Esterase-mediated synthesis of optically active GABA analogues containing a stereogenic all-carbon quaternary carbon atom

Article abstract of DOI:10.1016/j.tetasy.2010.07.010

Esterase from Horse Liver (HLAP) was able to hydrolyze a series of linear and cyclic β,β-dialkyl-γ-nitroesters, in spite of the well-known reluctance of hydrolytic enzymes to recognize and transform hindered substrates, such as those possessing a stereoge

Full text of DOI:10.1016/j.tetasy.2010.07.010

Tetrahedron: Asymmetry 21 (2010) 2183–2191
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Esterase-mediated synthesis of optically active GABA analogues containing
a stereogenic all-carbon quaternary carbon atom
b
a
b
a
Fulvia Felluga a, , Franco Ghelfi , Giuliana Pitacco , Fabrizio Roncaglia , Ennio Valentin ,
*
Cesare Daniele Venneri a
a Dipartimento di Scienze Chimiche, Università di Trieste, via L.Giorgieri, 1, 34127 Trieste, Italy
b Dipartimento di Chimica, Università di Modena e Reggio Emilia, via Campi, 183, 44100 Modena, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Esterase from Horse Liver (HLAP) was able to hydrolyze a series of linear and cyclic b,b-dialkyl-c-nitro-
esters, in spite of the well-known reluctance of hydrolytic enzymes to recognize and transform hindered
substrates, such as those possessing a stereogenic quaternary carbon atom next to the reaction site. The
Received 15 June 2010
Accepted 5 July 2010
Available online 4 August 2010
resulting optically active
c-nitroesters gave access to optically active b,b-disubstituted c-aminoacids as
well as -disubstituted succinic acids, both being biologically relevant compounds.
a,a
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Cl
The stereoselective synthesis of optically active substituted
amino acids has received considerable attention in recent years.1
These compounds are structurally related to -aminobutyric acid
1 (GABA), which is the main Central Nervous System (CNS) inhib-
itory neurotransmitter.2 Many non-natural
-amino acids have
c-
c
H2N
COOH
H2N
COOH
c
(R)-Baclofen 2
GABA 1
been designed and synthesized for the therapeutic treatment of
the diseases arising from a deficiency in the GABA system.3 Some
examples of commercial b-aryl- and b-alkyl GABA are (R)-Baclofen
2 (Fig. 1),4,5 a muscle relaxant and antispastic agent, and (S)-Pre-
gabalin 36,7 [(3-aminomethyl-5-methylhexanoic acid)], having
anticonvulsant, anxiolytic-like and analgesic properties. Gabapen-
tine 43a,8 [1-(aminomethyl)cyclohexylacetic acid] is an achiral
b,b-disubstituted GABA analogue, commercialized as NeurontinÒ
for the treatment of epilepsy, faintness, hypokinesis and cranial
traumas. It is also the only drug specifically licensed for the treat-
ment of neuropathic pain.
H2N
COOH
H2N
COOH
(S)-Pregabalin 3
Gabapentine 4
Figure 1. GABA and commercially available GABA derivatives.
It is worth noting that in addition to having a biological activity
in the CNS, chiral
natural antitumor compounds,10 some of which are known to form
helicoidal
-peptidomimetics,11 conformationally stable both in
c-aminoacids are also present in the structure of
Although these compounds have been shown to act with very
different mechanisms, they were all designed as lipophilic GABA
analogues.
c
solution and in solid state, even for oligopeptides consisting of as
The ability to exert their action is in fact strictly related to their
lipophilicity and the consequent capacity to cross the Blood–Brain
Barrier (BBB),9 which is prohibited for the highly hydrophilic GABA
itself, whose direct administration is not therapeutically useful for
this reason.
The chirality of non-racemic synthetic GABA analogues is very
important, as their activity is recognized to reside only in a single
enantiomer, as indicated in Figure 1.4,6
few as four residues.
For all these reasons, the enantioselective synthesis, as well as
the biological activity evaluation and practical applications of new
chiral linear and cyclic
c-aminoacids, has been the subject of many
publications,4,5,7,12–14 However, whereas b-monosubstituted
c-
aminobutyric acid derivatives, including b-alkyl,7,13,14 b-aryl4,5 and
b-heteroaryl12a substituted systems, have been extensively de-
scribed, very little has been reported on the synthesis of b,b-disub-
stituted GABA analogues, structurally related to Gabapentin.
A single example is present in the literature12b on the synthesis
* Corresponding author. Tel.: +39 040 558 3924; fax: +39 040 558 3903.
E-mail address: ffelluga@units.it (F. Felluga).
of an acyclic optically active b,b-dialkylated c-aminobutyric acid,
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.07.010

2184
F. Felluga et al. / Tetrahedron: Asymmetry 21 (2010) 2183–2191
namely (R)-b-benzyl-b-methylGABA, obtained from stereoselective
-benzylation of a chiral ester derived from 2-cyanopropanoic acid
ative configuration had already been made for 7d,28 while for 7e it
was made by means of DIFNOE experiments, whose results are
presented in Figure 2 for both compounds. A complete assignment
for all proton and carbon resonances was previously made through
2D experiments. As expected, the addition of the nitromethane
a
and (1S,2R,4R)-10-dicyclohexylsulfamoylisoborneol (Oppolzer’s
alcohol),15 used as a chiral auxiliary. Using this six-step route, the fi-
nal compound was obtained with 82% ee and in 65% total yield.
Among the cyclic Gabapentin-related analogues, cis-(1S,3R)-(1-
aminomethyl)-3-methylcyclohexaneacetic acid16 was shown to be
one of the most active compounds among a series of mono- and
polymethylsubstituted Gabapentin analogues, exhibiting a higher
affinity for the Gabapentin receptor binding site with respect to
the parent unsubstituted achiral aminoacid. It also showed a high-
er activity than its enantiomer and its diastereomeric trans-isomer.
It was obtained as a pure enantiomer by preparative HPLC separa-
tion of its racemic form,16 prepared in turn by a route involving the
diastereoselective addition of nitromethane to ethyl (E,Z)-2-(3-
methylcyclohexylidene)acetate as the key step.
carbanion to the corresponding
a,b-unsaturated esters 6d and 6e
took place from the less hindered side of the molecules, namely
that containing the equatorial position for 6d and the bridge
hydrogen atom for 6e. As a consequence, the nitromethyl group
in 7d is cis to the methyl group at C-3, while in 7e the same substi-
tuent is cis to the junction hydrogen atoms. Reduction of the nitro
group in 7a–e gave the corresponding c-lactams 8a–e, which were
hydrolyzed to the desired GABA analogues 9a–e, which were sep-
arated as hydrochlorides. In the reaction sequence presented here,
the enantiodifferentiating step was the enzymatic resolution of the
chiral racemic
c
-nitroesters 7a–e to the corresponding optically
-nitroacids 10a–e, with recovery of unreacted, enantioen-
-nitroesters 7a–e. All intermediates and products, pre-
Finally, a bicyclic derivative, namely (1S,5S,6R)-(ꢀ)-(6-(amino-
methyl)bicyclo[3.2.0]heptane-6-acetic acid,17–19 is a therapeutic
agent used against a variety of neurodegenerative and neuropatho-
logical disorders. Its synthesis is based on commercially available
(1R,5S)-(+)-cis-bicyclo[3.2.0]hept-2-en-6-one.19–21
active
riched
c
c
sented in Scheme 1, were isolated as pure compounds and were
fully characterized.
In the frame of our research, involving the use of hydrolytic en-
zymes in the synthesis of chiral compounds of biological and phar-
2.2. Kinetic resolution of
c-nitroesters 7a–e
maceutical interest, and in particular of
analogues, we developed a short and inexpensive route to a series
of acyclic and cyclic b,b-disubstituted- -aminobutyric acids using
commercial esterases in the enantiodifferentiating step. This work
is of interest not only for the biological potential relevance of these
compounds but also for the synthetic problem associated with the
obtainment of chiral compounds with a quaternary asymmetric
carbon atom.22 The method presented here also gives access to
c
-aminobutyric acid
Chiral racemic -nitroesters 7a–e were treated for kinetic reso-
c
lution with a series of commercially available hydrolytic enzymes,
such as esterases, lipases and proteases. Among them, only the
crude esterases from horse liver (HLAP, Horse Liver Acetone Pow-
der) and from porcine liver (PLAP, Porcine Liver Acetone Powder)
proved active towards the substrates, affording their respective
carboxylic acids 10a–e. For PLAP, however, the E value was gener-
ally too low to be useful for preparative purposes.
c
a,a
-disubstituted chiral non-racemic succinic acids, which are
Other enzymes, such as proteases (a-chymotrypsin, Subtilisin)
potentially of great relevance as valuable building blocks.
In fact, monosubstituted succinic acids have been reported in
their enantiomerically pure forms since 196023 as important syn-
thetic intermediates to homochiral building blocks, such as b-lac-
and Lipases (Aspergillus niger lipase, Pseudomonas sp. Lipase, Pseu-
domonas fluorescens lipase, Novozyme 435), were completely inef-
fective and the substrates were recovered unaltered after 48 h.
The results for kinetic enzymatic resolutions are summarized in
Table 1, which lists the ee values, enantiomeric ratios29 and yields
for the isolated acids 10a–e, and for the recovered unreacted esters
7a–e.
tams, b-and c-lactones and to chiral subunits of pseudopeptides,
which have been proven to be effective inhibitors of various
zinc-enzymes,24 and to have different biological activities. Only a
few examples of carboxylic acids possessing an all-carbon
a
-qua-
The reactions were stopped at approximately 20% conversions, in
order to calculate the enantiomeric ratio E29 for all enzymes. All res-
olutions were run up to the conversions indicated in Table 1, in order
to isolate the carboxylic acid products and the unreacted esters with
the highest possible ee’s. Since in all cases the enantioselectivity was
moderate, the reactions were allowed to exceed 50% conversion, un-
til the ee’s of the unreacted nitroesters were satisfactory.
ternary centre which can be obtained by catalytic methods are
known so far.25,26 Recently, one example has been published27 con-
cerning the asymmetric synthesis of
a-alkyl-a-aryl substituted
succinate derivatives, through the Cu-catalyzed 1,4-addition of
dialkylzinc reagents to b-arylacetates.
To the best of our knowledge, no other examples of chiral non-
racemic
in the literature.
a
,
a
-disubstituted succinic acids have been reported as yet
The enantioselectivities observed were quite low in the case of
the enzymatic resolutions of 7a,b,c and, accordingly, the resulting
carboxylic acids 10a,b,c were isolated with ee’s lower than 75%, at
low conversion values. Moreover, hydrolyses of 7a and 7c did not
proceed over 39% and 42% conversion, respectively, where the
unreacted nitroesters 7a and 7c had 39% and 63% ee, respectively.
Both compounds were therefore recycled and, after three consecu-
tive hydrolysis procedures, they could be recovered with 62% ee in
the former case and with 91% ee in the latter. The enantioselectiv-
ity was found to increase with the complexity of the substrate
structure, reaching its maximum value with the bicyclic system
7e (E = 40), which could be isolated as an almost enantiomerically
pure compound at 60% conversion.
2. Results and discussion
2.1. Synthesis and characterization of racemic c-nitroesters
The general strategy used for the synthesis of b,b-disubstituted
GABA analogues 9a–e is reported in Scheme 1. It is based on the
Horner–Wadsworth–Emmons homologation reaction carried out
on the substrates 5a–e which furnished the corresponding
a
,b-unsaturated esters 6a–e28 as mixtures of E and Z diastereo-
mers. The subsequent conjugate addition reaction between nitro-
methane and the Michael acceptors 6a–e, carried out under basic
The last steps in this reaction sequence were the conversion of
conditions, afforded the corresponding c-nitroesters 7a–e as race-
the chiral non-racemic
aminoacids 9a–e, through reduction of their nitro group to an amino
group, cyclizationinto the corresponding -lactams 8a–e and subse-
c-nitroesters 7a–e into their corresponding
mates. The base used in this step was DBU for 6a–c28a and tetrabu-
tylammonium fluoride in refluxing THF for 6d,e.28b
c
It should be noted that the formation of the
and 7e occurred with complete diastereoselectivity, as a single
stereoisomer was isolated in each case. The assignment of the rel-
c-nitroesters 7d
quent acidic hydrolysis. In the reduction step, carried out with H2
under catalytic conditions, the ring double bond in 7e was also re-
duced, so that both (+)-8e and (+)-9e were saturated systems.

F. Felluga et al. / Tetrahedron: Asymmetry 21 (2010) 2183–2191
2185
R1
R1
R
CO2H
R
CO2H
vi
or vii
CO2H
NO2
10a-e
11a-e
vii
v
R1
R1
R1
R
R1
R1
iv
i
R
CO2Et
R
CO2H
ii
iii
CO2Et
6a-e
O
R
R
O
N
NO2
7a-e
NH3
9a-e
H
5a-e
8a-e
O
O
CO2H
CO2H
CO2Et
NO2
(S)-(–)-7a
CO2Et
CO2H
O
CO2H
NH3+Cl-
N
H
NO2
5a
6a
(R)-(+)-11a
(S)-(–)-9a
(R)-(+)-10a
(S)-(+)-8a
CO2H
CO2H
CO2Et
NO2
(S)-(–)-7b
CO2Et
CO2H
CO2H
O
NH3+Cl-
(S)-(–)-9b
NO2
(R)-(+)-10b
N
H
(S)-(–)-11b
5b
6b
(S)-(+)-8b
O
CO2H
NO2
(S)-(–)-10c
CO2Et
CO2Et
NO2
(R)-(+)-7c
CO2
H
CO2H
CO2H
(R)-(+)-11c
O
NH3+Cl-
N
H
6c
5c
(R)-(+)-9c
(R)-(–)-8c
7
3
CO2H
CO2H
CO2H
1
CO2Et
NO2
5
3
O
CO2H
NO2
O
NH3+Cl-
1
N
CO2Et
H
(1S,3R)-(–)-11d
(1R,3S)-(+)-10d
(1S,3R)-(–)-7d
(1S,3R)-(–)-9d
(5S,7R)-(–)-8d
6d
5d
H
2
H
H
H
H
2
H
H
H
H
1
1
CO2H
5
6
6
5
3'
CO2H
O
5'
CO2Et
O
H
H
CO2H
NO2
CO2Et
NO2
H
NH3+Cl-
H
CO2H
H
5e
N
H
6e
(1R,5S,6R)-(–)-11e
(1S,5S,6R)-(+)-9e
(1S,5R,6S)-(+)-10e
(1R,5S,6R)-(–)-7e
(1S,3'R,5S)-(+)-8e
Scheme 1. General strategy for the synthesis of the b,b-disubstituted GABA analogues 9a–e. Reagents and conditions: (i) triethylphosphonoacetate, tert-BuOK, refluxing THF,
20 min; (ii) CH3NO2, DBU, rt, overnight; or equimolar CH3NO2, TBAF, refluxing THF; (iii) H2, Ra–Ni; (iv) 6 M HCl; (v) enzymatic resolution; (vi) spontaneous, 2 weeks; (vii) 1:1
6 N HCl/glacial AcOH under reflux, 2 h. Compounds 7–11 are given with the correct stereochemistry for the enantiomer shown, after enzymatic procedures.
3%
4%
alkanoic acid usually requires prolonged heating in a mineral
3%
H
acid.30
H
3
H
A similar Nef reaction occurring under the mild conditions of an
2%
H
Me
enzymatic hydrolysis, that is room temperature and a pH near neu-
trality, was first observed in the enzymatic resolution of ethyl ( )-
5,5-dimethyl-3-nitromethylhexanoate.7a
1
5
7
6
2%
4
O2N
1
CO2Et
H
H
EtO2C
NO2
The
tained from the corresponding optically active
and from the -nitroacids 10a–e, under acidic treatment with a
a,a
-disubstituted succinic acids 11a–e could also be ob-
4%
5%
4%
c-nitroesters 7a–e
c
7d
7e
1:1 solution of glacial AcOH and 6 M HCl, at reflux. The reaction
was very rapid and went to completion within two hours with
no loss of chirality observed in the products.
Figure 2. The main results of DIFNOE measurements for compounds 7d and 7e.
In all cases examined, when the hydrolysis was prolonged to
very high conversion values, the corresponding succinic acids
2.3. Determination of the absolute configurations of the chiral
11a–e were isolated instead of the expected
Evidently, long reaction times favour the spontaneous oxidative
Nef reaction occurring on the -nitroacids 10a–e leading to 11a–
e. It is noteworthy that the transformation of a nitroalkane to an
c
-nitroacids 10a–e.
non-racemic c-nitroesters and c-nitroacids
c
First, the absolute configuration was determined for (ꢀ)-9d16
and for (+)-9e.17 Although their syntheses had already been

2186
F. Felluga et al. / Tetrahedron: Asymmetry 21 (2010) 2183–2191
Table 1
Enzymatic hydrolysis of the racemic nitroesters 7a–ea
R1
R1
R
R1
enzyme
R
CO2Et
CO2Et
NO2
)-7a-e
R
CO2
H
+
NO2
(+) or (-)-7a-e
NO2
(+) or (-)-10a-e
(
Substrate
E
c
-Nitroacid
Unreacted c-Nitroester
Acid [yield, %]b
Conv.c (%) [time, h]
ee (%)
Ester [yield, %]b
Conv.c (%) [time, h]
ee (%)
7a
7b
7c
7d
7e
8
9
11
10
41
(+)-10a [15]
(+)-10b [18]
(ꢀ)-10c [15]
(+)-10d [20]
(+)-10e [18]
20 [7]
74d,e
75d,e
71g,e
78d,e
94i
(ꢀ)-7a [35]
(ꢀ)-7b [22]
(+)-7c [40]
(ꢀ)-7d [24]
(ꢀ)-7e [30]
39 [24]
75 [72]
42 [72]
75 [72]
60 [26]
39d,f
88d
23 [24]
20 [24]
24 [24]
21 [16]
63g,h
>99d
>99i,j
a
b
c
d
e
f
Reaction conditions: 1.0 g substrate, 0.5 g enzyme, 0.1 phosphate buffer, pH 7.4 (5 mL/mmol), rt.
Yields of isolated products.
Calculated conversion.
Determined by chiral HRGC.
After esterification of the carboxylic group.
62% after three hydrolyses.
g
h
i
Determined by chiral HPLC.
91% after three hydrolyses.
Determined by 1H NMR after coupling the carboxylic function with (S)-(ꢀ)-1-phenylethylamine, followed by integration of the corresponding nitromethylene proton
signals.
j
After hydrolysis of the CO2Et (1 M NaOH, followed by 1 M HCl, rt).
described in the literature, no data on their chiroptical pro-
perties were given and their absolute configurations were
uncertain.
3. Conclusion
In conclusion, an easy and short enantioselective synthesis of a
This assignment was made unambiguously for the precursors of
series of potentially useful b,b-disubstituted GABA analogues has
(ꢀ)-9d, namely the -nitroester (ꢀ)-7d, recovered from the enzy-
c
been developed, starting from the readily available racemic c-nitro
matic resolution. For this purpose, an authentic sample of (ꢀ)-7d
was prepared, starting from the commercially available parent
homochiral ketone (3R)-(+)-5d. The absolute configuration of the
asymmetric quaternary carbon atom, assigned as (S), followed
from the knowledge of its relative configuration, established by
DIFNOE experiments, as seen above.
ester precursors 7, through their enzymatic kinetic resolution.
Their ee’s ranged from 71 to 94 for acids and from 39 to >99 for
esters.
Although enantioselectivities observed may look modest, at
least for 7a–c, the results obtained are of interest. In fact, it is well
known that, because of steric repulsions, the most common hydro-
lases are unable to accept substrates in which the chiral centre
close to the hydrolyzable function is fully substituted, as is the case
By the same procedure the (1S,5S,6R)-absolute configuration
was attributed to (ꢀ)-7e, recovered from the enzymatic hydrolysis,
which was compared with a sample of (ꢀ)-7e prepared from the
commercially available ketone (1R,5S)-(+)-5e.
of esters of tertiary alcohols,22 or esters of
a
,a-disubstituted car-
boxylic acids. In this latter case, for instance, resolution is known
The opposite configuration was consequently assigned to their
to occur only when at least one of the
tron-withdrawing effects.31
This procedure gives also access to unknown optically active
2,2-dialkylsuccinic acids, whose monosubstituted analogues are
extensively studied compounds.
a-substituents exerts elec-
related
hydrolyses.
The GABA analogue b-benzyl-b-methyl-
c-nitroacids (+)-10d and (+)-10e, isolated from enzymatic
c-aminobutyric acid
(+)-9c, derived from (+)-7c, was assigned the (R)-configuration,
by comparison with the specific rotation value reported in the lit-
erature for the same enantiomer.12b
4. Experimental
As for the other two acyclic b,b-dialkyl-GABA analogues 9a and
9b, their absolute configurations were only tentatively assigned as
IR spectra were recorded on a Jasco FT-IR 200 spectrometer. 1
H
NMR and 13C NMR spectra were run on a Jeol EX-400 (400 MHz for
proton, 100.1 MHz for carbon), using deuteriochloroform as the
solvent and tetramethylsilane as the internal standard. Chemical
shifts are expressed in parts per million (d). Coupling constants
are given in hertz. Optical rotations were determined on a Perkin
Elmer Model 241 polarimeter, at 25 °C. CD spectra were recorded
on a Jasco J-710 spectropolarimeter. ESI-MS were run on a Bruker
Esquire 4000 instrument. Enzymatic hydrolyses were performed
using a pH-stat Controller PHM290 Radiometer, Copenhagen. Chi-
ral HRGC analyses were run on a Shimadzu GC-14B instrument, the
(S) by comparison of the CD spectra of their
c-lactam precursors 8a
and 8b with those of similar -lactams bearing no methyl group at
c
C-4. In fact, the
fect associated with the n–
c
-lactams 8a and 8b showed a negative Cotton ef-
*
p
transition of the lactam group at
220 nm, while (R)-(+)-4-butyl-2-pyrrolidinone and (R)-(+)-isobu-
tyl-2-pyrrolidinone showed a positive Cotton effect associated
with the same band.7a Further support of this hypothesis can be
found in the CD spectrum of (ꢀ)-8d, whose absolute configuration
at the quaternary carbon atom is (S), and which exhibited a strong
negative Cotton effect at 219 nm.
capillary columns being Chiraldex™ type G-TA,
c-cyclodextrin
Finally, succinic acids 11a–e were given the same configura-
(40 m ꢁ 0.25 mm) (carrier gas He, 180 kPa, split 1:100), or DiMePe
b-cyclodextrin (25 m ꢁ 0.25 mm) (carrier gas He, 110 kPa, split
1:50); Chiral HPLC analyses were run on a Hewlett Packard series
1100 instrument, the capillary column being Daicel OD20 (250 L.
tions as their
c-nitroacid precursors 10a–e, as epimerization at
the fully substituted chiral carbon atom is not possible. The same
can be said for succinic acids 11a–e derived directly from their
c-nitroester precursors 7a–e.

F. Felluga et al. / Tetrahedron: Asymmetry 21 (2010) 2183–2191
2187
mm ꢁ 4.6 I.D. mm); TLCs were performed on PolygramÒ Sil G/
UV254 silica gel pre-coated plastic sheets (eluent: light petroleum
40–70 °C/ethyl acetate mixtures). Flash chromatography was run
on silica gel, 230–400 mesh ASTM (Kieselgel 60, Merck), using light
petroleum 40–70 °C/ethyl acetate mixtures as the eluent. Elemen-
tal analyses (C, H, N) were carried out with a Carlo Erba 1106 ele-
mental analyzer, at the Department of Chemical Sciences and
Technologies of the University of Udine, Italy. Liver acetone
powder equine (HLAP), Liver acetone powder porcine (PLAP),
(R)-(+)-3-methylcyclohexanone and (+)-(1R,5S)-cis-bicyclo[3.2.0]
hept-2-en-6-one were purchased from Sigma–Aldrich.
4.14 (q, 2H, CH2O), 3.64 (br t, 1H), 2.23 (br t, 1H), 2.0–1.5 (m,
5H), 1.41 (1H), 1.28 (t, 3H, CH3CH2O), 1.14 (tq, 1H), 0.98, 0.94
(2d, J 6.4, 3H, CH3CH); 13C{1H} d 166.8 (2s), 162.8, 162.4 (2s, C@),
113.2 113.1 (d, C-2), 59.40, 59.35 (2q), 46.1 (t), 37.7 (t), 37.4 (t),
34.8 (d), 34.6 (t), 34.5 (t), 34.1 (d), 29.1 (t), 27.3 (t), 26.5 (t), 22.2,
22.1 (2q), 14.2, 14.0 (2q); ESI-MS 183.1 [M+H+], 205.2 [M+Na+].
The enantiomer (3R)-(ꢀ)-6d obtained from (R)-(+)-5d had
½
a 2D5
ꢂ
¼ ꢀ48:3 (c 1, CHCl3).
4.1.5. Ethyl (E,Z)-( )-bicyclo[3.2.0]hept-2-en-6-ylidene
acetate18a,b 6e
E/Z mixture in 2:1 ratio, 78% yield from 5e; IR (neat) 1714
4.1. Synthesis of the
a
,b-unsaturated esters. General procedure
(CO2Et), 1673 (C@C) cmꢀ1 1H NMR d 5.87, 5.86 (m, 3H, CH@CH
;
and CH@CO2Et), 4.11, 4.09 (2q, 2H, CH2O), 3.85 and 3.60 (2 br sig-
nals, 1H, H-5) 3.42 (br signal, 1H, H-1), 3.25 (ddd, J 18.0, 8.0, 2.6,
1H, H-7, E-isomer), 3.03 (ddm, H-7, Z-isomer), 2.85 (dq, J 5.8 and
2.9, 1 H, H-7, E-isomer), 2.74 (dd, J 6.0 and 8.9, 1H, H-4, Z-isomer),
2.62 (2 m, 2H, H-4), 2.45 (dq, J 11.7 and 3.3, H-7, Z-isomer), 2.39 (br
d, J 16.6, H-4, E-isomer), 1.25, 1.24 (2t, 3H, CH3CH2O); 13C{1H} d
172.5, 172.0 (2s, CO), 166.2, 166.0 (2s, C-2, E and Z-isomers),
133.5, 132.7 (2d, C-2, E and Z-isomers), 131.8, 130.0 (2d, C-3, Z
and E-isomers), 115.0, 114.6 (2d, CHCO2Et, Z and E-isomers), 59.5
(t, CH2O), 47.0, 45.9 (2d, C-1, Z and E-isomers), 43.6 and 42.3 (2d,
C-4, E and Z-isomers), 40.3, 39.3 (t, C-5, E and Z-isomers), 39.2
and 39.0 (2t, C-7, Z and E-isomers), 14.2 (q, CH3CH2O). ESI-MS
179.2 (M+H+), 201.0 (M+Na+).
To a solution of the appropriate ketone 5a–e (36 mmol) and tri-
ethyl phosphonoacetate (30 mmol) in anhydrous THF, t-BuOK
(30 mmol) was added portionwise and the mixture was heated at
gentle reflux for 20 min. After cooling to rt, the organic solution
was washed with 5% HCl, then with brine, dried over Na2SO4 and
the solvent was removed in vacuo to give a clear oil. The oily res-
idue was purified by flash chromatography (eluent: petroleum
ether 40–70 °C, ethyl acetate 98:2).
4.1.1. Ethyl (E,Z)-3-methylhept-2-enoate 6a
E/Z mixture in 2:1 ratio, 73% yield from 5a; IR (neat) 1717
(CO2Et), 1649 (C@C) cmꢀ1 1H NMR d 5.64 (m, H-2, Z-isomer),
;
5.62 (m, H-2, E-isomer), 4.14 (2q, 2H, CH2O), 2.13 (d, J 1.1, CH3C,
E-isomer), 2.11 (m, H-4, E-isomer), 2.00 (m, H-4, Z-isomer), 1.85
(d, J 1.1, CH3C, Z-isomer), 1.42 (m, 2H, H-5), 1.34–1.27 (t and m,
5H, CH3CH2O and H-6), 0.93–0.85 (2t, 3H, H-7); 13C{1H} NMR d
166.9 (s, C-1, E isomer), 166.3 (s, C-1, Z isomer), 160.7 (s, C-3, Z-iso-
mer), 160.3 (s, C-3, E-isomer), 115.9 (d, C-2, Z-isomer), 115.4 (d,
C-2, E-isomer), 60.4 (t, CH3CH2O, Z-isomer), 59.5 (t, CH3CH2O, E-iso-
mer), 40.7 (2t, C-4), 29.7 (2t), 25.2 (q, CH3C@), 22.2 (2t), 14.4 (2q,
CH3CH2O), 13.9 (2q, C-7); ESI-MS 171.2 (M+H+), 193.1 (M+Na).
The enantiomer (1R,5S)-(+)-6e obtained from commercial
(1R,5S)-(+)-5e, had ½a D25
¼ þ58:2 (c 1.1, CHCl3).
ꢂ
4.2. General procedure for the synthesis of racemic
nitroesters 7a–e
c-
To a solution of the a,b-unsaturated esters 6a–c (100 mmol) in
nitromethane (25 mL), DBU (100 mmol) was added dropwise and
the solution was stirred overnight at room temperature. In the syn-
thesis of 7d,e, nitromethane was used in an equimolar amount and
TBAF (1 M solution in THF, 1 mmol) was used as a base, and the
solution refluxed overnight. After evaporation of the solvent in va-
cuo, the residue was dissolved in diethyl ether and washed with 5%
HCl followed by brine; then the organic phase was dried over
anhydrous Na2SO4 and concentrated to give a dark brown oil,
which was purified by flash chromatography (eluent petroleum
ether/ethyl acetate 98:2).
4.1.2. Ethyl (E,Z)-3,5-dimethylhex-2-enoate 6b
E/Z mixture in 6:1 ratio, 80% yield from 5b; IR (neat) 1717
(CO2Et), 1648 (C@C) cmꢀ1 1H NMR d 5.65 (br s, H-2, Z-isomer),
;
5.58 (br s, H-2, E-isomer), 4.10 (q, 2H, CH2O), 2.54 (d, J 7.7, H-4, Z-iso-
mer), 2.09 (d, J 7.3, H-4, E-isomer), 2.11 (br s, CH3C, E-isomer), 1.85
(br s, CH3C, Z-isomer), 1.85 (m, 1H, H-5), 1.25 (t, CH3CH2O, E-isomer),
1.24 (t, CH3CH2O, Z-isomer), 0.89 (d, J 6.6, (CH3)2CH, Z-isomer), 0.85
(d, J 6.6, (CH3)2CH, E-isomer); 13C{1H} d 166.8 (s, C-1, E-isomer),
166.5 (s, C-1, Z-isomer), 159.5 (s, C-3, Z-isomer), 159.3 (s, C-3, E-iso-
mer), 117.1 (d, C-2, Z-isomer), 116.7 (d, C-2 E-isomer), 59.4 (2t,
CH2O), 50.6 (t, C-4, E-isomer), 41.7 (t, C-4, Z-isomer), 27.4 (d, C-5,
Z-isomer), 26.2 (d, C-5, E-isomer), 22.4 (4q, (CH3)2CH), 18.6 (2q,
CH3C@), 14.3 (2q, CH3CH2O); ESI-MS 171.0 [M+H+], 193.0 [M+Na+].
4.2.1. Ethyl ( )-3-methyl-3-(nitromethyl)heptanoate 7a
Oil, 69% yield, after purification; IR (neat) 1732 (CO2Et), 1551,
1376 (NO2) cmꢀ1 1H NMR d 4.58, 4.50 (AB system, JAB 11.0, 2H,
;
CH2NO2), 4.10 (q, 2H, CH2O), 2.42, 2.37 (AB system, JAB 15.9, 2H,
H-2), 1.38 (m, 2H, H-4), 1.25, 1.24 (m and t, 7H, H-5, H-6,
CH3CH2O), 1.08 (s, 3H, CH3C), 0.86 (t, 3H, CH3CH2). 13C{1H} d
171.1 (s, C-1), 82.4 (t, CH2NO2), 60.4 (t, CH2O), 40.9 (t, C-2), 37.6
(t, C-4), 36.9 (s, C-3), 25.4 (t, C-5), 23.1 (t, C-6), 22.9 (q, CH3C),
14.2 (q, CH3CH2O), 13.9 (q, C-7). ESI-MS 254.0 [M+Na+]. Anal. Calcd
for C11H21NO4: C, 57.12; H, 9.15; N, 6.06. Found: C, 57.05; H, 9.18;
N, 6.06.
4.1.3. Ethyl (E,Z)-3-methyl-4-phenylbut-2-enoate 6c
E/Z mixture in 4:1 ratio, 77% yield from 5c; IR (neat) 3063, 3028,
1602, 1495, 1453, 740, 700 (Ph), 1716 (CO2Et), 1650 (C@C) cmꢀ1; 1H
NMR d 7.28 (m, 3H, ArH), 7.15 (d, 2H, ArH), 5.78 (s, H-2, Z-isomer),
5.68 (s, H-2, E-isomer), 4.14 (q, 2H, CH2O), 4.02 (s, H-4, Z-isomer),
3.42 (s, H-4, E-isomer), 2.12 (s, CH3C, E-isomer), 1.78 (s, CH3C, E-iso-
mer), 1.26 (t, 3H, CH3CH2O); 13C{1H} d 166.8 (s, C-1, E-isomer), 166.7
(s, C-1, Z-isomer), 158.4 (s, C-3, Z-isomer), 157.6 (s, C-3, E-isomer),
137.8 (s, Ph), 129.2 (d, Ph), 128.6 (d, Ph), 126.7 (d, Ph) 117.3 (d, C-
2, E-isomer), 117.2 (d, C-2, Z-isomer), 59.7 (t, CH2O), 47.1 (t, C-4, E-
isomer), 38.9 (t, C-4, Z-isomer), 24.5 (q, CH3C@, Z-isomer), 18.7 (q,
CH3C@, E-isomer), 14.4 (q, CH3CH2O); ESI-MS 205.1 [M+H+].
4.2.2. Ethyl ( )-3,5-dimethyl-3-(nitromethyl)hexanoate 7b
Oil, 74% yield, after purification, IR (neat) 1732 (CO2Et), 1550,
1375 (NO2) cmꢀ1 1H NMR d 4.66 (part A of an AB system, JAB
;
11.0, 1H, CH2NO2), 4.55 (part B of an AB system, JAB 11.0, 1H,
CH2NO2), 4.15 (q, 2H, CH2O), 2.50, 2.46 (AB system, JAB 16.3, 2H,
H-2), 1.70 (sept, J 6.6, 1H, CH(CH3)2), 1.41 (dq, J1 14.7, J2 5.5, 2H,
H-4), 1.27 (t, 3H, CH3CH2O), 1.16 (s, 3H, CH3C), 0.96, 0.95 (2d, J
6.6, 6H, (CH3)2CH); 13C{1H} d 171.0 (s, CO), 82.7 (t, CH2NO2), 60.5
(t, CH2O), 46.3 (t, C-2), 41.0 (t, C-4), 37.6 (s, C-3), 25.2 (q, (CH3)2CH),
23.8 (q, CH3C), 23.2 (d, C-5), 14.2 (q, CH3CH2O); ESI-MS 186.0
4.1.4. Ethyl (E,Z)-( )-2-(3-methylcyclohexylidene)acetate 6d28b
E/Z mixture in 1:1 ratio, 82% yield from ( )-5d, IR (neat) 1716
(CO2Et), 1650 (C@C) cmꢀ1 1H NMR d 5.61, 5.59 (2s, 1H, H-2),
;

2188
F. Felluga et al. / Tetrahedron: Asymmetry 21 (2010) 2183–2191
[MꢀNO2], 232 [MH+], 254.0 [M+Na+]. Anal. Calcd for C11H21NO4: C,
(3 ꢁ 10 ml) using a centrifuge for the separation of the layers. For
the isolation of the -nitroacids 10a–e, the aqueous layer was acid-
57.12; H, 9.15; N, 6.06. Found: C, 57.15; H, 9.10; N, 6.17.
c
ified to pH 2 with 2 M HCl and extracted with CHCl3 (3 ꢁ 10 ml).
4.2.3. Ethyl ( )-3-benzyl-3-methyl-4-nitrobutanoate 7c
Oil, 72% yield, after purification; IR (neat) 3030, 1649, 1495,
4.3.1. Ethyl (S)-(ꢀ)-3-methyl-3-(nitromethyl)heptanoate 7a
The title compound was obtained with 39% ee at 39% conver-
sion (35% yield). Under the conditions used, hydrolysis did not pro-
ceed any further. After two consecutive hydrolyses, the product
1455, 764, 703 (Ph), 1731 (CO2Et), 1549, 1376 (NO2) cmꢀ1 1H
.
NMR d 7.29 (m, 3H, Ph), 7.17 (d, 2H, Ph), 4.68 (part A of an AB sys-
tem, JAB 11.3, 1H, CH2NO2), 4.64 (part B of an AB system, JAB 11.3,
1H, CH2NO2), 4.16 (q, 2H, CH2O), 2.87 (part A of an AB system,
JAB 13.4, 1H, CH2Ph), 2.82 (part B of an AB system, JAB 13.4, 1H,
CH2Ph), 2.43 (part A of an AB system, JAB 16.3, 1H, H-2), 2.38 (part
B of an AB system, JAB 16.3, 1H, H-2), 1.29 (t, 3H, CH3CH2O), 1.11 (s,
3H, CH3C); 13C{1H} d 171.0 (s, CO), 135.7 (s, Ph), 130.7, 128.3, 127.0
(d, Ph), 81.7 (t, CH2NO2), 60.5 (t, CH2O), 43.4 (t, CH2Ph), 40.3 (t, C-
2), 37.7 (s, C-3), 22.8 (q, CH3C), 14.3 (q, CH3CH2O); ESI-MS 266.1
[M+H+], 288.1 [M+Na+]. Anal. Calcd for C14H19NO4: C, 63.38; H,
7.22; N, 5.28. Found: C, 63.42; H, 7.30; N, 5.19.
was isolated with 62% ee (12% isolated yield); ½a D25
¼ ꢀ0:8 (c
ꢂ
0.65, CHCl3).
4.3.2. (R)-(+)-3-Methyl-3-(nitromethyl)heptanoic acid 10a
The title compound was obtained with 74% ee by stopping the
enzymatic hydrolysis with HLAP at 20% conversion (15% isolated
yield); ½a 2D5
ꢂ
¼ þ2:1 (c 0.5, CHCl3); IR (neat) 3400–2400 (br, OH),
1711 (CO), 1551, 1379 (NO2) cmꢀ1
;
1H NMR d 8.95 (broad, 1H,
CO2H), 4.52 (AB system, J 11.0, CH2NO2), 2.51 (AB system, JAB
16.0, CH2CO2H), 1.35 (m, 2H), 1.29 (m, 6H, H-4), 1.13 (s, 3H,
CH3–C), 0.89 (t, 3H, CH3CH2); 13C NMR d 177.0 (s, CO), 82.0 (t,
CH2NO2), 40.5 (t, CH2CO2H), 37.5 (t, C-4), 36.7 (s, C-3), 25.3 (t, C-
5), 23.0 (t, C-6), 22.7 (q, CH3–C), 13.8 (q, C-7). ESI-MS (negative
ion polarity) 202.0 [MꢀH]ꢀ. Anal. Calcd for C9H17NO4: C, 53.19;
H, 8.43; N, 6.89. Found: C, 53.24; H, 8.27; N, 6.80.
4.2.4. Ethyl ( )-3-methyl-1-(nitromethyl)cyclohexaneacetate 7d
Oil, 75% yield, after purification IR (neat) 1732 (CO2Et), 1548,
1377 (NO2) cmꢀ1 1H NMR d 4.53 (s, 2H, CH2NO2), 4.16 (q, 2H,
;
CH2O), 2.53 (AB system, JAB 17.5, 2H, CH2CO2Et), 1.64 (m, 4H),
1.59 (m, 2H), 1.42 (qt, 1H, H-5ax), 1.24 (t, 3H, CH3CH2O), 1.17 (qt,
1H, H-6ax), 0.89 (m, 1H), 0.88 (d, J 4.8, CH3CH), 0.78 (qd, 1H, H-
4
ax); 13C{1H} d 171.3 (s, CO), 84.6 (t, CH2NO2), 60.4 (t, CH3CH2O),
4.3.3. Ethyl (S)-(ꢀ)-3,5-dimethyl-3-(nitromethyl)hexanoate 7b
The title compound was obtained with 88% ee stopping the
enzymatic hydrolysis at 75% conversion (22% isolated yield),
41.7 (t, CH2CO2Et), 37.7 (s, C-1 of the ring), 35.7 (t), 34.2 (t), 32.7
(t), 27.1 (d, CHCH3), 22.4 (q, CH3CH), 21.0 (t), 14.1 (q, CH3CH2O). Irra-
diation of the signal at 0.88 (CH3CH) enhanced the signal at 4.53
(CH2NO2, 3%); irradiation of the signal at 2.53 (CH2CO2Et) enhanced
the signals at 1.42 (H-5ax, 4%) and at 1.64 (H-6eq, 5%); irradiation of
the signal at 1.17 (H-6ax) enhanced the signal at 4.53 (CH2NO2, 4%);
irradiation of the signal at 4.53 (CH2NO2) enhanced the signals at
0.78 (H-4ax, 1%), at 0.84 (CH3CH, 3%), and at 1.59 (H-5eq, 2%). ESI-
MS 244.2 [M+H+], 266.0 [M+Na+]; Anal. Calcd for C12H21NO4: C,
59.24; H, 8.70; N, 5.76. Found: C, 59.20; H, 8.63; N, 5.90.
½
a 2D5
ꢂ
¼ ꢀ1:3 (c 1.9, CHCl3).
4.3.4. (R)-(+)-3,5-Dimethyl-3-(nitromethyl)hexanoic acid 10b
The title compound was obtained with 75% ee by stopping the
enzymatic hydrolysis at 23% conversion (18% isolated yield),
½
a 2D5
ꢂ
¼ þ3:7 (c 0.35, CHCl3); IR (neat) 3500–2500 (br, OH), 1710
(CO), 1550, 1375 (NO2) cmꢀ1 1H NMR d 8.70 (broad, CO2H), 4.65
;
(d, part A of an AB system, JAB 11.2, 1H, CH2NO2), 4.55 (d, part B of
an AB system, JAB 11.2, 1H, CH2NO2), 2.56 (AB system, JAB 17.1, 2H,
H-2), 1.72 (m, 1H, CH(CH3)2), 1.41 (dd, J1 5.9, J2 11.5, 2H, H-4), 1.17
(s, 3H, CH3C), 0.96, 0.87 (2d, J 6.8, 6H, (CH3)2CH); d 175.9 (s, CO),
82.5 (t, CH2NO2), 46.4 (t, C-2), 40.7 (t, C-4), 37.4 (s, C-3), 25.2 (2q,
(CH3)2CH), 23.8 (s, CH3C), 23.2 (d, C-5); ESI-MS 226.1 (M+Na+);
ESI-MS (negative ion polarity) 202.0 [MꢀH]ꢀ. Anal. Calcd for
C9H17NO4: C, 53.19; H, 8.43; N, 6.89. Found: C, 53.31; H, 8.38; N, 6.75.
4.2.5. Ethyl ( )-6-(nitromethyl)bicyclo[3.2.0]hept-2-ene-6-
acetate 7e
Oil, 68% yield, after purification, IR (neat) 1731 (CO2Et), 1548,
1376 (NO2) cmꢀ1 1H NMR d 5.82 (m, 1H, H-2), 5.79 (m, 1H, H-3),
;
4.81, 4.75 (AB system, JAB 12.1, 2H, CH2NO2), 4.11 (q, 2H, CH2O),
3.26 (br s, 1H, H-1), 2.99 (br dd, J1 8.8, J2 8.0, 1H, H-5), 2.72, 2.67
(AB system, JAB 17.5, 2H, CH2CO2Et), 2.54 (ddd, 3J 7.3, 3J 8.8, 2J
16.1, 1H, H-4 trans to CH2COOEt), 2.36 (br d, 2J 16.1, 1H, H-4 cis
to CH2COOEt), 2.30 (dd, 3J 8.8, 2J 12.9, 1H, H-7 cis to H-1), 1.73
(dd, 3J 4.4, 2J 12.9, 1H, H-7 trans to H-1), 1.24 (t, 3H, CH3CH2O);
13C {1H} NMR d 171.4 (s, CO), 135.0 (d, C-2), 131.7 (d, C-3), 82.5
(t, CH2NO2), 60.6 (t, CH3CH2O), 42.4 (d, C-1), 40.4 (d, C-5), 39.4 (s,
C-6), 36.8 (t, CH2CO2Et), 36.5 (t, C-4), 34.5 (t, C-7), 14.2 (q,
CH3CH2O). DIFNOE measurements: irradiation of the signal at
2.70 (CH2COOEt) enhanced the signals at 1.73 (H-7 trans to H-1,
3%) and at 2.36 (H-4 cis to CH2COOEt, 5%); irradiation of the signal
at 3.29 (H-1) enhanced the signals at 2.30 (H-7 cis to H-1, 3%), at
2.99 (H-5, 2%), at 4.78 (CH2NO2, 2%); irradiation of the signal at
2.99 (H-5) enhanced the signal at 4.78 (CH2NO2, 5%); ESI-MS
240.2 [M+H+], 262.0 [M+Na+]. Anal. Calcd for C12H17NO4: C,
60.24; H, 7.16; N, 5.85. Found: C, 60.30; H, 7.22; N, 5.73.
4.3.5. Ethyl (R)-(+)-3-benzyl-3-methyl-4-nitrobutanoate 7c
The title compound was obtained with 63% ee at 42% conver-
sion (40% isolated yield). Under these conditions the hydrolysis
did not proceed any further. After two more hydrolyses a 91% ee
was reached ½a 2D5
¼ þ36:0 (c 1.8, CH3OH). Enantiomeric excess
ꢂ
was determined by HPLC using a chiral column Daicel OD20,
tR = 7.95 and 9.97 min for (+)- and (ꢀ)-7c, respectively (10:1 hex-
ane: i-PrOH; flow rate 0.5 ml/min).
4.3.6. (S)-(ꢀ)-3-Benzyl-3-methyl-4-nitrobutanoic acid 10c
The title compound was obtained with 71% ee by stopping the
enzymatic hydrolysis at 20% conversion (15% isolated yield),
½
a 2D5
ꢂ
¼ ꢀ4:4 (c 0.5, CHCl3); IR (neat) 3700–2500 (br, OH), 3030,
1642, 1495, 1454, 754, 703 (Ph), 1705 (CO), 1549, 1378 (NO2)
cmꢀ1 1H NMR d 8.42 (broad, CO2H), 7.32 (m, 3H, Ph), 7.18 (d, 2H,
;
4.3. General procedure for enzymatic hydrolyses
Ph), 4.67 (d, part A of an AB system, JAB 11.3, 1H, CHNO2), 4.48 (d, part
B of an AB system, JAB 11.3, 1H, CHNO2), 2.86 (AB system, J 13.2, 2H,
A suspension of the appropriate
c-nitroester 7a–e (1.0 g), in
CH2Ph), 2.51 (AB system, JAB 16.8, 2H, H-2), 1.13 (s, 3H, CH3C); 13
C
0.1 M KH2PO4/Na3PO4 buffer (pH 7.4), was hydrolyzed with HLAP
(0.5 g), or with PLAP (0.5 g), at room temperature under vigorous
stirring. The pH was kept at the initial value by continuous addi-
tion of 1 M NaOH. At the desired conversion value, the unreacted
NMR d 177.2 (s, CO), 135.5 (s, Ph), 130.8 (d, Ph), 128.7 (d, Ph),
127.2 (d, Ph), 81.6 (t, CH2NO2), 43.4 (t, CH2Ph), 40.2 (t, C-2), 37.6
(s, C-3), 22.9 (s, CH3C); ESI-MS: 260.1 [M+Na+]; ESI-MS (negative
ion polarity) 236.0 [MꢀH]ꢀ; Anal. Calcd for C12H15NO4: C, 60.75;
H, 6.37; N, 5.90. Found: C, 60.80; H, 6.24; N, 6.03.
c-nitroester was extracted from the suspension with ethyl acetate

F. Felluga et al. / Tetrahedron: Asymmetry 21 (2010) 2183–2191
2189
4.3.7. Ethyl (1S,3R)-(ꢀ)-3-methyl-1-
178.5 (s, CO), 54.4 (t, C-5), 44.1 (t, C-3), 40.7 (t), 38.8 (s, C-4),
26.9 (t), 25.6 (q, CH3C), 23.3 (t), 14.1 (q, CH3CH2); ESI-MS 156.0
[M+H+], 178.0 [M+Na+]; Anal. Calcd for C9H17NO: C, 69.63; H,
11.04; N, 9.02. Found: C, 69.75; H, 11.00; N, 9.12.
(nitromethyl)cyclohexaneacetate 7d
The title compound was obtained with >99% ee by stopping the
enzymatic hydrolysis at 75% conversion (24% isolated yield),
½
a 2D5
ꢂ
¼ ꢀ2:5 (c 1, CHCl3). The same compound (ꢀ)-7d, prepared
from (R)-(+)-5e, had [
a]
25 = ꢀ2.5 (c 1.8, CHCl3).
4.4.2. (S)-(+)-4-Isobutyl-4-methylpyrrolidin-2-one 8b
White solid, mp 54–56 °C, 90% yield from 7b; 88% ee,
4.3.8. Ethyl (1R,3S)-(+)-3-methyl-1-
(nitromethyl)cyclohexaneacetic acid 10d
½
a 2D5
ꢂ
¼ þ11:4 (c 1, CHCl3);
D
e219 ꢀ2.0 (MeOH); IR (Nujol) 3175
(NH), 1693 (CO) cmꢀ1 1H NMR d 6.68 (br s, 1H, NH), 3.15, 3.01
;
The title compound was obtained with 78% ee by stopping the
enzymatic hydrolysis at 24% conversion (20% isolated yield),
(AB system, JAB 9.9, 2H, 2 H-5), 2.22, 2.03 (AB system, JAB 16.5,
2H, 2 H-3), 1.70 (m, 1H, CH(CH3)2), 1.35 (d, J 6.2, CH2CH), 1.13 (s,
3H, CH3C), 0.90, 0.89 (2d, J 6.6, 6H, (CH3)2CH); 13C NMR d 178.2
(s, CO), 55.3 (t, C-5), 49.6 (t, C-3), 45.1 (t, CH2CH), 39.1 (s, C-4),
25.3 (q, CH3C), 25.0 (d, CH(CH3)2), 24.4, 24.2 (2q, CH(CH3)2); ESI-
MS 156.1 [M+H+], 178.1 [M+Na+]; Anal. Calcd for C9H17NO: C,
69.63; H, 11.04; N, 9.02. Found: C, 69.80; H, 10.96; N, 9.08.
½
a 2D5
ꢂ
¼ þ3:2 (c 0.35, CHCl3); IR (neat) 3500–3246 (br, OH), 1732
(CO), 1548, 1378 (NO2) cmꢀ1 1H NMR d 9.90 (broad, 1H, CO2H),
;
4.58 (AB system, JAB 11.0, 2H, CH2NO2), 2.69 (s, 2H, CH2CO2H),
1.78–1.40 (m, 7H), 0.97–0.84 (m, 5H); 13C NMR d 177.6 (s, CO),
84.3 (t, CH2NO2), 41.7 (t, CH2CO2H), 37.4 (s, C-1 of the ring), 35.3
(t), 34.2 (t), 32.7 (t), 27.1 (d, C-3 of the ring), 22.5 (q, CH3CH),
21.0 (t); ESI-MS 238.2 (M+Na+); ESI-MS (negative ion polarity)
214.0 [MꢀH]ꢀ; Anal. Calcd for C10H17NO4: C, 55.80; H, 7.96; N,
6.51. Found: C, 55.80; H, 7.85; N, 6.60.
4.4.3. (R)-(ꢀ)-4-Benzyl-4-methylpyrrolidin-2-one 8c
White solid, mp 110 °C, 82% yield from (+)-7c; (91% ee),
½
a 2D5
ꢂ
¼ ꢀ10:0 (c 0.8, CHCl3) [lit.12b ꢀ12.7 (c 2, CHCl3), 82% ee]. Spec-
troscopic and analytical data were in accordance with those
4.3.9. Ethyl (1R,5S,6R)-(ꢀ)-6-(nitromethyl)bicyclo[3.2.0]hept-2-
ene-6-acetate 7e
reported in the literature.
The title compound was obtained with >99% ee by stopping the
enzymatic hydrolysis at 60% conversion (30% isolated yield),
4.4.4. (5S,7R)-(ꢀ)-7-Methyl-2-azaspiro[4.5]decan-3-one 8d
White solid, mp 70–75 °C, 88% yield from 7d, >99% ee,
½
a 2D5
ꢂ
¼ ꢀ18:8 (c 1.0, CHCl3). The same compound (–)-7e, synthe-
½
a 2D5
ꢂ
¼ ꢀ11:8 (c 1.15, CHCl3);
D
e220 ꢀ2.0 (MeOH). The same com-
sized from (+)-(1R,5S)-5d, had ½a D25
ꢂ
¼ ꢀ18:8 (c 1.0, CHCl3).
pound, obtained from (R)-(ꢀ)-5d, had ½a D25
ꢂ
¼ ꢀ11:8 (c 0.85, CHCl3);
IR (Nujol) 3177 (NH), 1702 (CO) cmꢀ1
;
1H NMR d 6.87 (br s, 1H,
4.3.10. (1S,5R,6S)-(+)-[6-(Nitromethyl)bicyclo[3.2.0]hept-2-ene-
6-acetic acid 10e
NH), 3.03 (s, 2H, 2 H-5), 2.16 (s, 2H, 2 H-3), 1.62 (m, 4H), 1.40
(m, 1H, CHCH3), 1.32 (m, 1H), 1.12 (m, 1H), 0.90 (m, 1H), 0.83 (d,
J 6.4, CH3CH), 0.78 (m, 1H). 13C{1H} d 178.0 (s, CO), 56.0 (t,
CH2N), 45.2 (t), 40.9 (t, CH2CO), 39.5 (s), 36.0 (t), 34.2 (t), 28.7 (d,
CH), 22.4 (t), 22.2 (q, CH3CH). Anal. Calcd for C10H17NO: C, 71.81;
H, 10.25; N, 8.37. Found: C, 72.0; H, 10.3; N, 8.4. ESI-MS 168.0
(M+H+), 190.0 (M+Na+), 205.9 [M+K+]; Anal. Calcd. for C10H17NO:
C, 71.81; H, 10.25; N, 8.37. Found: C, 71.72; H, 10.32; N, 8.40.
The title compound was obtained with 94% ee by stopping the
enzymatic hydrolysis at 21% conversion (18% yield), ½a D25
¼ þ25:1
ꢂ
(c 1, CHCl3); IR (neat) 3500–2700 (broad, CO2H), 1709 (C@O),
1547, 1379 (NO2) cmꢀ1 1H NMR d 9.80 (broad, CO2H), 5.84 (br
;
m, 1H, H-2), 5.80 (br m, 1H, H-3), 4.75 (AB system, JAB 12.2, 2H,
CH2NO2), 3.26 (br m, 1H, H-1), 2.99 (dd, J1 8.3, J2 8.0, 1H, H-5),
2.76 (AB system, JAB 19.4, 2H, CH2CO2H), 2.54 (m, 1H, H-4), 2.36
(br d, 2J1 18.3, 1H, H-4) 2.30 (dd, 3J 9.3, 2J 11.2, 1H, H-7 cis to H-
1), 1.73 (dd, 3J 3.5, 2J 12.9, 1H, H-7 trans to H-1); 13C{1H} d 177.5
(s, CO), 135.0 (d, C-2), 131.8 (d, C-3), 82.4 (t, CH2NO2), 42.3 (d, C-
1), 40.4 (d, C-5), 39.1 (s, C-6), 36.45 (t, CH2CO2H), 36.4 (t, C-4),
34.5 (t, C-7); ESI-MS 234.1 (M+Na+); ESI-MS (negative ion polarity)
210.0 [MꢀH]ꢀ. Anal. Calcd for C10H13NO4: C, 56.86; H, 6.20; N, 6.63.
Found: C, 56.87; H, 6.32; N, 6.51.
4.4.5. (1S,30R,5S)-(+)-Spiro[bicyclo[3.2.0]heptane-6-pyrrolidin]-
50-one 8e
White solid, mp 85–86 °C, 84% yield from 7e; >99% ee,
½
a 2D5
ꢂ
¼ þ28:5 (c 1, CHCl3);
D
e215 ꢀ0.8 (MeOH). An enantiomerically
pure sample obtained from (+)-(1R,5S)-5d had mp 85–86 °C,
½
a 2D5
ꢂ
¼ þ28:6 (c 2, CHCl3). IR (neat) 3235 (NH), 1695 (CO) cmꢀ1
;
1H NMR d 6.59 (br s, 1H, NH), 3.36 (AB system, JAB 9.7, 2H, CH2NH),
2.74 (quint, 1H, H-1), 2.50 (dd, J 6.7 and 6.2, 1H, H-5), 2.32 (d, part
A of an AB system, J 15.6, 1H, CH2CO), 2.13 (ddd, J 12.5, 9.4, 2.3, 1H),
1.99 (d, part B of an AB system, J 15.6, 1H, CH2CO), 1.79 (m, 1H),
1.74–1.59 (m, 2H), 1.52–1.36 (m, 4H); 13C NMR d 178.0 (s, CO),
57.6 (t, CH2N), 45.7 (d, C-1), 40.7 (s, C-30), 39.1 (t, CH2CO), 37.8
(t), 33.2 (d, C-5), 32.4 (t), 28.5 (t), 25.3 (t). ESI-MS 166.1 [M+H+],
198.1 [M+Na+]. Anal. Calcd for C10H15NO: C, 72.69; H, 9.15; N,
8.48. Found: C, 72.78; H, 9.05; N, 8.57.
4.4. General procedure for the transformation of the nitroesters
7a–e into the corresponding c-lactams 8a–e
The nitroesters 7a–e (2.0 mmol) were dissolved in a solution of
ethyl acetate/ethanol in 1:1 ratio (10 mL), and Ra–Ni (Aldrich) was
added. The mixture was hydrogenated at room temperature and
atmospheric pressure until the disappearance of the starting mate-
rial (TLC, eluent: methanol). The catalyst was filtered off on a pad
of Celite and washed with ethanol and dichloromethane. The fil-
trate was evaporated to dryness in vacuo, then the residue was dis-
solved in toluene and the solution was heated at reflux to assure
complete cyclization. After removal of the solvent, the residue
was chromatographed on column (eluent: ethyl acetate), to give
4.5. Transformation of the chiral non-racemic
c-lactams 8a–e
into the corresponding -amino acid hydrochlorides 9a–e
c
The c-amino acids 9a–e were obtained by hydrolysis of the cor-
responding enantiomerically active
c-lactams 8a–e carried out in
the pure c-lactams 8a–e.
6 M HCl at reflux for 4 h.
4.4.1. (S)-(+)-4-Butyl-4-methylpyrrolidin-2-one 8a
4.5.1. (S)-(ꢀ)-3-(Aminomethyl)-3-methylheptanoic acid
hydrochloride 9a
White solid, mp 67–8 °C, 74% yield from 7a; 63% ee, ½a D25
¼ þ8:0
ꢂ
(c 1, CHCl3);
cmꢀ1
D
e219 ꢀ2.0 (MeOH); IR (Nujol) 3237 (NH), 1699 (CO)
The title compound was isolated with 63% ee from (+)-8a,
;
1H NMR d 6.43 (br s, 1H, NH), 3.08 (AB system, JAB 9.5, 2H,
½
a 2D5
ꢂ
¼ ꢀ2:0 (c 1, H2O), IR (neat) 3650–2380 (broad), 1710, 1465;
2 H-5), 2.11 (AB system, JAB 16.8, 2H, 2 H-3), 1.43 (m, 2H), 1.25
1H NMR (D2O) d 3.06, 3.02 (AB system, J 13.5, 2H, CH2NH3+),
2.46, 2.41 (AB system, J 16.0, 2H, 2 H-2), 1.35 (m, 2H), 1.22 (m,
(m, 4H), 1.12–1.10 (s, 3H, CH3C), 0.89 (t, 3H, CH3CH2); 13C NMR d

2190
F. Felluga et al. / Tetrahedron: Asymmetry 21 (2010) 2183–2191
4H), 1.02 (s, 3H, CH3C), 0.82 (t, 3H, CH3CH2); 13C NMR (D2O) d 176.9
(s), 47.9 (t, CH2NH3þ), 42.3 (t, CH2CO2H), 37.5 (t, C-4), 35.3 (s, C-3),
25.4 (t), 23.2 (t), 22.6 (q, CH3C), 13.9 (q, CH3CH2); ESI-MS 174.1 [M+].
4.6.1. (R)-(+)-2-Butyl-2-methylsuccinic acid 11a
The title compound was obtained with 74% ee from (R)-(+)-10a,
½
a 2D5
ꢂ
¼ þ2:2 (c 0.5, CHCl3); IR (nujol) 3500–2500 (broad, CO2H),
1730, 1711 (C@O); 1H NMR d 8.00 (broad, CO2H), 2.59 (d, part A
of an AB system, JAB 18.1, 1H, CHCO2H), 2.40 (d, part B of an AB sys-
tem, JAB 18.1, 1H, CHCO2H), 1.53 (m, 2H), 1.16 (s, 3H, CH3), 1.14 (m,
4H), 0.83 (t, J 6.8, 3H, CH3CH2); 13C NMR d 178.6 (s, CO2H), 171.8 (s,
CO2H), 41.1 (s, C-3), 38.2 (t, CH2CO2H), 37.7 (t, C-4), 26.0 (t), 23.9
(q, CH3C), 22.6 (t), 13.6 (q, CH3CH2); ESI-MS (negative ion polarity)
186.9 [MꢀH]ꢀ. Anal. Calcd for C9H16O4: C, 57.43; H, 8.57. Found: C,
57.50; H, 8.40.
4.5.2. (S)-(ꢀ)-3-(Aminomethyl)-3,5-dimethylhexanoic acid
hydrochloride 9b
The title compound was isolated with 88% ee from (+)-8b;
½
a 2D5
ꢂ
¼ ꢀ2:4 (c 1.25, CH3OH); IR (neat) 3500–2958 (br, OH), 1710
(CO) 1467 (NH), cmꢀ1 1H NMR (CD3OD) d 2.92 (AB system, JAB
;
13.1, 2H, CH2NH3þ), 2.35 (AB system, JAB 16.1, 2H, 2 H-2), 1.64
(m, 1H, H-5), 1.34–1.16 (ddd, part AB of an ABX system, 3J 4.9, 3J
5.5, 2J 13.7, 2H, 2 H-4), 1.01 (s, 3H, CH3C), 0.89 (2d, 6H, (CH3)2CH);
13C NMR (CD3OD) d 175.4 (s, CO2H), 49.1 (t, CH2NH3þ), 47.5 (t, C-4),
42.5 (t, C-2), 36.5 (s, C-3), 26.6, 26.5 (2q), 25.6 (d, C-5), 24.2 (q,
CH3C); ESI-MS 174.2 [M+], 197.1 [M+Na+].
4.6.2. (S)-(ꢀ)-2-Isobutyl-2-methylsuccinic acid 11b
The title compound was isolated with 88% ee from (S)-(ꢀ)-7b,
½
a 2D5
ꢂ
¼ ꢀ6:1 (c 0.25, CHCl3); IR (neat) 3400–2500 (broad, CO2H),
1720, 1715 (CO) cmꢀ1 1H NMR d 5.13 (broad, CO2H), 2.73 (d, part
;
4.5.3. (R)-(+)-4-Amino-3-benzyl-3-methylbutanoic acid
hydrochloride 9c
A of an AB system, JAB 18.1, 1H, H-3), 2.44 (d, part B of an AB sys-
tem, JAB 18.1, 1H, H-3), 1.65–1.58 (2 m, 3H, CHCH2), 1.24 (s, 3H,
CH3C), 0.85, 0.78 (2d, J 6.0, 6H, (CH3)2CH); 13C NMR d 178.7 (s,
CO2H), 171.7 (s, CO2H), 45.9 (t, CH2CO2H), 41.1 (t, CH2 isobutyl),
38.6 (s, C-3), 25.1, 24.9 (2q, (CH3)2CH), 24.7 (q, CH3C), 23.0 (d,
(CH3)2CH); ESI-MS (negative ion polarity) 188.1 [MꢀH]ꢀ; Anal.
Calcd for C9H16O4: C, 57.43; H, 8.57. Found: C, 57.50; H, 8.50.
The title compound was isolated with 91% ee from (ꢀ)-8c;
½
a 2D5
ꢂ
¼ þ13:0 (c 0.5, H2O) [lit12b = +13.6 (c 1, H2O, 82% ee)]. Other
spectroscopic and analytical data were in accordance with the
literature.15
4.5.4. (1S,3R)-(ꢀ)-1-(Aminomethyl)-3-methylcyclohexaneacetic
acid hydrochloride 9d
4.6.3. (R)-(+)-2-Benzyl-2-methylsuccinic acid 11c
The title compound was isolated with >99% ee from (ꢀ)-8d, mp
White solid, mp >180 °C, 91% ee from (R)-(+)-7c, ½a D25
¼ þ3:3 (c
ꢂ
172–174 °C; ½a 2D5
ꢂ
¼ ꢀ1:5 (c 0.9, H2O). The same compound, ob-
1 MeOH); IR (neat) 3600–2500 (broad, CO2H), 1732, 1712 (C@O),
1495, 1454, 745, 701 (Ph); 1H NMR (CD3OD) d 7.20 (m, 3H, Ph);
7.09 (d, 2H, Ph), 2.90 (s, 2H, CH2Ph), 2.64 (d, part A of an AB system,
JAB 16.8, 1H, CHCO2H), 2.34 (d, part B of an AB system, JAB 16.8, 1H,
CHCO2H), 1.17 (s, 3H, CH3); 13C NMR (CD3OD) d 180.5 (s, CO2H),
175.6 (s, CO2H), 138.8 (s, Ph), 131.9 (d, Ph), 129.6 (d, Ph), 128.3
(d, Ph), 46.5 (s, C-3), 46.0 (t, CH2CO2H), 43.3 (t, CH2Ph), 22.9 (q,
CH3); ESI-MS (negative ion polarity) 206.9 [MꢀH]ꢀ; Anal. Calcd
for C12H14O4: C, 64.85; H, 6.35. Found: C, 64.95; H, 6.28.
tained from (R)-(+)-5a, had ½a D25
ꢂ
¼ ꢀ1:5 (c 0.5, H2O); IR (neat)
3500–3246 (br, OH), 2927, 2070, 1478 (NH), 1670 (CO) cmꢀ1
;
1H
NMR (D2O) d 2.97 (br s, 2H, CH2NH3þ), 2.58 (AB system, JAB 15.4,
2H, CH2CO), 1.71 (br d, 1H), 1.59 (m, 4H), 1.48 (tq, 1H, CHCH3),
1.17 (dt, 1H), 0.86 (d J 6.2, 3H, CH3CH), 0.84 (m, 2H); 13C NMR
(D2O) d 177.2 (s, CO2H), 50.4 (t, CH2NH3þ), 41.8 (t, CH2CO), 36.2
(s), 34.6 (t), 33.0 (t), 27.4 (d), 22.7 (q), 21.4 (t); ESI-MS 186.1
[M+], 209.1 [M+Na+].
4.5.5. (1S,5S,6R)-(+)-6-(Aminomethyl)bicyclo[3.2.0]heptane-6-
acetic acid hydrochloride 9e
4.6.4. (1S,3R)-(ꢀ)-1-Carboxy-3-methylcyclohexaneacetic acid
11d
The title compound was isolated with >99% ee from (ꢀ)-8e, mp
White solid, mp 152–154 °C, 99% ee from (1S,3R)-(ꢀ)-7d,
158–160 °C; ½a 2D5
ꢂ
¼ þ8:0 (c 1.5, H2O). The enantiomerically pure
½
a 2D5
ꢂ
¼ ꢀ2:6 (c 0.8, CHCl3), IR (neat) 3500–2500 (broad, CO2H),
form, synthesized from commercial (+)-(1R,5S)-5e, had
1721, 1710 (C@O); 1H NMR d 2.54 (AB system, JAB 12.5, 2H,
CH2CO2H), 1.54 (m, 3H), 1.49–1.20 (m, 5H), 0.94–0.85 (m and d,
4H, CH3CH and CH); 13C NMR d 178.5 (s, CO2H), 171.9 (s, CO2H),
42.8 (s, C-1), 41.8 (t), 37.4 (t), 33.4 (t), 32.6 (t), 28.1 (d), 22.3 (q),
21.7 (t); ESI-MS (negative ion polarity) 199.1 [MꢀH]ꢀ; Anal. Calcd
for C10H16O4: C, 59.98; H, 8.05. Found: C, 60.12; H, 7.98.
½
a 2D5
ꢂ
¼ þ8:0 (c 1.0, H2O) {lit.17
[a]D = +13.0 (c 0.35, MeOH)}; IR
(neat): 3500–2470 (broad), 1720 (CO), 1407 (NH); 1H NMR
(CD3OD) d 3.28 (AB system, J 13.6, 2H, CH2NH3þ), 2.78 (quint,
1H), 2.56 (d, part A of an AB system, J 22.0, 1H, CH2CO2H), 2.46
(m, 1H), 2.45 (d, part B of an AB system, J 22.0, CH2CO2H), 1.92
(ddd, 2J 12.4, 9.4, 2.3, 1H), 1.78, 1.71, 1.63 (3 m, 1H each), 1.48,
1.39 (2 m, 2H each); 13C NMR (CD3OD) d 175.1 (s, CO2H), 49.5 (t,
CH2NH3þ), 46.1 (d, C-5), 37.9 (s, C-6), 37.3 (t, CH2CO2H), 35.3 (d,
C-1), 35.1 (t), 33.4 (t), 29.3 (t), 27.5 (t). ESI-MS 184.2 [M+].
4.6.5. (1R,5S,6R)-(ꢀ)-6-Carboxybicyclo[3.2.0]hept-2-en-6-acetic
acid 11e
The title compound was isolated with >99% ee from (1R,5S,6R)-
(ꢀ)-7e, ½a 2D5
¼ ꢀ14:9 (c 0.5, CHCl3); IR (nujol) 3500–2500 (broad,
ꢂ
4.6. Transformations of chiral non-racemic
and -nitro acids 10a–e into the corresponding succinic acids
11a–e
c
-nitroesters 7a–e
CO2H), 1721, 1710 (C@O); 1H NMR d 5.84 (m, 2H, CH@CH), 3.32
(br dd, J1 6.4, J2 6.6, 1H, H-1), 3.19 (br s, 1H, H-5), 2.89 (m, 1H,
H-4), 2.81 (d, part A of an AB system, JAB 18.3, 1H, CHCO2H), 2.51
(m, 1H, H-4), 2.48 (d, part B of an AB system, JAB 18.3, 1H, CHCO2H),
2.20 (m, 1H, H-7), 1.72 (m, 1H, H-7); 13C NMR d 177.9 (s, CO2H),
171.9 (s, CO2H), 134.4 (d), 130.8 (d), 42.2 (s, C-6), 41.6 (d, C-1,
41.1 (d, C-5), 38.1 (t, CH2CO2H), 35.4 (t), 34.5 (2t); ESI-MS (negative
ion polarity) 195.2 [MꢀH]ꢀ. Anal. Calcd for C10H12O4: C, 61.22; H,
6.16. Found: C, 61.34; H, 6.46.
c
A solution of the optically active
c-nitroacids 10a–e, isolated
from enzymatic resolutions, was refluxed in a 1:1 solution of
HCl/AcOH for 2 h to give, after elimination of the solvents, the cor-
responding succinic acids 11a–e. The same compounds also
formed spontaneously from the isolated
c-nitroacids 10a–e on
standing for months at room temperature. The opposite enantio-
mers of 11a–e were obtained from the corresponding optically ac-
Acknowledgements
tive
conditions.
The data given for the succinic acid derivatives 11a–e are rela-
tive to the products obtained with the best enantiomeric excesses.
c-nitroesters 7a–e when treated under the same acidic
We are grateful to the Ministero dell’Università e della Ricerca
(PRIN 2007) and to the University of Trieste for their financial
support.

F. Felluga et al. / Tetrahedron: Asymmetry 21 (2010) 2183–2191
2191
Pharmacol. 1991, 22, 299–324; (c) Pardridge, W. M. Ann. Rep. Med. Chem. 1985,
20, 305–313.
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