Synthesis and diastereoselective catalytic hydrogenation of optically active cyclobutyl α,β-dehydro-α-dipeptides

Article abstract of DOI:10.1016/S0957-4166(03)00485-3

Optically active cyclobutyl (Z)-α,β-dehydro-α-dipeptides have been efficiently synthesized through the coupling of conveniently protected glycine or (S)-phenylalanine residues with a (Z)-dehydro-α-amino acid derivative prepared, in turn, from (-)-verbenon

Full text of DOI:10.1016/S0957-4166(03)00485-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2445–2451
Synthesis and diastereoselective catalytic hydrogenation of
optically active cyclobutyl a,b-dehydro-a-dipeptides
Gemma P. Aguado, Albertina G. Moglioni,† Beatriz N. Brousse† and Rosa M. Ortun˜o*
Departament de Qu´ımica, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
Received 26 May 2003; accepted 16 June 2003
Abstract—Optically active cyclobutyl (Z)-a,b-dehydro-a-dipeptides have been efficiently synthesized through the coupling of
conveniently protected glycine or (S)-phenylalanine residues with a (Z)-dehydro-a-amino acid derivative prepared, in turn, from
(−)-verbenone as a chiral precursor. The alternative use of (R,R)- and (S,S)-Et–duphos–Rh as the hydrogenation catalyst led to
the stereoselective production of both diastereomeric saturated dipeptides in each case. Thus, the chirality of the catalyst employed
has been shown to be the factor governing the configuration of the newly created stereogenic centre. Regarding structural features,
both NMR and CD data establish a marked conformational bias for both the unsaturated and the saturated peptides synthesized
herein.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
but derived from the L-isomer, after incorporation into
a biosynthetic intermediate, through a dehydrogena-
tion–hydrogenation sequence.3b In the laboratory, the
most used methods for the synthesis of a,b-DHPs
involve condensation8 or b-elimination reactions.9 In
the latter cases, the introduction of suitable leaving
groups and the availability of appropriate reagents is
required.
Small peptides containing a,b-unsaturated amino acid
residues (dehydropeptides, DHPs) have been found in
the structure of natural products with a variety of
biological activities.1–4 Chemical and structural studies
of unsaturated peptides show interesting features for
these compounds that could be responsible for the
biological properties of some of them.5 For instance,
the binding abilities of peptide ligands towards metal
ions is highly increased when a DHAA residue is
incorporated into a di-, tri- or tetrapeptide.6 Otherwise,
the ability of a,b-DHAAs as b-turn inducers has been
shown by conformational analysis of model peptides.7
The (Z/E) stereochemistry of the double bond is a
crucial factor for these structures and for the activity.3
DHAAs and DHPs, in turn, are valuable synthetic
precursors for peptide surrogates constituted by unnat-
ural amino acid residues. For instance, they can be
reduced to afford saturated derivatives. The hydrogena-
tion of a,b-DHPs both in homogeneous and heteroge-
neous phases has been described to proceed with
variable stereoselectivity.10 The asymmetric catalytic
hydrogenation of achiral substrates has been accom-
plished by using chiral rhodium complexes.11 Neverthe-
less, examples on the hydrogenation of chiral DHPs
with chiral catalysts are very scarce in the literature.12
The oxidative conversion of peptides into dehydro ana-
logues has been proposed to account for the occurrence
of a,b-DHAA residues in microbial peptides. In fact, a
common biosynthetic pathway has been suggested for
the formation of dehydro- and
would not be directly incorporated into the peptides
D-amino acids. They
Among the peptides containing carbocyclic structural
units, some natural or designed cyclobutyl peptides are
relevant because of their interesting properties. For
instance, the antibiotic X-1092 is a dipeptide produced
by the microorganism Streptomyces species X-1092.13
Moreover, the incorporation of the cyclobutane ring in
conformationally constrained peptidomimetics has
resulted in the production of biologically active deriva-
* Corresponding author. E-mail: rosa.ortuno@uab.es
† Permanent address: Departamento de Qu´ımica Orga´nica, Facultad
de Farmacia y Bioqu´ımica, Universidad de Buenos Aires, 1113
Buenos Aires, Argentina.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00485-3

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G. P. Aguado et al. / Tetrahedron: Asymmetry 14 (2003) 2445–2451
tives such as the tuftsin analogue Thr-[MOm2]-Pro-Arg,
which exhibited high resistance to enzymatic hydrolysis
as compared to tuftsin.14
Moreover, hydrogenations promoted by such a catalyst
were chemoselective, being compatible with the Cbz–
amine protection. In addition, these reactions were
completed much faster than the hydrogenations cata-
lyzed by chiraphos–Rh (cf. 1 and 6 days, respectively)
thus avoiding eventual epimerization of the stereogenic
centers.16 For this reason, we carried out the hydro-
genation of dipeptides 3 and 4 in the presence of (R,R)-
and (S,S)-Et-duphos-Rh in order to establish whether
the configuration of the new stereogenic centre was
induced by the chirality of the substrate and/or the
catalyst. The use of (R,R)-Me–duphos–Rh was also inves-
tigated since this catalyst has been described to induce
better stereoselectivity in the hydrogenation of sterically
congested substrates than rhodium complexes based on
phospholanes bearing bulkier alkyl groups.12c,17
With all these features in mind, we have accomplished
the stereoselective synthesis of optically active
cyclobutyl DHPs by direct coupling of glycine and
(S)-phenylalanine, respectively, and a (Z)-dehydro-
amino acid obtained from (−)-verbenone as a chiral
precursor (Scheme 1). Their hydrogenation using differ-
ent chiral catalysts such as rhodium complexes with
(R,R)-Me–duphos, and (R,R)- and (S,S)-Et-duphos
has been investigated. For every case, we have consid-
ered the influence of the chirality in both the substrate
and the catalyst on the configuration of the newly
created stereogenic centre. The resultant cyclobutyl sat-
urated dipeptides possess three or four asymmetric
carbons with unambiguously determined absolute
configuration.
Table 1 shows the results obtained. Both in the hydro-
genation of 3 and 4, (R)-diastereoisomers were pro-
duced as the major isomers when (R,R)-Et-duphos-Rh
was employed as the catalyst (entries 1 and 4). A
similar result was obtained when using (R,R)-Me–
duphos–Rh for the reduction of 3 (entry 2). Alterna-
tively, the (S)-diastereoisomers predominated in the
reactions catalyzed by (S,S)-Et-duphos-Rh (entries 3
and 5). All these results show clearly that the chirality
of the catalyst is the factor governing the
diastereoselection.
2. Results and discussion
As previously reported, conveniently protected dehy-
dro-amino acid 1 was synthesized by Wadsworth–
Emmons condensation of a phosphonate, affording the
amino acid function, and an aldehyde prepared from
(−)-verbenone as the chiral precursor bearing the
cyclobutane moiety. The (Z)-configuration of the dou-
ble bond was established by NOE experiments.15 Actu-
ally, mild saponification of the methyl ester was carried
out using 1 M K2CO3 in (3:1) MeOH–H2O at room
temperature for 12 h. Subsequent treatment with 5%
HCl gave the keto acid 2 (Scheme 1) without epimeriza-
Furthermore, the diastereomeric excesses (de) were
higher for 6a/b than for 5a/b. This result suggests that
the additional stereogenic centre in 4, coming from
(S)-phenylalanine, can cooperate in a double asymmet-
ric induction. This hypothesis is also sustained by the
fact that hydrogenation of 4 catalyzed by (S,S)-Et-
duphos-Rh is slower and affords lower yield and lower
de than the hydrogenation of the same substrate cata-
lyzed by the enantiomeric rhodium complex (compare
entries 4 and 5 in Table 1). Thus, substrate 4 and the
(R,R)-catalyst are the matched pair while mismatching
would occur with the (S,S)-catalyst.
1
tion as verified by H and 13C NMR. Acid 2 was used
for coupling with the other amino acids. Thus, reaction
of 2 with glycine methyl ester, in the presence of
1-(3-dimethylamino-propyl)-3-ethylcarbodiimide
as
dehydrating agent and hydroxybenzotriazole (HOBt) as
a catalyst, at room temperature for 20 h afforded
dipeptide 3 in 85% yield. Similarly, condensation of
acid 2 with (S)-phenylalanine methyl ester gave dipep-
tide 4 in 81% yield. Both compounds were identified
and fully characterized by their spectral data and phys-
ical constants.
The (R)-configuration of 5a was unambiguously
assigned by X-ray structural analysis of a single crystal
obtained from the mixture 5a/b in ethanol.18 Suitable
crystals could not be obtained for 6a and 6b. Neverthe-
less, NMR studies allowed us to assign the configura-
tion as well as the preferred conformation for these
compounds. Thus, complete 1H and 13C resonance
assignments were performed using gradient-based 2D
techniques. NOESY experiments support the stereo-
chemistry depicted in Figure 1 for these molecules
showing (R)-configuration for the new stereogenic cen-
The choice of the hydrogenation catalyst was envi-
sioned on the basis of our preliminary results on the
reduction of cyclobutyl dehydroamino acids derived
from (−)-a-pinene and (−)-verbenone. We reported in
an early communication that good diastereoselectivity
was obtained when a (S,S)-Et-duphos-Rh was used.

G. P. Aguado et al. / Tetrahedron: Asymmetry 14 (2003) 2445–2451
2447
Scheme 1.
tre in 6a and (S)-configuration in 6b. It is noteworthy
that 6a contains an amino acid residue with (S)-
isomer thus suggesting
a
marked conformational
bias (Dl(Hb−Ha)=1.21 ppm for 6a and 0.98 ppm
for 6b). The NOESY data are in good agreement
with the Chem3D optimized structures for these
compounds (Fig. 1) in which the disposition of the
two chains containing the benzyl carbamate and
the second amino acid residue, respectively, are
favored by the formation of intramolecular hydrogen
bonds.
configuration, proceeding from (S)-phenylglycine (
amino acid), and the other one with (R)-configuration
-amino acid), as the result of the catalyst induced
L-
(D
diastereoselection.
The 1H NMR spectra show very different chemical
shifts for the two NH protons in each stereo-

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G. P. Aguado et al. / Tetrahedron: Asymmetry 14 (2003) 2445–2451
Table 1. Hydrogenationa of dehydropeptides 3 and 4 with catalysts [(COD)Rh(R,R)-Et-duphos)]OTf (R,R)-Et-7,
[(COD)Rh(S,S)-Et-duphos)]OTf (S,S)-Et-7, and [(COD)Rh(R,R)-Me-duphos)]OTf (R,R)-Me-8, and diastereomeric excess of
productsb
Entry
Substrate
Catalyst
Productc
Configurationd
% dee
% Yieldf
1
2
3
4
5
3
3
3
4
4
(R,R)-Et-7
(R,R)-Me-8
(S,S)-Et-7
(R,R)-Et-7
(S,S)-Et-7
5a
5a
5b
6a
6b
R
R
S
R
S
82
82
78
>99
90
96
96
90
88
82
a As MeOH solutions under 4 atm pressure for 1 day in entries 1–4 but 2 days in entry 5.
b Determined by 1H NMR.
c Major diastereomer.
d Refers to the new stereogenic center in the major diastereomer.
e At 100% conversion.
f Total yield of the purified mixture a/b.
Figure 1. Chem3D optimized structures (left) and preferred conformations from NMR data (right) for peptides 6a and 6b.
The CD spectra between 340 and 220 nm for unsatu-
rated DHPs 3 and 4, and saturated 5b and 6a, in
methanol, are shown in Figure 2. Two bands of simi-
lar shape are observed for 3 and 4. Both compounds
show a broad negative band centered at 290 nm,
which could be related to a negative Cotton effect,
and a positive band between 250 and 210 nm, being
lower intensity for 3. The CD spectrum of 6a shows a
broad negative band between 320 and 250 nm and a
positive one with a maximum at 220 nm. Peptide 5b
shows two broad negative bands of different intensities
between 320 and 250 and between 250 and 210 nm,
respectively. The shapes of these CD spectra follow
the same trend that those of some small peptides,
which are reported to be b-turn inducers.5a,7 There-
fore, all these features, jointly with the NMR data,
account for a remarkable conformational preference of
these molecules.

G. P. Aguado et al. / Tetrahedron: Asymmetry 14 (2003) 2445–2451
2449
Figure 2. CD spectra (methanol) of DHPs 3 and 4 (left), and saturated peptides 5b and 6a (right).
3. Conclusions
reduced pressure and the aqueous resultant solution
was extracted with ether. Subsequently, 5% HCl was
added to the aqueous phase to reach pH 2 and the
resultant acid solution was stirred for 12 h. The solu-
tion was extracted with ether, the combined extracts
were dried (MgSO4) and solvent was removed to afford
keto acid 2 (86 mg, 55% yield) as an oil that was
characterized and used for coupling with other amino
acids without further purification. [h]D −20.9 (c 0.76,
MeOH); IR (film): 3500–3000 (broad), 2958, 1704 cm−1;
1H NMR (acetone-d6): 0.90 (s, 3H, c-2%-CH3), 1.31 (s,
3H, t-2%-CH3), 1.89–2.25 (complex absorption, 2H, H4%a,
The easy and efficient synthesis of cyclobutyl a,b-DHPs
and their diastereoselective hydrogenation using
duphos–Rh complexes has been achieved. We have
shown that the configuration of the resultant stereo-
genic centre can be predicted by considering the chiral-
ity of the catalyst employed. A conformational bias can
be assumed for the synthesized peptides on the basis of
their NMR and CD spectroscopic data.
H
4%b), 2.01 (s, 3H, COCH3), 2.96–3.08 (complex absorp-
4. Experimental
4.1. General
tion, 2H, H1%, H3%), 5.11 (s, 2H, PhCH2), 6.59 (d, J=8.8
Hz, 1H, ꢀCH), 7.26–7.41 (complex absorption, 5H,
Ph), 7.54 (broad s, 1H, NH); 13C NMR (acetone-d6):
17.78 (c-2%-CH3), 22.86 (C4%), 29.23, 29.87 (t-2%-CH3,
and COCH3), 39.72 (C1%), 45.06 (C2%), 53.33 (C3%), 66.15
(PhCH2), 127.53, 127.74, 127.77, 128.29 (6C,
5CHaromatic, Ca), 137.41 (Cipso), 137.55 (Cb), 154.52
(NHCO2CH2Ph), 164.97 (CO2H), 205.91 (COCH3).
Commercial (−)-verbenone (90% e.e.) was used as syn-
thetic precursor without further purification. Com-
pound 1 was synthesized as described in the literature.15
Flash column chromatography was carried out on
Baker-silica gel (400 mesh). Melting points were deter-
mined on a hot stage and are uncorrected. CD data
were acquired on a spectropolarimeter equipped with a
diode-array detector and measurements were made
using methanol solutions contained in 1.0 nm path-
length cells. The CD spectra are the averages of four
scans acquired over a 1 h-period with the base-lines
4.3. (1%R,3%R)-1-Benzyloxycarbonylamino-2-(3%-acetyl-
2%,2%-dimethylcyclobutyl)-1-carboxylic acid N-methoxy-
carbonylmethyl-1-(Z)-enamide, 3
To a solution of acid 2 (85 mg, 0.2 mmol) in freshly
distilled DMF (1.5 mL) dry TEA (34 mL, 0.2 mmol),
methyl ester of glycine hydrochloride (46 mg, 0.4
mmol), HOBt (17 mg, 0.1 mmol), and 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide hydrochloride (142
mg, 0.7 mmol) were subsequently added under a nitro-
gen atmosphere. The resultant mixture was light-pro-
tected and stirred at rt for 20 h. After this period of
time, EtOAc (10 mL) was added and the solution was
washed with saturated aqueous NaHCO3 and dried
over MgSO4. The solvents were removed at reduced
pressure and the residue was chromatographed on
Baker-silica gel (1:1 CH2Cl2–EtOAc as eluent) to afford
dipeptide 3 as an oil (87 mg, 85% yield). [h]D −8.6 (c
1
subtracted. Standard H and 13C NMR spectra were
recorded at 250 and 62.5 MHz, respectively, unless
otherwise stated. Chemical shifts are given on the d
scale. Electron impact mass spectra were recorded at 70
eV.
4.2. Hydrolysis of compound 1: synthesis of (1%R,3%R)-
2-benzyloxycarbonylamino-3-(3%-acetyl-2%,2%-dimethyl-
cyclobutyl)-(Z)-2-propenoic acid, 2
A mixture of ester 1 (187 mg, 0.4 mmol) and K2CO3
(308 mg, 2.2 mmol) in (3:1) MeOH–H2O (2 mL) was
stirred at rt for 12 h. Then, MeOH was removed under

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G. P. Aguado et al. / Tetrahedron: Asymmetry 14 (2003) 2445–2451
0.58, MeOH); IR (film) 3306 (broad, NH), 2955, 1729,
spectroscopic data for oily 5b were determined from
enriched chromatographic fractions.
1
1705, 1667 (CꢀO), 1635 cm−1; H NMR (acetone-d6):
0.87 (s, 3H, c-2%-CH3), 1.26 (s, 3H, t-2%-CH3), 1.84–2.22
(complex absorption, 2H, H4%a, H4%b), 1.99 (s, 3H,
COCH3), 2.85–2.99 (complex absorption, 2H, H1%, H3%),
3.64 (s, 3H, CO2CH3), 3.98 (d, J=5.8 Hz, 2H,
CH2NH), 5.10 ( s, 2H, PhCH2O), 6.44 (d, J=8.8 Hz,
1H, ꢀCH), 7.25–7.38 (complex absorption, 5H, Ph),
7.69 (broad s, 2H, 2NH); 13C NMR (acetone-d6): 18.56
(c-2%-CH3), 23.68 (C4%), 30.06, 30.65 (COCH3, t-2%-
CH3), 40.19 (C1%), 41.75 (NHCH2), 45.83 (C2%), 52.05
(C3%), 54.13 (CH3CO2), 67.07 (PhCH2O), 128.52,
128.61, 128.63 (CHaromatic), 129.13 (Ca), 130.94 (Cb),
134.39 (Cipso), 155.40 (PhCH2OCONH), 165.50 (-
4.6.1. Compound 5a. Crystals, mp 75–79°C (from etha-
nol), [h]D +32 (c 0.09, methanol); IR (film) 3321 (broad,
1
NH), 2954, 1748, 1704, 1667 cm−1; 500 MHz H NMR
(acetone-d6): 0.81 (s, 3H, t-2%-CH3), 1.24 (s, 3H, c-2%-
CH3), 1.40–2.22 (complex absorption, 5H, H2a, H2b,
H4%a, H4%b, H1%), 1.98 (s, 3H, COCH3), 2.78–2.91 (m, 1H,
H3%), 3.66 (s, 3H, CO2CH3), 3.88–4.01 (complex absorp-
tion, 2H, NHCH2), 4.14 (m, 1H, H1), 5.02–5.12 (com-
plex absorption, 2H, OCH2), 6.46 (d, JNH,H1=7.7 Hz,
NHCO2), 7.28–7.38 (complex absorption, 5H, Ph), 7.71
(broad s, 1H, NH); 13C NMR (acetone-d6): 17.57 (c-2%-
CH3), 23.72 (C4%), 30.20, 30.36 (t-2%-CH3, COCH3),
33.42 (C2), 39.02 (C1%), 41.45 (MeCO2–CH2–NH), 43.32
(C2%), 52.09 (C3%), 54.73 (CO2CH3), 54.99 (C1), 66.77
(PhCH2O), 128.57, 128.59, 129.17 (CHaromatic), 138.08
(Cipso), 156.92 (NHCO2CH2Ph), 170.83 (CONHCH2),
173.20 (CO2CH3), 206.93 (COCH3); HRMS: calcd for
C22H30N2O6 (M): 418.4822; found: 418.2112. Calcd for
C20H27N2O5 (M−C2H3O): 375.4377; found: 375.1920.
CONHCH2CO2Me),
170.91
(CO2Me),
206.87
(COCH3). HRMS: calcd for C22H28N2O6 (M):
416.4664; found: 416.1946. Calcd for C21H25N2O5 (M−
CH3O): 385.4326; found: 385.1785. Calcd for
C16H18N2O5 (M−C6H10O): 318.1216; found: 318.1208.
4.4. (1%S,3%R)-1-Benzyloxycarbonylamino-2-(3%-acetyl-
2%,2%-dimethylcyclobutyl)-1-carboxylic acid (1%%S)-N-(1%%-
benzyl-1%%-methoxycarbonyl)methyl-1-(Z)-enamide, 4
1
4.6.2. Compound 5b. 500 MHz H NMR (acetone-d6):
Compound 4 was prepared in 81% yield following the
procedure described above for the synthesis of dipep-
tide 3. Crystals, mp 131–135°C; [h]D −30 (c 0.1,
MeOH); IR (film): 3311 (broad, NH), 3954, 1739, 1700,
0.84 (s, 3H, t-2%-CH3), 1.26 (s, 3H, c-2%-CH3), 1.40–2.22
(complex absorption, 5H, H2a, H2b, H4%a, H4%b, H1%), 1.97
(s, 3H, COCH3), 2.78–2.91 (m, 1H, H3%), 3.66 (s, 3H,
CO2CH3), 3.88–4.01 (complex absorption, 2H,
NHCH2), 4.10–4.16 (m, 1H, H1), 5.02–5.12 (complex
absorption, 2H, OCH2), 6.53 (d, JNH,H1=8.2 Hz, 1H,
NHCO2), 7.28–7.38 (complex absorption, 5H, Ph), 7.63
(broad s, 1H, NH); 13C NMR(acetone-d6): 17.24 (c-2%-
CH3), 24.26 (C4%), 30.08, 30.38 (t-2%-CH3, COCH3),
33.42 (C2), 39.45 (C1%), 41.45 (MeCO2–CH2–NH), 43.64
(C2%), 52.09 (C3%), 54.73 (CO2CH3), 55.04 (C1), 66.77
(PhCH2O), 128.57, 128.59, 129.17 (CHaromatic), 138.08
(Cipso), 156.92 (NHCO2CH2Ph), 170.83 (CONHCH2),
173.20 (CO2CH3), 206.93 (COCH3).
1
1667, 1633 cm−1; H NMR (acetone-d6): 0.85 (s, 3H,
c-2%-CH3), 1.25 (s, 3H, t-2%-CH3), 1.81–2.25 (complex
absorption, 2H, H4%a, H4%b), 2.01 (s, 3H, COCH3), 2.75–
3.11 (complex absorption, 4H, H1%, H3%, PhCH2), 3.63
(s, 3H, CO2CH3), 4.72 (m, 1H, CHCO2Me), 5.09 (s,
2H, PhCH2O), 6.34 (d, J=8.9 Hz, 1H, ꢀCH), 7.15–7.40
(complex absorption, 11H, 2Ph, NH), 7.65 (broad s,
1H, NH); 13C NMR (acetone-d6): 18.31 (c-2%-CH3),
23.41 (C4%), 29.73, 30.36 (t-2%-CH3, COCH3), 37.86
(CH2Ph), 39.93 (C1%), 45.11 (C2%), 51.91 (CO2CH3),
53.86 (C3%), 54.31 (C2), 66.80 (PhCH2O), 127.18, 128.34,
128.84, 129.82 (CHaromatic), 130.40 (C5), 133.80 (C6),
137.22 (Cipso), 155.03 (NHCO2CH2Ph), 164.56 (CON-
HCH), 172.16 (CO2CH3), 206.39 (COCH3). Anal. calcd
for C29H34N2O6: C, 68.76; H, 6.77; N, 5.53. Found: C,
68.43; H, 6.68; N, 5.41.
4.7. (1R,1%S,3%R)- and (1S,1%S,3%R)-1-benzyloxycarbonyl-
amino-2-(3%-acetyl-2%,2%-dimethylcyclobutyl)-1-carboxylic
acid (1%%S)-N-(1%%-benzyl-1%%-methoxycarbonyl)methyl
amide, 6a and 6b, respectively
Pure compound 6a was obtained by column chro-
matography of the reaction mixture and fully character-
ized. NMR spectroscopic data for 6b were determined
from enriched fractions.
4.5. General procedure for the catalytic hydrogenation
of dehydropeptides 3 and 4
Substrates 3 and 4 were hydrogenated as the respective
0.1 M MeOH solutions under 2 atmospheres pressure
in the presence of the catalyst (1:24 substrate/catalyst
ratio) at rt for 1 day (2 days for the hydrogenation of
4 by using (S,S)-Et–duphos–Rh as a catalyst). Solvent
was removed and the residue was chromatographed on
Baker-silica gel (1:1 CH2Cl2–EtOAc as eluent).
4.7.1. Compound 6a. Oil, [h]D −7.7 (c 1.2, MeOH); IR
(film): 3307 (broad, NH), 2954, 1733, 1703, 1667 cm−1;
1
500 MHz H NMR (acetone-d6): 0.77 (s, 3H, t-2%-CH3),
1.21 (s, 3H, c-2%-CH3), 1.41-2.10 (complex absorption,
5H, H2a, H2b, H4%a, H4%b, H1%), 1.97 (s, 3H, COCH3),
2.77 (m, 1H, H3%), 2.96–3.16 (complex absorption, 2H,
CH2Ph), 3.66 (s, 3H, CO2CH3), 4.06 (m, 1H, H1), 4.72
(m, 1H, H1%%), 5.03–5.11 (complex absorption, 2H,
OCH2Ph), 6.32 (d, JNH,H1=8.55 Hz, 1H, NHCO2),
7.11–7.41 (complex absorption, 10H, 2Ph), 7.53 (d,
JNH,H1%%=8.55 Hz, 1H, CHCONHCH); 13C NMR (ace-
tone-d6): 16.68 (c-2%-CH3), 22.83 (C4%), 29.65, 29.88
(t-2%-CH3, COCH3), 33.39 (C2), 37.29 (CHCH2Ph),
38.59 (C1%), 42.74 (C2%), 51.41 (CO2CH3), 52.86 (C1),
4.6. (1R,1%S,3%R)- and (1S,1%S,3%R)-1-benzyloxycarbonyl-
amino-2-(3%-acetyl-2%,2%-dimethylcyclobutyl)-1-carboxylic
acid N-methoxycarbonylmethyl amide, 5a and 5b,
respectively
Pure peptide 5a was obtained by crystallization of the
reaction mixture and was fully characterized. NMR

G. P. Aguado et al. / Tetrahedron: Asymmetry 14 (2003) 2445–2451
2451
53.39 (C3%), 54.27 (C1¦), 65.89 (PhCH2O), 126.60,
127.68, 128.26, 129.24 (10 CHaromatic), 136.85, 137.26 (2
Cipso), 155.97 (NHCO2CH2Ph, CONHCH), 171.50
(CO2CH3), 206.08 (COCH3); HRMS: Calcd. for
C29H36N2O6 (M): 508.2573; found: 508.2540. Calcd for
C27H33N2O5 (M−C2H3O): 465.2389; found: 465.2385.
5. (a) Pieroni, O.; Montagnoli, G.; Fissi, A.; Merlino, S.;
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Chem. Phar. Bull. 1990, 38, 2020.
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1
4.7.2. Compound 6b. 500 MHz H NMR (acetone-d6):
0.81 (s, 3H, t-2%-CH3), 1.24 (s, 3H, c-2%-CH3), 1.41–2.10
(complex absorption, 5H, H2a, H2b, H4%a, H4%b, H1%), 1.97
(s, 3H, COCH3), 2.77 (m, 1H, H3%), 2.96–3.16 (complex
absorption, 2H, CH2Ph), 3.66 (s, 3H, CO2CH3), 4.06
(m, 1H, H1), 4.72 (m, 1H, H1%%), 5.03–5.11 (complex
absorption, 2H, OCH2Ph), 6.45 (d, JNH,H1%=7.85 Hz,
1H, NHCO2), 7.11–7.41 (complex absorption, 10H,
2Ph), 7.43 (d, JNH,H1%%=7.90 Hz, 1H, CHCONHCH);
13C NMR (acetone-d6): 16.36 (c-2%-CH3), 23.42 (C4%),
29.65, 29.88 (t-2%-CH3, COCH3), 32.39 (C2), 37.29
(CHCH2Ph), 38.09 (C1%), 42.43 (C2%), 51.41 (CO2CH3),
53.44 (C1), 53.89 (C3%), 54.53 (C1%%), 65.89 (PhCH2O),
126.60, 127.68, 128.26, 129.24 (10 CHaromatic), 136.85,
137.26 (2 Cipso), 155.97 (NHCO2CH2Ph, CONHCH),
171.50 (CO2CH3), 206.08 (COCH3).
Acknowledgements
The authors thank Dr. Teodor Parella, NMR Service at
the UAB, for the NMR experiments leading to the
structural assignment of 6a and 6b. G.P.A. thanks the
Ministerio de Educacio´n (Spain) for a predoctoral Fel-
lowship. Financial support from MCyT (BQU2001-
1907) and AECI (Q2812001B) is gratefully
acknowledged.
13. (a) Adlington, R. M.; Baldwin, J. E.; Jones, R. H.;
Murphy, J. A.; Parisi, M. F. J. Chem. Soc., Chem.
Commun. 1983, 1479; (b) Baldwin, K. A.; Adlington, R.
M.; Parisi, M. F.; Ting, H.-H. Tetrahedron 1986, 42,
2575.
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