A new 2H-azirin-3-amine as a synthon for α-methyl glutamate

Article abstract of DOI:10.1002/hlca.200490226

The synthesis of a novel 2,2-disubstituted 2H-azirin-3-amine 10 as a building block for racemic Glu(2Me) is described. This synthon contains an ester group in the side chain. The reaction of 10 with thiobenzoic S-acid and the amino acid Z-Val-OH yielded the racemic monothiodiamide 17 and the dipeptide 18 as a mixture of diastereoisomers, respectively (Scheme 2). From 18, each of the protecting groups was removed selectively (Scheme 3).

Full text of DOI:10.1002/hlca.200490226

Helvetica Chimica Acta Vol. 87 (2004)
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A New 2H-Azirin-3-amine as a Synthon for a-Methyl Glutamate
by Florentine M. Hilty1), Kathrin A. Brun, and Heinz Heimgartner*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
Dedicated to Professor Peter Stanetty on the occasion of his 60th birthday
The synthesis of a novel 2,2-disubstituted 2H-azirin-3-amine 10 as a building block for racemic Glu(2Me) is
described. This synthon contains an ester group in the side chain. The reaction of 10 with thiobenzoic S-acid and
the amino acid Z-Val-OH yielded the racemic monothiodiamide 17 and the dipeptide 18 as a mixture of
diastereoisomers, respectively (Scheme 2). From 18, each of the protecting groups was removed selectively
(Scheme 3).
1. Introduction. In the last few years, we have shown that 2H-azirin-3-amines (−3-
amino-2H-azirines×) are versatile synthons for 2,2-disubstituted glycines (a,a-disub-
stituted a-amino acids) in peptide synthesis. A useful method for the introduction of
such amino acids into peptides is the so-called −azirine/oxazolone method× [1], which
proved to be a convenient preparative access to such peptides. This strategy has been
extensively applied in the synthesis of linear oligopeptides [2 8], endothiopeptides
[9 13], conformationally restricted cyclic peptides [14 17], and cyclic depsipeptides
[17 26] containing 2,2-disubstituted glycines.
Recently, enantiomerically pure 2H-azirin-3-amines became available, such as the
isovaline (Iva) synthons 1 and 2 [4][27], the Val(2Me), Leu(2Me), and the
Ala(2cPent) synthons 3, 4, and 5 [27], the Phe(2Me) synthons 6 and 7 [27][28], as
well as the synthons for Tyr(2Me) 8 and Dopa(2Me) 9 [29]. The latter two contain
protected phenolic hydroxy groups, and are the first examples of enantiomerically pure
building blocks with a functionalized side chain. All of these building blocks can be
used for the synthesis of stereochemically pure peptides.
In the present paper, we describe the synthesis of a novel building block 10 for
Glu(2Me), which contains an ester group as a new functional group in the side chain,
and its applicability in the synthesis of model peptides. This racemic synthon is a first
step towards the expansion of our library of enantiomerically pure 2H-azirin-3-amines.
2. Results.- 2.1. Synthesis of the 2H-Azirine 10. The 2H-azirin-3-amine 10, i.e., a
synthon for 2-methylglutamate (Glu(2Me)), was prepared in gram quantity according
to Scheme 1.
The synthesis started from freshly distilled 3,4,5,6-tetrahydro-2H-pyran-2-one (11),
which is commercially available. Methylation of 11 in a-position to the CˆO group by
deprotonation with lithium diisopropylamide (LDA), followed by treatment with MeI,
yielded 12. Instead of hexamethylphosphoric triamide (HMPA), 1,3-dimethylimida-
1
)
Part of the diploma thesis of F. M. H., Universit‰t Z¸rich, 2003.
¹ 2004 Verlag Helvetica Chimica Acta AG, Z¸rich

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Helvetica Chimica Acta Vol. 87 (2004)
zolidin-2-one (DMI), which is of lower toxicological risk, was used as an additive [30].
Although Li et al. used lithiumhexamethyldisilazanide as a base for similar reactions
[30], we preferred LDA in combination with DMI. Therefore, the yield (44%) was
lower than reported (70%) [31].
Hydroxy amide 13 was synthesized directly from 12 by the reaction with N-
methylaniline in the presence of AlCl3 at room temperature. Due to its carcinogenic
properties, the recommended solvent, 1,2-dichlorethane [32], was replaced with
CH2Cl2. The yield in CH2Cl2 (81%) is only slightly lower than in 1,2-dichlorethane
(88%).
In the next step, the OH group of 13 was oxidized with ruthenium trichloride
hydrate (RuCl3 ¥ H2O) and sodium metaperiodate (NaIO4) to form the carboxylic acid
14. This method, in which ruthenium tetroxide (RuO4) is the active species [33], has the
advantage that RuCl3 ¥ H2O can be used in catalytic amounts, and the stochiometric
oxidazing agent is NaIO4. The task of NaIO4 is to re-oxidize the reduced forms of the
Ru complex to RuO4. As a solvent, a mixture of CCl4, MeCN, and H2O in the ratio
2 :2 :3 was used [34] in a first attempt. As CCl4 is toxic and ecologically undesirable, it
was replaced with the same quantity of AcOEt [35]. As a result, the yield turned out to
be lower (73%) than with CCl4 (84%).
Methylation of 14 with CH2N2 gave the ester 15 in quantitative yield. The synthesis
of 10 by the method of Villalgordo and Heimgartner [36][37] was unsuccessful, even
though 15 is an N-alkyl-N-phenyl amide (Scheme 1). It is assumed that deprotonation

Helvetica Chimica Acta Vol. 87 (2004)
2541
Scheme 1
occurred in a-position to the ester group instead of the a-position to the amide group.
According to another well-established method, the amide 15 was first converted to the
corresponding thioamide 16 with Lawesson reagent in toluene at 1308 in 93% yield.
Finally, the synthesis of 10 was achieved by consecutive treatment of 16 with 2n COCl2
solution in CH2Cl2, deprotonation with 1,4-diazabicyclo[2.2.2]octane (DABCO) in
THF, and treatment with NaN3 in THF/DMF, in 90% yield.
2.2. Reactions of 10 with PhCOSH and Z-l-Valine. To demonstrate that the new
amino acid synthon 10 shows analogous chemical behavior as the already known 2H-
azirin-3-amines (cf. [1]), it was reacted with PhCOSH [27 29][38][39] (cf. [11][12]) to
give the monothiodiamide 17 in 99% yield (Scheme 2). The use of 10 as a synthon in
peptide synthesis was shown by the reaction with Z-l-valine (Scheme 2), which led to
the dipeptideamide 18 in 96% yield as a mixture of diastereoisomers. All attempts to
separate the diastereoisomers failed.
2.3. Selective Cleavage of the Protecting Groups in Dipeptide 18. With the aim of
proving the usefulness of the described coupling reaction, each of the protecting groups
of the dipeptide 18 was removed selectively under standard or slightly modified
conditions (Scheme 3). For example, the Z group was removed by hydrogenolysis to
give the N-deprotected dipeptide 19 in quantitative yield.

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Scheme 2
Scheme 3
Hydrolysis of the C-terminal amide group of 18 under standard conditions (3n HCl
in THF/H2O 1:1) afforded a mixture of starting material (40%), and the dipeptides 20
(27%) and 21 (14%) with a deprotected carboxy group in the side chain and main
chain, respectively. As the cleavage of the methyl ester in the side chain occurs so easily,
it was assumed that the reaction follows the mechanism presented in Scheme 4: under

Helvetica Chimica Acta Vol. 87 (2004)
2543
the reaction conditions, the tetrahydro-1,3-oxazepin-7-one 22 could be formed instead
of the oxazolone 23. Opening of the ring of 22 with H2O to form 20 is expected to
proceed smoothly.
Scheme 4
Another possibility for the hydrolysis of dipeptide amides is the treatment with HCl
gas in toluene, followed by hydrolysis with H2O. Thereby, the oxazolone 23 is formed as
an intermediate (Scheme 3). After treatment of 18 with HCl gas for 13 min in toluene
at 1008, oxazolone 23 was isolated in 71% yield after CC. In addition, 22% of starting
material 18 was recovered, but no acid 21 was obtained. The oxazolone 23 was not
hydrolized by stirring in H2O at room temperature overnight. Only after addition of
one drop of 6n HCl and stirring at 508 for several hours, was the acid 21 obtained in
71% yield. The direct conversion of 18 to 21, without purification of the intermediate
oxazolone, gave the acid 21 in an overall yield of 70%, and 15% of the starting material
18 and 12% of the oxazolone 23 were isolated from the reaction mixture.
Finally, the selective hydrolysis of the methyl ester in 18 was achieved under
standard conditions with LiOH in THF/MeOH/H2O 3 :1:1 in quantitative yield
(Scheme 3).
3. Conclusions. The novel racemic 2,2-disubstituted 2H-azirin-3-amine 10 was
prepared. This new synthon for a-methylglutamate was successfully reacted with Z-
protected valine and thereby incorporated into a model dipeptide. Each protecting
group could be removed selectively in good-to-excellent yield. Therefore, this synthon
can easily be used in peptide synthesis as a building block for Glu(2Me). The synthesis
of this racemic synthon is a first step towards the corresponding enantiomerically pure
2H-azirin-3-amine.
We thank the analytical departments of our institute for NMR and mass spectra, and for elemental analyses.
Financial support of the Swiss National Science Foundation, F. Hoffmann-La Roche AG, Basel, the Stiftung f¸r
wissenschaftliche Forschung an der Universit‰t Z¸rich, and the Prof. Dr. Hans E. Schmid-Stiftung is gratefully
acknowledged.
Experimental Part
1
1. General. See [27]. IR Spectra: Perkin-Elmer spectrometer. H- (600 MHz) and 13C-NMR (150.9 MHz)
spectra: Bruker AMX-600 instrument.
2. Preparation of the a-Methylglutamate Synthon 10. 2.1. 3,4,5,6-Tetrahydro-3-methylpyran-2(2H)-one (12).
A soln. of (i-Pr)2NH (15 ml, 106 mmol) in abs. THF (40 ml) was cooled to 08; 1.6m BuLi in hexane (67 ml,
107 mmol) was added, and the mixture was stirred for 30 min, cooled to À 658, and freshly distilled 3,4,5,6-
tetrahydro-2H-pyran-2-one (11; 10.060 g, 100 mmol) was added at À 658 to À 608. After stirring for 1 h, 1,3-

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dimethylimidazolidin-2-one (DMI; 14 ml, 129 mmol) was added at À 658, the mixture was stirred for 20 min,
and MeI (7 ml, 112 mmol) was added at À 658. After further stirring for 4 h at À 658, the reaction was
terminated by addition of a very small amount of H2O and AcOH. The org. layer was separated, and the aq.
layer was extracted with AcOEt. The combined org. layers were dried (Na2SO4) and evaporated. CC (hexane/
AcOEt 3 :2) yielded 4.098g (44%) of 12. Colorless oil. Rf (hexane/AcOEt 3 :2) 0.43. IR (neat): 2939m, 1738s,
1462m, 1380m, 1243m, 1156m, 1117m, 1085m, 1029m, 1014m, 944w, 905w, 752w. 1H-NMR: 4.40 4.25 (m,
CH2O); 2.65 2.55 (m, MeCH); 2.2 2.05 (m, 1 H of MeCHCH2); 1.95 1.85 (m, CH2); 1.6 1.5 (m, 1 H of
MeCHCH2); 1.24 (d, J ˆ 6.9, Me). 13C-NMR: 175.2 (s, CO); 68.3 (t, CH2O); 34.2 (d, CH); 26.7, 21.7 (2t, 2 CH2);
16.3 (q, Me).
2.2. 5-Hydroxy-2,N-dimethyl-N-phenylpentanamide (13). 2.2.1. Procedure 1. To a soln. of AlCl3 (1.124 g,
8.43 mmol, 2 equiv.) in 1,2-dichlorethane (3 ml), N-methylaniline (1.75 ml, 16.1 mmol, 3.8equiv.) was added at
15 258 (temp. control with ice bath). Thereby, the soln. turned black. Then, compound 12 (0.483 g, 4.23 mmol)
in 3 ml of 1,2-dichlorethane was added at 15 258, and the mixture was stirred for 5 h. To the grey-brown
suspension, 5 ml of H2O was added, and the mixture was stirred for 30 min. The org. layer was separated, and the
aq. layer was extracted with 1,2-dichlorethane and twice with CH2Cl2. The combined org. layers were dried
(MgSO4) and evaporated. CC (hexane/AcOEt 1:1 to AcOEt) yielded 0.822 g (88%) of 13. Slightly brown solid.
2.2.2. Procedure 2. To a soln. of AlCl3 (1.134 g, 8.5 mmol, 2 equiv.) in CH2Cl2 (3 ml), N-methylaniline
(1.75 ml, 16.1 mmol, 3.8equiv.) was added slowly at 15 25 8 (temp. control with ice bath). Thereby, the soln.
turned black. Compound 12 (0.489 g, 4.28 mmol) was added at 15 258, and the mixture was stirred for 5 h. To
the grey-brown suspension, 5 ml of H2O was added, and the mixture was stirred for 30 min and passed through
Celite. The layers were separated, and the aq. layer was extracted twice with CH2Cl2. The combined org. layers
were dried (MgSO4) and evaporated. CC (hexane/AcOEt 1:1 to AcOEt) yielded 0.785 g (81%) of 13. Slightly
brown solid. M.p. 68.9 69.58. Rf (CH2Cl2/MeOH 30 :1) 0.29 0.16. IR (KBr): 3383s, 2971m, 2946m, 2923m,
2864m, 1637s, 1594s, 1495m, 1465m, 1432m, 1391m, 1370w, 1331w, 1274m, 1227w, 1176w, 1116m, 1067m, 1024w,
1
986w, 954w, 909w, 775m, 701s. H-NMR: 7.45 7.3 (m, 3 Hm, Hp); 7.2 7.15 (m, 2 Ho); 3.55 3.5 (m, CH2OH);
3.26 (s, MeN); 2.45 2.35 (m, CH); 1.8 1.7 ( m, 1 H of CH2); 1.5 1.4 (m, CH2); 1.4 1.3 (m, 1 H of CH2); 1.04 (d,
J ˆ 6.7, Me). 13C-NMR: 176.7 (s, CO); 144.0 (s, 1 arom. C); 129.7 (d, 2 Cm); 127.7 (d, 1 Cp); 127.3 (d, 2 Co); 62.4 (t,
CH2OH); 37.3 (q, MeN); 36.2 (d, CH); 30.6, 30.3 (2t, 2 CH2); 18.3 (q, Me). CI-MS (NH3): 223 (15), 222 (100,
‡
‡
[M ‡ 1] ), 220 (15), 204 (7, [M OH] ). Anal. calc. for C13H19NO2 (221.30): C 70.56, H 8.65, N 6.33; found: C
70.38, H 8.67, N 6.27.
2.3. 4-Methyl-5-[methyl(phenyl)amino]-5-oxopentanoic acid (14). Compound 13 (3.21 g, 14.5 mmol) and
12.71 g (59.4 mmol, 4.1 equiv.) of NaIO4 were solved in a mixture of 24 ml of MeCN, 24 ml of AcOEt, and 36 ml
of H2O. A small amount of RuCl3 ¥ H2O was added at r.t. After 4 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 (Na2SO4), and evaporated. Recrystallization from AcOEt/
hexane 1 :1 yielded 2.48(73%) of 14. Colorless crystals. M.p. 116.1 116.78. Rf (CH2Cl2/MeOH 10 :1) 0.34. IR
(KBr): 3445w, 2961m, 1729s, 1611s, 1586s, 1497m, 1466m, 1454m, 1401m, 1333w, 1316w, 1274m, 1260m, 1193s,
1169m, 1115m, 1095w, 1073w, 1046w, 1027w, 1002w, 976w, 912w, 8 66w, 796w, 779m, 754w, 716w, 703m. 1H-NMR:
7.45 7.3 (m, 2 Hm, Hp); 7.2 7.15 (m, 2 Ho); 3.26 (s, MeN); 2.5 2.45 (m, MeCH); 2.35 2.2 (m, CH2); 2.0 1.9
(m, 1 H of CH2); 1.7 1.6 (m, 1 H of CH2); 1.05 (d, J ˆ 6.8, Me). 13C-NMR: 178.2 (s, COO); 175.9 (s, CON);
143.7 (s, 1 arom. C); 129.7 (d, 2 Cm); 127.8( d, 1 Cp); 127.2 (d, 2 Co); 37.4 (q, MeN); 35.6 (d, CH); 31.5, 28.8 (2t, 2
‡
CH2); 17.9 (q, Me). CI-MS (NH3): 237 (15), 236 (100, [M ‡ 1] ). Anal. calc. for C13H17NO3 (235.28): C 66.36, H
7.28, N 5.95; found: C 66.44, H 7.16, N 5.87.
2.4. Methyl 4-Methyl-5-[methyl(phenyl)amino]-5-oxopentanoate (15). To
a soln. of 14 (2.506 g,
10.65 mmol) in abs. THF (25 ml), 40 ml of a ca. 4n soln. of CH2N2 in Et2O (prepared according to [40])
were added at 08, the mixture was stirred until the yellow color disappeared. After 40 min, additional CH2N2
soln. (10 ml) was added, and the mixture remained yellow. The ice bath was removed, and the mixture was
stirred at r.t., until the yellow color disappeared again. After addition of another 4 ml of the CH2N2 soln., the
yellow color remained at r.t. for at least 90 min. Then, the excess of CH2N2 was destroyed with AcOH, the
solvent was evaporated, and the product was dried in high vacuum: 2.696 g (quant.) of 15. Colorless oil. The
product was used for the next step without further purification. Rf (hexane/AcOEt 2 :1) 0.31. IR (neat): 2953s,
1738s, 1653s, 1596s, 1497s, 1436s, 1390s, 1327s, 1268s, 1170s, 1116s, 1074m, 1035m, 1002m, 98 7m, 918w, 8 97w,
1
842w, 8 00w, 776m, 752m, 703s. H-NMR: 7.45 7.35 (m, 2 Hm, Hp); 7.2 7.15 (m, 2 Ho); 3.59 (s, MeO); 3.26 (s,
MeN); 2.5 2.4 (m, CH); 2.35 2.15 (m, CH2); 2.0 1.9 (m, 1 H of CH2); 1.7 1.6 (m, 1 H of CH2); 1.04 (d, J ˆ
6.7, Me). 13C-NMR: 175.9 (s, CON); 173.4 (s, COOMe); 143.8( s, 1 arom. C); 129.7 (d, 2 Cm); 127.7 (d, 1 Cp);
127.2 (d, 2 Co); 51.2 (q, MeO); 37.3 (q, MeN); 35.6 (d, CH); 31.6, 29.1 (2t, 2 CH2); 17.9 (q, Me). CI-MS (NH3):

Helvetica Chimica Acta Vol. 87 (2004)
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‡
251 (15), 250 (100, [M ‡ 1] ). Anal. calc. for C14H19NO3 (249.31): C 67.45, H 7.68, N 5.62; found: C 67.22, H 7.93,
N 5.54.
2.5. Methyl 4-Methyl-5-[methyl(phenyl)amino]-5-thioxopentanoate (16). To a soln. of 15 (2.599 g,
10.43 mmol) in toluene (10 ml), Lawesson reagent (2.57 g, 6.35 mmol, 1.2 equiv.) was added, and the mixture
was stirred for 30 min at 1308. The excess of Lawesson reagent was precipitated with Et2O, the precipitate was
filtered over Celite, and the filtrate was evaporated. CC (hexane/AcOEt 4 :1) yielded 2.564 g (93%) of 16. Pale
brown oil. Rf (hexane/AcOEt 4 :1) 0.18. IR (neat): 2969m, 2930m, 2868w, 1737s, 1595m, 1493s, 1444s, 1385s,
1332m, 1269m, 1198s, 1112m, 1074w, 1037m, 1002m, 919w, 8 77w, 8 53w, 8 34w, 774m, 702s. 1H-NMR: 7.5 7.35 (m,
2 Hm, Hp); 7.15 7.1 (m, 2 Ho): 3.71, 3.58(2 s, MeO, MeN); 2.8 2.7 ( m, CH); 2.3 2.1 (m, 3 H of 2 CH2); 1.8
1.55 (m, 1 H of 2 CH2); 1.32 (d, J ˆ 6.6, Me). 13C-NMR: 210.6 (s, CS); 173.3 (s, CO); 145.4 (s, 1 arom. C); 129.9,
128.4, 125.6 (3d, 5 arom. CH); 51.3 (q, MeO); 45.5 (q, MeN); 42.8( d, CH); 32.7, 31.7 (2t, 2 CH2); 22.0 (q, Me).
‡
CI-MS (NH3): 268(6), 267 (16), 266 (100, [ M ‡ 1] ). Anal. calc. for C14H19NO2S (265.37): C 63.36, H 7.22, N
5.28, S 12.08; found: C 63.34, H 7.20, N 5.28, S 12.11.
2.6. Methyl 3-(3-Amino-2,N-dimethyl-N-phenyl-2H-azirin-2-yl)propanoate (10). To a soln. of 16 (2.558g,
9.64 mmol) and 5 drops of abs. DMF in abs. CH2Cl2 (12 ml) at 08, 2n phosgene in toluene (6.5 ml, ca. 13 mmol,
1.3 equiv.) was added slowly, the ice bath was removed, the mixture stirred for 25 min, and the solvent
evaporated. The residue was dissolved in abs. THF (12 ml), DABCO (1.096 g, 9.77 mmol) was added, and the
soln. was stirred for 25 min at r.t. After filtration and addition of abs. DMF (12 ml), NaN3 (1.256 g, 19.32 mmol, 2
equiv.) was added, the mixture was stirred for 3 d at r.t. and then filtered over Celite, and the filtrate was
evaporated. CC (hexane/AcOEt 2 :1) yielded 2.143 g (90%) of 10 as a yellow oil. In the 1H- and 13C-NMR
spectra at 270 and 280 K, doubling of signals was observed, which almost disappeared at 300 K, and showed
EXSY cross-peaks. Therefore, it is assumed that two conformers are detected at r.t. They were analyzed by
HSQC and HMBC experiments at 270K. Rf (hexane/AcOEt 2 :1) 0.10. IR (neat): 2950w, 2920w, 1749s, 1656w,
1600s, 1502s, 1438m, 1375w, 1347w, 1319w, 1300m, 1286m, 1228m, 1198m, 1161m, 1112m, 1086w, 1071w, 1035w,
987w, 8 94w, 8 41w, 756m. 1H-NMR (600 MHz, 270 K): 7.60 (d, J ˆ 8.1, 2 Ho, minor conformer); 7.45 7.4 (m,
2 Hm) ; 7.2 7.1 ( m, 1 Hp); 7.05 (d, J ˆ 7.9, 1 Ho, major conformer); 3.54 (s, MeO, minor conformer); 3.53 (s, MeO,
major conformer); 3.45 (s, MeN, major conformer); 3.43 (s, MeN, minor conformer); 2.35 2.3 (m, 1 H of
CH2CO, minor conformer); 2.3 2.25 (m, 1 H of CH2CO, minor conformer, 1 H of CH2CO, major conformer,
1 H of CH2C(3), major conformer); 2.15 2.1 (m, CH2C(3), minor conformer, 1 H of CH2CO, major
conformer); 2.05 2.0 (m, 1 H of CH2C(3), major conformer); 1.48( s, Me, major conformer); 1.43 (s, Me, minor
conformer). 13C-NMR (151 MHz, 270 K): 173.9 (s, CO, minor conformer); 173.6 (s, CO, major conformer);
166.0 (s, C(3), major conformer); 164.9 (s, C(3), minor conformer); 142.1 (s, 1 arom. C, minor conformer); 142.1
(s, 1 arom. C, major conformer); 129.6 (d, 2 Cm, major conformer); 129.2 (d, 2 Cm, minor conformer); 123.2 (d, 1
Cp, minor conformer); 123.1 (d, 1 Cp, major conformer); 116.7 (d, 2 Co, minor conformer); 115.4 (d, 1 Co, major
conformer); 51.6 (q, MeO); 45.9 (s, C(2), major conformer); 37.7 (q, MeN, minor conformer); 37.1 (s, C(2),
minor conformer); 33.5 (q, MeN, major conformer); 32.1 (d, CH2C(2), major conformer); 31.2 (d, CH2C(2),
minor conformer); 29.9 (d, CH2CO, major conformer); 29.8( d, CH2CO, minor conformer); 24.5 (q, Me, major
‡
conformer); 23.5 (q, Me, minor conformer). CI-MS (NH3): 248(16), 247 (100, [ M ‡ 1] ). Anal. calc. for
C14H18N2O2 (246.30): C 68.27, H 7.37, N 11.37; found: C 67.99, H 7.17, N 10.99.
3. Reactions of the a-Methylglutamate Synthon 10 with PhCOSH and Z-l-Valine. 3.1. With PhCOSH.
Methyl 4-Methyl-5-[methyl(phenyl)amino]-4-[(phenylcarbonyl)amino]-5-thioxopentanoate (17). To PhCOSH
(110 mg, 0.8mmol), a soln. of 10 (182 mg, 0.74 mmol) in abs. CH2Cl2 (5 ml) was added, and the mixture was
stirred for 1 h at r.t. Prep. TLC (hexane/AcOEt 1 :1) gave 281 mg (99%) of 17. Pale yellow crystals. M.p. 133.9
134.98. Rf (hexane/AcOEt 2 :1) 0.18. IR (KBr): 3444m, 3246m, 3065m, 3004m, 2956m, 2924m, 2853w, 1732s,
1641s, 1601m, 1578m, 1548s, 1490s, 1463s, 1442m, 1363s, 1330m, 1294s, 1254m, 1219m, 1196m, 1177m, 1093s,
1026w, 1006m, 98 0m, 934w, 8 98w, 8 57w, 8 03w, 773m, 706s. 1H-NMR: 8.78 (br. s, NH); 7.8 7.75, 7.5 7.35 (2 m, 10
arom. H); 3.76, 3.62 (2s, MeO, MeN); 2.95 2.9 (m, 1 H of 2 CH2); 2.4 2.35 (m, 2 H of 2 CH2); 2.3 2.2 (m, 1 H
of 2 CH2); 1.68( s, Me). 13C-NMR: 206.8( s, CS); 173.8( s, COOMe); 164.6 (s, CON); ca. 147 (s, 1 arom. CN);
135.1 (s, 1 arom. C); 131.2, 129.5, 128.6, 128.3, 126.9, 126.5 (6d, 10 arom. CH); 65.0 (s, C(4)); 51.6 (q, MeO); the
signal for MeN was not observed; 32.3, 29.3 (2t, 2 CH2); 26.0 (q, Me). ESI-MS (MeOH, NaI): 407 (100, [M ‡
‡
Na] ). Anal. calc. for C21H24N2O3S (384.49): C 65.60, H 6.29, N 7.29, S 8.34; found: C 65.57, H 6.38, N 6.62, S 8.13.
3.2. With Z-l-Valine. Methyl (RS)-4-[((S)-2-{[(Benzyloxy)carbonyl]amino}-3-methyl-1-oxobutyl)amino]-
4-methyl-5-[methyl(phenyl)amino]-5-oxopentanoate (18). A soln. of 10 (1.03 g, 4.18mmol) and Z -l-valine
(1.11 g, 4.42 mmol) in CH2Cl2 (20 ml) was stirred at r.t. for 24 h, and evaporated. CC (CH2Cl2/MeOH 50 :1)
yielded 1.99 g (96%) of 18. Colorless foam. M.p. 103 1048. Rf (CH2Cl2/MeOH 50 :1) 0.16. IR (KBr): 3337m,
2963m, 1733s, 1672s, 1633s, 1594m, 1495s, 1454m, 1371m, 1233m, 1110m, 1026m, 774w, 703m. 1H-NMR: 7.46 (br.

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Helvetica Chimica Acta Vol. 87 (2004)
s, NH of Glu(2Me), diastereoisomer B); 7.45 7.25 (m, 10 arom. H); 7.16 (br. s, NH of Glu(2Me),
diastereoisomer A); 5.4 5.3 (m, NH of Val); 5.2 5.1 (m, PhCH2O); 4.0 3.9 (m, CH(2) of Val, B); 3.9 3.8( m,
CH(2) of Val, A); 3.65 (s, MeO, B); 3.64 (s, MeO, A); 3.27 (s, MeN, B); 3.26 (s, MeN, A); 2.7 2.45 (m, 1 H of 2
CH2); 2.45 2.15 (m, 2 H of 2 CH2); 2.15 2.0 (m, CH(3) of Val); 1.95 1.8( m, 1 H of 2 CH2); 1.42 (s, Me(3) of
Glu(2Me), A); 1.38( s, Me(3) of Glu(2Me), B); 0.95 0.85 (m, 2Me(4) of Val). 13C-NMR: 173.4, 171.9, 171.6,
169.2 (4s, COOMe, 2 CON); 156.1 (s, OCONH); 143.6, 143.4, 136.4 (3s, 2 arom. C); 129.5, 128.6, 128.43, 128.37,
128.0, 127.9 (6d, 10 arom. CH); 66.8( t, PhCH2O); 61.8, 61.5 (2s, C(2) of Glu(2Me)); 60.5, 60.2 (2d, CH(2) of
Val); 51.6, 51.5 (2q, MeO); 41.7, 41.6 (2q, MeN); 31.5, 30.8, 29.4, 29.2 (4t, 2 CH2 of Glu(2Me)); 31.4, 31.3 (2d,
CH(3) of Val); 23.2, 19.1, 19.0, 17.5, 17.2 (5q, Me(3) of Glu(2Me), 2 Me of Val). ESI-MS (MeOH, NaI): 520
‡
(100, [M ‡ Na] ). Anal. calc. for C27H35N3O6 (497.58): C 65.17, H 7.09, N 8.44; found: C 65.06, H 7.15, N 8.51.
4. Deprotection of Dipeptide 18. 4.1. Cleavage of the Z Group. Methyl (RS)-4-{[(S)-2-Amino-3-methyl-1-
oxobutyl]amino}-4-methyl-5-[methyl(phenyl)amino]-5-oxopentanoate (19). A soln. of dipeptide 18 (200 mg,
0.402 mmol) and a small amount of Pd/C (10% on activated charcoal) in MeOH (10 ml) was treated with H2 for
2.5 h at r.t. The mixture was filtered over Celite, and the filtrate was evaporated. Prep. TLC (CH2Cl2/MeOH
20 :1) gave 147 mg (quant.) of 19. Colorless, highly viscous substance. Rf (CH2Cl2/MeOH 10 :1) 0.25. IR (neat):
3322m, 2959s, 2874m, 1737s, 1638s, 1594m, 1495s, 1452m, 1368m, 1271m, 1222m, 1200s, 1174s, 1110m, 1082w,
1033w, 995w, 8 52w, 777w, 735w, 706m. 1H-NMR: 8.15, 7.80 (2 br. s, NH of Glu(2Me)); 7.45 7.3 (m, 5 arom. H);
3.68, 3.65 (2s, MeO); 3.28, 3.26 (2s, MeN); 3.11, 3.01 (2d, J ˆ 4.1 and 3.8, CH(2) of Val); 2.7 2.0 (m, 2 CH2,
CH(3) of Val); 1.95 1.9 (m, NH2 of Val); 1.48, 1.39 (2s, Me(3) of Glu(2Me)); 0.96, 0.93, 0.83, 0.79 (4d, J ˆ 7.0,
7.0, 6.9, and 6.9, 2 Me(4) of Val). 13C-NMR: 173.5, 173.3, 172.4, 172.2, 171.6 (5s, 3 CO); 144.5, 144.1 (2s, arom. C);
129.4, 129.3, 128.1, 128.0, 127.8, 127.7 (6d, 5 arom. CH); 60.9 (s, C(2) of Glu(2Me)); 60.33, 60.25 (2d, CH(2) of
Val); 51.6, 51.5 (2q, MeO); 41.6, 41.5 (2q, MeN); 32.9, 31.4 (2t, CH2); 30.8( d, CH(3) of Val); 29.4, 29.1 (2t, CH2);
‡
23.7, 23.3, 19.5, 19.4, 16.3 (5q, Me(3) of Glu(2Me), 2 Me(4) of Val). ESI-MS (MeOH): 749 (23, [2 M ‡ Na] ),
‡
‡
‡
‡
‡
727 (40, [2 M ‡ 1] ), 402 (17, [M ‡ K] ), 386 (100, [M ‡ Na] ), 364 (46, [M ‡ 1] ), 257 (24, [M N(Me)Ph] ).
4.2. Hydrolysis of the Amide Group. 4.2.1. Methyl 3-[(RS)-2-((S)-1-{[(Benzyloxy)carbonyl]amino}-2-
methylpropyl)-4-methyl-5-oxo-1,3-oxazol-4-yl]propanoate (23). A soln. of 18 (301 mg, 0.605 mmol) in toluene
(60 ml) was heated to 1058. For 13 min, HCl (g) was bubbled through the mixture. During this procedure, the
temp. fell to 90 958. The remaining HCl (g) was removed by bubbling N2 through the soln. for 20 min. The
mixture was transferred into another flask with hexane, and the crystals of N-methylanilide chloride precipitated
were filtered (55 mg, 0.39 mmol, 64%), and the resulting soln. was evaporated. CC (hexane/AcOEt 2 :1) yielded
182 mg of 23, which still contained some AcOEt, and 67 mg of starting material 18 (22%). Calculation of the
yield based on NMR integrals gave 168mg 23 (71%) and 14 mg AcOEt. This material was hydrolized to the
corresponding acid. For anal. purposes, 23 was dried in high vacuum. Rf (hexane/AcOEt 2 :1) 0.17. IR (neat):
3338m, 3066w, 3035w, 2966s, 2936m, 2877w, 1823s, 1732s, 1673s, 1526s, 1453m, 1375m, 1311s, 1233s, 1177s, 1146m,
1027m, 966m, 8 97s, 775w, 740w, 699m. 1H-NMR: 7.35 7.3 (m, 5 arom. H); 5.35 5.25 (m, NH of Val); 5.15 5.1
(m, PhCH2O); 4.55 4.45 (m, CH(2) of Val); 3.65, 3.63 (2s, MeO); 2.4 2.05 (m, CH(3) of Val, 2 CH2 of
Glu(2Me)); 1.40 (br. s, Me(3) of Glu(2Me)); 1.02, 0.98, 0.95 (3d, J ˆ 6.8, 6.9, 6.9, 2 Me(4) of Val). 13C-NMR:
179.5 (s, C(5)); 172.3 (s, COOMe); 163.0 (s, C(2)); ca. 156 (s, OCONH); 136.0 (s, 1 arom. C); 128.4, 128.1, 128.0
(3d, 5 arom. CH); 67.6 (s, C(4)); 67.1 (t, PhCH2O); 55.2, 54.7 (2d, CH(2) of Val); 51.6 (q, MeO); 32.3 (t, CH2);
30.7, 30.5 (2d, CH(3) of Val); 28.6 (t, CH2); 23.5, 23.3, 18.9, 18.8, 17.5, 17.1 (6q, Me(3) of Glu(2Me), 2 Me(4) of
‡
Val). ESI-MS (MeOH, NaI): 413 (100, [M ‡ Na] ). Anal. calc. for C20H26N2O6 (390.44): C 61.53, H 6.71, N 7.17;
found: C 61.78, H 6.80, N 7.04.
4.2.2. (RS)-2-[((S)-2-{[(Benzyloxy)carbonyl]amino}-3-methyl-1-oxobutyl)amino]-5-methoxy-2-methyl-5-
oxopentanoic Acid (21). 4.2.2.1. Procedure 1. From Oxazolone 23. A suspension of 158mg of crude 23
(containing AcOEt, i.e., 146 mg, 0.374 mmol of 23) in 2 ml H2O was stirred for 18h at r.t., 2 ml of THF were
added, and the suspension was stirred for 4 h at r.t. and for 1 h at 508. As no hydrolysis was observed, one drop of
6n HCl was added. After stirring at 508 for 2 h, the hydrolysis was complete. Brine was added, and the soln. was
extracted 3 Â with AcOEt. The combined org. layers were dried (MgSO4) and evaporated: 161 mg (quant.) of
crude 21. After Prep. TLC (CH2Cl2/MeOH 10 :1), 109 mg (71%) of pure 21 were obtained as a colorless foam.
4.2.2.2. Procedure 2. From Amide 18. A soln. of 18 (152 mg, 0.305 mmol) in toluene (30 ml) was heated to
1108. 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 20 min. The mixture was transferred
into another flask with hexane, and crystals of N-methylanilide chloride precipitated were filtered, and the
resulting soln. was evaporated. This crude material was solved 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 3 Â with AcOEt. The combined org. layers were dried (MgSO4), and evaporated. Prep. TLC

Helvetica Chimica Acta Vol. 87 (2004)
2547
(CH2Cl2/MeOH 10 :1) gave 87 mg (70%) of pure 21, and a mixture of 23 mg (15%) of starting material 18 and
18mg (12%) of oxazolone 23 (ratio determined by NMR).
4.2.2.3. Procedure 3. Under Standard Conditions from Amide 18. A soln. of 18 (152 mg, 0.305 mmol) in 3n
HCl (THF/H2O 1:1, 5 ml) was stirred for 1 h at r.t. The mixture was extracted with CH2Cl2, dried (MgSO4), and
evaporated. Prep. TLC (CH2Cl2/MeOH 10 :1) yielded 81 mg (40%) of starting material 18, and a mixture of
53 mg (27%) of 20 and 23 mg (14%) of 21 (ratio determined by NMR).
Data of 21. M.p. 60 628. 1H-NMR: ca. 8.9 (br., COOH); ca. 7.4 (br. s, NH of Glu(2Me)); 7.35 7.25 (m, 5
arom. H); 5.79 (d, J ˆ 8.6, NH of Val); 5.11 (s, PhCH2O); 4.15 4.1 (m, CH(2) of Val); 3.64, 3.62 (2s, MeO);
2.55 2.0 (m, CH(3) of Val, 2 CH2 of Glu(2Me)); 1.59 (s, Me(3) of Glu(2Me)); 1.0 0.9 (m, 2 Me(4) of Val).
13C-NMR: ca. 176, ca. 174, 171.5 (3s, COOH, COOMe, CCONH); ca. 157 (s, OCONH); ca. 135 (s, 1 arom. C);
128.5, 128.2, 128.0 (3d, 5 arom. CH); 67.2 (t, PhCH2O); 60.6 (d, CH(2) of Val); 60.0 (s, C(2) of Glu(2Me)); 52.0
(q, MeO); 31.4 (t, 1 CH2); 31.0 (d, CH(3) of Val); 29.3 (t, 1 CH2); 22.9, 19.3, 19.1 (3q, Me(3) of Glu(2Me), 2
‡
‡
Me(4) of Val). ESI-MS (MeOH): 447 (8, [M ‡ K] ), 432 (23), 431 (100, [M ‡ Na] ). Anal. calc. for
C20H28N2O7 ¥ 0.2 H2O (412.05): C 58.30, H 6.95, N 6.80; found: C 58.26, H 6.95, N 6.69.
4.3. Hydrolysis of the Ester Group. 4.1.1. (RS)-4-[((S)-2-{[(Benzyloxy)carbonyl]amino}-3-methyl-1-
oxobutyl)amino]-4-methyl-5-[methyl(phenyl)amino]-5-oxopentanoic Acid (20). To a soln. of 20 (213 mg,
0.428mmol) in 6 ml of a 3 :1 :1 mixture of THF, MeOH, and H 2O, LiOH ¥ H2O (54.5 mg, 1.30 mmol, 3 equiv.)
was added. The mixture was stirred at r.t. for 2 h, and then neutralized with 6n HCl. The aq. layer was extracted
with CH2Cl2, and the combined org. layers were washed with 1n HCl, dried (MgSO4), and evaporated: 213 mg
(quant.) of 20. Colorless solid. M.p. 80 818. Rf (CH2Cl2/MeOH 10 :1) 0.31. IR (KBr): 3422s (br.), 3065m,
2965m, 2929m, 1717s, 1633s, 1593m, 1495s, 1455m, 1388m, 1261m, 1236m, 1110m, 1085m, 1028m, 8 01w, 774w,
738w, 701m. 1H-NMR: 7.55 (br. s, NH of Glu(2Me)); 7.4 7.2 (m, 10 arom. H); 5.7 5.6 (m, NH of Val); 5.15 5.1
(m, PhCH2O); 3.95 3.85 (m, CH(2) of Val); 3.27, 3.24 (2s, MeN); 2.7 1.8( m, CH(3) of Val, 2 CH2 of
Glu(2Me)); 1.43, 1.39 (2s, Me(3) of Glu(2Me)); 0.95 0.85 (m, 2 Me(4) of Val). 13C-NMR: 176.4, ca. 172, ca. 171,
169.8(4 s, COOH, 2 CCON); 156.6, 156.5 (2s, OCONH); 143.4, 136.2 (2s, 2 arom. C); 129.6, 129.4, 128.4, 128.1,
128.0 (5d, 10 arom. CH); 67.0 (t, PhCH2O); 61.9, 61.2 (2s, C(2) of Glu(2Me)); 60.8, 60.2 (2d, CH(2) of Val); 41.7,
41.5 (2q, MeN); 31.4, 31.1 (2d, CH(3) of Val); 29.4, 28.9 (2t, 2 CH2 of Glu(2Me)); 23.2, 23.1, 19.1, 17.7, 17.5 (5q,
‡
‡
Me(3) of Glu(2Me), 2 Me(4) of Val). CI-MS (NH3): 484 (12, [M ‡ 1] ), 466 (9, [M OH] ), 395 (8), 394 (38),
‡
378(10), 377 (45, [ M
NMePh] ), 376 (8), 125 (8), 109 (8), 108 (100, PhCH 2OHഠ). Anal. calc. for
C26H33N3O6 ¥ 0.5 H2O (501.58): C 63.40, H 6.96, N 8.53; found: C 63.33, H 6.79, N 8.29.
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Received June 25, 2004