New optically active 2H-azirin-3-amines as synthons for enantiomerically pure 2,2-disubstituted glycines

Article abstract of DOI:10.1002/1522-2675(20010613)84:6<1756::AID-HLCA1756>3.0.CO;2-J

The synthesis of novel 2,2-disubstituted 2H-azirin-3-amines with a chiral amino group is described. Chromatographic separation of the diastereoisomer mixture yielded the pure diastereoisomers (1′R,2R)-4a-e and (1′R,2S)-4a-e (Scheme 1, Table 1), which are

Full text of DOI:10.1002/1522-2675(20010613)84:6<1756::AID-HLCA1756>3.0.CO;2-J

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Helvetica Chimica Acta ± Vol. 84 (2001)
New Optically Active 2H-Azirin-3-amines as Synthons for Enantiomerically
Pure 2,2-Disubstituted Glycines
by Kathrin A. Brun1), Anthony Linden, and Heinz Heimgartner*
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
Dedicated to Professor Edgar Heilbronner on the occasion of his 80th birthday
The synthesis of novel 2,2-disubstituted 2H-azirin-3-amines with a chiral amino group is described.
Chromatographic separation of the diastereoisomer mixture yielded the pure diastereoisomers (1'R,2R)-4a ± e
and (1'R,2S)-4a ± e (Scheme 1, Table 1), which are synthons for the (R)- and (S)-isomers of isovaline, 2-
methylvaline, 2-cyclopentylalanine, 2-methylleucine, and 2-(methyl)phenylalanine, respectively. The config-
uration at C(2) of the synthons was determined by X-ray crystallography relative to the known configuration of
the chiral auxiliary group. The reaction of 4 with thiobenzoic acid, benzoic acid, and the dipeptide Z-Leu-Aib-
OH (12) yielded the monothiodiamides 10, the diamides 11 (Scheme 2, Table 3), and the tripeptides 13
(Scheme 3, Table 4), respectively.
1. Introduction. ± Peptides containing non-protein amino acids are of considerable
interest due to their biological activity. A common modification to naturally occurring
a-amino acids is the substitution of the H-atom at the C(a) atom by an alkyl group.
These so-called a,a-disubstituted a-amino acids (2,2-disubstituted glycines) restrict the
conformational flexibility of peptides and stabilize or promote secondary structures,
such as b-turns or helices [1 ± 4]. A convenient synthetic access to such peptides is the
so-called ꢀazirine/oxazolone methodꢁ, in which 2,2-disubstituted 2H-azirin-3-amines are
used as amino-acid synthons [5] (cf. [6]). This method has been used successfully in the
synthesis of peptaibols [7 ± 12], endothiopeptides [13 ± 17], conformationally restricted
cyclic peptides [18 ± 20], and cyclic depsipeptides [21 ± 28].
For the incorporation of chiral, enantiomerically pure a,a-disubstituted glycines,
optically pure synthons are needed. Recently, we reported the preparation of the first
examples of such synthons for optically pure Phe(2Me) (see 1) [29] and Iva (see 2) [30].
The Iva synthons have been prepared via sulfone derivative 3, and the diastereoisomers
3a and 3b could be separated by means of column chromatography. Electrochemical
cleavage of the phenylsulfonyl group of the pure diastereoisomers then gave the
synthons 2a and 2b for (S)- and (R)-Iva, respectively.
Based on these first successful syntheses, it was of interest to expand the number of
2H-azirin-3-amines available as optically pure amino-acid synthons, to work out a
direct synthesis of the Iva building blocks, and to find a chiral auxiliary group, which can
be used generally. In the present paper, we describe the preparation of a series of new
optically pure 2H-azirin-3-amines which have potential use in peptide synthesis.
1
)
Part of the projected Ph.D. thesis of K.B., Universität Zürich.

Helvetica Chimica Acta ± Vol. 84 (2001)
1757
PhSO2
2'
N
N
N
2
N
2
N
N
electrolysis
OMe
1a (2'R)
b (2'S)
3a (2S)
b (2R)
2a (2S)
b (2R)
2. Results. ± 2.1. Preparation of the Azirines. The 2H-azirin-3-amines 4a ± e
(Scheme 1), i.e., synthons for isovaline (Iva), 2-methylvaline (Val(2Me)), 2-cyclo-
pentylalanine (Ala(2cPent)), 2-methylleucine (Leu(2Me)), and 2-methylphenylala-
nine (Phe(2Me)) (Table 1), were prepared in gram quantities. In all experiments, the
commercially available (R)-[1-(naphthalen-1-yl)ethyl]amine (5) was used as the chiral
auxiliary group.
Scheme 1
LDA ˆ lithium diisopropylamide; L.-R. ˆ Lawesson reagent; DABCO ˆ 1,4-diazabicyclo[2.2.2]octane
Table 1. Synthesis of 2H-Azirin-3-amines 4. Yields in [%].
R
Amide 8
Thioamide 9
Azirine 4
Synthon for
Et
a (84)
b (93)
c (41a))
d (82)
e (90)
a (88)
b (75)
c (58b))
d (99)
e (94)
a (58)
b (53)
c (62)
d (56)
e (59)
Iva
iPr
Val(2Me)
Ala(2cPent)
Leu(2Me)
Phe(2Me)
cPent
iBu
Bn
a) Yield relative to converted starting material 7, 74%. b) Yield relative to converted starting material 8c, 94%.

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Helvetica Chimica Acta ± Vol. 84 (2001)
The five diastereoisomer pairs of 4a ± e were prepared according to Scheme 1
(Table 1), by following previously described protocols (cf. [29]). The chiral auxiliary
group was introduced by coupling amine 5 with propanoyl chloride to give amide 6 in
quantitative yield. The N-methylation of the latter was achieved in 98% yield with MeI
in THF in the presence of LiClO4 which was added to avoid O-methylation [30]. The
N-methylated amide 7 was deprotonated with lithium diisopropylamide (LDA) and
alkylated with the respective alkyl halides R X to give the amides 8a ± e as
diastereoisomer mixtures. The latter were converted to the corresponding thioamides
9a ± e (diastereoisomer mixtures) with Lawesson reagent. Finally, the synthesis of the
azirines 4a ± e was achieved by consecutive treatment of 9a ± e with COCl2 solution in
CH2Cl2, deprotonation with 1,4-diazabicyclo[2.2.2]octane (DABCO) in THF, and
treatment with NaN3. The yields of these transformations are summarized in Table 1.
Separation of the (R,S)- and (R,R)-diastereoisomers of 4a ± e was achieved by
means of column chromatography (CC, SiO2) followed by MPLC (SiO2). The detailed
procedures and solvent systems are summarized in Table 2.
Table 2. Chromatographic Separation of (R,S)- and (R,R)-Diastereoisomers of 4a ± e
R
Separation method
Amount separated
Rf Valuesd)
4a
4b
4c
4d
4e
Et
MPLCa) (5Â)
CCb), MPLCa)
CCc), MPLCa)
CCb) (3Â)
1.5 g
2.0 g
1.2 g
1.7 g
2.9 g
0.33, 0.29
0.33, 0.29
0.28, 0.23
0.36, 0.31
0.32, 0.24
iPr
cPent
iBu
Bn
CCb), MPLCa)
a) AcOEt. b) Hexane/AcOEt 3 : 1. c) Hexane/AcOEt 2 : 1. d) Hexane/AcOEt 1 : 1.
2.2. Determination of the Relative Configuration of the 2H-Azirin-3-amines 4. In
every case, it was possible to obtain crystals suitable for X-ray diffraction analysis from
one of the two diastereoisomers (see ORTEP plots [31] in the Fig). The configuration
at C(2) of the azirine ring was determined relative to the known (R)-configuration of
the chiral auxiliary group. The absolute configurations of the molecules were not
confirmed crystallographically, but can be assigned on the basis of the known absolute
configuration in the substituted amino group.
2.3. Conversion of Azirines 4a ± e to Amino-Acid Derivatives. To demonstrate that
the new, optically pure amino-acid synthons show analogous chemical behavior in
reactions with thiocarboxylic and carboxylic acids as the already known 2H-azirin-3-
amines (cf. [5]), they were reacted with thiobenzoic acid [29][32][33] (cf. [14][15])
and, in some cases, with benzoic acid according to Scheme 2. A typical reaction was
carried out with equimolar amounts of 4 and the acid in CH2Cl2 at room temperature.
The yields and reaction times are summarized in Table 3. It is obvious that the reactions
with thiobenzoic acid proceed faster and in better yields than with benzoic acid.
In addition, the optically pure synthons 4a ± e were used to incorporate (R)- and
(S)-configured 2,2-disubstituted glycines (a,a-disubstituted a-amino acids), respec-
tively, into model tripeptides Z-Leu-Aib-Xaa-N(Me)R (13) by coupling 4 with the
dipeptide Z-Leu-Aib-OH (12; Scheme 3). Typically, these reactions were carried out in

Helvetica Chimica Acta ± Vol. 84 (2001)
1759
Figure. ORTEP Plots [31] of the molecular structures of a) (1'R,2R)-4a (synthon for (R)-Iva), b) (1'R,2S)-4b
(synthon for (S)-Val(2Me)), c) (1'R,2S)-4c (synthon for (S)-Ala(2cPent)), d) (1'R,2S)-4d (synthon for (S)-
Leu(2Me)), and e) (1'R,2S)-4e (synthon for (S)-Phe(2Me)) (50% Probability ellipsoids, arbitrary numbering of
atoms).

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Helvetica Chimica Acta ± Vol. 84 (2001)
Scheme 2a)
a) For a ± e, see Scheme 1 or Table 3.
Table 3. Reaction of the 2H-Azirin-3-amines 4 with Thiobenzoic Acid and Benzoic Acid (in CH2Cl2 at room
temperature)
Azirine 4
R
Reaction with PhCOSH
Reaction with PhCOOH
Thioamide 10
Yield [%]
Reaction
time [h]
Amide 11
Yield [%]
Reaction
time [h]
(1'R,2S)-4a
(1'R,2R)-4a
(1'R,2S)-4b
(1'R,2R)-4b
(1'R,2S)-4c
(1'R,2R)-4c
(1'R,2S)-4d
(1'R,2R)-4d
(1'R,2S)-4e
(1'R,2R)-4e
Et
(1'R,1S)-10a
(1'R,1R)-10a
(1'R,1S)-10b
(1'R,1R)-10b
(1'R,1S)-10c
(1'R,1R)-10c
(1'R,1S)-10d
(1'R,1R)-10d
(1'R,1S)-10e
(1'R,1R)-10e
93
99
98
94
95
68
95
99
97
96
19
19
48
23
19
2
17
15
18
20
(1'R,1S)-11a
(1'R,1R)-11a
84
90
39
40
iPr
cPent
iBu
Bn
(1'R,1S)-11e
(1'R,1R)-11e
79
92
44
64
CH2Cl2 at room temperature with equimolar amounts of 4 and 12. The yields and
reaction times are summarized in Table 4.
In conclusion, novel 2,2-disubstituted 2H-azirin-3-amines with a chiral substituted
amino group were prepared. After chromatographic separation of the diastereoisom-
ers, these new optically active synthons for 2,2-disubstituted glycines were successfully
reacted with several acids and incorporated into a model tripeptide. Therefore, these
synthons can easily be used in peptide synthesis as building blocks for enantiomerically
pure a,a-disubstituted a-amino acids.
Table 4. Reaction of the 2H-Azirin-3-amines 4 with Z-Leu-Aib-OH (12) (in CH2Cl2 at room temperature)
Azirine 4
R
Tripeptide 13
Yield [%]
Reaction time
(1'R,2S)-4a
(1'R,2R)-4a
(1'R,2S)-4b
(1'R,2R)-4b
(1'R,2S)-4c
(1'R,2R)-4c
(1'R,2S)-4d
(1'R,2R)-4d
(1'R,2S)-4e
(1'R,2R)-4e
Et
(S,S,R)-13a
(S,R,R)-13a
(S,S,R)-13b
(S,R,R)-13b
(S,S,R)-13c
(S,R,R)-13c
(S,S,R)-13d
(S,R,R)-13d
(S,S,R)-13e
(S,R,R)-13e
77
83
67
69
39
38
64
60
59
62
67 h
67 h
5.5 d
2 d
5.5 d
4 d
2 d
4 d
40 h
48 h
iPr
cPent
iBu
Bn

Helvetica Chimica Acta ± Vol. 84 (2001)
Scheme 3a)
1761
a) For a ± e, see Scheme 1 or Table 4.
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, and the Stiftung
für wissenschaftliche Forschung an der Universität Zürich is gratefully acknowledged. K. A. B. thanks the
Stipendienfonds der Basler Chemischen Industrie for a scholarship.
Experimental Part
1. General. Solvents were purified by standard procedures. Thin-layer chromatography (TLC): Merck TLC
aluminium sheets, silica gel 60 F254. Prep. TLC: Merck PLC plates (glass), silica gel 60 F254, 2 mm. Column
chromatography (CC): Uetikon-Chemie ꢀChromatographiegelꢁ C-560. Medium-pressure liquid chromatography
(MPLC): Merck LiChroprep Si 60, 15 ± 25 m; column: Kronlab HPP-VPC 540 Â 40 mm or Kronlab 4/98 ± PRO
480 Â 30 mm; detection at l 254 nm. M.p. Mettler-FP-5 apparatus or Büchi 510 apparatus; uncorrected. IR
Spectra: Perkin-Elmer-781 spectrophotometer or Perkin-Elmer-1600-FT-IR spectrophotometer; in KBr unless
1
otherwise stated; absorptions in cm
.
1H- (300 MHz) and 13C-NMR (75.5 MHz) Spectra: Bruker ARX-300
instrument; in CDCl3 at 300 K unless otherwise stated; d in ppm, coupling constants J in Hz; 13C-signal
multiplicity from DEPT spectra. MS: Finnigan SSQ-700 or -MAT-90 instrument for CI; Finnigan-TSQ-700 triple
quadrupole spectrometer for ESI; m/z (rel.%).
2. Synthesis of the Azirines. 2.1. N-Methyl-N-[(R)-1-(naphthalen-1-yl)ethyl]propanamide (7). N-[(R)-1-
(Naphthalen-1-yl)ethyl]propanamide (6). To a soln. of (R)-[1-(naphthalen-1-yl)ethyl]amine (5; 10.874 g,
63.502 mmol) in AcOEt (400 ml) at 08, Et3N (9 ml, 6.5 g, 65 mmol) was added, and the mixture was stirred for
5 min. Within 60 min, propanoyl chloride (5.50 ml, 5.82 g, 63 mmol) was added, keeping the temp. below 48.
After further stirring for 20 min at 08, the mixture was washed with 1n HCl and sat. aq. NaCl soln., dried
(MgSO4), and evaporated: 14.8 g (quant.) of 6. Crystalline, colorless solid. M.p. 124.4 ± 124.78. Rf (AcOEt) 0.47,
Rf (hexane/AcOEt 1 :1) 0.25. IR: 3305s, 3195w, 3170w, 3060w, 3055w, 2970s, 2930m, 2875m, 2740w, 1965w, 1915w,
1865w, 1800w, 1770w, 1730w, 1635s, 1600m, 1565w, 1530s, 1445m, 1425m, 1400m, 1370s, 1340m, 1300w, 1270w,
1260w, 1230s, 1170m, 1125m, 1095m, 1070m, 1040w, 1020m, 995m, 965m, 920m, 910m, 865m, 840w, 800s, 780s,
685m, 675m. 1H-NMR: 8.10 (d, J ˆ 8.0, 1 arom. H); 7.87 (d, J ˆ 7.5, 1 arom. H); 7.80 (d, J ˆ 7.9, 1 arom. H); 7.6 ±
7.4 ( m, 4 arom. H); 5.95 ± 5.9 (m, CH); 5.78 (br., NH); 2.17 (qd, J ˆ 7.6, 1.2, CH2); 1.66 (d, J ˆ 6.7, MeCH); 1.14

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Helvetica Chimica Acta ± Vol. 84 (2001)
(t, J ˆ 7.6, MeCH2). 13C-NMR: 172.6 (s, CO); 138.3, 133.9, 131.1 (3s, 3 arom. C); 128.7, 128.3, 126.5, 125.8, 125.1,
123.4, 122.4 (7d, 7 arom. CH); 44.4 (d, CH); 29.7 (t, CH2); 20.6 (q, MeCH); 9.8 (q, MeCH2). CI-MS (NH3): 245
‡
‡
‡
(19, [M ‡ NH4] ), 229 (15), 228 (100, [M ‡ 1] ), 155 (7, [M MeCH2CONH] ). Anal. calc. for C15H17NO
(227.16): C 79.26, H 7.54, N 6.16; found: C 79.55, H 7.74, N 6.01.
Propanamide 7. At 08, NaH (1.1 g, 46 mmol; washed with hexane) was added to a soln. of 6 (7.010 g,
30.84 mmol) and LiClO4 (3.612 g, 33.95 mmol) in abs. THF (100 ml). After stirring for 10 min at 08, MeI (2.5 ml
(5.7 g, 40 mmol) was added, and after further stirring for 10 min at 08, the soln. was heated under reflux for 2.5 h.
Addition of a new portion of NaH (1.1 g, 46 mmol; washed with hexane) and MeI (2 ml, 32 mmol) was followed
by heating under reflux for 20 min. Then, the mixture was carefully poured on ice, acidified with 1n HCl,
extracted with CH2Cl2, dried (MgSO4), and evaporated. CC (hexane/AcOEt 1:1) yielded 7.297 g (98%) of 7.
Pale yellow solid. M.p. 61.8 ± 62.48. Rf (Et2O) 0.40, Rf (hexane/AcOEt 1:1) 0.34. IR: 3040m, 2970m, 2930m,
2900m, 2870m, 1645s, 1630s, 1595m, 1570m, 1550w, 1530w, 1505m, 1485m, 1480m, 1465m, 1450m, 1445m, 1415m,
1395m, 1375m, 1345m, 1320m, 1285s, 1235m, 1210m, 1165m, 1120m, 1090m, 1060m, 1040m, 1025m, 1000m,
1
980m, 960w, 910w, 895w, 870w, 810s, 780s, 755m, 740w, 720w, 660w, 615w. H-NMR: 8.05 ± 8.0 (m, 1 arom. H);
7.85 ± 7.8 (m, 2 arom. H); 7.55 ± 7.45 (m, 4 arom. H); 6.64 (q, J ˆ 7.6, CH); 2.46 (s, MeN); 2.32 (q, J ˆ 7.6, CH2);
1.60 (d, J ˆ 6.8, MeCH); 1.20 (t, J ˆ 7.5, MeCH2). 13C-NMR: 173.0 (s, CO); 136.2, 133.7, 131.9 (3s, 3 arom. C);
128.5, 126.6, 125.8, 124.7, 123.9 (5d, 7 arom. CH); 47.7 (d, CH); 29.0 (q, MeN); 27.2 (t, CH2); 15.7 (q, MeCH); 9.3
.
‡
‡
(q, MeCH2). CI-MS (NH3): 243 (15), 242 (100, [M ‡ 1] ), 241 (6, M ). Anal. calc. for C16H19NO (241.33):
C 79.63, H 7.94, N 5.80; found: C 79.84, H 8.08, N 5.83.
2.2. Iva Synthon. (RS)-N,2-Dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]butanamide (8a). Within 7 min, 2n
LDA in THF/heptane/ethylbenzene (14.7 ml, 29.4 mmol) was added to a soln. of 7 (7.074 g, 29.31 mmol) and
LiClO4 (3.194 g, 30.02 mmol) in abs. THF (70 ml) at 788, and the mixture was stirred for 1 h at 788. Then,
EtBr (2.65 ml, 3.87 g, 35.5 mmol) was added at 788. After 40 min, the mixture was warmed to 558 within 4 h
and stored for another 18 h at 308. The resulting soln. was carefully poured on ice, neutralized with 1n HCl
(keeping the mixture still slightly basic), extracted with CH2Cl2, dried (MgSO4), and evaporated. CC (hexane/
AcOEt 5 :1) yielded 6.650 g (84%) of 8a. Colorless solid. M.p. 126.1 ± 126.98. Rf (hexane/AcOEt 1:1) 0.54 and
0.49, resp., for the diastereoisomers. IR: 2960s, 2920s, 2870m, 2850m, 1635s, 1595m, 1505m, 1460s, 1455s, 1435m,
1405s, 1370m, 1350m, 1335m, 1320m, 1295m, 1280m, 1250m, 1235m, 1210m, 1200w, 1165m, 1110m, 1100w,
1085m, 1050m, 1025m, 1005w, 980w, 960w, 900w, 810s, 785s, 750m, 730w, 710w, 665w, 620w. 1H-NMR: 8.05 ± 7.95
(m, 1 arom. H); 7.85 ± 7.8 (m, 2 arom. H); 7.5 ± 7.4 (m, 4 arom. H); 6.67, 6.66 (2q, J ˆ 6.8, CHN); 2.6 ± 2.5
(m, CHCO, MeN); 1.9 ± 1.7 (m, 1 H of CH2); 1.60, 1.58 (2d, J ˆ 6.8, MeCHN); 1.5 ± 1.35 (m, 1 H of CH2); 1.16,
1.09 (2d, J ˆ 6.8, MeCHCO); 0.93, 0.87 (2t, J ˆ 7.4, MeCH2). 13C-NMR: 175.7, 175.6 (2s, CO); 136.4, 136.3, 133.7,
131.9, 131.9 (5s, 3 arom. C); 128.4, 126.4, 126.4, 125.8, 124.7, 124.2, 124.1 (7d, 7 arom. CH); 47.7, 47.6 (2d, CHN);
38.0 (d, CHCO); 29.0, 29.0 (2q, MeN); 27.0, 26.9 (2t, CH2); 17.3, 17.0, 15.8, 15.5, 12.0 (5q, MeCHN, MeCHCO,
‡
MeCH2). CI-MS (NH3): 271 (20), 270 (100, [M ‡ 1] ). Anal. calc. for C18H23NO (269.39): C 80.25, H 8.61,
N 5.20; found: C 80.36, H 8.72, N 5.43.
(RS)-N,2-Dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]butanethioamide (9a). To a soln. of 8a (6.49 g,
24.1 mmol) in abs. toluene (30 ml), Lawesson reagent (5.86 g, 1.2 equiv.) was added, the mixture stirred for
17 h at 908 and 2 h at 1108 and then cooled to r.t., the precipitate filtered and washed with Et2O, and the filtrate
evaporated. CC (hexane/AcOEt 10 :1) yielded 6.06 g (88%) of 9a. Pale yellow oil. Recrystallization from
CH2Cl2, Et2O, and hexane gave colorless crystals. M.p. 145.5 ± 146.78. Rf (hexane/AcOEt 5 :1) 0.38 and 0.34,
resp., for the diastereoisomers. IR: 2970s, 2920s, 2860m, 2840m, 1595m, 1505m, 1475s, 1455s, 1440s, 1405s,
1370m, 1350w, 1335m, 1320s, 1295m, 1270m, 1240s, 1170m, 1135w, 1110m, 1080m, 1045m, 1020m, 990w, 970w,
950m, 910w, 875w, 810s, 785s, 745w, 720w, 675w, 620w, 605w. 1H-NMR: 8.0 ± 7.9 (m, 1 arom. H); 7.85 ± 7.8
(m, 2 arom. H); 7.6 ± 7.45 (m, 4 arom. H, CHN); 2.85 ± 2.75 (m, CHCS); 2.69 (s, MeN); 2.05 ± 1.9 (m, 1 H of
CH2); 1.69, 1.68 (2d, J ˆ 6.7, MeCHCS); 1.65 ± 1.5 (m, 1 H of CH2); 1.23, 1.21 (2d, J ˆ 6.6, 6.5, MeCHN); 0.91,
0.87 (2t, J ˆ 7.4, MeCH2CS). 13C-NMR: 209.4, 209.2 (2s, CS); 135.8, 135.7, 133.7, 132.1, 132.1 (5s, 3 arom. C);
129.0, 128.5, 126.8, 126.2, 125.3, 125.2, 125.0, 124.7, 124.6 (9d, 7 arom. CH); 56.9, 56.7 (2d, CHCS); 44.6, 44.4 (2d,
CHN); 33.2, 33.1 (2q, MeN); 30.9, 30.3 (2t, CH2); 21.1, 14.1, 13.8, 12.2, 12.1 (5q, MeCHCS, MeCHN, MeCH2).
‡
‡
CI-MS (NH3): 287 (6), 286 (37, [M ‡ 1] ), 133 (6), 132 (100, [M naphthCHCH2 ‡ 1] ). Anal. calc. for
C18H23NS (285.45): C 75.74, H 8.12, N 4.91; found: C 75.57, H 8.09, N 4.72.
(RS)-2-Ethyl-2,N-dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]-2H-azirin-3-amine (4a). To a soln. of 9a
(2.868 g, 10.05 mmol) and 3 drops of abs. DMF in abs. CH2Cl2 (20 ml) at 08, 2n phosgene in toluene (6 ml,
12 mmol) was added, the mixture stirred for 40 min at 08, and the solvent evaporated. The residue was dissolved
in abs. THF (15 ml), DABCO (1.141 g, 10.17 mmol) was added, and the soln. was stirred for 25 min at 08. After
filtration, NaN3 (1.314 g, 20.02 mmol) was added, the mixture stirred for 50 h at r.t. and then filtered over Celite,

Helvetica Chimica Acta ± Vol. 84 (2001)
1763
and the filtrate evaporated. The residue was dissolved in CH2Cl2, washed twice with aq. NaHCO3 soln. and once
with sat. aq. NaCl soln., dried (MgSO4), and evaporated. CC (hexane/AcOEt 2 :1) yielded 1.544 g (58%) of 4a
as pale yellow oil. The two diastereoisomers were separated by repeated MPLC (AcOEt): 0.674 g of (1'R,2S)-4a
(Rf (hexane/AcOEt 1:1) 0.33) as colorless crystals and 0.705 g of (1'R,2R)-4a (Rf 0.29) as an oil, from which it
was possible to grow crystals for X-ray crystal-structure determination.
Data of (1'R,2S)-4a: M.p. 63 ± 648. IR: 3440m, 3060m, 3040m, 2960s, 2910m, 2870m, 1825w, 1760s, 1715m,
1695m, 1680w, 1670w, 1660w, 1645w, 1630w, 1620w, 1610w, 1600m, 1570w, 1550w, 1530w, 1505m, 1485w, 1460m,
1450m, 1410m, 1395w, 1370m, 1340w, 1320m, 1265m, 1255m, 1235m, 1200m, 1165m, 1120w, 1105m, 1085m,
1040m, 1000m, 975w, 960w, 925m, 870w, 860w, 805w, 785s, 755w, 745w, 720m, 695w, 660w, 650w, 640w, 610w.
1H-NMR (300 MHz, (D6)DMSO, 350 K): 8.1 ± 8.05 (m, H C(8)(naphth)); 7.95 ± 7.9 (m, H C(5)(naphth));
7.9 ± 7.85 (m, H C(4)(naphth)); 7.55 ± 7.5 (m, 4 H(naphth)); 5.48 (q, J ˆ 6.9, CHN); 2.76 (s, MeN); 1.70 (d, J ˆ
6.9, MeCHN); 1.65 ± 1.45 (m, CH2); 0.98 (s, Me C(2)); 0.76 (t, J ˆ 7.5, MeCH2). 13C-NMR (75.5 MHz,
(D6)DMSO, 350 K): 165.2 (s, C(3)); 135.6 (s, C(1)(naphth)); 133.2 (s, C(4a)(naphth)); 130.6 (s, C(8a)-
(naphth)); 128.2 (d, CH(5)(naphth)); 127.7 (d, CH(4)(naphth)); 125.6, 125.1, 124.6, 123.4 (4d, 4 CH(naphth));
122.6 (d, CH(8)(naphth)); 53.7 (d, CHN); 42.9 (s, C(2)); 32.2 (q, MeN); 29.4 (t, CH2); 22.6 (q, Me C(2)); 17.0
‡
(q, MeCHN); 8.9 (q, MeCH2). CI-MS (NH3): 268 (20), 267 (100, [M ‡ 1] ), 265 (6), 209 (6), 111 (6). Anal. calc.
for C18H22N2 (266.39): C 81.16, H 8.32, N 10.52; found: C 81.21, H 8.37, N 10.73.
Data of (1'R,2R)-4a: M.p. 90 ± 918. IR: 3060w, 3040w, 2960s, 2930m, 2900m, 2870m, 1825w, 1760s, 1645w,
1600m, 1555w, 1545w, 1505m, 1460m, 1450m, 1410m, 1395w, 1370m, 1340w, 1320m, 1270m, 1250m, 1235m,
1200m, 1160m, 1100m, 1085m, 1040m, 1010w, 990w, 980w, 960w, 925w, 870w, 855w, 810s, 785s, 745w, 725w, 695w,
640w, 610w. 1H-NMR (300 MHz, (D6)DMSO, 350 K): 8.1 ± 8.05 (m, H C(8)(naphth)); 7.95 ± 7.9 (m,
H
C(5)(naphth)); 7.88 (d, J ˆ 7.7, H C(4)(naphth)); 7.6 ± 7.5 (m, 1 H(naphth)); 5.48 (q, J ˆ 6.9, CHN); 2.78
(s, MeN); 1.71 (d, J ˆ 6.9, MeCHN); 1.55 ± 1.25 (m, CH2); 1.21 (s, Me C(2)); 0.60 (t, J ˆ 7.5, MeCH2). 13C-NMR
(75.5 MHz, (D6)DMSO, 350 K): 165.3 (s, C(3)); 135.5 (s, C(1)(naphth)); 133.2 (s, C(4a)(naphth)); 130.5
(s, C(8a)(naphth)); 128.1 (d, CH(5)(naphth)); 127.7 (d, CH(4)(naphth)); 125.6, 125.1, 124.6, 123.5 (4d,
(4 CH(naphth)); 122.6 (d, CH(8)(naphth)); 53.7 (d, CHN); 42.8 (s, C(2)); 32.1 (q, MeN); 29.3 (t, CH2); 23.1
‡
(q, Me C(2)); 16.9 (q, MeCHN); 8.8 (q, MeCH2). CI-MS (NH3): 269 (6), 268 (20), 267 (100, [M ‡ 1] ), 227
(6), 184 (8). Anal. calc. for C18H22N2 (266.39): C 81.16, H 8.32, N 10.52; found: C 80.95, H 8.05, N 10.52.
2.3. Val(2Me) Synthon. (RS)-N,2,3-Trimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]butanamide (8b). Within
10 min, a soln. of 2n LDA (6 ml, 12 mmol) was added to a soln. of 7 (2.802 g, 11.61 mmol) and LiClO4 (1.243 g,
i
11.68 mmol) in abs. THF (30 ml) at 788, and the mixture was stirred for 35 min at 788. Then, PrI (1.4 ml,
2.4 g, 14 mmol) was added at 788. After 1 h, the mixture was warmed to r.t. and stirred for 2 h. As TLC showed
unconsumed 7, another portion of iPrI (0.5 ml, 5 mmol) was added. Then, the mixture was cooled to 788 and 2n
LDA (2 ml, 4 mmol) was added. After 45 min, the mixture was warmed to r.t. and stirred for further 30 min. The
resulting soln. was carefully poured on ice, neutralized with 1n HCl (keeping the mixture still slightly basic),
extracted with Et2O, dried (MgSO4), and evaporated. CC (hexane/AcOEt 5 :1) yielded 3.064 g (93%) of 8b.
Pale yellow solid. M.p. 94.5 ± 94.78. Rf (hexane/AcOEt 1:1) 0.55 and 0.49, resp., for the diastereoisomers. IR:
3040m, 2960s, 2930s, 2870m, 1930w, 1820w, 1620s, 1615s, 1550w, 1510m, 1480s, 1470s, 1460s, 1450s, 1405s, 1385m,
1370m, 1350m, 1325m, 1280m, 1260m, 1240m, 1210m, 1180m, 1170m, 1140w, 1125w, 1105s, 1075m, 1040m,
1025m, 980m, 970w, 920w, 910w, 890w, 870w, 800m, 785s, 765m, 750w, 720w, 665w, 640w, 625w. 1H-NMR: 8.1 ± 8.0
(m, 1 arom. H); 7.85 ± 7.8 (m, 2 arom. H); 7.55 ± 7.45 (m, 4 arom. H); 6.7 ± 6.65 (m, CHN); 2.50, 2.49 (2s, MeN);
2.35 ± 2.3 (m, CHCO); 2.05 ± 1.95 (m, Me2CH); 1.61, 1.58 (2d, J ˆ 6.6, 6.8, MeCHN); 1.13, 1.09 (2d, J ˆ 6.8,
MeCHCO); 0.96, 0.93, 0.88 (3d, J ˆ 6.7, 6.8, 6.6, Me2CH). 13C-NMR: 175.9, 175.7 (2s, CO); 136.3, 133.6, 131.9
(3s, 3 arom. C); 128.4, 126.4, 126.3, 125.9, 124.7, 124.4, 124.2 (7d, 7 arom. CH); 47.7, 47.6, 43.2, 43.1 (4d, CHN,
CHCO); 31.3, 30.4 (2d, Me2CH); 29.3, 29.1 (2q, MeN); 21.7, 21.5, 19.4, 19.0 (4q, MeCHN, MeCHCO); 15.8, 15.4,
‡
15.3, 14.4 (4q, Me2CH). CI-MS (NH3): 285 (20), 284 (100, [M ‡ 1] ). Anal. calc. for C19H25NO (283.41): C 80.52,
H 8.89, N 4.94; found: C 80.79, H 8.74, N 4.94.
(RS)-N,2,3-Trimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]butanethioamide (9b). To a soln. of 8b (3.842 g,
13.56 mmol) in abs. toluene (15 ml), Lawesson reagent (3.295 g, 8.147 mmol, 1.2 equiv.) was added, and the
mixture was stirred for 62 h at 1108. After cooling to r.t., the precipitate was filtered and washed with Et2O and
the filtrate evaporated. Twice repeated CC (hexane/AcOEt 10 :1) yielded 3.032 g (75%) of 9b as a pale yellow
oil and 0.433 g (13%) of starting 8b. 9b: Rf (hexane/AcOEt 10 :1) 0.30 and 0.25, resp., for the diastereoisomers.
IR (CHCl3): 3060w, 2960s, 2870w, 1600w, 1505m, 1480s, 1460m, 1445m, 1405s, 1385w, 1370m, 1330m, 1260m,
1245m, 1170w, 1110w, 1075m, 1045w, 1000w, 960w, 920w, 910w, 865w, 850w, 840w. 1H-NMR: 8.05 ± 7.95
(m, 1 arom. H); 7.85 ± 7.8 (m, 2 arom. H); 7.6 ± 7.45 (m, 4 arom. H, CHN); 2.70 (s, MeN); 2.65 ± 2.5 (m, CHCS);
2.35 ± 2.25 (m, Me2CH); 1.7 ± 1.6 (m, MeCHN); 1.25 ± 1.2 (m, MeCHCS); 1.0 ± 0.95, 0.9 ± 0.85 (2m, Me2CH).

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Helvetica Chimica Acta ± Vol. 84 (2001)
13C-NMR: 209.6, 209.3 (2s, CS); 135.8, 135.6, 133.6, 133.6, 132.1, 131.9 (6s, 3 arom. C); 128.9, 128.5, 128.4, 126.8,
126.7, 126.1, 126.1, 125.3, 125.2, 125.0, 124.9, 124.7, 124.6 (13d, 7 arom. C); 56.7, 56.5, 50.2, 50.0 (4d, CHN,
CHCS); 35.0, 33.3 (2d, Me2CH); 33.5 (q, MeN); 22.0, 21.5 (2q, MeCHN); 20.9, 19.7, 19.4, 19.1, 14.0, 13.6
‡
(6q, MeCHCS, Me2CH). CI-MS (NH3): 302 (5), 301 (20), 300 (100, [M ‡ 1] ), 146 (8). Anal. calc. for C19H25NS
(299.48): C 76.20, H 8.41, N 4.68; found: C 76.26, H 8.60, N 4.68.
(RS)-2-Isopropyl-2,N-dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]-2H-azirin-3-amine (4b). To a soln. of 9b
(4.130 g, 13.79 mmol) and 4 drops of abs. DMF in abs. CH2Cl2 (13 ml), 2n phosgene in toluene (8.5 ml, 19 mmol)
was added at 08. The mixture was stirred for 25 min at 08 and 30 min at r.t. and the solvent evaporated. The
residue was dissolved in abs. THF (15 ml), DABCO (1.575 g, 14.04 mmol) was added, and the soln. was stirred
for 20 min at 08. After filtration, NaN3 (1.803 g, 27.74 mmol) was added, the mixture stirred for 27 h at r.t. and
then filtered over Celite, the filter cake washed with Et20, the filtrate evaporated. The residue was dissolved in
CH2Cl2, washed with aq. NaHCO3 soln. (2Â) and sat. aq. NaCl soln. (1Â), dried (MgSO4), and evaporated. CC
(hexane/AcOEt 3 :1) and MPLC (AcOEt) gave 2.040 g (53%) of 4b, i.e. 787 mg of crystalline (1'R,2S)-4b (Rf
(hexane/AcOEt 1:1) 0.33), 1172 mg of (1'R,2R)-4b (Rf 0.29) as a pale yellow oil, and 81 mg of (1'R,2S)/
(1'R,2R)-4b (pale yellow oil). The structure of (1'R,2S)-4b was determined by X-ray crystallography.
Data of (1'R,2S)-4b: M.p. 92 ± 92.58. IR: 3432w, 3044w, 2957s, 2936m, 1764vs, 1597w, 1510w, 1458m, 1410w,
1381w, 1368m, 1318w, 1236w, 1199m, 1138w, 1098w, 1052s, 1008w, 949w, 810vs, 786s, 726w, 614w. 1H-NMR
(300 MHz, (D6)DMSO, 373 K): 8.1 ± 8.05 (m, 1 arom. H); 7.95 ± 7.85 (m, 2 arom. H); 7.6 ± 7.5 (m, 4 arom. H);
5.56 (q, J ˆ 6.9, CHN); 2.69 (s, MeN); 1.80 (sept., J ˆ 6.8, Me2CH); 1.72 (d, J ˆ 6.9, MeCHN); 1.09
(s, Me C(2)); 0.89, 0.81 (2d, J ˆ 6.8, Me2CH). 13C-NMR (75.5 MHz, (D6)DMSO, 373 K): 165.1 (s, C(3));
135.3, 133.1, 130.6 (3s, 3 arom. C); 128.1, 127.7, 125.5, 125.1, 124.5, 123.6, 122.6 (7d, 7 arom. CH); 53.0 (d, CHN);
46.0 (s, C(2)); 33.1 (d, (Me)2CH); 32.0 (q, MeN); 20.6 (q, Me C(2)); 18.7, 18.0 (2q, Me2CH); 17.0 (q, MeCHN).
‡
‡
‡
ESI-MS (MeOH): 363 (10), 313 (65, [M ‡ MeOH ‡ 1] ), 281 (100, [M ‡ 1] ), 155 (12, [naphthCHMe] ). Anal.
calc. for C18H23NO (269.39): C 81.38, H 8.63, N 9.99; found: C 81.12, H 8.70, N 9.87.
Data of (1'R,2R)-4b: IR: 3434w, 3050w, 2960s, 2870m, 1760vs, 1599w, 1510w, 1454m, 1412w, 1376w, 1321w,
1239w, 1196m, 1170w, 1102w, 1082w, 1047m, 982w, 944w, 864w, 804m, 780vs, 726w, 696w, 631w. 1H-NMR
(300 MHz, (D6)DMSO, 373 K): 8.15 ± 8.1 (m, 1 arom. H); 7.95 ± 7.85 (m, 2 arom. H); 7.65 ± 7.5 (m, 4 arom. H);
5.55 (q, J ˆ 6.9, CHN); 2.72 (s, MeN); 1.73 (d, J ˆ 6.9, MeCHN); 1.75 ± 1.65 (m, Me2CH); 1.21 (s, Me C(2));
0.84, 0.74 (2d, J ˆ 6.8, 6.9, Me2CH). 13C-NMR (75.5 MHz, (D6)DMSO, 373 K): 165.1 (s, C(3)); 135.3, 133.1,
130.5 (3s, 3 arom. C); 128.0, 127.6, 125.5, 125.0, 124.5, 123.6, 122.6 (7d, 7 arom. CH); 53.1 (d, CHN); 45.9
(s, C(2)); 33.2 (d, Me2CH); 31.7 (q, MeN); 20.9 (q, Me C(2)); 18.7, 18.0 (2q, Me2CH); 16.4 (q, MeCHN). CI-
‡
‡
MS (NH3): 326 (6), 282 (21), 281 (100, [M ‡ 1] ), 155 (15, [naphthCHMe] ).
2.4. Ala(2cPent) Synthon. (RS)-2-Cyclopentyl-N-methyl-N-[(R)-1-(naphthalen-1-yl)ethyl]propanamide
(8c). Within 20 min, a soln. of 2n LDA (17.5 ml, 35 mmol) was added to a soln. of 7 (6.999 g, 29.002 mmol)
and LiClO4 (3.088 g, 29.025 mmol) in abs. THF (70 ml) at 08, and the mixture was stirred for 7 min at 08. Then,
cyclopentyl bromide (3.1 ml, 4.3 g, 28.9 mmol) was added at 08 within 20 min. After 3 h, the mixture was
warmed to r.t. and stirred for 2 h. TLC showed still unconsumed 7. The mixture was stored at 48 for 18 h, then
poured carefully on ice, extracted with Et2O, dried (MgSO4), and evaporated. CC (hexane/AcOEt 5 :1) yielded
3.921 g (44%) of 8c as a colorless oil and 2.859 g (41%) of starting 7. 8c: Rf (hexane/AcOEt 2 :1) 0.47 and 0.38,
resp., for the diastereoisomers. IR (neat): 3049w, 2955vs, 2868m, 1738w, 1634vs, 1511m, 1461s, 1403s, 1372m,
1277m, 1240m, 1170w, 1110m, 1087w, 1044m, 806s, 782vs, 724w, 671w, 629w. 1H-NMR: 8.05 ± 8.0 (m, 1 arom. H);
7.85 ± 7.8 (m, 2 arom. H); 7.55 ± 7.45 (m, 4 arom. H); 6.7 ± 6.65 (m, CHN); 2.50 (s, MeN); 2.45 ± 2.2 (m, 2 H);
1.95 ± 1.8 (m, 2 H); 1.60, 1.58 (2d, J ˆ 6.1, 6.7, MeCHN); 1.55 ± 1.5 (m, 4 H); 1.16, 1.10 (2d, J ˆ 6.7, MeCHCO);
1.15 ± 0.9 (m, 1 H). 13C-NMR: 175.9, 175.8 (2s, CO); 136.5, 136.3, 133.6, 132.0, 131.9 (5s, 3 arom. C); 128.4, 128.3,
126.4, 126.3, 125.8, 124.7, 124.4, 124.2 (8d, 7 arom. CH); 47.6, 47.5, 43.8, 43.2, 42.0 (5d, CHN, CHCO,
CH(cPent)); 31.5, 31.4, 30.2, 30.1, 25.1, 25.0 (6t, 4 CH2); 29.2, 29.1 (2q, MeN); 16.8, 16.4, 15.8, 15.4 (4q, 2 Me).
‡
CI-MS (NH3): 311 (23), 310 (100, [M ‡ 1] ). Anal. calc. for C21H27NO (309.45): C 81.51, H 8.79, N 4.53; found:
C 81.28, H 8.59, N 4.50.
(RS)-2-Cyclopentyl-N-methyl-N-[(R)-1-(naphthalen-1-yl)ethyl]propanethioamide (9c). To a soln. of 8c
(3.703 g, 11.966 mmol) in abs. toluene (10 ml), Lawesson reagent (2.903 g, 7.177 mmol, 1.2 equiv.) was added,
the mixture stirred for 7 h at 1308 and then cooled to r.t., the precipitate filtered and washed with Et2O, and the
filtrate evaporated. CC (hexane/AcOEt 10 :1) yielded 2.242 g (58%) of 9c as colorless oil and 1.436 g (39%) of
starting 8c. 9c: Rf (hexane/AcOEt 5 :1) 0.41 and 0.26, resp., for the diastereoisomers. IR (neat): 3048m, 2950s,
2866s, 1934w, 1820w, 1736m, 1598m, 1510s, 1478s, 1406vs, 1371s, 1320s, 1240s, 1173m, 1111s, 1073s, 1045s, 990m,
970m, 930m, 868w, 805s, 780vs, 726w, 695m, 642w. 1H-NMR: 8.0 ± 7.95 (m, 1 arom. H); 7.85 ± 7.8 (m, 2 arom. H);
7.6 ± 7.55 (m, CHN); 7.55 ± 7.45 (m, 4 arom. H); 2.8 ± 2.45 (m, 2 H); 2.71, 2.69 (2s, MeN); 2.35 ± 1.85 (m, 2 H);

Helvetica Chimica Acta ± Vol. 84 (2001)
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1.69, 1.68 (2d, J ˆ 6.6, 6.7, Me); 1.65 ± 1.45 (m, 4 H); 1.24, 1.23 (2d, J ˆ 6.5, 6.2, Me); 1.2 ± 0.75 (m, 2 H).
13C-NMR: 209.3, 209.2 (2s, CS); 135.9, 135.5, 133.6, 132.0 (4s, 3 arom. C); 128.9, 128.4, 128.3, 126.7, 126.1, 125.2,
125.1, 124.9, 124.8, 124.6 (10d, 7 arom. C); 56.7, 56.4, 49.3, 49.0, 47.6, 46.2 (6d, 3 CH); 33.2 (q, MeN); 31.8, 31.5,
‡
30.5, 25.2, 25.1 (5t, 4 CH2); 20.6, 20.3, 14.0, 13.6 (4q, 2 Me). CI-MS (NH3): 327 (16), 326 (100, [M ‡ 1] ), 172 (9,
‡
[M naphthCHCH2 ‡ 1] ). Anal. calc. for C21H27NS (325.52): C 77.49, H 8.39, N 4.30, S 9.85; found: C 77.37,
H 8.25, N 4.25, S 9.69.
(RS)-2-Cyclopentyl-2,N-dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]-2H-azirin-3-amine (4c). To a soln. of
9c (2.097 g, 6.442 mmol) and 3 drops of abs. DMF in abs. CH2Cl2 (10 ml) at 08, 2n phosgene soln. in toluene
(4.2 ml, 8.4 mmol) was added, stirred for 15 min at 08 and 10 min at r.t., and evaporated. The residue was
dissolved in abs. THF (10 ml), DABCO (0.729 g, 6.498 mmol) was added, and the soln. was stirred for 20 min at
08. Then, NaN3 (0.848 g, 13.046 mmol) was added, the mixture stirred for 8 h at r.t. and then filtered over Celite,
the filter cake washed with Et2O, and the filtrate evaporated. CC (hexane/AcOEt 2 :1) followed by MPLC
(AcOEt) yielded 0.415 g of crystalline (1'R,2S)-4c (Rf (hexane/AcOEt 1:1) 0.28) and 0.818 g (1'R,2R)-4c (Rf
0.23) as a pale yellow oil. Total yield of 4c: 1.233 g (62%). The structure of (1'R,2S)-4c was determined by X-ray
crystallography.
Data of (1'R,2S)-4c: M.p. 95 ± 968. IR: 3046w, 2956s, 2867m, 1764vs, 1597w, 1510w, 1443w, 1410w, 1319w,
1236w, 1197m, 1100w, 1055s, 1025w, 903w, 810s. 1H-NMR (300 MHz, (D6)DMSO, 373 K): 8.1 ± 8.05
(m, 1 arom. H); 7.95 ± 7.85 (m, 2 arom. H); 7.6 ± 7.5 (m, 4 arom. H); 5.52 (q, J ˆ 6.8, CHN); 2.71 (s, MeN);
2.15 ± 2.05 (m, CH); 1.72 (d, J ˆ 6.9, MeCHN); 1.7 ± 1.45, 1.4 ± 1.25, 1.2 ± 1.1 (3m, 4 CH2); 1.06 (s, Me C(2)).
13C-NMR (75.5 MHz, (D6)DMSO, 373 K): 165.1 (s, C(3)); 135.4, 133.1, 130.6 (3s, 3 arom. C); 128.1, 127.7, 125.5,
125.1, 124.5, 123.6, 122.6 (7d, 7 arom. CH); 53.2 (d, CHN); 45.2 (d, CH); 44.6 (s, C(2)); 32.0 (q, MeN); 28.4,
‡
28.0, 24.4, 24.3 (4t, 4 CH2); 22.1 (q, Me C(2)); 16.7 (q, MeCHN). ESI-MS (MeOH): 635 (7, [2M ‡ Na] ), 419
‡
‡
‡
‡
(8), 339 (32, [M ‡ MeOH] ), 329 (100, [M ‡ Na] ), 307 (66, [M ‡ 1] ), 155 (25, [naphthCHMe] ), 153 (27).
Anal. calc. for C21H26N2 (306.45): C 82.31, H 8.55, N 9.14; found: C 82.49, H 8.21, N 9.12.
Data of (1'R,2R)-4c: IR (neat): 3049w, 2949s, 2866m, 1759vs, 1598w, 1510w, 1450w, 1413w, 1374w, 1319w,
1239w, 1196w, 1102w, 1056w. 1H-NMR (300 MHz, (D6)DMSO, 373 K): 8.15 ± 8.1 (m, 1 arom. H); 7.95 ± 7.85
(m, 2 arom. H); 7.6 ± 7.5 (m, 4 arom. H); 5.52 (q, J ˆ 6.8, CHN); 2.74 (s, MeN); 2.0 ± 1.9 (m, CH); 1.72 (d, J ˆ
6.9, MeCHN); 1.65 ± 1.6, 1.55 ± 1.25, 1.2 ± 1.0 (3m, 4 CH2); 1.23 (s, Me C(2)). 13C-NMR (75.5 MHz, (D6)DMSO,
373 K): 165.2 (s, C(3)); 135.4, 133.1, 130.5 (3s, 3 arom. C); 128.0, 127.6, 125.5, 125.0, 124.5, 123.6, 122.6 (7d,
7 arom. CH); 53.3 (d, CHN); 45.2 (d, CH); 44.4 (s, C(2)); 31.8 (q, MeN); 28.4, 28.0, 24.3, 24.2 (4t, 4 CH2); 22.5
‡
‡
(q, Me C(2)); 16.6 (q, MeCHN). ESI-MS (MeOH ‡ NaI): 330 (24, [M ‡ Na ‡ 1] ), 329 (100, [M ‡ Na] ), 155
‡
(4, [naphthCHMe] ). Anal. calc. for C21H26N2 (306.45): C 82.31, H 8.55, N 9.14; found: C 82.07, H 8.25, N 9.22.
2.5. Leu(2Me) Synthon. (RS)-N,2,4-Trimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]pentanamide (8d). Within
10 min, a soln. of 2n LDA (21 ml, 42 mmol) was added to a soln. of 7 (8.291 g, 34.355 mmol) and LiClO4
(3.656 g, 34.36 mmol) in abs. THF (80 ml) at 788, and the resulting mixture was stirred for 25 min at 788.
Then, iBuI (5 ml, 7.9 g, 43 mmol) was added at 788 and the mixture slowly warmed to 208 (7 h) and stored
overnight at 308. The soln. was poured carefully on ice, extracted with Et2O, dried (MgSO4), and evaporated.
CC (hexane/AcOEt 5 :1, then 2 :1) yielded 8.382 g (82%) of 8d as a colorless solid and 1.322 g (16%) of starting
7. After recrystallization (CH2Cl2, AcOEt, hexane) of an aliquot of 8d, colorless crystals were obtained. M.p.
131.4 ± 132.08. Rf (hexane/AcOEt 1 :1) 0.56 and 0.50, resp., for the diastereoisomers. IR: 3080w, 3060w, 3040m,
2950m, 2930m, 2900m, 2860m, 1960w, 1940w, 1830w, 1680w, 1640m, 1630s, 1595m, 1550w, 1530w, 1510m, 1470s,
1460s, 1455m, 1445m, 1430m, 1400m, 1385m, 1370m, 1350m, 1340m, 1325m, 1285m, 1235m, 1210m, 1175m,
1165m, 1130w, 1110s, 1080m, 1040m, 1025m, 1010w, 980w, 960w, 915w, 880w, 810s, 785s, 755w, 730w, 660w, 620w.
1H-NMR: 8.0 ± 7.95 (m, 1 arom. H); 7.85 ± 7.8 (m, 2 arom. H); 7.55 ± 7.45 (m, 4 arom. H); 6.7 ± 6.65 (m, CHN);
2.75 ± 2.65 (m, CHCO); 2.50, 2.50 (2s, MeN); 1.8 ± 1.6, 1.3 ± 1.05, 0.9 ± 0.75 (3m, 15 H, Me2CHCH2CHMe,
MeCHN). 1H-NMR (only 1 diastereoisomer, Rf 0.56): 8.0 ± 7.95 (m, 1 arom. H); 7.85 ± 7.8 (m, 2 arom. H); 7.55 ±
7.45 (m, 4 arom. H); 6.66 (q, J ˆ 6.8, CHN); 2.75 ± 2.65 (m, CHCO); 2.51 (s, MeN); 1.8 ± 1.7 (m, CH2); 1.60
(d, J ˆ 6.9, MeCHCO); 1.3 ± 1.25 (m, Me2CH); 1.07 (d, J ˆ 6.8, MeCHN); 0.91, 0.90 (2d, J ˆ 6.5, Me2CH).
13C-NMR: 176.0 (s, CO); 136.5, 133.7, 132.0 (3s, 3 arom. C); 128.5, 126.5, 126.4, 125.9, 124.8, 124.2 (6d,
7 arom. CH); 47.8 (d, CHN); 43.2, 43.0 (2t, CH2); 34.2, 34.1 (2d, CHCO); 29.1 (q, MeN); 25.9, 25.7 (2d,
Me2CH); 22.9, 22.7 (2q, Me2CH); 17.9, 17.5, 15.8, 15.6 (4q, MeCH, MeCH2). 13C-NMR (only 1 diastereoisomer,
Rf 0.56): 175.9 (s, CO); 136.4, 133.7, 131.9 (3s, 3 arom. C); 128.4, 126.4, 125.8, 124.7, 124.2 (5d, 7 arom. CH); 47.7
(d, CHN); 43.0 (t, CH2); 34.1 (d, CHCO); 29.0 (q, MeN); 25.9 (d, Me2CH); 22.8, 22.6 (2q, Me2CH); 17.8, 15.7
‡
(2q, MeCH, MeCH2). CI-MS (NH3): 299 (20), 298 (100, [M ‡ 1] ). Anal. calc. for C20H27NO (297.44): C 80.76,
H 9.15, N 4.71; found: C 80.80, H 8.98, N 4.73.

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Helvetica Chimica Acta ± Vol. 84 (2001)
(RS)-N,2,4-Trimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]pentanethioamide (9d). To a soln. of 8d (2.516 g,
8.459 mmol) in abs. toluene (15 ml), Lawesson reagent (2.134 g, 10.55 mmol) was added, the mixture stirred for
18 h at 1108, cooled to r.t. and filtered, the precipitate washed with Et2O, and the filtrate evaporated. CC
(hexane/AcOEt 10 :1) yielded 2.614 g (99%) of 9d. Recrystallization from hexane/Et2O gave colorless crystals.
M.p. 123.4 ± 124.38. Rf (hexane/AcOEt 5 :1) 0.41 and 0.35, resp., for the diastereoisomers. IR (CHCl3): 2960s,
2930s, 2860m, 2450w, 2420w, 2390w, 1600w, 1505m, 1480s, 1445s, 1405s, 1385m, 1370m, 1350w, 1320m, 1290m,
1260m, 1250m, 1170m, 1140w, 1110m, 1075m, 1060m, 1050m, 1040m, 1025w, 985m, 970w, 955w, 920w, 900w,
865w, 845w. 1H-NMR: 7.95 ± 7.8 (m, 3 arom. H); 7.6 ± 7.45 (m, 4 arom. H, CHN); 3.05 ± 3.0 (m, CHCS); 2.70
(s, MeN); 1.85 ± 0.65 (m, 15 H, Me2CHCH2CHMe, MeCHN). 13C-NMR: 209.1, 208.9 (2s, CS); 135.4, 133.2, 131.7
(3s, 3 arom. C); 128.5, 128.1, 126.4, 125.7, 124.8, 124.6, 124.2, 124.1 (8d, 7 arom. CH); 56.4, 56.3 (2d, CHN); 46.3
(t, CH2); 40.1 (d, CHCS); 32.6 (q, MeN); 25.2, 25.0 (2d, Me2CH); 22.6, 22.2, 22.0, 20.9, 20.7, 13.5, 13.3 (7q,
‡
Me2CHCH2Me, MeCHN). CI-MS (NH3): 315 (19), 314 (100, [M ‡ 1] ), 169 (7), 160 (25), 155 (7,
‡
[naphthCHMe] ). Anal. calc. for C20H27NS (313.51): C 76.62, H 8.68, N 4.47, S 10.23; found: C 76.88, H 8.52,
N 4.57, S 10.27.
(RS)-2-Isobutyl-2,N-dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]-2H-azirin-3-amine (4d). To a soln. of 9d
(1.756 g, 5.601 mmol) and 4 drops of abs. DMF in abs. CH2Cl2 (8 ml), 2n phosgene soln. in toluene (3.4 ml,
6.8 mmol) was added at 08. The soln. was stirred for 10 min at 08 and 30 min at r.t. and evaporated. The residue
was dissolved in abs. THF (8 ml), DABCO (0.633 g, 5.643 mmol) was added, and the soln. was stirred for 1.5 h at
08. After filtration, NaN3 (0.733 g, 11.277 mmol) was added, the mixture stirred for 22 h at r.t. and then filtered
over Celite, and the filtrate evaporated. The residue was dissolved in CH2Cl2, washed with aq. NaHCO3 soln.
(2Â) and sat. aq. NaCl soln. (1Â), dried (MgSO4), and evaporated. CC (hexane/AcOEt 3 :1) yielded 0.921 g
(56%) of 4d as a pale yellow oil. A diastereoisomer mixture (1.7 g) was separated by repeated CC (hexane/
AcOEt 3 :1): 0.768 g of (1'R,2S)-4d as colorless crystals (Rf (hexane/AcOEt 1:1) 0.36) and 0.755 g (1'R,2R)-4d
as a pale yellow oil (Rf 0.31). The structure of (1'R,2S)-4d was determined by X-ray crystallography.
Data of (1'R,2S)-4d: M.p. 73.6 ± 74.18. IR: 3070w, 3040m, 2960s, 2960s, 2905m, 2870m, 1755s, 1600w, 1510m,
1465m, 1450m, 1445m, 1410w, 1385m, 1380m, 1365m, 1315m, 1270m, 1260w, 1235m, 1195m, 1160m, 1130w,
1110w, 1095w, 1050s, 1015w, 960w, 940w, 920w, 810s, 785s, 725w, 650w, 625w, 615w. 1H-NMR (300 MHz,
(D6)DMSO, 373 K): 8.1 ± 8.05 (m, 1 arom. H); 7.95 ± 7.85 (m, 2 arom. H); 7.55 ± 7.5 (m, 4 arom. H); 5.48 (q, J ˆ
6.9, CHN); 2.74 (s, MeN); 1.69 (d, J ˆ 6.9, MeCHN); 1.65 ± 1.6 (m, Me2CH); 1.58 (dd, J ˆ 14.0, 6.1, 1 H of CH2);
1.29 (dd, J ˆ 13.5, 5.5, 1 H of CH2); 0.98 (s, Me C(2)); 0.91, 0.89 (2d, J ˆ 7.1, 6.6, Me2CH). 13C-NMR (75.5 MHz,
(D6)DMSO, 373 K): 165.1 (s, C(3)); 135.6, 133.2, 130.6 (3s, 3 arom. C); 128.2, 127.8, 125.7, 125.2, 124.7, 123.6,
122.7 (7d, 7 arom. CH); 53.6 (d, CHN); 46.1 (t, CH2); 41.5 (s, C(2)); 32.2 (q, MeN); 29.3 (d, Me2CH); 23.5
‡
(q, Me ± C(2)); 23.0, 22.3 (2q, Me2CH); 16.9 (q, MeCHN). CI-MS (NH3): 296 (22), 295 (100, [M ‡ 1] ), 251 (6),
186 (17), 184 (16). Anal. calc. for C20H26N2 (294.43): C 81.59, H 8.90, N 9.51; found: C 81.39, H 8.65, N 9.42.
Data of (1'R,2R)-4d: IR (neat): 3050w, 2952s, 2869m, 1758vs, 1510w, 1452w, 1414w, 1372w, 1319w, 1262w,
1194w, 1170w, 1116w, 1056w, 970w, 938w, 863w. 1H-NMR (300 MHz, (D6)DMSO, 373 K): 8.05 ± 8.0
(m, 1 arom. H); 7.95 ± 7.9 (m, 2 arom. H); 7.6 ± 7.5 (m, 4 arom. H); 5.49 (q, J ˆ 6.9, CHN); 2.74 (s, MeN); 1.70
(d, J ˆ 6.9, MeCHN); 1.50 (sept., J ˆ 6.6, Me2CH); 1.31 (dd, J ˆ 13.9, 6.9, 1 H of CH2); 1.22 (s, Me C(2)); 1.1 ±
1.0 (br., 1 H of CH2); 0.80, 0.76 (2d, J ˆ 6.6, Me2CH). 13C-NMR (75.5 MHz, (D6)DMSO, 373 K): 165.2 (s, C(3));
135.5, 133.2, 130.6 (3s, 3 arom. C); 128.2, 127.8, 125.6, 125.2, 124.6, 123.6, 122.7 (7d, 7 arom. CH); 53.5 (d, CHN);
46.0 (t, CH2); 41.5 (s, C(2)); 31.9 (q, MeN); 24.2 (d, Me2CH); 24.0 (q, Me C(2)); 22.9, 22.3 (2q, Me2CH); 16.8
‡
‡
‡
(q, MeCHN). ESI-MS (MeOH): 327 (10, [M ‡ MeOH ‡ 1] ), 295 (100, [M ‡ 1] ), 155 (43, [naphtCHMe] ),
‡
141 (38, [M naphthCHCH2 ‡ 1] ). Anal. calc. for C20H26N2 (294.43): C 81.59, H 8.90, N 9.51; found: C 81.59,
H 8.61, N 9.48.
2.6. Phe(2Me) Synthon. (RS)-N,2-Dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]-3-phenylpropanamide (8e).
Within 20 min, a soln. of 2n LDA (11.5 ml, 23.0 mmol) was added to a soln. of 7 (4.633 g, 19.20 mmol) in abs.
THF (50 ml) at 08. Then, benzyl bromide (2.3 ml, 3.3 g, 19.3 mmol) was added within 55 min keeping the temp.
below 58. After 60 min, the mixture was poured carefully on ice, extracted with Et2O, dried (MgSO4), and
evaporated. CC (hexane/AcOEt 5 :1) yielded 5.723 g (90%) of 8e as a pale yellow oil. Recrystallization from
Et2O and hexane gave colorless crystals. M.p. 105 ± 105.58. Rf (hexane/AcOEt 2 :1) 0.41 and 0.32, resp., for the
diastereoisomers. IR: 3030w, 2974m, 2933m, 2916w, 2872w, 1628vs, 1508m, 1475s, 1453s, 1453s, 1410s, 1372w,
1350w, 1322w, 1279m, 1238w, 1213w, 1164w, 1128m, 1108m, 1088m, 1043m, 1026w, 982w, 812s, 790s, 760m, 744m,
735w, 700s. 1H-NMR: 8.0 ± 7.5 (m, 3 arom. H); 7.5 ± 7.1 (m, 9 arom. H); 6.61 (q, J ˆ 6.8, CHN); 3.15 ± 3.05, 2.95 ±
2.8, 2.75 ± 2.65 (3m, CHCO, CH2); 2.46, 2.22 (2s, MeN); 1.58, 1.43 (2d, J ˆ 6.8, 6.9, MeCHN); 1.18, 1.16 (2d, J ˆ
6.8, 6.7, MeCHCO). 13C-NMR: 175.1, 174.9 (2s, CO); 140.3, 140.1, 136.3, 136.0, 133.7, 131.9 (6s, 4 arom. C);
129.0, 128.9, 128.4, 128.3, 128.2, 126.6, 126.4, 126.1, 125.9, 125.8, 124.8, 124.7, 124.1, 124.0 (14d, 12 arom. CH);

Helvetica Chimica Acta ± Vol. 84 (2001)
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47.9, 47.8 (2d, CHN); 40.4, 39.9 (2t, CH2); 38.7, 38.5 (2d, CHCO); 28.9, 28.8 (2q, MeN); 17.9, 17.1
‡
(2q, MeCHCO); 15.6, 15.5 (2q, MeCHN). CI-MS (NH3): 333 (23), 332 (100, [M ‡ 1] ), 227 (18), 199 (7).
Anal. calc. for C23H25NO (331.43): C 83.35, H 7.60, N 4.23; found: C 83.33, H 7.59, N 4.14.
(RS)-N,2-Dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]-3-phenylpropanethioamide (9e). To a soln. of 8e
(5.50 g (16.6 mmol)) in abs. toluene (20 ml), Lawesson reagent (4.0 g, 1.2 equiv.) was added, the mixture stirred
for 17 h at 1108 and then cooled to r.t., the precipitate filtered and washed with Et2O, and the filtrate evaporated.
After CC (hexane/AcOEt 5 :1), the solvent was evaporated, and the formed precipitate was filtered yielding
1.949 g of a pure diastereoisomer of 9e as colorless crystals. The filtrate was evaporated and the residue dried:
3.466 g of a pale yellow solid diastereoisomer mixture 9e/9e'. Total yield of 9e: 5.415 g (94%). M.p. (9e) 140.5 ±
141.08. Rf (hexane/AcOEt 5 :1) 0.35 and 0.29, resp., for 9e and 9e'. IR: 3442w, 3047w, 3008w, 2974s, 2950m, 2927s,
2911s, 2845m, 1598w, 1509s, 1482vs, 1444vs, 1407vs, 1368s, 1323s, 1295s, 1254vs, 1213w, 1174s, 1141w, 1114vs,
1082s, 1050s, 1038m, 1026m, 1009w, 984s, 968s, 929w, 906w, 873w, 852w, 810vs, 793vs, 785vs, 755vs, 726w, 708vs,
1
677w, 625w, 613w. H-NMR: 7.95 ± 7.9, 7.85 ± 7.8 (2m, 3 arom. H); 7.55 ± 7.4, 7.35 ± 7.3, 7.25 ± 7.1 (3m, 9 arom. H,
CHN); 3.3 ± 3.2 (m, CH2); 2.9 ± 2.85 (m, CHCS); 2.70 (s, MeN of 9e'); 2.32 (s, MeN of 9e); 1.67 (d, J ˆ 6.7,
MeCHN of 9e'); 1.50 (d, J ˆ 6.7, MeCHN of 9e); 1.31 (d, J ˆ 6.2, MeCHCS of 9e); 1.25 (d, J ˆ 6.4, MeCHCS of
9e'). 13C-NMR: 208.1 (s, CS); 140.0, 139.9, 135.5, 133.6, 132.0 (5s, 4 arom. C); 129.2, 129.1, 129.0, 128.9, 128.5,
128.4, 128.2, 128.2, 127.0, 126.7, 126.3, 126.0, 125.2, 125.2, 124.9, 124.3 (16d, 12 arom. CH); 56.9, 56.7 (2d, CHCS);
44.9, 44.6 (2d, CHN); 44.2, 43.1 (t, CH2); 33.0 (q, MeN); 21.9, 20.8 (2q, MeCHN); 13.8, 13.7 (2q, MeCHCS). CI-
‡
‡
MS (NH3; 9e): 349 (15), 348 (61, [M ‡ 1] ), 195 (11), 194 (100, [M naphthCHCH2 ‡ 1] ). Anal. calc. for
C23H25NS (347.50): C 79.50, H 7.25, N 4.03, S 9.23; found: C 79.41, H 7.13, N 3.98, S 9.26.
(RS)-2-Benzyl-2,N-dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]-2H-azirin-3-amine (4e). To a soln. of 9e
(5.135 g (14.78 mmol)) and 5 drops of abs. DMF in abs. CH2Cl2 (15 ml) at 08, 2n phosgene in toluene (9 ml,
18 mmol) was added and the mixture was stirred for 30 min at 08 and evaporated. The residue was dissolved in
abs. THF (15 ml), DABCO (1.662 g, 14.82 mmol) was added, and the mixture was stirred for 20 min at 08. After
filtration, NaN3 (1.922 g, 29.57 mmol) was added, the suspension stirred for 18 h at r.t. and then filtered over
Celite, the filter cake washed with Et2O and AcOEt, and the filtrate evaporated. The residue was dissolved in
CH2Cl2, the soln. washed with aq. NaHCO3 soln. (2Â) and the aq. soln. with CH2Cl2 (1Â) and the combined org.
phase dried (MgSO4) and evaporated. CC (hexane/AcOEt 3 :1) followed by MPLC (AcOEt) yielded 1.362 g of
(1'R,2S)-4e (Rf (hexane/AcOEt 1:1) 0.32) and 1.526 g of (1'R,2R)-4e (Rf 0.24). Total yield of 4e: 2.888 g
(59%). Crystallization of (1'R,2S)-4e from AcOEt afforded suitable crystals for X-ray crystal structure
determination. (1'R,2R)-4e was obtained as an oil.
Data of (1'R,2S)-4e: M.p. 109.5 ± 110.58. IR: 3441m, 3052m, 2972s, 2918m, 1765vs, 1741m, 1600m, 1510m,
1494w, 1452m, 1374m, 1318m, 1265m, 1240m, 1204m, 1168m, 1103m, 1071m, 1028w, 985w, 955w, 808m, 784s,
705s, 622w, 602w, 576w. 1H-NMR (300 MHz, (D6)DMSO, 373 K): 8.05 ± 8.0, 7.95 ± 7.85, 7.55 ± 7.45, 7.3 ± 7.15 (4m,
12 arom. H); 5.41 (q, J ˆ 6.9, CHN); 2.9 ± 2.7 (m, CH2); 2.61 (br. s, MeN); 1.53 (d, J ˆ 6.9, MeCHN); 1.04 (br. s,
Me C(2)). 13C-NMR (75.5 MHz, (D6)DMSO, 373 K): 164.8 (s, C(3)); 138.1, 135.3, 133.2, 130.6 (4s, 4 arom. C);
129.1, 128.2, 127.8, 127.3, 125.8, 125.4, 125.2, 124.7, 123.6, 122.7 (10d, 12 arom. CH); 53.2 (d, CHN); 43.7 (t, CH2);
42.4 (s, C(2)); 32.3 (q, MeN); 22.8 (q, Me C(2)); 16.5 (q, MeCHN). CI-MS (NH3): 330 (24), 329 (100, [M ‡
‡
1] ). Anal. calc. for C23H24N2 ´ 0.25 C4H7O2 (347.50): C 82.31, H 7.41, N 8.00; found: C 82.53, H 7.25, N 8.29.
Data of (1'R,2R)-4e: IR (neat): 3059m, 2974m, 2938m, 1760vs, 1614s, 1511m, 1495s, 1454s, 1373s, 1320m,
1
1240m, 1188m, 1080s, 1030m, 985w, 954w, 866w. H-NMR (300 MHz, (D6)DMSO, 373 K): 8.05 ± 7.9, 7.55 ± 7.5,
7.25 ± 7.1 (3m, 12 arom. H); 5.43 (q, J ˆ 6.9, CHN); 2.70 (br. s, MeN); 2.57 (br., CH2); 1.65 (d, J ˆ 6.9, MeCHN);
1.19 (br. s, Me C(2)). 13C-NMR (75.5 MHz, (D6)DMSO, 373 K): 165.1 (s, C(3)); 138.2, 135.7, 133.2, 130.5 (4s,
4 arom. C); 128.8, 128.2, 127.8, 127.4, 125.8, 125.4, 125.2, 124.7, 123.5, 122.6 (10d, 12 arom. CH); 53.8 (d, CHN);
44.0 (t, CH2); 42.4 (s, C(2)); 32.3 (q, MeN); 22.9 (q, Me C(2)); 17.0 (q, MeCHN). CI-MS (NH3): 330 (22), 329
‡
(100, [M ‡ 1] ).
3. Reactions of 4a ± e with Thiobenzoic and Benzoic Acid. 3.1. Reactions of 4a. N-{(S)-1-Methyl-1-
{{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}thioxomethyl}propyl}benzamide ((1'R,1S)-10a). To thiobenzoic
acid (53 mg, 0.38 mmol), a soln. of (1'R,2S)-4a (101 mg, 0.38 mmol) in abs. CH2Cl2 (5 ml) was added, and the
mixture was stirred for 19 h at r.t. Evaporation and prep. TLC (hexane/AcOEt 1:1) gave 143 mg (93%) of
(1'R,1S)-10a. Colorless foam. M.p. 88 ± 918. Rf (hexane/AcOEt 1:1) 0.35. IR: 3426w, 3211m, 3051w, 2974w,
2933w, 1659s, 1600w, 1579w, 1510vs, 1479vs, 1374s, 1333w, 1238w, 1174w, 1112w, 1071m, 1044w, 894w, 867w.
1H-NMR: 9.86 (br. s, NH); 8.0 ± 7.95, 7.9 ± 7.85, 7.8 ± 7.75, 7.6 ± 7.45 (4m, 12 arom. H, CHN); 3.05 ± 2.95 (m, 1 H of
CH2 of Iva); 2.85 (s, MeN); 2.05 ± 1.95 (m, 1 H of CH2 of Iva); 1.82 (s, Me(3) of Iva); 1.78 (d, J ˆ 6.7, MeCHN);
0.87 (t, J ˆ 7.4, Me(4) of Iva). 13C-NMR: 205.0 (s, CS); 164.1 (s, CO); 135.8, 134.9, 133.7, 131.9 (4s, 4 arom. C);
131.0, 129.3, 128.7, 128.4, 127.0, 126.9, 126.3, 125.4, 125.0, 123.7 (10d, 12 arom. CH); 64.9 (s, C(2) of Iva); 61.4

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(d, CHN); 35.9 (q, MeN); 28.5 (t, CH2(3) of Iva); 23.8, 13.1, 8.9 (3q, MeCHN, Me(3) of Iva, Me(4) of Iva). CI-
‡
‡
MS (NH3): 407 (7), 406 (28), 405 (100, [M ‡ 1] ), 283 (12, [M PhCONH2] ), 252 (10), 251 (66, [M
‡
‡
naphthCHCH2 ‡ 1] ), 217 (9), 155 (5, [naphtCHMe] ). Anal. calc. for C25H28N2OS (404.58): C 74.22, H 6.98,
N 6.92, S 7.93; found: C 74.15, H 6.86, N 6.75, S 7.73.
N-{(S)-1-Methyl-1-{{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}oxomethyl}propyl}benzamide ((1'R,1S)-
11a). As described for (1'R,1S)-10a, with benzoic acid (46 mg, 0.38 mmol), (1'R,2S)-4a (100 mg, 0.38 mmol),
and CH2Cl2 (4 ml); 39 h at r.t.: 123 mg (84%) of (1'R,1S)-11a. Colorless foam. M.p. 74 ± 768. Rf (hexane/AcOEt
1:1) 0.30. IR: 3348m, 3052w, 2976m, 1718w, 1660s, 1612vs, 1579m, 1511s, 1481s, 1391m, 1290w, 1240w, 1172w,
1105m, 1084m, 1044w, 925w, 881w. 1H-NMR: 8.41 (br. s, NH); 7.9 ± 7.8, 7.6 ± 7.4 (2m, 12 arom. H); 6.68 (q, J ˆ 6.8,
CHN); 2.85 ± 2.8 (m, 1 H of CH2 of Iva); 2.60 (s, MeN); 1.9 ± 1.85 (m, 1 H of CH2 of Iva); 1.75 (s, Me(3) of Iva);
1.68 (d, J ˆ 6.8, MeCHN); 0.91 (t, J ˆ 7.4, Me(4) of Iva). 13C-NMR: 172.4, 165.1 (2s, 2 CO); 135.5, 135.2, 133.7,
131.8 (4s, 4 arom. C); 131.1, 130.0, 128.8, 128.6, 128.4, 126.8, 126.6, 126.0, 125.2, 124.8, 123.4 (11d, 12 arom. CH);
62.2 (s, C(2) of Iva); 50.9 (d, CHN); 30.0 (q, MeN); 27.6 (t, CH2(3) of Iva); 22.1, 15.0, 8.8 (3q, MeCHN, Me(3) of
‡
‡
‡
Iva, Me(4) of Iva). ESI-MS (MeOH): 427 (16, [M ‡ K] ), 416 (30), 411 (98, [M ‡ Na] ), 389 (13, [M ‡ 1] ),
‡
‡
‡
267 (28, [M PhCONH2] ), 235 (44, [M [naphthCHCH2 ‡ 1] ), 204 (100, [M naphthCH(Me)NMe] ), 176
‡
‡
(78, [M naphthCH(Me)N(Me)CO] ), 155 (50, [naphtCHMe] ). Anal. calc. for C25H28N2O2 ´ 0.5 H2O
(397.52): C 75.54, H 7.35, N 7.05; found: C 75.59, H 7.33, N 6.63.
N-{(R)-1-Methyl-1-{{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}thioxomethyl}propyl}benzamide
((1'R,1R)-10a). As described for (1'R,1S)-10a, with thiobenzoic acid (53 mg, 0.38 mmol), (1'R,2R)-4a (101 mg,
0.38 mmol), and CH2Cl2 (5 ml); 19 h at r.t.: 152 mg (99%) of (1'R,1R)-10a. Colorless foam. M.p. 84 ± 868. Rf
(hexane/AcOEt 1:1) 0.36. IR: 3424w, 3208m, 3051w, 2973m, 2875w, 1733w, 1659s, 1600w, 1579w, 1510vs, 1479vs,
1375s, 1330m, 1273w, 1240m, 1174w, 1113w, 1071m, 1043m, 1028w, 895w, 867w. 1H-NMR: 9.86 (br. s, NH); 8.0 ±
7.95, 7.9 ± 7.85, 7.65 ± 7.6, 7.55 ± 7.45 (4m, 12 arom. H, CHN); 3.0 ± 2.9 (m, 1 H of CH2 of Iva); 2.87 (s, MeN); 1.95 ±
1.85 (m, 1 H of CH2 of Iva); 1.91 (s, Me(3) of Iva); 1.74 (d, J ˆ 6.7, MeCHN); 0.78 (t, J ˆ 7.4, Me(4) of Iva).
13C-NMR: 205.0 (s, CS); 164.1 (s, CO); 135.8, 134.8, 133.6, 131.9 (4s, 4 arom. C); 131.0, 129.2, 128.6, 128.4, 126.9,
126.3, 125.6, 125.0, 124.2 (9d, 12 arom. CH); 64.9 (s, C(2) of Iva); 61.0 (d, CHN); 36.3 (q, MeN); 28.3 (t, CH2(3)
of Iva); 24.8, 13.0, 9.1 (3q, MeCHN, Me(3) of Iva, Me(4) of Iva). CI-MS (NH3): 407 (8), 406 (28), 405 (100,
‡
‡
‡
[M ‡ 1] ), 283 (15, [M PhCONH2] ), 251 (48, [M naphthCHCH2 ‡ 1] ). Anal. calc. for C25H28N2OS ´ 0.33
H2O (404.58): C 73.13, H 7.04, N 6.82; found: C 73.11, H 6.90, N 6.58.
N-{(R)-1-Methyl-1-{{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}oxomethyl}propyl}benzamide ((1'R,1R)-11a).
As described for (1'R,1S)-10a, with benzoic acid (46 mg, 0.38 mmol), (1'R,2R)-4a (100 mg, 0.38 mmol), and
CH2Cl2 (4 ml); 40 h at r.t.: 132 mg (90%) of (1'R,1R)-11a. Colorless foam. M.p. 79 ± 818. Rf (hexane/AcOEt 1 :1)
0.29. IR: 3342w, 3052w, 2977w, 1718w, 1611vs, 1579w, 1511s, 1481s, 1393w, 1240w, 1172w, 1098w, 1083m, 1044w,
1
913w, 881w. H-NMR: 8.38 (br. s, NH); 8.1 ± 8.05, 8.0 ± 7.8, 7.55 ± 7.4 (3m, 12 arom. H); 6.72 (q, J ˆ 6.8, CHN);
2.85 ± 2.7 (m, 1 H of CH2 of Iva); 2.63 (s, MeN); 1.9 ± 1.75 (m, 1 H of CH2 of Iva); 1.84 (s, Me(3) of Iva); 1.66
(d, J ˆ 6.8, MeCHN); 0.79 (t, J ˆ 7.4, Me(4) of Iva). 13C-NMR: 172.5, 165.1 (2s, 2 CO); 135.5, 135.1, 133.6, 131.8
(4s, 4 arom. C); 130.0, 128.5, 128.4, 126.8, 126.6, 126.0, 126.0, 125.3, 124.8, 123.9 (9d, 12 arom. CH); 62.0 (s, C(2)
of Iva); 50.6 (d, CHN); 30.3 (q, MeN); 27.6 (t, CH2(3) of Iva); 22.4, 15.2, 8.9 (3q, MeCHN,
‡
Me(3) of Iva, Me(4) of Iva). ESI-MS (MeOH): 799 (9, [2M ‡ 1] ), 677 (15), 661 (7), 603 (9), 427 (15, [M ‡
‡
‡
‡
K] ), 416 (88), 411 (100, [M ‡ Na] ), 408 (91), 389 (17, [M ‡ 1] ), 339 (10), 307 (61), 267 (23, [M
‡
‡
‡
PhCONH2] ), 235 (35, [M naphthCHCH2 ‡ 1] ), 204 (88, [M naphthCH(Me)NMe] ), 176 (55, [M
‡
‡
naphthCH(Me)N(Me)CO] ), 155 (59, [naphtCHMe] ). Anal. calc. for C25H28N2O2 ´ 0.5 H2O (397.52):
C 75.54, H 7.35, N 7.05; found: C 75.62, H 7.22, N 6.56.
3.2. Reactions of 4b. N-{(S)-1,2-Dimethyl-1-{{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}thioxomethyl}-
propyl}benzamide ((1'R,1S)-10b). As described for (1'R,1S)-10a, with thiobenzoic acid (30 mg, 0.217 mmol),
(1'R,2S)-4b (60 mg, 0.214 mmol), and CH2Cl2 (2 ml), 48 h at r.t.: 88 mg (98%) of (1'R,1S)-10b. Colorless foam.
M.p. 79 ± 828. Rf (hexane/AcOEt 1:1) 0.47. 1H-NMR: 7.94 (br. s, NH); 7.9 ± 7.8, 7.65 ± 7.4 (2m, 12 arom. H, CHN);
2.80 (s, MeN); 2.35 (sept., J ˆ 6.8, C(3) of Val(2Me)); 1.92 (s, Me(3) of Val(2Me)); 1.74 (d, J ˆ 6.7, MeCHN);
1.22, 1.05 (2d, J ˆ 6.8, 6.7, 2 Me(4) of Val(2Me)). 13C-NMR: 205.4 (s, CS); 165.5 (s, CO); 135.4, 133.6, 131.9 (3s,
4 arom. C); 131.2, 129.0, 128.6, 126.9, 126.8, 126.2, 125.4, 125.0, 124.2 (9d, 12 arom. CH); 67.7 (s, C(2) of
Val(2Me)); 60.8 (d, CHN); 36.3 (q, MeN); 35.4 (d, C(3) of Val(2Me)); 21.8, 18.4, 18.1, 12.9 (4q, Me(3) of
‡
Val(2Me), 2 Me(4) of Val(2Me), MeCHN). CI-MS (NH3): 421 (9), 420 (29), 419 (100, [M ‡ 1] ), 266 (14), 265
‡
(82, [M naphthCHCH2 ‡ 1] ), 231 (9). Anal. calc. for C26H30N2OS ´ 0.33 H2O (424.16): C 73.55, H 7.28, N 6.60;
found: C 73.39, H 7.43, N 6.28.
N-{(R)-1,2-Dimethyl-1-{{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}thioxomethyl}propyl}benzamide
((1'R,1R)-10b). As described for (1'R,1S)-10a, with thiobenzoic acid (30 mg, 0.217 mmol), (1'R,2R)-4b (60 mg,

Helvetica Chimica Acta ± Vol. 84 (2001)
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0.214 mmol), and CH2Cl2 (2 ml); 23 h at r.t.: 85 mg (94%) of (1'R,1R)-10b. Colorless foam. M.p. 153 ± 1548. Rf
(hexane/AcOEt 1:1) 0.43. 1H-NMR: 8.42 (br. s, NH); 7.9 ± 7.8, 7.65 ± 7.35 (2m, 12 arom. H, CHN); 2.83
(s, MeN); 2.27 (sept., J ˆ 6.8, C(3) of Val(2Me)); 2.01 (s, Me(3) of Val(2Me)); 1.74 (d, J ˆ 6.7, MeCHN); 1.20,
1.05 (2d, J ˆ 6.9, 6.6, 2 Me(4) of Val(2Me)). 13C-NMR: 205.7 (s, CS); 165.1 (s, CO); 135.5, 135.2, 133.5, 132.0 (4s,
4 arom. C); 131.1, 129.0, 128.4, 128.3, 127.2, 126.9, 126.3, 125.4, 124.9, 124.6 (10d, 12 arom. CH); 67.5 (s, C(2) of
Val(2Me)); 61.0 (d, CHN); 36.6 (q, MeN); 35.2 (d, C(3) of Val(2Me)); 21.7, 18.5, 13.2 (3q, Me(3) of Val(2Me),
‡
2 Me(4) of Val(2Me), MeCHN). CI-MS (NH3): 421 (8), 420 (27), 419 (100, [M ‡ 1] ), 266 (6), 265 (37, [M
‡
naphthCHCH2 ‡ 1] ), 231 (7). Anal. calc. for C26H30N2OS ´ 0.2 H2O (422.20): C 73.97, H 7.26, N 6.63; found:
C 74.08, H 7.54, N 6.57.
3.3. Reactions of 4c. N-{(S)-1-Cyclopentyl-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-
thioxoethyl}benzamide (1'R,1S)-10c). As described for (1'R,1S)-10a, with thiobenzoic acid (44 mg,
0.318 mmol), (1'R,2S)-4c (93 mg, 0.304 mmol), and CH2Cl2 (2 ml); 19 h at r.t.; prep. TLC (hexane/AcOEt
2 :1): 128 mg (95%) of (1'R,1S)-10c. Colorless foam. M.p. 88 ± 918. Rf (hexane/AcOEt 2 :1) 0.31. IR: 3432m,
2946m, 2868m, 1667s, 1600w, 1579w, 1510s, 1478vs, 1376s, 1330m, 1280w, 1232w, 1174w, 1107w, 1060m, 1016w.
1H-NMR: 7.9 ± 7.8, 7.7 ± 7.3 (2m, 12 arom. H, CHN, NH); 2.81 (s, MeN); 2.59 (quint., J ˆ 8.4, CH(3) of
Ala(2cPent); 1.99 (s, Me(3) of Ala(2cPent)); 1.9 ± 1.8 (m, 2 H of cPent); 1.74 (d, J ˆ 6.7, CHNMe); 1.7 ± 1.5
(m, 6 H of cPent). 13C-NMR: 205.3 (s, CS); 165.5 (s, CO); 135.8, 135.1, 133.6, 132.0 (4s, 4 arom. C); 131.2, 128.8,
128.5, 126.8, 126.7, 126.1, 125.4, 125.0, 124.4 (9d, 12 arom. CH); 67.4 (s, C(2) of Ala(2cPent)); 60.6 (d, CHN);
47.7 (d, C(3) of Ala(2cPent)); 35.8 (q, MeN); 28.0, 27.8, 25.2 (3t, 4 CH2 of cPent); 23.6, 12.9 (2q, 2 Me). ESI-MS
‡
‡
‡
(MeOH/CH2Cl2/NaI): 911 (15, [2M ‡ Na] ), 467 (100, [M ‡ Na] ), 291 (57, [M naphthCHCH2 ‡ 1] ). Anal.
calc. for C28H32N2OS (444.64): C 75.64, H 7.25, N 6.30; found: C 75.14, H 7.14, N 6.42.
N-{(R)-1-Cyclopentyl-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-thioxoethyl}benzamide
((1'R,1R)-10c). As described for (1'R,1S)-10a, with thiobenzoic acid (42 mg, 0.311 mmol), (1'R,2R)-4c (94 mg
(0.307 mmol)), and CH2Cl2 (2 ml); 2 h at r.t.; prep. TLC (hexane/AcOEt 2 :1): 128 mg (68%) of (1'R,1R)-10c.
Colorless solid. M.p. 104 ± 1058. Rf (hexane/AcOEt 2 :1) 0.31. IR: 3309w, 3053w, 2952s, 2870m, 1740m, 1668s,
1641s, 1600w, 1579w, 1512vs, 1476vs, 1383vs, 1331m, 1230s, 1156m, 1104w, 1061s, 1014m, 970w, 932w, 856w.
1H-NMR: 7.95 (d, J ˆ 8.5, 1 arom. H); 7.85 ± 7.8, 7.75 ± 7.3 (2m, 11 arom. H, CHN, NH); 2.86 (s, MeN); 2.59
(quint., J ˆ 8.4, CH(3) of Ala(2cPent); 2.04 (s, Me(3) of Ala(2cPent)); 2.0 ± 1.95 (m, 1 H of cPent); 1.73 (d, J ˆ
6.7, MeCHN); 1.7 ± 1.45 (m, 7 H of cPent). 13C-NMR: 205.1 (s, CS); 165.1 (s, CO); 135.4, 133.5, 132.1 (3s,
4 arom. C); 131.0, 128.9, 128.4, 128.1, 127.1, 126.8, 126.2, 125.3, 124.9, 124.8 (10d, 12 arom. CH); 66.9 (s, C(2) of
Ala(2cPent)); 60.9 (d, CHN); 47.6 (d, C(3) of Ala(2cPent)); 36.3 (q, MeN); 28.1, 28.0, 25.3, 24.9 (4t, 4 CH2 of
‡
‡
cPent); 23.2, 13.2 (2q, 2 Me). ESI-MS (MeOH ‡ NaI): 469 (11), 468 (32, [M ‡ Na ‡ 1] ), 467 (100, [M ‡ Na] ).
Anal. calc. for C28H32N2OS ´ 0.5 H2O (444.64): C 74.13, H 7.33, N 6.18; found: C 73.84, H 7.09, N 6.17.
3.4. Reactions of 4d. N-{(S)-1,3-Dimethyl-1-{{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}thioxomethyl}-
butyl}benzamide ((1'R,1S)-10d. As described for (1'R,1S)-10a, with thiobenzoic acid (26 mg, 0.19 mmol),
(1'R,2S)-4d (54 mg, 0.18 mmol), and CH2Cl2 (2 ml); 17 h at r.t.: 75 mg (95%) of (1'R,1S)-10d. Colorless solid.
M.p. 174 ± 1758. Rf (hexane/AcOEt 1:1) 0.47. IR: 3446w, 3205s, 2956m, 2869w, 1660vs, 1600w, 1579w, 1512s,
1480vs, 1394s, 1373s, 1332w, 1303w, 1228w, 1175w, 1103w, 1068w, 1001w, 912w, 871w, 810m. 1H-NMR: 10.20 (br. s,
NH); 8.05 ± 8.0, 7.9 ± 7.85, 7.75 ± 7.7, 7.6 ± 7.45 (4m, 12 arom. H, CHN); 3.04 (dd, J ˆ 15.3, 7.4, 1 H of CH2(3) of
Leu(2Me)); 2.85 (s, MeN); 1.89 (dd, J ˆ 15.3, 4.9, 1 H of CH2(3) of Leu(2Me)); 1.79 (d, J ˆ 6.8, MeCHN); 1.77
(s, Me(3) of Leu(2Me)); 1.7 ± 1.6 (m, CH(4) of Leu(2Me)); 0.95, 0.88 (2d, J ˆ 6.6, 6.7, 2 Me(5) of Leu(2Me)).
13C-NMR: 205.7 (s, CS); 164.1 (s, CO); 136.2, 135.1, 133.8, 132.0 (4s, 4 arom. C); 131.1, 129.4, 128.8, 128.5, 127.2,
127.0, 126.4, 125.5, 125.1, 123.9 (10d, 12 arom. CH); 64.8 (s, C(2) of Leu(2Me)); 61.7 (d, CHN); 44.1 (t, C(3) of
Leu(2Me)); 36.3 (q, MeN); 25.4 (d, C(4) of Leu(2Me)); 24.6, 24.3, 23.4, 12.9 (4q, Me(3) of Phe(2Me), MeCHN,
‡
‡
2 Me(5) of Leu(2Me)). ESI-MS (MeOH/NaI): 457 (9), 456 (33, [M ‡ Na ‡ 1] ), 455 (100, [M ‡ Na] ). Anal.
calc. for C27H32N2OS ´ 0.33 H2O (438.64): C 73.93, H 7.51, N 6.39, S 7.31; found: C 74.07, H 7.65, N 6.33, S 7.48.
N-{(R)-1,3-Dimethyl-1-{{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}thioxomethyl}butyl}benzamide
((1'R,1R)-10d. As described for (1'R,1S)-10a, with thiobenzoic acid (26 mg, 0.19 mmol), (1'R,2R)-4d (54 mg,
0.18 mmol), and CH2Cl2 (2 ml); 15 h at r.t.: 78 mg (99%) of (1'R,1R)-10d. Colorless foam. M.p. 78 ± 818. Rf
(hexane/AcOEt 1:1) 0.40. IR: 3424w, 3211w, 3053w, 2955m, 2868w, 1735w, 1657s, 1600w, 1579w, 1510vs, 1477vs,
1394s, 1372m, 1332w, 1302w, 1231w, 1173w, 1105w, 1066w, 1042m, 1028w, 970w, 911w, 869w. 1H-NMR: 10.09
(br. s, NH); 8.0 ± 7.85 (m, 5 arom. H); 7.70 (q, J ˆ 6.7, CHN); 7.63 (d, J ˆ 7.1, 1 arom. H); 7.55 ± 7.45 (m, 6 ar-
om. H); 1.96 (dd, J ˆ 15.4, 9.8, 1 H of CH2(3) of Leu(2Me)); 2.84 (s, MeN); 1.88 (s, Me(3) of Leu(2Me)); 1.83
(dd, J ˆ 15.3, 3.7, 1 H of CH2(3) of Leu(2Me)); 1.74 (d, J ˆ 6.7, MeCHN); 1.5 ± 1.4 (m, CH(4) of Leu(2Me));
0.93, 0.51 (2d, J ˆ 6.5, 6.7, 2 Me(5) of Leu(2Me)). 13C-NMR: 205.5 (s, CS); 164.2 (s, CO); 136.2, 134.8, 133.8,
132.0 (4s, 4 arom. C); 131.1, 129.4, 128.7, 128.5, 127.0, 126.8, 126.4, 125.8, 125.1, 124.5 (10d, 12 arom. CH); 65.0

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(s, C(2) of Leu(2Me)); 61.0 (d, CHN); 43.8 (t, C(3) of Leu(2Me)); 36.5 (q, MeN); 25.7 (d, C(4) of Leu(2Me));
25.8, 24.4, 22.7, 13.2 (4q, Me(3) of Phe(2Me), MeCHN, 2 Me(5) of Leu(2Me)). ESI-MS (MeOH/NaI): 457 (8),
‡
‡
456 (33, [M ‡ Na ‡ 1] ), 455 (100, [M ‡ Na] ) Anal. calc. for C27H32N2OS ´ 0.3 H2O (438.64): C 73.93, H 7.51,
N 6.39, S 7.31; found: C 74.06, H 7.64, N 6.25, S 7.38.
3.5. Reactions of 4e. N-{(S)-1-Benzyl-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-thioxoe-
thyl}benzamide ((1'R,1S)-10e. As described for (1'R,1S)-10a, with thiobenzoic acid (43 mg, 0.31 mmol),
(1'R,2S)-4e (100 mg, 0.31 mmol), and CH2Cl2 (2 ml); 18 h at r.t.; CC (hexane/AcOEt 5 :1): 139 mg (97%) of
(1'R,1S)-10e. M.p. 93 ± 968. Rf (hexane/AcOEt 1:1) 0.45. IR: 3410m, 2929w, 1655m, 1618m, 1578w, 1509s, 1478vs,
1388s, 1375s, 1331w, 1241w, 1104w, 1063m, 1044w, 876w. 1H-NMR: 9.31 (br. s, NH); 7.95 ± 7.85, 7.8 ± 7.75, 7.7 ±
7.35, 7.2 ± 7.05 (4m, 17 arom. H, CHN); 4.20, 3.35 (AB, J ˆ 14.4, CH2(3) of Phe(2Me)); 2.90 (s, MeN); 1.91
(s, Me(3) of Phe(2Me)); 1.64 (d, J ˆ 6.7, MeCHN). 13C-NMR: 204.1 (s, CS); 164.8 (s, CO); 136.2, 135.6, 135.0,
133.6, 132.0 (5s, 5 arom. C); 131.2, 130.0, 129.2, 128.6, 128.5, 127.9, 127.1, 126.9, 126.2, 125.4, 125.0, 123.9 (12d,
17 arom. CH); 64.6 (s, C(2) of Phe(2Me)); 61.2 (d, CHN); 41.8 (t, PhCH2); 36.7 (q, MeN); 24.3, 12.7 (2q, Me(3)
‡
‡
of Phe(2Me), MeCHN). ESI-MS (MeOH ‡ NaI): 489 (100, [M ‡ Na] ), 473 (46, [M ‡ Li] ), 317 (13), 313 (36,
‡
‡
[M naphthCHCH2 ‡ 1] ), 279 (10), 238 (10), 176 (6), 155 (59, [naphtCHMe] ). Anal calc. for C30H30N2OS ´
0.2 H2O (470.25): C 76.62, H 6.52, N 5.96, S 6.82; found: C 76.64, H 6.64, N 5.78, S 6.96.
N-{(S)-1-Benzyl-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-oxoethyl}benzamide
((1'R,1S)-11e). As described for (1'R,1S)-10a, with benzoic acid (38 mg, 0.31 mmol), (1'R,2S)-4e (100 mg,
0.31 mmol), and CH2Cl2 (2 ml); 44 h at r.t. CC (CH2Cl2/MeOH 100 :1) gave 109 mg (79%) of (1'R,1S)-11e. M.p.
178 ± 1798. Rf (CH2Cl2/MeOH 20 :1) 0.61. Rf (CH2Cl2/MeOH 100 :1) 0.19. IR: 3434vs, 3049m, 2942m, 1662s,
1613s, 1529m, 1455w, 1396w, 1333w, 1236w, 1172w, 1138w, 1074w, 802w, 778w, 720w, 697w, 659w. 1H-NMR: 7.97
(br. s, NH); 7.85 ± 7.8, 7.75 ± 7.7, 7.55 ± 7.35, 7.3 ± 7.25, 7.15 ± 7.1 (5m, 17 arom. H); 6.55 (q, J ˆ 6.8, CHN); 4.01, 3.26
(AB, J ˆ 14.4, CH2(3) of Phe(2Me)); 2.67 (s, MeN); 1.83 (s, Me(3) of Phe(2Me)); 1.56 (d, J ˆ 6.8, MeCHN).
13C-NMR: 171.7 (s, CO); 165.6 (s, PhCO); 136.5, 135.4, 135.2, 133.6, 131.8 (5s, 5 arom. C); 131.2, 129.8, 128.7,
128.6, 128.4, 128.2, 126.9, 126.7, 126.0, 125.2, 124.8, 123.4 (12d, 17 arom. CH); 61.8 (s, C(2) of Phe(2Me)); 50.9
(d, CHN); 40.2 (t, C(3) of Phe(2Me)); 30.7 (q, MeN); 22.4, 14.6 (2q, MeCHN, Me(3) of Phe(2Me)). ESI-MS
‡
‡
‡
‡
(MeOH): 924 (11, [2M ‡ Na] ), 489 (86, [M ‡ K] ), 473 (100, [M ‡ Na] ), 451 (15, [M ‡ 1] ), 297 (14, [M
‡
‡
naphthCHCH2 ‡ 1] ), 266 (6, [M naphthCH(Me)NMe] ). Anal. calc. for C30H30N2O2 ´ 0.2 H2O (454.18):
C 79.34, H 6.74, N 6.17; found: C 79.29, H 6.70, N 6.07.
N-{(R)-1-Benzyl-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-thioxoethyl}benzamide
((1'R,1R)-10e. As described for (1'R,1S)-10a, with thiobenzoic acid (43 mg, 0.31 mmol), (1'R,2R)-4e (100 mg,
0.31 mmol), and CH2Cl2 (2 ml); 20 h at r.t.; CC (hexane/AcOEt 5 :1): 136 mg (96%) of (1'R,1R)-10e. M.p.
188.5 ± 1898. Rf (hexane/AcOEt 1 :1) 0.43. IR: 2980m, 2938m, 1656vs, 1599w, 1580w, 1510vs, 1482vs, 1446s, 1385s,
1366s, 1320m, 1304m, 1244w, 1216w, 1173w, 1109w, 1064s, 1025m, 805w, 781s, 757w, 729m, 710m, 693w. 1H-NMR:
8.0 ± 7.75, 7.7 ± 7.35, 7.2 ± 7.0 (3m, NH, 17 arom. H, CHN); 4.00, 3.64 (AB, J ˆ 14.1, CH2(3) of Phe(2Me)); 2.91
(s, MeN); 1.81 (s, Me(3) of Phe(2Me)); 1.74 (d, J ˆ 6.7, MeCHN). 13C-NMR: 204.2 (s, CS); 165.1 (s, CO); 136.9,
135.4, 134.7, 133.6, 132.1 (5s, 5 arom. C); 131.6, 130.5, 129.0, 128.5, 128.0, 127.1, 126.8, 126.7, 126.1, 125.7, 124.9,
124.6 (12d, 17 arom. CH); 64.2 (s, C(2) of Phe(2Me)); 60.4 (d, CHN); 44.2 (t, C(3) of Phe(2Me)); 36.0
(q, MeN); 25.2, 13.4 (2q, Me(3) of Phe(2Me), MeCHN). ESI-MS (MeOH/MeCN 1:1 ‡ 0.1% HCOOH): 467
‡
‡
‡
(46, [M ‡ Na] ), 433 (14), 314 (22), 313 (100, [M naphthCHCH2 ‡ 1] ), 155 (10, [naphtCHMe] ). Anal. calc.
for C30H30N2OS ´ 0.2 H2O (470.25): C 76.62, H 6.52, N 5.96, S 6.82; found: C 76.56, H 6.61, N 5.86, S 6.72.
N-{(R)-1-Benzyl-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-oxoethyl}benzamide ((1'R,1R)-
11e. As described for (1'R,1S)-10a, with benzoic acid (38 mg, 0.31 mmol), (1'R,2R)-4e (100 mg, 0.31 mmol), and
CH2Cl2 (2 ml); 64 h at r.t.; CC (CH2Cl2/MeOH 100 :1): 127 mg (92%) of (1'R,1R)-11e. M.p. 172 ± 1738. Rf
(CH2Cl2/MeOH 20 :1) 0.56. Rf (CH2Cl2/MeOH 100 :1) 0.11. IR: 3407s, 3372s, 3060m, 2978m, 1656s, 1636s,
1611vs, 1580w, 1531m, 1510m, 1483m, 1454m, 1392m, 1333w, 1256w, 1173w, 1106w, 1073m, 1044w, 1029w, 808w,
782w, 717w, 702w, 673w, 649w. 1H-NMR: 8.05 ± 8.0, 7.85 ± 7.8, 7.7 ± 7.65, 7.55 ± 7.35, 7.15 ± 7.0 (5m, 17 arom. H);
6.77 (q, J ˆ 6.8, CHN); 6.68 (s, NH); 3.64, 3.62 (AB, J ˆ 14.2, CH2(3) of Phe(2Me)); 2.66 (s, MeN); 1.66 (d, J ˆ
6.9, MeCHN); 1.58 (s, Me(3) of Phe(2Me)). 13C-NMR: 171.5 (s, CO); 166.0 (s, PhCO); 137.0, 135.8, 134.5, 133.7,
132.0 (5s, 5 arom. C); 131.4, 130.7, 128.5, 128.4, 128.0, 126.8, 126.6, 126.5, 125.8, 125.3, 124.7, 124.1 (12d,
17 arom. CH); 60.4 (s, C(2) of Phe(2Me)); 50.4 (d, CHN); 41.0 (t, C(3) of Phe(2Me)); 29.9 (q, MeN); 22.2, 15.1
‡
‡
(2q, MeCHN, Me(3) of Phe(2Me)). ESI-MS (MeOH): 489 (4, [M ‡ K] ), 473 (6, [M ‡ Na] ), 451 (2, [M ‡
‡
‡
‡
1] ), 297 (100, [M naphthCHCH2 ‡ 1] ), 266 (92, [M naphthCH(Me)NMe] ), 238 (23, [M
‡
‡
naphthCH(Me)N(Me)CO] ), 186 (10), 155 (9, [naphthCHMe] ). Anal. calc. for C30H30N2O2 ´ 0.2 H2O
(454.18): C 79.34, H 6.74, N 6.17; found: C 79.51, H 6.75, N 6.13.

Helvetica Chimica Acta ± Vol. 84 (2001)
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4. Synthesis of Model Peptides. 4.1. N-[(Benzyloxy)carbonyl]leucyl-a-aminoisobutyric Acid (Z-Leu-Aib;
12). Benzyl {1-{{{1,1-Dimethyl-2-[methyl(phenyl)amino]-2-oxoethyl}amino}oxomethyl}-3-methylbutyl}carba-
mate (Z-Leu-Aib-N(Me)Ph). To a soln. of Z-leucine (4.147 g, 15.631 mmol) in abs. Et2O (50 ml), 2,2,N-
trimethyl-N-phenyl-2H-azirin-3-amine (3.014 g, 17.297 mmol) in abs. Et2O (20 ml) was added at 08, and the
mixture was stirred for 2 h. Petroleum ether 50 ± 608 (80 ml) was added, and after 1 h, the precipitate was
filtered, the filtrate evaporated, and the residue recrystallized from CH2Cl2/Et2O/petroleum ether: 6.122 g
(89%) of Z-Leu-Aib-N(Me)Ph. Colorless crystals. M.p. 135.2 ± 135.78. Rf (CH2Cl2/MeOH 20 :1) 0.41. IR: 3290s,
3060m, 2960s, 2930m, 2870m, 1710s, 1670s, 1630s, 1590s, 1545s, 1540s, 1495s, 1470m, 1450m, 1435m, 1415m, 1395s,
1365s, 1285m, 1275s, 1240s, 1210m, 1170m, 1120m, 1090s, 1070m, 1045m, 1030m, 780m, 765m, 740m, 705s, 670m,
665m, 610m. 1H-NMR: 7.4 ± 7.25, 7.2 ± 7.15 (2m, 10 arom. H); 6.63 (br. s, NH); 5.2 ± 5.05 (m, PhCH2O, NH) ;
3.95 ± 3.85 (m, CH(2) of Leu); 3.25 (s, MeN); 1.65 ± 1.4 (m, CH2(3) and CH(4) of Leu, 2 Me(3) of Aib); 0.9 ±
0.85 (m, 2 Me(5) of Leu). 13C-NMR: 173.0, 170.5 (2s, 2 CO); 156.0 (s, CO (urethane)); 144.3, 136.3 (2s,
2 arom. C); 129.3, 128.4, 128.1, 128.0, 128.0, 127.9 (6d, 10 arom. CH); 66.8 (t, PhCH2O); 58.2 (s, C(2) of Aib);
53.5 (d, C(2) of Leu); 41.5 (t, C(3) of Leu); 41.3 (q, MeN); 24.5 (d, C(4) of Leu); 25.8, 23.0, 21.8 (3q, 2 Me(3) of
‡
‡
Aib, 2 Me(5) of Leu). CI-MS (NH3): 441 (15), 440 (56, [M ‡ 1] ), 334 (20), 333 (100, [M Ph(Me)N] ), 332
(7), 108 (7). Anal. calc. for C25H33N3O4 ´ 0.33 H2O (445.56): C 67.39, H 7.62, N 9.43; found: C 67.36, H 7.81,
N 9.53.
Z-Leu-Aib-OH (12). A soln. of Z-Leu-Aib-N(Me)Ph (5.969 g, 13.58 mmol) in 3n HCl in THF/H2O 1:1
(50 ml) was stirred for 14 h at r.t. Then, 1n HCl (20 ml) was added, the mixture extracted with Et2O (3Â), and
the org. soln. dried (MgSO4) and evaporated: 4.742 g (99%) of 12. Colorless foam. Recrystallization from Et2O
and petroleum ether gave colorless crystals. M.p. 118.4 ± 119.08. Rf (CH2Cl2/MeOH 10 :1) 0.40 ± 0.11. IR: 3350s,
3270s, 3200m, 3180m, 3170m, 3160m, 3130m, 3120m, 3100m, 3080s, 3060m, 3050m, 2950s, 2860m, 1725s, 1715s,
1690s, 1660s, 1650s, 1550s, 1530s, 1470s, 1450m, 1435m, 1395m, 1385m, 1365m, 1305m, 1280s, 1310m, 1230s, 1170s,
1130m, 1120m, 1050s, 790m, 750m, 740m, 695s, 655m. 1H-NMR: ca. 10 (br., COOH); 7.35 ± 7.3 (m, 5 arom. H);
7.08 (s, NH of Aib); 5.70 (d, J ˆ 8.2, NH of Leu); 5.10 (s, PhCH2O); 4.35 ± 4.3 (m, CH(2) of Leu); 1.7 ± 1.45
(m, CH2(3) and CH(4) of Leu, 2 Me(3) of Aib); 0.95 ± 0.9 (m, 2 Me(5) of Leu). 13C-NMR: 177.1, 172.4 (2s,
COOH, CO (amide)); 156.6 (s, CO (urethane)); 136.0 (s, 1 arom. C); 128.4, 128.1, 127.9 (3d, 5 arom. CH); 67.1
(t, PhCH2O); 56.7 (s, C(2) of Aib); 53.4 (d, C(2) of Leu); 41.2 (t, C(3) of Leu); 24.6 (d, C(4) of Leu); 24.3, 22.7,
‡
‡
21.9 (3q, 2 Me(3) of Aib, 2 Me(5) of Leu). CI-MS (NH3): 368 (16, [M ‡ H2O] ), 352 (18), 351 (100, [M ‡ 1] ),
217 (10). Anal. calc. for C18H26N2O5 (350.41): C 61.70, H 7.48, N 7.99; found: C 62.02, H 7.39, N 7.97.
4.2. Tripeptides Z-Leu-Aib-Xaa(2Me)-NR2. Benzyl {(S)-1-{{{1,1-Dimethyl-2-{{(S)-1-methyl-1-{{methyl-
[(R)-1-(naphthalen-1-yl)ethyl]amino}oxomethyl}propyl}amino}-2-oxoethyl}amino}oxomethyl}-3-methylbutyl}-
carbamate (Z-Leu-Aib-(S)-Iva-N(Me)(naphthEt); (S,S,R)-13a). To a soln. of 12 (377 mg, 1.08 mmol) in abs.
CH2Cl2 (5 ml), (1'R,2S)-4a (300 mg (1.13 mmol)) in abs. CH2Cl2 (5 ml) was added at 08, and the mixture was
stirred for 67 h at r.t. Evaporation and CC (hexane/AcOEt 2 :1, then 1:1) gave 509 mg (77%) of (S,S,R)-13a.
Colorless solid. M.p. 158 ± 1598. Rf (CH2Cl2/MeOH 20 :1) 0.28. IR: 3320m, 3050m, 2980m, 2880m, 1710m, 1695s,
1665s, 1660s, 1650m, 1630m, 1625m, 1615m, 1610s, 1540s, 1530s, 1515s, 1505s, 1495s, 1470m, 1465m, 1455m,
1390m, 1385m, 1370m, 1330m, 1315m, 1305m, 1290m, 1260m, 1220m, 1195m, 1170m, 1110m, 1080m, 1045m,
1
1030m, 805m, 780m, 740m, 700m. H-NMR: 7.9 ± 7.8 (m, NH, 3 arom. H); 7.55 ± 7.45 (m, 4 arom. H); 7.3 ± 7.25
(m, 5 arom. H); 6.73 (s, NH); 6.61 (q, J ˆ 6.6, CHN); 5.30 (d, J ˆ 6.6, NH of Leu); 5.10 (br. s, PhCH2O); 4.15 ±
4.1 (m, CH(2) of Leu); 2.53 (s, MeN); 2.45 ± 2.4 (m, CH(4) of Leu); 1.9 ± 1.5 (m, CH2(3) of Leu, CH2(3) and
Me(3) of Iva, 2 Me(3) of Aib, MeCHN); 0.94 (d, J ˆ 6.0, 2 Me(5) of Leu); 0.85 (t, J ˆ 7.4, MeCH2 of Iva).
13C-NMR: 172.0, 171.8, 171.4 (3s, 3 CO (amide)); 156.2 (s, CO (urethane)); 136.1, 135.4, 133.6, 131.8 (4s,
4 arom. C); 128.7, 128.5, 128.4, 128.1, 127.8, 126.6, 125.9, 125.2, 124.8, 123.7 (10d, 12 arom. CH); 67.0
(t, PhCH2O); 61.5, 57.5 (2s, C(2) of Aib, C(2) of Iva); 54.1, 50.7 (2d, MeCHN, C(2) of Leu); 41.3, 27.9 (2t,
C(3) of Leu, C(3) of Iva); 29.9 (q, MeN); 24.7 (d, C(4) of Leu); 25.1, 22.9, 22.1, 21.8, 14.9, 8.6 (6q, MeCHN,
‡
2 Me(3) of Aib, Me(3) of Iva, Me(4) of Iva, 2 Me(5) of Leu). ESI-MS (MeOH ‡ NaI): 640 (40, [M ‡ Na ‡ 1] ),
‡
639 (100, [M ‡ Na] ). Anal. calc. for C36H48N4O5 (616.80): C 70.10, H 7.84, N 9.08; found: C 70.03, H 7.85,
N 8.97.
Benzyl {(S)-1-{{{1,1-Dimethyl-2-{{(R)-1-methyl-1-{{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}oxometh-
yl}propyl}amino}-2-oxoethyl}amino}oxomethyl}-3-methylbutyl}carbamate (Z-Leu-Aib-(R)-Iva-N(Me)(naph-
thEt); (S,R,R)-13a). As described for (S,S,R)-13a, with 12 (378 mg, 1.08 mmol), CH2Cl2 (5 ml), (1'R,2R)-4a
(302 mg, 1.13 mmol), and CH2Cl2 (5 ml); 67 h at r.t.: 553 mg (83%) of (S,R,R)-13a. Colorless foam. M.p. 94 ±
968. Rf (CH2Cl2/MeOH 20 :1) 0.29. IR: 3320m, 3050w, 2960m, 2880m, 1705s, 1690s, 1680s, 1670s, 1620s, 1615s,
1550m, 1530s, 1525s, 1510s, 1505s, 1500s, 1470m, 1465m, 1390m, 1330m, 1310m, 1285m, 1240s, 1220m, 1195m,
1170m, 1120w, 1100m, 1080m, 1045m, 1030m, 805m, 780m, 760m, 755m, 700m, 695m. 1H-NMR: 7.95 ± 7.9

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Helvetica Chimica Acta ± Vol. 84 (2001)
(m, NH, 1 arom. H); 7.85 ± 7.8 (m, 2 arom. H); 7.55 ± 7.45 (m, 4 arom. H); 7.3 ± 7.25 (m, 5 arom. H); 6.73 (br.,
NH); 6.62 (q, J ˆ 6.7, MeCHN); 5.28 (d, J ˆ 6.7, NH of Leu); 5.10 (br., PhCH2O); 4.15 ± 4.1 (m, CH(2) of Leu);
2.55 (s, MeN); 2.45 ± 2.4 (m, CH(4) of Leu); 1.8 ± 1.45 (m, CH2(3) of Leu, CH2(3) and Me(3) of Iva, 2 Me(3) of
Aib, MeCHN); 0.94 (d, J ˆ 6.0, 2 Me(5) of Leu); 0.76 (t, J ˆ 7.5, MeCH2 of Iva). 13C-NMR: 172.0, 171.4 (2s,
3 CO (amide)); ca. 156 (s, CO (urethane)); 136.1, 135.3, 133.6, 131.8 (4s, 4 arom. C); 128.7, 128.4, 128.1, 127.9,
126.6, 126.0, 125.3, 124.8, 124.1 (9d, 12 arom. CH); 67.0 (t, PhCH2O); 61.3, 57.5 (2s, C(2) of Aib, C(2) of Iva);
54.2, 50.5 (2d, MeCHN, C(2) of Leu); 41.3, 28.0 (2t, C(3) of Leu, C(3) of Iva); 30.2 (q, MeN); 24.7 (d, C(4) of
Leu); 25.0, 22.9, 22.0, 21.9, 15.1, 8.6 (6q, MeCHN, 2 Me(3) of Aib, Me(3) of Iva, Me(4) of Iva, 2 Me(5) of Leu).
‡
‡
ESI-MS (MeOH ‡ NaI): 640 (40, [M ‡ Na ‡ 1] ), 639 (100, [M ‡ Na] ). Anal. calc. for C36H48N4O5 ´ H2O
(634.82): C 68.11, H 7.70, N 8.83; found: C 67.97, H 7.68, N 8.68.
Benzyl {(S)-1-{{{2-{{(S)-1,2-Dimethyl-1-{{methyl[(R)-1-naphthalen-1-yl)ethyl]amino}oxomethyl}propyl}-
amino}-1,1-dimethyl-2-oxoethyl}amino}oxomethyl}-3-methylbutyl}carbamate (Z-Leu-Aib-(S)-Val(2Me)-
N(Me)(naphthEt); (S,S,R)-13b). As described for (S,S,R)-13a, with 12 (453 mg, 1.29 mmol), CH2Cl2 (5 ml),
(1'R,2S)-4b (361 mg, 1.29 mmol), and CH2Cl2 (5 ml); 5.5 d at r.t.: 542 mg (67%) of (S,S,R)-13b. Colorless foam.
M.p. 96 ± 978. Rf (CH2Cl2/MeOH 20 :1) 0.22. Rf (hexane/AcOEt 1:1) 0.09. IR: 3310m, 3060m, 3040m, 2960m,
2930m, 2870m, 1725m, 1710m, 1690s, 1680s, 1610s, 1560m, 1530s, 1505s, 1470m, 1450m, 1390m, 1370m, 1330m,
1310m, 1250m, 1240m, 1215m, 1190m, 1170m, 1125w, 1120w, 1100m, 1080m, 1045m, 780m, 695m. 1H-NMR:
8.1 ± 8.05, 7.85 ± 7.75, 7.5 ± 7.35, 7.3 ± 7.25 (4m, 12 arom. H, NH); 6.72 (q, J ˆ 6.8, MeCHN); 6.48 (s, NH); 5.16
(d, J ˆ 7.6, NH of Leu); 5.05 ± 4.95 (m, PhCH2O); 4.1 ± 4.0 (m, CH(2) of Leu); 2.50 (s, MeN); 2.05 ± 1.4
(m, CH(3) and Me(3) of Val(2Me), 2 Me(3) of Aib, CH2(3) and CH(4) of Leu, MeCHN); 1.0 ± 0.9 (m, 2 Me(5)
of Leu, 2 Me(4) of Val(2Me)). 13C-NMR: 172.3, 172.0, 171.3 (3s, 3 CO (amide)); ca. 156 (s, CO (urethane));
136.3, 135.9, 133.6, 132.0 (4s, 4 arom. C); 128.4, 128.3, 128.2, 127.9, 126.3, 125.8, 125.2, 124.7, 124.5 (9d,
12 arom. CH); 67.1 (t, PhCH2O); 63.8, 57.9 (2s, C(2) of Aib, C(2) of Val(2Me)); 54.1, 50.0 (2d, MeCHN, C(2) of
Leu); 40.9 (t, C(3) of Leu); 32.7 (d, C(3) of Val(2Me)); 24.7 (d, C(4) of Leu); 29.9, 25.3, 22.7, 21.8, 17.9, 17.6, 17.0,
14.6 (8q, MeN, MeCHN, 2 Me(3) of Aib, Me(3) and 2 Me(4) of Val(2Me), 2 Me(5) of Leu). ESI-MS (NaI): 659
‡
‡
(28), 655 (40, [M ‡ Na ‡ 1] ), 654 (100, [M ‡ Na] ). Anal. calc. for C37H50N4O5 ´ 0.33 H2O (636.84): C 69.78,
H 7.91, N 8.80; found: C 69.94, H 8.05, N 8.59.
Benzyl {(S)-1-{{{2-{{(R)-1,2-Dimethyl-1-{{methyl[(R)-1-naphthalen-1-yl)ethyl]amino}oxomethyl}propyl}-
amino}-1,1-dimethyl-2-oxoethyl}amino}oxomethyl}-3-methylbutyl}carbamate (Z-Leu-Aib-(R)-Val(2Me)-
N(Me)(naphthEt); (S,R,R)-13b). As described for (S,S,R)-13a, with 12 (866 mg, 2.47 mmol), CH2Cl2 (5 ml),
(1'R,2R)-4b (695 mg, 2.48 mmol), and CH2Cl2 (9 ml); 2 d at r.t.; CC (CH2Cl2/MeOH 100 :4): 1070 mg (69%) of
(S,R,R)-13b. Colorless foam. M.p. 88 ± 898. Rf (CH2Cl2/MeOH 20 :1) 0.27. IR: 3300m, 3070w, 3040w, 2960m,
2870w, 1725m, 1710s, 1705s, 1695s, 1680s, 1615s, 1565m, 1550m, 1530s, 1515s, 1505s, 1465m, 1455m, 1390m,
1385m, 1370m, 1330m, 1310w, 1250m, 1220m, 1190m, 1170m, 1120w, 1100w, 1080m, 1040m, 780m, 695m.
1H-NMR: 8.01 (d, J ˆ 8.4, NH); 7.8 ± 7.75 (m, 2 arom. H); 7.55 ± 7.4 (m, 5 arom. H); 7.3 ± 7.25 (m, 5 arom. H);
6.50 (q, J ˆ 6.6, MeCHN); 6.42 (s, NH); 5.05 ± 5.0 (m, PhCH2O); 4.05 ± 3.95 (m, CH(2) of Leu); 2.48 (s, MeN);
2.24 (sept., J ˆ 6.6, CH(3) of Val(2Me)); 1.59 (d, J ˆ 6.7, MeCHN); 1.55 ± 1.4, 1.2 (m, s, 2 Me(3) of Aib, Me(3) of
Val(2Me), CH2(3) and CH(4) of Leu); 1.0 ± 0.9 (m, 2 Me(5) of Leu, 2 Me(4) of Val(2Me)). 13C-NMR: 172.2,
171.9, 171.6 (3s, 3 CO (amide)); 156.2 (s, CO (urethane)); 135.9, 133.4, 132.0 (3s, 4 arom. C); 128.5, 128.4, 128.2,
127.8, 126.8, 125.8, 125.1, 124.6 (8d, 12 arom. CH); 67.0 (t, PhCH2O); 63.6, 57.9 (2s, C(2) of Aib, C(2) of
Val(2Me)); 54.3, 50.7 (2d, MeCHN, C(2) of Leu); 40.8 (t, C(3) of Leu); 33.1 (d, C(3) of Val(2Me)); 30.4
(q, MeN); 24.6 (d, C(4) of Leu); 25.4, 24.9, 22.8, 21.7, 17.6, 17.5, 17.4, 14.8 (8q, MeCHN, 2 Me(3) of Aib, Me(3)
‡
‡
and 2 Me(4) of Val(2Me), 2 Me(5) of Leu). ESI-MS (NaI): 655 (45, [M ‡ Na ‡ 1] ), 654 (100, [M ‡ Na] ), 477
‡
‡
(6, [M naphthCHCH2] ), 446 (5, [M naphthCH(Me)NMe] ). Anal. calc. for C37H50N4O5 ´ 0.33H2O
(636.84): C 69.78, H 7.91, N 8.80; found: C 69.94, H 7.57, N 8.62.
Benzyl {(S)-1-{{{2-{{(S)-1-Cyclopentyl-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-oxo-
ethyl}amino}-1,1-dimethyl-2-oxoethyl}amino}oxomethyl}-3-methylbutyl}carbamate (Z-Leu-Aib-(S)-Ala(2c-
Pent)-N(Me)(naphthEt); (S,S,R-13c). As described for (S,S,R)-13a, with 12 (234 mg, 0.67 mmol), CH2Cl2
(2 ml), (1'R,2S)-4c (205 mg, 0.67 mmol), and CH2Cl2 (5 ml), 5.5 d at r.t.; CC (CH2Cl2/MeOH 50 :1): 170 mg
(39%) of (S,S,R)-13c. Colorless foam. M.p. 84 ± 858. Rf (CH2Cl2/MeOH 20 :1) 0.33. IR: 3308m, 3050w, 2958s,
2871m, 1681vs, 1610s, 1512vs, 1455s, 1388s, 1331m, 1311m, 1243s, 1172m, 1111m, 1055s, 982w. 1H-NMR: 8.1 ± 8.05
(m, 1 arom. H); 7.85 ± 7.75 (m, 2 arom. H); 7.5 ± 7.4 (m, 4 arom. H); 7.3 ± 7.2 (m, 5 arom. H); 7.18 (s, NH); 6.69
(q, J ˆ 6.8, MeCHN); 6.43 (s, NH); 5.13 (d, J ˆ 7.5, NH of Leu); 5.03, 4.97 (AB, J ˆ 12.2, PhCH2O); 4.05 ± 4.0
(m, CH(2) of Leu); 2.52 (s, MeN); 2.25 ± 2.2 (m, CH(3) of Ala(2cPent)); 1.7 ± 1.4 (m, MeCHN, 2 Me(3) of Aib,
Me(3) of Ala(2cPent), CH2(3) and CH(4) of Leu, 4 CH2 of cPent); 0.91, 0.90 (2d, J ˆ 6.3, 6.1, 2 Me(5) of Leu).
13C-NMR: 172.3, 172.0, 171.3 (3s, 3 CO (amide)); 156.3 (s, CO (urethane)); 136.4, 135.9, 133.6, 132.0 (4s,

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4 arom. C); 128.4, 128.2, 127.9, 126.2, 125.8, 125.2, 124.7, 124.6 (8d, 12 arom. CH); 67.1 (t, PhCH2O); 62.7, 57.8
(2s, C(2) of Aib, C(2) of Ala(2cPent)); 54.2 (d, CH(2) of Leu); 50.0 (d, MeCHN); 44.7 (d, CH(3) of
Ala(2cPent)); 40.9 (t, C(3) of Leu); 29.8 (q, MeN); 27.3, 27.0, 25.5 (3t, 4 CH2 of cPent); 24.7 (d, C(4) of
Leu); 25.4, 25.2, 22.7, 21.8, 18.8, 14.5 (6q, MeCHN, 2 Me(3) of Aib, Me(3) Ala(2cPent), 2 Me(5) of Leu).
‡
‡
ESI-MS (MeOH/NaI): 684 (20), 679 (87, [M ‡ Na] ), 503 (38, [M naphthCHCH2 ‡ 1] ), 472 (100,
‡
[M naphthCH(Me)NMe] ). Anal. calc. for C39H52N4O5 ´ H2O (674.91): C 69.41, H 8.06, N 8.30; found:
C 69.60, H 8.06, N 7.95.
Benzyl {(S)-{{{2-{{(R)-1-Cyclopentyl-1-methyl-2-{methyl[(R)-1-(naphthalen1-yl)ethyl]amino}-2-oxoethyl}-
amino}-1,1-dimethyl-2-oxoethyl}amino}oxomethyl}-3-methylbutyl}carbamate (Z-Leu-Aib-(R)-Ala(2cPent)-
N(Me)(naphthEt); (S,R,R)-13c). As described for (S,S,R)-13a, with 12 (457 mg, 1.30 mmol), CH2Cl2 (5 ml),
(1'R,2R)-4c (398 mg, 1.30 mmol), and CH2Cl2 (10 ml); 4 d at r.t.; CC (CH2Cl2/MeOH 100 :1): 328 mg (38%) of
(S,R,R)-13c. Colorless foam. M.p. 99 ± 102. Rf (CH2Cl2/MeOH 20 :1) 0.35. IR: 3322w, 3050w, 2957s, 2870w,
1680vs, 1612s, 1511vs, 1455m, 1387m, 1332w, 1242m, 1172w, 1108w, 1059w. 1H-NMR: 8.01 (d, J ˆ 8.4, 1 arom. H);
7.80, 7.77 (2d, J ˆ 8.4, 8.3, 2 arom. H); 7.55 ± 7.4 (m, 4 arom. H); 7.35 ± 7.25 (m, 5 arom. H, NH); 6.53 (q, J ˆ 6.7,
MeCHN); 6.36 (s, NH); 5.17 (d, J ˆ 6.6, NH of Leu); 5.08, 4.98 (AB, J ˆ 12.4, PhCH2O); 4.0 ± 3.95 (m, CH(2) of
Leu); 2.55 ± 2.5 (m, CH(3) of Ala(2cPent), MeN); 1.85 ± 1.45 (m, MeCHN, CH2(3) and CH(4) of Leu, 4 CH2 of
cPent); 1.53, 1.43 (2s, 2 Me(3) of Aib); 1.29 (s, Me(3) of Ala(2cPent)); 0.90, 0.89 (2d, J ˆ 6.3, 6.1, 2 Me(5) of
Leu). 13C-NMR: 172.0, 171.8, 171.5 (3s, 3 CO (amide)); 156.2 (s, CO (urethane)); 136.1, 135.8, 133.4, 132.1 (4s,
4 arom. C); 128.4, 128.2, 127.9, 127.8, 126.6, 125.8, 125.0, 124.9, 124.6 (9d, 12 arom. CH); 67.1 (t, PhCH2O); 62.3,
57.8 (2s, C(2) of Aib, C(2) of Ala(2cPent)); 54.4 (d, CH(2) of Leu); 50.6 (d, MeCHN); 45.7 (d, CH(3) of
Ala(2cPent)); 40.8 (t, C(3) of Leu); 30.2 (q, MeN); 27.4, 25.6, 25.4 (3t, 4 CH2 of cPent); 24.6 (d, C(4) of Leu);
25.3, 22.7, 21.7, 18.9, 14.7 (5q, MeCHN, 2 Me(3) of Aib, Me(3) of Ala(2cPent), 2 Me(5) of Leu). ESI-MS
‡
(MeOH/NaI): 680 (100, [M ‡ Na] ). Anal. calc. for C39H52N4O5 (656.89): C 71.31, H 7.98, N 8.53; found:
C 71.34, H 8.07, N 8.49.
Benzyl {(S)-1-{{{2-{{(S)-1,3-Dimethyl-1-{{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}oxomethyl}butyl}-
amino}-1,1-dimethyl-2-oxoethyl}amino}oxomethyl}-3-methylbutyl}carbamate (Z-Leu-Aib-(S)-Leu(2Me)-
N(Me)(naphthEt); (S,S,R)-13d). As described for (S,S,R)-13a, with 12 (716 mg, 2.04 mmol), CH2Cl2 (5 ml),
(1'R,2S)-4d (598 mg, 2.03 mmol), and CH2Cl2 (10 ml); 2 d at r.t.; CC (hexane/AcOEt 2 :1): 839 mg (64%) of
(S,S,R)-13d. Colorless foam. Rf (CH2Cl2/MeOH 20 :1) 0.37. IR: 3340m, 3320m, 3040m, 2960s, 2870m, 1725m,
1710s, 1695s, 1675s, 1665s, 1650s, 1615s, 1565m, 1545m, 1530s, 1515s, 1505s, 1495s, 1490s, 1470s, 1450s, 1395m,
1385m, 1370m, 1330m, 1320m, 1245m, 1220m, 1200m, 1170m, 1105m, 1085m, 1045m, 1030m, 980m, 950m, 805m,
780m, 735m, 675m, 650m, 630m. 1H-NMR: 8.28 (br. s, NH); 7.85 ± 7.75 (m, 3 arom. H); 7.55 ± 7.45 (m, 4 ar-
om. H); 7.35 ± 7.25 (m, 5 arom. H); 6.87 (br. s, NH); 6.58 (q, J ˆ 6.7, MeCHN); 5.28 (d, J ˆ 7.5, NH of Leu); 5.12
(br. s, PhCH2O); 4.18 (br., CH(2) of Leu); 2.65 ± 2.55 (m, CH(4) of Leu or of Leu(2Me)); 2.52 (s, MeN); 1.75 ±
1.55 (m, MeCHN, CH2(3) of Leu, CH2(3) and Me(3) of Leu(2Me), CH(4) of Leu(2Me) or Leu); 0.95 ± 0.9
(m, 2 Me(5) of Leu, 2 Me(5) of Leu(2Me)). 13C-NMR: 172.6, 171.7, 171.2 (3s, 3 CO (amide)); ca. 156 (s, CO
(urethane)); 136.2, 135.2, 133.7, 131.8 (4s, 4 arom. C); 128.8, 128.6, 128.4, 128.0, 127.9, 126.7, 126.0, 125.2, 124.8,
123.3 (10d, 12 arom. CH); 66.9 (t, PhCH2O); 61.1, 57.5 (2s, C(2) of Aib, C(2) of Leu(2Me)); 53.9, 50.9
(2d, MeCHN, C(2) of Leu); 43.2, 41.7 (2t, C(3) of Leu, C(3) of Leu(2Me)); 30.3 (q, MeN); 25.1, 24.7 (2d, C(4)
of Leu, C(4) of Leu(2Me)); 24.5, 23.6, 23.3, 23.0, 22.8, 21.9, 14.6 (7q, MeCHN, 2 Me(3) of Aib, Me(3) of
‡
Leu(2Me), 2 Me(5) of Leu(2Me), 2 Me(5) of Leu). CI-MS (NH3): 646 (7), 645 (17, [M ‡ 1] ), 492 (29), 491
‡
‡
(100, [M naphthCHCH2 ‡ 1] ), 461 (7), 460 (27, [M naphthCH(Me)NMe] ), 384 (17), 383 (80, [M Z-
‡
Leu ‡ 1] ), 357 (18), 100 (9). Anal. calc. for C38H52N4O5 (644.86): C 70.78, H 8.13, N 8.38; found: C 71.00,
H 7.91, N 8.44.
Benzyl {(S)-1-{{{-2-{{(R)-1,3-Dimethyl-1-{{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}oxomethyl}butyl}-
amino}-1,1-dimethyl-2-oxoethyl}amino}oxomethyl}-3-methylbutyl}carbamate (Z-Leu-Aib-(R)-Leu(2Me)-
N(Me)(naphthEt); (S,R,R)-13d. As described for (S,S,R)-13a, with 12 (711 mg, 2.03 mmol), CH2Cl2 (5 ml),
(1'R,2R)-4d (598 mg, 2.03 mmol), and CH2Cl2 (9 ml); 4 d at r.t.; CC (1. CH2Cl2/MeOH 50 :1, 2. hexane/AcOEt
1:1): 785 mg (60%) of (S,R,R)-13d. Colorless foam. Rf (CH2Cl2/MeOH 20 :1) 0.36. IR: 3330m, 3050m, 2960s,
2865m, 1710s, 1695s, 1680s, 1660s, 1635m, 1610s, 1550m, 1530s, 1510s, 1500s, 1495s, 1470m, 1450m, 1390m, 1385m,
1370m, 1330m, 1310m, 1260m, 1255m, 1245m, 1240m, 1220m, 1175m, 1170m, 1165m, 1160w, 1145w, 1140w,
1
1120m, 1105m, 1090m, 1045m, 1030m, 1010w, 800m, 780m, 740m, 695m. H-NMR: 8.21 (br. s, NH); 7.95 ± 7.9
(m, 1 arom. H); 7.85 ± 7.8 (m, 2 arom. H); 7.55 ± 7.4 (m, 4 arom. H); 7.3 ± 7.25 (m, 5 arom. H); 6.88 (br. s, NH);
6.66 (q, J ˆ 6.5, MeCHN); 5.35 ± 5.3 (m, NH); 5.12 (br., PhCH2O); 4.17 (br., CH(2) of Leu); 2.55 ± 2.45
(m, MeN); 2.0 ± 1.25 (m, 2 Me(3) of Aib, Me(3) of Leu(2Me), MeCHN, CH2(3) and CH(4) of Leu, CH2(3) and
CH(4) of Leu(2Me)); 0.95 ± 0.9, 0.6 ± 0.55 (2m, 2 Me(5) of Leu, 2 Me(5) of Leu(2Me)). 13C-NMR: 172.4, 171.7,

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Helvetica Chimica Acta ± Vol. 84 (2001)
171.3 (3s, 3 CO (amide)); 156.2 (s, CO (urethane)); 136.2, 135.0, 133.8, 131.8 (4s, 4 arom. C); 128.8, 128.4, 128.0,
127.9, 126.4, 126.0, 125.3, 124.8, 124.1 (9d, 12 arom. CH); 66.9 (t, PhCH2O); 61.1, 57.5 (2s, C(2) of Aib, C(2) of
Leu(2Me)); 54.1, 50.5 (2d, MeCHN, C(2) of Leu); 43.3, 41.6 (2t, C(3) of Leu, C(3) of Leu(2Me)); 30.2, 25.1
(2q, MeN, MeCHN); 25.1, 24.7 (2d, C(4) of Leu, C(4) of Leu(2Me)); 24.5, 24.1, 23.0, 22.9, 21.9, 15.1 (6q, 2 Me(3)
‡
of Aib, Me(3) of Leu(2Me), 2 Me(5) of Leu(2Me), 2 Me(5) of Leu). ESI-MS (NaI): 1314 (7, [2M ‡ Na ‡ 1] ),
‡
‡
‡
1313 (9, [2M ‡ Na] ), 669 (12), 668 (48, [M ‡ Na ‡ 1] ), 667 (100, [M ‡ Na] ), 377 (6). Anal. calc. for
C38H52N4O5 (644.86): C 70.78, H 8.13, N 8.38; found: C 70.68, H 8.22, N 8.30.
Benzyl {(S)-1-{{{2-{{(S)-1-Benzyl-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-oxoethyl}-
amino}-1,1-dimethyl-2-oxoethyl}amino}oxomethyl}-3-methylbutyl}carbamate (Z-Leu-Aib-(S)-Phe(2Me)-
N(Me)(naphthEt); (S,S,R)-13e). As described for (S,S,R)-13a, with 12 (355 mg, 1.01 mmol), CH2Cl2 (5 ml),
(1'R,2S)-4e (331 mg, 1.01 mmol), and CH2Cl2 (10 ml); 40 h at r.t.; CC (hexane/AcOEt 2 :1) and prep. TLC
(hexane/AcOEt 1:1): 406 mg (59%) of (S,S,R)-13e. Colorless foam. M.p. 97 ± 1008. Rf (CH2Cl2/MeOH 20 :1)
0.42. IR: 3336m, 3032w, 2957m, 2871w, 2362w, 2339w, 1677vs, 1617s, 1497vs, 1455s, 1395m, 1333w, 1241s, 1172w,
1118w, 1079m, 1044m, 1029w, 782m, 736m, 700m. 1H-NMR: 7.85 ± 7.8, 7.5 ± 7.45, 7.35 ± 7.2, 7.1 ± 7.05 (4m,
17 arom. H, 1 NH); 6.76 (br. s, NH); 6.52 (q, J ˆ 6.7, MeCHN); 5.22 (d, J ˆ 7.1, NH of Leu); 5.10 (br., PhCH2O);
4.15 ± 4.1 (m, CH(2) of Leu); 3.76, 3.19 (AB, J ˆ 14.6, CH2(3) of Phe(2Me)); 2.60 (s, MeN); 1.7 ± 1.45
(m, 2 Me(3) of Aib, Me(3) of Phe(2Me), CH2(3) of Leu, CH(4) of Leu, MeCHN); 0.95 ± 0.9 (m, 2 Me(5) of
Leu). 13C-NMR: 172.3, 171.4 (2s, 3 CO (amide)); ca. 156 (s, CO (urethane)); 136.4, 135.2, 133.6, 131.8 (4s,
5 arom. C); 129.8, 128.7, 128.5, 128.4, 128.1, 127.9, 126.9, 126.7, 125.9, 125.2, 124.8, 123.5 (12d, 17 arom. CH); 66.9
(t, PhCH2O); 61.3, 57.4 (2s, C(2) of Aib, C(2) of Phe(2Me)); 53.9, 50.8 (2d, MeCHN, C(2) of Leu); 41.4, 40.5
(2t, C(3) of Leu, C(3) of Phe(2Me)); 30.6 (q, MeN); 24.6 (d, C(4) of Leu); 25.1, 24.4, 22.9, 22.2, 21.8, 14.5
(6q, MeCHN, 2 Me(3) of Aib, Me(3) of Phe(2Me), 2 Me(5) of Leu). ESI-MS (NaI): 769 (6), 703 (11), 702 (49,
‡
‡
[M ‡ Na ‡ 1] ), 701 (100, [M ‡ Na] ). Anal. calc. for C41H50N4O5 ´ 0.33 H2O (684.88): C 71.90, H 7.46, N 8.18;
found: C 71.75, H 7.45, N 8.13.
Benzyl {(S)-1-{{{-2-{{(R)-1-Benzyl-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-oxoethyl}-
amino}-1,1-dimethyl-2-oxoethyl}amino}oxomethyl}-3-methylbutyl}carbamate
(Z Leu Aib (R) Phe-
(2Me) NMe(naphthEt); (S,R,R)-13e). As described for (S,S,R)-13a, with 12 (367 mg, 1.05 mmol), CH2Cl2
(5 ml), (1'R,2S)-4e (339 mg, 1.03 mmol), and CH2Cl2 (10 ml); 48 h at r.t.; CC (hexane/AcOEt 2 :1): 434 mg
(62%) of (S,R,R)-13e. Colorless foam. M.p. 99 ± 1028. Rf (CH2Cl2/MeOH 20 :1) 0.38. IR: 3326m, 3032w, 2957m,
2871w, 2361w, 1676vs, 1615s, 1511vs, 1455s, 1394m, 1332w, 1241s, 1172w, 1108w, 1072m, 1044m, 1029w, 782m,
738m, 701m. 1H-NMR: 8.0 ± 7.95, 7.85 ± 7.8, 7.55 ± 7.4, 7.3 ± 7.25, 7.2 ± 7.15, 7.05 (5m, br. s, 17 arom. H, 1 NH); 6.69
(q, J ˆ 6.7, MeCHN); 6.53 (br. s, NH); 5.15 ± 5.1 (m, NH); 4.97, 4.84 (AB, J ˆ 12.0, PhCH2O); 4.0 ± 3.95
(m, CH(2) of Leu); 3.51, 3.47 (AB, J ˆ 14.2, CH2(3) of Phe(2Me)); 2.63 (s, MeN); 1.6 ± 1.35 (m, 2 Me(3) of Aib,
Me(3) of Phe(2Me), CH2(3) of Leu, CH(4) of Leu, MeCHN); 0.9 ± 0.85 (m, 2 Me(5) of Leu). 13C-NMR: 172.1,
171.6, 171.4 (3s, 3 CO (amide)); 156.2 (s, CO (urethane)); 137.0, 135.9, 133.6, 132.0 (4s, 5 arom. C); 130.7, 128.5,
128.4, 128.1, 127.9, 126.6, 126.5, 125.8, 125.3, 124.7, 124.1 (11d, 17 arom. CH); 67.1 (t, PhCH2O); 60.2, 57.6 (2s,
C(2) of Aib, C(2) of Phe(2Me)); 54.3, 50.3 (2d, MeCHN, C(2) of Leu); 41.3, 41.0 (2t, C(3) of Leu, C(3) of
Phe(2Me)); 30.3 (q, MeN); 24.6 (d, C(4) of Leu); 25.5, 25.1, 22.8, 22.1, 21.7, 15.0 (6q, MeCHN, 2 Me(3) of Aib,
‡
Me(3) of Phe(2Me), 2 Me(5) of Leu). ESI-MS (NaI): 846 (7), 703 (13), 702 (46, [M ‡ Na ‡ 1] ), 701 (100,
‡
[M ‡ Na] ). Anal. calc. for C41H50N4O5 ´ 0.5H2O (687.88): C 71.59, H 7.47, N 8.14; found: C 71.54, H 7.46, N 8.12.
5. X-Ray Crystal-Structure Determination of (1'R,2R)-4a, (1'R,2S)-4b, (1'R,2S)-4c, (1'R,2S)-4d, and
(1'R,2S)-4e (see Table 5 and Fig.)2). All measurements were conducted at low temp. using graphite-
monochromated MoKa radiation (l 0.71069 Š). The data collection and refinement parameters are given in
Table 5, and views of the molecules are shown in the Fig. The intensities were corrected for Lorentz and
polarization effects, and for (1'R,2R)-4a, an empirical absorption correction, based on azimuthal scans of several
reflections [39], was also applied. Equivalent reflections, other than Friedel pairs, were merged. Each structure
was solved by direct methods, which revealed the positions of all non-H-atoms. The structure of (1'R,2S)-4e
contains highly disordered solvent molecules which fill a column-like cavity that runs parallel to the 65 axis. As
the solvent for the recrystallization was AcOEt, it was assumed that the disordered solvent molecules were
2
)
Crystallographic data (excluding structure factors) for the structures of (1'R,2R)-4a, (1'R,2S)-4b, (1'R,2S)-
4c, (1'R,2S)-4d, and (1'R,2S)-4e have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publications no. CCDC-160821 to CCDC-160825. Copies of the data can be obtained, free
of charge, on application to the CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: ‡44-(0)1223-
336033; email: deposit@ccdc.cam.ac.uk).

Helvetica Chimica Acta ± Vol. 84 (2001)
1775
Table 5. Crystallographic Data of Compounds (1'R,2R)-4a, (1'R,2S)-4b, (1'R,2S)-4c, (1'R,2S)-4d, and
(1'R,2S)-4e
(1'R,2R)-4a
(1'R,2S)-4b
(1'R,2S)-4c
(1'R,2S)-4d
(1'R,2S)-4e
Crystallized from
Empirical formula
oil
C18H22N2
hexane/Et2O
C19H24N2
hexane/Et2O
C21H26N2
AcOEt/hexane AcOEt
C20H26N2
C23H24N2 ´ 1/4
C4H8O2
350.48
colorless,
prism
Mr
266.39
colorless,
prism
280.41
colorless,
prism
306.45
colorless,
prism
294.44
colorless,
prism
Crystal color, habit
Crystal dimensions
[mm]
Temperature [K]
Crystal system
Space group
Z
0.40 Â 0.42
0.20 Â 0.40
 0.45
173 (1)
monoclinic
P21
0.10 Â 0.25
 0.32
160 (1)
monoclinic
P21
0.35 Â 0.38
0.30 Â 0.33
 0.45
 0.48
 0.40
173 (1)
orthorhombic
P212121
4
173 (1)
orthorhombic hexagonal
P21212
4
173 (1)
P65
6
2
2
Reflections for cell
determination
2q Range for cell
determination [8]
Unit cell
25
25
2732
23
20
35 ± 39
35 ± 39
2 ± 60
37 ± 40
10 ± 16
13.441 (2)
8.664 (2)
8.4449 (2)
7.472 (2)
16.277 (3)
parameters a [Š]
b [Š]
c [Š]
14.400 (2)
8.124 (2)
90
1572.3 (5)
1.125
7.655 (3)
12.279 (2)
91.69 (2)
814.0 (4)
1.144
7.6820 (2)
13.4962 (4)
90.489 (1)
875.52 (4)
1.162
28.232 (1)
8.383 (2)
90
1768.3 (5)
1.106
16.277 (3)
13.119 (5)
90
3010 (2)
1.160
b [8]
V [A ]
3
Ê
3
Dx [g cm
]
1
m(MoKa) [mm
]
0.0661
0.965; 1.000
0.0670
±
0.0678
±
0.0645
±
0.0693
±
Transmission factors
(min; max)
Diffractometer
Rigaku
AFC5R
w/2q
Rigaku
AFC5R
w/2q
Nonius
KappaCCD
f and w
60
Rigaku
AFC5R
w
Rigaku
AFC5R
w/2q
Scan type
2qmax [8]
60
55
55
55
Total reflections
measured
3147
2125
24574
2815
3165
Symmetry independent 3021
reflections
1997
1536
5084
4190
2708
2318
2607
1539
Reflections used
(I > 2s(I))
2388
Parameters refined
Final R
wR
Weights: p in
w ˆ [s2(Fo) ‡ (pFo)2]
Goodness of fit
Secondary extinction 1.1 (2) ´ 10
coefficient
270
190
208
304
253
0.0450
0.0396
0.005
0.0432
0.0384
0.005
0.0450
0.0466
0.015
0.0372
0.0347
0.005
0.0464
0.0346
0.005
1
1.824
1.683
4.3 (4) ´ 10
1.524
1.0 (1) ´ 10
1.885
8 (1) ´ 10
1.596
5.8 (8) ´ 10
6
6
5
7
7
Final Dmax/s
0.0003
0.20; 0.16
0.0002
0.19; 0.16
0.0005
0.31; 0.21
0.0004
0.18; 0.13
0.005
0.17; 0.15
SHELXS86 [34]
3
d1 (max; min) [e Š
Structure solution
program
]
SHELXS86 [34] SHELXS86 [34] SHELXS97 [35] SIR92 [36]
Structure refinement
program
TEXSAN [37] TEXSAN [37] teXsan [38] TEXSAN [37] teXsan [38]

1776
Helvetica Chimica Acta ± Vol. 84 (2001)
AcOEt. Three solvent atoms were located in the asymmetric unit and refined with site-occupation factors of 0.5.
Upon symmetry expansion, it was found that these solvent atoms are linked into an infinite chain along the 65
axis. The form of the chain suggests that it is built from overlapping AcOEt molecules, and the site-occupation
factors for the defined atoms would be consistent with this. Thus, the ratio of solvent molecules to substrate
molecules in (1'R,2S)-4e is ca. 1 :4.
The non-H-atoms of each structure were refined anisotropically. All of the H-atoms in (1'R,2R)-4a and
(1'R,2S)-4d were located in difference electron density maps, and their positions were allowed to refine together
with individual isotropic displacement parameters. In each of the other structures, the H-atoms were fixed in
geometrically calculated positions (d(C H) ˆ 0.95 Š), and each was assigned a fixed isotropic displacement
parameter with a value equal to 1.2Ueq of its parent C-atom. The H-atoms of the solvent molecule of (1'R,2S)-4e
were not included in the model. Refinement of each structure was carried out on F using full-matrix least-
squares procedures, which minimized the function Sw(j Fo j j Fc j )2. Corrections for secondary extinction were
applied. For (1'R,2S)-4c, five reflections whose intensities were considered to be extreme outliers, were omitted
from the final refinement. Neutral-atom scattering factors for non-H-atoms were taken from [40], and the
scattering factors for H-atoms were taken from [41]. Anomalous dispersion effects were included in Fcalc [42];
the values for f ' and f '' were those of [43]. The values of the mass attenuation coefficients were taken from [44].
The crystals of each compound were enantiomerically pure, but the absolute configuration was not
determined for any of the structures. In each case, the enantiomer used in the refinement was chosen to agree
with the known (R)-configuration at the methyl-substituted C-atom adjacent to the naphthalene moiety. The
configuration at the chiral centre in the azirine ring of each structure could then be established relative to the
configuration of the known chiral centre.
REFERENCES
[1] B. V. V. Prasad, P. Balaram, CRC Crit. Rev. Biochem. 1984, 16, 307.
[2] I. L. Karle, P. Balaram, Biochemistry 1990, 29, 6747.
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Received April 4, 2001