 138.4 (C), 128.8 (CH), 128.1 (CH), 126.8 (CH),
70.4 (CH2), 62.6 (CH2), 55.4 (CH2), 49.4 (CH2), 23.6 (CH2), 23.1
(CH2), 15.1 (CH2), 13.8 (CH).
Cl
NaIO4
RuCl3
OH
30
83% (per
2 steps)
O
O
NaN3
O
O
CH2(CO2Me)2
NaH
O
O
O
S
O
O
93%
N3
O
Cl
O
64%
Cl
32
31
29
H2, Pd-C
H
H
O
CO2Me
CO2Me
Boc2O
MeOH
O
O
reflux
76%
DMAP
100%
N
H
O
N
O
O
Boc
33
1. DIBAL
2. Et3SiH,
BF3.Et2O
NH2
(S)-20
(1R,6S)-21
94%
H
H
H
COOH
Cl-
CO2H
CO2Me
NaOH
100%
HCl
92%
N
N
N
+
H2
Boc
Boc
17.
(1R,6S)-28
34
(1R,6S)- HCl
Scheme 3. Synthesis of enantiomerically pure amino acid (1S,6R)-17.
4.3. tert-Butyl 1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-
3-carboxylate 27
H
H
CO2Me
LiBH4
83%
OH
To a solution of alcohol 26 (21.7 g, 0.100 mol) in MeOH (300 mL),
10% Pd-C (8 g) was added under an argon atmosphere, followed by
Boc2O (32.7 g, 0.250 mol). The mixture was hydrogenated at 50 °C
and 70 bar for 48 h. The catalyst was filtered off, and the filtrate
was evaporated to dryness to give product 27. Yield 20.7 g (91%).
Colorless oil. Anal. Calcd for C12H21NO3: C, 63.41; H, 9.31; N, 6.16.
Found: C, 63.19; H, 8.94; N, 6.46. MS (CI): 228 (MH+). 1H NMR
(500 MHz, CDCl3) d 3.86–3.65 (br m, 1H), 3.63–3.19 (br m, 4H),
3.01 (br s, 1H), 2.15 (br s, 1H), 1.93 (dt, J = 12.5, 5.7 Hz, 1H), 1.66
(s, 1H), 1.44 (s, 9H), 1.03–0.90 (m, 1H), 0.66–0.58 (m, 1H), 0.37 (t,
J = 5.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) d 154.9 (C@O), 79.2 (C),
69.0 (CH2), 44.3 and 44.0 (CH2), 40.8 and 39.6 (CH2), 28.0 (CH3),
22.1 (C), 21.8 (CH2), 14.1 (CH2), 13.4 (CH).
N
N
Boc
Boc
34
(1R,6S)-27
Scheme 4.
4. Experimental
4.1. General
Solvents were purified according to standard procedures.
Alcohol 2415 and chloride 2916 were prepared using reported
procedures. All other starting materials were purchased from
Acros, Merck, Fluka, and UkrOrgSyntez. Melting points were
measured on MPA100 OptiMelt automated melting point system.
Analytical TLC was performed using Polychrom SI F254 plates.
Column chromatography was performed using Kieselgel Merck
60 (230–400 mesh) as the stationary phase. 1H and 13C NMR
spectra were recorded on a Bruker 170 Avance 500 spectrometer
(at 499.9 MHz for Protons and 124.9 MHz for Carbon-13) and
Varian Unity Plus 400 spectrometer (at 400.4 MHz for protons
and 100.7 MHz for Carbon-13). Chemical shifts are reported in
ppm downfield from TMS as the internal standard. Elemental anal-
yses were performed at the Laboratory of Organic Analysis, Depart-
ment of Chemistry, National Taras Shevchenko University of Kyiv.
Mass spectra were recorded on an Agilent 1100 LCMSD SL instru-
ment [chemical ionization (APCI), electrospray ionization (ESI)]
and Agilent 5890 Series II 5972 GCMS instrument [electron impact
ionization (EI)]. Flash chromatography was performed using
Combiflash Companion chromatograph with 12 g or 40 g RediSep
column. Chiral stationary phase HPLC analyses of 27 were
performed on an Agilent 1100/1200 instrument, Chiralpak IA
250 mm  4.6 mm column, Hexanes–i-PrOH (95:5) as eluent,
4.4.
3-(tert-Butoxycarbonyl)-3-azabicyclo[4.1.0]heptane-1-
carboxylic acid 28
A mixture of alcohol 27 (20.2 g, 92.9 mmol) and Dess–Martin
periodinane (47.3 g, 0.111 mol) in CH2Cl2 (500 mL) was refluxed
overnight, then cooled and diluted with hexanes (170 mL). The
precipitate was filtered off, and the filtrates were evaporated to
dryness. The crude aldehyde obtained was used in the next step
without further purification. Next, it was dissolved in acetone
(300 mL), and H2O (300 mL), Na2HPO4 (66.8 g, 0.557 mol),
2-methyl-2-butene (26.1 g, 0.372 mol), and NaClO2 (80%, 31.5 g,
0.279 mol) were added. The mixture was stirred vigorously for
24 h. Most of the acetone was removed in vacuo, and the residue
was extracted with CH2Cl2 (4 Â 150 mL). The combined organic
extracts were dried over Na2SO4 and evaporated in vacuo. The
residue was triturated with 10% aq K2CO3 (300 mL). The resulting
mixture was washed with CH2Cl2 (3 Â 100 mL). The aqueous phase
was acidified with 10% aq citric acid to pH = 1–3 and extracted
with CH2Cl2 (4 Â 150 mL). The combined organic extracts were
dried over Na2SO4 and evaporated in vacuo to give product 28.
0.6 mL/min, 2 lL injection volume, 25 °C, detection at 215 nm.

A. V. Tymtsunik et al. / Tetrahedron: Asymmetry 26 (2015) 1268–1272
1271
Yield 16.4 g (73% per two steps). Colorless oil. For other spectro-
scopic and physical data, see Ref. 13.
was added. Hydrogen was bubbled through this mixture under vig-
orous stirring at rt until the starting material has disappeared
(monitored by TLC; ca. 3 h). The suspension was filtered, and the
filtrate was diluted with additional MeOH (400 mL). The solution
was refluxed for 16 h and then evaporated in vacuo to give crude
(1R,6S)-21 as a white solid, which was used without further purifi-
cation. An analytical sample was obtained by recrystallization from
diethyl ether/methanol mixture. Yield 3.29 g (76%). White solid.
4.5. 3-Azabicyclo[4.1.0]heptane-1-carboxylic acid, hydrochlo-
ride 17ÁHCl
Saturated HCl in dioxane (75 mL) was added to a solution of 28
(5.08 g, 21.2 mmol) in EtOAc (150 mL). The mixture was stirred
overnight and evaporated in vacuo. The residue was triturated
with acetone and filtered. The solid was dried in vacuo to give
the hydrochloride of 17 as a white solid. Yield 4.60 g (96%).
Colorless solid. Mp >200°C (dec.). Anal. Calcd for C7H12ClNO2:
C, 47.33; H, 6.81; Cl, 19.96; N, 7.89. Found: C, 47.53; H, 7.13;
Cl, 19.60; N, 8.06. 1H NMR (500 MHz, D2O) d 4.18 (d, J = 14.0 Hz,
1H), 3.14–3.04 (m, 1H), 2.97 (d, J = 14.0 Hz, 1H), 2.63 (td, J = 12.4,
3.9 Hz, 1H), 2.22–2.09 (m, 1H), 1.91 (d, J = 14.8 Hz, 1H), 1.81
(dd, J = 15.0, 7.9 Hz, 1H), 1.57 (dd, J = 9.3, 5.2 Hz, 1H), 1.06–0.97
(m, 1H). 13C NMR (126 MHz, D2O) d 176.2 (C@O), 42.7 (CH2), 37.8
(CH2), 20.9 (CH2), 19.6 (CH), 18.5 (C), 18.3 (CH2).
Mp 132–134 °C. [a D
]
22 = À35.8 (c 1.0, CHCl3). For other spectroscopic
and physical data, see Ref. 13.
4.9. (1R,6S)-3-tert-Butyl 1-methyl 2-oxo-3-azabicyclo[4.1.0]hep-
tane-1,3-dicarboxylate 33
4-(Dimethylamino)pyridine (1.36 g, 11.1 mmol) was added to a
solution of lactam (1R,6S)-21 (3.76 g, 22.2 mmol) in CH3CN
(60 mL). Next, a solution of Boc2O (7.27 g, 33.3 mmol) in CH3CN
(20 mL) was added over 2 h. The mixture was stirred at rt
overnight and evaporated. The residue was dissolved in EtOAc
(150 mL), washed with 10% aq citric acid to pH ca. 4 and H2O, then
dried over Na2SO4 and evaporated. The pure product 33 was
obtained after chromatography (Hex/EtOAc (2:1) as eluent,
Rf = 0.37). Yield 5.98 g (quant.). Yellowish oil, which crystallized
4.6. (R)-Dimethyl 2-(2-chloroethyl)cyclopropane-1,1-dicarboxy-
late 31
Chloride 29 (23.6 g, 0.126 mol) and dimethyl malonate
(15.1 mL, 0.133 mol) were dissolved in absolute toluene (400 mL)
under argon. Lithium tert-butoxide (21.2 g, 0.265 mol) was added
to the reaction mixture in portions at 0 °C. The mixture was stirred
at room temperature overnight and then quenched with 20% aq
NH4Cl (25 mL). After 15 min, H2O (200 mL) was added, and the
phases were separated. The aqueous phase was washed with
toluene (200 mL). The combined organic extracts were dried over
Na2SO4 and evaporated. The crude mixture was purified by frac-
tional distillation at 1.4 mbar to give diester 31 as a colorless liq-
upon standing. Mp 43–44 °C. [
spectroscopic and physical data, see Ref. 13.
a
]
22 = À6.0 (c 1.0, CHCl3). For other
D
4.10. (1R,6S)-3-tert-Butyl 1-methyl 3-azabicyclo[4.1.0]heptane-
1,3-dicarboxylate 34
A solution of DIBAL (0.7 M in toluene, 16.2 mL, 11.3 mmol) was
added dropwise to the solution of the imide 32 (2.66 g, 9.9 mmol)
in THF (50 mL) at À80 °C under argon atmosphere. This mixture
was stirred at À80 °C for 1 h, and saturated aq NH4Cl (5 mL) was
added. The suspension obtained was allowed to warm to rt, stirred
for 30 min, and then filtered. The solid residue was washed thor-
oughly with THF (3 Â 50 mL), and the combined filtrates were
evaporated to give a crude mixture of diastereomeric hemiamidals
(2.73 g), which was used without further purification.
uid. Yield 17.7 g (64%). Bp 81–82 °C (1.4 mbar). [
a
]
22 = À30.5 (c
D
1.0, CHCl3). Anal. Calcd for C9H13ClO4: C, 48.99; H, 5.94; Cl, 16.07.
Found: C, 49.36; H, 5.61; Cl, 16.23. MS (EI): 220/222 (M+). 1H
NMR (400 MHz, CDCl3) d 3.76 (s, 3H), 3.73 (s, 3H), 3.58 (t,
J = 6.6 Hz, 2H), 2.10–2.02 (m, 1H), 1.96–1.87 (m, 1H), 1.76–1.68
(m, 1H), 1.50–1.41 (m, 2H). 13C NMR (100 MHz, CDCl3) d 169.9,
168.0, 52.3, 52.2, 42.9, 33.0, 31.4, 25.4, 20.2.
A solution of hemiamidals (2.73 g) and triethylsilane (1.58 mL,
9.9 mmol) in CH2Cl2 (80 mL) was cooled to À80 °C under an argon
atmosphere, and BF3ÁEt2O (1.22 mL, 9.9 mmol) was added. This
mixture was stirred at the same temperature for 30 min. The sec-
ond portion of triethylsilane (1.58 mL, 9.9 mmol) and then—
BF3ÁEt2O (1.22 mL, 9.9 mmol) were added. The resulting solution
was stirred for 1.5 h and then quenched with saturated aq NaHCO3
(100 mL). This mixture was stirred vigorously at rt for 20 min, and
the phases were separated. The aqueous layer was washed with
CH2Cl2 (50 mL). The combined extracts were dried over Na2SO4,
evaporated, and dried in vacuo to give product 34. Yield 2.36 g
4.7. (S)-Dimethyl 2-(2-azidoethyl)cyclopropane-1,1-dicarboxy-
late 32
Diester 31 (17.7 g, 80.2 mmol) was dissolved in CH3CN (160 mL)
and H2O (40 mL). Sodium azide (7.82 g, 120 mmol), sodium iodide
(60 mg, 0.4 mmol), and tetrabutylammonium bromide (260 mg,
0.8 mmol) were added. The resulting mixture was refluxed until
the reaction was completed (monitored by NMR, ca. 6 d). After
cooling to rt, the mixture was diluted with H2O (250 mL) and
extracted with tert-butyl methyl ether (2 Â 200 mL). The combined
extracts were dried over Na2SO4 and evaporated to give 32 as a col-
orless liquid which was used without further purification. Yield
(94%). Colorless oil. [
scopic and physical data, see Ref. 13.
a
]
22 = À61.9 (c 1.0, CHCl3). For other spectro-
D
16.9 g (93%).
[a]
22 = À61.1 (c 1.0, CHCl3). Anal. Calcd for
D
4.11. (1R,6S)-3-(tert-Butoxycarbonyl)-3-azabicyclo[4.1.0]heptane-
1-carboxylic acid (1R,6S)-28
C9H13N3O4: C, 47.57; H, 5.77; N, 18.49. Found: C, 47.24; H, 5.63;
N, 18.27. MS (EI): 199 (M+ÀN2), 140, 108. 1H NMR (500 MHz,
CDCl3) d 3.71 (s, 3H), 3.67 (s, 3H), 3.32 (t, J = 6.6 Hz, 2H), 1.95–
1.86 (m, 1H), 1.65 (td, J = 12.9, 6.3 Hz, 1H), 1.48 (td, J = 14.0,
6.9 Hz, 1H), 1.44–1.38 (m, 1H), 1.38–1.33 (m, 1H). 13C NMR
(126 MHz, CDCl3) d 169.8 (C@O), 167.9 (C@O), 52.24 (CH3), 52.17
(CH3), 50.1 (CH2), 33.2 (C), 27.8 (CH2), 25.1 (CH), 20.2 (CH2).
At first, aq NaOH (2 M, 9 mL, 18.0 mmol) was added to a
solution of (1R,6S)-3-tert-butyl 1-methyl 3-azabicyclo[4.1.0]hep-
tane-1,3-dicarboxylate 34 (2.30 g, 9.0 mmol) in MeOH (50 mL).
The resulting mixture was stirred at rt overnight and evaporated.
The residue was dissolved in H2O (50 mL), washed with Et2O
(30 mL), acidified by the addition of 1 M aq NaHSO4 to pH = 3
and extracted with CHCl3 (2 Â 50 mL). Extracts was dried over
Na2SO4 and evaporated to give the product (1R,6S)-28 as colorless
4.8. (1R,6S)-Methyl 2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxy-
late (1R,6S)-21
solid. Yield 2.16 g (100%). Mp 96–97 °C. [
For other spectroscopic and physical data, see Ref. 13.
a
]
22 = À57.2 (c 1.0, CHCl3).
D
The crude azide 31 (5.80 g, 25.5 mmol) was dissolved in MeOH
(400 mL) (the dilution is critical!) and 10% Pd on charcoal (5.0 g)

1272
A. V. Tymtsunik et al. / Tetrahedron: Asymmetry 26 (2015) 1268–1272
Chem. 2011, 46, 4769–4807; (d) Li, J. W.-H.; Vederas, J. C. Science 2009, 325,
161–165; (e) Rizzo, S.; Waldmann, H. Chem. Rev. 2014, 114, 4621–4639.
2. (a) Stammer, C. H. Tetrahedron 1990, 46, 2231–2254; (b) Wessjohann, L. A.;
Brandt, W. Chem. Rev. 2003, 103, 1625–1648.
4.12. (1R,6S)-3-Azabicyclo[4.1.0]heptane-1-carboxylic acid,
hydrochloride (1R,6S)-17ÁHCl
3. (a) Aladesanmi, A. J. Tetrahedron 1988, 44, 3749–3756; (b) Aladesanmi, A. J.;
Adewunmi, C. O.; Kelley, C. J.; Leary, J. D.; Bischoff, T. A.; Zhang, X.; Snyder, J. K.
Phytochemistry 1988, 27, 3789–3792; (c) Aladesanmi, A. J.; Hoffmann, J. J.
Phytochemistry 1994, 35, 1361–1362.
4. Hercouet, A.; Bessieres, B.; Le Corre, M. Tetrahedron: Asymmetry 1996, 7, 1267–
1268.
(1R,6S)-17ÁHCl was obtained following the procedure for the
22
racemate. Yield 770 mg (92%). Mp 208–212°C (dec.).
[
a]
=
D
À38.8 (c 1.0, H2O). Other spectroscopic and physical data were
consistent with that obtained for the racemate.
5. Hanessian, S.; Reinhold, U.; Saulnier, M.; Claridge, S. Bioorg. Med. Chem. Lett.
1998, 8, 2123–2128.
6. Mori, M.; Kubo, Y.; Ban, Y. Tetrahedron 1988, 44, 4321–4330.
7. Medda, A. K.; Lee, H.-S. Synlett 2009, 921–924.
4.13. tert-Butyl 1-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-
3-carboxylate (1R,6S)-27
8. Adamovskyi, M. I.; Artamonov, O. S.; Tymtsunik, A. V.; Grygorenko, O. O.
Tetrahedron Lett. 2014, 55, 5970–5972.
9. Tymtsunik, A. V.; Ivon, Ye. M.; Komarov, I. V.; Grygorenko, O. O. Tetrahedron
Lett. 2014, 55, 3312–3315.
To a solution of ester 34 (200 mg, 0.78 mmol) in THF (8 mL),
LiBH4 (51 mg, 2.34 mmol) was added at 0 °C. The reaction mixture
was stirred at rt overnight, and then quenched carefully with
MeOH (5 mL). The reaction mixture was evaporated in vacuo to
dryness, diluted with 10% aq K2CO3 (30 mL), and extracted with
CH2Cl2 (5 Â 30 mL). The combined organic extracts were dried over
MgSO4 and evaporated in vacuo to give the product (1R,6S)-27.
Yield 147 mg (83%). An analytical sample was obtained using flash
chromatography (gradient Hexanes–EtOAc as eluent). Colorless oil.
Other spectroscopic and physical data were consistent with that
obtained for the racemate.
10. (a) Spiteller, P.; von Nussbaum, F. In Enantioselective Synthesis of b-Amino Acids;
Juaristi, E., Soloshonok, V. A., Eds., 2nd ed.; John Wiley and Sons: Hoboken, NJ,
2005; pp 19–91; (b) Grygorenko, O. O. Tetrahedron 2015, submitted.
11. Madsen, K.; White, H. S.; Clausen, R. P.; Frølund, B.; Larsson, O. M.; Krogsgaard,
P.; Schousboe, A. In Handbook of Neurochemistry and Molecular Neurobiology:
Neural Membranes and Transport; Lajtha, Abel, Reith, Maarten E. A., Eds., 3rd
ed.; Springer: New York, NY, 2007; pp 285–304.
12. (a) Abele, S.; Vögtli, K.; Seebach, D. Helv. Chim. Acta 1999, 82, 1539–1558; (b)
Chung, Y. J.; Huck, B. R.; Christianson, L. A.; Stanger, H. E.; Krauthäuser, S.;
Powell, D. R.; Gellman, S. H. J. Am. Chem. Soc. 2000, 122, 3995–4004; (c) Chung,
Y. J.; Christianson, L. A.; Stanger, H. E.; Powell, D. R.; Gellman, S. H. J. Am. Chem.
Soc. 1998, 120, 10555–10556; (d) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T.
S.; Moore, J. S. Chem. Rev. 2001, 101, 3893–4011; (e) Vasudev, P. G.; Chatterjee,
S.; Shamala, N.; Balaram, P. Chem. Rev. 2011, 111, 657–687.
Acknowledgements
13. Napolitano, C.; Boriello, M.; Cardullo, F.; Donati, D.; Paio, A.; Manfredini, S.
Tetrahedron 2010, 66, 5492–5497.
The work was supported by Enamine Ltd and in part—by DAAD
Leonhard-Euler Program (project ID 57041849). The authors thank
Ms. Kseniya Krasnopolska for ee determination. Y.M.I. thanks Prof.
Dr. Peter Langer and Mrs. Mariia Miliutina for their help during his
visit to Rostock University.
14. Alvaro, G.; Cardullo, F.; Castiglioni, E. WO 2010/007032, 2010.
15. (a) Winkler, J. D.; Axten, J.; Hammach, A. H.; Kwak, Y.-S.; Lengweiler, U.; Lucero,
M. J.; Houk, K. N. Tetrahedron 1998, 54, 7045–7056; (b) Grainger, R. S.; Patel, B.;
Kariuki, B. M.; Male, L.; Spencer, N. J. Am. Chem. Soc. 2011, 133, 5843–5852.
16. (a) Hercouet, A.; Bessières, B.; Le Corre, M. Tetrahedron: Asymmetry 1996, 7,
1267–1268; (b) Tang, W.; Wei, X.; Yee, N. K.; Patel, N.; Lee, H.; Savoie, J.;
Senanayake, C. H. Org. Proc. Res. Dev. 2011, 15, 1.
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