Stereoselective synthesis of pinane-based β- And γ-amino acids via conjugate addition of lithium amides and nitromethane

Article abstract of DOI:10.1016/j.tetasy.2010.09.009

Michael addition of dibenzylamine to (-)- and (+)-tert-butyl myrtenate, (-)-2 and (+)-2, derived from (-)- and (+)-myrtenal, furnished monoterpene-based β-amino acid derivatives in highly stereospecific reactions. The resultant amino esters (-)-3 and (+)-

Full text of DOI:10.1016/j.tetasy.2010.09.009

Tetrahedron: Asymmetry 21 (2010) 2498–2504
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of pinane-based b- and
c-amino acids via
conjugate addition of lithium amides and nitromethane
⇑
Zsolt Szakonyi, Árpád Balázs, Tamás A. Martinek, Ferenc Fülöp
Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged Eötvös utca 6, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Michael addition of dibenzylamine to (ꢀ)- and (+)-tert-butyl myrtenate, (ꢀ)-2 and (+)-2, derived from
(ꢀ)- and (+)-myrtenal, furnished monoterpene-based b-amino acid derivatives in highly stereospecific
reactions. The resultant amino esters (ꢀ)-3 and (+)-3 were transformed to unsubstituted, mono- and
disubstituted and Fmoc-protected amino acids (ꢀ)-6-11 and (+)-6-11, which are promising building
blocks for the synthesis of b-peptides and 1,3-heterocycles. The microwave-assisted conjugate addition
Received 26 August 2010
Accepted 21 September 2010
Available online 8 November 2010
of nitromethane to
and (+)-13 in highly stereospecific reactions. Compounds (ꢀ)-13 and (+)-13 were successfully trans-
formed into
-amino acids (ꢀ)-16 and (+)-16 in two steps.
a
,b-unsaturated esters (ꢀ)-12 and (+)-12 likewise resulted in nitro esters (ꢀ)-13
c
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
used as nucleophiles, resulting in c-amino acids, versatile building
blocks for the syntheses of pharmacologically active natural
The discovery of the pharmacological importance of alicyclic
b-amino acids increased the demand for the asymmetric syntheses
of these versatile building blocks.1 There are several well-known
methods via which to obtain the alicyclic-type family of b-amino
acids in homochiral form, including classical resolution and kinetic
resolution, as well as a variety of asymmetric syntheses, for exam-
ple, the enantioselective syntheses of b-lactams followed by ring
opening, the selective reduction of enantiopure b-enaminoesters,
the enantioselective desymmetrization of achiral anhydrides fol-
lowed by Curtius degradation, or chiral ammonia equivalent
compounds.8
We recently described the transformations of enantiomerically
pure a-pinene, d-pinene, 3-carene and apopinene to b-amino acid
derivatives,9 which proved to be excellent building blocks for the
syntheses of monoterpene-fused saturated 1,3-heterocycles9a–d
and stable H12 foldameric helices,9g and which were also applied
in Ugi four-centre three-component reactions9h or as chiral cata-
lysts in the enantioselective addition of Et2Zn to aromatic
aldehydes.9d
Further to their interest in organic syntheses, monoterpene-
based amino acid derivatives have a wide range of pharmacological
activities:10 pinane-based amino esters possess marked anticon-
vulsant activity;10a their amides have been reported to be tyrosine
kinase Axl inhibitors,10b and apopinane-based urea and thiourea
derivatives exhibit a multidrug-resistance reversing effect on a
mouse lymphoma cell line.10c
TMS-SAMP addition to
further transformations.2–6
Besides the above-mentioned methods, the conjugate addition
of amine nucleophiles to ,b-unsaturated carbonyl compounds is
x-halo-substituted enoates followed by
a
one of the most popular and useful procedures. Davies et al. re-
cently published a comprehensive review of this field, covering
the scope, limitations and synthetic applications of the use of enan-
tiomerically pure lithium amides as homochiral ammonia equiva-
lents in conjugate addition reactions.1d Most of these methods
involve the use of chiral lithium amides, and only a few examples
Our present aim was the preparation and transformations of a
new family of monoterpene-based b- and
c-amino acid derivatives,
starting from esters of (ꢀ)- and (+)-myrtenic acid derived from
commercially available (ꢀ)-myrtenal and (+)-
a-pinene. Our previ-
are to be found whereby chiral
a,b-unsaturated esters are applied
ous results relating to the preparation of amino acids9f–h suggested
that these new chiral building blocks might serve as promising
substrates for the synthesis of chiral catalysts, 1,3-heterocycles
and foldamers.
as the source of chirality in the conjugate addition of achiral
amides.7
Besides their applications in b-amino acid synthesis, a,b-unsat-
urated esters are also excellent substrates for other types of conju-
gate addition, whereas nitroalkanes (e.g., nitromethane) can be
2. Results and discussion
The Michael acceptor (ꢀ)-tert-butyl myrtenate (ꢀ)-2 was
synthesized from commercially available (ꢀ)-myrtenal (ꢀ)-1 by a
⇑
Corresponding author. Tel.: +36 62 545564; fax: +36 62 545705.
E-mail address: fulop@pharm.u-szeged.hu (F. Fülöp).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.09.009

Z. Szakonyi et al. / Tetrahedron: Asymmetry 21 (2010) 2498–2504
COOtBu
2499
CHO
COOtBu
2 steps
lit.11,13
i
N
Ph
(-)-2
(-)-1
R
Ph
(+)-3-5
ii
iii
iv
COOtBu
COOtBu
COOH
NH
Ph
NH2
N
Ph
(+)-6
iv
(+)-7
(+)-8
Ph
iv
COOH
COOH
COOH
v
NHFmoc
NH2 HCl
NH HCl
Ph
(+)-10
(+)-11
(+)-9
Scheme 1. Reagents and conditions: (i) 2.4 equiv of the appropriate lithium amide (3: lithium dibenzylamide, 4: lithium (S)-N-benzyl-N-
(R)-N-benzyl-N-
89%; (iv) 10% aq HCl/Et2O, rt, 12 h, 71–89%; (v) 10% NaHCO3/H2O to pH 8.0, MeCN, 0 °C, 1.0 equiv Fmoc-OSu, then 12 h, rt, 63%.
a
-methylbenzylamide, 5: lithium
a
-methylbenzylamide), dry THF, ꢀ78 °C, 6–8 h, then NH4Cl(aq), 12–87%; (ii) 10% Pd/C, AcOH, 1 atm H2, rt, 2 h, 89%; (iii) 10% Pd/C, AcOH, 1 atm H2, rt, 12 h,
14
**
literature method in a two-step reaction: the oxidation of myrtenal
to myrtenic acid, which was converted to the tert-butyl ester.11
Since the (+) enantiomer of myrtenal is commercially unavailable,
311G (Figure 1, absolute configurations according to Scheme 1).
This suggests that the dibenzylamide approaches from the steri-
cally less hindered side (opposite the methyl substituents), thereby
furnishing (S)-C3 stereoselectivity. Inspection of the enolate inter-
mediate suggests that the protonation of C2 in the second step
again takes place on the sterically less shielded face, which eventu-
ally leads to the trans relative configuration. Since the steric effects
play a crucial role in the course of the reaction and the surround-
ings of the reaction centre are tightly packed even at the less
it was prepared from (+)-a-pinene according to a literature method
by allylic oxidation with selenium dioxide.12 The asymmetric Mi-
chael addition to compounds (ꢀ)-2 and (+)-2 followed a literature
protocol, with the application of in situ generated achiral lithium
dibenzylamide to exploit the effect of the chiral, conformationally
constrained pinane ring system.7c NMR studies on the crude prod-
uct proved that the addition was highly stereospecific (de >99%),
resulting in trans dibenzylamino esters (ꢀ)-3 and (+)-3 as single
products in excellent yields (Scheme 1). The configurations of the
new chiral centres of (ꢀ)-3 and (+)-3 were determined in NOESY
experiments, based on the observation of NOE effects between
H–C-2 and H–C-7 and also between H–C-3 and Me–C-6.
shielded face, a-methyl substituents could not modify the orient-
ing effect of the Michael acceptor, but only caused decreased reac-
tivity through the increased steric repulsion.
Hydrogenolysis of (ꢀ)-3 and (+)-3 over palladium on carbon
(Pd/C) for 2 h resulted in the formation of monobenzyl derivatives
(ꢀ)-6 and (+)-6 in acceptable yields. A longer reaction time led to
primary amino esters (ꢀ)-7 and (+)-7 in excellent yields. Com-
pounds (ꢀ)-5-7 and (+)-5-7 were successfully hydrolysed to amino
acids (ꢀ)-8-10 and (+)-8-10 under acidic conditions. Starting from
(ꢀ)-10 and (+)-10, Fmoc-protected amino acids (ꢀ)-11 and (+)-11
were also prepared, as promising building blocks for peptide chem-
istry (Scheme 1).
Since it has been reported that the conjugate addition of lithium
dialkylamides to alicyclic a,b-unsaturated esters results in cis ami-
no esters as main products,1d our aim was to study the effect of a
more bulky substituent on the nitrogen with a view to shifting
the regioselectivity towards cis products. The steric effect of the
a-methyl substituent of (S)- and (R)-N-benzyl-N-a-methylbenzyl-
amine on the reactivity and stereoselectivity was also investigated
by preparing (+)-4 and (+)-5. We observed similar trans stereose-
lectivity in each case, but the yield dropped from 87% to 45% when
the (S)-amide (+)-4 was used. When (R)-N-benzyl-N-a-methylben-
zylamine was applied as ammonia equivalent, only a very low
When (ꢀ)-tert-butyl myrtenate was used in the Michael addi-
tion of nitromethane in order to obtain c-amino acids, our first at-
tempts under both conventional and microwave heating failed,
probably due to the steric and electronic effects of the bulky tert-
butyl group. Therefore, (ꢀ)- and (+)-methyl myrtenate (ꢀ)-12
and (+)-12 were prepared from (ꢀ)- and (+)-myrtenal (ꢀ)-1 and
(+)-1 according to a literature process,13 and were successfully ap-
plied in the conjugate addition. On the use of conventional heating
(Method A), NMR studies on the crude product proved that the
addition took place highly stereospecifically (de >99%), resulting
in trans isomers (ꢀ)-13 and (+)-13 as single products, similarly as
in the lithium amide reaction. The configurations of the new stere-
ogenic centres in 13 were determined in NOESY experiments. The
yield (12%) was achieved for (+)-5 (Scheme 1).
It is likely that the addition proceeds via an enolate intermedi-
ate.1d Quantum chemical modelling of the possible intermediates
with configurations (R)- and (S)-C3 revealed a stability difference
of 4.75 kcal/mol in favour of (S)-C3 at the level of B3LYP/6-
In the present experiments, all of the reactions were carried out on both
enantiomers, although only one of them features in the Schemes.

2500
Z. Szakonyi et al. / Tetrahedron: Asymmetry 21 (2010) 2498–2504
identical microwave conditions in the presence of 1 equiv of DBU
and 10 mol % of TBAB in nitromethane. Since the minor cis adduct
could be detected in the crude reaction mixture together with a
trace amount of 12, we propose that the conjugate addition of
nitromethane under the applied conditions is reversible and leads
to equilibrium. Next, LiOH-mediated hydrolysis of nitro ester 13
furnished nitro acid 15 in an excellent yield, and the nitro moiety
was subsequently reduced over Raney Ni to provide the target c-
amino acid 16 in good yield (Scheme 2).
3. Conclusions
In conclusion, the highly stereospecific addition of lithium
amides to tert-butyl 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-car-
boxylate (+)-2 and (ꢀ)-2 proved to be an efficient method for the
synthesis of a new family of pinane-based b-amino acids via a
two-step transformation of the resulting N,N-dibenzyl b-aminoest-
ers (+)-3 and (ꢀ)-3. The microwave-assisted conjugate addition of
nitromethane to the
a
,b-unsaturated methyl esters (ꢀ)-12 and
(+)-12 resulted in highly stereospecifically nitro esters (ꢀ)-13
and (+)-13, which were successfully transformed into
acids (ꢀ)-16 and (+)-16 in a two-step procedure.
c-amino
4. Experimental
4.1. General experimental procedures
1H NMR spectra were recorded on a Bruker Avance DRX 400
spectrometer at 400.13 MHz (1H) and 100.61 MHz (13C) [d = 0
(TMS)] in CDCl3, DMSO-d6 or D2O in a 5-mm tube. Chemical shifts
are expressed in ppm (d) relative to TMS as internal reference. J val-
ues are given in hertz (Hz). Microanalyses were performed on a
Perkin–Elmer 2400 elemental analyser. Optical rotations were ob-
tained with a Perkin–Elmer 341 polarimeter. Melting points were
determined on a Kofler apparatus and are uncorrected. Chromato-
graphic separations were carried out on Merck Kieselgel 60 (230–
400 mesh ASTM). Reactions were monitored with Merck Kieselgel
60 F254-precoated TLC plates (0.25 mm thickness). Ab intio quan-
tum chemical calculations were carried out by using GAUSSIAN 03
**
Figure 1. Geometries obtained at the B3LYP/6-311G level for the (R)-C3 (top) and
(S)-C3-enolate (bottom) intermediates.
disadvantage of this method is that, even after prolonged heating,
the yield remains only moderate (<40%). However, when micro-
wave irradiation was used, we obtained the desired nitro ester
13 in a short time (25 min) in high yield (73%). Moreover, under
microwave conditions the cis-diastereomer 14 was also formed
as a minor product and was isolated in 6% yield. In order to inves-
tigate the formation of the cis product, a control experiment was
performed in which the major trans adduct was irradiated under
**
software at the B3LYP/6-311G level with a default setup.
The enantiomeric purities of the compounds prepared were
determined by means of GC measurements involving direct sepa-
ration of the enantiomers on
a CHIRASIL-DEX CB column
(2500 ꢁ 0.25 mm ID), at 110 °C for (+)-2 and (ꢀ)-2 and at 110 °C
for (+)-7 and (ꢀ)-7. IR spectra were measured with an FT-IR
spectrometer.
COOMe
NO2
COOMe
NO2
COOMe
i
+
(-)-12
(-)-13
(-)-14
ii
COOH
NO2
COOH
iii
NH2 HCl
(+)-16
(-)-15
Scheme 2. Reagents and conditions: (i) Method A: 1 equiv DBU, 10 mol % TBAB, nitromethane, reflux, 13: 39%; Method B: 1 equiv DBU, 10 mol % TBAB, nitromethane, 100 °C,
MW, 13: 73%, 14: 6%; (ii) 2 equiv LiOHꢂH2O, THF/water, reflux, 91%; (iii) 1 atm H2, Raney Ni, MeOH, then 10% HCl/EtOH, 63%.

Z. Szakonyi et al. / Tetrahedron: Asymmetry 21 (2010) 2498–2504
2501
(ꢀ)-(1S,5S)-Myrtenal and (+)-(1R,5R)-
a
-pinene are commer-
(20 mL), n-BuLi solution (5.4 mL of a 1.6 M solution in n-hexane)
and 0.80 g (3.6 mmol) of 2 in dry THF (5 mL) gave the desired prod-
uct (+)-5 after chromatographic purification on silica gel (n-hex-
ane/Et2O = 19:1). Isolated compound: 0.19 g (12%); an oil;
cially available. THF was dried over Na wire; all other chemicals
and solvents were used as supplied. (ꢀ)-(1R,5S)- and (+)-(1S,5R)-
tert-butyl and methyl 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-car-
boxylates (+)-2, (+)-3, (ꢀ)-2 and (ꢀ)-3 were prepared by the liter-
ature methods, and were identical with those reported therein.11,13
½
a 2D0
ꢃ
¼ þ56:0 (c 0.125, MeOH); 1H NMR (CDCl3) d (ppm): 0.89
(3H, s), 1.14 (1H, d, J = 9.9 Hz), 1.13 (3H, s), 1.31 (3H, d,
J = 6.9 Hz), 1.51 (9H, s), 1.75–1.81 (1H, m), 1.85–1.95 (1H, m),
2.17–2.11 (1H, m), 2.23–2.33 (1H, m), 2.75 (1H, d, J = 8.2 Hz),
3.72 (1H, d, J = 15.6 Hz), 3.75–3.81 (1H, m), 3.95 (1H, d,
J = 15.4 Hz), 4.20–4.28 (1H, m), 7.10–7.50 (10H, m); 13C NMR
(CDCl3) d (ppm): 20.8, 23.3, 28.3, 29.1, 33.6, 39.6, 42.2, 45.9, 50.1,
51.1, 54.3, 59.4, 80.5, 126.9, 127.3, 128.2, 128.3, 128.4, 128.5,
4.2. General procedure for the lithium amide addition reactions
At first, 1.6 M n-BuLi solution was added dropwise to a stirred
solution of secondary amine in dry THF at ꢀ78 °C under an argon
atmosphere, followed by stirring for 30 min prior to the addition
of a solution of the acceptor in THF at ꢀ78 °C. After the appropriate
reaction time (6 h for 3, 8 h for 4 and 5), saturated aqueous NH4Cl
solution was added and the solution was warmed to room temper-
ature, partitioned between Et2O (3 ꢁ 200 mL) and brine, dried
(Na2SO4) and concentrated in vacuo. Purification by column chro-
matography gave the desired product.
143.8, 145.2, 176.0. IR = 3447, 2925, 1731, 1367, 1149, 700 cmꢀ1
.
Anal. Calcd for C29H39NO2 (433.63): C, 80.33; H, 9.07; N, 3.23.
Found: C, 80.50; H, 9.27; N, 3.01.
4.3. (1S,2S,3S,5R)-tert-Butyl 3-benzylamino-6,6-dimethylbi-
cyclo[3.1.1]heptane-2-carboxylate (+)-6
4.2.1. (1S,2S,3S,5R)-tert-Butyl 3-(dibenzylamino)-6,6-dimethylbi-
cyclo[3.1.1]heptane-2-carboxylate (+)-3
To a suspension of 10% Pd/C (0.55 g) in glacial AcOH (50 mL),
amino ester (+)-3 (2.30 g, 5.5 mmol) in glacial AcOH (10 mL) was
added, and the resulting mixture was stirred under H2 (1 atm) at
room temperature for 2 h. The solution was diluted with CH2Cl2
(100 mL) and filtered through a pad of CeliteÒ, and the solvent
was removed. The oily crude product obtained was dissolved in
CH2Cl2 (200 mL) and was washed with 10% NaOH solution
(50 mL). The organic phase was dried with Na2SO4, filtered and
concentrated in vacuo before purification via column chromatogra-
phy (silica gel, toluene/EtOH = 9:1), affording a colourless oily
product (+)-6. Isolated compound: 1.61 g (89%); an oil;
According to general procedure 4.2 8.90 g (45.1 mmol) of diben-
zylamine in dry THF (100 mL), n-BuLi solution (27 mL of a 1.6 M
solution in n-hexane) and 4.00 g (18.0 mmol) of (+)-3 in dry THF
(25 mL) gave the desired product after chromatographic purifica-
tion on silica gel (n-hexane/Et2O = 19:1). Isolated compound:
6.10 g (81%); an oil; ½a D20
ꢃ
¼ þ46:0 (c 0.265, MeOH); 1H NMR
(CDCl3) d (ppm): 0.84 (3H, s), 1.05 (1H, d, J = 9.9 Hz), 1.18 (3H, s),
1.42 (9H, s), 1.86–1.99 (2H, m), 2.14–2.26 (2H, m), 2.31–2.40
(1H, m), 2.89 (1H, dd, J = 1.6, 9.6 Hz), 3.59 (1H, d, J = 14.1 Hz),
3.73 (1H, d, J = 14.1 Hz), 4.04–4.11 (1H, m), 7.16–7.38 (10H, m);
13C NMR (CDCl3) d (ppm): 23.3, 28.0, 28.4, 29.1, 33.0, 39.3, 41.9,
45.8, 51.1, 51.5, 54.6, 80.0, 127.0, 128.4, 129.0, 140.8, 174.7.
IR = 2913, 1726, 1450, 1364, 1147, 739 cmꢀ1. Anal. Calcd for
½
a 2D0
ꢃ
¼ þ39:0 (c 0.155, MeOH); 1H NMR (CDCl3) d (ppm): 0.84
(3H, s), 1.19 (1H, d, J = 10.3 Hz), 1.23 (3H, s), 1.42 (9H, s), 1.72
(1H, ddd, J = 3.1, 4.4, 13.4 Hz), 1.93–1.99 (1H, m), 2.30–2.46 (1H,
m), 2.61 (1H, dd, J = 2.5, 5.3 Hz), 3.64–3.70 (1H, m), 3.73 (1H, d,
J = 13.0 Hz), 3.84 (1H, d, J = 13.0 Hz), 7.21–7.37 (5H, m); 13C NMR
(CDCl3) d (ppm): 22.9, 27.4, 28.4, 31.1, 35.6, 38.4, 41.4, 43.9, 50.4,
52.3, 54.8, 80.5, 127.2, 128.6, 128.7, 140.7, 175.0. IR = 3467, 2923,
1710, 1455, 1064, 699 cmꢀ1. Anal. Calcd for C21H31NO2 (329.48):
C, 76.55; H, 9.48; N, 4.25. Found: C, 76.68; H, 9.69; N, 4.02.
The (1R,2R,3R,5S)-enantiomer (ꢀ)-6 was synthesized analo-
C28H37NO2 (419.60): C, 80.15; H, 8.89; N, 3.34. Found: C, 80.27;
H, 9.03; N, 3.17.
The (1R,2R,3R,5S)-enantiomer (ꢀ)-3 was synthesized analo-
gously to (+)-3, from (+)-(1S,5R)-tert-butyl 6,6-dimethylbicy-
clo[3.1.1]hept-2-ene-2-carboxylate (+)-2; ½a D20
¼ ꢀ49:0 (c 0.265,
ꢃ
MeOH); all the spectroscopic data were similar to those for the
(1S,2S,3S,5R)-enantiomer. Anal. Calcd for C28H37NO2 (419.60): C,
80.15; H, 8.89; N, 3.34. Found: C, 80.30; H, 9.05; N, 3.08.
gously to (+)-6; ½a D20
¼ ꢀ38:0 (c 0.155, MeOH); all the spectroscopic
ꢃ
data were similar to those for the (1S,2S,3S,5R)-enantiomer (+)-6.
Anal. Calcd for C21H31NO2 (329.48): C, 76.55; H, 9.48; N, 4.25; Found:
C, 76.71; H, 9.63; N, 4.05.
4.2.2. (1S,2S,3S,5R)-tert-Butyl 3-[benzyl((S)-1-phenylethyl)
amino]-6,6-dimethylbicyclo[3.1.1]heptane-2-carboxylate (+)-4
Following general procedure 4.2 in a reaction time of 8 h, 1.91 g
4.4. (1S,2S,3S,5R)-tert-Butyl 3-amino-6,6-dimethylbicyclo
(9.0 mmol) of (S)-(ꢀ)-N-benzyl-
a
-methylbenzylamine in dry THF
[3.1.1]heptane-2-carboxylate (+)-7
(20 mL), n-BuLi solution (5.4 mL of a 1.6 M solution in n-hexane)
and 0.80 g (3.6 mmol) of (ꢀ)-2 in dry THF (5 mL) gave the desired
product (+)-4 after chromatographic purification on silica gel (n-
hexane/Et2O = 19:1). Isolated compound: 0.70 g (45%); an oil;
To a suspension of 10% Pd/C (1.10 g) in glacial AcOH (100 mL),
amino ester (+)-3 (4.60 g, 11.0 mmol) in glacial AcOH (20 mL) was
added, and the resulting mixture was stirred under H2 (1 atm) at
room temperature for 12 h. The solution was diluted with CH2Cl2
(200 mL) and filtered through a pad of CeliteÒ, and the solvent was
removed. The oily crude product obtained was dissolved in CH2Cl2
(200 mL) and was washed with 10% NaOH solution (50 mL). The or-
ganic phase was dried with Na2SO4, filtered and concentrated in va-
cuo before purification via column chromatography (silica gel,
toluene/EtOH = 4:1), affording colourless oily product (+)-7. Isolated
½
a 2D0
ꢃ
¼ þ86:0 (c 0.25, MeOH); 1H NMR (CDCl3) d (ppm): 0.91 (3H,
s), 0.98 (1H, d, J = 9.9 Hz), 1.16 (3H, s), 1.38 (3H, d, J = 6.8 Hz),
1.43 (9H, s), 1.86–1.95 (2H, m), 2.08–2.17 (2H, m), 2.27–2.34
(1H, m), 2.79 (1H, dd, J = 1.7, 8.2 Hz), 3.76 (1H, d, J = 15.8 Hz),
3.90–4.00 (2H, m), 4.20–4.29 (1H, m), 7.10–7.36 (10H, m); 13C
NMR (CDCl3) d (ppm): 18.8, 23.3, 28.2, 28.6, 31.1, 33.3, 39.4, 42.2,
45.8, 50.5, 51.6, 53.2, 60.4, 79.8, 126.6, 126.9, 128.1, 128.2, 128.3,
128.4, 143.3, 145.5, 174.7. IR = 3250, 2927, 1728, 1367, 1147,
697 cmꢀ1. Anal. Calcd for C29H39NO2 (433.63): C, 80.33; H, 9.07;
N, 3.23. Found: C, 80.52; H, 9.25; N, 3.11.
compound: 2.36 g (90%); an oil; ½a D20
ꢃ
¼ þ20:0 (c 0.25, MeOH); 1H
NMR (CDCl3) d (ppm): 0.85 (3H, s), 1.20 (1H, d, J = 9.8 Hz), 1.25
(3H, s), 1.48 (9H, s), 1.55 (1H, ddd, J = 2.8, 5.3, 13.7 Hz), 1.69 (2H,
br s), 1.92–1.99 (1H, m), 2.34–2.55 (4H, m), 3.81–3.89 (1H, m). 13
C
4.2.3. (1S,2S,3S,5R)-tert-Butyl 3-[benzyl((R)-1-phenylethyl)
amino]-6,6-dimethylbicyclo[3.1.1]heptane-2-carboxylate (+)-5
Following general procedure 4.2 in a reaction time of 8 h, 1.91 g
NMR (CDCl3) d (ppm): 22.9, 27.5, 28.5, 30.1, 32.1, 38.1, 41.5, 43.9,
44.8, 58.3, 80.6, 175.1. IR = 3367, 2924, 1725, 1367, 1160,
847 cmꢀ1. Anal. Calcd for C14H25NO2 (239.35): C, 70.25; H, 10.53;
N, 5.85. Found: C, 70.40; H, 10.63; N, 5.69.
(9.0 mmol) of (R)-(ꢀ)-N-benzyl-a-methylbenzylamine in dry THF

2502
Z. Szakonyi et al. / Tetrahedron: Asymmetry 21 (2010) 2498–2504
The (1R,2R,3R,5S)-enantiomer (ꢀ)-7 was synthesized analo-
½
a 2D0
ꢃ
¼ ꢀ17:2 (c 0.125, MeOH); all the spectroscopic data and the
gously to (+)-7; ½a D20
ꢃ
¼ ꢀ22:0 (c 0.25, MeOH); all the spectroscopic
mp were similar to those for the (1S,2S,3S,5R)-enantiomer (+)-10.
Anal. Calcd for C10H18ClNO2 (219.71): C, 54.67; H, 8.26; N, 6.38.
Found: C, 54.79; H, 8.35; N, 6.21.
data were similar to those for the (1S,2S,3S,5R)-enantiomer. Anal.
Calcd for C14H25NO2 (239.35): C, 70.25; H, 10.53; N, 5.85. Found:
C, 70.37; H, 10.65; N, 5.70.
4.6. (1S,2S,3S,5R)-3-[((9H-Fluoren-9-yl)methoxy)carbonylami-
4.5. General procedure for the hydrolysis of amino esters
no]-6,6-dimethylbicyclo[3.1.1]heptane-2-carboxylic acid (+)-11
The appropriate amino ester (10 mmol) was dissolved in a mix-
ture of Et2O (15 mL) and 10% aqueous HCl solution (100 mL), which
was followed by stirring at room temperature for 24 h. The mixture
was then evaporated to dryness and the resulting white crystalline
product was washed with Et2O and filtered off.
At first, 0.34 g (1.56 mmol) of (1R,2R,3S,5R)-amino acid (+)-10
was dissolved in 6 mL of distilled water at 0 °C. 0.50 g (6 mmol)
of NaHCO3, 5 mL of MeCN and 0.51 g (1.5 mmol) of Fmoc-OSu were
added to the solution at 0 °C. After stirring overnight at room tem-
perature, the solution was acidified with 10% aqueous HCl solution
and, after stirring for 1 h, the reaction mixture was extracted with
EtOAc (3 ꢁ 20 mL). The combined organic layer was dried (Na2SO4)
and evaporated, and the crude product was purified by flash chro-
matography on a silica gel column (toluene/EtOH = 9:1), resulting
in a white crystalline product. Isolated compound: 0.40 g (63%);
4.5.1. (1S,2S,3S,5R)-3-(Dibenzylamino)-6,6-dimethylbicyclo
[3.1.1]heptane-2-carboxylic acid hydrochloride (+)-8
Isolated compound: 2.84 g (71%); mp: 163–166 °C; ½a D20
¼ þ22:0
ꢃ
(c 0.125, MeOH); 1H NMR (DMSO-d6, 51 °C) d (ppm): 0.71 (3H, s),
1.24 (3H, s), 1.38 (1H, d, J = 10.4 Hz), 2.04–2.10 (1H, m), 2.31–2.49
(4H, m), 3.43–3.49 (1H, m), 4.19–4.41 (4H, m), 4.55–4.64 (1H, m),
7.37–7.62 (10H, m), 10.13 (1H, br s). 13C NMR (DMSO-d6, 51 °C) d
(ppm): 22.8, 26.3, 27.4, 30.5, 39.3, 40.9, 44.8, 46.8, 54.3, 54.9,
128.8, 129.1, 132.1, 133.3, 174.8. IR = 3386, 2936, 1721, 1457, 752,
700 cmꢀ1. Anal. Calcd for C24H30ClNO2 (399.95): C, 72.07; H, 7.56;
N, 3.50. Found: C, 72.35; H, 7.69; N, 3.28.
mp: 90–92 °C; ½a 2D0
ꢃ
¼ þ21:0 (c 0.125, MeOH); 1H NMR (CDCl3) d
(ppm): 0.80 (3H, s), 1.03 (1H, d, J = 10.5 Hz), 1.27 (3H, s), 1.57–
1.63 (1H, m), 1.91–1.96 (1H, m), 2.37–2.45 (1H, m), 2.50–2.57
(1H, m), 2.59–2.72 (2H, m), 4.21 (1H, t, J = 5.9 Hz), 4.26 (1H, br s),
4.49–4.64 (2H, m), 4.98–5.06 (1H, m), 7.29–7.36 (2H, m), 7.37–
7.44 (2H, m), 7.58 (2H, d, J = 7.7 Hz), 7.77 (2H, dd, J = 3.8, 7.5 Hz),
11.28 (1H, br s). 13C NMR (CDCl3) d (ppm): 23.0, 26.7, 29.3, 35.6,
37.9, 39.9, 42.3, 43.7, 47.7, 55.3, 67.6, 120.4, 120.5, 125.4, 127.5,
128.2, 141.8, 157.2, 176.4. IR = 3345, 2945, 1730, 1543, 1268,
741 cmꢀ1. Anal. Calcd for C25H27NO4 (405.49): C, 74.05; H, 6.71;
N, 3.45. Found: C, 74.26; H, 6.89; N, 3.27.
The (1R,2R,3R,5S)-enantiomer (ꢀ)-8 was synthesized analo-
gously to (+)-8, from the 1R,2R,3R,5S enantiomer (ꢀ)-3; ½a D20
¼
ꢃ
ꢀ24:0 (c 0.125, MeOH); all the spectroscopic data and the mp were
similar to those for the (1S,2S,3S,5R)-enantiomer (+)-8. Anal. Calcd
for C24H30ClNO2 (399.95): C, 72.07; H, 7.56; N, 3.50. Found: C,
72.29; H, 7.70; N, 3.26.
The (1R,2R,3R,5S)-enantiomer (ꢀ)-11 was synthesized analo-
gously to (+)-11, from the (1R,2R,3R,5S)-enantiomer (ꢀ)-10;
½
a 2D0
ꢃ
¼ ꢀ19:6 (c 0.125, MeOH); all the spectroscopic data and the
4.5.2. (1S,2S,3S,5R)-3-Benzylamino-6,6-
dimethylbicyclo[3.1.1]heptane-2-carboxylic acid hydrochloride
(+)-9
mp were similar to those for the (1S,2S,3S,5R)-enantiomer (+)-11.
Anal. Calcd. for C25H27NO4 (405.49): C, 74.05; H, 6.71; N, 3.45.
Found: C, 74.19; H, 6.85; N, 3.33.
Isolated compound: 2.51 g (81%); mp: 217–219 °C;
½
a 2D0
ꢃ
¼ þ28:0 (c 0.125, MeOH); 1H NMR (CDCl3) d (ppm): 0.73
4.7. Conjugate addition of nitromethane to (ꢀ)-12
(3H, s), 1.19 (3H, s), 1.67 (1H, d, J = 10.4 Hz), 1.93–1.99 (1H, m),
2.08 (1H, ddd, J = 2.5, 5.0, 16.6 Hz), 2.27–2.46 (3H, m), 3.13 (1H,
dd, J = 1.9, 5.7 Hz), 4.14 (2H, dd, J = 13.1, 25.5 Hz), 4.17–4.25 (1H,
m), 7.38–7.46 (3H, m), 7.59–7.66 (2H, m). 13C NMR (CDCl3) d
(ppm): 22.8, 27.5, 30.7, 31.0, 39.0, 40.7, 44.3, 49.2, 49.4, 49.7,
129.4, 129.7, 131.1, 132.9, 175.3. IR = 3386, 2945, 1722, 1184,
695 cmꢀ1. Anal. Calcd for C17H24ClNO2 (309.83): C, 65.90; H,
7.81; N, 4.52. Found: C, 65.73; H, 7.92; N, 4.65.
Method A: A 10 mL round-bottomed flask containing 200 mg
(1.11 mmol) of (1R,5S)-methyl myrtenate, 36.2 mg (10 mol %) of
n-tetrabutylammonium bromide, 2 mL of nitromethane and
168 lL (1 equiv) of DBU was heated at reflux for 20 h. Next, the sol-
vent was evaporated off under reduced pressure and the residue
was purified by flash column chromatography on silica gel; elution
with 9:1 n-hexane/EtOAc gave (ꢀ)-13.
The (1R,2R,3R,5S)-enantiomer (ꢀ)-9 was synthesized analo-
Method B: Microwave-assisted conjugate addition of nitrometh-
ane to (ꢀ)-12 and (+)-12. A CEM Discover 10 mL vial containing
400 mg (2.22 mmol) of (1R,5S)-methyl myrtenate, 72.4 mg
(10 mol %) of n-tetrabutylammonium bromide, 2 mL of nitrometh-
gously to (+)-9, from the (1R,2R,3R,5S)-enantiomer (ꢀ)-6;
½
a 2D0
ꢃ
¼ ꢀ30:0 (c 0.125, MeOH); all the spectroscopic data and the
mp were similar to those for the (1S,2S,3S,5R)-enantiomer (+)-9.
Anal. Calcd for C17H24ClNO2 (309.83): C, 65.90; H, 7.81; N, 4.52.
Found: C, 65.73; H, 7.92; N, 4.65.
ane and 336 lL (1 equiv) of DBU and sealed with a Teflon cap was
irradiated at 100 °C (250 W) for 25 min with a ramp time of 3 min
under continuous cooling (Powermax). Next, the solvent was evap-
orated off under reduced pressure and the residue was purified by
flash column chromatography on silica gel; elution with 9:1 n-hex-
ane/EtOAc gave the pure compounds 13 and 14.
4.5.3. (1S,2S,3S,5R)-3-Amino-6,6-
dimethylbicyclo[3.1.1]heptane-2-carboxylic acid hydrochloride
(+)-10
Isolated compound: 1.96 g (89%); mp: 220–222 °C; ½a D20
¼
ꢃ
þ19:0 (c 0.125, MeOH); 1H NMR (CDCl3) d (ppm): 0.77 (3H, s),
1.20 (3H, s), 1.46 (1H, d, J = 10.1 Hz), 1.78–1.87 (1H, m), 1.91–
1.96 (1H, m), 2.30–2.47 (4H, m), 2.85–2.89 (1H, m), 4.11–4.20
(1H, m), 8.27 (3H, br s), 12.74 (1H, br s). 13C NMR (CDCl3) d
(ppm): 22.7, 27.5, 30.9, 32.8, 38.6, 40.6, 42.8, 44.0, 50.5, 175.2.
IR = 2923, 1719, 1220, 1195 cmꢀ1. Anal. Calcd for C10H18ClNO2
(219.71): C, 54.67; H, 8.26; N, 6.38. Found: C, 54.51; H, 8.11; N,
6.13.
4.7.1. (1S,2S,3S,5R)-Methyl 6,6-dimethyl-3-
(nitromethyl)bicyclo[3.1.1]heptane-2-carboxylate (ꢀ)-13
Isolated compound: 94 mg (39%, Method A) or 490 mg (73%,
Method B); ½a 2D0
ꢃ
¼ ꢀ0:4 (c 0.25, MeOH); 1H NMR (CDCl3) d
(ppm): 0.84 (1H, d, J = 10.6 Hz), 0.87 (3H, s), 1.24 (3H, s), 1.63–
1.70 (1H, m), 1.96–2.01 (1H, m), 2.27–2.35 (1H, m), 2.38–2.45
(1H, m), 2.50–2.54 (1H, m), 2.70 (1H, dd, J = 2.6, 6.7 Hz), 3.37–
3.47 (1H, m), 3,71 (3H, s), 4.36 (1H, dd, J = 8.6, 11.7 Hz), 4.52 (1H,
dd, J = 5.8, 11.7 Hz). 13C NMR (CDCl3) d (ppm): 22.1, 27.3, 29.1,
31.0, 31.5, 38.6, 40.8, 43.4, 48.1, 52.5, 83.4, 174.6. IR = 2924,
The (1R,2R,3R,5S)-enantiomer (ꢀ)-10 was synthesized analo-
gously to (+)-10, from the (1R,2R,3R,5S)-enantiomer (ꢀ)-7;

Z. Szakonyi et al. / Tetrahedron: Asymmetry 21 (2010) 2498–2504
2503
1731, 1634, 1533, 1376, 1160 cmꢀ1. Anal. Calcd for C12H19NO4
(241.13): C, 59.73; H, 7.94; N, 5.81. Found: C, 59.62; H, 8.01; N,
5.76.
(D2O) d (ppm): 0.86 (3H, s), 0.93 (1H, d, J = 9.8 Hz), 1.25 (3H, s),
1.55–1.65 (3H, s), 1.99–2.04 (1H, m), 2.31–2.38 (1H, m), 2.42–
2.51 (2H, m), 2.75–2.78 (1H, m), 2.81–2.90 (1H, m), 3.04–3.16
(2H, m). 13C NMR (D2O) d (ppm): 21.1, 26.0, 27.8, 30.1, 30.5, 37.3,
39.9, 42.8, 48.2, 48.7, 179.7. IR = 3434, 2943, 2906, 1711, 1613,
1498, 1385, 1200 cmꢀ1. Anal. Calcd for C11H20ClNO2 (233.74): C,
56.52; H,8.62; N, 5.99. Found: C, 56.79; H, 8.47; N, 6.13.
The (1R,2R,3R,5S)-enantiomer (+)-13 was synthesized analo-
gously to (ꢀ)-13, from (1S,5R)-methyl myrtenate; ½a D20
¼ þ0:4 (c
ꢃ
0.25, MeOH); all the spectroscopic data and the mp were similar
to those for the (1S,2S,3S,5R)-enantiomer (ꢀ)-13. Anal. Calcd for
C12H19NO4 (241.13): C, 59.73; H, 7.94; N, 5.81. Found: C, 59.59;
The (1R,2R,3R,5S)-enantiomer (ꢀ)-16 was synthesized analo-
H, 8.13; N, 5.68.
gously to (+)-16, from (+)-15; ½a D20
¼ ꢀ1:5 (c 0.25, MeOH); all the
ꢃ
spectroscopic data and the mp were similar to those for the
4.7.2. (1S,2S,3R,5R)-Methyl 6,6-dimethyl-3-(nitromethyl)
bicyclo[3.1.1]heptane-2-carboxylate (ꢀ)-14
(1S,2S,3S,5R)-enantiomer (+)-16 Anal. Calcd for C11H20ClNO2
(233.74): C, 56.52; H,8.62; N, 5.99. Found: C, 56.83; H, 8.49; N,
6.25.
Isolated compound: 40 mg (6%, Method B); mp: 75–77 °C;
½
a 2D0
ꢃ
¼ ꢀ0:8 (c 0.25, MeOH); 1H NMR (CDCl3) d (ppm): 0.98 (3H,
s), 1.26 (3H, s), 1.43 (1H, d, J = 10.7 Hz), 1.54–1.61 (1H, m), 1.95–
2.00 (1H, m), 2.12–2.17 (1H, m), 2.18–2.31 (2H, m), 3.05–3.17
(1H, m), 3.34 (1H, d, J = 10.4 Hz), 3.62 (3H, s), 4.42 (1H, dd,
J = 8.1, 13.6 Hz), 4.52 (1H, dd, J = 7.7, 13.6 Hz). 13C NMR (CDCl3) d
(ppm): 21.2, 26.5, 26.9, 27.6, 31.2, 39.3, 40.0, 43.9, 45.0, 52.0,
Acknowledgements
We are grateful to the Hungarian Research Foundation (OTKA
NK81371) for the financial support and acknowledge the receipt
of Bolyai János Fellowships for Zsolt Szakonyi and Tamás A.
Martinek.
80.8, 174.8. IR = 2922, 1724, 1680, 1546, 1374, 1195, 1148 cmꢀ1
.
Anal. Calcd for C12H19NO4 (241.13): C, 59.73; H, 7.94; N, 5.81.
Found: C, 59.66; H, 7.90; N, 5.87.
References
The (1R,2R,3S,5S)-enantiomer (+)-14 was synthesized analo-
gously to (ꢀ)-14, from (1S,5R)-methyl myrtenate; ½a D20
¼ þ0:7 (c
ꢃ
1. (a) Fülöp, F. Chem. Rev. 2001, 101, 2181–2204; (b) Kuhl, A.; Hahn, M. G.; Dumic´,
M.; Mittendorf, J. Amino Acids 2005, 29, 89–100; (c)Enantioselective Synthesis of
b-Amino Acids; Juaristi, E., Soloshonok, V. A., Eds.; Wiley-Interscience: New
York, 2005; (d) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry
2005, 16, 2833–2891; (e) Fülöp, F.; Martinek, T. A.; Tóth, G. K. Chem. Soc. Rev.
2006, 35, 323–334; (f) Horne, W. S.; Gellman, S. H. Acc. Chem. Res. 2008, 41,
1399–1408.
0.25, MeOH); all the spectroscopic data and the mp were similar
to those for the (1S,2S,3R,5R)-enantiomer (ꢀ)-14. Anal. Calcd for
C12H19NO4 (241.13): C, 59.73; H, 7.94; N, 5.81. Found: C, 59.61;
H, 8.02; N, 5.93.
2. Forró, E.; Fülöp, F. Mini-Rev. Org. Chem. 2004, 1, 93–102.
4.8. (1S,2S,3S,5R)-6,6-Dimethyl-3-(nitromethyl)bicyclo[3.1.1]
heptane-2-carboxylic acid (ꢀ)-15
3. Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107, 4437–4492.
4. Cimarelli, C.; Palmieri, G. Journal. Org. Chem. 1996, 61, 5557–5563.
5. Hameršak, Z.; Roje, M.; Avdagic´, A.; Šunjic, V. Tetrahedron: Asymmetry 2007, 18,
635–644.
A 25 mL round-bottomed flask containing 300 mg (1.24 mmol)
of nitro ester (ꢀ)-13 followed by 5 mL each of THF and water
and 106 mg (2 equiv) of LiOHꢂH2O was heated at reflux for 2 h.
The solvent was evaporated off under reduced pressure and
10 mL of water was added to the residue, which was followed by
extraction with EtOAc (3 ꢁ 15 mL). The combined organic layer
was dried over anhydrous Na2SO4, filtered and evaporated to give
6. (a) Enders, D.; Wiedemann, J.; Bettray, W. Synlett 1995, 369–371; (b) Enders,
D.; Wiedemann, J. Liebigs Ann./Recueil 1997, 699–706.
7. (a) Asao, N.; Shimada, T.; Sudo, T.; Tsukada, N.; Yazawa, K.; Gyoung, Y. S.;
Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1997, 62, 6274–6282; (b) Bunnage, M.
E.; Chippindale, A. M.; Davies, S. G.; Parkin, R. M.; Smith, A. D.; Withey, J. M. Org.
Biomol. Chem. 2003, 1, 3698–3707; (c) Bunnage, M. E.; Davies, S. G.; Parkin, R.
M.; Roberts, P. M.; Smith, A. D.; Withey, J. M. Org. Biomol. Chem. 2004, 2, 3337–
3354; (d) Garrido, N. M.; Díez, D.; Domínguez, S. H.; García, M.; Sánchez, R.;
Davies, S. G. Tetrahedron: Asymmetry 2006, 17, 2183–2186; (e) Cailleau, T.;
Cooke, J. W. B.; Davies, S. G.; Ling, K. B.; Naylor, A.; Nicholson, R. L.; Price, P. D.;
Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007,
5, 3922–3931.
nitro acid (ꢀ)-15. Isolated compound: 260 mg (91%); ½a D20
¼ ꢀ0:6
ꢃ
(c 0.25, MeOH); 1H NMR (CDCl3)
d (ppm): 0.86 (1H, d,
J = 10.3 Hz), 0.92 (3H, s), 1.25 (3H, s), 1.64–1.71 (1H, m), 1.97–
2.03 (1H, m), 2.28–2.37 (1H, m), 2.40–2.48 (1H, m), 2.52–2.57
(1H, m), 2.76 (1H, dd, J = 2.5, 6.6 Hz), 3.36–3.47 (1H, m), 4.37
(1H, dd, J = 8.7, 11.7 Hz), 4.53 (1H, dd, J = 6.0, 11.7 Hz). 13C NMR
(CDCl3) d (ppm): 26.7, 28.4, 30.4, 31.0, 38.1, 40.2, 42.7, 47.3, 47.4,
82.8, 179.8. IR = 2947, 1701, 1551, 1380, 1286, 1156 cmꢀ1. Anal.
Calcd for C11H17NO4 (227.12): C, 58.14; H, 7.54; N, 6.16. Found:
C, 58.12; H, 7.51; N, 6.10.
8. (a) Ordoñez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 3–99; (b)
Moglioni, A. G.; Brousse, B. N.; Álvarez-Larena, Á.; Moltrasio, G. Y.; Ortuño, R. M.
Tetrahedron: Asymmetry 2002, 13, 451–454; (c) Aguilera, J.; Guitérrez-Abad, R.;
Mor, Á.; Moglioni, A. G.; Moltrasio, G. Y.; Ortuño, R. M. Tetrahedron: Asymmetry
2008, 19, 2864–2869; (d) Shankaran, K.; Donnelly, K. L.; Shah, S. K.;
Guthikonda, R. N.; MacCoss, M.; Humes, J. L.; Pacholok, S. G.; Grant, S. K.;
Kelly, T. M.; Wong, K. K. Bioorg. Med. Chem. Lett. 2004, 14, 4539–4544; (e)
Receveur, J.-M.; Bryans, J. S.; Field, M. J.; Singh, L.; Horwell, D. C. Bioorg. Med.
Chem. Lett. 1999, 9, 2329–2334; (f) Gajcy, K.; Pe˛kala, J.; Fra˛ckowiak-Wojtasek,
B.; Librowski, T.; Lochyn´ ski, S. Tetrahedron: Asymmetry 2010, 21, 2015–2020.
9. (a) Szakonyi, Z.; Martinek, T. A.; Hetényi, A.; Fülöp, F. Tetrahedron: Asymmetry
2000, 11, 4571–4579; (b) Szakonyi, Z.; Fülöp, F. ARKIVOC 2003, 14, 225–232; (c)
Gyónfalvi, S.; Szakonyi, Z.; Fülöp, F. Tetrahedron: Asymmetry 2003, 14, 3965–
3972; (d) Szakonyi, Z.; Balázs, Á.; Martinek, T. A.; Fülöp, F. Tetrahedron:
Asymmetry 2006, 17, 199–204; (e) Szakonyi, Z.; Martinek, T. A.; Sillanpää, R.;
Fülöp, F. Tetrahedron: Asymmetry 2007, 18, 2442–2447; (f) Szakonyi, Z.;
Martinek, T. A.; Sillanpää, R.; Fülöp, F. Tetrahedron: Asymmetry 2008, 19,
2296–2303; (g) Hetényi, A.; Szakonyi, Z.; Mándity, I. M.; Szolnoki, É.; Tóth, G.
K.; Martinek, T. A.; Fülöp, F. Chem. Commun. 2009, 177–179; (h) Szakonyi, Z.;
Sillanpää, R.; Fülöp, F. Mol. Div. 2010, 14, 59–65.
10. (a) Tolstikova, T. G.; Morozova, E. A.; Pavlova, A. V.; Bolkunov, A. V.; Dolgikh, M.
P.; Koneva, E. A.; Volcho, K. P.; Salakhutdinov, N. F.; Tolstikov, G. A. Dokl. Chem.
2008, 422, 248–250; (b) Fülöp, F.; Szakonyi, Z., PCT Int. Appl., WO 2008/059299
A1, 36 pp.; (c) Singh, R.; Ding, P.; Holland, S.; Goff, D., PCT Int. Appl., WO 2008/
045978 A1, 155 pp.
11. Krishnamurti, R.; Kuivila, H. G. J. Org.Chem. 1986, 51, 4947–4953.
12. Shibuya, K. Synth. Commun. 1994, 24, 2923–2941.
13. Wiese, B.; Knuehl, G.; Flubacher, D.; Priess, J. W.; Ulricksen, B.; Broedner, K.;
Helmchen, G. Eur. Journal. Org.Chem. 2005, 3246–3262.
The (1R,2R,3R,5S)-enantiomer (+)-15 was synthesized analo-
gously to (ꢀ)-15, from (+)-13; ½a D20
¼ þ0:7 (c 0.25, MeOH); all
ꢃ
the spectroscopic data and the mp were similar to those for the
(1S,2S,3S,5R)-enantiomer (ꢀ)-15. Anal. Calcd for
C11H17NO4
(227.12): C, 58.14; H, 7.54; N, 6.16. Found: C, 58.25; H, 7.42; N,
6.33.
4.9. (1S,2S,3S,5R)-3-(Aminomethyl)-6,6-dimethylbicyclo[3.1.1]
heptane-2-carboxylic acid hydrochloride (+)-16
A 50 mL round-bottomed flask containing 200 mg (0.88 mmol)
of nitro acid 15 was hydrogenated with H2 gas at atmospheric
pressure over Raney Ni in 15 mL of MeOH for 2 h. The mixture
was then filtered and evaporated, and the product was purified
by recrystallization as the hydrochloride, giving amino acid hydro-
chloride (ꢀ)-16 as a white solid. Isolated compound: 130 mg
14. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A.; Vreven, T., Jr.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
(63%); mp: 196–198 °C; ½a D20
ꢃ
¼ þ1:4 (c 0.25, MeOH); 1H NMR

2504
Z. Szakonyi et al. / Tetrahedron: Asymmetry 21 (2010) 2498–2504
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
GAUSSIAN 03, Revision D.02; Gaussian: Wallingford CT, 2004.
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;