Stereocontrolled synthesis of unnatural tetrapeptides containing L -valine units. part 3

Article abstract of DOI:10.1002/hlca.201000202

The stereoselective synthesis of the new nonproteinogenic branched tetrapeptides 9a-9d and 15a,b, containing two L-valine units and unnatural α-amino acids, was accomplished starting from the chiral synthon 1a, a monolactim ether easily obtained from L-va

Full text of DOI:10.1002/hlca.201000202

Helvetica Chimica Acta – Vol. 94 (2011)
127
Stereocontrolled Synthesis of Unnatural Tetrapeptides Containing l-Valine
Units
Part 31)
by Daniele Balducci and Gianni Porzi*
Department of Chemistry ꢀG. Ciamicianꢁ, Alma Mater Studiorum University of Bologna, Via Selmi 2,
I-40126 Bologna (phone/fax: þ 39-051-2099512; e-mail: gianni.porzi@unibo.it)
The stereoselective synthesis of the new nonproteinogenic branched tetrapeptides 9a – 9d and 15a,b,
containing two l-valine units and unnatural a-amino acids, was accomplished starting from the chiral
synthon 1a, a monolactim ether easily obtained from l-valine.
Introduction. – The present communication is a continuation of our studies directed
at the stereoselective synthesis of pseudopeptides with the objective that the unnatural
peptides, as some natural ones, could exhibit biological activity with the advantage of
proteolytic stability. The presence of a-alkyl a-amino acids may influence the
conformation of these unnatural peptides altering their properties [3]. Thus, we have
focused our attention towards new peptidomimetic structures containing nonproteino-
genic a-alkylated a-amino acids (modified proline or aspartic acid) and l-valine units
[4]. This communication is connected with previous articles which addressed the
stereocontrolled synthesis of unnatural tetrapeptides, C-terminal at both ends of the
chain, containing l-valine units [1][2]. Here, we report a versatile and simple approach
to the stereoselective synthesis of branched unnatural tetrapeptides containing two l-
valine units, one 2-methyl-d-aspartic acid and one other a-amino acid. The latter a-
amino acid was either (2R)-2,4-diaminobutanoic acid (in 9a), its (2R)-2-methyl (i.e., d-
isovaline; in 9b), or its (2S)-2-methyl derivative (i.e., l-isovaline; in 15a), or d-
ornithine (in 9c), its 2-methyl (in 9d), or the corresponding 2-methyl-l derivative (in
15b).
The synthetic strategy adopted in the stereocontrolled synthesis of the title
pseudotetrapeptides is based on the experience already acquired in previous
approaches [1][2][4] making use of the chiral monolactim ether 1a, easily obtained
from l-valine [5]. Schçllkopfꢁs strategy, aimed to the asymmetric synthesis of
nonproteinogenic dipeptides, was based on the use of the bis-lactim ether which is
subsequently converted to the corresponding monolactim derivative [6].
Result and Discussion. – The stereoselective synthesis of unnatural tetrapeptides
8a – 8d and 14a,b was performed making use of the chiral synthons 2 or 3, 4a – 4d and
1
)
For Part 1 and 2, see [1][2].
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢃrich

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Helvetica Chimica Acta – Vol. 94 (2011)
10a,b (synthesized as reported in [4c] and [2], resp.), starting from the chiral
monolactim ether 1a (Schemes 1 – 3).
Scheme 1
The intermediates 5a – 5d were obtained in very good yields by hydrogenolysis
under Birch conditions [4f] of the 3-(aminoalkyl)-substituted 5-ethoxy-3,6-dihydro-6-
isopropylpyrazin-2(1H)-ones 4a – 4d. The subsequent acidic hydrolysis under mild
conditions gave the salts 6a – 6d, which can act as a nucleophile through the newly
formed a-amino group (Scheme 2). These intermediates were then treated with
electrophile 3, synthesized starting from the chiral synthon 1a, as already reported [4c]
(Scheme 1). The coupling reaction between 6a,c and the activated ester 3 to give 7a,c
occurred in good yields. Conversely, the substrates 6b,d did not react with 3 even by
refluxing in THF. The products 7b,d were obtained in satisfactory yields by carrying out
the coupling reaction with acid 2 in the presence of the activating reagent 4-(4,6-
dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride [4b] (DMTMM)
(Scheme 2). The different reactivity of the substrates 6a,c and 6b,d is most likely due
to the greater steric hindrance of the latter substrate caused by the presence of a Me
group at the C(a) with respect to the NH2 group. The acidic hydrolysis of 7a – 7d under
mild conditions gave the pseudotetrapeptides 8a – 8d which were converted into the
corresponding acetyl derivatives 9a – 9d containing two l-valine units (red), 2-methyl-
d-aspartic acid (green), and either d-ornithine or its 2-methyl derivative and (2R)-2,4-
diaminobutanoic acid or its (2R)-2-methyl derivative (i.e., d-isovaline; blue;
Scheme 2).
To synthesize the tetrapseudopeptides 14a,b (Scheme 3), which differ from 8b,d in
the configuration of 2-methylornithine unit, we employed the masked dipeptides 10a,b,
which were easily obtained starting from the chiral synthon 1a [2]. After debenzylation
of 10a,b, performed under Birch conditions, the intermediates 11a,b were recovered
and subsequently hydrolyzed under mild acidic conditions. The amino derivatives 12a,b
obtained were treated with acid 2 in the presence of DMTMM [4b] to yield 13a,b,
which, following the same reaction sequence as described in Scheme 2, furnished via the
14a,b tetrapseudopeptides 15a,b as the acetyl derivatives in overall satisfactory yields
(Scheme 3).
The authors are grateful to Prof. Sergio Sandri for helpful advice and discussions and to the
University of Bologna for financial support (ꢀRicerca Fondamentale Orientataꢁ).

Helvetica Chimica Acta – Vol. 94 (2011)
129
Scheme 2
i) Li/NH3, ꢀ 788, dry THF/tBuOH 9 :1. ii) 0.5n HCl in EtOH, r.t. iii) 6a,c was treated with 3 in CH2Cl2/
Et3N, while 6b,d was treated with 2 in THF/Et3N in the presence of DMTMM [4b]. iv) 0.5n HCl in
EtOH, r.t. v) AcCl in CH2Cl2/Et3N.
Experimental Part
General. Dry THF was distilled from sodium benzophenone ketyl (¼sodium diphenylketyl).
Column chromatography (CC): silica gel 60 (SiO2; 230 – 400 mesh); eluent hexane/AcOEt. Optical
rotation: Perkin-Elmer-343 polarimeter; at 258. 1H- and 13C-NMR Spectra: Gemini spectrometer, at 300
and 75 MHz, resp.; CDCl3 as solvent, unless otherwise stated; d in ppm rel. to CDCl3, J in Hz.
The synthesis and spectroscopic data of compounds 2 and 3 are reported in [4c] and the data of
compounds 4a – 4d and 10a,b in [2].
(3R,6S)-3-[2-(Dibenzylamino)ethyl]-5-ethoxy-3,6-dihydro-6-isopropylpyrazin-2(1H)-one (5a). In-
termediate 4a (5 g, 10 mmol) in dry THF/tBuOH 9 :1 (40 ml), was added to a soln. of Li (0.07 g, 10 mmol)
in liq. NH3 (ca. 60 ml), cooled at ca. ꢀ 788, and stirred under Ar. After 5 min, the reaction was quenched
with NH4Cl (1 g) and the cooling bath removed allowing the complete evaporation of NH3. After
addition of H2O, the product was extracted with AcOEt, and the org. soln. concentrated, and the residue
subjected to CC: 5a (85% after CC). Oil. [a]2D5 ¼þ 62.9 (c ¼ 1.1, CHCl3). 1H-NMR: 0.86 (d, J ¼ 7, 3 H ) ;
0.98 (d, J ¼ 7, 3 H); 1.15 (t, J ¼ 7.2, 3 H); 1.88 – 1.98 (m, 1 H); 2.06 – 2.4 (m, 2 H); 2.64 (t, J ¼ 7, 2 H); 3.59
(q, AB, J ¼ 13.6, 4 H); 3.7 – 3.9 (m, 3 H); 4.0 – 4.14 (m, 1 H); 5.95 – 6.1 (br. s, 1 H); 7.2 – 7.4 (m, 10 arom.
H). 13C-NMR: 14.0; 16.2; 18.1; 30.9; 32.1; 49.2; 55.3; 58.1; 58.2; 60.8; 126.4; 127.8; 128.7; 139.8; 158.2;
172.8. Anal. calc. for C25H33N3O2 (407.26): C 73.68, H 8.16, N 10.31; found: C 73.92, H 8.18, N 10.28.

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Helvetica Chimica Acta – Vol. 94 (2011)
Scheme 3
i) Li/NH3, ꢀ788, dry THF/tBuOH 9 :1. ii) 0.5n HCl in EtOH, r.t. iii) 2 in the presence of DMTMM [4b] in
THF/Et3N. iv) 0.5n HCl in EtOH, r.t. v) AcCl in CH2Cl2/Et3N.
(3R,6S)-3-[2-(Dibenzylamino)ethyl]-5-ethoxy-3,6-dihydro-6-isopropyl-3-methylpyrazin-2(1H)-one
1
(5b). As described for 5a, from 4b: 5b (88% after CC). Oil. [a]2D5 ¼ þ14.3 (c ¼ 1.4, CHCl3). H-NMR:
0.83 (d, J ¼ 7, 3 H); 0.96 (d, J ¼ 7, 3 H); 1.15 (t, J ¼ 7, 3 H); 1.41 (s, 3 H); 1.77 – 1.87 (m, 1 H); 2.05 – 2.42
(m, 4 H); 3.62 (s, 4 H); 3.7 – 4.02 (m, 3 H); 5.72 – 5.78 (br. s, 1 H); 7.2 – 7.4 (m, 10 arom. H). 13C-NMR:
13.9; 16.1; 18.2; 28.8; 30.9; 38.3; 48.6; 58.0; 58.2; 58.7; 60.6; 126.4; 127.8; 128.6; 139.6; 156.1; 174.3. Anal.
calc. for C26H35N3O2 (421.58): C 74.07, H 8.37, N 9.97; found: C 74.34, H 8.39, N 9.95.
(3R,6S)-3-[3-(Dibenzylamino)propyl]-5-ethoxy-3,6-dihydro-6-isopropylpyrazin-2(1H)-one (5c).
1
As described for 5a, from 4c: 5c (83% after CC). Oil. [a]2D5 ¼ þ47.1 (c ¼ 1.0, CHCl3). H-NMR: 0.86
(d, J ¼ 7, 3 H); 0.98 (d, J ¼ 7, 3 H); 1.27 (t, J ¼ 7.2, 3 H); 1.5 – 2.0 (m, 4 H); 2.1 – 2.3 (m, 1 H); 2.46 (t, J ¼ 7,
2 H); 3.57 (s, 4 H); 3.8 – 3.84 (m, 1 H); 4.0 – 4.2 (m, 3 H); 5.98 – 6.14 (br. s, 1 H); 7.2 – 7.44 (m, 10 arom.
H). 13C-NMR: 14.0; 16.1; 18.0; 22.1; 31.5; 32.0; 52.9; 57.0; 58.0; 58.1; 60.9; 126.4; 127.9; 128.6; 139.7; 158.3;
172.6. Anal. calc. for C26H35N3O2 (421.58): C 74.07, H 8.37, N 9.97; found: C 73.84, H 8.35, N 10.01.
(3R,6S)-3-[3-Dibenzylamino)propyl]-5-ethoxy-3,6-dihydro-6-isopropyl-3-methylpyrazin-2(1H)-one
(5d). As described for 5a, from 4d: 5d (85%). Oil. [a]D: product not sufficiently pure. 1H-NMR: 0.86 (d,
J ¼ 7, 3 H); 0.99 (d, J ¼ 7, 3 H); 1.2 – 1.36 (m, 3 H); 1.41 (s, 3 H); 1.30 – 1.45 (m, 2 H); 1.48 – 1.6 (m, 1 H);
1.88 – 2.0 (m, 1 H); 2.2 – 2.3 (m, 1 H); 2.41 (t, J ¼ 6.9, 2 H); 3.55 (q, AB, J ¼ 14.8, 4 H); 3.76 – 3.88 (m,
1 H); 4.05 – 4.15 (m, 2 H); 5.64 – 5.8 (br. s, 1 H); 7.15 – 7.45 (m, 10 arom. H). 13C-NMR: 14.1; 16.0; 18.2;
21.8; 28.7; 30.9; 39.5; 53.3; 58.0; 58.2; 59.8; 60.7; 126.5; 127.9; 128.6; 139.7; 156.1; 174.6.
N-[(2R)-2-Amino-4-(dibenzylamino)]-1-oxobutyl]-l-valine Ethyl Ester Hydrochloride (1:2) (6a).
To a soln. of 5a (4.07 g, 10 mmol) in EtOH (60 ml) was added 0.5m HCl (20 ml), and the mixture was

Helvetica Chimica Acta – Vol. 94 (2011)
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stirred at r.t. for ca. 12 h. The acidic soln. was concentrated, and the crude product stirred with a 10% aq.
K2CO3 soln. The product was extracted with AcOEt, the org. soln. washed with H2O, and the org. solvent
evaporated: 6a (90%). Wax. [a]2D5 ¼ ꢀ31.4 (c ¼ 1.5, MeOH). 1H-NMR (CD3OD): 0.87 (d, J ¼ 6.9, 3 H);
0.93 (d, J ¼ 6.9, 3 H); 1.31 (t, J ¼ 7.2, 3 H); 2.0 – 2.2 (m, 1 H); 2.4 – 2.6 (m, 2 H); 3.20 – 3.44 (m, 2 H); 4.1 –
4.3 (m, 4 H); 4.4 – 4.6 (br. s, 4 H); 4.95 (s, 4 H); 7.45 – 7.75 (m, 10 arom. H). 13C-NMR (CD3OD): 14.8;
19.2; 19.8; 27.5; 31.7; 52.3; 58.7; 59.8; 59.9; 62.6; 130.6; 131.3; 132.8; 169.3; 172.6. Anal. calc. for
C25H37Cl2N3O3 (498.49): C 60.24, H 7.48, N 8.43; found: C 59.89, H 7.07, N 8.71.
4-(Dibenzylamino)-d-isovalyl-l-valine Ethyl Ester Hydrochloride (1:2) (6b). As described for 6a,
1
from 5b: 6b (89% after CC). Wax. [a]2D5 ¼ ꢀ21.6 (c ¼ 0.2, MeOH). H-NMR (CD3OD): 0.90 (d, J ¼ 7,
3 H); 0.92 (d, J ¼ 7, 3 H); 1.28 (t, J ¼ 7, 3 H ) ; 1.7 (s, 3 H); 2.0 – 2.2 (m, 1 H); 2.6 – 2.8 (m, 2 H); 3.0 – 3.4 (m,
2 H); 4.1 – 4.3 (m, 3 H); 4.3 – 4.6 (m, 4 H); 7.4 – 7.66 (m, 10 arom. H). 13C-NMR: 14.8; 19.8; 20.1; 22.8;
31.3; 32.4; 58.8; 60.4; 61.0; 62.6; 130.6; 130.8; 131.6; 132.9; 171.3; 172.7. Anal. calc. for C26H39Cl2N3O3
(512.51): C 60.93, H 7.67, N 8.2; found: C 61.03, H 7.69, N 8.18.
N5,N5-Dibenzyl-d-ornithyl-l-valine Ethyl Ester Hydrochloride (1:2) (6c). As described for 6a, from
5c: 6c (86% after CC). Wax oil. [a]2D5 ¼ ꢀ22.9 (c ¼ 1.0, MeOH). 1H-NMR (CD3OD): 1.0 (d, J ¼ 6.9, 3 H);
1.01 (d, J ¼ 6.9, 3 H); 1.32 (t, J ¼ 7, 3 H); 1.8 – 2.1 (m, 5 H); 2.14 – 2.26 (m, 1 H); 3.1 – 3.2 (m, 2 H); 4.04 –
4.16 (m, 1 H); 4.2 – 4.3 (q, J ¼ 7, 2 H); 4.3 – 4.48 (m, 4 H); 7.4 – 7.65 (m, 10 arom. H). 13C-NMR (CD3OD):
14.8; 19.0; 19.9; 21.0; 30.2; 31.8; 52.9; 54.0; 58.3; 59.7; 59.8; 62.5; 130.5; 130.8; 131.3; 132.7; 170.4; 172.8.
Anal. calc. for C26H39Cl2N3O3 (512.51): C 60.93, H 7.67, N 8.2; found: C 60.81, H 7.7, N 8.16.
N5,N5-Dibenzyl-2-methyl-d-ornithyl-l-valine Ethyl Ester Hydrochloride (1:2) (6d). As described for
6a, from 5d: 6d (88% after CC). Wax. [a]D25 ¼ ꢀ19.1 (c ¼ 1.2, CHCl3). 1H-NMR (CD3OD): 0.99 (d, J ¼ 7,
6 H); 1.3 (t, J ¼ 6.9, 3 H); 1.67 (s, 3 H); 1.8 – 2.0 (m, 3 H); 2.0 – 2.3 (m, 2 H); 3.14 (t, J ¼ 7.2, 2 H); 4.12 – 4.3
(m, 3 H); 4.44 (s, 4 H); 7.45 – 7.65 (m, 10 arom. H). 13C-NMR (CD3OD): 14.8; 19.7; 19.9; 22.8; 31.3; 35.1;
52.9; 58.6; 60.8; 61.5; 62.5; 130.7; 130.8; 131.5; 132.8; 172.4; 172.9. Anal. calc. for C27H41Cl2N3O3 (526.54):
C 61.59, H 7.85, N 7.98; found: C 61.38, H 7.87, N 7.97.
N-{(2R)-4-(Dibenzylamino)-2-{{2-[(2R,5S)-6-ethoxy-2,3,4,5-tetrahydro-2-methyl-5-isopropyl-3-oxo-
pyrazin-2-yl]acetyl}amino}-1-oxobutyl}-l-valine Ethyl Ester (7a). The activated ester 3 (1.81 g, 4.3 mmol)
was added to a soln. of 6a (2.15 g, 4.3 mmol) and Et3N (1.8 ml, 13 mmol) in dry CH2Cl2 (30 ml) under Ar,
and the mixture was stirred at r.t. for 24 h. The org. phase was rapidly washed with 0.1m HCl, then with
H2O, and dried (CaCl2). After evaporation the residue was purified by CC: 7a (85%). Oil. [a]2D5 ¼ þ20.0
(c ¼ 0.2, CHCl3). 1H-NMR: 0.8 – 1.0 (m, 12 H); 1.2 – 1.4 (m, 6 H); 1.42 (s, 3 H); 1.88 – 2.18 (m, 2 H);
2.18 – 2.38 (m, 1 H); 2.45 (d, J ¼ 15, 1 H); 2,5 – 2.7 (m, 3 H); 2.86 (d, J ¼ 15, 1 H); 3.5 – 3.7 (br. s, 4 H);
4.0 – 4.3 (m, 5 H); 4.32 – 4.4 (dd, J ¼ 5.7, 8.1, 1 H); 4.4 – 4.58 (m, 1 H); 5.71 (br. s, 1 H); 6.77 (d, J ¼ 8.7,
1 H); 7.2 (d, J ¼ 8.1, 1 H); 7.24 – 7.42 (m, 10 arom. H). 13C-NMR: 14.0; 16.2; 17.9; 18.1; 18.9; 28.6; 30.5;
30.7; 47.3; 50.3; 52.5; 57.3; 7.8; 58.4; 58.7; 61.3; 61.5; 127.0; 128.2; 129.0; 138.6; 157.6; 171.0; 171.8; 172.6.
Anal. calc. for C37H53N5O6 (663.85): C 66.94, H 8.05, N 10.55; found: C 67.05, H 8.03, N 10.52.
4-(Dibenzylamino)-N-{2-[(2R,5S)-6-ethoxy-2,3,4,5-tetrahydro-2-methyl-5-isopropyl-3-oxopyrazin-
2-yl]acetyl}-d-isovalyl-l-valine Ethyl Ester (7b). The intermediate 6b (1.02 g, 2 mmol) was added to a
soln. of 2 (0.51 g, 2 mmol) dissolved in dry THF (15 ml) and Et3N (0.55 ml, 4 mmol). After 10 min,
DMTMM [4b] (0.56 g, 2.4 mmol) was added, and the mixture was stirred at r.t. for 12 h. The mixture was
concentrated, and the residue dissolved with AcOEt. The org. soln. was washed with 1m NaOH and then
with 1m HCl and concentrated. The residue was purified by CC: 7b (ca. 70%). Oil. [a]2D5 ¼ þ33.4 (c ¼ 2.5,
CHCl3). 1H-NMR: 0.84 – 0.94 (m, 9 H); 0.99 (d, J ¼ 7, 3 H); 1.23 (t, J ¼ 7, 3 H); 1.26 (t, J ¼ 7, 3 H); 1.40 (s,
3 H); 1.43 (s, 3 H); 1.9 – 2.3 (m, 4 H); 2.39 (d, J ¼ 15, 1 H); 2.6 – 2.78 (m, 2 H); 2.95 (d, J ¼ 15, 1 H); 3.58
(q, AB, J ¼ 13.2, 4 H); 3.98 – 4.28 (m, 5 H); 4.38 (dd, J ¼ 5.4, 8.4, 1 H); 5.99 (br. s, 1 H); 7.18 – 7.4 (m, 10
arom. H, 1 CONH); 8.19 (br. s, 1 H). 13C-NMR: 13.8; 13.9; 16.1; 17.8; 18.2; 18.7; 22.7; 28.7; 30.4; 30.7;
33.9; 47.7; 49.7; 57.4; 57.9; 58.2; 58.4; 60.6; 60.7; 61.1; 126.9; 128.1; 129.0; 138.2; 157.2; 170.1; 171.6; 173.4;
173.7. Anal. calc. for C38H55N5O6 (677.87): C 67.33, H 8.18, N 10.33; found: C 67.24, H 8.2, N 10.35.
N2-{2-[(2R,5S)-6-Ethoxy-2,3,4,5-tetrahydro-2-methyl-5-isopropyl-3-oxopyrazin-2-yl]acetyl}-N5,N5-
dibenzyl-d-ornithyl-l-valine Ethyl Ester (7c). As described for 7a, from 6c: pure 7c (80% after CC). Oil.
1
[a]2D5 ¼ þ13.8 (c ¼ 1.0, CHCl3). H-NMR: 0.8 – 1.16 (m, 12 H); 1.18 – 1.38 (m, 6 H); 1.4 – 2.0 (m, 4 H);
1.46 (s, 3 H); 2.03 – 2.25 (m, 2 H); 2.38 – 2.48 (m, 2 H); 2.74 (q, AB, J ¼ 15, 2 H); 3.57 (s, 4 H); 3.96 – 4.30
(m, 5 H); 4.30 – 4.50 (m, 2 H); 5.97 (br. s, 1 H); 6.56 (d, J ¼ 8.4, 1 H); 6.91 (d, J ¼ 7.8, 1 H ) ; 7.2 – 7.5 ( m, 10

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Helvetica Chimica Acta – Vol. 94 (2011)
arom. H). 13C-NMR: 14.0; 14.1; 16.3; 17.7; 18.3; 18.9; 23.2; 27.9; 30.2; 30.9; 31.0; 47.0; 52.7; 52.9; 57.0; 58.1;
58.4; 58.6; 61.0; 61.6; 126.7; 128.1; 128.6; 139.5; 157.5; 170.1; 171.6; 173.2. Anal. calc. for C38H55N5O6
(677.87): C 67.33, H 8.18, N 10.33; found: C 67.45, H 8.21, N 10.3.
N2-{2-[(2R,5S)-6-Ethoxy-2,3,4,5-tetrahydro-2-methyl-5-isopropyl-3-oxopyrazin-2-yl]acetyl}-N5,N5-
dibenzyl-2-methyl-d-ornithyl-l-valine Ethyl Ester (7d). As described for 7b, from 6d: 7d (65% after CC).
[a]D: product not sufficiently pure. 1H-NMR: 0.8 – 1.0 (m, 12 H); 1.2 – 1.3 (m, 6 H); 1.47 (s, 3 H); 1.53 (s,
3 H); 1.6 – 1.8 (m, 3 H); 2.1 – 2.38 (m, 3 H); 2.42 (t, J ¼ 6.6, 2 H); 2.54 (d, J ¼ 14.4, 1 H); 2.97 (d, J ¼ 14.4,
1 H); 3.57 (s, 4 H); 4.0 – 4.3 (m, 5 H); 4.49 (dd, J ¼ 5.5, 8.1, 1 H); 5.75 (br. s, 1 H); 6.8 (s, 1 H); 6.85 (d, J ¼
8.4, 1 H); 7.2 – 7.4 (m, 10 arom. H). 13C-NMR: 14.0; 14.1; 16.2; 17.7; 18.3; 18.9; 21.6; 23.1; 28.4; 30.8; 31.0;
35.3; 48.1; 53.1; 57.4; 58.0; 58.6; 58.7; 60.4; 61.0; 61.4; 126.7; 128.0; 128.7; 139.4; 157.3; 169.8; 171.8; 173.4;
173.8.
N-{(1R)-3-(Dibenzylamino)-1-{{[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]amino}carbonyl}prop-
yl}-2-methyl-d-asparaginyl-l-valine Ethyl Ester Hydrochloride (1:2) (8a). As described for 6a, by
submitting 7a to acid hydrolysis: 8a (70% after CC). Wax. [a]2D5 ¼ ꢀ18 (c ¼ 0.3, MeOH). 1H-NMR
(CD3OD): 0.9 – 1.14 (m, 12 H); 1.3 (t, J ¼ 7, 6 H); 1.68 (s, 3 H); 2.02 – 2.42 (m, 4 H); 3.03 (d, J ¼ 16.5,
1 H); 3.25 (d, J ¼ 16.5, 1 H); 3.3 – 3.4 (m, 2 H); 4.1 – 4.36 (m, 6 H); 4.4 – 4.6 (m, 5 H); 7.5 – 7.7 (m, 10 arom.
H). 13C-NMR (CD3OD): 14.9; 19.1; 19.4; 19.9; 20.0; 22.8; 28.0; 31.6; 32.0; 39.3; 41.4; 51.8; 52.9; 58.9; 59.7;
60.5; 62.5; 62.6; 130.8; 131.0; 131.5; 132.7; 171.4; 172.3; 172.8; 172.9; 173.0. Anal. calc. for C37H57Cl2N5O7
(754.78): C 58.88, H 7.61, N 9.28; found: C 58.78, H 7.62, N 9.25.
N-[(1S)-1-(Ethoxycarbonyl)-2-methylpropyl]-2-methyl-d-a-asparaginyl-4-(dibenzylamino)-d-iso-
valyl-l-valine Ethyl Ester Hydrochloride (1:2) (8b). As described for 6a, by submitting 7b to acid
hydrolysis: 8b (65% after CC). Wax. [a]D: product not sufficiently pure. 1H-NMR (CD3OD): 0.9 – 1.1 (m,
12 H); 1.2 – 1.4 (m, 9 H); 1.73 (s, 3 H); 2.1 – 2.34 (m, 3 H); 2.75 – 2.85 (m, 1 H); 3.03 (q, AB, J ¼ 16.2, 2 H);
3.3 – 3.4 (m, 2 H); 4.15 – 4.35 (m, 10 H ) ; 7.4 – 7.7 ( m, 10 arom. H). 13C-NMR (CD3OD): 14.8; 14.9; 19.1;
19.6; 19.8; 20.1; 22.5; 24.0; 31.6; 32.0; 32.8; 41.9; 58.3; 58.9; 59.5; 59.9; 60.8; 60.9; 62.6; 130.7; 130.8; 131.5;
132.6; 171.1; 172.3; 172.8; 1750; 176.2.
N-[(1S)-1-(Ethoxycarbonyl)-2-methylpropyl]-2-methyl-d-a-asparaginyl-N5,N5-dibenzyl-d-ornithyl-
l-valine Ethyl Ester Hydrochloride (1:2) (8c). As described for 6a, by submitting 7c to acid hydrolysis: 8c
(70% after CC). Wax. [a]D: product not sufficiently pure. 1H-NMR (CD3OD): 0.9 – 1.1 (m, 12 H); 1.1 –
1.4 (m, 6 H); 1.69 (s, 3 H); 1.7 – 1.9 (m, 2 H); 1.9 – 2.1 (m, 2 H); 2.1 – 2.3 (m, 2 H); 3.03 (d, J ¼ 17.1, 1 H);
3.1 – 3.24 (m, 2 H); 3.34 (d, J ¼ 17.1, 1 H); 4.1 – 4.28 (m, 4 H); 4.29 (d, J ¼ 6.6, 1 H); 4.30 (d, J ¼ 6.6, 1 H);
4.38 – 4.58 (m, 5 H); 7.45 – 7.65 (m, 10 arom. H). 13C-NMR (CD3OD): 14.9; 19.1; 19.5; 19.9; 20.2; 21.6;
23.0; 30.6; 31.5; 31.9; 41.2; 53.4; 54.3; 58.4; 59.6; 59.7; 60.4; 60.5; 62.4; 130.7; 130.9; 131.4; 132.7; 171.3;
172.3; 172.9; 173.2; 173.8.
N-[(1S)-1-(Ethoxycarbonyl)-2-methylpropyl]-2-methyl-d-a-asparaginyl-N5,N5-dibenzyl-2-methyl-d-
ornithyl-l-valine Ethyl Ester Hydrochloride (1:2) (8d). As described for 6a, by submitting 7d to acid
1
hydrolysis: 8d (66% after CC). Wax. [a]D25 ¼ ꢀ9.7 (c ¼ 0.7, MeOH). H-NMR (CD3OD): 0.9 – 1.1 (m,
12 H); 1.27 (t, J ¼ 7.4, 3 H); 1.28 (t, J ¼ 7.4, 3 H); 1.5 (s, 3 H); 1.69 (s, 3 H); 1.8 – 2.0 (m, 4 H); 2.1 – 2.3 (m,
2 H); 2.9 – 3.2 (m, 4 H); 4.1 – 4.3 (m, 6 H); 4.40 (s, 4 H); 7.4 – 7.6 (m, 10 arom. H). 13C-NMR (CD3OD):
14.8; 14.9; 19.6; 20.0; 22.9; 23.1; 31.5; 31.7; 35.9; 41.6; 53.5; 58.3; 58.5; 59.8; 60.1; 60.2; 60.6; 61.3; 62.5;
130.7; 131.0; 131.4; 132.7; 171.2; 172.3; 172.9; 173.8; 175.6. Anal. calc. for C39H61Cl2N5O7 (782.84): C
59.84, H 7.85, N 8.95; found: C 60.04, H 7.87, N 8.92.
N2-Acetyl-N-[(1R)-3-(dibenzylamino)-1-{{[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]amino}carbo-
nyl}propyl}-2-methyl-d-asparaginyl-l-valine Ethyl Ester (9a). Et3N (0.3 ml, 2 mmol) was added to 8a
(1.5 g, 2 mmol) in CH2Cl2 (10 ml) and the soln. cooled to ꢀ 108. AcCl (0.15 ml, 2.1 mmol) was then
added, and after 10 – 15 min, the cooling bath was removed. The mixture was stirred for 2 – 3 h (TLC
monitoring) and then the org. solvent evaporated. The residue was dissolved in AcOEt, the org. soln.
washed with 2n HCl, dried (Na2SO4), and concentrated, and the residue purified by CC: 9a (90%). Oil.
[a]D: product not sufficiently pure. 1H-NMR: 0.9 – 1.0 (m, 12 H); 1.2 – 1.4 (m, 6 H); 1.67 (s, 3 H); 2.0 – 2.4
(m, 7 H); 2.6 (d, J ¼ 14.2, 1 H); 2.93 (d, J ¼ 14.2, 1 H); 3.0 – 3.18 (m, 2 H); 3.90 – 4.30 (m, 8 H); 4.3 – 4.46
(m, 2 H); 4.6 – 4.8 (m, 1 H); 7.3 – 7.7 (m, 10 arom. H, 1 CONH); 7.85 (br. s, 2 H); 8.15 (d, J ¼ 8.0, 1 H).
13C-NMR: 14.1; 17.6; 18.0; 18.1; 23.5; 24.0; 27.6; 29.6; 30.7; 30.9; 42.4; 50.3; 51.5; 57.2; 57.7; 59.5; 61.0; 61.2;
129.0; 130.6; 170.8; 171.4; 171.5; 171.6; 172.0; 173.7.

Helvetica Chimica Acta – Vol. 94 (2011)
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N2-Acetyl-N-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-2-methyl-d-a-asparaginyl-4-(dibenzylamino)-
d-isovalyl-l-valine Ethyl Ester (9b). As described for 9a, from 8b: 9b (85% after CC). Oil. [a]D: product
not sufficiently pure. 1H-NMR: 0.85 – 1.1 (m, 12 H); 1.23 (t, J ¼ 7, 3 H); 125 (t, J ¼ 7, 3 H); 1.39 (s, 3 H);
1.63 (s, 3 H); 2.01 (s, 3 H); 2.12 – 2.22 (m, 2 H); 2.38 – 2.5 (m, 3 H); 2.79 (d, J ¼ 14.1, 1 H); 2.98 – 3.1 (m,
2 H); 3.95 – 4.23 (m, 8 H); 4.26 – 4.36 (m, 1 H); 4.36 – 4.41 (m, 1 H); 7.3 – 7.6 (m, 10 arom. H); 7.53 (d, J ¼
8.4, 1 H); 7.85 (br. s, 1 H); 7.99 (d, J ¼ 8.1, 1 H); 8.16 (br. s, 1 H). 13C-NMR: 14.0; 14.1; 17.8; 17.9; 18.9;
20.9; 23.3; 23.5; 23.8; 30.7; 30.8; 31.7; 42.9; 48.8; 56.9; 57.5; 57.8; 59.1; 59.7; 61.0; 128.8; 130.4; 171.1; 171.2;
171.8; 171.9; 173.6.
N2-Acetyl-N-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-2-methyl-d-a-asparaginyl-N5,N5-dibenzyl-
d-ornithyl-l-valine Ethyl Ester (9c). As described for 9a, from 8c: 9c (88% after CC). Oil. [a]2D5 ¼ þ33
(c ¼ 1.9, CHCl3). 1H-NMR: 0.9 – 1.0 (m, 12 H); 1.2 – 1.4 (m, 6 H); 1.5 – 1.7 (m, 3 H); 1.66 (s, 3 H); 1.9 – 2.0
(m, 1 H); 2.04 (s, 3 H); 2.18 – 2.28 (m, 2 H); 2.4 – 2.6 (m, 2 H); 2.62 (d, J ¼ 13.8, 1 H); 3.02 (d, J ¼ 13.8,
1 H); 3.5 – 3.7 (m, 4 H); 4.1 – 4.3 (m, 4 H); 4.3 – 4.4 (m, 1 H); 4.45 (dd, J ¼ 4.8, 8.7, 1 H); 4.51 (dd, J ¼ 4.8,
8.7, 1 H); 6.57 (d, J ¼ 8.7, 1 H); 6.70 (d, J ¼ 7.5, 1 H); 7.2 – 7.4 (m, 10 arom. H); 7.48 (s, 1 H); 8.37 (d, J ¼ 8.1,
1 H). 13C-NMR: 14.0; 17.4; 17.6; 18.8; 18.9; 22.9; 23.9; 29.2; 30.8; 30.9; 42.0; 52.6; 53.0; 57.0; 57.5; 58.1;
59.0; 60.9; 61.0; 126.7; 128.0; 128.6; 139.4; 170.9; 171.2; 171.5; 171.6; 173.6. Anal. calc. for C40H59N5O8
(737.93): C 65.11, H 8.06, N 9.49; found: C 64.98, H 8.04, N 9.52.
N2-Acetyl-N-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-2-methyl-d-a-asparaginyl-N5,N5-dibenzyl-2-
methyl-d-ornithyl-l-valine Ethyl Ester (9d). As described for 9a, from 8d: pure 9d (87% after CC). Oil.
[a]2D5 ¼ þ27 (c ¼ 0.7, CHCl3). 1H-NMR: 0.9 – 1.0 (m, 12 H); 1.2 – 1.38 (m, 6 H); 1.48 (s, 3 H); 1.48 – 2.0 (m,
4 H); 1.69 (s, 3 H); 2.03 (s, 3 H); 2.1 – 2.3 (m, 2 H); 2.42 (d, J ¼ 13.8, 1 H); 2.43 – 2.57 (m, 2 H); 2.94 (d,
J ¼ 13.8, 1 H); 3.57 (s, 4 H); 4.0 – 4.3 (m, 4 H); 4.38 (dd, J ¼ 5.2, 8, 1 H); 4.52 (dd, J ¼ 5, 8.4, 1 H); 6.73 (d,
J ¼ 8.4, 1 H); 6.83 (br. s, 1 H); 7.2 – 7.5 (m, 10 arom. H); 7.56 (s, 1 H); 8.24 (d, J ¼ 8, 1 H). 13C-NMR: 14.0;
17.7; 18.9; 19.0; 21.0; 22.8; 23.7; 24.0; 30.7; 31.1; 34.5; 43.4; 52.9; 57.1; 57.9; 58.0; 59.2; 60.3; 60.9; 61.0;
126.9; 128.1; 128.9; 138.7; 170.5; 171.1; 171.7; 171.9; 173.4; 173.7. Anal. calc. for C41H61N5O8 (751.95): C
65.49, H 8.18, N 9.31; found: C 65.75, H 8.15, N 9.33.
(3S,6S)-3-[2-(Dibenzylamino)ethyl]-5-ethoxy-3,6-dihydro-6-isopropyl-3-methylpyrazin-2(1H)-one
(11a). As described for 5a, from 10a: pure 11a (85% after CC). Oil. [a]2D5 ¼ ꢀ16.9 (c ¼ 1.3, CHCl3).
1H-NMR: 0.72 (d, J ¼ 7, 3 H); 0.96 (d, J ¼ 7, 3 H); 1.15 (t, J ¼ 7.2, 3 H); 1.36 (s, 3 H); 1.9 – 2.0 (m, 1 H);
2.2 – 2.6 (m, 4 H); 3.48 (d, J ¼ 15, 2 H); 3.7 (d, J ¼ 15, 2 H); 3.8 – 4.0 (m, 3 H); 5.93 (br. s, 1 H); 7.2 – 7.4 (m,
10 arom. H). 13C-NMR: 14.0; 16.1; 18.3; 26.8; 28.6; 30.5; 37.8; 48.9; 57.9; 58.1; 59.0; 60.8; 126.5; 127.9;
128.6; 139.8; 155.8; 174.6. Anal. calc. for C26H35N3O2 (421.58): C 74.07, H 8.37, N 9.97; found: C 74.25, H
8.38, N 9.95.
(3S,6S)-3-[3-(Dibenzylamino)propyl]-5-ethoxy-3,6-dihydro-6-isopropyl-3-methylpyrazin-2(1H)-
one (11b). As described for 5a, from 10b: 11b (85% after CC). Oil. [a]D: product not sufficiently pure.
1H-NMR: 0.89 (d, J ¼ 7, 3 H); 1.02 (d, J ¼ 7, 3 H); 1.28 (t, J ¼ 7, 3 H); 1.37 (s, 3 H); 1.4 – 1.7 (m, 3 H); 1.9 –
2.0 (m, 1 H); 2.3 – 2.5 (m, 1 H); 2.43 (t, J ¼ 7, 2 H); 3.55 (q, AB, J ¼ 15.3, 4 H); 3.99 – 4.03 (m, 1 H); 4.06 –
4.18 (m, 2 H); 5.8 (br. s, 1 H); 7.2 – 7.4 (m, 10 arom. H). 13C-NMR: 14.1; 16.2; 18.3; 22.2; 28.7; 30.5; 38.3;
53.4; 57.9; 59.9; 60.8; 126.5; 127.9; 128.6; 139.7; 156.0; 175.0.
4-(Dibenzylamino)-l-isovalyl-l-valine Ethyl Ester Hydrochloride (1:2) (12a). As described for 6a,
from 11a: 12a (80% after CC). Wax. [a]D: product not sufficiently pure. 1H-NMR (CD3OD): 1.0 – 1.1 (m,
6 H); 1.33 (t, J ¼ 7, 3 H); 1.77 (s, 3 H); 2.2 – 2.4 (m, 1 H); 2.54 – 2.7 (m, 1 H); 2.8 – 3.0 (m, 1 H); 3.2 – 3.5
(m, 3 H); 4.2 – 4.34 (m, 2 H); 4.34 – 4.6 (m, 5 H); 7.45 – 7.65 (m, 10 arom. H). 13C-NMR (CD3OD): 15.0;
19.8; 19.9; 23.4; 31.2; 32.2; 49.9; 58.1; 58.5; 60.6; 60.7; 62.6; 130.6; 131.2; 132.7; 171.4; 173.2.
N5,N5-Dibenzyl-2-methyl-l-ornithyl-l-valine Ethyl Ester Hydrochloride (1:2) (12b). As described
1
for 6a, from 11b: pure 12b (87% after CC). Wax. [a]2D5 ¼ ꢀ8.9 (c ¼ 0.9, MeOH). H-NMR (CD3OD):
1.0 – 1.1 (m, 6 H); 1.2 – 1.4 (m, 3 H); 1.70 (s, 3 H); 1.84 – 2.24 (m, 4 H); 2.24 – 2.40 (m, 1 H); 3.14 (t, J ¼ 7.8,
2 H); 4.10 – 4.27 (m, 2 H); 4.3 – 4.5 (m, 5 H); 7.5 – 7.6 (m, 10 arom. H). 13C-NMR (CD3OD): 14.9; 19.1;
19.5; 19.9; 23.3; 31.4; 35.4; 58.8; 59.3; 60.5; 61.6; 62.7; 130.8; 130.9; 131.5; 132.8; 172.5; 173.7. Anal. calc.
for C27H41Cl2N3O3 (526.54): C 61.59, H 7.85, N 7.98; found: C 61.51, H 7.81, N 7.95.
4-(Dibenzylamino)-N-{2-[(2R,5S)-6-ethoxy-2,3,4,5-tetrahydro-2-methyl-5-isopropyl-3-oxopyrazin-
2-yl]acetyl}-l-isovalyl-l-valine Ethyl Ester (13a). As described for 7b, from 12a: pure 13a (90% after
1
CC). Oil. [a]2D5 ¼ ꢀ73.8 (c ¼ 1.2, CHCl3). H-NMR: 0.8 – 1.0 (m, 9 H); 1.0 (d, J ¼ 7, 3 H); 1.26 (t, 6 H);

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Helvetica Chimica Acta – Vol. 94 (2011)
1.45 (s, 3 H); 1.50 (s, 3 H); 1.80 – 2.34 (m, 4 H); 2.35 (d, J ¼ 14, 1 H); 2.44 – 2.80 (m, 2 H); 2.88 (d, J ¼ 14,
1 H); 3.54 (q, AB, J ¼ 13.2, 4 H); 4.0 – 4.3 (m, 6 H); 6.10 (br. s, 1 H); 7.2 – 7.4 (m, 10 arom. H); 7.60 (d, J ¼
8.2, 1 H); 8.51 (br. s, 1 H). 13C-NMR: 14.0; 14.1; 15.9; 18.2; 19.1; 23.3; 29.2; 30.3; 30.6; 34.3; 48.5; 50.2;
57.9; 58.4; 58.5; 59.0; 60.8; 61.2; 61.6; 127.3; 128.4; 129.4; 138.0; 157.2; 170.8; 172.0; 173.7; 174.2. Anal.
calc. for C38H55N5O6 (677.87): C 67.33, H 8.18, N 10.33; found: C 67.55, H 8.15, N 10.32.
N2-{2-[(2R,5S)-6-Ethoxy-2,3,4,5-tetrahydro-2-methyl-5-isopropyl-3-oxopyrazin-2-yl]acetyl}-N5,N5-
dibenzyl-2-methyl-l-ornithyl-l-valine Ethyl Ester (13b). As described for 7b, from 12b: 13b (85% after
CC). Oil. [a]2D5 ¼ ꢀ11.5 (c ¼ 1.0, MeOH). 1H-NMR: 0.8 – 1.0 (m, 12 H); 1.1 – 1.4 (m, 6 H); 1.45 (s, 3 H);
1.48 (s, 3 H); 1.5 – 2.1 (m, 4 H); 2.1 – 2.4 (m, 2 H); 2.4 – 2.6 (m, 2 H); 2.52 (d, J ¼ 14.7, 1 H); 3.02 (d, J ¼
14.7, 1 H); 3.60 (br. s, 4 H); 3.9 – 4.0 (m, 1 H); 4.0 – 4.1 (m, 1 H); 4.1 – 4.26 (m, 3 H); 4.42 (dd, J ¼ 5.1, 8.4,
1 H); 6.06 (br. s, 1 H); 6.75 (s, 1 H); 6.94 (d, J ¼ 8.4, 1 H); 7.25 – 7.45 (m, 10 arom. H). 13C-NMR: 14.0;
14.1; 16.6; 17.9; 18.2; 19.1; 19.7; 21.2; 21.8; 22.6; 27.0; 28.9; 30.4; 31.9; 38.5; 48.0; 52.9; 57.8; 58.7; 59.1; 60.2;
61.4; 127.0; 128.2; 129.9; 138.8; 157.7; 171.5; 173.1; 174.0; 174.5. Anal. calc. for C39H57N5O6 (691.90): C 67.7,
H 8.3, N 10.12; found: C 67.87, H 8.32, N 10.08.
N-[(1S)-1-(Ethoxycarbonyl)-2-methylpropyl]-2-methyl-d-a-asparaginyl-4-(dibenzylamino)-l-valine
Ethyl Ester Hydrochloride (1:2) (14a). As described for 8b, from 13a: pure 14a (80% after CC). Wax.
[a]2D5 ¼ þ13.3 (c ¼ 1.1, MeOH). 1H-NMR (CD3OD): 0.9 – 1.1 (m, 12 H); 1.2 – 1.4 (m, 9 H); 1.69 (s, 3 H);
2.1 – 2.3 (m, 3 H); 2.78 – 2.9 (m, 1 H); 3.06 (d, J ¼ 16.8, 1 H); 3.21 (d, J ¼ 16.8, 1 H); 3.3 – 3.4 (m, 2 H);
4.1 – 4.42 (m, 9 H); 4.64 (d, J ¼ 13.5, 1 H); 7.4 – 7.7 (m, 10 arom. H). 13C-NMR (CD3OD): 14.8; 14.9; 19.6;
19.9; 20.0; 20.1; 22.8; 23.9; 31.6; 33.0; 39.5; 41.5; 50.7; 58.4; 58.8; 59.7; 60.7; 60.9; 62.6; 130.7; 130.8; 131.2;
131.4; 132.4; 132.5 171.4; 172.3; 172.9; 173.0; 176.5. Anal. calc. for C38H59Cl2N5O7 (768.81): C 59.37, H
7.74, N 9.11; found: C 59.57, H 7.77, N 9.08.
N-[(1S)-1-(Ethoxycarbonyl)-2-methylpropyl]-2-methyl-d-a-asparaginyl-N5,N5-dibenzyl-2-methyl-l-
ornithyl-l-valine Ethyl Ester Hydrochloride (1:2) (14b). As described for 8d, from 13b: pure 14b (75%
after CC). Wax. [a]2D5 ¼ ꢀ6.4 (c ¼ 0.7, MeOH). 1H-NMR (CD3OD): 0.9 – 1.1 (m, 12 H); 1.2 – 1.4 (m,
6 H); 1.59 (s, 3 H); 1.66 (s, 3 H); 1.8 – 2.0 (m, 4 H); 2.1 – 2.3 (m, 2 H); 3.04 (q, AB, J ¼ 18.4, 2 H); 3.0 – 3.1
(m, 2 H); 4.1 – 4.3 (m, 6 H); 4.4 (br. s, 4 H); 7.44 – 7.6 (m, 10 arom. H). 13C-NMR (CD3OD): 14.9; 19.5;
19.6; 20.0; 22.9; 23.5; 34.6; 41.6; 53.7; 58.4; 59.8; 60.2 60.5; 61.4; 62.5; 130.6; 131.0; 131.3; 132.7; 170.8;
172.3; 172.8; 173.6; 175.9. Anal. calc. for C39H61Cl2N5O7 (782.84): C 59.84, H 7.85, N 8.95; found: C 59.94,
H 7.88, N 8.98.
N2-Acetyl-N-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-2-methyl-d-a-asparaginyl-4-(dibenzylamino)-
l-isovalyl-l-valine Ethyl Ester (15a). As described for 9b, from 14a: 15a (78% after CC). Oil. [a]D:
1
product not sufficiently pure. H-NMR: 0.8 – 1.0 (m, 12 H); 1.1 – 1.5 (m, 6 H); 1.3 (s, 3 H); 1.7 (s, 3 H);
2.0 – 2.1 (m, 3 H); 2.1 – 2.3 (m, 2 H); 2.4 – 2.7 (m, 3 H); 2.78 (d, J ¼ 14.4, 1 H); 2.85 – 3.1 (m, 2 H); 3.8 – 4.3
(m, 8 H); 4.3 – 4.5 (m, 2 H); 7.2 – 7.6 (m, 10 arom. H); 7.6 (d, J ¼ 8.1, 1 H); 7.8 (s, 1 H); 7.9 (d, J ¼ 8.4, 1 H);
8.17 (br. s, 1 H). 13C-NMR: 14.0; 14.1; 17.7; 18.4; 19.0; 19.1; 23.9; 29.6; 30.5; 31.0; 43.2; 49.4; 56.7; 57.6;
58.1; 59.6; 59.9; 60.9; 129.1; 130.5; 171.5; 171.6; 171.7; 173.7; 173.8.
N2-Acetyl-N-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-2-methyl-d-a-asparaginyl-N5,N5-dibenzyl-2-
methyl-l-ornithyl-l-valine Ethyl Ester (15b). As described for 9d, from 14b: pure 15b (80% after CC).
[a]2D5 ¼ þ73 (c ¼ 0.7, CHCl3). 1H-NMR: 0.9 – 1.0 (m, 12 H); 1.25 (t, J ¼ 7, 3 H); 1.27 (t, J ¼ 7, 3 H); 1.46 –
2.0 (m, 4 H); 1.5 (s, 3 H); 1.69 (s, 3 H); 2.02 (s, 3 H); 2.1 – 2.26 (m, 2 H); 2.34 – 2.5 (m, 3 H); 2.90 (d, J ¼
13.6, 1 H); 3.58 (s, 4 H); 4.05 – 4.25 (m, 4 H); 4.39 (dd, J ¼ 5, 8, 1 H); 4.52 (dd, J ¼ 5.6, 8.0, 1 H); 6.74 (s,
1 H); 6.93 (d, J ¼ 8, 1 H); 7.2 – 7.4 (m, 10 arom. H); 7.63 (s, 1 H); 8.18 (d, J ¼ 8, 1 H). 13C-NMR: 14.0; 17.8;
18.9; 20.9; 21.7; 23.9; 30.7; 31.0; 35.9; 43.5; 52.9; 57.1; 57.8; 59.1; 60.4; 60.8; 126.7; 128.0; 128.6; 139.1;
170.3; 171.1; 171.9; 173.3; 173.6. Anal. calc. for C41H61N5O8 (751.95): C 65.49, H 8.18, N 9.31; found: C
65.52, H 8.22, N 9.29.
REFERENCES
[1] D. Balducci, A. Bottoni, M. Calvaresi, G. Porzi, S. Sandri, Tetrahedron: Asymmetry 2006, 17, 3273.
[2] G. M. Almiento, D. Balducci, A. Bottoni, M. Calvaresi, G. Porzi, Tetrahedron: Asymmetry 2007, 18,
2695 and refs. cit. therein.

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[3] B.-h. Baek, M.-r. Lee, K.-Y. Kim, U.-I. Cho, D. W. Boo, I. Shin, Org. Lett. 2003, 5, 971 and refs. cit.
therein; K. Suat, S. D. S. Jois, Curr. Pharm. Des. 2003, 9, 1209; T. Kieber-Emmons, R. Murali, M. I.
Greene, Curr. Opin. Biotechnol. 1997, 8, 435.
[4] a) D. Balducci, A. Bottoni, M. Calvaresi, G. Porzi, Mol. Phys. 2009, 107, 653 and refs. cit. therein;
b) D. Balducci, A. Bottoni, M. Calvaresi, G. Porzi, S. Sandri, Tetrahedron: Asymmetry 2007, 18, 1448;
c) D. Balducci, A. Grandi, G. Porzi, S. Sandri, Tetrahedron: Asymmetry 2006, 17, 1521; d) D.
Balducci, E. Emer, F. Piccinelli, G. Porzi, M. Recanatini, S. Sandri, Tetrahedron: Asymmetry 2005,
16, 3785; e) D. Balducci, A. Grandi, G. Porzi, S. Sandri, Tetrahedron: Asymmetry 2005, 16, 1453;
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Received January 26, 2010