Studies on the application of the Passerini reaction and enzymatic procedures to the synthesis of tripeptide mimetics

Article abstract of DOI:10.1016/j.tet.2007.05.044

A new, efficient method for the multicomponent synthesis of tripeptide mimetics is presented. Simple, chemoenzymatic transformations of Passerini reaction products enable the introduction of varied amino acid moieties into the tripeptide scaffold, with co

Full text of DOI:10.1016/j.tet.2007.05.044

Tetrahedron 63 (2007) 7647–7653
Studies on the application of the Passerini reaction and enzymatic
procedures to the synthesis of tripeptide mimetics
Wiktor Szymanski,a Magdalena Zwolinskaa and Ryszard Ostaszewskib,
*
aFaculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warszawa, Poland
bInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 14 November 2006; revised 24 April 2007; accepted 10 May 2007
Available online 17 May 2007
Abstract—A new, efficient method for the multicomponent synthesis of tripeptide mimetics is presented. Simple, chemoenzymatic transfor-
mations of Passerini reaction products enable the introduction of varied amino acid moieties into the tripeptide scaffold, with control of the
stereochemistry. Additionally, this method allows the convenient introduction of a methyl group to the amide nitrogen, leading to derivatives
of N-methylated amino acids—compounds of interest for medicinal chemistry.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Generation of a peptide scaffold with no modification of
nitrogen in the peptide bond (Scheme 1, R3¼H) requires
the use of ammonia as amine component 3, which is severely
limited by the formation of side products.12
Small peptides and their simple analogues form a vast group
of bioactive compounds. Among them, compounds with
various activities can be found, such as anti-parasitic,1
anti-inflammatory,2 and anti-tumor3 agents, HIV-protease
inhibitors,4 calpain,5 and protesome6 inhibitors.
The aim of our study was to establish a multicomponent
procedure that would yield target compounds 6, with full
stereocontrol over the chiral center formed. We were also
interested in the possibility of synthesizing both peptides
(R3¼H) and their N-alkylated analogues (R3¼alkyl). Thus,
we decided to employ the Passerini reaction as the
multicomponent process, and to use an enzymatic hydrolysis
as the key enantiopurity determining step (Scheme 1,
‘Passerini pathway’). The synthetic concept is depicted in
Scheme 2.
The utility of small peptides as potential drugs is severely
limited by pharmacokinetic factors, mainly fast metabolic
degradation. Synthesis of simple analogues of small pep-
tides, the so-called ‘peptidomimetics’, aims to solve this
problem. Commonly used methods include variations to
the structure of the peptide chain,7 introduction of non-
coded amino acids,8 and N-alkylation of amide groups.9
In last few years, combinatorial methods using multicompo-
nent reactions have been closely examined as a fast and
convenient solution for the synthesis of diverse classes of
compounds.10 Tripeptide scaffold 6 is readily obtained in
the Ugi multicomponent reaction (Scheme 1, ‘Ugi path-
way’), between isocyanide 1, aldehyde 2, amine 3, and
acid component 4. This approach, despite its simplicity,
has several drawbacks, which make it very difficult to use.
The main problem is the lack of stereocontrol over the center
of asymmetry, which is generated in the Ugi reaction.10
Moreover, generation of peptide analogues requests the
use of chiral isocyanides derived from a-amino acids, which
undergo rapid racemization under Ugi reaction conditions.11
2. Results and discussion
2.1. Synthesis of non-racemic a-hydroxyamides 8
Racemic a-acetoxyamides rac-7 were synthesized by the
Passerini reaction (Scheme 2) with good to excellent yields
(73–99%). The results are shown in Table 1. Initially, a group
of lipases were tested as catalysts for the stereoselective
hydrolysis of racemic compounds 7. The group consisted
of: wheat germ lipase, Novozym 435A, porcine pancrease
lipase, Candida rugosa lipase, Amano AK lipase, Rhizopus
niveus lipase, Candida lipolytica lipase, Pseudomonas
cepacia lipase, and pig liver esterase. Of the tested enzymes,
only wheat germ lipase performed the hydrolysis, and thus it
was used on a preparative scale. The results are also shown in
Table 1.
Keywords: Tripeptides; Passerini reaction; Enzymatic hydrolysis; Non-
coded amino acids; N-Methylated peptides.
* Corresponding author. Tel.: +48 22 343 2120; e-mail: rysza@icho.edu.pl
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.044

7648
W. Szymanski et al. / Tetrahedron 63 (2007) 7647–7653
R1
1
2
NC
O
R1
R2
R3
1
R3
N
R4
O
NC
O
R1
R2
3
4
NH2
N
H
NHCBz
2
5
5-6 steps
R2
O
O
AcOH
CBzNH
6
OH
R4
Ugi Pathway
Passerini Pathway
Scheme 1. Basic synthetic concepts.
R3
high yield, exceeding the theoretical yield of 50% obtained
in the kinetic resolution of a racemate.
R1
HN
OH
R2
R1 HN
HN
6
R2
1
2
5
2.2. Synthesis of primary and secondary amines 9
R1
HN
OAc
R2
O
O
9
8
diastereoisomeric
R3
ref. 15
+
The next step was to establish an effective procedure for the
transformation of alcohols 8 into amine derivatives 9. This
goal was accomplished by SN2 type substitution of methane-
sulfonic acid esters derived from alcohols 8 (Scheme 3).
Enantiopure compounds obtained from the correlation study
were used in these syntheses (Table 2).
R1 HN
HN
R1
HN
OAc
O
rac-7
6
R2
R2
O
O
ent-9
7
Scheme 2. Synthetic concept.
(S)-8
In three out of four cases, it was possible to obtain products
with high optical purity (namely (R)-7a, (S)-8d, and (S)-8c),
although the reaction time had to be prolonged in the case of
product c. The enantioselectivity was lowest in the case of
leucine analogue d, and clearly an additional optimization
study is required for improved selectivity. We believe how-
ever, that the utility of biocatalysts in enantioselective hy-
drolysis of racemic a-acetoxyamides is clearly visible.
a
R1
HN
NH2
R2
R1
HN
NHMe
R1
HN
OMs
R2
(S)-10
R1
HN
N3
b
d
c
R2
R2
(R)-11
O
O
O
O
(R)-9
(R)-9
(R3=H)
(R3=CH3)
Scheme 3. Synthesis of amines 9. Reagents and conditions: (a) MsCl, Et3N,
DMAP, CH2Cl2, 20 ꢀC, 30 min; (b) CH3NH2 (40% in water), DMF, 50 ꢀC,
24 h; (c) NaN3, DABCO, DMAP, benzo-15-crown-5, CH2Cl2, 40 ꢀC, 24 h;
(d) H2, Pd/C, methanol, 4 h.
In order to assign the configuration of the obtained products,
compounds (S)-8 and (S)-7 were synthesized from commer-
cially available, optically pure a-amino acids, using proce-
dures described in the literature.13,14
Table 2. Transformation of alcohols 8 into amines 9
(S)-8 Yield of
(S)-10/%
Reaction with
methylamine
Synthesis of primary amines
It should also be emphasized that during our research on the
synthesis of unnatural amino acids,15 we have established
a convenient method for the transformation of compounds
(S)-8 and (R)-7 into each other with the inversion of config-
uration. A method for the basic hydrolysis of compounds
(R)-7 to (S)-8 is also described. These transformations allow
the synthesis of a chosen enantiomer of compound 8 with
Product Yield/% Yield of
(R)-11/%
Amine
Yield/%
a
b
c
99
99
94
97
— —
(R)-9c 77
63
98
93
91
(R)-9a
(R)-9b
(R)-9d
(R)-9e
99
99
99
95
—
(R)-9f
—
85
d
Table 1. Chemoenzymatic synthesis of non-racemic compounds 8
No.
Passerini synthesis of rac-7
Structure Yield/%
WGL mediated biotransformation of rac-7
Time
24 h
Product
Yield/%
ee/%
Ec
a
b
c
R1¼EtOC(O)CH2
99
89
79
73
(S)-8
(R)-7
(S)-8
(R)-7
(S)-8
(R)-7
(S)-8
(R)-7
22
43
47
52
50
29
53
43
37a
94a
94b
55b
94b
96b
46
7
R2¼C6H5CH2
R1¼4-CH3OC6H4CH2
R2¼C6H5CH2
48 h
27 d
22 h
59
R1¼C6H5CH2
>150
3.4
R2¼C6H5CH2
d
R1¼4-CH3OC6H4CH2
R2¼(CH3)2CHCH2
38
a
Optical purity.
Determined by HPLC with Daicel Chiracel OD-H column.
Calculated from the conversion-independent equation.
b
c

W. Szymanski et al. / Tetrahedron 63 (2007) 7647–7653
7649
All the amines 9 were obtained in good overall yields,
4. Experimental
although the yield in the case of azide (R)-11a is signifi-
cantly lower, probably due to the existence of an extra
electrophilic center (ester moiety) in the structure of the
substrate.
4.1. General
Optical rotations were measured with a JASCO DIP-360
polarimeter. NMR spectra were measured with a Varian
200 GEMINI and Varian 400 GEMINI spectrometers, with
TMS used as an internal standard. TLCs were performed
with silica gel 60 (230–400 mesh, Merck) and silica gel 60
PF254 (Merck). HPLC experiments were carried out on
DAICEL CHIRACEL OD-H column with a pre-column,
eluent: hexane/isopropanol 9:1 (v/v), flow: 1 mL/min.
CHN analysis was performed on Perkin Elmer 240 Elemen-
tal Analyzer and CHNS analysis on Heraeus Vario EL III
apparatus. MS spectra were recorded on an API-365
(SCIEX) apparatus.
2.3. Synthesis of tripeptide analogues 6
Target tripeptide analogues were prepared by EDC mediated
coupling of amines 9 with model amino acids (glycine for
6a,d,e,h,i, (S)-alanine for 6j, and (S)-phenylalanine for
6b,c,f), bearing a benzyloxycarbonyl (CBz) protecting
group on the nitrogen atom (Scheme 4).
R3
N
R4
O
O
R1
a
NHCBz
(R)-9
6
+
HO
N
H
NHCBz
R4
R2
O
4.1.1. General procedure for the synthesis of Passerini
reaction products rac-7. To a 1 M solution of acetic acid
(1 equiv) in CH2Cl2 were added aldehyde (1.1 equiv) and
then isocyanide (1.1 equiv) at room temperature. After com-
pletion of the reaction, the solvent was evaporated and the
product was purified by flash chromatography (silica gel,
hexane/ethyl acetate, 4:1, v/v).
Scheme 4. Synthesis of tripeptide analogues 6. Reagents and conditions: (a)
EDC, HOBt, CH2Cl2, 20 ꢀC, 20 h.
Yields of compounds 6 are shown in Table 3.
Table 3. Synthesis of compounds 6
4.1.1.1. Ethyl rac-(2-acetoxy-3-phenyl-propionyl-
amino)acetate (rac-7a). Reaction time: 70 h. Yield: 99%,
318 mg of white crystals. Mp 70–71 ꢀC (ethyl acetate/hex-
ane); Rf¼0.07 (ethyl acetate/hexane, 8:2, v/v); Anal.
C15H19NO5 requires: C, 61.42%; H, 6.53%; N, 4.78%;
found: C, 61.52%; H, 6.62%; N, 4.64%; 1H NMR (400 MHz,
CDCl3): d 1.26 (t, 3H, J¼7.2 Hz, CH3CH2), 2.01 (s, 3H,
CH3CO), 3.09 (dd, 1H, J¼14.4 Hz, J¼7.6 Hz, CH2CHOAc),
3.23 (dd, 1H, J¼14.4 Hz, J¼4.8 Hz, CH2CHOAc), 3.97 (dd,
2H, J¼9.6 Hz, J¼5.2 Hz, CH2NH2), 4.18 (q, 2H, J¼7.2 Hz,
CH3CH2), 5.40 (dd, 1H, J¼7.6 Hz, J¼4.8 Hz, CHOAc), 6.56
(br s, 1H, NH), 7.18–7.27 (m, 5H, ArH); 13C NMR
(100 MHz, CDCl3): d 14.0, 20.7, 37.6, 41.0, 61.6, 74.1,
126.9, 128.3, 129.3, 130.3, 135.8, 169.3, 169.4; IR (Nujol):
n 3311, 3261, 1737, 1676, 1658, 1542, 1456, 1375, 1228,
6
R1
R2
R3
R4
H
Yield/%
84
a
b
c
d
e
f
g
h
i
EtOCOCH2
EtOCOCH2
4-CH3OC6H4CH2 C6H5CH2
4-CH3OC6H4CH2 C6H5CH2
4-CH3OC6H4CH2 C6H5CH2
C6H5CH2
C6H5CH2
H
H
H
H
CH3
H
H
C6H5CH2 71
C6H5CH2 70
H
H
C6H5CH2 97
H
73
70
C6H5CH2
C6H5CH2
4-CH3OC6H4CH2 (CH3)2CHCH2
4-CH3OC6H4CH2 (CH3)2CHCH2
4-CH3OC6H4CH2 (CH3)2CHCH2 CH3
80
87
42
H
CH3
H
All of the target compounds were obtained in analyti-
cally pure form with moderate yields (42–97%), although
the yields of reactions with secondary amines (products
6e and 6i) proved to be lower, probably due to steric
hindrance.
1206, 1056, 1024 cmꢁ1
.
4.1.1.2. Acetic acid rac-1-(4-methoxy-benzylcarba-
moyl)-2-phenylethyl ester (rac-7b). Reaction time: 90 h.
Yield: 89%, 583 mg of white crystals. Mp 79–81 ꢀC (ethyl
acetate/hexane); Rf¼0.68 (ethyl acetate/hexane, 4:6, v/v);
Anal. C19H21NO4 requires: C, 69.71%; H, 6.47%; N,
3. Summary
A method for the multicomponent preparation of tripeptide
mimetics is presented. Simple, chemoenzymatic transforma-
tions of Passerini reaction product enable the introduction of
varied amino acid moieties into the tripeptide scaffold, with
control of stereochemistry. Additionally, this method allows
the convenient introduction of a methyl moiety to the amide
nitrogen, leading to the derivatives of N-methylated amino
acids, something that is very difficult with conventional
procedures.9
1
4.28%; found: C, 69.75%; H, 6.49%; N, 4.28%; H NMR
(400 MHz, CDCl3): d 2.05 (s, 3H, CH3CO), 3.21 (m, 2H,
CH2NH), 3.79 (s, 3H, CH3O), 4.33 (m, 2H, CH2CHO),
5.41 (t, 1H, J¼6 Hz, CHC(O)), 6.10 (s, 1H, NH), 6.80–
7.26 (m, 9H, 2ArH); 13C NMR (100 MHz, CDCl3): d 20.9,
37.6, 42.6, 55.2, 74.3, 113.9, 126.9, 128.4, 129.0, 129.6,
129.6, 135.7, 159.0, 168.6, 169.4; IR (Nujol): n 3291, 1749,
1660, 1559, 1514, 1458, 1225, 1247, 1231, 1036 cmꢁ1; re-
tention time of enantiomers: tR¼11.99 min, tS¼13.57 min.
Considering the enormous number of aldehydes that can
be used in the Passerini reaction, the above-described
method is capable of yielding enantiomerically enriched
tripeptides with non-coded amino acids. Initial experiments
were carried out in our laboratory and proved very promis-
ing, although a convenient way for the configuration assign-
ment is yet to be established.
4.1.1.3. Acetic acid rac-1-benzylcarbamoyl-2-phenyl-
ethyl ester (rac-7c). Reaction time: 90 h. Yield: 79%,
942 mg of yellow oil. Mp 83–84 ꢀC (ethyl acetate/hexane);
Rf¼0.15 (ethyl acetate/hexane, 8:2, v/v); Anal. C18H19NO3
requires: C, 72.71%; H, 6.44%; N, 4.71%; found: 72.48%;
1
H, 6.46%; N, 4.70%; H NMR (200 MHz, CDCl3): d 2.06

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W. Szymanski et al. / Tetrahedron 63 (2007) 7647–7653
(s, 3H, CH3), 3.18–3.23 (m, 2H, CH2), 4.35–4.40 (m, 2H,
CH2), 5.42 (t, 1H, J¼5.72 Hz, C(O)CH), 6.30 (s, 1H,
NH), 7.05–7.29 (m, 10H, 2ArH); 13C NMR (50 MHz,
CDCl3): d 21.6, 38.3, 43.8, 75.0, 127.5, 128.1, 128.9,
130.2, 136.3, 138.0, 169.3, 169.9; retention time of enantio-
mers: tR¼15.61 min, tS¼19.72 min.
J¼13.9 Hz, J¼4.1 Hz, CH2CHO), 3.72 (s, 2H, CH2),
4.28–4.34 (m, 3H, ArCH2N, CHOH), 6.77 (s, 1H, NH),
6.80–7.31 (m, 9H, 2ArH); 13C NMR (50 MHz, CDCl3):
d 41.0, 42.7, 55.4, 73.0, 114.1, 127.1, 128.8, 129.2, 129.7,
130.0, 136.9, 159.1, 172.5; IR (Nujol): n 3363, 1633, 1537,
1513, 1456, 1255, 1086, 1027, 698 cmꢁ1; retention time of
enantiomers: tR¼9.74 min, tS¼10.62 min.
4.1.1.4. Acetic acid rac-1-{[(4-methoxybenzyl)amine]-
carbonyl}-3-methylbutyl ester (rac-7d). Reaction time:
96 h. Yield: 73%, 642 mg of yellow oil. Rf¼0.12 (ethyl ace-
tate/hexane, 8:2, v/v); Anal. C16H23NO4 requires: C,
65.51%; H, 7.90%; N, 4.77%; found: C, 65.52%; H, 8.00%;
N, 4.76%; 1H NMR (CDCl3, 400 MHz): d 0.86–0.94 (m, 6H,
(CH3)2CH), 1.66–1.76 (m, 3H, CH2CH(CH3)2), 2.08 (s, 3H,
CH3CO), 3.76 (s, 3H, CH3O), 4.3–4.4 (m, 2H, ArCH2),
5.16–5.24 (m, 1H, COCH(O)CH2), 6.32–6.38 (m, 1H,
NH), 6.82–6.86 (m, 2H, ArH2), 7.12–7.18 (m, 2H, ArH2);
13C NMR (100 MHz, CDCl3): d 21.7, 23.0, 24.4, 40.7,
42.5, 55.2, 72.8, 114.0, 128.9, 158.9, 170.1; retention time
of enantiomers: tR¼7.26 min, tS¼8.97 min.
4.1.2.5. Acetic acid (R)-1-benzylcarbamoyl-2-phenyl-
ethyl ester ((R)-7c). Yield: 29%. eeR (HPLC): 94%. Other
analyses are consistent with rac-7c.
4.1.2.6. (S)-1-Benzylcarbamoyl-2-phenylethanol ((S)-
8c). Yield: 50%, 21.5 mg of white crystals. eeS (HPLC):
96%; [a]2D0¼ꢁ44.4 (c 3.4, ethyl acetate); mp 87–89 ꢀC
(ethyl acetate/hexane); Rf¼0.52 (ethyl acetate/hexane, 4:6,
v/v); Anal. C16H17NO2 requires: C, 75.27%; H, 6.71%; N,
1
5.49%; found: C, 75.43%; H, 6.85%; N, 5.47%; H NMR
(200 MHz, CDCl3): d 2.90 (m, 2H, PhCH2NH), 3.22
(m, 1H, C(O)CH), 4.38 (m, 2H, CH2CHOH), 6.82 (s, 1H,
NH), 7.14–7.30 (m, 10H, 2ArH); 13C NMR (50 MHz,
CDCl3): d 41.4, 43.6, 73.4, 127.5, 128.0, 128.3, 129.2,
129.2, 129.2, 130.1, 137.3, 138.3, 173.1; IR (Nujol): n
3395, 3368, 1629, 1533, 1455, 1089, 700; retention time
of enantiomers: tR¼15.23 min, tS¼21.00 min.
4.1.2. General procedure for the enzymatic hydrolysis
of Passerini reaction products. Ester rac-7 (50 mg) was
dissolved in 10 mL of solvent (water/Et2O, 8:2, v/v). Lipase
from wheat germ (E.C. 3.1.1.3, 3 mg) was added in
one portion to the suspension and stirred on a shaker at
300 rpm at room temperature for the amount of time given
in Table 1. Extraction with ethyl acetate, concentration
in vacuo, and purification of the resulting residue by flash
chromatography (silica gel, hexane/ethyl acetate) afforded
ester (R)-7 and alcohol (S)-8.
4.1.2.7. Acetic acid (R)-1-{[(4-methoxybenzyl)amine]-
carbonyl}-3-methylbutyl ester ((R)-7d). Yield: 43%. eeR
(HPLC): 46%. Other analyses are consistent with rac-7d.
4.1.2.8. (S)-2-Hydroxy-N-(4-methoxybenzyl)-4-methyl-
pentanamide ((S)-8d). Yield: 53%, 25 mg of white crys-
tals. eeS (HPLC): 38%; [a]2D0¼ꢁ11.5 (c 1.0, CHCl3); mp
106–107 ꢀC (methylene chloride/hexane); Rf¼0.62 (ethyl
acetate/hexane, 4:6, v/v); Anal. C14H21NO3 requires: C,
66.85%; H, 8.35%; N, 5.57%; found: C, 67.07%; H, 8.53%;
N, 5.57%; 1H NMR (400 MHz, CDCl3): d 0.82–1.2 (m, 6H,
(CH3)2CH), 1.46–1.73 (m, 2H, CH2), 1.73–1.96 (m, 1H,
CH(CH3)2), 3.768 (s, 3H, CH3O), 4.06–4.18 (m, 1H, CO-
CH(OH)CH2), 4.22–4.46 (m, 2H, ArCH2), 6.819–6.840 (d,
2H, J¼8.4 Hz, ArH2), 6.88–7.03 (m, 1H, NH), 7.10–7.20
(m, 2H, ArH2); 13C NMR (100 MHz, CDCl3): d 21.3, 23.4,
24.4, 42.5, 43.7, 55.2, 70.6, 114.0, 129.0, 158.9, 174.6.
4.1.2.1. Ethyl (R)-(2-acetoxy-3-phenyl-propionyl-
amino)acetate ((R)-7a). Yield: 43%. [a]2D0¼+13.3 (c 0.5,
CHCl3). Optical purity: 94%. Other analyses are consistent
with rac-7a.
4.1.2.2. Ethyl (S)-(2-hydroxy-3-phenyl-propionylami-
ne)acetate ((S)-8a). Yield: 22%, 15.5 mg of yellow oil.
[a]2D0¼ꢁ25.1 (c 0.5, CHCl3). Optical purity: 37%; Rf¼0.55
(ethyl acetate/hexane, 4:6, v/v); 1H NMR (400 MHz,
CDCl3): d 1.27 (t, 3H, J¼7.2 Hz, CH3CH2), 2.85 (dd, 1H,
J¼14.0 Hz, J¼8.8 Hz, CH2CHOH), 3.23 (dd, 1H,
J¼14.0 Hz, J¼4.0 Hz, CH2CHOH), 3.92–4.08 (m, 2H,
CH2NH2), 4.18 (q, 2H, J¼7.2 Hz, CH3CH2), 4.34 (dd, 1H,
J¼8.8 Hz, J¼3.6 Hz, CHOH), 7.15 (br s, 1H, NH), 7.21–
7.32 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3): d 14.0,
40.62, 40.79, 61.49, 72.83, 126.8, 128.5, 129.4, 137.0, 169.7,
173.4. HRMS (ESI, [M+Na]+) 274.1054 (C13H17NO4Na:
274.1050).
4.1.3. Synthesis of compounds 6e and 6i. The transforma-
tion of alcohols (S)-8b and (S)-8d into N-methylated amides
6e and 6i, respectively, is further exemplified by the synthe-
sis of 6e.
4.1.3.1. Methanesulfonic acid (S)-1-(4-methoxy-
benzylcarbamoyl)-2-phenylethyl ester ((S)-10b). Solution
of alcohol (S)-8 (571 mg, 2.0 mmol, from correlation
study15) in CH2Cl2 (6 mL) was cooled to ꢁ50 ꢀC. Triethyl-
amine (1.12 mL, 8.0 mmol) and methanesulfonyl chloride
(232 mL, 3.0 mmol) were added in one portion. The mixture
was stirred for 30 min at room temperature, the solvent was
evaporated and the product was purified by flash chromato-
graphy (silica gel, hexane/ethyl acetate, 4:6, v/v). Yield:
99%, 716 mg of white crystals. [a]2D0¼ꢁ66.1 (c 1.0,
CHCl3); Rf¼0.60 (hexane/ethyl acetate, 4:6, v/v); mp 119–
120 ꢀC (ethyl acetate/hexane); Anal. C18H21NO5S requires:
C, 59.49%; H, 5.82%; N, 3.58%; found: 59.48%; H, 5.86%;
4.1.2.3. Acetic acid (R)-1-(4-methoxy-benzylcarba-
moyl)-2-phenylethyl ester ((R)-7b). Yield: 52%. eeR
(HPLC): 55%. Other analyses are consistent with rac-7b.
4.1.2.4. (S)-2-(4-Methoxybenzyl)carbamoyl-1-phenyl-
ethanol ((S)-8b). Yield: 47%, 20.7 mg of white crystals.
eeS (HPLC): 94%; [a]D20¼ꢁ49.7 (c 1.0, CHCl3); Rf¼0.43
(ethyl acetate/hexane, 4:6, v/v); mp 78–80 ꢀC (ethyl ace-
tate/hexane); Anal. C17H19NO3 requires: C, 71.56%; H,
6.71%; N, 4.91%; found: C, 71.62%; H, 6.76%; N, 4.87%;
1H NMR (200 MHz, CDCl3): d 2.60 (br s, 1H, OH), 2.90
(dd, 1H, J¼13.9 Hz, J¼8.2 Hz, CH2CHO), 3.23 (dd, 1H,
1
N, 3.88%; H NMR (200 MHz, CDCl3): d 2.53 (s, 3H,

W. Szymanski et al. / Tetrahedron 63 (2007) 7647–7653
7651
CH3SO2), 3.12 (dd, 1H, J¼14.4 Hz, J¼9.1 Hz, CH2CHO),
3.53 (dd, 1H, J¼14.4 Hz, J¼3.6 Hz, CH2CHO), 3.86 (s,
3H, CH3O), 4.42–4.50 (m, 2H, ArCH2N), 5.22 (dd, 1H,
J¼9.1 Hz, J¼3.6 Hz, CHC(O)), 6.67 (s, 1H, NH), 6.89–
7.43 (m, 9H, 2ArH); 13C NMR (50 MHz, CDCl3): d 37.89,
38.71, 43.07, 55.42, 81.66, 114.21, 127.60, 128.89, 129.08,
129.87, 135.64, 167.56.
1H, COCHCH2), 5.1–5.14 (m, 2H, ArCH2), 5.68–5.74 (m,
1H, NH), 6.28–6.34 (m, 1H, NH), 6.8–7.4 (m, 9H, ArH);
13C NMR (100 MHz, CDCl3): d 22.0, 23.0, 24.8, 29.6,
36.3, 42.9, 54.9, 55.2, 66.9, 76.6 114.0, 114.1, 120.2, 128.0,
128.2, 128.5, 128.9, 129.0, 130.1, 136.3, 156.2, 158.9, 169.4,
169.9; HRMS (ESI, [M+Na]+) 478.2336 (C25H33N3O5Na:
478.2312).
4.1.3.2. (R)-N-(4-Methoxybenzyl)-2-methylamine-3-
phenyl-propionamide ((R)-9c). To a solution of methane-
sulfonic acid ester (S)-10b (182 mg, 0.50 mmol) in DMF
was added methylamine (40% solution in water, 2.5 mL)
and the mixture was stirred at 50 ꢀC for 22 h. Then the reac-
tion mixture was dissolved in ethyl ether (10 mL) and water
(3 mL). The phases were separated and the aqueous phase
was extracted with ether (3ꢂ7 mL). Collected organic
phases were dried (MgSO4) and the product was purified
by flash chromatography (silica gel, ethyl acetate/methanol,
9:1, v/v). Yield: 77%, 128 mg of colorless oil; Rf¼0.40 (ethyl
4.1.4. Synthesis of compounds 6a–6d and 6f–6h. The
transformation of alcohols (S)-8a–d into amides 6a–6d
and 6f–6h is further exemplified by the synthesis of 6c.
4.1.4.1. (R)-2-Azido-N-(4-methoxy-benzyl)-3-phenyl-
propionamide ((R)-11b). To a solution of methanesulfonic
acid ester (S)-10b (200 mg, 0.55 mmol) in CH2Cl2 (3.0 mL)
were added 1,4-diaza-bicyclo[2.2.2]octane (102 mg,
0.90 mmol), 4-dimethylaminopyridine (10 mg), sodium
azide (72 mg, 1.1 mmol), and benzo-15-crown-5 (10 mg).
After 20 h the product was purified by flash chromatography
(silica gel, hexane/ethyl acetate, 4:1, v/v). Yield: 98%,
169 mg of colorless oil. Rf¼0.83 (hexane/ethyl acetate,
4:6, v/v); [a]D20¼ꢁ29.8 (c 1.0, chloroform); Anal.
C17H18N4O2 requires: C, 65.79%; H, 5.85%; N, 18.05%;
found: C, 65.60%; H, 6.08%; N, 17.95%; 1H NMR
(400 MHz, CDCl3): d 3.06 (dd, 1H, J¼8.0 Hz, J¼14.4 Hz,
PhCH2), 3.35 (dd, 1H, J¼4.4 Hz, J¼14.4 Hz, PhCH2), 3.86
(s, 3H, CH3O), 4.22 (dd, 1H, J¼4.4 Hz, J¼8.0 Hz, CHN3),
4.30–4.37 (m, 2H, PhCH2NH), 6.48 (br s, 1H, NH), 6.82–
7.29 (m, 9H, 2ArH); 13C NMR (100 MHz, CDCl3): d 38.4,
42.9, 55.2, 65.4, 114.0, 127.1, 128.6, 129.9, 129.4, 129.5,
136.0, 159.0, 168.2; IR (Nujol): n 3322, 2097, 2061, 1640,
1
acetate/methanol, 9:1, v/v); H NMR (200 MHz, CDCl3):
d 2.30 (s, 3H, CH3NH), 2.83 (dd, 1H, J¼13.6 Hz, J¼8.4 Hz,
PhCH2), 3.16 (dd, 1H, J¼13.6 Hz, J¼5.6 Hz, PhCH2), 3.43
(dd, 1H, J¼8.4 Hz, J¼5.6 Hz, CHNHCH3), 3.77 (s, 3H,
CH3O), 4.31–4.34 (m, 2H, ArCH2N), 6.07 (s, 1H, CH3NH),
6.80–7.29 (m, 9H, 2ArH), 7.48 (s, 1H, NHCO). This com-
pound was used in further synthesis without purification.
4.1.3.3. ({[(R)-1-(4-Methoxy-benzylcarbamoyl)-2-phe-
nylethyl]-methyl-carbamoyl}-methyl)-carbamic
acid
benzyl ester (6e). To a solution of amine (R)-9c (24 mg,
0.07 mmol) in CH2Cl2 (2.0 mL) were added Cbz-protected
glycine (15 mg, 0.07 mmol) and 1-hydroxybenzotriazole
(15 mg, 0.11 mmol). The solution was cooled to 0 ꢀC and
EDC (16 mg, 0.08 mmol) was added in one portion. After
20 h the solvent was evaporated and the residue was taken
up in ethyl acetate (15 mL). This solution was washed
with 5% aqueous citric acid solution (2ꢂ5 mL), saturated
NaHCO3 solution (2ꢂ5 mL), and brine (5 mL). The organic
phase was dried (MgSO4) and evaporated to yield the analyt-
ically pure compound. Yield: 70%, 24 mg of yellow oil.
Rf¼0.66 (hexane/ethyl acetate, 4:6, v/v); [a]D20¼37.6 (c
1535, 1453, 1245 cmꢁ1
.
4.1.4.2. (R)-2-Amino-N-(4-methoxy-benzyl)-3-phenyl-
propionamide ((R)-9b). Azide (R)-11b (115 mg,
0.37 mmol) was dissolved in methanol (8 mL). To this mix-
ture, 10% Pd/C (10 mg) was added and hydrogen was fluxed
through the solution (from a rubber balloon through a needle)
for a period of 2 h. Then the reaction mixture was filtered
through a bed of Celite and the solvent was evaporated.
Yield: 99%, 104 mg of yellow greasy solid. Recrystalliza-
tion from ethyl acetate/hexane afforded analytical sample.
1
1.0, chloroform); H NMR (400 MHz, CDCl3): d 2.91 (s,
1
3H, CH3N), 2.97 (dd, 1H, J¼8 Hz, J¼14.4 Hz, phe CH2),
3.34 (dd, 1H, J¼7.2 Hz, J¼14.4 Hz, phe CH2), 3.77 (s,
3H, CH3O), 3.74–4.38 (m, 5H, PhCH2NH, gly CH2, phe
CH), 5.09 (s, 2H, PhCH2O), 5.24–5.29 (m, 1H, NH), 5.60
(s, 1H, NH), 6.28 (s, 1H, NH), 6.78–7.35 (m, 14H, ArH);
13C NMR (100 MHz, CDCl3): d 29.7, 30.2, 34.1, 42.9,
55.2, 58.1, 66.9, 114.0, 126.8, 128.0, 128.5, 128.6, 128.9,
129.9, 136.3, 136.6, 156.1, 158.9, 169.0, 169.3; HRMS
(ESI, [M+Na]+) 512.2163 (C28H31N3O5Na: 554.2156).
[a]D20¼ꢁ58.0 (c 1.0, chloroform); mp 84–85 ꢀC; H NMR
(400 MHz, CDCl3): d 1.54 (s, 2H, NH2), 2.73 (dd, 1H, J¼
9.2 Hz, J¼13.6 Hz, PhCH2CH), 3.25 (dd, 1H, J¼4.0 Hz,
J¼13.6 Hz, PhCH2CH), 3.63 (dd, 1H, J¼4.0 Hz, J¼
8.8 Hz, CHNH2), 3.77 (s, 3H, CH3O), 4.30–4.40 (m, 2H,
PhCH2NH), 6.82–7.31 (m, 9H, 2ArH), 7.56 (s, 1H, NH);
13C NMR (100 MHz, CDCl3): d 40.8, 42.4, 55.1, 56.3,
113.8, 126.6, 128.5, 128.8, 128.9, 129.2, 130.3, 137.7,
158.7, 173.8; IR (Nujol): n 3236, 1626, 1510, 1450, 1244,
1021 cmꢁ1
.
In an analogous manner, compound 6i was synthesized using
(S)-8d as a substrate.
4.1.4.3. {(S)-1-[(R)-1-(4-Methoxy-benzylcarbamoyl)-
2-phenyl-ethylcarbamoyl]-2-phenylethyl}-carbamic acid
benzyl ester (6c). To a solution of amine (R)-11b (47 mg,
0.16 mmol) in CH2Cl2 (1.5 mL) were added Cbz-protected
phenylalanine (50 mg, 0.16 mmol) and 1-hydroxybenzotri-
azole (33 mg, 0.25 mmol). The solution was cooled to
0 ꢀC and EDC (35 mg, 0.18 mmol) was added in one portion.
After 20 h the solvent was evaporated and the residue was
taken up in ethyl acetate (15 mL). This solution was washed
with 5% aqueous citric acid solution (2ꢂ5 mL), saturated
4.1.3.4.
({[(R)-1-(4-Methoxy-benzylcarbamoyl)-3-
methyl-butyl]-methyl-carbamoyl}-methyl)-carbamic acid
benzyl ester (6i). Yield: 42%, 49 mg of yellow oil. Rf¼0.53
(hexane/ethyl acetate, 4:6, v/v); [a]D20¼84.8 (c 1.0, chloro-
1
form); H NMR (400 MHz, CDCl3): d 0.84–0.98 (m, 6H,
(CH3)2CH), 1.41–1.74 (m, 3H, CH2CH(CH3)2), 2.88 (s, 3H,
CH3N(CH)CO), 3.78 (s, 3H, CH3O), 3.94–4.04 (m, 2H,
COCH2NH), 4.22–4.38 (m, 2H, ArCH2NH), 5.0–5.1 (m,

7652
W. Szymanski et al. / Tetrahedron 63 (2007) 7647–7653
NaHCO3 solution (2ꢂ5 mL), and brine (5 mL). The organic
phase was dried (MgSO4) and evaporated to yield the analyt-
ically pure compound. Yield: 70%, 65 mg of white crystals.
Rf¼0.55 (hexane/ethyl acetate, 4:6, v/v); mp 198–199 ꢀC
(ethyl acetate/hexane); [a]D20¼5.4 (c 1.0, DMSO); 1H NMR
(400 MHz, DMSO-d6): d 2.48–2.50 (m, 2H), 2.60–2.61
(m, 2H), 2.78–2.79 (m, 2H), 3.00–3.01 (m, 2H), 3.34–3.35
(m, 2H), 3.70 (s, 3H), 4.22–4.23 (m, 3H), 4.56 (m, 1H), 4.86–
4.88 (m, 2H), 6.85–8.48 (m, 19H); 13C NMR (100 MHz,
DMSO-d6): d 37.4, 37.9, 40.4, 41.5, 54.0, 55.0, 65.2,
113.7, 126.2, 126.3, 127.5, 127.7, 127.9, 128.0, 128.2, 128.5,
129.2, 129.3, 130.9, 136.9, 137.8, 138.0, 155.9, 158.2, 170.8,
171.3; HRMS (ESI, [M+Na]+) 588.2494 (C34H35N3O5Na:
588.2469); IR (Nujol): n 3288, 1692, 1643, 1541, 1513,
1263, 748, 699.
4.1.4.7. [(S)-1-((R)-1-Benzylcarbamoyl-2-phenyl-ethyl-
carbamoyl)-2-phenylethyl]-carbamic acid benzyl ester
(6f). Yield: 97%, 35 mg of yellow oil. Rf¼0.50 (hexane/ethyl
acetate, 4:6, v/v); [a]2D0¼12.8 (c 1.0, chloroform); 1H NMR
(400 MHz, CDCl3): d 2.67–3.54 (m, 4H), 4.20–4.30 (m, 2H),
4.80–4.92 (m, 2H), 5.01–5.11 (m, 1H), 5.49–5.51 (m, 1H),
6.89–7.42 (m, 20H); 13C NMR (CDCl3, 100 MHz): d 40.7,
41.5, 51.0, 55.0, 65.2, 65.4, 113.6, 126.2, 126.3, 127.1,
127.4, 127.7, 128.3, 128.4, 129.2, 129.3, 131.2, 136.9, 137.8,
138.0, 139.0, 155.8, 158.1, 178.8, 171.6, 172.6; HRMS (ESI,
[M+Na]+) 588.2385 (C33H33N3O4Na: 588.2363).
4.1.4.8.
{[(R)-1-(4-Methoxy-benzylcarbamoyl)-3-
methyl-butylcarbamoyl]-methyl}-carbamic acid benzyl
ester (6g). Yield: 80%, 94 mg of white crystals. Rf¼0.39
(hexane/ethyl acetate, 4:6, v/v); mp 137–139 ꢀC (ethyl ace-
tate/hexane); [a]D20¼21.3 (c 1.0, chloroform); Anal.
C24H31N3O5 requires: C, 65.29%; H, 7.08%; N, 9.25%;
found: C, 65.08%; H, 6.97%; N, 9.51%; 1H NMR (200 MHz,
CDCl3): d 0.8–1.0 (m, 6H, (CH3)2CH), 1.5–1.7 (m, 3H,
CH2CH(CH3)2), 3.74 (s, 3H, CH3O), 3.78–3.85 (d, 2H,
JHH¼4.4 Hz, COCH2NH), 4.18–4.4 (m, 2H, ArCH2(NH)),
4.4–4.6 (m, 1H, COCH(NH)(CH2)), 5.0–5.1 (m, 2H,
ArCH2), 5.7–5.8 (m, 1H, NH), 6.88–7.0 (m, 1H, NH), 6.8–
7.4 (m, 9H, ArH); 13C NMR (50 MHz, CDCl3): d 22.4, 23.2,
25.1, 41.6, 43.4, 44.9, 52.2, 55.6, 67.5, 114.4, 128.4, 128.5,
128.9, 129.3, 165.2, 169.5, 172.0; IR (Nujol): n 3315, 3276,
In an analogous manner, compounds 6a, 6b, 6d, and 6f–6h
were synthesized.
4.1.4.4.
[(R)-2-(2-Benzyloxycarbonylamino-acetyl-
amino)-3-phenyl-propionylamino]-acetic acid ethyl ester
(6a). Yield: 84%, 46 mg of transparent oil. Rf¼0.31 (hexane/
ethyl acetate, 4:6, v/v); [a]D20¼13.8 (c 1.0, ethanol); 1H
NMR (200 MHz, CDCl3): d 1.54 (t, 3H, J¼7.2 Hz,
CH3CH2), 2.94–3.01 (m, 2H, CH2 phe), 3.62–3.89 (m, 4H,
2ꢂgly), 4.07 (q, 2H, J¼7.2 Hz, CH3CH2), 4.72–4.76 (m,
1H, CH phe), 5.69 (s, 1H, NH), 6.93 (s, 1H, NH), 7.05–
7.24 (m, 10H, 2ArH); 13C NMR (50 MHz, CDCl3): d 14.4,
38.5, 41.6, 44.7, 54.6, 61.8, 67.5, 127.3, 128.3, 128.5, 128.8,
128.8, 129.6, 136.5, 136.6, 157.0, 169.7, 169.8, 171.5. HRMS
(ESI, [M+Na]+) 464.1776 (C23H27N3O6Na: 446.1792).
1728, 1656, 1629, 1548, 1516, 1255, 1222, 1034, 696 cmꢁ1
.
4.1.4.9. {(S)-1-[(R)-1-(4-Methoxy-benzylcarbamoyl)-
3-methyl-butylcarbamoyl]-ethyl}-carbamic acid benzyl
ester (6h). Yield: 87%, 64 mg of white crystals. Rf¼0.41
(hexane/ethyl acetate, 4:6, v/v); mp 146–148 ꢀC (ethyl
4.1.4.5.
[(R)-2-((S)-2-Benzyloxycarbonylamino-3-
acetate/hexane); [a]D20¼15.5 (c 1.0, chloroform); H NMR
1
phenyl-propionylamino)-3-phenyl-propionylamino]-ace-
tic acid ethyl ester (6b). Yield: 71%, 31 mg of white
crystals. Rf¼0.60 (hexane/ethyl acetate, 4:6, v/v); mp 155–
157 ꢀC (ethyl acetate/hexane); [a]2D0¼18.4 (c 1.0, dioxane);
Anal. C30H33N3O6 requires: C, 67.78%; H, 6.26%; N,
(400 MHz, CDCl3): d 0.8–1.0 (m, 6H, (CH3)2CH), 1.2–
1.38 (m, 3H, CH3CH), 1.46–1.8 (m, 3H, (CH3)2CHCH2),
3.72 (s, 3H, CH3O), 4.16–4.42 (m, 3H, CHCH3, ArCH2NH),
4.42–4.56 (m, 1H, COCH(NH)CH2), 4.8–5.2 (dd, 2H,
JHH¼12 Hz, ArCH2), 5.56–5.64 (m, 1H, NH), 6.85–6.9
(m, 1H, NH), 6.95–7.01 (m, 1H, NH), 6.75–7.35 (m, 9H,
ArH); 13C NMR (100 MHz, CDCl3): d 21.9, 22.9, 24.8,
29.7, 40.8, 42.9, 43.4, 54.1, 55.2, 67.0, 113.9, 126.9, 127.5,
127.9, 128.0, 128.2, 128.4, 128.5, 128.6, 128.7, 128.7, 128.9,
136.0, 158.8, 171.2, 171.8; HRMS (ESI, [M+Na]+)
478.2320 (C25H33N3O5Na: 478.2312).
1
7.90%; found: C, 67.90%; H, 6.45%; N, 8.06%; H NMR
(400 MHz, CDCl3): d 1.23 (t, 3H, J¼7.2 Hz, CH3CH2),
2.84–2.94 (m, 2H, CH2 phe), 2.97–3.02 (m, 2H, CH2 phe),
3.78 (s, 2H, CBz), 4.14 (q, 2H, J¼7.2 Hz, CH3CH2), 4.28–
4.32 (m, 1H, CH phe), 4.72–4.74 (m, 1H, CH phe), 4.97–
5.03 (m, 2H, gly), 5.40 (s, 1H, NH), 6.62 (s, 1H, NH), 7.09 (s,
1H, NH), 7.17–7.34 (m, 15H, 3ArH); 13C NMR (100 MHz,
CDCl3): d 14.1, 36.3, 38.1, 41.3, 53.9, 56.7, 61.4, 67.1,
127.0, 127.1, 127.9, 128.2, 128.5, 128.6, 128.7, 129.2, 129.3,
136.0, 136.1, 136.1, 156.1, 169.4, 170.8, 171.2; HRMS (ESI,
[M+Na]+) 554.2284 (C30H33N3O6Na: 554.2261).
Acknowledgements
This work was financially supported by Warsaw University
of Technology and by Polish State Committee for Scientific
Research, Grant PBZ–KBN 126/T09/07.
4.1.4.6.
{[(R)-1-(4-Methoxy-benzylcarbamoyl)-2-
phenyl-ethylcarbamoyl]-methyl}-carbamic acid benzyl
ester (6d). Yield: 73%, 57 mg of white crystals. Rf¼0.22
(hexane/ethyl acetate, 4:6, v/v); mp 186–188 ꢀC (ethyl ace-
tate/hexane); [a]2D0¼ꢁ5.1 (c 1.0, dioxane); 1H NMR
(400 MHz, DMSO-d6): d 2.48–2.50 (m, 2H), 2.85–2.90
(m, 2H), 2.96–2.97 (m, 2H), 3.34–3.35 (m, 2H), 3.55–3.63
(m, 2H), 3.70 (s, 3H), 4.17–4.18 (m, 2H), 4.52–4.53 (m, 2H),
4.99 (s, 2H), 6.83–8.43 (m, 14H); 13C NMR (100 MHz,
DMSO-d6): d 37.9, 41.5, 43.4, 54.1, 55.0, 65.4, 113.6,
119.8, 127.7, 127.8, 128.1, 128.3, 128.5, 129.2, 131.0, 137.0,
137.7, 156.5, 158.2, 168.8, 170.6; HRMS (ESI, [M+Na]+)
498.2010 (C27H29N3O5Na: 498.1999).
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