Stereoselective synthesis of cyclobutyl γ-amino acids leading to branched peptides with a cyclobutane core

Article abstract of DOI:10.1016/j.tetasy.2008.12.019

Alternative synthetic routes are provided to synthesize γ-amino acids in their free form or conveniently protected for their selective incorporation into ramified γ-peptides with a cyclobutane core. The key synthetic-step involves the stereoselective conjugate addition of nitromethane to chiral cyclobutyl alkenoates prepared from (-)-verbenone.

Full text of DOI:10.1016/j.tetasy.2008.12.019

Tetrahedron: Asymmetry 19 (2008) 2864–2869
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of cyclobutyl
peptides with a cyclobutane core
c-amino acids leading to branched
Jordi Aguilera a, Raquel Gutiérrez-Abad a, Àlex Mor a, Albertina G. Moglioni b,
Graciela Y. Moltrasio b, Rosa M. Ortuño a,
*
a Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
b Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Alternative synthetic routes are provided to synthesize
protected for their selective incorporation into ramified
thetic-step involves the stereoselective conjugate addition of nitromethane to chiral cyclobutyl alkeno-
ates prepared from (ꢀ)-verbenone.
c
-amino acids in their free form or conveniently
Received 15 October 2008
Accepted 16 December 2008
Available online 20 January 2009
c-peptides with a cyclobutane core. The key syn-
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Due to these relevant biological and therapeutic properties, the
search for efficient and versatile synthetic strategies to gain access
The biological activity of some
c
-amino acids is well known
to a variety of
c-amino acids, as well as their incorporation into c-
and, consequently, they play a prominent role in the clinical treat-
ment of diseases related to the central nervous system (CNS) such
as epilepsy, neuropathic pain, and anxiety. The most simple repre-
peptides, is a very active research field.10
In our laboratory, we have shown that the presence of a cyclo-
butane ring in the backbone or as a substituent moiety of the main
13
sentative of this family of amino acids, the
c
-amino butyric acid
skeleton of
a
-,11 b-,12 and
c
-
peptides induces well determined
(GABA), is a neurotransmitter that is thought to play a major inhib-
itor role in the CNS.1 However, GABA itself has not been shown to
be useful for clinical uses;2 much effort has been devoted to pro-
ducing GABAergic drugs and prodrugs. Among the earlier em-
conformations of these compounds in solution and in the solid
state. In addition, we have developed efficient and stereoselective
methodologies to synthesize different types of cyclobutane amino
acids, starting from (ꢀ)-verbenone or (ꢀ)-a-pinene as commer-
ployed prototype GABA agents, baclofen has shown
a
low
cially available and inexpensive chiral precursors.14–17
absorption by CNS.3 Gabapentin (GBP, NeurontinÒ) is a more re-
cent GABAergic agonist, which displays important anticonvulsant4
and analgesic5 activity as well as other interesting properties
(Chart 1). Moreover, several derivatives bearing substituents at
the cyclohexane ring, including chiral compounds, have been
shown to be useful for the treatment of diabetic retinopathy,6
and gabapentin-lactam (GBP-L) is neuroprotective in retinal ische-
mia, whereas GBP is not neuroprotective in vivo.7 As a follow-up
compound to gabapentin for the treatment of epilepsy, neuro-
pathic pain, anxiety, and social phobia, (S)-pregabalin (LyricaÒ)
has been developed. This drug displays a new mechanism of action,
Recently, we described the stereoselective addition of nitro-
methane to cyclobutyl alkenoates derived from (ꢀ)-verbenone to
afford nitrocompounds that could be transformed into cyclobutyl
c
-amino acids.18 On the basis of these preliminary results, we re-
port on the development of alternative synthetic routes to prepare
c-amino acids containing an additional functional group linked to
the cyclobutane ring, in a highly stereoselective and efficient man-
ner. These compounds are orthogonally protected and, therefore,
are convenient for selective coupling with other amino acids to af-
ford branched peptides with a cyclobutane core. As a simple exam-
ple, the synthesis of a c-dipeptide derived from a cyclobutane c-
and acts as a voltage-dependent calcium channel
a
2-d subunit
amino acid and a GABA residue is reported.
ligand.8
2. Results and discussion
c-Peptides (c-oligomers derived from
c-residues), although less
studied than
a
- or b-oligomers, have shown an ability to fold to
We have recently described the use of (ꢀ)-verbenone as a chiral
precursor in the synthesis of cyclobutyl aldehydes, 1a–c,19 bearing
different substitutions on the ring. Wittig olefinization of these
compounds by using suitable phosphoranes afforded alkenoate 2
(route 1) and alkenoates 10a–c14 (route 2) (Scheme 1) as mixtures
of Z/E isomers, which could be chromatographically isolated. With
give secondary structures, some of which have displayed impor-
tant biological activities, which are presumably related to their
conformational bias.9
* Corresponding author. Tel.: +34 93 5811 602; fax: +34 93 5811 265.
E-mail address: rosa.ortuno@uab.es (R.M. Ortuño).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.019

J. Aguilera et al. / Tetrahedron: Asymmetry 19 (2008) 2864–2869
2865
CO2H
NH2
CO2H
NH2
CO2H
NH2
O
Cl
CO2H
NH2
NH
H
baclofen
GBP-L
gabapentin
(GBP, NeurontinR)
GABA
(S)-pregabalin
Chart 1.
H
CO2Me
NO2
CO2Me
CH3NO2
O
ref 14
route 2
ref 19
O
R
R
R
TBAF
58-85 %
H
H
10a
: R = ketal
1a: R=
(ketal)
(-)-(S)-verbenone
11a: R = ketal
O
10b: R = CO2Me
10c: R = CH2OBn
O
11b: R = CO2Me
11c: R = CH2OBn
1b: R = CO2Me
1c: R = CH2OBn
R = ketal
HCO2NH4
10% Pd/C
route 1
R = ketal
84%
R = CH2OBn
49%
CO2tBu
H
O
O
O
O
O
H
H
H
NH
+
O
O
2
14
BnO
H
BnO
NH
H
NH
CH3NO2
TBAF
Boc2O
85%
12'
(30%)
12 (70%)
98%
DMAP, Et3N
42% 6 M HCl
H
CO2tBu
NO2
H
H
O
O
O
O
O
H
H
N
CO2H
NH2
Boc
3
15
BnO
H
HCO2NH4
1) 1 M LiOH
2) CH2N2
13
96%
100%
(major isomer)
20% Pd(OH)2/C
H
O
CO2Me
NHBoc
CO2tBu
NH2
H
O
O
GABA-NHBoc
O
HOBt, EDAC
71%
H
H
16
4
CbzCl
3 M NaOH
via Lieben
70%
O
O
O
CO2tBu
H
NH
O
H
H
CO2Me
NHBoc
O
CO2tBu
NHCbz
H
MeO
O
H
NHBoc
5
H
17
6
PPTS
acetone
97%
CO2tBu
H
CO2tBu
NHCbz
H
O
NaOBr, 100%
O
NHCbz
RO
H
H
7
8: R = H
MeI, Cs2CO3
71%
9
: R = Me
Scheme 1.
respect to these substrates, the addition of nitromethane in the
presence of tetrabutylammonium fluoride was carried out in order
to introduce a synthon providing a functional group that could be
easily transformed into the amino function and the additional car-
group (methyl or tert-butyl). Moreover, the reaction between
nitromethane and both Z- and E-isomers converged in the same
product. The configuration of the new stereogenic center was as-
signed to be (S) by X-ray structural analysis of lactam 14 (Scheme
1).19 The configuration of compounds 3 and 11b was assigned by
comparison of the NMR data of these products or some derivatives
with 11a and 14. When nitromethane addition was carried out on
the benzyl ether 11c, a 7:3 mixture of diastereoisomers 12/120 was
produced showing the influence on the stereoselectivity of the sub-
stituent at the C3 position of the cyclobutane ring, probably due to
bon atom of the c-amino acid skeleton. The conjugate addition of
nitromethane to conveniently functionalized olefins has been suc-
cessfully used in the stereoselective synthesis of pharmacologically
relevant products.20 We found that the addition of nitromethane to
substrates 2 and 10a–b was totally stereoselective, providing ad-
ducts as single diastereoisomers independent of the ester alkyl

2866
J. Aguilera et al. / Tetrahedron: Asymmetry 19 (2008) 2864–2869
the steric effects. The stereochemical outcome of the process was
rationalized by assuming that the preferential attack of nitrometh-
ane was to the less hindered C2-re face of the double bond, which is
opposite to the gem-dimethyl group in the most stable conforma-
tion (Fig. 1). Similar results have been found in the stereoselective
addition of diazomethane21 and alkyl hydroxylamines14 to these
substrates.
and the resulting mixture was stirred for 15 h. Afterwards, the sol-
vent was evaporated under vacuo. The resulting crude was dis-
solved in hot diethyl ether, and the solution was filtered through
a sintered glass funnel. Again, the solvent was evaporated under
vacuo, and the resulting crude was purified by flash chromatogra-
phy (1:1 hexane–ethyl acetate) to afford 2 (3.9 g, 86%) as a 53:47
mixture of Z/E olefins. IR: 2979, 2935, 2879, 1717, 1713, 1647,
1420, 1368 cmꢀ1 1H NMR (CDCl3) for isomer Z: 1.08 (s, 3H), 1.17
.
R'
(s, 3H), 1.26 (s, 3H), 1.50 (s, 9H), 1.93–1.98 (m, 1H), 2.05–2.10
(m, 1H), 2.20–2.30, (m, 1H), 3.82–4.05 (complex, 4H), 5.64–5.75
C2-re
3
4
(m, 1H), 6.06 (dd, J3,2 = 11.6 Hz, J3,4 = 10.2 Hz, 1H). 1H NMR
(CDCl3) for isomer E:
d 1.04 (s, 3H), 1.17 (s, 3H), 1.26
Me
Me
H
H
(s, 3H), 1.50 (s, 9H), 1.72–1.83 (m, 1H), 2.20–2.30 (m, 1H), 2.46–
2.55 (m, 1H), 3.82–4.05 (m, 4H), 5.64–5.75 (m, 1H), 6.84 (dd,
H
4
3J2,1 = 15.6 Hz, J2,3 = 7.4 Hz). 13C NMR (CDCl3): 18.11, 23.18,
H
R
23.42, 23.68, 25.17, 28.08, 28.14, 30.91, 31.41, 39.83, 43.66,
44.16, 44.69, 49.73, 49.87, 63.62, 65.45, 65.51, 79.98, 109.55,
109.76, 121.94, 123.08, 147.68, 148.62, 165.77, 165.97. Anal. Calcd
for C17H28O4: C, 68.89 ; H, 9.52. Found C, 69.08; H, 9.55.
Figure 1. The attack of nitromethane to the double bond occurs on the C2-re face,
which is the less hindered side of the double bond.
Reduction of the nitro group was accomplished by treatment of
the nitro esters with ammonium formate in the presence of 10%
Pd/C in boiling methanol. In the case of methyl esters 10a, c, lac-
tams 12, 120, and 13 were, respectively, obtained without isolation
of the intermediate amino esters, which underwent in situ cycliza-
tion to lactams. Conversely, in the case of the very poor nucleo-
philic tert-butyl nitroester 3, amino ester 4 could be isolated.
This compound was already suitable for incorporation into pep-
tides as verified by the coupling of 4 with Boc-NH-GABA under
4.2. (S)-tert-Butyl 3-[(1R,3R)-2,2-dimethyl-3-(2-methyl-1,3-
dioxolan-2-yl)cyclobutyl]-4-nitrobutanoate, 3
To a solution of alkenes 2 (4.1 g, 13.9 mmol) in 150 mL of anhy-
drous THF under nitrogen atmosphere were subsequently added
nitromethane (0.9 mL, 15.8 mmol) and 1.0 M TBAF in THF
(16.1 mL, 16.8 mmol). The resulting mixture was let to stir for
18 h. Next, the solvent was evaporated at reduced pressure, and
the resulting crude was chromatographed on silica gel (4:1, hex-
ane–ethyl acetate) to afford compound 3 as a colorless oil (4.2 g,
the usual conditions (HOBt, EDAC) to provide
c-dipeptide 5 in
71% yield. Alternatively, the amino group in 4 was protected as a
Cbz carbamate to afford 6 in 70% yield. Deprotection of the methyl
ketone under mild conditions (PPTS, boiling acetone, 2 h) afforded
compound 7 in almost quantitative yield without epimerization.
Lieben degradation by using sodium hypobromite in dioxane at
0 °C quantitatively furnished acid 8. Subsequent methylation un-
der treatment with methyl iodide and cesium carbonate gave
orthogonally protected compound 9 in 71% yield. This product is
useful as it can be submitted to successive peptide couplings
through selective deprotection of the three functional groups.
According to route 2, the diastereomeric mixture of lactams 12
and 120 could not be resolved, while acid hydrolysis with 6 M HCl
provided the free amino acid 13 which was enriched in the major
diastereomer by crystallization.
85%). [
a]
D = ꢀ22.0 (c 1.00, CH2Cl2). IR: 2980, 2950, 2876, 1724,
1549, 1463, 1428, 1369 cmꢀ1
.
1H NMR (CDCl3): 1.09 (s, 3H), 1.16
(s, 3H), 1.20 (s, 3H), 1.23 (s, 9H), 1.60 (m, 1H), 1.73 (m, 1H), 1.90
(m, 1H), 2.03–2.09 (m, 1H), 2.23–2.29 (complex absorption, 2H),
2.38–2.53 (m, 1H), 3.78–3.96 (complex absorption, 4H), 4.36–
4.51 (complex absorption, 2H). 13C NMR (CDCl3): 16.40, 23.16,
23.67, 27.97, 31.79, 35.53, 35.92, 41.22, 42.91, 48.97, 63.58,
65.40, 76.43, 81.11, 109.42, 170.50. HRMS: calcd for C18H31NO6Na
(M+Na): 380.2044. Found: 380.2040.
4.3. (S)-tert-Butyl 4-amino-3-[(1R,3R)-2,2-dimethyl-3-(2-
methyl-1,3-dioxolan-2-yl)cyclobutyl]butanoate, 4
In turn, lactam 14 provided, almost quantitatively, the N-Boc
derivative 15 which, upon mild hydrolysis with 1 M LiOH followed
by methylation, led to compound 16. Ketal protection was re-
moved under similar conditions to those described above in route
1 (transformation of 6 into 7) to afford a methyl ketone which, un-
der Lieben degradation and subsequent methylation, as described
in route 1, provided the protected derivative 17.
To a solution of 3 (5.0 g, 14.0 mmol) in 125 mL of anhydrous
methanol were subsequently added ammonium formate (3.2 g,
49.4 mmol) and 20% Pd(OH)2/C (1.1 g). The resulting mixture was
heated at reflux for 2 h. Afterwards, the reaction mixture was fil-
tered through CeliteÒ, and the solvent was eliminated under vacuo
to obtain a yellow oil identified as amine 4 (4.6 g, 96%). [
a]
D = ꢀ8.3
(c 0.48, CH2Cl2). IR: 3384, 2978, 1725, 1461, 1392, 1368, 1256,
1224, 1156, 1102, 1038, 949, 863, 842, 734 cmꢀ1. 1H NMR (CDCl3):
1.10 (s, 3H), 1.18 (s, 3H), 1.23 (s, 3H), 1.45 (s, 9H), 1.55–1.72 (com-
plex absorption, 2H), 1.81–1.97 (complex absorption, 2H), 2.02–
2.16 (complex absorption, 4H), 2.26 (dd, J = 14.5 Hz, J0 = 3.6 Hz),
2.57 (dd, J = 12.9 Hz, J0 = 6.7 Hz, 1H), 2.75 (dd, J = 12.9 Hz,
J0 = 3.9 Hz, 1H), 3.78–3.97 (complex absorption, 4H). 13C NMR
(CDCl3): 16.53, 23.44, 23.77, 28.00, 31.99, 36.67, 41.04, 41.99,
43.68, 49.19, 63.60, 65.42, 109.59, 172.50. HRMS: calcd for
C18H33NO4Na (M+Na): 328.2482. Found: 328.2484.
3. Conclusion
We have reported highly stereoselective and alternative syn-
thetic-routes to prepare cyclobutyl
form or conveniently protected to be incorporated into branched
-peptides with a cyclobutane core.
c-amino acids, in their free
c
4. Experimental
4.1. tert-Butyl 3-[(1R,3R)-2,2-dimethyl-3-(2-methyl-1,3-di-
oxolan-2-yl)cyclobutyl]-acrylate, 2
4.4. (S)-tert-Butyl 4-(4-(tert-butoxycarbonylamino)butana-
mido)-3-[(1R,3R)-2,2-dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)-
cyclobutyl]butanoate, 5
t
To a solution of Ph3P@CHCO2 Bu (8.3 g, 14.9 mmol) in 20 mL of
anhydrous methanol under a nitrogen atmosphere was added a
A mixture containing GABA-NHBoc (372 mg, 1.8 mmol), EDAC
(702 mg, 3.7 mmol), HOBt (248 mg, 1.8 mmol), and triethylamine
solution of aldehyde 1a19 (3.01 g) in 80 mL of anhydrous methanol,

J. Aguilera et al. / Tetrahedron: Asymmetry 19 (2008) 2864–2869
2867
(0.56 mL, 4.1 mmol) in dry DMF (15 mL) was stirred for 30 min,
and then amine 4 (400 mg, 1.7 mmol) in dry DMF (10 mL) was
added. After stirring at room temperature for 40 h, most of the
DMF was removed under vacuo. The residue was dissolved in ethyl
acetate (50 mL), and the solution was washed with saturated aque-
ous sodium bicarbonate (4 ꢁ 20 mL). The organic phase was dried
over magnesium sulfate, and the solvents were removed. The reac-
tion crude was purified by column chromatography on neutral sil-
ica gel (1:5 ethyl acetate–hexane) to afford pure 5 (608 mg, 71%
7.41 (complex absorption, 5H). 13C NMR (CDCl3): 17.19, 22.85,
28.46, 30.66, 31.64, 37.66, 42.77, 43.71, 44.25, 54.06, 67.71,
81.52, 110.00, 124.44, 128.87, 137.09, 156.31, 172.13, 207.85.
HRMS: calcd for C24H35NO5Na (M+Na): 440.2407. Found:
440.2398.
4.7. Benzyl (2S,10R,30R)-3-(tert-butoxycarbonyl)-2-(20,20-di-
methyl-30-carboxycyclobutyl)propylcarbamate, 8
yield). [
a
]
D = +7.3 (c 3, CH2Cl2). IR: 3316, 2975, 2877, 1711, 1691,
To an ice cooled solution of ketone 8 (220 mg, 0.5 mmol) in
18 mL of dioxane–water (7:2) was added 40 mL of a sodium hypo-
bromite solution, prepared from bromine (0.4 mL, 8.43 mmol) and
sodium hydroxide (1.3 g, 31.6 mmol) in 3:1 water–dioxane; the
resulting mixture was stirred for 5 h at 0 °C. Next, 10 mL of sodium
bisulfate was added, and the mixture was brought to acidic pH by
adding 5% hydrochloric acid. The acid solution was extracted with
dichloromethane (4 ꢁ 30 mL), the organic extracts were dried over
anhydrous magnesium sulfate, and the solvent was removed to af-
1648, 1524, 1452 cmꢀ1
.
1H NMR (CDCl3): 1.08 (s, 3H), 1.22 (s,
3H), 1.44–1.45 (ds, 18H), 1.55–1.65 (complex absorption, 2H),
1.80 (m, 2H), 1.87–1.92 (m, 1H), 1.95–2.10 (complex absorption,
3H), 2.19 (t, J = 7 Hz, 2H), 2.26 (dd, J = 14 Hz, J0 = 2.2 Hz, 1H),
2.94–3.02 (m, 1H), 3.13–3.18 (m, 2H), 3.35 (ddd, J = 13 Hz, J0 = 5 Hz,
J00 = 4 Hz, 1H), 3.77–3.99 (complex absorption, 4H), 4.81 (br s, 1H),
4.81 (br s, 1H). 13C NMR (CDCl3): 16.65, 23.80, 23.86, 26.18, 28.06,
28.36, 32.11, 33.75, 36.28, 37.68, 39.83, 41.08, 41.31, 44.33, 49.33,
63.69, 64.48, 79.15, 80.94, 110.06, 156.25, 172.54, 172.84. HRMS:
calcd for C27H48N2NaO7, (M+Na): 535.3354. Found: 335.3352.
ford carboxylic acid 8 (221 mg, quantitative). [
a]
D = +93.3 (c 0.15,
CH2Cl2). IR: 3341, 2957, 1709, 1707, 1524, 1455 cmꢀ1
.
1H NMR
(CDCl3): 1.12 (s, 3H), 1.29 (s, 3H), 1.45 (s, 9H), 1.75–1.89 (m, 1H),
1.90–2.14 (complex absorption, 4H), 2.17–2.32 (m, 1H), 2.59–
2.75 (m, 1H), 3.00–3.15 (m, 1H), 3.20–3.38 (m, 1H), 5.03–5.23
(complex absorption, 3H), 7.30–7.43 (complex absorption, 5H).
13C NMR (CDCl3): 17.38, 23.97, 28.47, 30.09, 31.30, 37.56, 42.80,
43.38, 44.43, 45.92, 67.08, 81.45, 128.50, 128.89, 136.89, 156.97,
172.48, 178.21. HRMS: calcd for C23H33NO6Na (M+Na): 442.2200.
Found: 442.2197.
4.5. (S)-tert-Butyl 4-(benzyloxycarbonylamino)-3-[(1R,3R)-2,2-
dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)cyclobutyl]butanoate,
6
To an ice cooled solution of 60% sodium hydride (189 mg,
4.9 mmol) in 20 mL of anhydrous THF was subsequently added a
solution of amine 5 (1.0 g, 3.1 mmol) in 40 mL of anhydrous THF
and benzyl chloroformate (0.7 mL, 4.4 mmol). The resulting mix-
ture was let to react for 15 h, after which, 30 mL of water was
added and THF was evaporated under vacuo. To the resulting crude
was added 40 mL of dichloromethane, and the resulting solution
was washed with saturated aqueous sodium bicarbonate
(4 ꢁ 20 mL). The organic phase was dried over magnesium sulfate,
and the solvent was removed at reduced pressure. The reaction
crude was purified by column chromatography on neutral silica
gel (1:4 ethyl acetate–hexane) to afford a colorless oil identified
4.8. (1R,3R)-Methyl 3-[(S)-1-(benzyloxycarbonylamino)-4-tert-
butoxy-4-oxobutan-2-yl)-2,2-dimethylcyclobutanecarboxylate,
9
To a solution of carboxylic acid 8 (150 mg, 0.4 mmol) in 40 mL
of dimethylformamide, cesium carbonate (140 mg, 0.4 mmol) and
iodomethane (0.1 mL, 1.60 mmol) were subsequently added. The
resulting mixture was left to stir for 16 h at room temperature.
Afterwards, ethyl acetate (40 mL) was added, and the solution
was washed with saturated aqueous sodium bicarbonate
(4 ꢁ 20 mL). The organic phase was dried over magnesium sulfate,
and the solvent was removed at reduced pressure. The residue was
chromatographed on silica gel (1:1 hexane–diethyl ether) to afford
as compound 6 (1.0 g, 70%). [
a]
D = +14.6 (c 0.55, CH2Cl2). IR:
3339, 2977, 2952, 2880, 1724, 1518, 1455, 1368, 1247 cmꢀ1
.
1H
NMR (CDCl3): 1.07 (s, 3H), 1.14 (s, 3H), 1.20 (s, 3H), 1.41 (s, 9H),
1.54–1.66 (complex absorption, 2H), 1.87–2.05 (complex absorp-
tion, 4H), 2.23 (dd, J = 18.5 Hz, J00 = 7.2 Hz, 1H), 2.98 (m, 1H), 3.32
(ddd, J = 12.7 Hz, J0 = 5.7 Hz, J00 = 3.2 Hz, 1H), 3.72–3.98 (complex
absorption, 4H), 5.07 (s, 2H), 5.20 (dd, J = 5.7 Hz, J0 = 6.0 Hz, 1H),
7.24–7.38 (complex absorption, 5H). 13C NMR (CDCl3): 16.48,
23.63, 23.72, 27.92, 31.95, 36.80, 37.28, 40.97, 42.50, 44.03,
49.29, 63.54, 65.34, 66.35, 80.60, 109.56, 127.84, 127.91, 128.30,
136.59, 156.33. HRMS: calcd for C26H39NO6Na (M+Na): 484.2670.
Found: 484.2671.
pure ester 9 (110 mg, 71%). [
a
]
D = +64.4 (c 0.29, CH2Cl2). IR: 3366,
2951, 1721, 1720, 1518, 1455 cmꢀ1
.
1H NMR (CDCl3): 0.98 (s,
3H), 1.26 (s, 3H), 1.45 (s, 9H), 1.71–1.85 (m, 1H), 1.90–2.11 (com-
plex absorption, 4H), 2.16–2.34 (m, 1H), 2.54–2.71 (m, 1H), 2.98–
3.12 (m, 1H), 3.20–3.35 (m, 1H), 3.67 (s, 3H), 5.00–5.21 (complex
absorption, 3H), 7.29–7.44 (complex absorption, 5H). 13C NMR
(CDCl3): 17.01, 23.67, 28.00, 30.85, 37.09, 42.34, 42.66, 43.92,
45.56, 51.12, 66.53, 80.90, 109.53, 127.97, 128.41, 136.33, 156.41,
171.84, 172.84. HRMS: calcd for C24H35NO6Na (M+Na): 456.2357.
Found: 456.2349.
4.6. (S)-tert-Butyl 3-[(1R,3R)-3-acetyl-2,2-dimethylcyclobutyl)-
4-(benzyloxy-carbonylamino]butanoate, 7
A mixture containing compound 6 (250 mg, 0.5 mmol), PPTS
(41 mg, 0.2 mmol), and water (2 mL, 111 mmol) in acetone
(40 mL) was heated at reflux for 2 h. Afterwards, acetone was evap-
orated under vacuo. The resulting crude was poured into 40 mL of
ethyl acetate, and the solution was washed with saturated aqueous
sodium bicarbonate (3 ꢁ 20 mL). The organic phase was dried over
magnesium sulfate. The solvent was removed at reduced pressure,
and the residue was chromatographed on silica gel (ethyl acetate)
4.9. (S)-Methyl-3-[(1R,3R)-2,2-dimethyl-3-(2-methyl-1,3-di-
oxolan-2-yl)cyclobutyl]-4-nitrobutanoate, 11a
Nitromethane (2.3 mL, 42 mmol) was added to a mixture of
9.4 g of 10a15 (37 mmol) and 42 mL of TBAF (1 M in THF, 42 mmol)
in 400 mL of THF at ꢀ5 °C. The mixture was stirred for 3 h, and the
solvent was evaporated under vacuo. The crude was dissolved in
EtOAc (350 mL) and washed with brine (3 ꢁ 15 mL). The organic
phase was dried over magnesium sulfate, and the solvent was
evaporated at reduced pressure. The residue was chromatographed
on silica gel (1:4 ethyl acetate–hexane) to afford 11a (11.1 g, 95%
yield). 1H NMR (CDCl3): 1.09 (s, 3H), 1.15 (s, 3H), 1.21 (s, 3H),
1.60 (m, 1H), 1.72 (m, 1H), 1.87–1.96 (m, 1H), 2.03–2.11 (complex
to afford pure methyl-ketone 7 (220 mg, 97%) as an oil. [a]D = +37.4
(c 2.12, CH2Cl2). IR: 3365, 2954, 1724, 1705, 1523, 1455.84 cmꢀ1
.
1H NMR (CDCl3): 0.92 (s, 3H), 1.35 (s, 3H), 1.44 (s, 9H), 1.73–2.26
(complex absorption, 9H), 2.65–2.82 (m, 1H), 2.98–3.14 (m, 1H),
3.19–3.34 (m, 1H), 5.00–5.28 (complex absorption, 3H), 7.29–

2868
J. Aguilera et al. / Tetrahedron: Asymmetry 19 (2008) 2864–2869
absorption, 1H), 2.37–2.40 (complex absorption, 2H), 2.44–2.59
(m, 1H), 3.68 (s, 3H), 3.75–4.02 (complex absorption, 4H), 4.42–
4.47 (complex absorption, 2H). 13C NMR (CDCl3): 16.46, 23.15,
23.67, 31.75, 34.19, 35.71, 41.22, 42.99, 48.93, 51.66, 63.59,
65.41, 76.35, 109.41, 171.71.
and the residue was chromatographed on silica gel (1:1 ethyl ace-
tate–hexane) to afford 15 as a white powder (277 mg, 98% yield).
Crystals, mp 110–112 °C (pentane). [
a]
D = ꢀ23.7 (c 2.55, CH2Cl2).
IR: 2978, 1793, 1692, 1458 cmꢀ1 1H NMR (CDCl3): 1.06 (s, 3H),
.
1.14 (s, 3H), 1.23 (s, 3H), 1.53 (s, 9H), 1.71 (m, 1H), 1.92 (dd,
J = 7.5 Hz, J0 = 11.5 Hz, 1H), 2.15 (m, 1H), 2.27 (m, 1H), 2.56 (dd,
J = 7.5 Hz, J0 = 15 Hz, 1H), 3.25 (dd, J = 11 Hz, J0 = = 15 Hz, 1H), 3.90
(complex absorption, 5H). 13C NMR (CDCl3): 17.72, 23.38, 24.40,
28.26, 33.40, 39.30, 41.84, 47.27, 49.32, 50.61, 64.22, 64.54,
83.42, 110.47, 150.80, 174.43. HRMS: calcd for C19H31NO5Na
(M+Na): 376.2094. Found: 376.2088.
4.10. (S)-4-[(1R,3R)-3-Benzyloxymethyl-2,2-dimethylcyclo-
butyl]pyrrolidin-2-one, 12
A mixture containing 250 mg of nitroester 11c (0.71 mmol),
346 mg of ammonium formate (5 mmol), and 125 mg of 20%
Pd(OH)2/C in 25 mL of dry methanol was heated at reflux over-
night. Afterwards, reaction mixture was filtered through Celite,
and solvent was removed under vacuo and chromatographed on
silica gel (30:1 methylene chloride–methanol) to afford 12 as a
mixture of diastereomers in a 7:3 ratio (103 mg, 49% yield). Spec-
troscopic data for major epimer are as follows. 1H NMR (CDCl3):
0.93 (s, 3H), 1.29 (s, 3H), 1.8–2.1 (m, 3H), 2.20 (m, 1H), 2.37 (m,
2H), 2.93 (m, 1H), 3.41–3.52 (m, 4H), 4.48 (s, 2H), 6.9 (br s, 1H),
7.36–7.41 (complex absorption, 5H). 13C NMR (CDCl3): 17.60,
25.33, 32.11, 36.05, 36.31, 41.16, 42.31, 47.55, 49,12, 71.50,
73.23, 127.11, 129.62, 138.34, 178.76.
4.14. (S)-Methyl-4-(tert-butoxycarbonylamino)-3-[(1R,3R)-2,2-
dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)cyclobutyl]butanoate,
16
An aqueous solution of 1 M LiOH (0.61 mL) was added to a solu-
tion of lactam 15 (100 mg, 0.31 mmol) in 5 mL of THF. The mixture
was stirred for 2 h, after which the solvents were evaporated under
vacuo until dryness. The product was extracted with methanol
(3 ꢁ 10 mL), and the organic solvent was evaporated. The resulting
carboxylic acid was methylated without previous purification
using a saturated solution of diazomethane in dichloromethane
4.11. (S)-4-Amino-3-[(1R,3R)-3-benzyloxymethyl-2,2-dimethyl-
cyclobutyl] butanoic acid, 13
to afford 16 as a colorless oil (120 mg, quantitative). [
a
]
.
D = ꢀ34 (c
1.20, CH2Cl2). IR: 3378, 2952, 1720, 1714, 1511 cmꢀ1
1H NMR
(CDCl3): 1.10 (s, 3H), 1.17 (s, 3H), 1.24 (s, 3H), 1.44 (s, 9H), 1.61
(m, 1H), 1.69 (m, 1H), 1.87 (m, 1H), 2.10 (complex absorption,
3H), 2.29 (m, 1H), 2.90 (m, 1H), 3.23 (m, 1H), 3.68 (s, 3H), 3.77–
4.01 (complex absorption, 4H), 4.74 (br s, 1H). 13C NMR (CDCl3):
16.81, 23.67, 24.15, 28.31, 31.98, 35.99, 37.04, 41.28, 42.07,
44.41, 49.44, 51.72, 63.8, 65.59, 109.81, 156.15, 173.41. HRMS:
Calc. for C20H35NO6Na (M+Na): 408.2357. Found: 408.2358.
At first, 80 mg of the mixture 11 (0.28 mmol) was dissolved in
4 mL of 6 M HCl and heated at reflux for 3 h. After that time, sol-
vent was removed under vacuo and chromatographed on silica
gel (10:1 dichloromethane–methanol) to afford 13 as a diastereo-
meric mixture (35 mg, 42% yield). Spectroscopic data for the major
epimer are as follows. 1H NMR (D2O): 0.93 (s, 3H), 1.08 (s, 3H), 1.71
(m, 1H), 1.87–1.92 (m, 2H), 1.95 (m, 1H), 2.17 (m, 1H), 2.37 (m,
1H), 2.57 (m, 1H), 2.71–2.87 (m, 2H), 3.28 (m, 1H), 3.40 (m, 1H),
3.55 (m, 1H), 4.57 (s, 2H), 7.32 (complex absorption, 5H). 13C
NMR (D2O): 15.52, 25.15, 30.99, 35.69, 39.49, 41.45, 42.45, 42.76,
43.58, 44.59, 62.74, 128.50, 130.01, 139.92, 180.89. HRMS: calcd
For C11H21NO3 (M+HꢀBn): 216,1594. Found: 216,1596.
4.15. (1R,3R)-Methyl-3-((S)-1-(tert-butoxycarbonylamino)-4-
methoxy-4-oxobutan-2-yl)-2,2-dimethylcyclobutane-
carboxylate, 17
Following a similar procedure to that described above for the
synthesis of 9, compound 17 was obtained (69% yield from 16).
4.12. (S)-4-[(1R,3R)-2,2-Dimethyl-3-(2-methyl-1,3-dioxolan-2-
yl)cyclobutyl]-pyrrolidin-2-one, 14
[a]
D = ꢀ13 (c 2.5, CH2Cl2). IR: 3388, 2952, 1720, 1712, 1510,
1164 cmꢀ1 1H NMR (CDCl3): 0.97 (s, 3H), 1.31 (s, 3H), 1.42 (s,
.
9H), 1.73 (m, 1H), 1.83–2.34 (complex absorption, 5H), 2.56 (m,
1H), 2.94 (m, 1H), 3.21 (m, 1H), 3.67 (s, 3H), 3.70 (m, 3H), 4.75
(br s, 1H). 13C NMR (CDCl3): 16.95, 23.49, 28.35, 30.78, 35.40,
36.99, 41.69, 42.70, 44.13, 45.55, 51.00, 51.59, 79.11, 155.89,
172.72, 172.98. HRMS: calcd for C19H31NO5Na (M+Na): 380.2044.
Found: 380.2046.
A mixture containing nitroester 11a (1.1 g 3.38 mmol), ammo-
nium formate (0.78 g, 28 mmol), and 10% Pd/C (1.2 mg) in
100 mL dry methanol was heated at reflux overnight. The reaction
mixture was filtered through CeliteÒ, and the solvent was evapo-
rated to obtain 14 as a white solid (722 mg, 84% yield). Crystals,
mp 70–71 °C (acetone). [
a
]
D = ꢀ15 (c 0.65, CH2Cl2). IR: 3176,
2954, 2885, 1707, 1459 cmꢀ1
.
1H NMR (CDCl3): 1.07 (s, 3H), 1.16
Acknowledgments
(s, 3H), 1.23 (s, 3H), 1.52 (m, 1H), 1.70–2.00 (complex absorption,
3H), 2.12 (dd, J = 7.5 Hz, J0 = 12 Hz, 1H), 2.30–2.55 (complex
absorption, 2H), 2.95 (dd, J = 6 Hz, J0 = 9 Hz, 1H), 3.41 (m, 1H),
3.78–4.04 (complex absorption, 4H), 5.84 (br s, 1H). 13C NMR
(CDCl3): 17.67, 23.76, 29.94, 32.31, 36.44, 37.02, 41.45, 46.22,
47.83, 50.05, 63.93, 64.17, 110.22, 177.26. Anal. Calcd for: C,
61.97; H, 9.29; N, 5.16. Found: C, 62.27; H, 8.83; N, 4.74.
Financial support from Ministerio de Ciencia e Innovación
(CTQ2007-61704/BQU) and Generalitat de Catalunya (2005SGR-
103) is gratefully acknowledged. R.G. thanks the Ministerio de Edu-
cación for a predoctoral fellowship.
References
4.13. (S)-tert-Butyl-4-[(1R,3R)-2,2-dimethyl-3-(2-methyl-1,3-
1. Roberts, E. Biochem. Pharmacol. 1974, 23, 2637.
dioxolan-2-yl)cyclobutyl]-2-oxopyrrolidine-1-carboxylate, 15
2. (a) Velmupalli, S.; Barletta, M. Arch. Int. Pharmacodyn. 1984, 267, 46; (b)
Nurnberger, J. I.; Berrettini, W. H.; Simmons-Alling, S.; Guroff, J. I.; Gershon, E. S.
Psychiat. Res. 1986, 19, 113.
3. Wall, G. M.; Baker, J. K. J. Med. Chem. 1989, 32, 1340. and references cited
therein.
4. Cczuczwar, S. J.; Patsalos, P. N. CNS Drugs 2001, 15, 339.
5. Gu, Y.; Huang, L.-Y. M. Pain 2001, 93, 85.
6. Bryans, J. S.; Hu, L.-Y.; Hutson, S. M.; Lanoue, K. F.; Lieth, E.; Rafferty, M. F.;
Ryder, T. R.; Su, T.-Z.; Welty, D. F.; Wustrow, D. J. PCT Int. Appl. 2001 (Chem.
Abstr., 2001, 135, 46446j).
To a solution of lactam 14 (200 mg, 0.8 mmol) in 5 mL of anhy-
drous dichloromethane, 99 mg of DMAP, 0.12 mL of triethylamine,
and 0.36 mL of Boc2O were subsequently added, and the resulting
mixture was stirred overnight. Afterwards, the mixture was
washed with sodium bicarbonate (3 ꢁ 2 mL), and the organic
phase was dried over magnesium sulfate. Solvent was removed,

J. Aguilera et al. / Tetrahedron: Asymmetry 19 (2008) 2864–2869
2869
7. Jehle, T.; Feuerstein, T. J.; Lagreze, W. A. Ophtalmologe 2001, 98, 237.
8. (a) Bryans, J. S.; Wustrow, D. J. Med. Res. Rev. 1999, 19, 149; (b) Belliotti, T.; Capiris,
T.; Ekhato, V.; Kinsora, J. J.; Field, M. J.; Heffner, T. G.; Meltzer, L. T.; Schwarz, J. B.;
Taylor, C. P.; Thorpe, A. J.; Vartanian, M. G.; Wise, L. D.; Zhi-Su, T.; Weber, M.;
Wustrow, D. J. J. Med. Chem. 2005, 48, 2294. and references cited therein.
9. (a) Hintermann, T.; Gadermann, K.; Jaun, B.; Seebach, D. Helv. Chim. Acta 1998,
81, 983; (b) Seebach, D.; Hook, D. F.; Glatti, A. Biopolymers 2006, 84, 23.
10. Ordoñez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 3.
11. Aguado, G. P.; Moglioni, A. G.; Brousse, B. N.; Ortuño, R. M. Tetrahedron:
Asymmetry 2003, 14, 2445.
15. Aguado, G. P.; Moglioni, A. G.; García-Expósito, E.; Branchadell, V.; Ortuño, R.
M. J. Org. Chem. 2004, 69, 7971.
16. Ortuño, R. M.; Moglioni, A. G.; Moltrasio, G. Curr. Org. Chem. 2005, 9, 237.
17. Ortuño, R. M. In Enantioselective Synthesis of b-Amino Acids; Juaristi, E.,
Soloshonok, V. A., Eds., 2nd ed.; John Wiley and Sons: New Jersey, 2005; pp
117–137.
18. Moglioni, A. G.; Brousse, B. N.; Álvarez-Larena, Á.; Moltrasio, G. Y.; Ortuño, R.
M. Tetrahedron: Asymmetry 2002, 13, 451.
19. Moglioni, A. G.; García-Expósito, E.; Aguado, G. P.; Parella, T.; Moltrasio, G. Y.;
Branchadell, V.; Ortuño, R. M. J. Org. Chem. 2000, 65, 3934.
12. (a) Izquierdo, S.; Kogan, M. J.; Parella, T.; Moglioni, A. G.; Branchadell, V.; Giralt,
E.; Ortuño, R. M. J. Org. Chem. 2004, 69, 5093; (b) Izquierdo, S.; Rúa, F.; Sbai, A.;
Parella, T.; Álvarez-Larena, Á.; Branchadell, V.; Ortuño, R. M. J. Org. Chem. 2005,
70, 7963; (c) Rúa, F.; Boussert, S.; Parella, T.; Diez-Pérez, I.; Branchadell, V.;
Giralt, E.; Ortuño, R. M. Org. Lett. 2007, 9, 3643.
13. Aguilera, J.; Moglioni, A. G.; Moltrasio, G. Y.; Ortuño, R. M. Tetrahedron:
Asymmetry 2008, 19, 302.
14. Moglioni, A. G.; Muray, E.; Castillo, J. A.; Álvarez-Larena, Á.; Moltrasio, G. Y.;
Branchadell, V.; Ortuño, R. M. J. Org. Chem. 2002, 67, 2402.
20. (a) Domingos, J. L. O.; Lima, E. C.; Dias, A. G.; Costa, P. R. R.
Tetrahedron: Asymmetry 2004, 15, 2313; (b) Izquierdo, S.; Aguilera, J.;
Buschmann, H.; García, M.; Torrens, A.; Ortuño, R. M. Tetrahedron:
Asymmetry 2008, 19, 651.
21. (a) Moglioni, A. G.; García-Expósito, E.; Álvarez-Larena, Á.; Branchadell, V.;
Moltrasio, G. Y.; Ortuño, R. M. Tetrahedron: Asymmetry 2000, 11, 4903; (b)
Muray, E.; Illa, O.; Amsallem, D.; Moglioni, A. G.; Gornitzka, H.;
Branchadell, V.; Baceiredo, A.; Ortuño, R. M. Tetrahedron: Asymmetry
2002, 13, 2593.