Stereodivergent synthesis of the first bis(cyclobutane) γ-dipeptides and mixed γ-oligomers

Article abstract of DOI:10.1016/j.tetasy.2008.01.020

Diastereomeric bis(cyclobutane) γ-dipeptides, a new class of γ-peptides, have been synthesized efficiently from both enantiomers of conveniently protected 3-amino-2,2-dimethyl-1-carboxylic acid. These amino acids have been prepared in very good overall yields through enantiodivergent synthetic routes starting from (-)-cis-pinononic acid. Mixed γ-oligomers have also been prepared from GABA and cyclobutane residues.

Full text of DOI:10.1016/j.tetasy.2008.01.020

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 302–308
Stereodivergent synthesis of the first bis(cyclobutane)
c-dipeptides and mixed c-oligomers
Jordi Aguilera,a Albertina G. Moglioni,b Graciela Y. Moltrasiob and Rosa M. Ortunoa,*
˜
a
`
Departament de Quı´mica, Universitat Autonoma de Barcelona, 08193 Bellaterra, Barcelona, Spain
bDepartamento de Quı´mica Orga´nica, Facultad de Farmacia y Bioquı´mica, Universidad de Buenos Aires, Argentina
Received 7 November 2007; accepted 15 January 2008
Abstract—Diastereomeric bis(cyclobutane) c-dipeptides, a new class of c-peptides, have been synthesized efficiently from both enantio-
mers of conveniently protected 3-amino-2,2-dimethyl-1-carboxylic acid. These amino acids have been prepared in very good overall
yields through enantiodivergent synthetic routes starting from (ꢀ)-cis-pinononic acid. Mixed c-oligomers have also been prepared from
GABA and cyclobutane residues.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
According to our research program on the synthesis and
structural study of conformationally restricted amino acids
and peptides,4 we decided to synthesize cyclobutane c-ami-
no acids to incorporate them in c-oligomers and investigate
their behaviour as foldamers.
c-Amino acids play important roles in the mechanism of
the neurotransmission in mammalian systems and, there-
fore, some natural or designed derivatives are being used
in the clinical treatment of central nervous system (CNS)
disorders.1 Otherwise, c-peptides, although less investi-
gated than a- or b-oligomers, display an ability to fold
giving defined secondary structures, some of which
show important biological activities which are presumably
related to their conformational bias.2
Thus, we herein report on the stereodivergent synthesis of
both the enantiomers of 3-amino-2,2-dimethylcyclo-
butane-1-carboxylic acid derivatives from (ꢀ)-cis-pinononic
acid. These compounds are suitably protected for their
incorporation into oligomers and herein we report for the
first time the preparation of diastereomeric bis(cyclo-
butane)-c-dipeptides as well as other c-peptides.
Some years ago, Burgess synthesized compounds 1 and 2
from (+)-a-pinene.3 X-ray diffraction analyses showed that
both the molecules have an extended conformation. More-
over, crystal packing of compound 1 displays a b-sheet ori-
entation of intermolecularly hydrogen-bonded molecules.
In contrast, product 2 did not stack in such a regular
arrangement. This is the only precedent on the synthesis
and the study of cyclobutane containing c-peptides.
2. Results and discussion
We recently described the preparation of compound 4 from
(ꢀ)-cis-pinononic acid, 3, obtained, in turn, from commer-
cially available (ꢀ)-verbenone (Scheme 1).5
Methylation of the carboxylic acid with MeI in the
presence of Cs2CO3 followed by a Schmidt rearrangement
promoted by treatment with sodium azide and methane-
sulfonic acid led to protected amino acid 4 in 64% yield
for the two steps. Saponification of the methyl ester under
mild conditions (0.25 M NaOH) allowed the preparation of
acid 5 in 91% yield without epimerization.6 This product
was coupled with MeO-GABA under the usual conditions
(EDAC as a dehydrating agent and HOBt as a catalyst) to
afford c-dipeptide 6, which contains a rigid cyclobutane
O
O
AcHN
BocHN
NHiPr
NHiPr
1
2
*
Corresponding author. Tel.: +34 93 5811602; fax: +34 93 5811265;
e-mail: rosa.ortuno@uab.es
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.01.020

J. Aguilera et al. / Tetrahedron: Asymmetry 19 (2008) 302–308
303
O
O
1) CH3I, Cs2CO3, 85%
RuCl3, NaIO4
100%
2) NaN3, CH3SO3H, 75%
OH
O
(-)-verbenone
3
O
O
0.25 M NaOH
91%
AcHN
AcHN
OH
OCH3
4
5
O
TFA H3N
CO2CH3
5
AcHN
EDAC, HOBt, Et3N, DMF, 24 h
51%
NH
CO2CH3
6
Scheme 1.
residue and a flexible segment proceeding from GABA.
This product was studied by 1H NMR to establish its abil-
ity to fold in solution by means of intramolecular hydro-
gen-bond formation.
obtained as a by-product, in 21% yield. The formation of
ureas had been observed in the reactions involving the b-
series and can be attributable to the presence of traces of
water.7 The ratio of urea increases with the steric hindrance
of the isocyanate structural surroundings that makes it dif-
ficult and, consequently, retards the carboxylate addition,
which competes with rapid water addition.
The temperature coefficients for both the NH protons were
determined between 233 and 308 K and showed values of
Dd/DT = ꢀ5.9 (acetamide) and ꢀ4.5 (peptide amide)
ppb/K,7 which appear not to be compatible with the pres-
ence of intramolecular hydrogen bonds. We can assume,
therefore, that dipeptide 6 adopts an extended conforma-
tion in solution, similar to the peptide surrogates 1 and 2
in the solid state, which were described by Burgess.
Owing to this result, we thought that the preparation of a
bis(cyclobutane) dipeptide using this protocol would not be
successful. Therefore, we decided to prepare the orthogo-
nally protected amino acid monomers and to synthesize
the target dipeptides through the classic peptide coupling
methods. Thus, acid 3 was converted into acyl azide 12
(Scheme 3), which was submitted to a Curtius rearrange-
ment in the presence of benzyl alcohol to produce carba-
mate 13. Lieben degradation of the methyl ketone
followed by the methylation of the resultant acid 14 led
to completely protected c-amino acid (ꢀ)-15 in 66% overall
yield from 3, with mp 93–95 °C and [a]D = ꢀ36 (c 4.0,
CH2Cl2).
Next, we considered the incorporation of a second cyclo-
butane residue to introduce rigidity in the molecule but a
difficulty arose from the fact that it was not possible to
hydrolyze acetamide 4 without concomitant deprotection
of the carboxylic acid. Thus, finding alternative synthetic
methodologies emerged as a crucial goal. Previously, to pre-
pare highly rigid bis(cyclobutane) c-peptides derived from
2-aminocyclobutane-1-carboxylic acid in our laboratory,
we performed the addition of a carboxylic acid to the iso-
cyanate resulting from the Curtius rearrangement of an acyl
azide.8 This protocol afforded dimers in good yields and
made the synthetic sequence shorter when compared to
the classical coupling of an acid with an amine. We chose
the reaction between easily available Boc-NH-GABA9
and isocyanante 9 as a model to study the feasibility of
the method when applied to 2,2-dimethylcyclobutane deriv-
atives. For this purpose, half-ester 7, previously prepared in
our laboratory as depicted in Scheme 2,10 was reacted with
ethyl chloroformate followed by the treatment with sodium
azide to produce acyl-azide 8 in 98% for two steps. The
treatment of an equimolar mixture of 8 and Boc-NH-
GABA in boiling anhydrous toluene gave dipeptide 10 in
26% yield. The reaction was monitored by IR following
the disappearance of the signal corresponding to the acyl
azide at 2136 cmꢀ1 and the formation of the isocyanate by
the new signal at 2260 cmꢀ1 that, in turn, disappeared upon
completion (ca. 5 h). From this reaction, urea 11 was also
Alternatively, half-ester 7 was converted into the amino-
acid derivative 16 whose configuration is opposite to
(ꢀ)-15 (Scheme 3). Nevertheless, this compound was trans-
formed into enantiomer (+)-15 to verify that the stereo-
chemical integrity of these molecules was preserved
throughout the synthetic sequence. Thus, the tert-butyl
ester was submitted to the action of trifluoroacetic acid in
the presence of triethylsilane and the resulting carboxylic
acid 17 was methylated with diazomethane to give (+)-15
in 45% overall yield from 3, with mp 94–95 °C and
1
[a]D = +34 (c 3.1, CH2Cl2). The H NMR spectra of both
the enantiomers were superimposable proving that epimer-
ization did not occur.
Once these compounds were synthesized, carboxylic acid
17 was coupled with amine 18 (Scheme 4) to provide, after
seven days, bis(cyclobutane) c-dipeptide 19 in 67% yield.
The high rigidity and steric hindrance of the cyclobutane
residues resulted in long reaction times to produce peptides

304
J. Aguilera et al. / Tetrahedron: Asymmetry 19 (2008) 302–308
1) Cl3C(NH)OtBu
1) ClCO2Et
2) NaN3
O
O
2) NaOBr
3
HO
OtBu
98% (two steps)
54% (two steps)
7
O
O
O
toluene
reflux
O C N
OtBu
N3
OtBu
9
8
O
O
Boc-NH-GABA
NH
(26%)
+
OtBu
10
BocHN
O
O
O
(21%)
NH NH
tBuO
OtBu
11
Scheme 2.
1) ClCO2Et
2) NaN3
BnOH
O
O
O
heat
3
NHCbz
NHCbz
90%
(two steps)
92%
N3
12
13
O
O
NaOBr
CH2N2
NHCbz
80%
HO
100%
MeO
14
(-)-15
1) ClCO2Et
2) NaN3
O
TFA, Et3SiH
94%
CbzHN
7
OtBu
3) BnOH, heat
16
88% (three steps)
O
O
CH2N2
100%
CbzHN
CbzHN
OH
OMe
(+)-15
17
Scheme 3.
efficiently. Even longer reaction times (nine days) were
affording c-dipeptide 20, which is the diastereomer of 19,
needed for coupling amine 18 with carboxylic acid 14
in 63% yield.

J. Aguilera et al. / Tetrahedron: Asymmetry 19 (2008) 302–308
305
was crystallized to afford pure 4 (1.75 g, 80% yield).
[a]D = +111 (c 2.9, CH2Cl2). Mp 127–129 °C (EtOAc–pen-
tane). IR: 3283, 2957, 1697, 1636, 1558, 1458, 1294,
17
EDAC, HOBt,
O
H2, 10% Pd/C
100%
Et3N, DMF
1
1191 cmꢀ1. H NMR (CDCl3): 0.90 (s, 3H), 1.29 (s, 3H),
H2N
16
OtBu
rt, 7 days
67%
1.9 (s, 3H), 2.07 (dt, J = 12, 10 Hz, 1H), 2.33 (dt,
3J = 12, 8 Hz, 1H), 2.60 (dd, J = 10, 8 Hz, 1H), 3.66 (s,
3H), 4.12 (m, 1H), 5.72 (br s, NH). 13C NMR (CDCl3):
17.57, 23.55, 26.52, 29.31, 43.56, 46.31, 50.30, 51.88,
170.28, 173.76. HRMS: calcd for C10H17NO3Na, M+Na:
222.1101. Found: 222.1111.
18
O
CbzHN
O
HN
OtBu
19
4.2. (1S,3R)-3-Acetamido-2,2-dimethylcyclobutane-1-carb-
oxylic acid 5
EDAC, HOBt,
Et3N, DMF
O
HN
20
14 +18
CbzHN
O
To an ice-cooled solution of ester 4 (1.0 g, 5 mmol) in 1:10
THF–water (88 mL), 0.25 M sodium hydroxide (10 mmol)
was added and the resultant mixture was stirred for 2 h.
(Reaction progress was monitored by TLC). The reaction
mixture was washed with dichloromethane (20 mL), and
5% HCl was added to the aqueous phase to reach pH 2.
The acid solution was extracted with ethyl acetate
(4 ꢁ 50 mL) and dried over magnesium sulfate. Solvent
was removed at reduced pressure to afford crude 5, which
was purified by crystallization (670 mg, 72% yield).
[a]D = +105 (c 2.1, MeOH). Mp 223–225 °C (EtOAc–pen-
tane). {Lit.6: [a]D = +198.3 (c 0.5, MeOH), mp 226–
228 °C.} IR: 3331, 2952, 1697, 1653, 1554, 1425, 1373,
rt, 9 days
63%
OtBu
Scheme 4.
3. Conclusion
We have herein provided an efficient methodology for the
preparation of enantiomeric cyclobutane c-amino acids
and their incorporation into different types of c-peptides
with modulated rigidity, from extended GABA derivatives
to presumably more rigid bis(cyclobutane) c-peptides.
In particular, poly(cyclobutane) c-peptides, a new class of
c-oligomers, appear as promising scaffolds to induce a
variety of foldings and, perhaps, self-aggregation. Active
investigations are being carried out in our laboratory to
study the secondary and tertiary structures of these
oligomers.
1
1190 cmꢀ1. H NMR (methanol-d4): 0.92 (s, 3H), 1.25 (s,
3H), 1.93 (s, 3H), 2.20 (m, 1H), 2.6 (m, 1H), 4.06 (m,
1H), 8.1 (br s, 1H). 13C NMR (methanol-d4): 17.43,
22.71, 25.09, 29.24, 42.56, 45.88, 49.38, 169.28, 173.85.
HRMS: calcd for C9H15NO3Na, M+Na: 208.0944. Found:
208.0946.
4.3. Methyl 4-[(10S,30R)-30-acetamido-20,20-dimethylcyclo-
butane-10-carboxamido]-butanoate 6
4. Experimental
A mixture containing acid 5 (386 mg, 2.85), EDAC (1.8 g,
5.4 mmol), and triethylamine (0.9 mL, 5.4 mmol) in dry
DMF (15 mL) was stirred for 40 min and then GABA-
OMe triflate (950 mg, 4.0 mmol) in dry DMF (15 mL)
was added. After stirring at room temperature for 24 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 aqueous sodium bicarbonate
(4 ꢁ 20 mL). The organic phase was dried over magnesium
sulfate and the solvents were removed. The reaction crude
was purified by column chromatography on neutral silica
gel (1:1 ethyl acetate–hexane) and subsequent crystalliza-
tion to afford pure 6 (393 mg, 51% yield). [a]D = +50 (c
0.5, CH2Cl2). Mp 92–93 °C (EtOAc). IR: 3295, 2959,
4.1. (1S,3R)-3-Acetamido-2,2-dimethylcyclobutane-1-carb-
oxylic acid methyl ester 4
A mixture containing (ꢀ)-cis-pinononic acid11 (4.8 g,
28.2 mmol), cesium carbonate (11.0 g, 33.8 mmol) and
2.1 mL of methyl iodide in dry DMF (65 mL) was stirred
at room temperature for 18 h. Ethyl acetate (50 mL) was
then added and the resultant solution was washed with sat-
urated aqueous sodium bicarbonate. The organic liquors
were dried over magnesium sulfate and the solvent was
evaporated under vacuo to provide (ꢀ)-cis-pinononic acid
methyl ester11 (4.5 g, 85% yield). To a solution of this ester
(2.0 g, 11 mmol) in monoglyme (25 mL), cooled at ꢀ40 °C,
methanesulfonic acid (14 mL) and sodium azide (2.1 g)
were subsequently added. The mixture was stirred at
ꢀ40 °C for 15 min and at room temperature for 3 days.
Then, 40% aqueous ammonia was added to reach pH 8–9
and volatiles were removed at reduced pressure. The resi-
due was poured into saturated aqueous sodium chloride
and extracted with dichloromethane (4 ꢁ 20 mL). The or-
ganic extracts were dried over magnesium sulfate and the
solvent was evaporated to afford an orange solid, which
1
1731, 1633, 1550 cmꢀ1. H NMR (CDCl3): 0.914 (s, 3H),
1.33 (s, 3H), 1.9 (m, 2H), 2.02 (s, 3H), 2.13 (m, 1H), 2.37
(complex absorption, 4H), 3.33 (m, 2H), 3.71 (s, 3H),
3.15 (m, 1H), 5.67 (t, 1H), 6.12 (d, J = 6 Hz, 1H). 13C
NMR (CDCl3): 17.29, 23.23, 24.68, 25.9, 29.40, 31.52,
39.14, 44.76, 45.86, 50.41, 51.67, 169.94, 172.17, 173.89.
HRMS: calcd for C14H24N2NaO4, M+Na: 307.1628.
Found: 307.1616. Anal. Calcd for: C, 59.13; H, 8.51; N,
9.85. Found: C, 58.24; H, 9.05; N, 9.65.

306
J. Aguilera et al. / Tetrahedron: Asymmetry 19 (2008) 302–308
4.4. tert-Butyl (1S,3R)-3-azidocarbonyl-2,2-dimethylcyclo-
butane-1-carboxylate 8
1.47 (s, 3H), 2.05 (s, 3H), 2.57 (dd, J = 8.75 Hz,
J0 = 20.5 Hz, 1H), 2.89 (complex absorption, 2H), 3.1
(dd, J = 8 Hz, J0 = 11.25 Hz, 1H). 13C NMR (acetone-
d6): 16.25, 27.4, 27.9, 30.3, 45.46, 46.69, 53.82, 179.1.
To an ice-cooled solution of half-ester 7, prepared accord-
ing to Ref. 3, (300 mg, 1.3 mmol) in dry acetone, triethyl-
amine (0.29 mL, 2.0 mmol) and ethyl chloroformate
(0.2 mL, 2.0 mmol) were subsequently added and the mix-
ture was stirred at 0 °C for 3 h. Then sodium azide (145 mg,
2.2 mmol) in 5 mL of water was added and the resultant
solution was stirred at room temperature for 1.5 h. The
reaction mixture was extracted with dichloromethane
(4 ꢁ 15 mL), and the organic extracts were dried over mag-
nesium sulfate. Solvents were removed at reduced pressure
to give acyl azide 8 as an oil (323 mg, 98% yield), which was
characterized by their spectroscopic data and used in the
next step without further purification. IR: 2962, 2136,
4.7. Benzyl (1S,3R)-3-acetyl-2,2-dimethylcyclobutyl-1-
carbamate 13
A solution of 12 (310 mg, 1.6 mmol) and benzyl alcohol
(0.4 mL, 3.3 mmol) in toluene (9 mL) was heated to reflux
for 3.5 h. Toluene was removed at a reduced pressure and
then excess benzyl alcohol was eliminated by liophilization.
The residue was chromatographed on silica gel (1:1 to 2:1
ethyl acetate–hexane) to afford carbamate 13 (402 mg,
92% yield). [a]D = ꢀ82 (c 0.51, CH2Cl2). Mp 78–81 °C
(ether–pentane). IR: 3386, 2957, 1701, 1683 cmꢀ1 1H
.
1
1722, 1459, 1333, 1139 cmꢀ1. H NMR (acetone-d6): 1.29
NMR (CDCl3): 0.84 (s, 3H), 1.41 (s, 3H), 2.08 (s, 3H),
2.1 (m, 2H), 2.75 (dd, J = 4.25 Hz, J0 = 6.5 Hz, 1H), 3.93
(m, 1H), 4.82 (complex absorption, 1H), 5.1 (dd, J =
6.5 Hz, J0 = 11 Hz, 2H), 7.38 (complex absorption, 5H).
13C NMR (CDCl3): 16.42, 24.84, 28.98, 30.30, 46.49,
50.69, 51.30, 66.78, 128.13, 128.18, 128.55, 136.32,
155.96, 206.79. HRMS: calcd for (C16H21NNaO3,
M+Na): 298.1414. Experimental: 298.1417.
(s, 3H), 1.35 (s, 3H), 1.45 (s, 9H), 1.93 (m, 1H), 2.49 (m,
1H), 2.87 (complex absorption, 2H). 13C NMR (acetone-
d6): 18.06, 20.11, 27.3, 30.03, 45.11, 46.25, 47.58, 80.20,
171.20, 179.53.
4.5. Dipeptide 10 and urea 11
Triethylamine (0.4 mL, 1.7 mmol) was added to a solution
containing Boc-NH-GABA (350 mg, 1.7 mmol) in 3 mL of
anhydrous toluene. After stirring at room temperature for
15 min, acyl azide 8 (290 mg, 1.1 mmol) in toluene (3 mL)
was added and the mixture was heated at reflux for 5 h
(the reaction progress was monitored by IR following the
signals for the acyl azide at 2136 cmꢀ1 and the isocyanate
at 2260 cmꢀ1). After the elimination of toluene at reduced
pressure, the residue was dissolved in ethyl acetate (15 mL)
and the solution was washed with saturated aqueous so-
dium bicarbonate (4 ꢁ 5 mL) and dried over magnesium
sulfate. Solvent was removed and the residue was chro-
matographed on silica gel (1:1 ethyl acetate–hexane) to
afford dipeptide 10 (85 mg, 26% yield) and urea 11
(90 mg, 21% yield). Dipeptide 10: [a]D = +98 (c 2.75,
CH2Cl2). Mp 88–90 °C (hexane). IR: 3309, 2930, 1712,
4.8. Benzyl (1S,3R)-3-methoxycarbonyl-2,2-dimethylcyclo-
butyl-1-carbamate (ꢀ)-15
An ice-cooled solution of sodium hypobromite [prepared
from bromine (2 mL, 6.3 mmol) and sodium hydroxide
(5.5 g, 137 mmol)] in 75 mL of water was added to a solu-
tion of ketone 13 (1.2 g, 4.5 mmol) in 3:1 dioxane–water,
previously cooled at ꢀ5 °C. The mixture was diluted with
further dioxane (12 mL) and stirred at ꢀ5 °C for 5 h. Then,
the reaction mixture was washed with dichloromethane
(2 ꢁ 50 mL), treated with sodium sulfite and, finally, 5%
HCl was added to reach pH 2–3. The acid solution was
extracted with ethyl acetate (4 ꢁ 50 mL) and the organic
extracts were dried over magnesium sulfate. The solvent
was removed to afford acid 14 (1 g, 80% yield), which
1
1647, 1523 cmꢀ1. H NMR (CDCl3): 0.90 (s, 3H), 1.25 (s,
1
3H), 1.4 (s, 18H), 1.82 (m, 2H), 1.95 (m, 1H), 2.2 (m, 3H),
2.49 (t, J = 7, 9.5 Hz, 1H), 3.03 (m, 2H), 3.15 (m, 1H),
4.05 (dd, J = 8.5, 17 Hz, 1H), 4.97 (m, 1H), 6.56 (d, J =
8.5 Hz, 1H). 13C NMR (CDCl3): 17.40, 26.21, 25.9, 28.6,
28.8, 29.35, 33.9, 40.28, 46.44, 50.27, 79.64, 80.83, 158.01,
172.62, 173.15. Anal. Calcd for C20H36N2O5: C, 62.47; H,
9.44; N, 7.29. Found: C, 62.70; H, 9.66; N, 7.26. Urea 11:
[a]D = +56 (c 0.63, CH2Cl2). Mp 210–211 °C (ether–
was identified by its H and 13C NMR spectra and used
1
in the next steps without further purification. H NMR
(CDCl3): 0.99 (s, 3H), 1.35 (s, 3H), 2.06 (m, 1H), 2.33
(m, 1H), 2.58 (m, 1H), 3.94 (m, 1H), 5.11 (complex absorp-
tion, 3H), 7.37 (complex absorption, 5H), 10.15 (br s, 1H).
13C NMR (methanol-d4): 15.68, 25.75, 27.58, 42.13, 45.65,
49.75, 65.46, 127.09, 127.30, 127.81, 158.36, 174.35.
pentane). IR: 3320, 2959, 1723, 1647 cmꢀ1
.
1H NMR
This acid was treated with an excess of diazomethane, as a
dichloromethane solution, to quantitatively afford ester
(ꢀ)-15. [a]D = +36 (c 4.05, CH2Cl2). Mp 93–95 °C (ether–
(CDCl3): 0.92 (s, 6H), 1.30 (s, 6H), 1.46 (s, 18H), 1.95
(dd, J = 9, 22 Hz, 2H), 2.3 (m, 2H), 2.5 (m, 2H), 3.91 (t,
J = 9, 18 Hz, 2H), 4.64 (br s, 1H). 13C NMR (CDCl3):
17.47, 27.11, 28.92, 29.72, 43.9, 46.59, 80.93. HRMS: calcd
for C23H40N2O5Na, M+Na: 447.2829. Found: 447.2841.
pentane). IR: 3331, 2956, 1725, 1686 cmꢀ1 1H NMR
.
(CDCl3): 0.90 (s, 3H), 1.29 (s, 3H), 2.05 (m, 1H), 2.36
(m, 1H), 2.57 (dd, J = 8 Hz, J0 = 9.75 Hz, 1H), 3.67 (s,
3H), 3.92 (dd, J = 8 Hz, J0 = 17.25 Hz, 1H), 4.91
(d,J = 11.75 Hz, 1H), 5.05 (d, J = 19 Hz, 1H), 5.12 (d,
J = 20.25 Hz, 1H), 7.36 (complex absorption, 5H). 13C
NMR (CDCl3): 16.68, 26.41, 28.48, 42.62, 45.81, 51.31,
66.57, 76.96, 127.93, 128.57, 136.014, 155.66, 172.57. Anal.
Calcd for C13H21NO4: C, 65.96; H, 7.27; N, 4.81. Found:
C, 65.72; H, 7.30; N, 5.16.
4.6. (1R,3S)-3-Azidocarbonyl-2,2-dimethylcyclobutyl
methyl ketone 12
This azide was prepared in 90% yield according to the pro-
cedure described above for 8. IR: 2957, 2134, 1703, 1523,
1354, 1177 cmꢀ1 1H NMR (acetone-d6): 0.92 (s, 3H),
.

J. Aguilera et al. / Tetrahedron: Asymmetry 19 (2008) 302–308
307
4.9. Benzyl (1R,3S)-3-tert-butoxycarbonyl-2,2-dimethyl-
cyclobutyl-1-carbamate 16
4.12. Dipeptide 19
By using a similar procedure than that described above for
the synthesis of 6, dipeptide 19 was obtained after 7 days of
reaction time in 67% yield. [a]D = +30 (c 0.7, CH2Cl2). Mp
229–231 °C (hexane). IR: 3330, 3321, 2959, 1726, 1694,
Following similar procedures than those described above
for the synthesis of acyl azide 8 and carbamate 13 through
a Curtius rearrangement in the presence of benzyl alcohol,
respectively, compound 6 was prepared in 88% overall
yield for the three steps. [a]D = +31 (c 0.7, CH2Cl2). Mp
92–94 °C (ether–pentane). IR: 3351, 2925, 1710,
1
1659 cmꢀ1. H NMR (CDCl3): 0.91 (s, 3H), 1.31 (s, 3H),
1.47 (s, 9H), 1.93 (complex absorption, 2H), 2.30 (complex
absorption, 3H), 2.6 (m, 1H), 3.9 (m, 1H), 4.1 (m, 1H), 5.13
(complex absorption, 3H), 5.37 (d, 1H), 7.37 (complex
absorption, 5H). 13C NMR (CDCl3): 16.92, 16.99, 26.23,
26.42, 28.96, 28.97, 29.17, 44.03, 44.8, 45.34, 45.61, 49.97,
51.49, 66.77, 80.49, 128.11, 128.51, 156.00, 171.50,
172.30. Anal. Calcd for C16H38N2O5: C, 68.10; H, 8.35;
N, 6.11. Found: C, 68.21; H, 7.98; N, 6.34.
1
1697 cmꢀ1. H NMR (CDCl3): 0.95 (s, 3H), 1.30 (s, 3H),
1.46 (s, 9H), 2.02 (dd, J = 9.5 Hz, J0 = 18 Hz), 2.31 (a.c,
1H), 2.51 (dd, J = 6.75 Hz, J0 = 9.5 Hz), 3.9 (dd, J =
9.5 Hz, J0 = 18 Hz, 1H), 4.9 (d, J = 9.5 Hz, 1H), 5.1 (d,
J = 21 Hz, 1H), 5.13 (d, J = 21 Hz, 1H), 7.37 (complex
absorption, 5H). 13C NMR (CDCl3): 16.92, 26.7, 28.32,
29.96, 43.86, 45.98, 51.49, 66.79, 80.55, 128.19, 128.57,
155.85, 171.50. Anal. Calcd for C19H27NO4: C, 68.44; H,
8.16; N, 4.20. Found: C, 68.43; H, 8.19; N, 4.27.
4.13. Dipeptide 20
By using a similar procedure to that described above for
the synthesis of 6, dipeptide 20 was obtained after 9 days
reaction time in 63% yield. [a]D = +43 (c 0.71, CH2Cl2).
Mp 165–167 °C (hexane). IR: 3355, 3306, 2953, 1720,
4.10. Benzyl (1R,3S)-3-methoxycarbonyl-2,2-dimethyl-
cyclobutyl-1-carbamate (+)-15
1
1699, 1660 cmꢀ1. H NMR (CDCl3): 0.922 (s, 3H), 0.934
A mixture containing compound 16 (700 mg, 2.1 mmol),
trifluoroacetic acid (2.1 mL, 27.3 mmol) and triethylsilane
(0.84 mL, 5.2 mmol) in anhydrous dichloromethane
(6 mL) was stirred at room temperature for 2 h. The sol-
vent was evaporated and the excess of trifluoroacetic acid
was removed by liophilization affording acid 17 as a solid,
which was identified by its 1H NMR spectrum and used in
the next steps without purification. 1H NMR (CDCl3): 0.99
(s, 3H), 1.35 (s, 3H), 2.06 (m, 1H), 2.33 (m, 1H), 2.58 (m,
1H), 3.94 (m, 1H), 5.11 (complex absorption, 3H), 7.37
(complex absorption, 5H), 10.15 (br s, 1H). This acid was
methylated by the action of an excess of diazomethane as
a dichloromethane solution to provide quantitatively (+)-
15. [a]D = +34 (c 3.11, CH2Cl2). Mp 94–95 °C (ether–pen-
tane). IR: 3331, 2956, 1725, 1686 cmꢀ1. 1H NMR (CDCl3):
0.90 (s, 3H), 1.29 (s, 3H), 2.05 (m, 1H), 2.36 (m, 1H), 2.57
(dd, J = 8 Hz, J0 = 9.75 Hz, 1H), 3.67 (s, 3H), 3.92 (dd,
J = 8 Hz, J0 = 17.25 Hz, 1H), 4.91 (d, J = 11.75 Hz, 1H),
5.05 (d, J = 19 Hz, 1H), 5.12 (d, J = 20.25 Hz, 1H), 7.36
(complex absorption, 5H). 13C NMR (CDCl3): 16.68,
26.41, 28.48, 42.62, 45.81, 51.31, 66.57, 76.96, 127.93,
128.57, 136.014, 155.66, 172.57. Anal. Calcd for
C13H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C, 66.12;
H, 7.34; N, 5.04.
(s, 3H), 1.29 (s, 3H), 1.31 (s, 3H), 1.47 (s, 9H), 2.01 (com-
plex absorption, 2H), 2.26 (complex absorption, 3H), 2.52
(m, 1H), 3.91 (m, 1H), 4.1 (m, 1H), 5.1 (complex absorp-
tion, 3H), 5.37 (complex absorption, 1H), 7.38 (complex
absorption, 5H). 13C NMR (CDCl3): 16.76, 16.98, 26.26,
28.86, 28.23, 28.97, 29.15, 43.97, 44.05, 44.81, 45.020,
51.56, 51.64, 66.75, 80.62, 128.12, 128.55, 136.49, 155.96,
170.33, 172.33. HRMS: calcd for C26H38N2NaO5,
M+Na: 481.2673. Experimental: 481.2659.
Acknowledgements
´
Financial support from Ministerio de Educacion y Ciencia
(CTQ2004-01067/BQU and CTQ2007-61704/BQU) and
Generalitat de Catalunya (2005SGR-103) is gratefully
acknowledged.
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4. See, for instance: (a) Ortuno, R. M.; Moglioni, A. G.;
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R. M. In Enantioselective Synthesis of b-Amino Acids;
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´
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Boussert, S.; Dıez-Perez, I.; Parella, T.; Branchadell, V.;
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1
without further purification. H NMR (CDCl3): 0.93 (s,
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´
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Caamano, O.; Fernandez, F.; Garcıa-Mera, X.; Lopez, C.
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