New optically active 2H-azirin-3-amines as synthons for enantiomerically pure 2,2-disubstituted glycines: Synthesis of synthons for Tyr(2Me) and Dopa(2Me), and their incorporation into dipeptides

Article abstract of DOI:10.1002/1522-2675(200210)85:10<3422::AID-HLCA3422>3.0.CO;2-N

The synthesis of novel unsymmetrically 2,2-disubstituted 2H-azirin-3-amines with chiral auxiliary amino groups is described. Chromatographic separation of the mixture of diastereoisomers yielded (1′R,2S)-2a,b and (1′R.2R)-2a,b (c.f. Scheme 1 and Table 1), which are synthons for (S)- and (R)-2-methyltyrosine and 2-methyl-3′,4′-dihydroxyphenylalanine. Another new synthon 2c, i.e., a synthon for 2-(azidomethyl)alanine, was prepared but could not be separated into its pure diastereoisomers. The reaction of 2 with thiobenzoic acid, benzoic acid, and the amino acid Fmoc-Val-OH yielded the monothiodiamides 11, the diamides 12 (cf. Scheme 3 and Table 3), and the dipeptides 13 (cf. Scheme 4 and Table 4), respectively. From 13, each protecting group was removed selectively under standard conditions (cf. Schemes 5-7 and Tables 5-6). The configuration at C(2) of the amino acid derivatives (1R,1′R)-11a, (1R,1′R)-11b, (1S,1′R)-12b, and (1R,1′R)-12b was determined by X-ray crystallography relative to the known configuration of the chiral auxiliary group.

Full text of DOI:10.1002/1522-2675(200210)85:10<3422::AID-HLCA3422>3.0.CO;2-N

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Helvetica Chimica Acta Vol. 85 (2002)
New Optically Active 2H-Azirin-3-amines as Synthons for Enantiomerically
Pure 2,2-DisubstitutedGlycines: Synthesis of Synthons for Tyr(2Me) and
Dopa(2Me), andTheir Incorporation into Dipeptides
by Kathrin A. Brun1), Anthony Linden, and Heinz Heimgartner*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday
The synthesis of novel unsymmetrically 2,2-disubstituted 2H-azirin-3-amines with chiral auxiliary amino
groups is described. Chromatographic separation of the mixture of diastereoisomers yielded (1'R,2S)-2a,b and
(1'R,2R)-2a,b (c.f. Scheme 1 and Table 1), which are synthons for (S)- and (R)-2-methyltyrosine and 2-methyl-
3',4'-dihydroxyphenylalanine. Another new synthon 2c, i.e., a synthon for 2-(azidomethyl)alanine, was prepared
but could not be separated into its pure diastereoisomers. The reaction of 2 with thiobenzoic acid, benzoic acid,
and the amino acid Fmoc-Val-OH yielded the monothiodiamides 11, the diamides 12 (cf. Scheme 3 and Table 3),
and the dipeptides 13 (cf. Scheme 4 and Table 4), respectively. From 13, each protecting group was removed
selectively under standard conditions (cf. Schemes 5 7 and Tables 5 6). The configuration at C(2) of the
amino acid derivatives (1R,1'R)-11a, (1R,1'R)-11b, (1S,1'R)-12b, and (1R,1'R)-12b was determined by X-ray
crystallography relative to the known configuration of the chiral auxiliary group.
1. Introduction. Recently, we reported the preparation of new optically active 2H-
azirin-3-amines 1 as synthons for enantiomerically pure 2,2-disubstituted glycines (a,a-
disubstituted a-amino acids) [1].
R
R = Et, iPr,
N
cyclopentyl, iBu, Bn
N
1
It has been shown that these 2H-azirin-3-amines can successfully be used in peptide
synthesis [1][2]. All prepared 2H-azirin-3-amines 1 possess aliphatic or aromatic side
chains. It was of interest to extend the series of available synthons to examples with
functionalized side chains, e.g., side chains with OH groups. In the present paper, the
synthesis of 2H-azirin-3-amines 2a and 2b with protected phenolic hydroxy groups as
synthons for enantiomerically pure 2-methyltyrosine (Tyr(2Me)) and 2-methyl-3',4'-
dihydroxyphenylalanine (Dopa(2Me)), and their use in peptide synthesis are
described. Additionally, the new 2H-azirin-3-amine 2c with a N3 group in the side
chain is presented as the unexpected product of an attempt to prepare 2d, a benzyl
(Bn)-protected synthon for Ser(2Me).
1
)
Part of the Ph.D. thesis of K. A. B., Universit‰t Z¸rich, 2002.

Helvetica Chimica Acta Vol. 85 (2002)
3423
BnO
BnO
N
N
BnO
N
N
2b
2a
N3
O
N
N
N
N
2c
2d
2. Results. 2.1. Preparation of the 2H-Azirines. The 2H-azirin-3-amines 2a c
(Scheme 1), i.e., synthons for 2-methyltyrosine (Tyr(2Me)), 2-methyl-3',4'-dihydroxy-
phenylalanine (Dopa(2Me)), and 2-(azidomethyl)alanine (Ala(2AMe)) (Table 1),
were prepared in gram quantities. As reported in our previous paper [1], the
commercially available (R)-[1-(naphthalen-1-yl)ethyl]amine (3) was used as the chiral
auxiliary group in all experiments.
Scheme 1
O
O
LDA, R-X
R
N
N
5a R = 4-BnOC6H4CH2
4
b
c
R = 3,4-(BnO)2C6H3CH2
R = 4-BnOCH2
L.-R.
S
R
N
R
N
COCl2
DABCO
NaN3
N
2a R = 4-BnOC6H4CH2
10a R = 4-BnOC6H4CH2
b
c
R = 3,4-(BnO)2C6H3CH2
R = N3CH2
b
c
R = 3,4-(BnO)2C6H3CH2
R = 4-BnOCH2
LDA ˆ lithium diisopropylamide; L.-R. ˆ Lawesson reagent; DABCO ˆ 1,4-diazabicyclo[2.2.2]octane.
The three pairs of diastereoisomers of 2a c were prepared according to Scheme 1
(Table 1) by applying the previously described protocols (cf. [3]). The chiral auxiliary
group was introduced as described for 1a e [1]. The amide 4 [1] was deprotonated with

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R
Helvetica Chimica Acta Vol. 85 (2002)
Table 1. Synthesis of 2H-Azirin-3-amines 2 (Yields in [%])
Alcohol 7
Bromide 6
Amide 5
Thioamide 10
Azirine 2
Synthon
4-BnOC6H4CH2
3,4-(BnO)2C6H3CH2
4-BnOCH2
a (90)
b (quant.)
a (quant.)
b (quant.)
a (92)
b (88)
c (92)
a (78)
b (85)
c (49)
a (81)
b (62)
Tyr(2Me)
Dopa(2Me)
N3CH2
c (26)
Ala(2AMe)
lithium diisopropylamide (LDA) and alkylated with the respective halides RÀX to
give the amides 5a c as mixtures of diastereoisomers.
The halides 6a and 6b, which were used for the synthesis of 5a and 5b, respectively,
were prepared from the corresponding benzylic alcohols 7a and 7b, which were
obtained from phenol 8 and aldehyde 9, respectively [4] (Scheme 2). The amide 5c was
prepared by alkylation with benzyl chloromethyl ether (6c), which was commercially
available.
Scheme 2
NaH, DMF,
BnBr
PBr3, CH2Cl2
OH
OH
Br
HO
BnO
BnO
BnO
BnO
8
7a
6a
O
OH PBr3, CH2Cl2
Br
NaBH4, THF
H
BnO
OBn
OBn
OBn
9
7b
6b
The amides 5a c were then converted to the corresponding thioamides 10a c
(mixtures of diastereoisomers) by treatment with Lawesson reagent. Finally, the
synthesis of the azirines 2a c was achieved by consecutive reaction of 10a c with
COCl2 solution in CH2Cl2, deprotonation with 1,4-diazabicyclo[2.2.2]octane (DAB-
CO) in THF, and treatment with NaN3 (cf. [1]). The yields of these transformations are
given in Table 1. The conversion of 10c under the conditions described leads to the
unexpected product 2c instead of 2d. During the reaction sequence described, the BnO
group of the side chain was replaced by the N3 group. This substitution could be
prevented neither by using less than 1 equiv. of NaN3 nor by adding NaN3 very slowly to
the intermediate chloroenamine; therefore, it is suspected that the substitution is faster
than the formation of the azirine.
Separation of the (R,S)- and (R,R)-diastereoisomers of 2a and 2b was achieved by
means of column chromatography (CC; SiO2), followed by MPLC (SiO2). The detailed
procedures and solvent systems are summarized in Table 2.
The diastereoisomers of azirine 2c could not be separated by means of
chromatography, neither by TLC, CC, and MPLC nor by GC. The two diastereoisomers
could not be differentiated with NMR techniques either.

Helvetica Chimica Acta Vol. 85 (2002)
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Table 2. Chromatographic Separation of the (R,S)- and (R,R)-Diastereoisomers of 2a and 2b
R
Separation method
Amount separated
Rf-Valuesc)
2a
2b
4-BnOC6H4CH2
3,4-(BnO)2C6H3CH2
CCa), MPLCb)
1.5 g
4.9 g
0.25, 0.16
0.29, 0.20
CCa) (3Â), MPLCb)
a) Hexane/AcOEt 2 : 1. b) AcOEt. c) Hexane/AcOEt 1 : 1.
2.2. Reaction of 2H-Azirines 2a c with Thiocarboxylic and Carboxylic Acids. With
the aim of demonstrating 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 PhCOSH (cf.
[1][3][6 9]) and PhCOOH (cf. [1][3][7]) (Scheme 3). A typical reaction was carried
out with equimolar amounts of 2 and the acid in CH2Cl2 at room temperature. The
yields and reaction times are given in Table 3. It is obvious that the reactions with
PhCOSH proceeded faster and gave the products in better yields than with PhCOOH.
The same difference has been observed with azirines 1a e [1]. In the case of the
Tyr(2Me) synthon 2a, the (1'R,2S)-diastereoisomer reacts significantly slower and gave
the products in lower yields than its (1'R,2R)-isomer. On the other hand, such a
different behavior of the Dopa(2Me) synthons 2b was not observed.
Scheme 3a)
O
O
R
R
CH2Cl2
r.t.
N
XH
N
+
2
X
1'
N
N
H
X = S, O
2a-c
11a-c X = S
12a-b X = O
a) For a c, see Scheme 1.
Table 3. Reaction of the 2H-Azirin-3-amines 2 with PhCOSH and PhCOOH (in CH2Cl2 at room temperature)
Azirine 2
R
Reaction with PhCOSH
Reaction with PhCOOH
Yield Reaction
Thioamide 11 Yield Reaction Amide 12
[%]
time [h]
[%]
time [h]
(1'R,2S)-2a
(1'R,2R)-2a
(1'R,2S)-2b
(1'R,2R)-2b
2c
4-BnOC6H4CH2
(1S,1'R)-11a
(1R,1'R)-11a
64
90
8
88
97
18(1
2.5
9
20
4.5
S,1'R)-12a
39
19
23
336
314
(1R,1'R)-12a 67
S,1'R()1-12b 91
(1R,1'R)-12b 90
3,4-(BnO)2C6H3CH2 (1S,1'R)-11b
(1R,1'R)-11b
N3CH2
3
11c
2.3. Determination of the Relative Configuration of the New Synthons. As most of
the prepared azirines were not crystalline compounds or, in the case of (1'R,2S)-2a,
suitable crystals for the X-ray crystallographic analysis could not be obtained, the
configurations were determined in derivatives 11 and 12. Suitable crystals were

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Helvetica Chimica Acta Vol. 85 (2002)
obtained from the four products of the conversion of (1'R,2R)-2a, (1'R,2S)-2b and
(1'R,2R)-2b with PhCOSH and PhCOOH, respectively, i.e. from the monothiodiamides
(1R,1'R)-11a and (1R,1'R)-11b, and the diamides (1S,1'R)-12b and (1R,1'R)-12b (see
Fig.). The configuration at C(2) of the amino acid derivatives (C(4) in the Figure) was
determined relative to the known (R)-configuration of the chiral auxiliary group.
Except for (1R,1'R)-11a, the absolute configurations of the molecules were not
confirmed crystallographically, but could be assigned on the basis of the known
absolute configuration of the amino substitutent.
2.4. The Use of Azirines 2a and 2b in Peptide Chemistry. The optically pure amino
acid synthons 2a and 2b were used to incorporate the corresponding (S)- and (R)-
configured 2,2-disubstituted glycines (a,a-disubstituted a-amino acids), respectively,
into dipeptides of the type Fmoc-Val-Xaa-N(Me)NaphthEt 13 by coupling 2 with
Fmoc-valine (Fmoc-Val-OH, Scheme 4). Typically, these reactions were carried out in
CH2Cl2 at room temperature with equimolar amounts of 2 and Fmoc-Val-OH. The
yields and reaction times are listed in Table 4. As can be seen, the coupling of the
Dopa(2Me) synthons 2b is slower than in the case of the Tyr(2Me) synthons 2a,
probably due to increased sterical hindrance resulting from the second Bn protecting
group in the side chain.
Scheme 4
O
R
OH
N
+
O
N
H
O
N
Fmoc-Val-OH
2a R = 4-BnOC6H4CH2
b R = 3,4-(BnO)2C6H3CH2
CH2Cl2
r.t.
O
O
O
N
H
N
N
H
R
O
13a R = 4-BnOC6H4CH2
b R = 3,4-(BnO)2C6H3CH2
Table 4. Reaction of the 2H-Azirin-3-amines 2 with Fmoc-Val-OH (in CH2Cl2 at room temperature)
Azirine 2
R
Dipeptide 13
Yield [%]
Reaction time [h]
(1'R,2S)-2a
(1'R,2R)-2a
(1'R,2S)-2b
(1'R,2R)-2b
4-BnOC6H4CH2
(S,S,R)-13a
(S,R,R)-13a
(S,S,R)-13b
(S,R,R)-13b
52
70
56
58142
20
66
137
3,4-(BnO)2C6H3CH2

Figure. ORTEP Plots [10] of the molecular structures of a) (1R,1'R)-11a (derivative of (R)-Tyr(2Me)), b) (1R,1'R)-11b (derivative of (R)-
Dopa(2Me)), c) (1S,1'R)-12b (derivative of (S)-Dopa(2Me)), and d) (1R,1'R)-12b (derivative of (R)-Dopa(2Me)) (50% Probability
ellipsoids, arbitrary numbering of atoms)

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Helvetica Chimica Acta Vol. 85 (2002)
Each of the protecting groups of the dipeptides 13 was removed selectively under
standard conditions. The Fmoc group at the N-terminus was cleaved under basic
conditions with Et2NH to give the dipeptides 14 (Scheme 5). Typically, these reactions
were carried out without solvent at room temperature and in an excess of Et2NH. The
yields and reaction times are given in Table 5.
Scheme 5
O
O
H
N
O
N
N
H
R
O
13a R = 4-BnOC6H4CH2
b R = 3,4(BnO)2C6H3CH2
Et2NH
r.t.
O
H
N
N
H2N
R
O
14a R = 4-BnOC6H4CH2
b R = 3,4-(BnO)2C6H3CH2
Table 5. Removal of the Fmoc Group of the Dipeptides 13 with Et2NH and Cleavage of the Bn Groups in the Side
Chains with Pd/C and H2
13
R
14
Yield [%] Reaction 15
Yield [%] Reaction
time [h]
time [h]
(S,S,R)-13a 4-BnOC6H4CH2
(S,R,R)-13a
(S,S,R)-13b 3,4-(BnO)2C6H3CH2 (S,S,R)-14b
(S,S,R)-14a quant.
(S,R,R)-14a 94
1
2
7
(S,S,R)-15a 47
(S,R,R)-15a 71
1 S,S,R)-15(b 60
48
40
22
8
(S,R,R)-13b (S,R,R)-14b 77
4
(S,R,R)-15b
8
5
25
The Bn protecting groups of the side chains were removed by hydrogenolysis to give
dipeptides 15 (Scheme 6). Typically, these reactions were carried out in MeOH with a
catalytic amount of Pd/C (10% on charcoal) and H2 at room temperature. The yields
and reaction times are collected in Table 5.
The amide group at the C-terminus was hydrolyzed under acidic conditions to give
the dipeptide acids 16 (Scheme 7). Optimal conditions for the hydrolysis of amides with
this special chiral auxiliary group have been determined earlier [2]. Typically, these
reactions were carried out in 3n HCl (MeCN/H2O 1:1) at 608. For the hydrolysis of 13
to the dipeptide acids 16, however, the solubility of the dipeptide amides (S,S,R)-13a
and (S,S,R)-13b in the 1:1 mixture of MeCN/H2O was insufficient; longer reaction
times would have been neccessary, which leads to increased decomposition. Therefore,

Helvetica Chimica Acta Vol. 85 (2002)
3429
Scheme 6
O
O
H
N
O
N
N
H
R
O
13a R = 4-BnOC6H4CH2
b R = 3,4-(BnO)2C6H3CH2
H2, Pd/C
MeOH
15a R = 4-HOC6H4CH2
b R = 3,4-(HO)2C6H3CH2
Scheme 7
O
O
H
N
O
N
N
H
R
O
13a R = 4-BnOC6H4CH2
b R = 3,4-(BnO)2C6H3CH2
3N HCl (MeCN/H2O)
60°
O
O
O
O
H
H
N
N
O
N
OH
O
N
NH
H
H
R
R
O
O
16a R = 4-BnOC6H4CH2
b R = 3,4-(BnO)2C6H3CH2
17a R = 4-BnOC6H4CH2
b R = 3,4-(BnO)2C6H3CH2
the ratio of MeCN and H2O was changed, while keeping the concentration of HCl
constant (3N). The reaction conditions, yields and reaction times are given in Table 6.
Surprisingly, an undesired side reaction of the amino group took place, leading to
the product 17 (Scheme 7), which cannot be hydrolyzed further under the possible
reaction conditions. This side product was fully characterized in the case of (S,S)-17a.
The formation of these side products can be explained by an acid-catalyzed cleavage of
the benzylic CÀN bond of the amide group under the more drastic hydrolysis
conditions.
3. Conclusions. It can be stated that the new synthons were successfully used for
the synthesis of dipeptides. Each protecting group could be removed selectively, but

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Helvetica Chimica Acta Vol. 85 (2002)
Table 6. Hydrolysis of the Dipeptide Amides 13 (in 3n HCl (MeCN/H2O) at 608)
Dipeptide
R
MeCN/H2O 1 : 1
MeCN/H2O 2 : 1
MeCN/H2O 3 : 1
13
Yield [%] Recov- Reaction Yield [%] Reaction Yield [%] Reaction
ered
13 [%]
time [h]
time [h]
time [h]
16
833
51
9
17
16
17
681.75
1
16
17
(S,S,R)-13a 4-BnOC6H4CH2
(S,R,R)-13a
(S,S,R)-13b 3,4-(BnO)2C6H3CH2
(S,R,R)-13b
49
5
19
783
55
27
30
19
3
22
3
67
30
42
1
25
one limitation in the use of the chiral auxiliary group has to be mentioned: after
successful coupling to give the peptide amide, the auxiliary group has to be cleaved by
acid hydrolysis. In some cases, the yields after the hydrolysis are poor. The resulting side
product is of no use for further reactions in peptide synthesis.
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
f¸r wissenschaftliche Forschung an der Universit‰t Z¸rich is gratefully acknowledged. K. A. B. thanks the
−Stipendienfonds der Basler Chemischen Industrie× for a scholarship.
Experimental Part
1. General. See [1].
2. Synthesis of the 2H-Azirines. 2.1. Tyr(2Me) Synthon. 2.1.1. [4-(Benzyloxy)phenyl]methanol (7a). To an
orange soln. of (4-hydroxyphenyl)methanol (8; 10.011 g, 80.643 mmol) in DMF (220 ml) at 08, NaH (3.5 g, ca.
80 mmol; washed with hexane) was added. At r.t., BnBr (9.5 ml, 80 mmol) was added, and the mixture was
stirred for 6 h, while the color was changing to blue-green. The soln. was evaporated (10 mbar, 508), and the
residue was dissolved in CH2Cl2 and washed with H2O. The color of the soln. turned to orange, and after
evaporation, the residue solidified overnight. CC (hexane/AcOEt 2 :1) yielded 15.463 g (90%) of 7a. M.p.
84.5 858. Rf (hexane/AcOEt 2 :1) 0.13. IR: 3322s, 3060m, 3034m, 2915m, 2866m, 1956w, 1888w, 1610s, 1585m,
1513vs, 1469m, 1454s, 1423m, 1382s, 1299m, 1246vs, 1173s, 1112m, 1082w, 998vs, 936w, 914m, 8 63m, 8 12s, 777s,
740vs, 716m, 696vs, 640m, 615m. 1H-NMR (CD3OD): 7.45 7.25 (m, 7 arom. H); 7.0 6.95 (m, 2 arom. H); 5.06,
4.59 (2s, 2 CH2); 1.63 (br. s, OH). 13C-NMR (CD3OD): 158.3 (s, 1 arom. CO); 136.9, 133.3 (2s, 2 arom. C); 130.0,
.
‡
128.5, 127.9, 127.3 (4d, 7 arom. CH); 114.9 (d, 2 arom. CH); 70.0, 64.9 (2t, 2 CH2). EI-MS (NH3): 214 (15, M ),
‡
91 (100, C7H7 ). Anal. calc. for C14H14O2 (214.26): C 78.48, H 6.59; found: C 78.22, H 6.62.
2.1.2. 4-(Benzyloxy)-1-(bromomethyl)benzene (6a). To a soln. of 7a (7.035 g, 32.834 mmol) in CH2Cl2
(150 ml) under Ar at 08, PBr3 (3.2 ml, 33.7 mmol) was added dropwise. The mixture was kept dark with Al foil
around the flask. After 1.5 h, the mixture was warmed to r.t. and stirred for another 30 min. The soln. was poured
on ice and extracted with Et2O; the org. phase was dried (MgSO4) and evaporated (keeping in the dark as long
as possible): 9.184 g (quant. yield) of 6a, which was very unstable (decomposition within several h) and had to
be used for further reactions immediately. M.p. 85 868. Rf (hexane/AcOEt 2 :1) 0.54. Rf (hexane/AcOEt 5 :1)
0.42. IR: 3030m, 2934m, 2874w, 1612m, 1579m, 1515vs, 1466w, 1454m, 1384m, 1316w, 1298m, 1253vs, 1231s,
1204m, 1173s, 1126w, 1098w, 1082w, 1007s, 919w, 8 66w, 8 38m, 8 10w, 743vs, 699s, 598s. 1H-NMR (CD3OD): 7.45
7.3 (s, 7 arom. H); 6.93 (dt, J ˆ 8.7, 2.5, 2 arom. H); 5.05 (s, CH2O); 4.48( s, CH2Br). 13C-NMR (CD3OD): 158.8 (s,
1 arom. CO); 136.6, 130.1 (2s, 2 arom. C); 130.4, 128.5, 127.9, 127.3 (4d, 7 arom. CH); 115.1 (d, 2 arom. CH); 70.0
.
.
‡
‡
‡
(t, CH2O); 33.7 (t, CH2Br). EI-MS: 278(1, M
,
81Br), 276 (1, M
,
79Br), 198(4), 197 (26, [ M À Br] ), 119 (8),
‡
‡
‡
‡
107 (14, C7H7O ), 93 (13), 91 (100, C7H7 ), 79 (16), 78(9), 77 (27, C 6H5 ), 69 (9), 67 (5), 65 (17, C5H5 ), 51 (8,
‡
C4H3 ).
2.1.3. (RS)-2-[4-(Benzyloxy)benzyl]-N-methyl-N-[(R)-1-(naphthalen-1-yl)ethyl]propanamide (5a). To a
soln. of N-methyl-N-[(R)-1-(naphthalen-1-yl)ethyl]propanamide (4 [1]; 6.868 g, 28.459 mmol) in abs. THF
(30 ml) at 08, 2n LDA in THF/heptane/PhEt (17 ml, 34.0 mmol) was added within 30 min. Then, 6a (7.894 g,
28.482 mmol) in abs. THF (40 ml) was added within 35 min, keeping the temp. below 58. After 60 min, the

Helvetica Chimica Acta Vol. 85 (2002)
3431
mixture was carefully poured on ice, extracted with Et2O, dried (MgSO4), and evaporated. CC (hexane/AcOEt
4 :1, then 2 :1) yielded 11.419 g (92%) of 5a. Colorless oil. Rf (hexane/AcOEt 2 :1) 0.34 and 0.26, resp., for the
diastereoisomers. IR (CHCl3): 3007s, 2875w, 2359w, 1731w, 1625vs, 1510vs, 1464m, 1454m, 1409m, 1376m,
1297m, 1248s, 1109m, 1084w, 1043w, 1025m, 916w, 8 64w, 8 37w, 8 07m. 1H-NMR: 8.0 7.75 (m, 3 arom. H); 7.5
7.25 (m, 9 arom. H); 7.14, 7.04 (2d, J ˆ 8.6, 2 arom. H); 6.89, 6.73 (2d, J ˆ 8.6, 2 arom. H); 6.62, 6.60 (2q, J ˆ 6.7,
CHN); 5.04, 4.95 (2s, PhCH2O); 3.1 2.95, 2.9 2.8, 2.7 2.55 (3m, CH2CH); 2.43, 2.20 (2s, MeN); 1.57, 1.41 (2d,
J ˆ 6.8, 1 Me); 1.18, 1.14 (2d, J ˆ 6.7, 1 Me). 13C-NMR: 175.1, 175.0 (2s, CO); 157.2, 157.1, 137.1, 136.3, 136.0,
133.6, 132.7, 132.5, 131.9 (9s, 6 arom. C); 130.0, 129.9, 128.5, 128.3, 127.8, 127.3, 126.5, 126.4, 125.8, 124.8, 124.7,
124.1, 114.7, 114.6 (14d, 16 arom. CH); 69.9 (t, PhCH2O); 47.8( d, CHN); 39.6, 39.1 (2t, CH2); 38.9, 38.7 (2d,
‡
CHCO); 28.9, 28.8 (2q, MeN); 17.9, 17.2, 15.6, 15.5 (4q, 2 Me). CI-MS (NH3): 455 (16, [M ‡ NH4] ), 440 (11),
‡
‡
439 (43), 438(100, [ M ‡ 1] ), 108(14, [PhCH 2O ‡ 1] ). Anal. calc. for C30H31NO2 (437.58): C 82.35, H 7.14,
N 3.20; found: C 82.40, H 7.22, N 3.04.
2.1.4. (RS)-2-[4-(Benzyloxy)benzyl]-N-methyl-N-[(R)-1-(naphthalen-1-yl)ethyl]propanethioamide (10a).
To a soln. of 5a (5.970 g, 13.64 mmol) in abs. toluene (15 ml), Lawesson reagent (3.3 g, 1.2 equiv.) was added;
the mixture was stirred for 3.5 h at 1258, cooled to r.t., the precipitate was washed with Et2O, and the filtrate was
evaporated. CC (hexane/AcOEt 5 :1) yielded 4.797 g (78%) of 10a. Colorless solid. M.p. 128 129 8. Rf (hexane/
AcOEt 5 :1) 0.27 and 0.21, resp., for the diastereoisomers. IR: 3444w, 3039w, 2967m, 2923m, 1613m, 1582w,
1510vs, 1486vs, 1453s, 1406vs, 1377m, 1322s, 1297m, 1249vs, 1172s, 1110s, 1085m, 1044s, 1028m, 98 7m, 969m,
904w, 8 41m, 8 05s, 778vs, 732s, 694m, 678w, 624w. 1H-NMR: 7.9 7.8( m, 3 arom. H); 7.5 7.3 (m, 9 arom. H,
CHN); 7.16 (d, J ˆ 8.6, 2 arom. H); 6.86 (d, J ˆ 8.6, 2 arom. H); 5.05 (s, PhCH2O); 3.25 3.15 (m, CH2); 2.85
2.8( m, CSCH); 2.30 (s, MeN); 1.47 (d, J ˆ 6.8, Me); 1.30 (d, J ˆ 6.1, Me). 13C-NMR: 208.3 (s, CS); 157.2 (s, 1
arom. CÀO); 137.1, 135.6, 133.6, 132.3, 132.0 (5s, 5 arom. C); 130.1, 128.8, 128.5, 127.8, 127.3, 126.7, 126.0, 125.2,
124.8, 124.4, 114.7 (11d, 16 arom. CH); 69.9 (t, PhCH2O); 56.8( d, CHN); 45.0 (d, CHCS); 43.3 (t, CH2); 32.9 (q,
‡
MeN); 21.9, 13.9 (2q, MeCHN, MeCHCS). ESI-MS (CH2Cl2, MeOH): 492 (6, [M ‡ K] ), 484 (16, [M ‡
‡
‡
‡
‡
MeOH] ), 476 (13, [M ‡ Na] ), 454 (100, [M ‡ 1] ), 300 (82, [M À naphthCHCH2 ‡ 1] ), 266 (36), 155 (20,
‡
[naphthCHMe] ). Anal. calc. for C30H31NOS (453.65): C 79.43, H 6.89, N 3.09, S 7.07; found: C 79.31, H 6.94,
N 3.03, S 6.97.
2.1.5. (RS)-2-[4-(Benzyloxy)benzyl]-2,N-dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]-2H-azirin-3-amine
(2a). To a soln. of 10a (1.959 g, 4.32 mmol) and 4 drops of abs. DMF in abs. CH2Cl2 (10 ml) at 08, 2n COCl2
in toluene (2.6 ml, 5.2 mmol) was added, the mixture was stirred for 25 min at 08, and the solvent was
evaporated. The residue was dissolved in abs. THF (10 ml), DABCO (0.488 g, 4.35 mmol) was added, and the
soln. was stirred for 15 min at 08. Then, NaN3 (0.569 g, 8.75 mmol) was added, the mixture was stirred for 20 min
at 08 and 7 h at r.t., and then filtered over Celite, the filter cake was washed with Et2O, and the filtrate was
evaporated. CC (hexane/AcOEt 2 :1, then 1 :1) yielded 1.525 g (81%) of 2a. The two diastereoisomers were
separated by means of MPLC (AcOEt).
Data of (1'R,2S)-2a: M.p. 68 69 8. Rf (hexane/AcOEt 1 :1) 0.25. IR (neat): 3033m, 2974m, 2937m, 1761vs,
1610s, 1583m, 1510vs, 1454s, 1419m, 1374s, 1298m, 1240vs, 1176s, 1107m, 1067m, 1026s, 954w, 915w, 8 62w, 8 39m,
805s, 78 2s, 738s, 697s, 621w. 1H-NMR ((D6)DMSO, 370 K): 8.05 8.0 (m, 1 arom. H); 7.95 7.9 (m, 1 arom. H);
7.87 ( d, J ˆ 7.8, 1 arom. H); 7.55 7.3 (m, 9 arom. H); 7.11 (d, J ˆ 8.6, 2 arom. H); 6.92 (d, J ˆ 8.6, 2 arom. H); 5.41
(q, J ˆ 6.9, CHN); 5.09 (s, PhCH2O); 2.84, 2.76 (AB, J ˆ 14.5, CH2C(2)); 2.61 (br. s, MeN); 1.54 (d, J ˆ 6.9,
MeCHN); 1.05 (br. s, MeC(2)). 13C-NMR ((D6)DMSO, 370 K): 164.8( s, C(3)); 156.5 (s, 1 arom. CO); 137.0,
135.4, 133.1, 130.6, 130.5 (5s, 5 arom. C); 130.0, 128.1, 127.7, 127.7, 127.0, 126.8, 125.7, 125.1, 124.6, 123.5, 122.6,
114.2 (12d, 16 arom. CH); 69.2 (t, PhCH2O); 53.4 (d, CHN); 42.8( t, CH2ÀC(2)); 42.5 (s, C(2)); 32.3 (q, MeN);
‡
22.7, 16.5 (2q, MeÀC(2), MeCHN). ESI-MS (MeOH): 469 (9), 468(38), 467 (100, [ M ‡ MeOH] ), 436 (8),
‡
‡
‡
435 (26, [M ‡ 1] ), 281 (5, [M À naphthCHCH2 ‡ 1] ), 155 (6, [naphthCHMe] ). Anal. calc. for C30H30N2O
(434.58): C 82.91, H 6.96, N 6.45; found: C 82.62, H 6.77, N 6.61.
Data of (1'R,2R)-2a: Rf (hexane/AcOEt 1:1) 0.16. IR (neat): 3033m, 2972s, 2910s, 1758vs, 1610s, 1582m,
1510vs, 1453s, 1415m, 1373s, 1297s, 1240vs, 1175s, 1107s, 1064s, 1026s, 954w, 913w, 8 62m, 8 41m, 8 03s, 78 1s, 738s,
1
697s, 617w. H-NMR ((D6)DMSO, 380 K): 8.05 7.85 (m, 3 arom. H); 7.55 7.5 (m, 4 arom. H); 7.5 7.1 (m, 5
arom. H); 7.05 7.0 (m, 2 arom. H); 6.85 6.8 (m, 2 arom. H); 5.42 (q, J ˆ 6.9, CHN); 5.05 (s, PhCH2O); 2.70 (s,
MeN); 2.6 2.55 (m, CH2C(2)); 1.65 (d, J ˆ 6.9, MeCHN); 1.19 (s, MeC(2)). 13C-NMR ((D6)DMSO, 380 K):
165.1 (s, C(3)); 156.4 (s, 1 arom. CO); 133.9, 135.7, 133.1, 130.5, 130.4 (5s, 5 arom. C); 129.7, 128.1, 127.7, 127.6,
127.0, 126.8, 125.6, 125.0, 124.6, 123.4, 122.5, 114.2 (12d, 16 arom. CH); 69.2 (t, PhCH2O); 53.8( d, CHN); 43.0 (t,
CH2ÀC(2)); 42.5 (s, C(2)); 32.1 (q, MeN); 22.8, 16.9 (2q, MeÀC(2), MeCHN). ESI-MS (MeOH): 468(36), 467
‡
‡
‡
‡
(100, [M ‡ MeOH] ), 435 (54, [M ‡ 1] ), 281 (19, [M À naphthCHCH2 ‡ 1] ), 155 (37, [naphthCHMe] ).
Anal. calc. for C30H30N2O (434.58): C 82.91, H 6.96, N 6.45; found: C 82.67, H 6.93, N 6.35.

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Helvetica Chimica Acta Vol. 85 (2002)
2.2. Dopa(2Me) Synthon. 2.2.1. 3,4-Bis(benzyloxy)benzenemethanol (7b). A soln. of 3,4-bis(benzyloxy)-
benzaldehyde (9, 12.797 g, 40.195 mmol) in abs. THF (100 ml) was added dropwise to a suspension of NaBH4
(1.56 g, 41.237 mmol) in abs. THF (200 ml). The mixture was stirred for 4.5 h at r.t., and then the reaction was
quenched by dropwise addition of H2O (40 ml). The resulting mixture was passed through a Celite pad. The
filtrate was dried (MgSO4) and evaporated: 13.169 g of crude 7b (quant.) as a colorless solid. M.p. 73 73.58. Rf
(hexane/AcOEt 1:1) 0.30. IR: 3288s, 3063m, 3034m, 2918m, 2874m, 1605w, 1589m, 1515vs, 1467w, 1455s, 1424m,
1386s, 1292w, 1257vs, 1228s, 1164m, 1130vs, 1069w, 1047w, 1004vs, 942w, 914w, 8 60w, 8 09m. 1H-NMR: 7.45 7.25
(m, 10 arom. H); 6.99 (d, J ˆ 1.8, 1 arom. H); 6.9 6.8 (m, 2 arom. H); 5.15, 5.14 (2s, 2 CH2); 4.56 (s, PhCH2O);
1.57 (s, OH). 13C-NMR: 149.1, 148.5 (2s, 2 arom. CO); 137.2, 137.2, 134.4 (3s, 3 arom. C); 128.4, 127.7, 127.2, 127.2,
120.1 (5d, 11 arom. CH); 115.2, 114.1 (2d, 2 arom. CH); 71.4, 71.2 (2t, 2 CH2); 65.1 (t, CH2OH). CI-MS (NH3):
‡
‡
338(15, [ M ‡ NH4] ), 304 (8), 303 (100, [M À OH] ). Anal. calc. for C21H20O3 (320.39): C 78.73, H 6.29; found:
C 78.38, H 6.47.
2.2.2. 1,2-Bis(benzyloxy)-4-(bromomethyl)benzene (6b). To a soln. of 7b (12.022 g, 37.523 mmol) in abs.
CH2Cl2 (200 ml) at 08 under Ar, PBr3 (3.6 ml, 37.9 mmol) was added dropwise. After 30 min, the mixture was
warmed to r.t. and stirred for 1 h. The soln. was poured on ice and extracted with Et2O; the org. phase was dried
(MgSO4) and evaporated: 14.350 g (quant. yield) of 6b. This compound was unstable and had to be quickly
reacted further. Rf (hexane/AcOEt 2 :1) 0.44. IR (neat): 2966s, 1955w, 1774m, 1724w, 1604s, 1514vs, 1454vs,
1383s, 1266vs, 1012vs, 909s, 8 07s, 732vs, 695vs, 653s, 606s. 1H-NMR: 7.45 7.25 (s, 10 arom. H); 6.99 (d, J ˆ 1.9, 1
arom. H); 6.9 6.85 (m, 2 arom. H); 5.15, 5.14 (2s, 2 CH2O); 4.43 (s, CH2Br). 13C-NMR: 149.2, 149.0 (2s, 2 arom.
CO); 137.0, 136.9, 130.8(3 s, 3 arom. C); 128.4, 127.8, 127.3, 127.1, 122.3 (5d, 11 arom. CH); 115.9, 114.7 (2d, 2
arom. CH); 71.3, 71.2 (2t, CH2O); 34.0 (t, CH2Br).
2.2.3. (RS)-2-[3,4-Bis(benzyloxy)benzyl]-N-methyl-N-[(R)-1-(naphthalen-1-yl)ethyl]propanamide (5b).
As described for 5a, with LDA (2n soln., 17.5 ml, 35.0 mmol), 4 [1] (7.005 g, 29.027 mmol), and abs. THF
(30 ml); 30 min at 08; with 6b (11.121 g, 29.015 mmol), and abs. THF (30 ml); addition within 35 min, below 58;
2 h at 08; CC (hexane/AcOEt 5 :1, then 4 :1): 13.814 g (88%) of 5b. Colorless oil. Rf (hexane/AcOEt 1:1) 0.49
and 0.42, resp., and Rf (hexane/AcOEt 2 :1) 0.28and 0.22, resp., for the diastereoisomers. IR (neat): 3034 s,
2967s, 1952w, 1736s, 1630vs, 1509vs, 1261vs, 1135vs, 1024vs, 909m, 8 51s, 805vs, 735s, 697vs, 622m, 597m. 1H-NMR:
7.95 7.75 (m, 3 arom. H); 7.5 7.2 (m, 14 arom. H); 6.85 6.55 (m, 3 arom. H, CHN); 5.2 5.0 (m, 2 PhCH2O);
3.05 2.95, 2.85 2.75, 2.6 2.45 (3m, CH2CH); 2.37, 2.12 (2s, MeN); 1.55, 1.38(2 d, J ˆ 6.8, 1 Me); 1.15 1.1 (m,
1 Me). 13C-NMR: 175.1, 174.9 (2s, CO); 148.7, 148.5, 147.4, 137.5, 137.4, 137.3, 136.0, 133.6, 133.6, 131.9 (10s, 8
arom. C); 128.4, 128.3, 127.6, 127.5, 127.3, 127.2, 126.6, 126.4, 125.8, 124.7, 124.0, 124.0, 122.0, 121.9, 116.3, 115.4,
115.1 (17d, 20 arom. CH); 71.4, 71.2 (2t, PhCH2O); 47.8( d, CHN); 40.0, 39.4 (2t, CH2); 38.8, 38.5 (2d, CHCO);
‡
28.9, 28.8 (2q, MeN); 17.9, 17.1, 15.6 (3q, 2 Me). ESI-MS (MeOH, CH2Cl2, NaI): 566 (100, [M ‡ Na] ), 544 (8,
‡
‡
[M ‡ 1] ), 404 (17, [M À N(Me)naphthEt ‡ MeOH] ), 322 (22). Anal. calc. for C37H37NO3 (543.71): C 81.74,
H 6.86, N 2.58; found: C 81.97, H 6.87, N 2.53.
2.2.4. (RS)-2-[3,4-Bis(benzyloxy)benzyl]-N-methyl-N-[(R)-1-(naphthalen-1-yl)ethyl]propanethioamide
(10b). As described for 10a, with 5b (12.742 g, 23.44 mmol), abs. toluene (30 ml), and Lawesson reagent
(5.665 g, 1.2 equiv.); 5 h at 1308; 2 Â CC (hexane/AcOEt 4 :1): 11.149 g (85%) of 10b. Colorless oil. Rf (hexane/
AcOEt 2 :1) 0.44 and 0.40, resp., for the diastereoisomers. IR (neat): 2927s, 1952w, 1822w, 1732s, 1600s, 1514vs,
1504vs, 1470s, 1455vs, 1404s, 1254s, 1136s, 910m, 8 46m, 773s, 738s, 696s, 611m. 1H-NMR: 7.9 7.7 (m, 3 arom. H);
7.55 7.15 (m, 14 arom. H, CHN); 6.85 6.6 (m, 3 arom. H); 5.2 5.0 (m, 2 PhCH2O); 3.25 3.05, 2.85 2.8 (2m,
CHCH2); 2.57, 2.20 (2s, MeN); 1.64, 1.43 (2d, J ˆ 6.8, 6.7, 1 Me); 1.26, 1.18 (2d, J ˆ 6.0, 6.3, 1 Me). 13C-NMR:
208.1, 208.0 (2s, CS); 148.6, 148.4, 147.4 (3s, 2 arom. CO); 137.4, 135.6, 133.6, 133.5 (4s, 6 arom. C); 128.9, 128.9,
128.5, 128.3, 128.2, 127.7, 127.5, 127.3, 127.2, 127.1, 126.9, 126.7, 126.0, 125.2, 124.9, 124.4, 122.1, 116.4, 115.4, 114.9
(20d, 20 arom. CH); 71.4, 71.2 (2t, 2 PhCH2O); 56.8, 56.6 (2d, CHN); 44.9, 44.7 (2d, CHCS); 43.7, 42.6 (2t, CH2);
‡
32.9 (q, MeN); 21.9, 20.8, 13.7 (3q, MeCHN, MeCHCS). CI-MS (NH3): 561 (9), 560 (18, [M ‡ 1] ), 407 (30),
‡
406 (100, [M À naphthCHCH2 ‡ 1] ), 316 (36). Anal. calc. for C37H37NO2S (559.77): C 79.39, H 6.66, N 2.50,
S 5.73; found: C 79.22, H 6.95, N 2.44, S 5.43.
2.2.5. (RS)-2-[3,4-Bis(benzyloxy)benzyl]-2,N-dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]-2H-azirin-3-
amine (2b). As described for 2a, with 10b (8.149 g, 14.56 mmol), 4 drops of abs. DMF, abs. CH2Cl2 (15 ml),
and 2n COCl2 in toluene (9 ml, 18mmol); 15 min at 0 8; evaporation; abs. THF (20 ml), and DABCO (1.634 g,
14.57 mmol); 20 min at 08; NaN3 (1.893 g, 29.123 mmol); 20 min at 08; 26 h at r.t.; CC (hexane/AcOEt 2 :1):
4.913 g (62%) of 2b. The diastereoisomers were separated by means of CC and MPLC (AcOEt), and each was
obtained as an oil.
Data of (1'R,2S)-2b: Rf (hexane/AcOEt 1:1) 0.29. IR (neat): 3034m, 2973s, 2912s, 1952w, 1760vs, 1588s,
1
1504vs, 1454vs, 1425s, 1373s, 1264vs, 1136vs, 1102m, 1067s, 1025s, 910w, 8 52m. H-NMR ((D6)DMSO, 373 K):

Helvetica Chimica Acta Vol. 85 (2002)
3433
8.05 7.95, 7.95 7.9, 7.85 7.8 (3m, 3 arom. H); 7.55 7.25 (m, 14 arom. H); 6.94 (d, J ˆ 8.3, 1 arom. H); 6.93 (d,
J ˆ 1.7, 1 arom. H); 6.71 (dd, J ˆ 8.1, 2.1, 1 arom. H); 5.38 (q, J ˆ 6.9, CHN); 5.08, 5.07 (2s, 2 PhCH2O); 2.79,
2.73 (AB, J ˆ 14.7, CH2C(2)); 2.56 (br. s, MeN); 1.52 (d, J ˆ 6.9, MeCHN); 1.01 (br. s, MeC(2)). 13C-NMR
((D6)DMSO, 373 K): 164.7 (s, C(3)); 148.0, 146.8, 137.2, 137.1, 135.4, 133.1, 131.7, 130.6 (8s, 8arom. C); 128.1,
127.7, 127.6, 127.0, 126.8, 125.6, 125.1, 124.6, 123.5, 122.5, 122.2, 117.0, 115.1 (13d, 20 arom. CH); 70.7, 70.6 (2t, 2
PhCH2O); 53.4 (d, CHN); 43.2 (t, CH2ÀC(2)); 42.3 (s, C(2)); 32.3 (q, MeN); 22.7, 16.6 (2q, MeÀC(2),
‡
MeCHN). ESI-MS (CH2Cl2, MeOH, NaI): 574 (28), 573 (68, [ M ‡ MeOH ‡ 1] ), 564 (14), 563 (34, [M ‡
‡
‡
Na] ), 542 (39), 541 (100, [M ‡ 1] ). Anal. calc. for C37H36N2O2 (540.71): C 82.19, H 6.71, N 5.18; found:
C 82.05, H 6.66, N 4.94.
Data of (1'R,2R)-2b: Rf (hexane/AcOEt 1:1) 0.20. IR (neat): 3034m, 2939m, 1952w, 1760vs, 1588m, 1513vs,
1454s, 1425s, 1374s, 1264vs, 1136s, 1066s, 1025s, 911w, 8 54w. 1H-NMR ((D6)DMSO, 373 K): 8.0 7.85 (m, 3 arom.
H); 7.5 7.25 (m, 14 arom. H); 6.87 (d, J ˆ 8.2, 1 arom. H); 6.82 (d, J ˆ 1.6, 1 arom. H); 6.64 (dd, J ˆ 8.1, 1.8, 1
arom. H); 5.40 (q, J ˆ 6.8, CHN); 5.04, 4.91 (2s, 2 PhCH2O); 2.97, 2.63, 2.53 (3 br., CH2ÀC(2), MeN); 1.62 (d,
J ˆ 6.9, MeCHN); 1.17 (s, MeC(2)). 13C-NMR ((D6)DMSO, 373 K): 165.1 (s, C(3)); 148.0, 146.8, 137.1, 137.0,
135.6, 133.2, 131.8, 130.5 (8s, 8 arom. C); 128.2, 127.7, 127.6, 127.6, 127.0, 126.8, 125.7, 125.1, 124.6, 123.4, 122.5,
121.9, 116.7, 115.1 (14d, 20 arom. CH); 70.6, 70.5 (2t, 2 PhCH2O); 53.7 (d, CHN); 43.7 (t, CH2ÀC(2)); 42.5 (s,
C(2)); 32.1 (q, MeN); 22.9, 16.9 (2q, MeÀC(2), MeCHN). ESI-MS (CH2Cl2, MeOH, NaI): 573 (65, [M ‡
‡
‡
MeOH ‡ 1] ), 541 (100, [M ‡ 1] ). Anal. calc. for C37H36N2O2 (540.71): C 82.19, H 6.71, N 5.18; found: C 82.17,
H 6.55, N 5.38.
2.3. Ser(2Me) Synthon. 2.3.1. (RS)-3-(Benzyloxy)-2,N-dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]propan-
amide (5c). As described for 5a, with LDA (2n soln., 16 ml, 32.0 mmol), 4 [1] (6.302 g, 26.11 mmol), abs. THF
(65 ml), and a 60% soln. of benzyl chlormethyl ether (6.1 ml, ca. 26 mmol); addition within 20 min, below 58;
45 min at 08; CC (hexane/AcOEt 4 :1, then 2 :1) yielded 8.696 g (92%) of 5c. Colorless oil. Rf (hexane/AcOEt
2 :1) 0.31 and 0.24, resp., for the diastereoisomers. IR (neat): 3421w, 3030w, 2974s, 2935m, 2862m, 1951w, 1818w,
1633vs, 1511s, 1454s, 1411s, 1372m, 1324m, 1296m, 1240m, 1209m, 1172m, 1103s, 1044s, 1027s, 910w, 8 05s, 782vs,
737s, 698s. 1H-NMR: 8.05 7.95 (m, 1 arom. H); 7.85 7.75 (m, 2 arom. H); 7.5 7.1 (m, 9 arom. H); 6.65 6.6 (m,
CHN); 4.6 4.4 (m, PhCH2O); 3.9 3.75, 3.55 3.45, 3.05 2.95 (3m, CH2CH); 2.51, 2.49 (2s, MeN); 1.59, 1.58
(2d, J ˆ 6.8, 1 Me); 1.17, 1.08 (2s, J ˆ 6.9, 1 Me). 13C-NMR: 174.3, 174.0 (2s, CO); 141.0, 138.5, 136.2, 136.0, 133.7,
131.9 (6s, 4 arom. C); 128.5, 128.4, 128.3, 128.2, 128.1, 127.4, 127.3, 126.8, 126.5, 126.4, 125.8, 124.8, 124.7, 124.2,
124.0 (15d, 12 arom. CH); 73.4, 73.3 (2t, PhCH2O); 65.1 (t, CH2CH); 47.9 (d, CHN); 37.2 (d, CHCH2); 29.1 (q,
‡
MeN); 15.6, 14.4, 14.2 (3q, 2 Me). CI-MS (NH3): 363 (27), 362 (100, [M ‡ 1] ), 332 (10), 242 (8), 208 (17, [ M À
‡
‡
naphthCHCH2 ‡ 1] ), 200 (7), 155 (6, [naphthCHMe] ). Anal. calc. for C24H27NO2 (361.48): C 79.74, H 7.53,
N 3.87; found: C 79.77, H 7.82, N 3.80.
2.3.2. (RS)-3-(Benzyloxy)-2,N-dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]propanethioamide (10c). As
described for 10a, with 5c (8.407 g, 23.26 mmol), abs. toluene (25 ml), and Lawesson reagent (5.634 g,
1.2 equiv.); 6 h at 1308; CC (hexane/AcOEt 5 :1) yielded 4.323 g (49%) of 10c. Slightly yellow oil. Rf (hexane/
AcOEt 2 :1) 0.44. IR (neat): 2930s, 1594s, 1485vs, 1452vs, 1407s, 1370m, 1296m, 1258vs, 1178m, 1112vs, 98 4s,
805s, 78 2s, 739m, 698s, 620w. 1H-NMR: 7.95 7.8, 7.6 7.15, 6.95 6.85 (3m, 12 arom. H, CHN); 4.6 4.4 (m,
PhCH2O); 4.0 3.8, 3.7 3.6, 3.35 3.2 (3m, CHCH2); 2.72, 2.72 (2s, MeN); 1.69, 1.68(2 d, J ˆ 6.8, 6.7, 1 Me);
1.26, 1.22 (2d, J ˆ 6.6, 1 Me). 13C-NMR: 206.6, 206.3 (2s, CS); 138.4, 135.6, 133.6, 132.0 (4s, 4 arom. C); 132.8,
128.9, 128.5, 128.3, 128.2, 127.5, 127.4, 126.8, 126.7, 126.1, 125.2, 124.9, 124.8, 124.6, 124.4, 114.0, 113.8 (17d, 12
arom. CH); 76.4, 75.8, 73.4 (3t, 2 CH2O); 56.7, 56.6 (2d, CHN); 43.2, 43.2 (2d, CHCS); 33.3 (q, MeN); 18.1, 13.8
‡
(3q, 2 Me). CI-MS (NH3): 379 (14), 378(49, [ M ‡ 1] ), 348(14), 225 (14), 224 (100, [ M À naphthCHCH2 ‡
‡
‡
1] ), 194 (28, [M À naphthEtNMe ‡ 1] ). Anal. calc. for C24H27NOS (377.55): C 76.43, H 7.21, N 3.71, S 8.49;
found: C 76.22, H 7.48, N 3.47, S 8.26.
2.3.3. (RS)-2-(Azidomethyl)-2,N-dimethyl-N-[(R)-1-(naphthalen-1-yl)ethyl]-2H-azirin-3-amine (2c). As
described for 2a, with 10c (2.510 g, 6.65 mmol), 4 drops of abs. DMF, abs. CH2Cl2 (10 ml), and 2n COCl2 in
toluene (4.3 ml, 8.6 mmol); 15 min at 08; 30 min at r.t.; evaporation; with abs. THF (10 ml), DABCO (0.768g,
6.85 mmol); 40 min at 08; NaN3 (0.431 g, 6.63 mmol); 1 h at 08, dilution with abs. THF (25 ml); 24 h at r.t.; CC
(hexane/AcOEt 5 :1): 0.498g (26%) of the unexpected azirine 2c. Rf (hexane/AcOEt 1:1) 0.28. IR (neat):
3410w, 3051w, 2976m, 2917w, 2098vs, 1767vs, 1619w, 1599w, 1510w, 1450m, 1420w, 1375m, 1318w, 1278s, 1193m,
1170m, 1103m, 1073m, 98 9w, 956w, 8 90w, 8 65w. 1H-NMR (300 MHz, (D6)DMSO, 370 K): 8.1 8.05 (m, 1 arom.
H); 7.95 7.9 (m, 2 arom. H); 7.6 7.5 (m, 4 arom. H); 5.48( q, J ˆ 6.9, CHN); 3.38, 3.27 (AB, J ˆ 13.2, CH2N3);
2.84 (s, MeN); 1.73 (d, J ˆ 6.9, MeCHN); 0.93 (br. s, MeC(2)). 13C-NMR (75.5 MHz, (D6)DMSO, 350 K): 162.7
(s, C(3)); 135.2, 133.2, 130.6 (3s, 3 arom. C); 128.2, 127.9, 125.8, 125.2, 124.7, 123.6, 122.5 (7d, 7 arom. CH); 56.8
(t, CH2N3); ca. 54 (d, CHN); ca. 42 (s, C(2)); 32.7 (q, MeN); 20.2, 17.1 (2q, 2 Me). CI-MS (NH3): 295 (20), 294

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Helvetica Chimica Acta Vol. 85 (2002)
‡
‡
(100, [M ‡ 1] ), 267 (9), 266 (46, [M À N2 ‡ 1] ), 254 (14), 253 (9), 242 (7), 203 (13), 184 (27,
‡
‡
[naphthEtNMe] ), 170 (7), 142 (10), 140 (6, [M À naphthCHCH2 ‡ 1] ), 125 (17), 112 (5), 97 (18). Anal.
calc. for C17H19N5 (293.37): C 69.69, H 6.53, N 23.87; found: C 69.49, H 6.64, N 23.76.
3. Reactions of the Azirines 2a 2c with PhCOSH and PhCOOH. 3.1. Reactions of (1'R,2S)-2a. 3.1.1. N-
((S)-1-[4-(Benzyloxy)benzyl]-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-thioxoethyl)benz-
amide ((1S,1'R)-11a). To PhCOSH (32 mg, 0.23 mmol), a soln. of (1'R,2S)-2a (100 mg, 0.23 mmol) in abs.
CH2Cl2 (2 ml) was added, and the soln. was stirred for 18h at r.t. Evaporation, CC (hexane/AcOEt 3 :1), and
prep. TLC (hexane/AcOEt 1:1) gave 84 mg (64%) of (1S,1'R)-11a. M.p. 94 958. Rf (hexane/AcOEt 1 :1) 0.47.
IR: 3418m, 2925s, 1732w, 1656m, 1611w, 1580w, 1510vs, 1478vs, 1374m, 1241m, 1176w, 1104w, 1063m, 1044w,
1025w, 8 78w, 8 04w, 78 1m, 714w, 696w. 1H-NMR: 9.25 (br. s, NH); 7.9 7.85, 7.8 7.75, 7.6 7.3 (3m, 17 arom. H,
CHN); 7.00 (d, J ˆ 8.6, 2 arom. H); 6.83 (d, J ˆ 8.6, 2 arom. H); 5.01 (s, PhCH2O); 4.10, 3.29 (AB, J ˆ 14.6,
CH2(3) of Tyr(2Me)); 2.88 (s, MeN); 1.90 (s, Me(3) of Tyr(2Me)); 1.65 (d, J ˆ 6.7, NCHMe). 13C-NMR: 204.4 (s,
CS); 164.8( s, CO); 157.8( s, 1 arom. CO); 137.0, 135.8, 135.2, 133.7, 132.1 (5s, 6 arom. C); 131.2, 131.1, 129.3,
128.7, 128.6, 127.9, 127.5, 127.2, 127.0, 126.3, 125.5, 125.1, 124.0, 114.5 (14d, 21 arom. CH); 70.0 (t, PhCH2O); 64.9
(s, C(2) of Tyr(2Me)); 61.2 (d, CHN); 41.1 (t, C(3) of Tyr(2Me)); 36.8( q, MeN); 24.4, 12.9 (2q, Me(3) of
‡
Tyr(2Me), NCHMe). ESI-MS (CH2Cl2, MeOH, NaI): 597 (10), 596 (34), 595 (100, [M ‡ Na] ), 579 (76). Anal.
calc. for C37H36N2O2S (572.77): C 77.59, H 6.34, N 4.89, S 5.60; found: C 77.65, H 6.59, N 4.52, S 5.44.
3.1.2. N-((S)-1-[4-(Benzyloxy)benzyl]-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-oxo-
ethyl)benzamide ((1S,1'R)-12a). As described for (1S,1'R)-11a, with PhCOOH (28mg, 0.23 mmol), (1 'R,2S)-
2a (100 mg, 0.23 mmol), and abs. CH2Cl2 (2 ml); 19 h at r.t.; prep. TLC (hexane/AcOEt 1:1): 49 mg (38%) of
(1S,1'R)-12a. M.p. 192 1938. Rf (hexane/AcOEt 1 :1) 0.37. IR: 3311m, 3049w, 2976w, 1654s, 1615vs, 1579m,
1511vs, 1479m, 1545m, 1393m, 1336w, 1302m, 1246s, 1179m, 1106w, 1068m, 1039w, 1026w, 8 8w2, 8 38w, 8 02m,
779m, 726m, 696m, 658w, 648w, 613w. 1H-NMR: 7.95 (br. s, NH); 7.85 7.7, 7.55 7.25 (2m, 17 arom. H); 7.05 (d,
J ˆ 8.6, 2 arom. H); 6.86 (d, J ˆ 8.7, 2 arom. H); 6.56 (q, J ˆ 6.8, CHN); 5.01 (s, PhCH2O); 3.92, 3.19 (AB, J ˆ
14.5, CH2(3) of Tyr(2Me)); 2.65 (s, MeN); 1.80 (s, Me(3) of Tyr(2Me)); 1.57 (d, J ˆ 6.8, NCHMe). 13C-NMR:
171.8, 165.7 (2s, 2 CO); 157.9 (s, 1 arom. CO); 137.0, 135.5, 135.4, 133.7, 131.9 (5s, 6 arom. C); 131.3, 130.9, 128.9,
128.7, 128.6, 127.9, 127.5, 126.9, 126.1, 125.3, 124.9, 123.6, 114.7 (13d, 21 arom. CH); 70.0 (t, PhCH2O); 62.0 (s,
C(2) of Tyr(2Me)); 51.0 (d, CHN); 39.5 (t, C(3) of Tyr(2Me)); 30.8( q, MeN); 22.4, 14.8(2 q, NCHMe, Me(3) of
‡
‡
Tyr(2Me)). ESI-MS (CH2Cl2 , MeOH): 595 (11, [M ‡ K] ), 579 (19, [M ‡ Na] ), 403 (36, [M À
‡
‡
‡
naphthCHCH2 ‡ 1] ), 372 (100, [M À naphthEt(Me)N] ), 344 (66, [M À naphthEt(Me)NCO] ), 155 (7,
‡
[naphthCHMe] ). Anal. calc. for C37H36N2O3 ¥ 0.33 H2O (562.71): C 78.97, H 6.57, N 4.98; found: C 78.94,
H 6.49, N 4.92.
3.2. Reactions of (1'R,2R)-2a. 3.2.1. N-((R)-1-[4-(Benzyloxy)benzyl]-1-methyl-2-{methyl[(R)-1-(naphtha-
len-1-yl)ethyl]amino}-2-thioxoethyl)benzamide ((1R,1'R)-11a). As described for (1S,1'R)-11a, with PhCOSH
(33 mg, 0.24 mmol), (1'R,2R)-2a (100 mg, 0.23 mmol), and abs. CH2Cl2 (2 ml); 2.5 h at r.t.; prep. TLC (hexane/
AcOEt 1:1): 119 mg (90%) of (1R,1'R)-11a. Crystals suitable for an X-ray crystal-structure determination were
obtained from Et2O/CH2Cl2/hexane. The configuration at C(2) of Tyr(2Me) is (R). M.p. 147 1488. Rf (hexane/
AcOEt 1:1) 0.44. IR: 3412m, 3051w, 2933m, 1659s, 1607w, 1579w, 1509vs, 1480s, 1453m, 1384m, 1366m, 1322w,
1296m, 1234vs, 1179m, 1109w, 1065m, 1026w, 1008w, 921w, 8 65w, 8 40w, 8 07w, 78 2s, 718w, 696w, 652w, 610w.
1H-NMR: 8.0 7.65, 7.6 7.3 (2m, NH, 17 arom. H, CHN); 6.94 (d, J ˆ 8.6, 2 arom. H); 6.73 (d, J ˆ 8.7, 2 arom.
H); 4.98( s, PhCH2O); 3.95, 3.53 (AB, J ˆ 14.3, CH2(3) of Tyr(2Me); 2.90 (s, MeN); 1.82 (s, Me(3) of Tyr(2Me));
1.82 (d, J ˆ 6.7, NCHMe). 13C-NMR: 204.4 (s, CS); 165.1 (s, CO); 157.7 (s, 1 arom. CO); 137.0, 135.4, 134.9,
133.7, 132.2 (5s, 6 arom. C); 131.5, 131.4, 129.3, 129.1, 128.6, 128.0, 127.5, 127.2, 126.9, 126.2, 125.9, 125.0, 124.8,
114.6 (14d, 21 arom. CH); 70.0 (t, PhCH2O); 64.5 (s, C(2) of Tyr(2Me)); 60.4 (d, CHN); 43.3 (t, C(3)
of Tyr(2Me)); 36.1 (q, MeN); 25.3, 13.5 (2q, Me(3) of Tyr(2Me), NCHMe). ESI-MS (MeOH, CHCl3):
‡
‡
861 (12, [2 (M À naphthCHCH2 ‡ 1) ‡ Na] ), 575 (18), 574 (41), 573 (100, [M ‡ 1] ), 420 (15), 419 (47,
‡
[M À naphthCHCH2 ‡ 1] ). Anal. calc. for C37H36N2O2S (572.77): C 77.59, H 6.34, N 4.89, S 5.60; found:
C 77.45, H 6.21, N 4.77, S 5.38.
3.2.2. N-((R)-1-[4-(Benzyloxy)benzyl]-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-oxo-
ethyl)benzamide ((1R,1'R)-12a). As described for (1S,1'R)-11a, with PhCOOH (28mg, 0.23 mmol),
(1'R,2R)-2a (100 mg, 0.31 mmol), and abs. CH2Cl2 (2 ml); 23 h at r.t.; prep. TLC (hexane/AcOEt 1:1): 86 mg
(67%) of (1R,1'R)-12a. Rf (hexane/AcOEt 1:1) 0.34. M.p. 163 1648. IR: 3416w, 3361m, 3054w, 2977w, 1655s,
1619vs, 1580m, 1533s, 1510vs, 1480s, 1454s, 1392s, 1301m, 1240s, 1177m, 1107w, 1073m, 1043w, 1026m, 922w,
867w, 8 38w, 8 06m, 78 1s, 719m, 696m, 672w, 648w, 612w. 1H-NMR: 8.05 8.0, 7.85 7.8, 7.7 7.65, 7.55 7.3 (4m, 17
arom. H); 6.93 (d, J ˆ 8.6, 2 arom. H); 6.80 (s, NH); 6.8 6.75 ( m, CHN); 6.73 (d, J ˆ 8.7, 2 arom. H); 4.97 (s,

Helvetica Chimica Acta Vol. 85 (2002)
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PhCH2O); 3.60, 3.54 (AB, J ˆ 14.3, CH2(3) of Tyr(2Me)); 2.67 (s, MeN); 1.66 (d, J ˆ 6.8, NCHMe); 1.60 (s,
Me(3) of Tyr(2Me)). 13C-NMR: 171.7, 166.1 (2s, 2 CO); 137.1, 135.9, 134.8, 133.8, 132.1 (5s, 6 arom. C); 131.7,
131.5, 129.3, 128.6, 128.6, 128.0, 127.4, 126.9, 126.7, 125.9, 125.5, 124.8, 124.3, 114.6 (14d, 21 arom. CH); 70.0 (t,
PhCH2O); 60.8( s, C(2) of Tyr(2Me)); 50.4 (d, CHN); 40.2 (t, C(3) of Tyr(2Me)); 30.1 (q, MeN); 22.4, 15.3 (2q,
‡
‡
NCHMe, Me(3) of Tyr(2Me)). ESI-MS (CH2Cl2, MeOH): 595 (6, [M ‡ K] ), 579 (8, [M ‡ Na] ), 403 (30,
‡
‡
‡
[M À naphthCHCH2 ‡ 1] ), 372 (100, [M À naphthEt(Me)N] ), 344 (69, [M À naphthEt(Me)NCO] ), 155 (6,
‡
[naphthCHMe] ). Anal. calc. for C37H36N2O3 ¥ 0.5 H2O (565.71): C 78.56, H 6.59, N 4.95; found: C 78.37, H 6.59,
N 4.72.
3.3. Reactions of (1'R,2S)-2b. 3.3.1. N-((S)-1-[3,4-Bis(benzyloxy)benzyl]-1-methyl-2-{methyl[(R)-1-(naph-
thalen-1-yl)ethyl]amino}-2-thioxoethyl)benzamide ((1S,1'R)-11b). As described for (1S,1'R)-11a, with PhCOSH
(36 mg, 0.26 mmol), (1'R,2S)-2b (142 mg, 0.26 mmol), and abs. CH2Cl2 (2 ml); 3 h at r.t.; prep. TLC (hexane/
AcOEt 3 :2): 158mg (89%) of (1 S,1'R)-11b. Colorless foam. M.p. 85 878. Rf (hexane/AcOEt 1:1) 0.46. IR:
3418m, 3195w, 3060w, 2934w, 1656m, 1601w, 1579w, 1510vs, 1478vs, 1374s, 1332w, 1267s, 1220m, 1161w, 1138m,
1063m, 1044w, 1021m, 8 77w 1H-NMR: 9.32 (br. s, NH); 7.9 7.85, 7.75 7.7, 7.55 7.25 (3m, 22 arom. H, CHN);
6.8 6.75 ( m, 2 arom. H); 6.6 6.55 (m, 1 arom. H); 5.10 (s, PhCH2O); 4.88, 4.85 (AB, J ˆ 12.0, PhCH2O); 4.08,
3.27 (AB, J ˆ 14.3, CH2(3) of Dopa(2Me)); 2.80 (s, MeN); 1.86 (s, Me(3) of Dopa(2Me)); 1.58( d, J ˆ 6.7,
NCHMe). 13C-NMR: 204.2 (s, CS); 164.5 (s, CO); 148.6, 147.8 (2s, 2 arom. CO); 137.3, 137.2, 135.5, 135.0, 133.6,
129.8(6 s, 7 arom. C); 131.2, 129.2, 128.6, 128.5, 128.3, 127.6, 127.2, 127.2, 126.9, 126.2, 125.4, 124.9, 123.9, 122.8,
117.1, 114.9 (16d, 25 arom. CH); 71.3, 71.0 (2t, 2 PhCH2O); 64.7 (s, C(2) of Dopa(2Me)); 61.1 (d, CHN); 41.5 (t,
C(3) of Dopa(2Me)); 36.6 (q, MeN); 24.2, 12.8(2 q, Me(3) of Dopa(2Me), NCHMe). ESI-MS (MeOH, NaI):
‡
702 (55), 701 (100, [M ‡ Na] ), 423 (7). Anal. calc. for C44H42N2O3S ¥ 0.2 H2O (682.49): C 77.43, H 6.26, N 4.10,
S 4.70; found: C 77.45, H 6.37, N 4.06, S 4.75.
3.3.2. N-((S)-1-[3,4-Bis(benzyloxy)benzyl]-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-
oxoethyl)benzamide ((1S,1'R)-12b). As described for (1S,1'R)-11a, with PhCOOH (68mg, 0.56 mmol),
(1'R,2S)-2b (300 mg, 0.56 mmol), and abs. CH2Cl2 (4 ml); 14 d at r.t.; CC (hexane/AcOEt 2 :1) and prep. TLC
(hexane/AcOEt 1:1): 335 mg (91%) of (1S,1'R)-12b. Colorless solid. Crystals suitable for an X-ray crystal-
structure determination were obtained from AcOEt/MeOH/hexane. The configuration at C(2) in Dopa(2Me) is
(S). Rf (hexane/AcOEt 1 :1) 0.38. M.p. 180 1818. IR: 3310m, 3049w, 2940w, 1656s, 1610vs, 1535m, 1509s, 1480m,
1454m, 1423w, 1397m, 1265s, 1230w, 1157w, 1138w, 1071m, 1026w, 8 8 3w. 1H-NMR: 7.93 (br. s, NH); 7.8 5 7.8 m( ,
3 arom. H); 7.75 (d, J ˆ 7.0, 1 arom. H); 7.5 7.25 (m, 18arom. H); 6.83 ( d, J ˆ 8.2, 1 arom. H); 6.77 (d, J ˆ 1.9, 1
arom. H); 6.65 (dd, J ˆ 8.2, 2.0, 1 arom. H); 6.53 (q, J ˆ 6.7, CHN); 5.10 (s, PhCH2O); 4.89, 4.80 (AB, J ˆ 11.9,
PhCH2O); 3.87, 3.18 (AB, J ˆ 14.6, CH2(3) of Dopa(2Me)); 2.60 (s, MeN); 1.77 (s, Me(3) of Dopa(2Me)); 1.53
(d, J ˆ 6.8, NCHMe). 13C-NMR: 171.7, 165.4 (s, 2 CO (amide)); 148.8, 148.0 (2s, 2 arom. CO); 137.3, 137.1, 135.3,
133.6, 131.8, 130.0 (6s, 7 arom. C); 131.3, 128.7, 128.5, 128.3, 128.3, 127.6, 127.2, 126.8, 126.0, 125.2, 124.8, 123.5,
122.5, 117.1, 115.0 (15d, 25 arom. CH); 71.4, 71.0 (2t, 2 PhCH2O); 61.8( s, C(2) of Dopa(2Me)); 50.9 (d, CHN);
39.7 (t, C(3) of Dopa(2Me)); 30.6 (q, MeN); 22.4, 14.7 (2q, Me(3) of Dopa(2Me), NCHMe). ESI-MS (MeOH,
‡
NaI): 685 (100, [M ‡ Na] ). Anal. calc. for C44H42N2O4 (662.83): C 79.73, H 6.39, N 4.23; found: C 79.61, H 6.38,
N 4.22.
3.4. Reactions of (1'R,2R)-2b. 3.4.1. N-((R)-1-[3,4-Bis(benzyloxy)benzyl]-1-methyl-2-{methyl[(R)-1-
(naphthalen-1-yl)ethyl]amino}-2-thioxoethyl)benzamide ((1R,1'R)-11b). As described for (1S,1'R)-11a, with
PhCOSH (36 mg, 0.26 mmol), (1'R,2R)-2b (143 mg, 0.26 mmol), and abs. CH2Cl2 (2 ml); 20 h at r.t.; prep. TLC
(hexane/AcOEt 1:1): 156 mg (88%) of (1R,1'R)-11b. Crystals suitable for an X-ray crystal-structure
determination were obtained from Et2O/hexane. The configuration at C(2) in Dopa(2Me) ist (R). Rf
(hexane/AcOEt 1:1) 0.42. M.p. 83 868. IR: 3424m, 2933w, 1656w, 1510vs, 1479m, 1384w, 1267m, 1138w,
1065w, 1024w. 1H-NMR: 7.95 7.9, 7.85 7.8, 7.7 7.65, 7.6 7.55, 7.5 7.2 (5m, 22 arom. H, CHN, NH); 6.71 (d, J ˆ
1.7, 1 arom. H); 6.66 (d, J ˆ 8.2, 1 arom. H); 6.48 (dd, J ˆ 8.2, 1.9, 1 arom. H); 5.06 (s, PhCH2O); 4.73, 4.70 (AB,
J ˆ 12.0, PhCH2O); 3.92, 3.53 (AB, J ˆ 14.4, CH2(3) of Dopa(2Me)); 2.86 (s, MeN); 1.73 (s, Me(3) of
Dopa(2Me)); 1.72 (d, J ˆ 6.8, NCHMe). 13C-NMR: 204.2 (s, CS); 164.8( s, CO); 148.5, 147.7 (2s, 2 arom. CO);
137.3, 137.0, 135.4, 133.6, 130.4 (5s, 7 arom. C); 131.5, 129.0, 128.6, 128.3, 128.2, 127.6, 127.6, 127.2, 127.0, 126.8,
126.1, 125.7, 124.9, 124.6, 123.2, 117.3, 114.9 (17d, 22 arom. CH); 71.3, 70.7 (2t, 2 PhCH2O); 64.2 (s, C(2) of
Dopa(2Me)); 60.3 (d, CHN); 43.9 (t, C(3) of Dopa(2Me)); 35.8( q, MeN); 25.0, 13.4 (2q, Me(3) of Dopa(2Me),
‡
‡
NCHMe). HPLC-ESI-MS: 1379 (9, [2M ‡ Na] ), 1003 (26), 903 (8), 827 (11), 701 (100, [ M ‡ Na] ), 509 (40,
‡
[M À naphthCHCH2 ‡ 1] ). Anal. calc. for C44H42N2O3S ¥ 0.25 H2O (683.39): C 77.33, H 6.27, N 4.12, S 4.69;
found: C 77.29, H 6.80, N 4.25, S 4.84.
3.4.2. N-((R)-1-[3,4-Bis(benzyloxy)benzyl]-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-
oxoethyl)benzamide ((1R,1'R)-12b). As described for (1S,1'R)-11a, with PhCOOH (68mg, 0.56 mmol),

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Helvetica Chimica Acta Vol. 85 (2002)
(1'R,2R)-2b (300 mg, 0.56 mmol), and abs. CH2Cl2 (4 ml); 13 d at r.t.; CC (hexane/AcOEt 2 :1): 330 mg (90%)
of (1R,1'R)-12b. Colorless solid. Crystals suitable for an X-ray crystal-structure determination were obtained
from AcOEt. The configuration at C(2) in Dopa(2Me) is (R). M.p. 103 1048. Rf (hexane/AcOEt 1:1) 0.36.
M.p. 87 898. IR: 3340m, 3052w, 2980m, 2938m, 1657s, 1611vs, 1536s, 1512vs, 1482s, 1454s, 1424m, 1376s, 1333m,
1266vs, 1232s, 1166m, 1138s, 1069s, 1039m, 1027m, 908w, 8 47w. 1H-NMR: 8.1 8.0, 7.85 7.7, 7.55 7.2 (3m, 22
arom. H); 6.76 (q, J ˆ 6.7, CHN); 6.7 6.65 (m, 2 arom. H); 6.48( dd, J ˆ 8.2, 2.0, 1 arom. H); 5.06 (s, PhCH2O);
4.72, 4.68( AB, J ˆ 12.0, PhCH2O); 3.53 (s, CH2(3) of Dopa(2Me)); 2.64 (s, MeN); 1.66 (d, J ˆ 6.8, NCHMe);
1.51 (s, Me(3) of Dopa(2Me)). 13C-NMR: 171.5, 165.8( s, 2 CO (amide)); 148.5, 147.6 (2s, 2 arom. CO); 137.3,
137.0, 135.9, 134.3, 133.7, 130.4 (6s, 7 arom. C); 131.6, 128.6, 128.5, 128.3, 128.2, 127.6, 127.2, 126.8, 126.5, 125.8,
125.3, 124.7, 124.1, 123.3, 117.4, 115.0 (16d, 25 arom. CH); 71.3, 70.7 (2t, 2 PhCH2O); 60.4 (s, C(2) of
Dopa(2Me)); 50.3 (d, CHN); 40.5 (t, C(3) of Dopa(2Me)); 29.9 (q, MeN); 22.2, 14.1 (2q, Me(3) of Dopa(2Me),
‡
‡
NCHMe). ESI-MS (MeOH, NaI): 685 (87, [M ‡ Na] ), 509 (48, [M À naphthCHCH2 ‡ 1] ), 478(100, [ M À
‡
‡
‡
naphthEt(Me)N] ), 450 (59, [M À naphthEt(Me)NCO] ), 203 (32), 181 (35), 155 (23, [naphthCHMe] ).
Anal. calc. for C44H42N2O4 ¥ 1.5 H2O (689.86): C 76.60, H 6.57, N 4.06; found: C 76.88, H 6.62, N 4.60.
3.5. Reactions of 2c. 3.5.1. N-((RS)-1-(Azidomethyl)-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]-
amino}-2-thioxoethyl)benzamide (11c). As described for (1S,1'R)-11a, with PhCOSH (38mg, 0.28mmol), 2c
(80 mg, 0.27 mmol), and abs. CH2Cl2 (2 ml); 4.5 h at r.t.; prep. TLC (hexane/AcOEt 2 :1): 110 mg (97%) of 11c.
Colorless foam. Rf (hexane/AcOEt 2 :1) 0.24. M.p. 64 668. IR: 3416w, 3051w, 2934w, 2100vs, 1665w, 1600w,
1580w, 1511m, 1480s, 1390s, 1282w, 1242w, 1172w, 1105w, 1066w, 1045w, 1025w. 1H-NMR: 7.85 7.8, 7.65 7.3 (2m,
12 arom. H, CHN, NH); 4.48, 4.36 (AB, J ˆ 18.4, CH2); 2.77 (s, MeN); 1.77 (d, J ˆ 6.7, NCHMe); 1.75 (s, Me(3)).
13C-NMR: 202.2 (s, CS); 165.4 (s, CO); 134.9, 134.1, 133.6 (3s, 4 arom. C); 131.5, 129.2, 128.5, 127.3, 126.7,
126.2, 125.4, 124.9, 124.3 (9d, 12 arom. CH); 64.6 (s, C(2)); 60.4 (d, CHN); 57.3 (t, CH2); 35.8( q, MeN);
‡
‡
22.4, 13.0 (2q, NCHMe, Me(3)). ESI-MS (MeOH, NaI): 489 (7), 454 (40, [M ‡ Na] ), 404 (45, [M À N2 ‡ 1] ),
‡
‡
309 (9, [M À N3 ‡ 1] ), 384 (10), 372 (11), 250 (15, [M À N2 À naphthCHCH2 ‡ 1] ), 187 (8), 155 (100,
‡
[naphthCHMe] ).
4. Synthesis of Model Peptides. 4.1. Dipeptides with (S)-Tyr(2Me). 4.1.1. [(9H-Fluoren-9-yl)methyl] N-((S)-
1-{[((S)-1-[4-(Benzyloxy)benzyl]-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-oxoethyl)amino]-
carbonyl}-2-methylpropyl)carbamate (Fmoc-Val-(S)-Tyr(2Me)(OBn)-NMe(naphthEt), (S,S,R)-13a). To Fmoc-
Val-OH (236 mg, 0.695 mmol), a soln. of (1'R,2S)-2a (302 mg, 0.695 mmol) in abs. CH2Cl2 (6 ml) was added, and
the mixture was stirred for 20 h at r.t. Evaporation, CC (hexane/AcOEt 3 :2), and prep. TLC (hexane/AcOEt
1:1) yielded 282 mg (52%) of (S,S,R)-13a. Colorless foam. M.p. 98 99 8. Rf (hexane/AcOEt 1:1) 0.33. IR:
3334w, 3040w, 2962m, 1724s, 1676s, 1615s, 1511vs, 1451s, 1391m, 1330w, 1240s, 1178w, 1107w, 1071w, 1027w, 8 05w,
782m, 759w, 741m, 697w. 1H-NMR: 7.85 7.8, 7.75 7.7, 7.6 7.2 (3m, 20 arom. H, NH of Tyr(2Me)); 6.95 (d, J ˆ
8.6, 2 arom. H); 6.78 (d, J ˆ 8.6, 2 arom. H); 6.54 (q, J ˆ 6.7, CHN); 5.28( d, J ˆ 8.0, NH of Val); 4.90 (br.,
PhCH2O); 4.45 4.3 (m, CH2O of Fmoc); 4.22 (t, J ˆ 6.9, CH of Fmoc); 4.02 (br., CH(2) of Val); 3.68, 3.01 (AB,
J ˆ 15.0, CH2(3) of Tyr(2Me)); 2.56 (s, MeN); 2.2 2.15 (m, CH(3) of Val); 1.66 (s, Me(3) of Tyr(2Me)); 1.52 (d,
J ˆ 6.6, MeCHN); 0.97, 0.90 (2d, J ˆ 6.5, 6.7, 2 Me(4) of Val). 13C-NMR: 171.2, 169.3 (2s, 2 CO (amide)); 157.8( s,
CO (urethane)); 143.7, 141.2, 136.9, 135.4, 133.7, 131.8, 128.2 (7s, 10 arom. C); 130.6, 128.7, 128.6, 128.4, 127.8,
127.6, 127.3, 127.0, 126.5, 125.9, 125.2, 124.9, 124.8, 123.5, 119.9, 114.7 (16d, 24 arom. CH); 69.8, 66.8 (2t, 2 CH2O);
61.7 (s, C(2) of Tyr(2Me)); 60.6 (d, C(2) of Val); 50.8, 47.2 (2d, CH of Fmoc, CHN); 39.8( t, C(3) of Tyr(2Me));
31.0 (d, C(3) of Val); 30.5 (q, MeN); 22.3, 19.1, 17.5, 14.6 (4q, CHNMe, Me(3) of Tyr(2Me), 2 Me(4) of Val).
‡
ESI-MS (CH2Cl2, MeOH, NaI): 796 (100, [M ‡ Na] ). Anal. calc. for C50H51N3O5 ¥ H2O (791.99): C 75.83,
H 6.75, N 5.31; found: C 76.10, H 6.90, N 5.37.
4.1.2. (S)-2-{[(S)-2-Amino-3-methyl-1-oxobutyl]amino}-2-[4-(benzyloxy)benzyl]-N-methyl-N-[(R)-1-
(naphthalen-1-yl)ethyl]propanamide (H-Val-(S)-Tyr(2Me)(OBn)-NMe(naphthEt), (S,S,R)-14a). To (S,S,R)-
13a (52 mg, 0.067 mmol), Et2NH (1 ml) was added, and the soln. was stirred for 1 h and evaporated. Prep. TLC
(hexane/AcOEt 1:1) gave 37 mg (quant. yield) of (S,S,R)-14a. M. p. 69 708. Rf (AcOEt) 0.17. IR: 3324w,
2960m, 1674m, 1614s, 1511vs, 1386m, 1331w, 1301w, 1240m, 1177w, 1107w, 1068w, 8 06w, 78 2m, 738w, 696w.
1H-NMR (CDCl3): 8.1 7.85 (m, 3 arom. H); 7.6 7.3 (m, 9 arom. H); 7.1 6.7 (m, 4 arom. H); 6.55 (q, J ˆ 6.6,
CHN); 5.03 (m, PhCH2O); 3.81 (d, J ˆ 3.8, CH(2) of Val); 3.40, 3.10 (AB, J ˆ 14.2, CH2(3) of Tyr(2Me); 2.60 (s,
MeN); 2.3 2.2 (m, CH(3) of Val); 1.59 (s, Me(3) of Tyr(2Me); 1.52 (d, J ˆ 6.7, CHNMe); 1.12, 1.10 (2d, J ˆ 7.5,
6.1, 2 Me(4) of Val). 13C-NMR: 172.4, 171.7 (2s, 2 CO (amide)); 157.7 (s, 1 arom. C); 136.9, 135.7, 133.6, 131.9 (4s,
5 arom. C); 131.1, 128.5, 128.2, 127.8, 127.3, 126.6, 125.9, 125.1, 124.7, 124.1, 114.6 (11d, 16 arom. CH); 69.9 (t,
PhCH2O); 60.6 (d, C(2) of Val); 60.3 (s, C(2) of Tyr(2Me)); 50.4 (d, CHN); 40.6 (t, C(3) of Tyr(2Me)); 30.4 (d,
C(3) of Val); 23.0, 19.5, 15.9, 14.6 (4q, MeN, CHNMe, Me(3) of Tyr(2Me), 2 Me(4) of Val). ESI-MS (MeOH,

Helvetica Chimica Acta Vol. 85 (2002)
3437
‡
‡
‡
NaI): 600 (19), 574 (25, [M ‡ Na] ), 552 (100, [M ‡ 1] ), 398(39, [ M À naphthCHCH2 ‡ 1] ), 155 (7,
‡
[naphthCHMe] ). Anal. calc. for C35H41N3O3 ¥ 0.5 H2O (560.74): C 74.97, H 7.55, N 7.49; found: C 75.04, H 7.38,
N 7.19.
4.1.3. [(9H-Fluoren-9-yl)methyl] N-((S)-1-{[((S)-1-(4-Hydroxybenzyl)-1-methyl-2-{methyl[(R)-1-(naph-
thalen-1-yl)ethyl]amino}-2-oxoethyl)amino]carbonyl}-2-methylpropyl)carbamate (Fmoc-Val-(S)-Tyr(2Me)-
NMe(naphthEt), (S,S,R)-15a). A soln. of (S,S,R)-13a (38mg, 0.049 mmol) and 5 mg Pd/C (10% on activated
charcoal) in MeOH (1 ml) was treated with H2 for 2 d at r.t. The mixture was filtered over Celite, and the filtrate
was evaporated. Prep. TLC (hexane/AcOEt 1:1) gave 16 mg (47%) of (S,S,R)-15a. M.p. 111 1128. Rf (hexane/
AcOEt 1:1) 0.25. IR: 3391s, 2963m, 1725m, 1666s, 1614s, 1514vs, 1450s, 1392m, 1240m, 1106m, 1071w, 1043w,
805w, 78 2m, 760w, 742m. 1H-NMR: 7.85 7.7, 7.55 7.2 (2m, 15 arom. H, NH); 6.89 (d, J ˆ 8.4, 2 arom. H); 6.65
(d, J ˆ 9.0, 2 arom. H); 6.52 (q, J ˆ 6.7, CHN); 5.38( d, J ˆ 7.5, NH of Val); 4.4 4.15 (m, CHCH2 of Fmoc);
4.05 3.95 (m, CH(2) of Val); 3.64, 3.00 (AB, J ˆ 14.6, CH2(3) of Tyr(2Me)); 2.56 (s, MeN); 2.2 2.15 (m, CH(3)
of Val); 1.64 (s, Me(3) of Tyr(2Me)); 1.51 (d, J ˆ 6.6, MeCHN); 0.96, 0.89 (2d, J ˆ 6.1, 6.7, 2 Me(4) of Val).
13C-NMR: 171.3 (s, 2 CO (amide)); 155.1 (s, CO (urethane)); 143.7, 141.2, 135.2, 133.6, 127.5 (5s, 9 arom. C);
130.7, 128.7, 128.6, 127.6, 127.0, 126.6, 125.9, 125.2, 125.0, 124.8, 123.4, 119.9, 115.3 (13d, 19 arom. CH); 67.0 (t,
CH2O of Fmoc); 61.7 (s, C(2) of Tyr(2Me)); 60.6 (d, C(2) of Val); 50.8, 47.1 (2d, CH of Fmoc, CHN); ca. 40 (t,
C(3) of Tyr(2Me)); 30.8( q, MeN); 30.5 (d, C(3) of Val); 22.2, 19.2, 17.5, 14.6 (4q, CHNMe, Me(3) of Tyr(2Me),
‡
‡
2 Me(4) of Val). ESI-MS (MeOH, NaI): 706 (100, [M ‡ Na] ), 530 (18, [M À naphthCHCH2 ‡ 1] ), 485 (30,
‡
‡
‡
[M À BnOC6H4CH2 À 1] ), 413 (36, [M À Fmoc-Val À Bn] ), 397 (6, [M À BnOC6H4CH2 À Fmoc] ). Anal.
calc. for C43H45N3O5 (683.85): C 75.52, H 6.63, N 6.14; found: C 75.14, H 7.14, N 6.03.
4.1.4. (S)-2-[4-(Benzyloxy)benzyl]-2-{[(S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3-methyl-1-
oxobutyl]amino}-2-methylpropanoic Acid (Fmoc-Val-(S)-Tyr(2Me)(OBn)-OH, (S,S)-16a).
A soln. of
(S,S,R)-13a (118mg, 0.152 mmol) in 3 n HCl (MeCN/H2O 2 :1, 4.5 ml) was stirred for 105 min at 608. The
mixture was extracted with CH2Cl2, dried (MgSO4), and evaporated. Prep. TLC (CH2Cl2/MeOH 20 :1) gave
25 mg (27%) of (S,S)-16a and 64 mg (68%) of [(9H-fluoren-9-yl)methyl] N-{(S)-1-[({(S)-1-[4-(benzyloxy)-
benzyl]-1-methyl-2-(methylamino)-2-oxoethyl}amino)carbonyl]-2-methylpropyl}carbamate (Fmoc-Val-(S)-
Tyr(2Me)-NHMe, (S,S)-17a).
Data of (S,S)-16a: M.p. 72 738. Rf (CH2Cl2/MeOH 20 :1) 0.15. IR: 3417vs, 2928s, 1714s, 1682s, 1652s,
1634m, 1614m, 1538m, 1513vs, 1454m, 1372w, 1243m, 1119w, 1027w, 759w, 740w, 696w. 1H-NMR: 7.71 (d, J ˆ 7.4,
2 arom. H); 7.6 7.55, 7.4 7.2 (2m, 11 arom. H); 7.00 (d, J ˆ 8.6, 2 arom. H); 6.75 6.7 (m, 2 arom. H, NH of
Tyr(2Me)); 5.86 (d, J ˆ 9.2, NH of Val); 4.75 (s, PhCH2O); 4.4 4.2 (m, CHCH2 of Fmoc); 4.0 3.95 (m, CH(2)
of Val); 3.43, 3.16 (AB, J ˆ 13.7, CH2(3) of Tyr(2Me)); 2.15 2.0 (m, CH(3) of Val); 1.67 (s, Me(3) of Tyr(2Me));
0.93 (br., 2 Me(4) of Val). 13C-NMR: 176.6, 171.2 (2s, COOH, CO (amide)); 157.8, 156.5 (2s, CO (urethane), 1
arom. CO); 143.7, 141.2, 136.8, 127.9 (4s, 6 arom. C); 130.8, 128.3, 127.7, 127.3, 127.0, 125.0, 119.9, 114.6 (8d, 17
arom. CH); 69.7, 67.2 (2t, PhCH2O, CH2O of Fmoc); 61.3 (s, C(2) of Tyr(2Me)); 60.7 (d, C(2) of Val); 47.1 (d, CH
of Fmoc); 40.6 (t, C(3) of Tyr(2Me)); 31.0 (d, C(3) of Val); 22.7, 19.0, 17.9 (3q, Me(3) of Tyr(2Me), 2 Me(4) of
‡
Val). ESI-MS (MeOH, NaI): 629 (100, [M ‡ Na] ), 552 (36), 404 (11). Anal. calc. for C37H38N2O6 ¥ H2O
(624.74): C 71.14, H 6.45, N 4.48; found: C 71.51 H 6.46, N 4.20.
Data of (S,S)-17a: M.p. 81 828. Rf (CH2Cl2/MeOH 10 :1) 0.49. IR: 3366m, 2963w, 1706s, 1655s, 1545vs,
1
1511vs, 1451w, 1348s, 1242m, 1176w, 1079w, 1027w, 924w, 8 42w, 760w, 732w, 698w. H-NMR: 8.0 7.7, 7.6 7.25
(2m, 13 arom. H); 6.95 (d, J ˆ 8.5, 2 arom. H); 6.76 (d, J ˆ 8.4, 2 arom. H); 6.69 (s, NH); 6.50 (br. s, NH);
5.30 (d, J ˆ 6.4, NH of Val); 4.87 (s, PhCH2O); 4.45 4.15 (m, CHCH2 of Fmoc); 3.9-3.8( m, CH(2) of Val); 3.17,
3.08( AB, J ˆ 13.6, CH2(3) of Tyr(2Me)); 2.74 (s, MeN); 2.15 2.05 (m, CH(3) of Val); 1.63 (s, Me(3) of
Tyr(2Me)); 0.93, 0.89 (2d, J ˆ 6.8, 2 Me(4) of Val). 13C-NMR: 173.7, 170.7 (2s, 2 CO (amide)); 157.9 (s, CO
(urethane)); 143.6, 143.5, 141.2, 136.7 (4s, 7 arom. C); 130.9, 128.4, 127.8, 127.7, 127.3, 127.0, 125.0, 124.8, 119.9,
114.7 (10d, 17 arom. CH); 69.8, 67.0 (2t, PhCH2O, CH2O of Fmoc); 61.3 (d, C(2) of Val); 60.8( s, C(2) of
Tyr(2Me)); 47.1 (d, CH of Fmoc); 42.8( t, C(3) of Tyr(2Me)); 30.3 (d, C(3) of Val); 26.6, 22.8, 19.1, 17.6 (4q,
‡
MeN, Me(3) of Tyr(2Me), 2 Me(4) of Val). ESI-MS (MeOH, NaI): 642 (100, [M ‡ Na] ), 236 (18,
‡
[M À HÀC(iPr)ÀCOÀTyr(2Me)(OBn)ÀNH2Me] ). Anal. calc. for C38H41N3O5 (619.76): C 73.64, H 6.67,
N 6.78; found: C 73.41 H 6.86, N 6.56.
4.2. Dipeptides with (R)-Tyr(2Me). 4.2.1. [(9H-Fluoren-9-yl)methyl] N-((S)-1-{[((R)-1-[4-(Benzyloxy)-
benzyl]-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-oxoethyl)amino]carbonyl}-2-methylpro-
pyl)carbamate (Fmoc-Val-(R)-Tyr(2Me)(OBn)-NMe(naphthEt), (S,R,R)-13a). As described for (S,S,R)-13a,
with Fmoc-Val-OH (195 mg, 0.575 mmol), (1'R,2R)-2a (250 mg, 0.575 mmol), and abs. CH2Cl2 (7 ml); 66 h at
r.t.; prep. TLC (hexane/AcOEt 1:1): 310 mg (70%) of (S,R,R)-13a. Colorless foam. M.p. 111 1138. Rf (hexane/
AcOEt 1:1) 0.39. IR: 3336w, 3038w, 2962m, 1724m, 1686s, 1613s, 1511vs, 1451s, 1390m, 1328m, 1299m, 1240s,

3438
Helvetica Chimica Acta Vol. 85 (2002)
1177m, 1106w, 1068m, 1027m, 8 39w, 8 05w, 78 1m, 740s, 696w. 1H-NMR: 8.0 7.95, 7.8 7.7, 7.55 7.25 (3m, 22
arom. H); 6.94 (d, J ˆ 8.3, 2 arom. H); 6.75 6.6 (m, 2 arom. H, CHN, NH of Tyr(2Me)); 5.26 (d, J ˆ 8.6, NH of
Val); 4.95 4.85 (m, PhCH2O); 4.35 4.15 (m, CH2CH of Fmoc); 3.95 (br., CH(2) of Val); 3.45 3.3 (m, CH2(3)
of Tyr(2Me)); 2.57 (br. s, MeN); 2.1 2.05 (m, CH(3) of Val); 1.61 (d, J ˆ 6.7, MeCHN); 1.53 (s, Me(3) of
Tyr(2Me)); 0.91, 0.85 (2d, J ˆ 6.3, 6.4, 2 Me(4) of Val). 13C-NMR: 171.1, 169.7 (2s, 2 CO (amide)); 157.6, 156.2
(2s, CO (urethane), 1 arom. CO); 143.8, 143.6, 141.2, 136.9, 135.5, 133.6, 131.9 (7s, 9 arom. C); 131.3, 128.6, 128.4,
127.8, 127.6, 127.3, 127.0, 126.6, 125.9, 125.2, 125.0, 124.7, 124.2, 119.9, 114.6 (15d, 24 arom. CH); 69.8, 67.0 (2t, 2
CH2O); 60.6 (s, C(2) of Tyr(2Me)); 60.1 (d, C(2) of Val); 50.4, 47.1 (2d, CH of Fmoc, CHN); 40.6 (t, C(3) of
Tyr(2Me)); 30.6 (d, C(3) of Val); 30.3 (q, MeN); 22.4, 19.5, 17.2, 15.2 (4q, CHNMe, Me(3) of Tyr(2Me), 2 Me(4)
‡
‡
of Val). ESI-MS (CH2Cl2, MeOH, NaI): 797 (94, [M ‡ Na] ), 413 (100, [M À Fmoc-Val À Bn] ). Anal. calc. for
C50H51N3O5 (773.97): C 77.59, H 6.64, N 5.43; found: C 77.40, H 6.72, N 5.29.
4.2.2. (R)-2-{[(S)-2-Amino-3-methyl-1-oxobutyl]amino}-2-[4-(benzyloxy)benzyl]-N-methyl-N-[(R)-1-
(naphthalen-1-yl)ethyl]propanamide (H-Val-(R)-Tyr(2Me)(OBn)-NMe(naphthEt), (S,R,R)-14a). As descri-
bed for (S,S,R)-14a, with (S,R,R)-13a (100 mg, 0.129 mmol), and Et2NH (2 ml); 2 h at r.t.; prep. TLC (AcOEt/
MeOH 20 :1): 67 mg (94%) of (S,R,R)-14a. M.p. 88 898. Rf (AcOEt) 0.13. IR: 3291m, 3041w, 2960w, 1737w,
1670s, 1612vs, 1511vs, 1454m, 1391m, 1301w, 1240s, 1178w, 1105w, 1070m, 1042w, 1026w, 8 43w, 8 05w, 78 2m, 741w,
697w, 648w, 612w. 1H-NMR: 8.05 8.0, 7.9 7.8, 7.5 7.3 (3m, 12 arom. H, NH); 6.98( d, J ˆ 8.6, 2 arom. H); 6.81
(d, J ˆ 8.6, 2 arom. H); 6.70 (q, J ˆ 6.6, CHN); 5.01 (s, PhCH2O); 3.51, 3.33 (AB, J ˆ 14.2, CH2(3) of Tyr(2Me));
3.45 3.25 (m, CH(2) of Val); 2.59 (br. s, MeN); 2.35 2.3 (m, CH(3) of Val); 1.62 (d, J ˆ 6.8, MeCHN); 1.55 (s,
Me(3) of Tyr(2Me)); 0.92, 0.75 (2d, J ˆ 7.0, 6.8, 2 Me(4) of Val). 13C-NMR: 172.4, 171.7 (2s, 2 CO (amide)); 157.5
(s, CO (urethane)); 137.0, 135.8, 133.6, 132.0, 129.3 (5s, 6 arom. C); 131.4, 128.5, 128.3, 127.8, 127.3, 126.6, 125.8,
125.2, 124.7, 124.3, 114.4 (11d, 16 arom. CH); 69.9 (t, PhCH2O); 60.3 (s, C(2) of Tyr(2Me)); 60.2 (d, C(2) of Val);
50.2 (d, CHN); 40.8( t, C(3) of Tyr(2Me)); 30.0, 30.0 (d, q, C(3) of Val, MeN); 22.6, 19.6, 15.9, 15.1 (4q, CHNMe,
‡
Me(3) of Tyr(2Me), 2 Me(4) of Val). ESI-MS (CHCl3 , MeOH): 552 (100, [M ‡ 1] ), 398(1, [ M À
‡
naphthCHCH2 ‡ 1] ). Anal. calc. for C35H41N3O3 ¥ 0.3 H2O (557.74): C 75.37, H 7.53, N 7.53; found: C 75.25,
H 7.66, N 7.24.
4.2.3. [(9H-Fluoren-9-yl)methyl] N-((S)-1-{[((R)-1-(4-Hydroxybenzyl)-1-methyl-2-{methyl[(R)-1-(naph-
thalen-1-yl)ethyl]amino}-2-oxoethyl)amino]carbonyl}-2-methylpropyl)carbamate (Fmoc-Val-(R)-Tyr(2Me)-
NMe(naphthEt), (S,R,R)-15a). As described for (S,S,R)-15a, with (S,R,R)-13a (81 mg, 0.105 mmol), Pd/C
(10% on activated charcoal, 25 mg ), MeOH (2 ml), and H2; 40 h at r.t.: 51 mg (71%) of (S,R,R)-15a. M.p. 131
1328. Rf (hexane/AcOEt 1 :1) 0.24. IR (neat): 3301s, 2964s, 1678vs, 1514vs, 1392s, 1331s, 1225vs, 1173m, 1105s,
1
1071s, 1041m, 8 34w, 8 04m, 78 2s, 760s, 741s, 650w. H-NMR: 7.96, 7.8 7.7, 7.5 7.2 ( d, J ˆ 7.8, 2 m, 15 arom. H);
6.85 (d, J ˆ 7.9, 2 arom. H); 6.65-6.55 (m, 2 arom. H, CHN, NH of Tyr(2Me)); 5.34 (d, J ˆ 9.1, NH of Val); 4.25
4.1 (m, CH2CH of Fmoc); 3.9 3.85 (m, CH(2) of Val); 3.35, 3.27 (AB, J ˆ 14.1, CH2(3) of Tyr(2Me)); 2.54 (br. s,
MeN); 2.05 2.0 (m, CH(3) of Val); 1.60 (d, J ˆ 6.4, MeCHN); 1.45 (s, Me(3) of Tyr(2Me)); 0.9 0.85 (m, 2
Me(4) of Val). 13C-NMR: 171.1, 169.8(2 s, 2 CO (amide)); ca. 156, 154.9 (2s, CO (urethane), 1 arom. CO); ca.
144, 143.4, 141.1, ca. 136, 133.6, ca. 122 (6s, 8 arom. C); 131.5, 128.5, 128.3, 127.6, 127.0, 126.6, 125.9, 125.2, 125.0,
124.7, ca. 124, 119.9, 115.2 (13d, 19 arom. CH); 67.0 (t, CH2O of Fmoc); 60.3 (s, C(2) of Tyr(2Me)); 60.1 (d, C(2)
of Val); 50.5, 46.9 (2d, CH of Fmoc, CHN); 40.9 (t, C(3) of Tyr(2Me)); 30.6 (d, C(3) of Val); 30.3 (q, MeN); 22.3,
19.4, 17.3, 15.1 (4q, CHNMe, Me(3) of Tyr(2Me), 2 Me(4) of Val). ESI-MS (MeOH, CH2Cl2): 722 (12, [M ‡
‡
‡
K] ), 708(12), 707 (55), 706 (100, [ M ‡ Na] ). Anal. calc. for C43H45N3O5 ¥ 0.5 H2O (692.86): C 74.54, H 6.69,
N 6.06; found: C 74.55, H 6.61, N 5.89.
4.2.4. (R)-2-[4-(Benzyloxy)benzyl]-2-{[(S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3-methyl-1-
oxobutyl]amino}-2-methylpropanoic Acid (Fmoc-Val-(R)-Tyr(2Me)(OBn)-OH, (S,R)-16a). As described for
(S,S)-16a, with (S,R,R)-13a (121 mg, 0.156 mmol), and 3n HCl (MeCN/H2O 1:1, 5 ml); 3 h at 608: 48mg (51%)
of (S,R)-16a, 24 mg (19%) of (S,R,R)-13a, and 29 mg (30%) of (S,R)-17a.
Data of (S,R)-16a: M.p. 98 99 8. Rf (CH2Cl2/MeOH 20 :1) 0.16. IR: 3409m, 2930w, 1718s, 1511vs, 1451m,
1390w, 1242s, 1178w, 1119w, 1027w, 759w, 741m, 696w. 1H-NMR: 7.73 (d, J ˆ 7.5, 2 arom. H); 7.6 7.55, 7.4 7.25
(2m, 11 arom. H); 7.02 (d, J ˆ 8.5, 2 arom. H); 6.79 (d, J ˆ 8.6, 2 arom. H); 6.70 (s, NH of Tyr(2Me)); 5.89 (d, J ˆ
9.4, NH of Val); 4.88 (s, PhCH2O); 4.45 4.1 (m, CHCH2 of Fmoc, CH(2) of Val); 3.35 3.2 (m, CH2(3) of
Tyr(2Me)); 2.05 1.95 (m, CH(3) of Val); 1.58( s, Me(3) of Tyr(2Me)); 0.9 0.85 (m, 2 Me(4) of Val). 13C-NMR:
176.6, 175.9 (2s, COOH, CO (amide)); 157.8, 156.7 (2s, CO (urethane), 1 arom. CO); 143.7, 141.2, 136.8, 127.9
(4s, 6 arom. C); 131.0, 128.4, 127.8, 127.7, 127.3, 127.0, 125.0, 119.9, 114.6 (9d, 17 arom. CH); 69.8, 67.3 (2t,
PhCH2O, CH2O of Fmoc); 60.8( s, C(2) of Tyr(2Me)); 60.2 (d, C(2) of Val); 47.0 (d, CH of Fmoc); 40.3 (t, C(3)
of Tyr(2Me)); 30.9 (d, C(3) of Val); 23.1, 19.2, 17.5 (3q, Me(3) of Tyr(2Me), 2 Me(4) of Val). ESI-MS (MeOH,

Helvetica Chimica Acta Vol. 85 (2002)
3439
‡
NaI): 629 (100, [M ‡ Na] ). Anal. calc. for C37H38N2O6 ¥ H2O (624.74): C 71.14, H 6.45, N 4.48; found: C 71.45
H 6.48, N 4.39.
4.3. Dipeptides with (S)-Dopa(2Me). 4.3.1. [(9H-Fluoren-9-yl)methyl] N-((S)-1-{[((S)-1-[3,4-
Bis(benzyloxy)benzyl]-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-oxoethyl)amino]carbonyl}-
2-methylpropyl)carbamate (Fmoc-Val-(S)-Dopa(2Me)(OBn)2-NMe(naphthEt), (S,S,R)-13b). As described for
(S,S,R)-13a, with Fmoc-Val-OH (253 mg, 0.745 mmol) in abs. CH2Cl2 (5 ml), (1'R,2S)-2b (400 mg, 0.740 mmol),
and abs. CH2Cl2 (10 ml); 137 h at r.t.: 363 mg (56%) of (S,S,R)-13b. Colorless foam. M.p. 89 908. Rf (hexane/
AcOEt 1:1) 0.42. IR: 3334m, 3036w, 2962m, 1724m, 1676m, 1618s, 1509vs, 1452s, 1375w, 1332w, 1269m, 1222m,
1
1138w, 1026w, 8 48w, 8 05w, 78 2w, 759w, 740m, 697w. H-NMR: 7.85 7.8, 7.75 7.7, 7.5 7.15, 6.75 6.7, 6.5 6.45
(5m, 28arom. H, NH, CHN); 5.21 ( d, J ˆ 6.7, NH of Val); 5.07, 5.02 (2s, 2 PhCH2O); 4.45 4.35, 4.35 4.2, 4.2
4.1, 4.05 3.95 (4m, CH2CH of Fmoc, CH(2) of Val); 3.65, 2.59 (AB, J ˆ 14.7, CH2(3) of Dopa(2Me)); 2.45 (s,
MeN); 2.2 2.15 (m, CH(3) of Val); 1.56 (s, Me(3) of Dopa(2Me)); 1.43 (d, J ˆ 6.7, MeCHN); 0.95, 0.87 (2d, J ˆ
6.5, 6.7, 2 Me(4) of Val). 13C-NMR: 171.2, 169.2 (2s, 2 CO (amide)); 156.1 (s, CO (urethane)); 148.7, 148.1, 143.7,
141.2, 137.3, 137.2, 135.4, 133.7, 131.8, 129.4 (10s, 12 arom. C); 128.7, 128.6, 128.3, 127.6, 127.4, 127.2, 127.0, 126.5,
125.9, 125.2, 124.9, 124.8, 123.5, 122.4, 119.9, 117.1, 115.0 (17d, 28arom. CH); 71.3, 71.1 (2 t, 2 PhCH2O); 66.7 (t,
CH2O of Fmoc); 61.4 (s, C(2) of Dopa(2Me)); 60.6 (d, C(2) of Val); 50.7, 47.2 (2d, CH of Fmoc, CHN); 40.4 (t,
C(3) of Dopa(2Me)); 31.0 (d, C(3) of Val); 30.4 (q, MeN); 22.3, 19.1, 17.5, 14.6 (4q, CHNMe, Me(3) of
‡
Dopa(2Me), 2 Me(4) of Val). ESI-MS (MeOH, NaI): 902 (100, [M ‡ Na] ), 613 (14). Anal. calc. for
C57H57N3O6 (880.10): C 77.80, H 6.53, N 4.77; found: C 77.91, H 6.56, N 4.68.
4.3.2. (S)-2-{[(S)-2-Amino-3-methyl-1-oxobutyl]amino}-2-[3,4-bis(benzyloxy)benzyl]-N-methyl-N-[(R)-
1-(naphthalen-1-yl)ethyl]propanamide (H-Val-(S)-Dopa(2Me)(OBn)2-NMe(naphthEt), (S,S,R)-14b). As de-
scribed for (S,S,R)-14a, with (S,S,R)-13b (74 mg, 0.084 mmol), and Et2NH (2 ml); 1 h at r.t.: 48mg (87%) of
(S,S,R)-14b. M. p. 65 668. Rf (AcOEt) 0.23. IR: 3396w, 2960m, 1674s, 1620vs, 1511vs, 1454s, 1385m, 1332w,
1269s, 1139w, 1069m, 1025w, 8 05w, 78 2m, 737w, 697w. 1H-NMR: 8.17 (br. s, NH); 8.0 7.9, 7.8 7.75, 7.55 7.25,
6.8 6.75, 6.65 6.5 (5 m, 20 arom. H, 2 NH, CHN); 5.15 5.05 (m, 2 PhCH2O); 4.05 4.0 (m, CH(2) of Val);
3.65 2.85 (m, CH2(3) of Dopa(2Me)); 2.45 2.4 (m, MeN); 2.3 2.25 (m, CH(3) of Val); 1.55 (s, Me(3) of
Dopa(2Me)); 1.55 1.4 (m, MeCHN); 0.95 0.75 (m, 2 Me(4) of Val). 13C-NMR: 171.5, 170.6 (2s, 2 CO
(amide)); 148.5, 148.0, 137.3, 137.2, 135.6, 133.6, 131.9, 129.3 (8s, 8 arom. C); 128.5, 128.3, 127.7, 127.4, 127.2, 126.6,
125.9, 125.1, 124.7, 124.0, 123.2, 117.6, 114.9 (13d, 20 arom. CH); 71.4, 71.1 (2t, 2 PhCH2O); 61.0 (s, C(2) of
Dopa(2Me)); 59.8( d, C(2) of Val); 50.4 (d, CHN); 41.2 (t, C(3) of Dopa(2Me)); 30.4 (d, C(3) of Val); 30.1 (q,
MeN); 23.0, 19.4, 19.1, 16.5, 14.7 (5q, CHNMe, Me(3) of Dopa(2Me), 2 Me(4) of Val). ESI-MS (MeCN, NaI):
‡
‡
‡
680 (25, [M ‡ Na] ), 658(100, [ M ‡ 1] ), 504 (24, [M À naphthCHCH2 ‡ 1] ), 473 (7, [M À naphthEtNMe ‡
‡
1] ). Anal. calc. for C42H47N3O4 ¥ 0.5 H2O (666.86): C 75.64, H 7.26, N 6.30; found: C 75.32, H 7.11, N 5.96.
4.3.3. [(9H-Fluoren-9-yl)methyl] N-((S)-1-{[((S)-1-[3,4-Bis(hydroxy)benzyl]-1-methyl-2-{methyl[(R)-1-
(naphthalen-1-yl)ethyl]amino}-2-oxoethyl)amino]carbonyl}-2-methylpropyl)carbamate (Fmoc-Val-(S)-Dopa-
(2Me)-NMe(naphthEt), (S,S,R)-15b). As described for (S,S,R)-15a, with (S,S,R)-13b (100 mg, 0.114 mmol),
Pd/C (10% on activated charcoal, 5 mg), MeOH (2 ml), and H2; 22 h at r.t.: 48mg (60%) of ( S,S,R)-15b. M.p.
127 1288. Rf (hexane/AcOEt 1 :1) 0.14. IR: 3332s, 3050w, 2964m, 1678s, 1614s, 1511vs, 1450s, 1398m, 1375m,
1
1334m, 1285s, 1240s, 1110m, 1072m, 1043w, 8 67w, 8 05w, 78 2m, 760w, 741m. H-NMR: 8.0 7.7, 7.6 7.2 (2m, 15
arom. H, NH); 6.67 (d, J ˆ 8.0, 1 arom. H); 6.55 6.5 (m, 2 arom. H, CHN); 6.31 (d, J ˆ 7.9, 1 arom. H); 5.71 (d,
J ˆ 9.8, NH of Val); 4.45 4.4, 4.35 4.3, 4.2 4.15, 4.05 4.0 (4m, CHCH2 of Fmoc, CH(2) of Val); 3.7 3.65,
3.0 2.9 (2m, CH2(3) of Dopa(2Me)); 2.65 (s, MeN); 2.15 2.1 (m, CH(3) of Val); 1.68( s, Me(3) of
Dopa(2Me)); 1.62 (d, J ˆ 6.7, MeCHN); 1.04, 0.98(2 d, J ˆ 6.6, 6.7, 2 Me(4) of Val). 13C-NMR: 171.3, 169.9 (2s, 2
CO (amide)); 157.4 (s, CO (urethane)); 143.8, 143.7, 143.3, 141.2, 135.1, 133.7, 131.7, 127.5 (8s, 10 arom. C); 128.8,
128.7, 127.7, 127.0, 126.6, 126.0, 125.3, 125.0, 123.2, 121.3, 119.9, 117.1, 114.5 (13d, 18arom. CH); 67.5 ( t, CH2 of
Fmoc); 62.7 (s, C(2) of Dopa(2Me)); 61.4 (d, C(2) of Val); 51.1, 47.0 (2d, CH of Fmoc, CHN); 38.6 (t, C(3) of
Dopa(2Me)); 30.9 (d, C(3) of Val); 30.8( q, MeN); 21.5, 19.3, 17.9, 14.6 (4q, CHNMe, Me(3) of Tyr(2Me), 2
‡
Me(4) of Val). ESI-MS (CH2Cl2, MeOH, NaI): 722 (100, [M ‡ Na] ). Anal. calc. for C43H45N3O6 ¥ H2O (717.87):
C 71.95, H 6.60, N 5.85; found: C 72.23, H 6.73, N 5.69.
4.3.4. (S)-2-[3,4-Bis(benzyloxy)benzyl]-2-{[(S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3-meth-
yl-1-oxobutyl]amino}-2-methylpropanoic Acid (Fmoc-(S)-Dopa(2Me)(OBn)2-OH, (S,S)-16b). As described
for (S,S)-16a, with (S,S,R)-13b (109 mg, 0.124 mmol), and 3n HCl (MeCN/H2O 3 :1, 4 ml); 1 h at 608: 26 mg
(30%) of (S,S,)-16b and 38mg (42%) of ( S,S)-17b.
Data of (S,S)-16b: M.p. 91 928. Rf (CH2Cl2/MeOH 20 :1) 0.16. IR: 3403m, 2962w, 1720s, 1509vs, 1452s,
1
1376w, 1265s, 1139w, 1027w, 759w, 740m, 696w, 621w. H-NMR: 7.71 (d, J ˆ 7.4, 2 arom. H); 7.53 (d, J ˆ 6.6, 2
arom. H); 7.45 7.2 (m, 14 arom. H); 6.7 6.6 (m, 3 arom. H, NH of Dopa(2Me)); 5.79 (d, J ˆ 9.0, NH of Val);

3440
Helvetica Chimica Acta Vol. 85 (2002)
5.02, 4.92 (2s, 2 PhCH2O); 4.35 4.1 (m, CHCH2 of Fmoc); 4.0 3.9 (m, CH(2) of Val); 3.35, 3.11 (AB, J ˆ 13.7,
CH2(3) of Dopa(2Me)); 2.05 1.9 (m, CH(3) of Val); 1.57 (s, Me(3) of Dopa(2Me)); 0.95 0.85 (m, 2 Me(4) of
Val ) . 13C-NMR: 176.4, 171.2 (2s, COOH, CO (amide)); 156.4 (s, CO (urethane)); 148.5, 148.2, 143.6, 141.2, 137.2,
137.1, 128.8 (7s, 9 arom. C); 128.3, 127.6, 127.4, 127.2, 127.0, 125.0, 122.9, 119.9, 117.1, 114.7 (10d, 21 arom. CH);
71.2, 70.5 (2t, 2 PhCH2O, CH2O of Fmoc); 61.0 (d, C(2) of Val); 60.5 (s, C(2) of Dopa(2Me)); 47.0 (d, CH of
Fmoc); 41.1 (t, C(3) of Dopa(2Me)); 30.9 (d, C(3) of Val); 22.7, 19.0, 17.8(3 q, Me(3) of Dopa(2Me), 2 Me(4) of
‡
Val). ESI-MS (CH2Cl2, MeOH, NaI): 737 (14), 735 (100, [M ‡ Na] ), 661 (14), 617(10). Anal. calc. for
C44H44N2O7 (712.84): C 74.14, H 6.22, N 3.93; found: C 74.00, H 6.30, N 3.65.
4.4. Dipeptides with Val-(R)-Dopa(2Me). 4.4.1. [(9H-Fluoren-9-yl)methyl] N-((S)-1-{[((R)-1-[3,4-Bis-
(benzyloxy)benzyl]-1-methyl-2-{methyl[(R)-1-(naphthalen-1-yl)ethyl]amino}-2-oxoethyl)amino]carbonyl}-2-
methylpropyl)carbamate (Fmoc-Val-(R)-Dopa(2Me)(OBn)2-NMe(naphthEt), (S,R,R)-13b). As described for
(S,S,R)-13a, with Fmoc-Val-OH (253 mg, 0.745 mmol) in abs. CH2Cl2 (5 ml), (1'R,2R)-2b (400 mg,
0.740 mmol), and abs. CH2Cl2 (10 ml); 142 h at r.t.; CC (hexane/AcOEt 3 :2): 377 mg (58%) of (S,R,R)-13b.
Colorless foam. M.p. 92 948. Rf (hexane/AcOEt 1 :1) 0.55. IR: 3402m, 3037w, 2963m, 1725m, 1681s, 1620m,
1510vs, 1452s, 1391m, 1330w, 1269s, 1222m, 1138w, 1070m, 1026m, 8 04w, 78 2m, 759w, 740s, 697w. 1H-NMR:
7.95 7.9, 7.8 7.7, 7.5 7.2 (3 m, 25 arom. H, CHN); 6.7-6.6 (m, 1 arom. H, NH); 6.55 6.5 (m, 2 arom. H); 5.19 (d,
J ˆ 8.2, NH of Val); 5.03, 5.00 (2s, 2 PhCH2O); 4.35 4.25, 4.25 4.15, 3.95 3.9 (3m, CH2CH of Fmoc, CH(2) of
Val); 3.37, 3.29 (AB, J ˆ 14.6, CH2(3) of Dopa(2Me)); 2.51 (br. s, MeN); 1.65 1.5 (m, CH(3) of Val); 1.60 (d,
J ˆ 6.7, MeCHN); 1.43 (s, Me(3) of Dopa(2Me)); 0.88, 0.82 (2d, J ˆ 6.3, 6.4, 2 Me(4) of Val). 13C-NMR: 171.2,
169.7 (2s, 2 CO (amide)); 156.2 (s, CO (urethane)); 148.6, 148.2, 143.7, 141.3, 137.4, 135.7, 133.7, 132.0, 129.7 (9s,
12 arom. C); 128.6, 128.4, 127.7, 127.4, 127.3, 127.1, 126.7, 126.0, 125.1, 124.8, 124.2, 123.2, 120.0, 118.1, 115.0 (15d,
28arom. CH); 71.4, 71.3 (2 t, 2 PhCH2O); 67.0 (t, CH2O of Fmoc); 60.5 (d, C(2) of Val); 60.2 (s, C(2) of
Dopa(2Me)); 50.6, 47.2 (2d, CH of Fmoc, CHN); 41.3 (t, C(3) of Dopa(2Me)); 30.7 (d, C(3) of Val); 30.3 (q,
MeN); 22.6, 19.5, 17.4, 15.3 (4q, CHNMe, Me(3) of Dopa(2Me), 2 Me(4) of Val). ESI-MS (MeOH, NaI): 903
‡
(100, [M ‡ Na] ), 824 (7), 223 (8). Anal. calc. for C57H57N3O6 ¥ 0.3 H2O (886.11): C 77.26, H 6.56, N 4.74; found:
C 77.04, H 6.55, N 5.24.
4.4.2. (R)-2-{[(S)-2-Amino-3-methyl-1-oxobutyl]amino}-2-[3,4-bis(benzyloxy)benzyl]-N-methyl-N-[(R)-
1-(naphthalen-1-yl)ethyl]propanamide (H-Val-(R)-Dopa(2Me)(OBn)2-NMe(naphthEt), (S,R,R)-14b). As de-
scribed for (S,S,R)-14a, with (S,R,R)-13b (100 mg, 0.114 mmol), and Et2NH (2 ml); 4 h at r.t.; prep. TLC
(AcOEt/MeOH 20 :1) and prep. TLC (CH2Cl2/MeOH 10 :1): 58mg (77%) of ( S,R,R)-14b. M.p. 71 738. Rf
(CH2Cl2/MeOH 10 :1) 0.45. IR: 3404s, 2960m, 1668m, 1623vs, 1512vs, 1454s, 1385m, 1269s, 1139w, 1070m, 1025w,
1
805m, 78 2w, 736w, 697w. H-NMR: 8.17 (br. s, NH); 8.0 7.9, 7.85 7.75, 7.45 7.2, 6.95 6.55 (4m, 20 arom. H,
3 NH, CHN); 5.1 5.05 (m, 2 PhCH2O); 4.0 3.9 (m, CH(2) of Val); 3.5 3.15 (m, CH2(3) of Dopa(2Me));
2.55 2.4 (m, MeN); 2.25 2.2 (m, CH(3) of Val); 1.57 (d, J ˆ 6.7, MeCHN); 1.46 (s, Me(3) of Dopa(2Me));
0.95 0.65 (m, 2 Me(4) of Val). 13C-NMR: 171.5 (s, 2 CO (amide)); 148.3, 147.9, 137.3, 135.6, 133.6, 131.9, 129.9
(7s, 8 arom. C); 128.3, 128.3, 127.6, 127.4, 127.3, 127.2, 126.6, 125.8, 125.2, 124.8, 124.0, 123.6, 118.2, 114.8 (14d, 20
arom. CH); 71.5, 71.1 (2t, 2 PhCH2O); 61.0 (s, C(2) of Dopa(2Me)); 59.4 (d, C(2) of Val); 50.5 (d, CHN); 41.7 (t,
C(3) of Dopa(2Me)); 30.1 (d, C(3) of Val); 22.5, 19.0, 16.7, 15.3, 14.1 (5q, MeN, CHNMe, Me(3) of Dopa(2Me),
‡
‡
2 Me(4) of Val). ESI-MS (MeOH, NaI): 658(100, [ M ‡ 1] ), 504 (83, [M À naphthCHCH2 ‡ 1] ), 473 (27,
‡
‡
[M À naphthEtNMe ‡ 1] ), 179 (21, [dibenzofulvene] ). Anal. calc. for C42H47N3O4 (657.85): C 76.68, H 7.20,
N 6.39; found: C 76.67, H 7.23, N 6.23.
4.4.3. [(9H-Fluoren-9-yl)methyl] N-((S)-1-{[((R)-1-[3,4-Bis(hydroxy)benzyl]-1-methyl-2-{methyl[(R)-1-
(naphthalen-1-yl)ethyl]amino}-2-oxoethyl)amino]carbonyl}-2-methylpropyl)carbamate (Fmoc-Val-(R)-Dopa-
(2Me)-NMe(naphthEt), (S,R,R)-15b). As described for (S,S,R)-15a, with (S,R,R)-13b (100 mg, 0.114 mmol),
5 mg Pd/C (10% on activated charcoal), MeOH (2 ml), and H2; 25 h at r.t.: 68mg (85%) of ( S,R,R)-15b. M.p.
131 1328. Rf (hexane/AcOEt 1:1) 0.19. IR: 3390vs, 2928s, 1681s, 1614s, 1514vs, 1504s, 1450s, 1392m, 1285m,
1110m, 1071m, 78 2w, 760w, 741w. 1H-NMR: 7.9 7.75, 7.6 7.25 (2m, 15 arom. H); 6.7 6.55, 6.45 6.4 (2m, 3
arom. H, CHN); 6.08(br. s, NH of Dopa(2Me)); 5.71 (d, J ˆ 9.8, NH of Val); 4.45 4.35, 4.2 4.05 (2m, CHCH2
of Fmoc, CH(2) of Val); 3.41, 3.21 (AB, J ˆ 14.2, CH2(3) of Dopa(2Me)); 2.55 (s, MeN); 2.1 2.05 (m, CH(3) of
Val); 1.62 (d, J ˆ 7.7, MeCHN); 1.34 (s, Me(3) of Dopa(2Me)); 0.95, 0.93 (2d, J ˆ 6.5, 6.6, 2 Me(4) of Val).
13C-NMR: 170.7, 170.6 (2s, 2 CO (amide)); 157.5 (s, CO (urethane)); 143.7, 143.5, 143.1, 141.2, 135.6, 133.6, 131.9,
128.1 (8s, 10 arom. C); 128.5, 128.4, 127.7, 127.1, 126.6, 125.9, 125.1, 124.9, 124.7, 123.9, 123.2, 119.9, 117.7, 114.5
(14d, 18arom. CH); 67.7 ( t, CH2 of Fmoc); 60.3 (d, C(2) of Val); 60.0 (s, C(2) of Dopa(2Me)); 50.1, 47.0 (2d, CH
of Fmoc, CHN); 40.3 (t, C(3) of Dopa(2Me)); 30.9 (d, C(3) of Val); 29.7 (q, MeN); 21.6, 19.6, 16.7, 14.8(4 q,
‡
CHNMe, Me(3) of Tyr(2Me), 2 Me(4) of Val). ESI-MS (CH2Cl2, MeOH, NaI): 810 (8), 723 (100, [M ‡ Na] ),

Helvetica Chimica Acta Vol. 85 (2002)
3441
596 (9), 382 (8). Anal. calc. for C43H45N3O6 ¥ H2O (717.87): C 71.95, H 6.60, N 5.85; found: C 72.01, H 6.76,
N 5.76.
4.4.4. (R)-2-[3,4-Bis(benzyloxy)benzyl]-2-{[(S)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-3-meth-
yl-1-oxobutyl]amino}-2-methylpropanoic Acid (Fmoc-(R)-Dopa(2Me)(OBn)2-OH, (S,R)-16b). As described
for (S,R)-16a, with (S,R,R)-13b (100 mg, 0.114 mmol), and 3n HCl (MeCN/H2O 1:1, 4 ml); 3 h at 608: 20 mg
(25%) of (S,R)-16b, 55 mg (55%) of (S,R,R)-13b, and 16 mg (19%) of (S,R)-17b.
Data of (S,R)-16b: M.p. 83 848. Rf (CH2Cl2/MeOH 20 :1) 0.29. IR: 3408s, 2928m, 1715s, 1513vs, 1453m,
1266s, 1138w, 1026w, 740m, 697w. 1H-NMR: 7.73 (d, J ˆ 7.5, 2 arom. H); 7.55 7.5 (m, 2 arom. H); 7.45 7.25 (m,
14 arom. H); 6.75 6.6 (m, 3 arom. H, NH of Dopa(2Me)); 5.82 (d, J ˆ 9.0, NH of Val); 5.06, 4.99 (2s, 2
PhCH2O); 4.4 4.1 (m, CHCH2 of Fmoc, CH(2) of Val); 2.25 2.2 (m, CH2(3) of Dopa(2Me)); 2.0 1.95 (m,
CH(3) of Val); 1.51 (s, Me(3) of Dopa(2Me)); 0.85 0.8 (m, 2 Me(4) of Val). 13C-NMR: 176.2, ca. 172 (2s,
COOH, CO (amide)); ca. 157 (s, CO (urethane)); 148.5, 148.1, 143.6, 141.2, 137.2 (5s, 9 arom. C); 128.3, 127.6,
127.3, 127.2, 127.0, 125.0, 123.0, 119.9, 117.1, 114.8(10 d, 21 arom. CH); 71.2, 67.3 (2t, 2 PhCH2O, CH2O of Fmoc);
60.7 (s, C(2) of Dopa(2Me)); 60.1 (d, C(2) of Val); 47.0 (d, CH of Fmoc); 40.9 (t, C(3) of Dopa(2Me)); 30.9 (d,
C(3) of Val); 23.0, 19.2, 17.5 (3q, Me(3) of Dopa(2Me), 2 Me(4) of Val). ESI-MS (MeOH, NaI): 736 (100,
‡
[M ‡ Na] ). Anal. calc. for C44H44N2O7 ¥ 0.5 H2O (730.86): C 73.21, H 6.28, N 3.88; found: C 73.08, H 6.49,
N 3.88.
5. X-Ray Crystal-Structure Determination of (1R,1'R)-11a, (1R,1'R)-11b, (1S,1'R)-12b, and (1R,1'R)-12b
(see Table 7 and Figure)2). All measurements were conducted at low temp. with graphite-monochromated
MoKa radiation (l ˆ 0.71073 ä). The data collection and refinement parameters are given in Table 7, and views
of the molecules are shown in the Figure. The intensities were corrected for Lorentz and polarization effects, but
not for absorption. Equivalent reflections, other than Friedel pairs, were merged. Each structure was solved by
direct methods by means of SIR92 [11], which revealed the positions of all non-H-atoms.
When the peptide molecule (1R,1'R)-12b had been fully modelled, it was found that the unit-cell contains
two quite large voids (385 ä3 each), which are assumed to be occupied by solvent molecules. Only a few weak
peaks of electron density could be located, and these did not represent any logical molecule, so the solvent
molecules must be highly disordered within each cavity. Therefore, the SQUEEZE routine [12] of the program
PLATON [13] was employed. This routine removes the contribution of the solvent region of the structure from
the reflection intensity data and, when successful, allows the solvent molecules to be omitted entirely from the
refinement model. For this structure, the procedure gave satisfactory R factors for the refinement and suitable
geometric parameters for the peptide molecule, and there were no significant peaks of residual electron density
to be found in the voids of the structure. The electron count in the solvent region was calculated to be 121 e per
unit cell. It is assumed that the solvent molecules are AcOEt, as the compound was recrystallized from this
solvent. If so, one molecule in each void would contribute a total of 96 e to the electron count, which falls a little
short of the calculated electron count, but is not completely unreasonable. However, there is insufficient
information to guarantee that the solvent molecules are indeed AcOEt, and other molecules could be
conceivable. For the purposes of the calculation of Mr, the density, F(000) and the linear absorption coefficient,
it was assumed that the solvent is indeed AcOEt, and that the ratio of peptide/AcOEt in the structure is 2 :1 (4
peptide molecules plus 2 voids per unit cell).
The non-H-atoms of each structure were refined anisotropically, except for C(44) of (1R,1'R)-11b, which
was refined only isotropically. All of the H-atoms in (1R,1'R)-12b were placed in geometrically calculated
positions and refined with a riding model where each H-atom was assigned a fixed isotropic displacement
parameter with a value equal to 1.2Ueq of its parent atom (1.5Ueq for the Me groups). For (1R,1'R)-11b and
(1S,1'R)-12b, the amide H-atom was placed in the position indicated by a difference-electron-density map, and
its position was allowed to refine together with an isotropic displacement parameter. All remaining H-atoms in
(1R,1'R)-11b and (1S,1'R)-12b, as well as all H-atoms in (1R,1'R)-12b were fixed in geometrically calculated
positions (d(CÀH) ˆ 0.95 ä), and each was assigned a fixed isotropic displacement parameter with a value
equal to 1.2Ueq of its parent atom. Refinement of (1R,1'R)-11a, (1R,1'R)-11b, and (1S,1'R)-12b was carried out
2
on F by full-matrix least-squares procedures, which minimized the function Sw j Fo jÀj Fc j ). In the case of
2
)
Crystallographic data (excluding structure factors) for (1R,1'R)-11a, (1R,1'R)-11b, (1S,1'R)-12b, and
(1R,1'R)-12b have been deposited with the Cambridge Crystallographic Data Centre as supplementary
publications no. CCDC-186661 CCDC-186664. 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).

3442
Helvetica Chimica Acta Vol. 85 (2002)
Table 7. Crystallographic Data of Compounds (1R,1'R)-11a, (1R,1'R)-11b, (1S,1'R)-12b, and (1R,1'R)-12b
(1R,1'R)-11a
(1R,1'R)-11b
(1S,1'R)-12b
(1R,1'R)-12b
Crystallized from
Empirical formula
Et2O / CH2Cl2 /
hexane
C37H36N2O2S
Et2O / hexane
AcOEt / MeOH / AcOEt
hexane
C44H42N2O3S
C44H42N2O4
C44H42N2O4 ¥
0.5 C4H8O2
706.88
Mr [g molÀ1
]
572.76
678.89
662.83
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
Crystal system
Space group
colorless, plate
colorless, needle
colorless, needle
colorless, needle
0.08 Â 0.10 Â 0.30
160(1)
orthorhombic
P212121
0.08 Â 0.23 Â 0.50
0.05 Â 0.05 Â 0.25
0.02 Â 0.10 Â 0.30
173(1)
160(1)
monoclinic
P21
160(1)
monoclinic
P21
monoclinic
P21
2
Z
2
2
4
Reflections for cell
determination
16
3364
4359
4054
2q Range for cell
determination [8]
Unit cell parameters a [ä]
20 33
4
50
4
55
4-50
18.869(3)
16.9854(2)
6.0837(1)
17.5054(2)
104.5299(5)
1751.05(4)
1.287
11.8540(2)
11.0932(2)
13.9586(3)
99.7186(9)
1809.20(6)
1.217
11.2289(1)
14.2751(2)
25.4518(3)
90
4079.76(8)
1.151
b [ä] 6.089(5)
c [ä]
b [8]
14.562(3)
112.64(1)
V [ä3] 1544(1)
1.232
Dx [g cmÀ3
]
m(MoKa) [mmÀ1
]
0.140
0.137
0.0774
0.0744
Diffractometer
Rigaku AFC5R
Nonius
Nonius
Nonius
KappaCCD
w
KappaCCD
f and w
50
KappaCCD
f and w
55
Scan type
2q(max) [8]
w/2q
55
50
Total reflections
measured
7964
53094
41965
55261
Symmetry independent
reflections
Reflections with I > 2s(I)
Parameters refined
Final R [on F; I > 2s(I)]
wR
7066
6111
8241
7203
5546
4756
378450
0.0857
0.0849
3609
455
0.0953
0.0976
[F; I > 2s(I)]
6505
455
0.0424
0.0419
[F; I > 2s(I)]
0.0545
0.1407 [F2; all
reflections]
[F; I > 2s(I)]
a
Weights: wÀ1
Goodness of fit
Secondary extinction
coefficient
s2(Fo) ‡ (0.005Fo)2 s2(Fo) ‡ (0.018Fo)2 s2(Fo) ‡ (0.018Fo)2
)
2.706
3.232
3.1 (5) Â 10À6
1.309
2.8(3) Â 10À6
1.028
0.033 (2)
Final Dmax/s
0.0002
0.002
0.0004
0.001
D1 (max; min) [e äÀ3
Structure refinement
program
]
1.01; À0.69
0.43; À0.50
0.22; À0.21
0.40; À0.40
teXsan [22]
teXsan
teXsan
SHELXL97 [23]
a) wÀ1 ˆ s2(Fo) ‡ (0.0969P)2 where P ˆ (Fo2 ‡ 2Fc2)/3
(1R,1'R)-12b, the refinement was carried out on F2 by minimizing the corresponding function based on F2.
Corrections for secondary extinction were applied, except in the case of (1R,1'R)-11a. For (1R,1'R)-11b and
(1S,1'R)-12b, three and six reflections, respectively, 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 [14],
and the scattering factors for H-atoms were taken from [15]. Anomalous dispersion effects were included in Fc
[16]; the values for f' and f'' were those of [17]. The values of the mass attenuation coefficients were taken from [18].

Helvetica Chimica Acta Vol. 85 (2002)
3443
The crystals of each compound were enantiomerically pure, and, in each case, the enantiomer used in the
refinement was chosen to agree with the known (R)-configuration at the Me-substituted C-atom adjacent to the
naphthalene moiety. The configuration at the stereogenic centre in the amino acid of each structure could then
be established relative to the configuration of the known chiral center. In the case of (1R,1'R)-11a, the absolute
configuration was further confirmed independently by refinement of the absolute structure parameter [19][20]
during the crystal-structure determination. This parameter attained a value of À 0.04(12), which confirmed that
the refined model represented the true enantiomorph.
The crystal of (1R,1'R)-11b was very small and weakly diffracting, and the overall quality of the refinement
results is quite poor. The atomic parameters and derived geometry of the molecule should be considered
to be only approximate, and attempts at refining the absolute structure parameter gave inconclusive
results. Nonetheless, the configuration of the molecule is clearly defined. The crystal of (1R,1'R)-11a was also
quite small and weakly diffracting, which again detracted from the quality of the results. There are significant
peaks of residual electron density near the S-atom (up to 1.0 e äÀ3). However, a disordered model does not
improve the results, and the structure does not appear to suffer from any other disorder or the presence of
solvent.
For (1R,1'R)-11a and (1R,1'R)-11b, the amide group is not involved in any H-bonding interactions. In both
(1S,1'R)-12b and (1R,1'R)-12b, the amide group forms an intermolecular H-bond with the central carbonyl O-
atom of a neighboring molecule. These interactions link the molecules into infinite one-dimensional chains
which run parallel to the y- and x-axes, respectively, and have graph set motifs [21] of C(5).
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[14] E. N. Maslen, A. G. Fox, M. A. O×Keefe, in −International Tables for Crystallography×, Ed. A. J. C. Wilson,
Kuwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 6.1.1.1, p. 477.
[15] R. F. Stewart, E. R. Davidson, W. T. Simpson, J. Chem. Phys. 1965, 42, 3175.
[16] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17, 78 1.
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Academic Publishers, Dordrecht, 1992, Vol. C, Table 4.2.6.8, p. 219.
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Academic Publishers, Dordrecht, 1992, Vol. C, Table 4.2.4.3, p. 200.
[19] H. D. Flack, G. Bernardinelli, Acta Crystallogr., Sect. A 1999, 55, 908.
[20] H. D. Flack, G. Bernardinelli, J. Appl. Crystallogr. 2000, 33, 1143.
[21] J. Bernstein, R. E. Davis, L. Shimoni, N.-L. Chang, Angew. Chem. 1995, 107, 1689.
[22] −teXsan: Single Crystal Structure Analysis×, Molecular Structure Corporation, The Woodlands, Texas,
Version 1.10, 1999.
[23] G. M. Sheldrick, −SHELXL97, Program for the Refinement of Crystal Structures×, University of Gˆttingen,
Germany, 1997.
Received May 30, 2002