α-Amino acids as acid components in the Passerini reaction: influence of N-protection on the yield and stereoselectivity

Article abstract of DOI:10.1016/j.tet.2008.07.064

The Passerini reaction offers an easy access to depsipeptides, when both acid and isocyanide are derived from α-amino acids. However, racemisation of isocyanides derived from α-amino acid esters severely limits their use in the Passerini reaction. In order to overcome this limitation, a study on the influence of the α-amino acid N-protecting group on the yield and diastereoisomeric ratio of the product of the Passerini reaction was performed. Six different protecting groups were tested. Their influence turns out to be crucial and is not constant when the amino acid is changed. After optimisation, the Passerini reaction products with cyclohexanone as the carbonyl component were obtained with 99% yield and >98% de.

Full text of DOI:10.1016/j.tet.2008.07.064

Tetrahedron 64 (2008) 9780–9783
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
a-Amino acids as acid components in the Passerini reaction:
influence of N-protection on the yield and stereoselectivity
*
_
Stanis1aw Ber1ozecki, Wiktor Szymanski, Ryszard Ostaszewski
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The Passerini reaction offers an easy access to depsipeptides, when both acid and isocyanide are derived
Received 28 March 2008
Received in revised form 7 July 2008
Accepted 17 July 2008
from
limits their use in the Passerini reaction. In order to overcome this limitation, a study on the influence of
the -amino acid N-protecting group on the yield and diastereoisomeric ratio of the product of the
Passerini reaction was performed. Six different protecting groups were tested. Their influence turns out
to be crucial and is not constant when the amino acid is changed. After optimisation, the Passerini
reaction products with cyclohexanone as the carbonyl component were obtained with 99% yield and
>98% de.
a-amino acids. However, racemisation of isocyanides derived from a-amino acid esters severely
a
Available online 22 July 2008
Keywords:
Passerini reaction
Isocyanides
Ó 2008 Elsevier Ltd. All rights reserved.
Diastereoselectivity
1. Introduction
witnessed, however, that the lability of the proton in the a position
of the isocyanide in general results in racemisation. Another
drawback of the Passerini reaction is its sensitivity to the steric
hindrance of the carbonyl compounds. Therefore, aldehydes per-
form much better than ketones.
In recent years, the Passerini reaction has became a powerful
tool in combinatorial synthesis. Of special interest are cases in
which N-protected amino acids are used as the acid compounds
(Scheme 1). Such reagents allow a convenient synthesis of dep-
In this paper, we report our studies on the influence of the type
of N-protection on the yield and stereoselectivity of the Passerini
reaction with ketones. For the model study, we have chosen an
sipeptides1 and
b-peptide analogues through a Passerini reaction–
deprotection–acyl migration strategy.2–4 Many such compounds
have confirmed the biological activities, such as AM-Toxins,5
antibiotics (e.g., valinomycines)6 and protease inhibitors.7
isocyanide derived from
and two amino acids,
L
-phenylalanine (R1¼Bn), cyclohexanone
L
-phenylalanine and D-valine, bearing various
protections of the amino group.
O
O
O
PGHN
NC
OH
2. Results and discussion
MeO
+
+
R2
R1
The collected results of our study with protected D-valine as the
O
O
O
acid component in the Passerini reaction are presented in Table 1.
A great influence of the type of protecting group can be seen,
both on the yield and on the diastereoisomeric ratio of the product.
In terms of the yield, best results (over 74% in ca. 20 h) were
obtained in reactions with Boc and phthaloyl protected amino
acids, regardless of the isocyanide’s configuration (Table 1, entries
6, 8 and 11, 12). Reaction with CBz-protected substrate proved to be
sensitive to the configuration of the isocyanide, as after 25 h of
reaction the yield of the diastereoisomer derived from (R)-iso-
cyanide (Table 1, entry 5) was higher than the yield of the di-
astereoisomer derived from (S)-isocyanide (Table 1, entry 4) after
27 h. Substrates with benzoyl and acetyl groups (Table 1, entries 1, 2
and 9, 10) reacted much slower, and in the case of the acetylamino
acid the influence of isocyanide’s configuration is crucial. In the
H
N
NHPG
MeO
R1
R2
O
Scheme 1. Studied Passerini reaction.
It is noteworthy that in only two cases3,4 a chiral isocyanide
derived from an amino acid other than glycine is used. In both
cases, the Boc-protected amino acids are used as the acid compo-
nents. The authors report no epimerisation on the isocyanide-
derived chirality centre in the course of the reaction. We have
* Corresponding author. Tel.: þ48 22 343 2120.
E-mail address: rysza@icho.edu.pl (R. Ostaszewski).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.064

_
S. Berłozecki et al. / Tetrahedron 64 (2008) 9780–9783
9781
Table 1
reaction conditions is negligible (Scheme 2, kepy0). An experiment
was performed to support this thesisddiastereoisomerically
enriched depsipeptide was stirred in the Passerini reaction condi-
tions for 40 h and no change in diastereoisomeric excess was ob-
served. Based on these assumptions, we propose two distinct kinetic
relationships, which would lead to differences in the influence of
amino acid protecting group on the diastereoisomeric ratio.
Results of the study with N-protected
D
-valine (R4¼i-Pr)
No.
PG
Bz
R–NC config.
t [h]
Yield [%]
Comp.
dra
1
2
S
R
20
35
30
42
1
16:84
81:19
3
Trt
S
115
<1
2
3
nd
4
5
CBz
S
R
27
25
52
89
18:82
87:13
6
7
8
Phth
S
RS
R
17
20
20
74
84
78
4
85:15
52:48
18:82
O
O
O
H
N
P-MCR
k1
NC
Ph
NHPG
MeO
MeO
MeO
O
O
R4
9
10
Ac
S
R
21
60
21
9
5
6
18:82
69:31
O
Ph
kep
krac
11
12
Boc
S
R
20
23
79
87
5:95
96:4
O
O
O
H
N
P-MCR
k2
Reactions in cyclohexanone at 40 ꢀC.
NHPG
NC
Ph
MeO
Ph
a
Determined by HPLC analysis.
R4
O
reaction with the trityl-protected amino acid (Table 1, entry 3), no
formation of the product was observed.
Scheme 2. System kinetics.
According to the first hypothesis, the reactions with some of the
protected amino acids proceed faster, and the racemisation rate of
the isocyanide is relatively lower (k1>krac), which leads to conver-
sion of the substrate before it racemises. According to the second
hypothesis, the racemisation of isocyanide is fast (krac>k1, k2), but
with some of the protected amino acids one of the di-
astereoisomeric products is formed faster (k1>k2), which leads to
the dynamic kinetic resolution (DKR) of the isocyanide.
The best diastereoisomeric ratio of the product was obtained in
the reaction with Boc-protected amino acid (Table 1, entries 11, 12),
and Boc protection is clearly the group of choice, as both the yields
and the diastereoisomeric ratios are the highest. The acetyl
protection is the worst out of those tested, as the yields are low and
mixtures of diastereoisomers are formed in the reactions.
To investigate the influence of the type of amino acid, we
performed an analogous study using N-protected L-phenylalanine.
It is possible to suggest a correlation of the yield and diaster-
eoselectivity of the reactions. The fastest reactions (giving products
in highest yields after comparable time) also give products with
high diastereoisomeric ratios (e.g., Table 1, entries 11, 12, and Table
2 entries 6, 7, and 11, 12). This is also valid when two enantiomers of
isocyanide are compared in the reaction with one amino acid (e.g.,
Table 2, entries 1, 2 and 8, 10). This observation strongly supports
the first hypothesis.
In order to obtain further information on the nature of the
phenomenon, we studied the reactions with racemic isocyanides
(Table 1, entry 8 and Table 2, entry 9). In these reactions, roughly
equimolar mixtures of diastereoisomeric products were obtained,
which suggests that the second hypothesis is not occurring.
The results are presented in Table 2.
The best yields were obtained in the reactions with Boc and
phthaloyl protected amino acids (Table 2, entries 6, 7, and 11, 12), as
was the case for the derivatives of D-valine, however, a bigger in-
fluence of the isocyanide configuration can be seen. The reaction
with CBz-protected phenylalanine yielded no product (Table 2,
entry 5). With other protecting groups (Bz, Trt and Ac), the products
were obtained in moderate yields, and an influence of the iso-
cyanide configuration on the yield was observed, especially in the
case of acetyl-protected phenylalanine (Table 2, entries 8–10).
Virtually only one diastereoisomer was obtained in the reactions
with amino acids bearing the trityl, phthaloyl and Boc protections
(Table 2, entries 3, 4, 6, 7 and 11, 12). These results, combined with
the yields, again point to the Boc protection as the best choice.
We also carried out a study on the possible cause of the different
distributions of the product diastereoisomers (Scheme 2). Two basic
assumptions were taken. First, the Passerini reaction is irreversible.8
Second, the epimerisation of the depsipeptide product under the
3. Summary
A study on the influence of the protecting group in the amino
acid as the acid component of the Passerini reaction on the yield
and diastereoselectivity of this reaction was performed. Six differ-
ent protecting groups were tested and the influence of the pro-
tecting group proved to be crucial. tert-Butoxycarbonyl (Boc) group
was chosen as the best N-protecting group in the studied system.
An initial study on the nature of this phenomenon was also con-
ducted. It leads to a suggestion that with some N-protections used
for amino acids, the reaction proceeds faster and the racemisation
of the isocyanide is slower. This results in fast formation of one
diastereoisomer of the product.
Table 2
Results of the study with N-protected
L
-phenylalanine (R4¼Bn)
No.
PG
Bz
R–NC config.
t [h]
Yield [%]
Comp.
dra
94:6
7:93
1
2
S
R
20
20
39
48
7
3
4
Trt
S
R
24
20
66
49
8
<1:99
>99:1
The use of Boc-protected amino acids in the Passerini reaction
with cyclic ketone leads to the product in very high yields and high
diastereoisomeric ratios, for both of the studied model amino acids.
5
CBz
S
60
<1
9
d
6
7
Phth
S
R
14
40
84
82
10
<1:99
>99:1
8
9
10
Ac
S
RS
R
20
20
23
67
51
36
11
12
16:84
54:46
75:25
4. Experimental
4.1. General
11
12
Boc
S
R
20
16
86
>99
99:1
1:99
Reactions in cyclohexanone at 40 ꢀC.
Optical rotations were measured with a JASCO DIP-360 polar-
imeter. NMR spectra were measured with a Varian 200 GEMINI and
a
Determined by HPLC analysis.

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S. Berłozecki et al. / Tetrahedron 64 (2008) 9780–9783
9782
Varian 400 GEMINI spectrometers, with TMS used as an internal
standard. CHN analyses were performed on Perkin Elmer 240
Elemental Analyzer. MS spectra were recorded on an API-365
(SCIEX) apparatus.
128.9, 129.6, 136.6, 170.8, 172.2; IR (CH2Cl2) n: 3436, 3347, 3055,
3034, 2942, 2865, 1741, 1680, 1510, 1453, 1349, 1311, 1217,
1140 cmꢁ1; retention time: tR¼12.7 min.
20
Compound (R,R)-4: [
a
]
ꢁ7.7 (c 1.7, benzene). Anal. C30H34N2O7
D
requires: C, 67.40%; H, 6.41%; N, 5.24%. Found: C, 67.55%; H, 6.37%;
4.2. General procedure for the synthesis of Passerini
reaction products
N, 5.09%. 1H NMR (200 MHz, C6D6):
d
0.89 (d, J¼6.6 Hz, 3H, CH3CH),
1.09 (d, J¼6.8 Hz, 3H, CH3CH), 1.18–1.50 (m, 6H, (CH2)3), 1.60–2.40
(m, 4H, CH2CCH2), 2.70–2.95 (m, 1H, PhCH2), 3.20 (s, 3H, CH3O),
3.21–3.40 (m, 2H, PhCH2, (CH3)2CH), 4.90 (d, J¼7.6 Hz, 1H, i-PrCH),
5.17 (dd, J¼14.4, 6.8 Hz, 1H, BnCH), 6.82–7.60 (m, 10H, 2ꢂArH, NH);
Protected amino acid (0.50 mmol) was placed in a 10 mL round
bottom flask followed by methyl (S)-(ꢁ)- or (R)-(þ)-2-isocyano-
3-phenylpropionate (0.50 mmol) and 1 mL of cyclohexanone. The
mixture was stirred at 40 ꢀC for the time given in Tables 1 and 2.
The dr was determined by analytical HPLC (250ꢂ4,6) filled with
13C NMR (50 MHz, C6D6):
d 19.5, 21.2, 21.6, 25.2, 29.2, 31.5, 33.7,
38.4, 51.5, 54.0, 58.4, 84.2, 123.6, 127.0, 128.7, 129.6, 132.0, 134.2,
137.2, 167.0, 168.4, 171.8, 172.4; IR (CH2Cl2) : 3380, 3057, 2942,
n
Kromasil C-18 5
mm, eluting with isocratic mixture of methanol/
2863, 1774, 1746, 1716, 1680, 1514, 1451, 1389, 1364, 1208,
water (7:3 v/v) (1 mL/min), with Merck Hitashi UV detector L-7400,
h¼228 nm and Merck Hitashi L-6000A pump. The volatiles were
evaporated under reduced pressure, and the residue was separated
via semi-preparative HPLC (250ꢂ20) filled with Poligroprep RP-18
12u, eluting with isocratic mixture of methanol/water (7:3 v/v)
(20 mL/min), with Shimadzu RID-6A RI detector and Shimadzu
LC-8A preparative liquid chromatography. Both diastereoisomers
1140 cmꢁ1; retention time: tR¼14.9 min.
20
Compound (R,S)-4: [
a]
3.0 (c 1.8, benzene). Anal. C30H34N2O7
D
requires: C, 67.40%; H, 6.41%; N, 5.24%. Found: C, 67.08%; H, 6.69%;
N, 5.13%. 1H NMR (200 MHz, CDCl3):
d
1.02 (d, J¼6.8 Hz, 3H, CH3CH),
1.21 (d, J¼6.8 Hz, 3H, CH3CH), 1.10–2.40 (m, 6H, (CH2)3), 2.65–3.65
(m, 7H, CH2CCH2, PhCH2, (CH3)2CH), 3.76 (s, 3H, CH3O), 4.72 (d,
J¼7.0 Hz, 1H, i-PrCH), 4.90 (dd, J¼12.2, J¼8.4 Hz, 1H, BnCH), 6.86 (d,
J¼7.6 Hz, 1H, NH), 7.25–7.95 (m, 9H, 2ꢂArH); 13C NMR (50 MHz,
were received in the form of a white foam.
20
Compound (R,R)-1:
[
a]
ꢁ34.8 (c 1.5, benzene). Anal.
CDCl3): d 19.5, 21.3, 21.4, 25.0, 29.5, 30.2, 34.2, 38.0, 52.5, 53.5, 58.0,
D
C
29H36N2O6 requires: C, 68.48%; H, 7.13%; N, 5.51%. Found: C,
83.9, 123.9, 127.0, 128.6, 129.5, 131.8, 134.8, 136.9, 166.7, 168.5, 172.1,
68.13%; H, 7.24%; N, 5.35%. 1H NMR (200 MHz, C6D6):
d
0.95 (d,
172.3; IR (CH2Cl2) n: 3373, 3056, 2942, 2863, 1774, 1747, 1715, 1679,
J¼7.0 Hz, 3H, CH3CH), 1.01 (d, J¼6.8 Hz, 3H, CH3CH), 1.20–2.40 (m,
11H, (CH3)2CH, (CH2)5), 3.10–3.25 (m,1H, PhCH2), 3.24 (s, 3H, CH3O),
4.88 (dd, J¼7.8, 5.2 Hz,1H, BnCH), 5.04–5.20 (m,1H, i-PrCH), 6.69 (d,
J¼7.8 Hz, 1H, NH), 6.94 (d, J¼7.8 Hz, 1H, NH), 7.00–7.82 (m, 10H,
1521, 1451, 1388, 1364, 1210, 1141 cmꢁ1; retention time: tR¼
13.2 min.
20
Compound (R,S)-5: [
a
]
75.2 (c 1.7, benzene); HRMS (ESI)
D
469.2330 (C24H34N2O6Na: 469.2309); 1H NMR (200 MHz, CDCl3):
2ꢂArH); 13C NMR (50 MHz, C6D6):
d
18.8, 20.3, 22.4, 25.9, 31.7, 33.1,
d
1.03 (d, J¼7.2 Hz, 3H, CH3CH), 1.07 (d, J¼6.8 Hz, 3H, CH3CH), 1.10–
33.8, 52.3, 54.5, 59.5, 84.3, 127.7, 129.2, 129.4, 129.4, 130.4, 132.2,
2.40 (m, 11H, (CH2)5, (CH3)2CH), 2.08 (s, 3H, CH3CO), 3.05–3.30 (m,
2H, PhCH2), 3.76 (s, 3H, CH3O), 4.45 (dd, J¼7.4, 6.0 Hz, 1H, i-PrCH),
4.80–4.93 (m, 1H, BnCH), 6.07 (d, J¼7.8 Hz, 1H, NH), 6.65 (d,
J¼7.8 Hz, 1H, NH), 7.16–7.45 (m, 5H, ArH); 13C NMR (50 MHz,
135.2, 137.7, 168.4, 171.7, 172.6, 172.8; IR (CH2Cl2) n: 3439, 2942,
2864, 1741, 1671, 1513, 1485, 1451, 1205, 1140 cmꢁ1; retention time:
tR¼8.0 min.
20
Compound (R,S)-1: [
a
]
58.2 (c 1.5, benzene); HRMS (ESI)
CDCl3): d 18.4, 19.7, 21.6, 21.7, 23.4, 25.3, 30.8, 31.3, 33.7, 37.9, 52.5,
D
521.2478 (C29H36N2O6Na: 521.2466); 1H NMR (200 MHz, C6D6):
53.4, 58.4, 83.4, 127.2, 128.7, 129.6, 136.6, 164.1, 171.0, 171.2, 172.4; IR
d
0.96 (d, J¼7.2 Hz, 3H, CH3CH), 1.01 (d, J¼6.8 Hz, 3H, CH3CH), 1.20–
(CH2Cl2) n: 3436, 3330, 3055, 3034, 2941, 2862, 1742, 1679, 1509,
2.40 (m, 11H, (CH3)2CH, (CH2)5), 3.18 (s, 3H, CH3O), 3.20–3.40 (m,
1H, PhCH2), 4.60–4.80 (m, 1H, BnCH), 5.04–5.20 (m, 1H, i-PrCH),
1451, 1371, 1208, 1139 cmꢁ1; retention time: tR¼5.2 min.
20
Compound (R,R)-5:
[a
]
ꢁ19.5 (c 1.3, benzene). Anal.
D
6.80–8.00 (m, 12H, 2ꢂArH, 2ꢂNH); 13C NMR (50 MHz, C6D6):
d
19.3,
C
24H34N2O6 requires: C, 64.55%; H, 7.67%; N, 6.27%. Found: C,
20.3, 22.4, 25.9, 31.4, 32.3, 34.4, 38.6, 52.3, 54.6, 60.1, 84.4, 127.6,
128.2, 129.2, 129.3, 130.4, 132.4, 135.2, 138.0, 168.8, 171.6, 172.8; IR
64.73%; H, 7.91%; N, 6.05%. NMR (200 MHz, CDCl3): 0.96 (d,
d
J¼7.0 Hz, 3H, CH3CH), 1.02 (d, J¼6.8 Hz, 3H, CH3CH), 1.18–2.33 (m,
11H, (CH2)5, (CH3)2CH), 2.01 (s, 3H, CH3CO), 3.08–3.18 (m, 2H,
PhCH2), 3.69 (s, 3H, CH3O), 4.49 (dd, J¼9.0, 4.6 Hz,1H, i-PrCH), 4.76–
4.80 (m, 1H, BnCH), 5.88 (d, J¼8.2 Hz, 1H, NH), 6.48 (d, J¼7.8 Hz, 1H,
(CH2Cl2) n: 3436, 2967, 2942, 2865, 1742, 1670, 1514, 1485, 1451,
1205, 1216, 1158, 1140 cmꢁ1; retention time: tR¼12.0 min.
20
Compound (R,R)-3:
[
a]
ꢁ29.8 (c 1.6, benzene). Anal.
D
C
30H38N2O7 requires: C, 66.90%; H, 7.11%; N, 5.20%. Found: C,
NH), 7.08–7.38 (m, 5H, ArH); 13C NMR (50 MHz, CDCl3):
d 18.0, 19.7,
66.85%; H, 7.11%; N, 5.18%; 1H NMR (200 MHz, CDCl3):
d
0.93 (d,
21.7, 23.5, 25.3, 31.0, 32.5, 32.6, 39.0, 52.5, 53.5, 58.1, 83.3, 127.3,
128.8, 129.6, 136.5, 170.7, 171.0, 172.2; IR (CH2Cl2) : 3435, 3333,
J¼6.8 Hz, 3H, CH3CH), 1.03 (d, J¼6.8 Hz, 3H, CH3CH), 1.10–2.40 (m,
10H, (CH2)5, (CH3)2CH), 3.05–3.18 (m, 2H, PhCH2), 3.68 (s, 3H,
CH3O), 4.21–4.37 (m, 2H, BnCH), 4.78–4.92 (m, 1H, i-PrCH), 5.10 (s,
2H, PhCH2O), 5.21 (d, J¼8.4 Hz, 1H, CBzNH), 6.50 (d, J¼8.0 Hz, 1H,
NH), 7.03–7.50 (m, 10H, 2ꢂArH, NH); 13C NMR (50 MHz, CDCl3):
n
3055, 3033, 2942, 2864, 1742, 1678, 1511, 1451, 1371, 1210, 1189,
1138 cmꢁ1; retention time: tR¼4.0 min.
20
Compound (R,R)-6:
[
a]
ꢁ32.4 (c 1.5, benzene). Anal.
D
C
27H40N2O7 requires: C, 64.30%; H, 7.94%; N, 5.56%. Found: C,
d
17.6, 19.7, 21.6, 25.2, 31.0, 32.1, 32.9, 38.0, 52.5, 53.4, 59.7, 67.4,
64.36%; H, 8.19%; N, 5.52%. 1H NMR (200 MHz, CDCl3):
d
0.99 (d,
83.2,127.2, 128.4,128.5,128.8,128.8,129.6,136.4,156.9,170.7,172.1;
J¼6.8 Hz, 3H, CH3CH), 1.08 (d, J¼6.8 Hz, 3H, CH3CH), 1.50 (s, 9H,
(CH3)3), 1.20–2.40 (m, 11H, (CH3)2CH, (CH2)5), 3.10–3.25 (m, 1H,
PhCH2), 3.75 (s, 3H, CH3O), 4.20–4.30 (m, 1H, BnCH), 4.80–5.10 (m,
2H, i-PrCH, BocNH), 6.60–70 (m, 1H, NH), 7.00–7.40 (m, 5H, ArH);
IR (CH2Cl2) n: 3435, 3334, 3055, 3034, 2942, 2865, 1741, 1724, 1681,
1510, 1453, 1362, 1349, 1312, 1215, 1140 cmꢁ1; retention time:
tR¼17.0 min.
20
Compound (R,S)-3: [
a
]
51.5 (c 1.2, benzene). Anal. C30H38N2O7
13C NMR (50 MHz, CDCl3):
d
17.6, 19.8, 21.6, 25.3, 28.6, 30.9, 32.0,
D
requires: C, 66.90%; H, 7.11%; N, 5.20%. Found: C, 66.84%; H, 6.92%;
33.1, 38.0, 52.5, 53.3, 59.3, 80.2, 83.0,127.2,128.8,129.5,136.4,156.3,
N, 5.06%. 1H NMR (200 MHz, CDCl3):
d
0.93 (d, J¼6.8 Hz, 3H,
170.9, 172.1, 172.2; IR (CH2Cl2) n: 3440, 3318, 3056, 3033, 2971, 2941,
CH3CH), 1.02 (d, J¼6.6 Hz, 3H, CH3CH), 1.10–2.35 (m, 10H, (CH2)5,
(CH3)2CH), 3.00–3.20 (m, 2H, PhCH2), 3.65 (s, 3H, CH3O), 4.05–4.22
(m, 2H, BnCH), 4.75–4.95 (m, 1H, i-PrCH), 5.11 (s, 2H, PhCH2O), 5.21
(d, J¼8.2 Hz, 1H, CBzNH), 6.58 (d, J¼7.2 Hz, 1H, NH), 7.03–7.42 (m,
2866, 1742, 1712,1682, 1502, 1452, 1367,1211,1174,1160, 1140 cmꢁ1
;
retention time: tR¼11.6 min.
Compound (R,S)-6: [a]
20 52.3 (c 1.8, benzene). Anal. C27H40N2O7
D
requires: C, 64.30%; H, 7.94%; N, 5.56%. Found: C, 64.46%; H, 8.16%;
N, 5.45%. 1H NMR (200 MHz, CDCl3):
1.00 (d, J¼6.6 Hz, 3H, CH3CH),
1.08 (d, J¼6.8 Hz, 3H, CH3CH), 1.52 (s, 9H, (CH3)3), 1.20–2.40 (m,11H,
10H, 2ꢂArH, NH); 13C NMR (50 MHz, CDCl3):
d
18.0, 19.7, 21.6, 25.3,
d
30.9, 32.0, 33.0, 38.0, 52.5, 53.5, 60.1, 67.5, 83.4, 127.2, 128.6, 128.7,

_
S. Berłozecki et al. / Tetrahedron 64 (2008) 9780–9783
9783
(CH3)2CH, (CH2)5), 3.10–3.25 (m, 1H, PhCH2), 3.73 (s, 3H, CH3O),
4.10–4.20 (m, 1H, BnCH), 4.80–5.10 (m, 2H, i-PrCH, BocNH), 6.78–
6.90 (m, 1H, NH), 7.20–7.50 (m, 5H, ArH); 13C NMR (50 MHz, CDCl3):
(m, 10H, c-Hex), 3.08–3.65 (m, 4H, 2ꢂPhCH2), 3.69 (s, 3H, CH3O),
4.80–4.95 (m, 1H, NHCH), 5.17 (dd, J¼11.6, 5.0 Hz, 1H, NCH), 6.62 (d,
J¼6.6 Hz, 1H, NH), 7.05–7.82 (m, 14H, 3ꢂArH); 13C NMR (50 MHz,
d
17.9, 19.8, 21.6, 25.3, 28.7, 30.7, 32.0, 33.1, 37.9, 52.5, 53.8, 59.6,
CDCl3): d 21.4, 21.5, 25.2, 30.6, 34.1, 35.1, 38.0, 52.5, 53.6, 53.9, 84.3,
80.2, 83.2, 127.2, 128.7, 129.6, 136.7, 156.5, 170.8, 172.3, 172.5; IR
123.9, 127.2, 128.8, 128.9, 129.1, 129.5, 131.7, 134.6, 136.6, 136.8,
(CH2Cl2)
n
: 3443, 3326, 3056, 3033, 2970, 2941, 2866, 1742, 1700,
167.2,168.0,172.3,172.5; IR (CH2Cl2) n: 3384, 2944, 2863,1775, 1747,
1681, 1501, 1453, 1368, 1209, 1175, 1161, 1140 cmꢁ1; retention time:
1716, 1682, 1605, 1513, 1469, 1453, 1390, 1364, 1211, 1140 cmꢁ1
;
tR¼14.6 min.
retention time: tR¼14.1 min.
20
20
Compound (S,S)-7: [
a
]
3.0 (c 1.1, benzene). Anal. C33H36N2O6
Compound (S,R)-11: [
a
]
ꢁ21.8 (c 1.2, benzene); HRMS (ESI)
D
D
requires: C, 71.20%; H, 6.52%; N, 5.03%. Found: C, 70.86%; H, 6.75%;
517.2316 (C28H34N2O6: 517.2309); 1H NMR (200 MHz, CDCl3):
0.90–2.20 (m, 10H, c-Hex), 1.97 (s, 3H, CH3CO), 2.95–3.23 (m, 4H,
N, 4.81%. 1H NMR (200 MHz, CDCl3):
d
1.05–2.30 (m, 10H, c-Hex),
d
3.05–3.60 (m, 4H, 2ꢂPhCH2), 3.69 (s, 3H, CH3O), 4.78–4.90 (m, 2H,
2ꢂBnCH), 6.58 (d, J¼6.6 Hz, 1H, NH), 6.80 (d, J¼7.8 Hz, 1H, NH),
2ꢂPhCH2), 3.69 (s, 3H, CH3O), 4.60–4.90 (m, 2H, 2ꢂBnCH), 6.04 (d,
J¼7.0 Hz, 1H, NH), 6.70 (d, J¼7.8 Hz, 1H, NH), 7.11–7.42 (m, 10H,
7.03–7.72 (m, 14H, 3ꢂArH); 13C NMR (50 MHz, CDCl3):
d
21.5, 25.2,
2ꢂArH); 13C NMR (50 MHz, CDCl3):
d 21.2, 21.5, 23.3, 25.2, 31.2, 33.6,
32.2, 32.8, 37.6, 38.0, 52.5, 53.6, 54.7, 83.9, 97.3, 127.1, 127.3, 127.6,
37.5, 37.8, 52.5, 53.4, 54.5, 83.8, 127.2, 127.5, 128.7, 129.1, 129.5,
128.7, 129.0, 129.1, 129.5, 129.6, 168.0, 170.4, 172.4; IR (CH2Cl2)
n
:
129.6, 136.2, 136.8, 170.6, 171.1, 172.5; IR (CH2Cl2) n: 3376, 2943,
3436, 3329, 3055, 3033, 2986, 2942, 2861, 1744, 1660, 1603, 1581,
2862, 1775, 1746, 1715, 1681, 1605, 1511, 1489, 1469, 1453, 1390,
1515, 1485, 1452, 1364, 1350, 1212, 1180, 1140 cmꢁ1; retention time:
1363, 1234, 1211, 1240 cmꢁ1; retention time: tR¼8.8 min.
tR¼11.8 min.
Compound (S,S)-11: [a]
20 24.0 (c 0.9, benzene). Anal. C28H34N2O6
D
20
Compound (S,R)-7: [
a
]
ꢁ34.9 (c 1.2, benzene). Anal. C33H36N2O6
requires: C, 67.98%; H, 6.96%; N, 5.66%. Found: C, 67.76%; H, 7.19%; N,
5.58%. NMR (200 MHz, CDCl3): 1.10–2.22 (m, 10H, c-Hex), 1.88 (s,
D
requires: C, 71.20%; H, 6.52%; N, 5.03%. Found: C, 70.97%; H, 6.55%;
d
N, 5.12%. 1H NMR (200 MHz, CDCl3):
d
0.95–2.22 (m, 10H, c-Hex),
3H, CH3CO), 2.95–3.23 (m, 4H, 2ꢂPhCH2), 3.66 (s, 3H, CH3O), 4.60–
4.83 (m, 2H, 2ꢂBnCH), 5.87 (d, J¼6.8 Hz, 1H, NH), 6.60 (d, J¼7.8 Hz,
1H, NH), 7.07–7.32 (m, 10H, 2ꢂArH); 13C NMR (50 MHz, CDCl3):
3.02–3.36 (m, 4H, 2ꢂPhCH2), 3.56 (s, 3H, CH3O), 4.75–4.92 (m, 2H,
2ꢂBnCH), 6.60 (d, J¼6.6 Hz, 1H, NH), 6.88 (d, J¼7.8 Hz, 1H, NH),
7.13–7.80 (m, 14H, 3ꢂArH); 13C NMR (50 MHz, CDCl3):
d
21.3, 21.5,
d 21.4, 23.2, 25.2, 32.3, 32.6, 37.6, 37.9, 52.5, 53.5, 54.2, 83.7, 127.2,
25.2, 31.6, 33.3, 37.6, 37.8, 52.5, 53.5, 56.0, 83.9, 127.2, 127.3, 127.6,
128.7, 129.0, 129.2, 129.5, 129.6, 132.3, 133.8, 136.2, 136.9, 168.1,
127.4, 128.7, 129.0, 129.4, 129.6, 136.4, 136.7, 170.7, 172.2; IR (CH2Cl2)
n
: 3434, 3332, 3056, 3032, 2942, 2862, 1744, 1676, 1604, 1510, 1451,
170.4, 172.3, 172.4; IR (CH2Cl2)
n
: 3436, 3335, 2985, 2942, 2861,
1370, 1211, 1180, 1140 cmꢁ1; retention time: tR¼6.6 min.
20
1744, 1660, 1603, 1580, 1515, 1485, 1453, 1364, 1212, 1180,
Compound (S,R)-12:
[a
]
ꢁ36.2 (c 1.6, benzene). Anal.
D
1140 cmꢁ1; retention time: tR¼14.5 min.
C
31H39N2O7 requires: C, 67.48%; H, 7.14%; N, 5.08%. Found: C,
Compound (S,S)-8: [
a
]
20 33.5 (c 1.3, benzene). Anal. C45H46N2O5
67.32%; H, 7.34%; N, 4.92%; 1H NMR (200 MHz, CDCl3):
d
0.90–2.20
D
requires: C, 77.78%; H, 6.69%; N, 4.03%. Found: C, 77.73%; H, 6.73%;
(m, 10H, c-Hex), 1.49 (s, 9H, (CH3)3), 2.60–3.35 (m, 4H, 2ꢂPhCH2),
3.74 (s, 3H, CH3O), 4.35–5.05 (m, 3H, 2ꢂBnCH, BocNH), 6.90–7.00
(m, 1H, NH), 7.00–7.60 (m, 10H, 2ꢂArH); 13C NMR (50 MHz, CDCl3):
N, 3.84%. HRMS (ESI) 717.3278 (C45H46N2O5Na: 717.3299); 1H NMR
(200 MHz, C6D6):
d 0.90–2.04 (m, 10H, c-Hex), 2.65–3.30 (m, 4H,
2ꢂPhCH2), 3.20 (s, 3H, CH3O), 3.82–3.97 (m, 1H, BnCH), 5.10–5.20
d 21.4, 25.2, 28.6, 31.8, 33.1, 37.8, 52.4, 53.7, 55.6, 80.6, 83.6, 127.1,
(m, 1H, BnCH), 6.31 (d, J¼8.0 Hz, 1H, NH), 6.95–7.70 (m, 26H,
127.4, 128.7, 129.1, 129.5, 136.4, 156.1, 170.4, 172.3; IR (CH2Cl2) n:
5ꢂArH, NH); 13C NMR (50 MHz, C6D6):
d
21.8, 22.5, 25.4, 31.2, 38.5,
3437, 3331, 2983, 2941, 2863, 1744, 1699, 1680, 1604, 1498, 1453,
41.6, 51.8, 53.7, 58.6, 72.3, 82.3, 126.8, 126.9, 127.4, 128.2, 128.4,
128.8, 129.4, 129.5, 130.2, 130.3, 130.5, 137.0, 139.1, 146.9, 171.7,
1393, 1368, 1207, 1168, 1140 cmꢁ1; retention time: tR¼18.7 min.
20
Compound (S,S)-12: [
a]
8.0 (c 1.3, benzene). Anal. C31H39N2O7
D
172.3, 172.9; IR (CH2Cl2)
n
: 3417, 2942, 2862, 1740, 1680, 1602, 1509,
requires: C, 67.48%; H, 7.14%; N, 5.08%. Found: C, 67.29%; H, 7.35%; N,
1495, 1495, 1449, 1419, 1361, 1211, 1181, 1156, 1138 cmꢁ1; retention
4.92%. 1H NMR (200 MHz, CDCl3):
d
1.10–2.40 (m, 10H, c-Hex), 1.47
time: tR¼25.5 min.
(s, 9H, (CH3)3), 3.00–3.60 (m, 4H, 2ꢂPhCH2), 3.77 (s, 3H, CH3O),
4.45–5.05 (m, 3H, 2ꢂBnCH, BocNH), 6.75–6.90 (m, 1H, NH), 7.18–
20
Compound (S,R)-8: [
a
]
ꢁ42.5 (c 1.2, benzene); HRMS (ESI)
D
717.3304 (C45H46N2O5Na: 717.3299); 1H NMR (200 MHz, CDCl3):
7.42 (m, 10H, 2ꢂArH); 13C NMR (50 MHz, CDCl3):
d 21.4, 25.2, 28.6,
d
0.97–2.00 (m, 10H, c-Hex), 2.40–3.20 (m, 4H, 2ꢂPhCH2), 3.60–3.75
31.9, 33.1, 38.1, 52.5, 53.4, 55.3, 80.6, 83.5, 127.3, 128.7, 129.0, 129.5,
136.7, 156.1, 170.5, 172.2; IR (CH2Cl2) n: 3436, 3326, 2983, 2941,
(m, 1H, BnCH), 3.78 (s, 3H, CH3O), 4.82–4.96 (m, 1H, BnCH), 6.12 (d,
J¼7.6 Hz, 1H, NH), 7.05–7.65 (m, 26H, 5ꢂArH, NH); 13C NMR
2863, 1743, 1709, 1604, 1499, 1499,1453, 1392, 1367, 1211, 1169,
(50 MHz, CDCl3):
d
21.5, 22.1, 25.1, 31.5, 33.2, 38.0, 41.0, 52.6, 53.4,
1140 cmꢁ1; retention time: tR¼18.7 min.
58.3, 71.9, 82.4, 126.8, 127.3, 128.2, 128.6, 128.8, 129.2, 129.7, 129.9,
136.3, 138.3, 146.4, 172.1, 172.2, 172.6; IR (CH2Cl2) : 3430, 3336,
n
Acknowledgements
2942, 2862, 2151,1741,1680, 1741,1680,1602,1496,1449,1361,1209,
1181, 1155, 1138 cmꢁ1; retention time: tR¼25.9 min.
This work was financially supported by Polish State Committee
for Scientific Research, Grant PBZ–KBN 126/T09/07.
20
Compound (S,R)-10: [
a
]
ꢁ103.6 (c 1.4, benzene); HRMS (ESI)
D
582.2349 (C34H34N2O7: 582.2366); 1H NMR (200 MHz, CDCl3):
d
1.00–2.40 (m, 10H, c-Hex), 3.00–3.60 (m, 4H, 2ꢂPhCH2), 3.75 (s,
References and notes
3H, CH3O), 4.80–5.00 (m, 1H, NHCH), 5.18 (dd, J¼11.0, 5.6 Hz, 1H,
NCH), 6.69 (d, J¼8.0 Hz, 1H, NH), 7.05–7.92 (m, 14H, 3ꢂArH);
1. Do¨mling, A. Chem. Rev. 2006, 106, 17–89.
13C NMR (50 MHz, CDCl3):
d 21.2, 21.3, 24.9, 30.3, 33.9, 35.0, 38.0,
2. Banfi, L.; Guanti, G.; Riva, R. Chem. Commun. 2000, 985–986.
3. Owens, T. D.; Araldi, G. L.; Nutt, R. F.; Semple, J. E. Tetrahedron Lett. 2001, 42,
6271–6274.
4. Banfi, L.; Guanti, G.; Riva, R.; Basso, A.; Calcagno, E. Tetrahedron Lett. 2002, 43,
4067–4069.
5. Horikawa, E.; Kodaka, M.; Nakahara, Y.; Okunoa, H.; Nakamuraa, K. Tetrahedron
Lett. 2001, 42, 8337–8339.
6. Dory, Y. L.; Mellor, J. M.; McAleer, J. F. Tetrahedron 1996, 52, 1343–1360.
7. Otto, H.-H.; Schirmeister, T. Chem. Rev. 1997, 97, 133–171.
8. Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
52.4, 53.2, 53.6, 84.1, 123.6, 126.9, 127.0, 128.5, 128.7, 128.9, 129.4,
131.5, 134.4, 136.6, 166.8, 167.8, 171.9, 171.9; IR (CH2Cl2) : 3376,
n
2943, 2862, 1775, 1746, 1715, 1681, 1605, 1511, 1489, 1469, 1453,
1390, 1363, 1234, 1211, 1240 cmꢁ1; retention time: tR¼15.0 min.
20
Compound (S,S)-10:
[a
]
ꢁ87.5 (c 1.8, benzene). Anal.
D
C
34H34N2O7 requires: C, 70.10%; H, 5.88%; N, 4.80%. Found: C,
69.90%; H, 5.76%; N, 4.71%. 1H NMR (200 MHz, CDCl3):
d
1.05–2.35