A new 2H-azirin-3-amine as a synthon for 2-methylaspartate

Article abstract of DOI:10.1002/hlca.200590238

The synthesis of a novel 2,2-disubstituted 2H-azirin-3-amine 3a as a building block for racemic Asp(2Me) is described. This synthon contains an ester group in the side chain. The reaction of 3a with thiobenzoic acid and the amino acid Z-Val-OH yielded the racemic monothiodiamide 10a and the dipeptide 11 as a mixture of diastereoisomers, respectively (Scheme 2). In 11, each of the protecting groups was removed selectively (Scheme 3). First attempts toward the preparation of enantiomerically pure synthons for Asp(2Me) with a chiral auxiliary group in the side chain are described. Synthons 3b with a 1-(naphthalen-1-yl)ethyl ester group and 3c with a menthyl ester group were prepared and reacted with thiobenzoic acid to form monothiodiamides 10b and 10c (Scheme 2). However, the diastereoisomers of the synthons 3b and 3c could not be separated by chromatography.

Full text of DOI:10.1002/hlca.200590238

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A New 2H-Azirin-3-amine as a Synthon for 2-Methylaspartate
by Kathrin A. Brun and Heinz Heimgartner*
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
The synthesis of a novel 2,2-disubstituted 2H-azirin-3-amine 3a as a building block for racemic Asp(2Me) is
described. This synthon contains an ester group in the side chain. The reaction of 3a with thiobenzoic acid and
the amino acid Z-Val-OH yielded the racemic monothiodiamide 10a and the dipeptide 11 as a mixture of dia-
stereoisomers, respectively (Scheme 2). In 11, each of the protecting groups was removed selectively (Scheme 3).
First attempts toward the preparation of enantiomerically pure synthons for Asp(2Me) with a chiral auxiliary
group in the side chain are described. Synthons 3b with a 1-(naphthalen-1-yl)ethyl ester group and 3c with a
menthyl ester group were prepared and reacted with thiobenzoic acid to form monothiodiamides 10b and
10c (Scheme 2). However, the diastereoisomers of the synthons 3b and 3c could not be separated by chromatog-
raphy.
1. Introduction. – In the last few years, we have reported the synthesis of some new
optically active 2H-azirin-3-amines 1 as synthons for enantiomerically pure 2,2-disub-
stituted glycines (a,a-disubstituded a-amino acids) [1][2]. Synthons 1f and 1g contain
protected hydroxy or phenolic hydroxy groups, and are first examples of enantiomeri-
cally pure building blocks with a functionalized side chain. As an extension of this
approach, we have recently presented the synthesis of a new 2H-azirin-3-amine 2 as
a racemic synthon for Glu(2Me) containing an ester group in the side chain [3].
All these synthons can easily be used as precursors for their corresponding 2,2-di-
substituted glycines in peptide synthesis. A useful method for their introduction into
peptides is the so-called ‘azirine/oxazolone method’ [4].
In the present paper, we describe the synthesis of a novel building block 3a for 2-
methylaspartate (Asp(2Me)) with an ester group as functional group in the side
chain, and its applicability in the synthesis of model peptides. In addition, two other
© 2005 Verlag Helvetica Chimica Acta AG, Zürich

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building blocks for Asp(2Me), 3b and 3c, are described1). Both have a chiral auxiliary
group in the side chain. However, the diastereoisomers of these synthons could not be
separated by column or layer chromatography.
2. Results. – 2.1. Synthesis of 2H-Azirines 3a–3c. The 2H-azirin-3-amines 3a–3c,
i.e., synthons for Asp(2Me), were prepared in gram quantities according to Scheme 1.
The synthesis was started from the commercially available a-acetylbutanolactone.
Methylation in a-position to the C=O group by deprotonation with MeONa, followed
by treatment with MeI, yielded 4 [6], which was treated with EtONa to give 5 [7]. The
hydroxy amide 6 was obtained directly from 5 by the reaction with N-methylaniline in
the presence of AlCl3 in CH2Cl2 at room temperature. Subsequently, the OH group of 6
Scheme 1
1
)
Enantioselective syntheses of a-alkylated aspartates have been described by Seebach et al. [5].

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was oxidized with ruthenium RuCl3 ·H2O and NaIO4 to yield the carboxylic acid 7.
These two last steps (i.e., 5 !6 !7 have been optimized earlier for the higher homol-
gue [3]).
Methylation of 7 with CH2N2 gave the ester 8a in quantitative yield. The esters 8b
and 8c were obtained as mixtures of diastereoisomers2) from 7, and the corresponding
alcohols by using DCC and 4-(pyrrolidin-1-yl)pyridine as the coupling agent and aux-
iliary, respectively (Scheme 1) [8]. The amide groups of 8a–8c were converted to the
corresponding thioamides 9a–9c3) by treatment with Lawesson reagent in toluene at
1308 in yields between 89 and 96%. Finally, the syntheses of 3a–3c4) were achieved
by consecutive treatment of 9a–9c with COCl2 in CH2Cl2, deprotonation with 1,4-di-
azabicyclo[2.2.2]octane (DABCO) in THF, and treatment with NaN3 in THF/DMF,
in yields between 20 and 29%. A unidentified side product was isolated in all cases
in similar amounts.
2.2. Reactions of 3a–3c with Thiobenzoic S-Acid (PhCOSH) and Z- -Valine. To
L
demonstrate that the new amino-acid synthons 3a–3c show analogous chemical behav-
ior as the already known 2H-azirin-3-amines (cf. [4]), they were reacted with PhCOSH
[1][2][9–11] (cf. [12][13]) to give the monothiodiamides 10a–10c in yields between 80
and 93% (Scheme 2)5). The use of 3a as a synthon in peptide synthesis was shown by the
reaction with Z-L-valine, which led to the dipeptide amide 11 in 78% yield as a ca. 1:1
mixture of diastereoisomers.
Scheme 2
2.3. Selective Cleavage of the Protecting Groups in the Dipeptide 11. With the aim of
establishing the usefulness of the described coupling reaction in the synthesis of pepti-
des, each of the protecting groups of the dipeptide 11 was removed selectively under
standard or slightly modified conditions (Scheme 3). For example, the Z group was
2
)
)
)
)
The ratio in 8b was ca. 2 :1 (1H-NMR) but could not be determined in the case of 8c.
Ratio of diastereoisomers: 9b: 3 :2, 9c: 4 :3 (1H-NMR).
The ratio of the diastereoisomers of 3b and 3c could not be determined.
Compounds 10b and 10c were obtained as mixtures of diastereoisomers (ratio ca. 1:1 and 2 :1, respectively
(1H-NMR)).
3
4
5

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Scheme 3
removed by hydrogenolysis to give the N-deprotected dipeptide 12 in 76% yield. The
selective hydrolysis of the methyl ester group in 11 was achieved under standard con-
ditions with LiOH in THF/MeOH/H2O 3 :1:1 in 93% yield. Finally, hydrolysis of the C-
terminal amide group of 11 was carried out via the corresponding oxazolone [3], by
treatment with HCl (gas) in toluene, followed by the hydrolysis with H2O in 43% yield.
We thank the analytical services of our institute for NMR and mass spectra, and for elemental analyses.
Financial support by the Swiss National Science Foundation, F. Hoffmann-La Roche AG, Basel, the Stiftung
für wissenschaftliche Forschung an der Universität Zürich, and the Prof. Dr. Hans E. Schmid-Stiftung is gratefully
acknowledged.
Experimental Part
1. General. See [3].
2. Preparation of the 2-Methylaspartate Synthon 3a. 2.1. 3-Acetyl-2,3,4,5-tetrahydro-3-methylfuran-2-one (4)
[6][14]. To a soln. of Na (1.06 g, 46.1 mmol) in 20 ml of MeOH, 2-acetylbutanolactone (5 ml, 5.95 g, 46.4 mmol)
was added at 08. After 10 min, MeI (3.05 ml, 6.95 g, 49.0 mmol) was added at 08, and the soln. was stirred for 10
min at 08, 3 h at r.t., and 17 h under reflux (oil bath at 758). The solvent was evaporated, and the precipitate
formed was dissolved in H2O. The mixture was extracted with Et2O (3×), and the org. layers were combined,
dried (MgSO4), and evaporated. Distillation gave 4.503 g of 4 (68%). Colorless liquid. B.p. 1608/8 mbar. Rf (hex-
ane/AcOEt 2 :1) 0.23. IR (neat): 2986m, 2940m, 1770vs, 1713vs, 1486w, 1457m, 1384s, 1360s, 1270m, 1178s, 1133s,
1091vs, 1029vs, 966m, 920m. 1H-NMR: 4.35–4.2 (m, CH2O); 2.95–2.85 (m, 1 H of CH2); 2.33 (s, MeCO); 2.1–
2.0 (m, 1 H of CH2); 1.54 (s, Me). 13C-NMR: 203.2 (s, CO (lactone)); 176.2 (s, CO (ketone)); 65.8 (t, CH2O); 56.4
(s, C(CO)2); 32.2 (t, CH2); 25.4, 20.7 (2q, 2 Me). ESI-MS (MeOH+NaI): 197 (6, [M+Na+MeOH]+), 165 (100,
[M+Na]+).

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2.2. 2,3,4,5-Tetrahydro-3-methylfuran-2-one (5) [6][14][15]. To a soln. of Na (0.585 g, 25.4 mmol) in 125 ml
of EtOH, 4 (16.42 g, 115.5 mmol) was added, and the mixture was stirred under reflux for 5 h. Then, NH4Cl
(7.5 g) was added, and, after evaporation, the residue was solved in as little H2O as possible, and extracted
with Et2O (3×). The org. layers were combined, dried (MgSO4), and evaporated. Distillation gave 10.278 g
(89%) of 5. Colorless liquid. B.p. 1158/8 mbar. Rf (hexane/AcOEt 2 :1) 0.43. IR (neat): 2978m, 2938w, 2882w,
1769vs, 1457w, 1381m, 1295w, 1222w, 1176s, 1136m, 1119w, 1047m, 1023s, 973w, 957w, 915w. 1H-NMR:
4.4–4.3, 4.25–4.15 (2m, CH2O); 2.7–2.55, 2.5–2.4, 2.0–1.85 (3m, CH2, CH); 1.29 (d, J=7.0, Me). 13C-NMR:
180.0 (s, CO); 66.1 (t, CH2O); 34.0 (d, CH); 30.6 (t, CH2); 15.0 (q, Me). ESI-MS (MeOH+NaI): 169 (12),
123 (100, [M+Na]+).
2.3. 4-Hydroxy-2,N-dimethyl-N-phenylbutanamide (6). To a soln. of AlCl3 (13.4 g, 100.5 mmol, 2 equiv.) in
CH2Cl2 (40 ml), N-methylaniline (20.5 ml, 20.2 g, 188.4 mmol, 3.75 equiv.) was added slowly at 08. Thereby, the
soln. turned dark. Then, a soln. of 5 (5.01 g, 50.0 mmol) in CH2Cl2 (30 ml) was added at 08, and the mixture was
stirred for 5 h at r.t. To the grey-brown suspension, 60 ml of H2O were added, and the mixture was stirred for
30 min at 08, passed through Celite, and the layers were separated. The aq. layer was extracted twice with
CH2Cl2, and the combined org. layers were washed with H2O (2×), with sat. aq. NaCl and NH4Cl soln., and
with NaHCO3 (10%; 2×), dried (MgSO4), and evaporated. Consecutive CC with hexane/AcOEt 1:1 to
AcOEt and AcOEt (2×) yielded 7.111 g (69%) of 6. Colorless solid. M.p. 75–768. Rf (AcOEt) 0.24. IR
(KBr): 3386s, 2984w, 2967m, 2920m, 2870m, 2827w, 1894w, 1634vs, 1592vs, 1492s, 1464s, 1433m, 1393m,
1372w, 1337s, 1291m, 1275m, 1207w, 1170w, 1144w, 1114s, 1073w, 1054m, 999w, 962w, 926w, 783s, 704s.
1H-NMR: 7.45–7.2 (m, 5 arom. H); 3.7–3.6, 3.6–3.5 (2m, CH2OH); 3.26 (s, MeN); 2.65–2.6 (m, CHCO);
2.35 (br. s, OH); 1.95–1.85, 1.65–1.5 (2m, CH2); 1.05 (d, J=6.9, Me). 13C-NMR: 177.2 (s, CO); 144.1 (s, 1
arom. C); 129.9, 127.9, 127.4 (3d, 5 arom. CH); 60.6 (t, CH2OH); 37.6 (q, MeN); 36.6 (t, CH2); 36.6 (d, CH);
17.9 (q, Me). ESI-MS (MeOH): 231 (15), 230 (100, [M+Na]+). Anal. calc. for C12H17NO2 (207.27): C 69.54,
H 8.27, N 6.76; found: C 69.59, H 8.04, N 6.72.
2.4. 3-Methyl-4-[methyl(phenyl)amino]-4-oxobutanoic acid (7). The hydroxy amide 6 (8.279 g, 39.94 mmol)
and 35.005 g (163.66 mmol, 4.1 equiv.) of NaIO4 were solved in a mixture of 80 ml of MeCN, 80 ml of AcOEt,
and 120 ml of H2O. A small amount of RuCl3 ·H2O was added at r.t. After 7 h, the color of the suspension
changed from light yellow to brown, which indicated the end of the conversion. H2O was added, and the aq.
layer was extracted with AcOEt. The org. layers were combined, dried (MgSO4), and evaporated. Recrystalli-
zation from AcOEt yielded 7.018 g (79%) of 7. Colorless crystals. M.p. 151–1528. Rf (AcOEt) 0.27. IR (KBr):
2970m, 2935m, 2756m, 2611m, 1909w, 1722vs, 1613vs, 1588vs, 1493s, 1437m, 1344w, 1326w, 1285s, 1241s, 1202s,
1
1175w, 1147m, 1115m, 1073w, 1037w, 1000w, 950w, 913w, 787m, 707s. H-NMR: 7.5–7.3 (m, 5 arom. H); 3.22
(s, MeN); 2.9–2.8, 2.75–2.7, 2.25–2.2 (3m, CH, CH2); 0.97 (d, J=6.9, Me). 13C-NMR: 177.9, 175.4 (2s, 2
CO); 145.0 (s, 1 arom. C); 130.8, 129.2, 128.6 (3d, 5 arom. CH); 38.8 (t, CH2); 38.0 (q, MeN); 34.3 (d, CH);
17.9 (q, Me). ESI-MS (MeOH+NaI): 245 (12), 244 (100, [M+Na]+). Anal. calc. for C12H15NO3 (221.26): C
65.14, H 6.83, N 6.33; found: C 65.16, H 6.63, N 6.32.
2.5. Methyl 3-Methyl-4-[methyl(phenyl)amino]-4-oxobutanoate (8a). To a soln. of 7 (2.503 g, 11.31 mmol) in
abs. THF (25 ml), 40 ml of a ca. 0.5N soln. of CH2N2 in Et2O (prepared according to [16]) was added at 08, and the
mixture was stirred for 1.25 h and remained yellow. The ice-bath was removed, and the mixture was stirred at r.t.
for 60 min. The yellow color remained. Then, the excess of CH2N2 was destroyed with AcOH, the solvent was
evaporated, and the product was dried: 2.742 g (quant.) of 8a. Red solid. The product was used for the next step
without further purification. For characterization, a small amount was purified by prep. TLC (hexane/AcOEt
2 :1). Colorless solid. M.p. 96–978. Rf (hexane/AcOEt 1:1) 0.28; Rf (hexane/AcOEt 2 :1) 0.13. IR (KBr):
2974m, 2946w, 2876w, 2854w, 1982w, 1910w, 1726vs, 1648vs, 1595m, 1495s, 1466m, 1453m, 1441s, 1427m,
1404m, 1390m, 1375w, 1358s, 1329w, 1292m, 1274s, 1204s, 1184s, 1157w, 1145m, 1116m, 1073w, 1040w, 1006m,
946w, 927w, 906w, 783m, 707s. 1H-NMR: 7.45–7.35 (m, 5 arom. H); 3.65 (s, MeO); 3.27 (s, MeN); 2.9–2.5
(m, CH2); 2.25–2.2 (m, CH); 1.00 (d, J=6.2, Me). 13C-NMR: 175.3, 172.8 (2s, 2 CO); 143.8 (s, 1 arom. C);
129.6, 127.7, 127.5 (3d, 5 arom. CH); 51.4 (q, MeO); 37.8 (t, CH2); 37.5 (q, MeN); 28.8 (d, CH); 17.8 (q, Me).
ESI-MS (MeOH): 259 (15), 258 (100, [M+Na]+), 204 (2, [MꢀMeO]+). Anal. calc. for C13H17NO3 (235.28): C
66.36, H 7.28, N 5.95; found: C 66.12, H 7.19, N 5.78.
2.6. Methyl 3-Methyl-4-[methyl(phenyl)amino]-4-thioxobutanoate (9a). To a soln. of 8a (2.613 g, 11.11
mmol) in toluene (11 ml), Lawesson reagent (2.70 g, 6.68 mmol, 1.2 equiv.) was added, and the mixture was stir-
red for 35 min at 1308 and evaporated. CC (hexane/AcOEt 5 :1) yielded 2.484 g (89%) of 9a as a colorless solid.
M.p. 106–1078. Rf (hexane/AcOEt 1 :1) 0.55; Rf (hexane/AcOEt 2 :1) 0.35. IR (KBr): 2971m, 2952w, 2927w,
2866w, 1963w, 1887w, 1729vs, 1595w, 1496s, 1447m, 1456m, 1436s, 1385s, 1357s, 1333w, 1276s, 1228m, 1198s,
1173s, 1135w, 1105m, 1054w, 1035m, 1022w, 1005m, 980s, 922m, 901w, 776m, 700s. 1H-NMR: 7.5–7.15 (m, 5

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arom. H); 3.72, 3.62 (2s, MeO, MeN); 3.3–3.2 (m, CH2); 2.35–2.3 (m, CH); 1.07 (d, J=6.5, Me). 13C-NMR: 209.5
(s, CS); 172.6 (s, CO); 145.4 (s, 1 arom. C); 129.8, 128.4, 125.0 (3d, 5 arom. CH); 51.3 (q, MeO); 45.7 (q, MeN);
41.5 (t, CH2); 39.5 (d, CH); 21.4 (q, Me). ESI-MS (MeOH): 276 (6), 275 (18), 274 (100, [M+Na]+), 252 (100,
[M+1]+), 204 (7, [MꢀMeO]+). Anal. calc. for C13H17NO2S (251.35): C 62.12, H 6.82, N 5.57, S 12.76; found:
C 62.52, H 6.53, N 5.48, S 12.58.
2.7. Methyl 2-{2-Methyl-3-[methyl(phenyl)amino]-2H-azirin-2-yl}ethanoate (3a). To a soln. of 9a (2.361 g,
9.393 mmol) and 5 drops of abs. DMF in abs. CH2Cl2 (10 ml) at 08, a 2N soln. of COCl2 in toluene (6.1 ml, ca.
12.2 mmol, 1.3 equiv.) was added slowly, the ice-bath was removed, the mixture stirred for 30 min, and the sol-
vent was evaporated. The residue was dissolved in abs. THF (10 ml), 1,4-diazabicyclo[2.2.2]octane (DABCO;
1.054 g, 9.396 mmol) was added, and the soln. was stirred for 20 min at r.t. After filtration and addition of
abs. DMF (10 ml), NaN3 (1.233 g, 18.97 mmol, 2 equiv.) was added, the mixture was stirred for 6 d at r.t. and
then filtered over Celite, and the filtrate was evaporated. CC (hexane/AcOEt 2 :1) yielded 0.438 g (20%) of
3a as a yellow oil and 0.524 mg of an unknown side-product. Rf (hexane/AcOEt 1:1) 0.31; Rf (hexane/AcOEt
2 :1) 0.15. IR (neat): 3064w, 2952w, 2922w, 2135w, 1758vs, 1738vs, 1655m 1599s, 1503s, 1458w, 1437m, 1391w,
1376w, 1339w, 1284m, 1228m, 1197m, 1178w, 1147w, 1113m, 1085w, 1059w, 1044w, 1008w, 953w, 756m. ESI-
MS (MeOH): 487 (5, [2M+Na]+), 258 (15, [8a+Na]+), 256 (12), 255 (100, [M+Na]+), 233 (5, [M+1]+).
3. Reactions of 3a with PhCOSH and Z-L-Valine. 3.1. With PhCOSH: Methyl 3-Methyl-4-[methyl(phenyl)-
amino]-3-[(phenylcarbonyl)amino]-4-thioxobutanoate (10a). To a soln. of 3a (66 mg, 0.284 mmol) in CH2Cl2
(1 ml), PhCOSH (44 mg, 0.318 mmol) in CH2Cl2 (3 ml) was added, and the mixture was stirred for 1.25 h at
r.t. Prep. TLC (hexane/AcOEt 2 :1) gave 84 mg (80%) of 10a. Pale yellow crystals. M.p. 140–1418. Rf (hex-
ane/AcOEt 1:1) 0.40. IR (KBr): 3227s, 3053w, 3024w, 2991w, 2945w, 1827w, 1739vs, 1651vs, 1598w, 1577w,
1513s, 1484s, 1463vs, 1434s, 1369s, 1357s, 1323w, 1302w, 1247m, 1200s, 1146w, 1098s, 1075m, 1064m, 1027w,
1
1011w, 982w, 961w, 925w, 879m, 778m, 709s. H-NMR (CDCl3, filtered over bas. Alox): 8.14 (br. s, NH); 7.7–
7.65 (m, 2 arom. H); 7.5–7.35 (m, 3 arom. H); 7.3–7.2 (m, 5 arom. H); 3.76, 3.59 (2s, MeO, MeN); 3.72, 3.01
(AB, J=16.1, CH2); 1.86 (s, Me). 13C-NMR (CDCl3, filtered over bas. Alox): 206.2 (s, CS); 171.4, 165.4 (2s, 2
CO); ca. 147 (s, 1 arom. CN); 134.8 (s, 1 arom. C); 131.2, 129.5, 128.4, 128.2, 126.9, 125.9 (6d, 10 arom. CH);
63.4 (s, C); 51.5 (q, MeO); 43.1 (t, CH2); 26.8 (q, Me); the signal for MeN was not observed. ESI-MS
(MeOH): 395 (7), 394 (25), 393 (100, [M+Na]+), 339 (14, [MꢀMeO]+), 264 (10, [MꢀN(Ph)Me]+). Anal.
calc. for C22H22N2O3S (370.47): C 64.84, H 5.99, N 7.56, S 8.66; found: C 64.87, H 5.79, N 7.48, S 8.52.
3.2. With Z-
L
-Valine: Methyl (RS)-3-[((S)-2-{[(Benzyloxy)carbonyl]amino}-3-methyl-1-oxobutyl)amino]-3-
-valine
methyl-4-[methyl(phenyl)amino]-4-oxobutanoate (11). A soln. of 3a (231 mg, 0.994 mmol) and Z-
L
(251 mg, 0.999 mmol) in CH2Cl2 (5 ml) was stirred at r.t. for 22 h and evaporated. CC (hexane/AcOEt 2 :1 to
1:1) yielded 377 mg (78%) of 11 (ca. 2 :3 mixture of diastereoisomers). Rf (CH2Cl2/MeOH 20 :1) 0.48. Rf (hex-
ane/AcOEt 1:1) 0.16. IR (KBr): 3327w, 3034w, 2962m, 1732vs, 1641s, 1594m, 1494vs, 1453m, 1387m, 1350m,
1
1214s, 1105m, 1024m, 901w, 703m. H-NMR: 7.5–7.2 (m, 10 arom. H, NH); 5.5–5.35 (m, NH); 5.15–5.05 (m,
PhCH2O); 3.95–3.85 (m, CH(2) of Val); 3.63, 3.60 (2s, MeO); 3.5–3.4 (m, 1 H of CH2); 3.29, 3.27 (2s, MeN);
2.55–2.35 (m, 1 H of CH2); 2.1–2.0 (m, CH(3) of Val); 1.58 (s, Me(3) of Asp(2Me)); 0.91, 0.89, 0.82, 0.81
(4d, J=6.5, 5.2, 6.8, 6.9, 2 Me(4) of Val). 13C-NMR: 171.4, 171.1 (2s, CO (ester), 2 CO (amide)); 156.1 (s, CO
(urethane)); 143.6 (s, 1 arom. CN); 136.5 (s, 1 arom. C); 129.61, 129.57, 128.5, 128.4, 128.0 (5d, 10 arom.
CH); 66.8 (t, PhCH2O); 60.1 (d, CH(2) of Val); 59.6, 59.4 (2s, C(2) of Asp(2Me)); 51.6, 51.5 (2q, MeO); 41.6
(q, MeN); 40.2, 39.9 (2t, CH2 of Asp(2Me)); 31.4, 31.3 (2d, CH(3) of Val); 23.5, 19.7, 18.9, 17.0, 16.9 (5q,
Me(3) of Asp(2Me), 2 Me(4) of Val). ESI-MS (MeOH): 522 (100, [M+K]+), 511 (8), 507 (30), 506 (100,
[M+Na]+), 377 (6, [MꢀN(Me)Ph]+). Anal. calc. for C26H33N3O6 ·H2O (487.16): C 64.10, H 6.91, N 8.63;
found: C 64.10, H 6.81, N 8.52.
4. Deprotection of the Dipeptide 11. 4.1. Cleavage of the Z Group: Methyl (RS)-3-[(S)-2-Amino-3-methyl-1-
oxobutyl)amino}-3-methyl-4-[methyl(phenyl)amino]-4-oxobutanoate (12). A soln. of 11 (99 mg, 0.205 mmol)
and a small amount of Pd/C (10% on activated charcoal) in MeOH (5 ml) was treated with H2 for 3 h at r.t.
The mixture was filtered over Celite, and the filtrate was evaporated. Prep. TLC (CH2Cl2/MeOH 10 :1) gave
55 mg (76%) of 12. Colorless oil. Rf (CH2Cl2/MeOH 10 :1) 0.30. IR (neat): 3320m, 2958s, 1737s, 1644vs,
1593s, 1494vs, 1449m, 1350m, 1210m, 1110w, 1075w, 1016w, 891w, 777w, 706m. ESI-MS (MeOH, NaI): 386
(26), 373 (21), 372 (100, [M+Na]+), 350 (10, [M+1]+), 257 (2), 243 (8, [MꢀN(Me)Ph]+), 215 (2, [Mꢀ
CON(Me)Ph]+), 194 (5). Anal. calc. for C18H27N3O4 ·0.25 H2O (353.94): C 61.08, H 7.83, N 11.83; found: C
61.09, H 7.26, N 11.54.
4.2. Hydrolysis of the Ester Group: (RS)-3-[((S)-2-{[(Benzyloxy)carbonyl]amino}-3-methyl-1-oxobutyl)-
amino]-3-methyl-4-[methyl(phenyl)amino]-4-oxobutanoic Acid (13). To a soln. of 11 (91 mg, 0.188 mmol) in
2.5 ml of a 3 :1:1 mixture of THF, MeOH, and H2O, LiOH·H2O (24 mg, 0.572 mmol, 3 equiv.) was added.

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The mixture was stirred at r.t. for 1 h, and then neutralized with 6
N
HCl. The aq. layer was extracted with CH2Cl2,
dried (MgSO4), and evaporated. Prep. TLC (CH2Cl2/MeOH 10 :1) yielded 82 mg (93%) of 13 (ca. 2 :3 mixture
of diastereoisomers). Colorless foam. M.p. 68–718. Rf (CH2Cl2/MeOH 10 :1) 0.26. IR (KBr): 3314w, 3064w,
1
2965w, 1723vs, 1638s, 1592m, 1495s, 1453m, 1390m, 1231m, 1108w, 1026w, 907w, 774w, 739w, 700m. H-NMR:
7.5–7.2 (m, 10 arom. H, NH); 5.7–5.55 (m, NH of Val); 5.15–5.1 (m, PhCH2O); 4.0–3.95, 3.9–3.85 (2m,
CH(2) of Val); 3.65–3.35 (m, 1 H of CH2); 3.24 (s, MeN); 2.8–2.45 (m, 1 H of CH2); 2.1–1.95 (m, CH(3) of
Val); 1.59 (s, Me(3) of Asp(2Me)); 0.89, 0.82 (2d, J=6.8, 6.7, 2 Me(4) of Val). 13C-NMR: 173.1, 172.7, ca. 170
(3s, 3 CO); 156.4 (s, CO (urethane)); ca. 143 (s, 1 arom. CN); ca. 136.5 (s, 1 arom. C); 129.6, 128.4, 128.1,
127.94, 127.88, 127.6 (6d, 10 arom. CH); 66.9 (t, PhCH2O); 59.2 (d, CH(2) of Val); ca. 57 (s, C(2) of
Asp(2Me)); ca. 42 (t, CH2 of Asp(2Me)); 41.4 (q, MeN); 31.5, 31.0 (2d, CH(3) of Val); 23.4, 19.2, 17.2, 17.0
(4q, Me(3) of Asp(2Me), 2 Me(4) of Val). ESI-MS (MeOH): 508 (5, [M+K]+), 494 (5), 493 (29), 492 (100,
[M+Na]+), 385 (4). Anal. calc. for C25H31N3O6 ·0.33 H2O (475.54): C 63.14, H 6.71, N 8.84; found: C 63.09, H
6.75, N 8.51.
4.3. Hydrolysis of the Amide Group: (RS)-2-[((S)-2-{[(Benzyloxy)carbonyl]amino}-3-methyl-1-oxobutyl)-
amino]-4-methoxy-2-methyl-4-oxobutanoic Acid (14). A soln. of 11 (150 mg, 0.310 mmol) in toluene (30 ml)
was heated to 1158. For 20 min, HCl (g) was bubbled through the mixture. During this procedure, the temp.
fell to 100–958. The remaining HCl (g) was removed by bubbling N2 through the soln. for 25 min. The mixture
was transferred into another flask with hexane, and crystals of N-methylanilide chloride precipitated, they were
filtered, and the resulting soln. was evaporated. This crude material (100 mg) was dissolved in 2 ml of THF and
2 ml of H2O, and 1 drop of 6N HCl was added. After stirring at 508 for 2.5 h, the hydrolysis was complete. Brine
was added, and the soln. was extracted with AcOEt (3×). The combined org. layers were dried (MgSO4) and
evaporated. Prep. TLC (CH2Cl2/MeOH 10 :1) gave 52 mg (43%) of pure 14 (ca. 2 :3 mixture of diastereoisom-
ers). M.p. 145–1468. Rf (CH2Cl2/MeOH 10 :1) 0.18. IR (KBr): 3338m, 3066w, 3035w, 2963m, 1727vs, 1659s, 1520s,
1455m, 1390w, 1375w, 1321w, 1294m, 1121w, 1095w, 1027w, 1014m, 908w, 883w, 813w, 778w, 734w. 1H-NMR: 7.54
(s, NH of Asp(2Me)); 7.35–7.3 (m, 5 arom. H); 5.78 (d, J=9.2, NH of Val); 5.12 (br., PhCH2O); 4.2–4.15 (m,
CH(2) of Val); 3.7–3.5 (m, 1 H of CH2, MeO); 3.05–2.9 (m, 1 H of CH2); 2.1–2.0 (m, CH(3) of Val); 1.69, 1.67
(2s, Me(3) of Asp(2Me)); 0.94, 0.90 (2d, J=6.9, 7.1, 2 Me(4) of Val). 13C-NMR: 175.3, 175.0, 171.2, 171.0 (4s, 3
CO); 156.9 (s, CO (urethane)); 136.0 (s, 1 arom. C); 128.4, 128.1, 127.9 (3d, 5 arom. CH); 67.1 (t, PhCH2O); 59.7
(d, CH(2) of Val); 57.8 (s, C(2) of Asp(2Me)); 51.7, 51.6 (2q, MeO); 39.9, 39.6 (2t, CH2 of Asp(2Me)); 31.9 (d,
CH(3) of Val); 29.1, 22.7, 19.0, 18.8, 17.4 (5q, Me(3) of Asp(2Me), 2 Me(4) of Val). ESI-MS (MeOH): 439 (10,
[M+2 Naꢀ1]+), 419 (5), 418 (24), 417 (100, [M+Na]+), 274 (4). Anal. calc. for C19H26N2O7 ·0.25 H2O (398.92):
C 57.20, H 6.70, N 7.02; found: C 57.20, H 6.53, N 6.66.
5. Synthesis of 2-Methylaspartate Synthons with a Chiral Group in the Side Chain. 5.1. 1-(Naphthalen-1-
yl)ethyl as Chiral Group. 5.1.1. 1-(Naphthalen-1-yl)ethyl 3-Methyl-4-[methyl(phenyl)amino]-4-oxobutanoate
(8b; ca. 2 :1 mixture of two diastereoisomers). To a suspension of 7 (1.503 g, 6.793 mmol) in CH2Cl2 (20 ml),
DCC (1.539 g, 7.459 mmol, 1.1 equiv.), (RS)-1-(Naphthalen-1-yl)ethanol (1.286 g, 7.467 mmol, 1.1 equiv.), and
4-(pyrrolidin-1-yl)pyridine (0.105 g, 0.71 mmol, 0.1 equiv.) were added. The mixture was stirred for 2 h, the
urea was removed by filtration, and the filtrate was washed with H2O (3×), 5% AcOH (3×), and H2O (2×),
dried (MgSO4), and evaporated. CC (CH2Cl2/MeOH 50 :1) yielded 2.247 g (88%) of 8b as a colorless oil. Rf
(hexane/AcOEt 1 :1) 0.34. IR (neat): 3059w, 2979w, 2934w, 1732vs, 1655vs, 1596s, 1496s, 1462m, 1421m,
1391m, 1357m, 1267m, 1185s, 1116m, 1090w, 1071m, 1038m, 1005w, 965w, 933w, 860w, 801m, 777s, 736w, 701s.
1H-NMR: 8.05–8.0 (m, 1 arom. H); 7.9–7.75 (m, 2 arom. H); 7.6–7.4 (m, 4 arom. H); 7.35–7.15 (m, 5 arom.
H); 6.62 (q, J=6.4, CHO); 3.20, 3.18 (2s, MeN); 3.05–2.85 (m, 2 H of CH2CH); 2.35–2.25 (m, 1 H of CH2CH);
1.69, 1.67 (2d, J=6.5, Me); 1.00, 0.96 (2d, J=6.3, 6.8, Me). 13C-NMR: 174.8, 171.4 (2s, 2 CO); 143.8 (s, 1 arom.
CN); 137.2, 133.7, 130.1 (3s, 3 arom. C); 129.5, 128.7, 128.2, 127.6, 127.5, 126.2, 125.5, 125.3, 123.1 (9d, 12 arom.
CH); 69.3 (d, CHO); 38.5, 38.4 (2t, CH2); 37.4 (q, MeN); 33.0, 32.8 (2d, CH); 21.6, 17.9, 17.8 (3q, 2 Me). ESI-MS
(MeOH): 400 (4), 399 (26), 398 (100, [M+Na]+), 244 (4), 204 (8, [MꢀNaphthEtO]+), 155 (2, [NaphthEt]+).
Anal. calc. for C24H25NO3 (375.47): C 76.77, H 6.71, N 3.73; found: C 76.52, H 6.49, N 3.51.
5.1.2. 1-(Naphthalen-1-yl)ethyl 3-Methyl-4-[methyl(phenyl)amino]-4-thioxobutanoate (9b; ca. 3 :2 mixture
of two diastereoisomers). To a soln. of 8b (1.783 g, 4.75 mmol) in toluene (5 ml), Lawesson reagent (1.16 g,
2.87 mmol, 1.2 equiv.) was added, and the mixture was stirred for 80 min at 1308 and evaporated. Consecutive
CC with hexane/AcOEt 5 :1 and hexane/AcOEt 10 :1 yielded 1.721 g (93%) of 9b as a colorless solid. M.p. 70–
728. Rf (hexane/AcOEt 2 :1) 0.41. IR (neat): 3050w, 2975w, 2929w, 2869w, 1731vs, 1595w, 1493s, 1472m, 1386s,
1355s, 1337m, 1278m, 1224w, 1190s, 1109m, 1090m, 1072m, 1034m, 1004m, 952w, 920w, 803m, 778s, 737w,
701s. 1H-NMR: 8.05–8.0 (m, 1 arom. H); 7.9–7.8 (m, 2 arom. H); 7.6–7.4 (m, 4 arom. H); 7.35–7.3 (m, 3
arom. H); 7.15–7.1 (m, 2 arom. H); 6.65–6.55 (m, CHO); 3.62 (s, MeN); 3.35–3.2 (m, 2 H of CH2CH); 2.5–

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2.35 (m, 1 H of CH2CH); 1.68, 1.66 (2d, J=6.6, Me); 1.07, 1.03 (2d, J=6.5, 6.6, Me). 13C-NMR: 209.3 (s, CS);
171.3 (s, CO); 145.3 (s, 1 arom. CN); 137.4, 137.2, 133.7, 130.2 (4s, 3 arom. C); 129.9, 128.7, 128.3, 128.2,
126.2, 126.2, 125.5, 125.3, 125.2, 123.3, 123.2, 123.1, 123.0 (13d, 12 arom. CH); 69.2 (d, CHO); 45.6 (q, MeN);
42.22, 42.15 (2t, CH2); 39.7, 39.6 (2d, CH); 21.44, 21.36, 21.3 (3q, 2 Me). ESI-MS (MeOH): 430 (23,
[M+K]+), 416 (8), 415 (29), 414 (100, [M+Na]+), 398 (12, [8b+Na]+), 155 (23, [NaphthEt]+). Anal. calc. for
C24H25NO2S·0.5 H2O (400.54): C 71.97, H 6.54, N 3.50, S 8.01; found: C 72.17, H 6.13, N 3.36, S 7.29.
5.1.3. 1-(Naphthalen-1-yl)ethyl 2-[2-Methyl-3-[methyl(phenyl)amino]-2H-azirin-2-yl]ethanoate (3b; mix-
ture of two diastereoisomers). To a soln. of 9b (1.576 g, 4.025 mmol) and 5 drops of abs. DMF in abs. CH2Cl2
(7 ml) at 08, a 2N soln. of COCl2 in toluene (2.6 ml, ca. 5.2 mmol, 1.3 equiv.) was added slowly, the ice bath
was removed, the mixture was stirred for 30 min, and the solvent was evaporated. The residue was dissolved
in abs. THF (6 ml), DABCO (0.455 g, 4.056 mmol) was added, and the soln. was stirred for 20 min at r.t.
After filtration and addition of abs. DMF (6 ml), NaN3 (0.528 g, 8.123 mmol, 2 equiv.) was added, the mixture
was stirred for 45 h at r.t. and then filtered over Celite, and the filtrate was evaporated. CC (hexane/AcOEt 5 :1
to 1:1) yielded 0.307 g (20%) of 3b as a pale yellow oil and 0.299 mg of an unknown side product. Rf (hexane/
AcOEt 2 :1) 0.21. IR (neat): 3049w, 2979w, 2258w, 2107w, 1757vs, 1656w 1599s, 1503vs, 1451m, 1374m, 1239s,
1170s, 1112s, 1090m, 1044s, 1006w, 968w, 941w, 860w, 801s, 779s, 755s, 692m. ESI-MS (MeOH+NaI): 455 (8),
396 (27), 395 (100, [M+1]+).
5.1.4. Reaction of 3b with PhCOSH: 1-(Naphthalen-1-yl)ethyl 3-Methyl-4-[methyl(phenyl)amino]-3-[(phe-
nylcarbonyl)amino]-4-thioxobutanoate (10b; ca. 1 :1 mixture of two diastereoisomers). To 3b (30 mg, 0.081
mmol), PhCOSH (12 mg, 0.087 mmol) in CH2Cl2 (3 ml) was added, and the mixture was stirred for 11 h at
r.t. Prep. TLC (hexane/AcOEt 2 :1) gave 40 mg (97%) of 10b as a mixture of diastereoisomers. Colorless
foam. Rf (hexane/AcOEt 1:1) 0.42. IR (KBr): 3387w, 3227w, 3058w, 2979w, 2929w, 1730s, 1658s, 1595w,
1579w, 1511s, 1489vs, 1463s, 1368vs, 1248m, 1240m, 1205m, 1171m, 1143w, 1104s, 1069s, 1043m, 1004w, 930w,
874w, 800m, 777s, 706s. 1H-NMR (CDCl3, filtered over bas. Alox): 8.54, 8.13 (2 br. s, NH); 8.05–7.95 (m, 1
arom. H); 7.85–7.8 (m, 1 arom. H); 7.75–7.65 (m, 2 arom. H); 7.6–7.55 (m, 1 arom. H); 7.5–7.4 (m, 4 arom.
H); 7.35–7.1 (m, 8 arom. H); 6.65–6.55 (m, CHO); 3.92, 3.80 (2d, J=16.2, 1 H of CH2); 3.70, 3.68 (2s,
MeN); 3.09, 2.88 (2d, J=16.0, 16.3, 1 H of CH2); 1.86, 1.83 (2s, Me(3)); 1.60, 1.57 (2s, Me). 13C-NMR
(CDCl3, filtered over bas. Alox): 206.2 (s, CS); 170.0, 165.2, 165.1 (3s, 2 CO); 137.0, 136.8, 134.9, 134.7, 133.6,
129.9 (6s, 5 arom. C); 131.1, 129.5, 128.8, 128.4, 128.3, 128.2, 126.8, 126.2, 126.0, 125.5, 125.2, 123.5, 123.1,
122.8 (14d, 17 arom. CH); 69.9, 69.5 (2d, CHO); 63.5, 63.3 (2s, C); ca. 52 (q, MeN); 43.6, 42.9 (2t, CH2); 26.9,
26.6, 21.8, 21.4 (4q, Me). ESI-MS (H2O/MeCN 1 :1+0.1% HCOOH): 511 (61, [M+1]+), 357 (100, [Mꢀ
NaphthEt]+), 155 (17, [NaphthEt]+). Anal. calc. for C31H30N2O3S·0.2 H2O (475.54): C 72.40, H 5.96, N 5.45, S
6.26; found: C 72.16, H 6.06, N 5.10, S 5.87.
5.2. Menthyl (=5-Methyl-2-(1-methylethyl)cyclohexyl) as Chiral Group. 5.2.1. 5-Methyl-2-(1-methylethyl)-
cyclohexyl 3-Methyl-4-[methyl(phenyl)amino]-4-oxobutanoate (8c; mixture of two diastereoisomers). To a sus-
pension of 7 (1.507 g, 6.811 mmol) in CH2Cl2 (20 ml), DCC (1.549 g, 7.507 mmol, 1.1 equiv.), (ꢀ)-Menthol (1.605
g, 10.27 mmol, 1.5 equiv.), and 4-(pyrrolidin-1-yl)pyridine (0.108 g, 0.729 mmol, 0.1 equiv.) were added. The
mixture was stirred for 3 h, the urea was removed by filtration, and the filtrate was washed with H2O (3×),
5% AcOH (3×), and H2O (3×), dried (MgSO4), and evaporated. CC (hexane/AcOEt 5 :1) yielded 2.099 g
(86%) of 8c. Rf (hexane/AcOEt 1:1) 0.52; Rf (hexane/AcOEt 5 :1) 0.14. IR (neat): 2956s, 2870m, 1728s,
1660vs, 1596m, 1497s, 1456m, 1421w, 1389m, 1269w, 1191s, 1148w, 1117w, 1074w, 1037w, 1010w, 988w, 916w,
844w, 774w, 701m. 1H-NMR: 7.45–7.3 (m, 5 arom. H); 4.64 (td, J=10.9, 4.3, CHO); 3.25 (s, MeN); 2.9–2.8
(m, CH2CO); 2.2–2.15 (m, 1 H); 1.95–1.8 (m, 2 H); 1.7–1.65 (m, 2 H); 1.5–1.3 (m, 2 H); 1.1–0.85 (m, 3 H, 2
Me); 0.99 (d, J=6.7, Me); 0.74 (d, J=6.9, Me). 13C-NMR: 175.1, 171.8 (2s, 2 CO); 143.9 (s, 1 arom. C); 129.5,
127.6, 127.5 (3d, 5 arom. CH); 74.1 (d, CHO); 47.0 (d, CHCO); 40.8, 38.5 (2t, 2 CH2); 37.5 (q, MeN); 34.2 (t,
CH2); 33.0, 32.8, 31.3, 26.0 (4d, 3 CH); 23.4 (t, CH2); 21.9, 20.6, 17.7, 16.2 (4q, 4 Me). ESI-MS (MeOH): 742
(12), 741 (33, [2M+Na]+), 383 (25), 382 (100, [M+Na]+), 360 (2, [M+1]+). Anal. calc. for C22H33NO3 ·0.33
H2O (365.50): C 72.29, H 9.28, N 3.83; found: C 72.47, H 8.73, N 3.72.
5.2.2. 5-Methyl-2-(1-methylethyl)cyclohexyl 3-Methyl-4-[methyl(phenyl)amino]-4-thioxobutanoate (9c). To
a soln. of 8c (1.668 g, 4.640 mmol) in toluene (5 ml), Lawesson reagent (1.13 g, 2.79 mmol, 1.2 equiv.) was
added, and the mixture was stirred for 30 min at 1308 and evaporated. CC (hexane/AcOEt 10 :1) yielded
1.681 g (96%) of 9c (ca. 4 :3 mixture of two diastereoisomers). Colorless solid. Rf (CH2Cl2) 0.43. IR (neat):
3064w, 2955s, 2928s, 2869m, 1726vs, 1595w, 1493s, 1469s, 1454s, 1385s, 1345m, 1279m, 1230w, 1193s, 1152w,
1135w, 1110m, 1079w, 1057w, 1036w, 1010w, 1001w, 983w, 941w, 917w, 877w, 844w, 809w, 773w, 700m. 1H-
NMR: 7.5–7.2 (m, 5 arom. H); 4.65–4.6 (m, CHO); 3.72, 3.70 (2s, MeN); 3.25–3.1 (m, CH2CO); 2.4–2.3 (m,
CHCS); 1.95–1.75 (m, 2 H); 1.7–1.6 (m, 2 H); 1.45–1.25 (m, 3 H); 1.05–1.0 (m, 2 H, 1 Me); 0.95–0.85 (m, 2

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Me); 0.73, 0.71 (2d, J=7.1, 7.6, MeCHCS). 13C-NMR: 209.6 (s, CS); 171.7 (s, CO); 145.5 (s, 1 arom. C); 129.7,
128.3 (2d, 5 arom. CH); 74.0 (d, CHO); 47.0, 46.9 (2d, CHCS); 45.6 (q, MeN); 42.3, 42.0, 40.8 (3t, CH2CO, CH2);
39.7, 39.6, 31.3, 26.1, 25.9 (5d, 3 CH); 34.2, 23.3 (2t, 2 CH2); 21.9, 21.2, 21.1, 20.6, 16.2 (5q, 4 Me). ESI-MS
(MeOH): 400 (8), 399 (25), 398 (100, [M+Na]+), 260 (6), 238 (3), 220 (3, [MꢀMenthol]+). Anal. calc. for
C22H33NO2S (375.58): C 70.36, H 8.86, N 3.73, S 8.54; found: C 70.34, H 8.68, N 3.53, S 8.37.
5.2.3. 5-Methyl-2-(1-methylethyl)cyclohexyl 2-{2-Methyl-3-[methyl(phenyl)amino]-2H-azirin-2-yl}etha-
noate (3c). To a soln. of 9c (1.535 g, 4.087 mmol) and 5 drops of abs. DMF in abs. CH2Cl2 (7 ml) at 08, a 2
N
soln. of COCl2 in toluene (2.7 ml, ca. 5.4 mmol, 1.3 equiv.) was added slowly, the ice bath was removed, the mix-
ture was stirred for 20 min, and the solvent was evaporated. The residue was dissolved in abs. THF (6 ml),
DABCO (0.459 g, 4.092 mmol) was added, and the soln. was stirred for 20 min at r.t. After filtration and addition
of abs. DMF (6 ml), NaN3 (0.533 g, 8.2 mmol, 2 equiv.) was added, the mixture was stirred for 4 d at r.t. and then
filtered over Celite, and the filtrate was evaporated. CC (hexane/AcOEt 10 :1) yielded 0.362 g (24%) of 3c as
pale yellow oil and 0.350 mg of an unknown side product. Rf (hexane/AcOEt 2 :1) 0.38. IR (neat): 2955vs,
2223m, 2104w, 1758vs, 1725s, 1656w 1599s, 1502vs, 1457m, 1283w, 1148w, 1113w, 1039w, 987w, 753m, 691m.
1H-NMR: 7.55–7.05 (m, 5 arom. H); 4.6–4.45 (m, CHO); 3.45–3.1 (m, MeN); 3.0–2.95, 2.75–2.55 (2m,
CH2CO); 1.85–1.75, 1.65–1.55 (2m, 3 CH2); 1.35–1.15 (m, 2 CH, MeC(2)); 1.05–0.6 (m, CH, 3 Me). ESI-MS
(MeOH+MeOH): 379 (100, [M+1]+).
5.2.4. Reaction of 3c with PhCOSH: 5-Methyl-2-(1-methylethyl)cyclohexyl 3-Methyl-4-[methyl(phenyl)-
amino]-3-[(phenylcarbonyl)amino]-4-thioxobutanoate (10c; ca. 2 :1 mixture of two diastereoisomers). To a
soln. of 3c (75 mg, 0.210 mmol) in CH2Cl2 (1 ml), PhCOSH (35 mg, 0.253 mmol) in CH2Cl2 (3 ml) was added,
and the mixture was stirred for 24 h at r.t. Prep. TLC (hexane/AcOEt 2 :1) gave 86 mg (83%) of 10c. Rf (hex-
ane/AcOEt 2 :1) 0.36. IR (neat): 3375m, 3228m, 3062m, 2955vs, 2870s, 1722s, 1661s, 1594w, 1581w, 1516s, 1490s,
1367s, 1208m, 1148m, 1105m, 1075m, 1028w, 1005w, 988w, 923w, 876w, 844w, 800w, 774w, 706m. 1H-NMR: 8.31
(br. s, NH); 7.67 (d, J=7.3, 2 arom. H); 7.5–7.35 (m, 3 arom. H); 7.3–7.25 (m, 5 arom. H); 4.65–4.55 (m, CHO);
3.77, 3.76 (2s, MeN); 6.67 (dd, J=15.8, 2.9, 1 H of CH2CO); 2.99, 2.93 (2d, J=17.6, 16.4, 1 H of CH2CO); 1.87 (s,
Me(3) of Asp(2Me)); 1.75–1.55 (m, 4 H); 1.45–1.2 (m, 2 H); 1.0–0.8 (m, 3 H, 1 Me); 0.76, 0.70 (2d, J=7.0, Me);
0.61, 0.56 (2d, J=7.0, 6.9, Me). 13C-NMR: 206.3 (s, CS); 170.6, 165.0 (2s, 2 CO); ca. 147 (s, 1 arom. C); 134.8 (s, 1
arom. C); 131.2, 129.5, 128.3, 128.2, 126.9, 126.0 (6d, 10 arom. CH); 74.6 (d, CHO); 63.4 (s, C(2) of Asp(2Me));
ca. 52 (q, MeN); 46.6 (d, CH); 43.6, 40.7, 40.6, 34.0 (4t, 3 CH2); 31.2 (d, CH); 26.7 (q, Me(3) of Asp(2Me)); 25.8
(d, CH); 23.1, 23.0 (2t, 2 CH2); 21.8, 20.5, 20.4, 15.9, 15.7 (5q, 3 Me). ESI-MS (MeOH): 519 (11), 518 (27), 517
(100, [M+Na]+). Anal. calc. for C29H38N2O3S·0.2 H2O (475.54): C 69.90, H 7.68, N 5.62, S 6.42; found: C 69.86,
H 7.04, N 5.43, S 5.79.
REFERENCES
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Received September 5, 2005