Chiral heterospirocylic 2H-azirin-3-amines as synthons for 3-amino-2,3,4,-tetrahydrofuran-3-carboxylic acid and their use in peptide synthesis

Article abstract of DOI:10.1002/hlca.200390124

The heterospirocyclic N-methyl-N-phenyl-5-oxa-1-azaspiro[2.4]hept-1-e n-2-amine (6) and N-(5-oxa-1-azaspiro[2.4]hept-1-en-2-yl)-(S)-proline methyl ester (7) were synthesized from the corresponding heterocyclic thiocarboxamides 12 and 10, respectively, by consecutive treatment with COCl₂, 1,4-diazabicyclo[2.2.2]octane, and NaN₃ (Schemes 1 and 2). The reaction of these 2H-azirin-3-amines with thiobenzoic and benzoic acid gave the racemic benzamides 13 and 14, and the diastereoisomeric mixtures of the N-benzoyl dipeptides 15 and 16, respectively (Scheme 3). The latter were separated chromatographically. The configurations and solid-state conformations of all six henzamides were determined by X-ray crystallography. With the aim of examining the use of the new synthons in peptide synthesis the reactions of 7 with Z-Leu-Aib-OH to yield a tetrapeptide 17 (Scheme 4), and of 6 with Z-Ala-OH to give a dipeptide 18 (Scheme 5) were performed. The resulting diastereoisomers were separated by means of MPLC or HPLC. NMR Studies of the solvent dependence of the chemical shifts of the NH resonances indicate the presence of an intramolecular H-bond in 17. The dipeptides (S,R)-18 and (S,S)-18 were deprotected at the N-terminus and were converted to the crystalline derivatives (S,R)-19 and (S,S)-19, respectively, by reaction with 4-bromobenzoyl chloride (Scheme 5). Selective hydrolysis of (SR)-18 and (S.S)-18 gave the dipeptide acids (R,S)-20 and (SS)-20, respectively. Coupling of a diastereoisomeric mixture of 20 with H-Phe-O′Bu led to the tripeptides 21 (Scheme 5). X-Ray crystal-structure determinations of (S,R)-19 and (S,S)-19 allowed the determination of the absolute configurations of all diastereoisomers isolated in this series.

Full text of DOI:10.1002/hlca.200390124

Helvetica Chimica Acta Vol. 86 (2003)
1371
Chiral Heterospirocyclic 2H-Azirin-3-amines as Synthons for 3-Amino-
2,3,4,5-tetrahydrofuran-3-carboxylic Acid and Their Use in Peptide Synthesis
by Simon Stamm1), Anthony Linden, and Heinz Heimgartner*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
Dedicated to Professor Jack D. Dunitz on the occasion of his 80th birthday
The heterospirocyclic N-methyl-N-phenyl-5-oxa-1-azaspiro[2.4]hept-1-e n-2-amine (6) and N-(5-oxa-1-
azaspiro[2.4]hept-1-en-2-yl)-(S)-proline methyl ester (7) were synthesized from the corresponding heterocyclic
thiocarboxamides 12 and 10, respectively, by consecutive treatment with COCl2, 1,4-diazabicyclo[2.2.2]octane,
and NaN3 (Schemes 1 and 2). The reaction of these 2H-azirin-3-amines with thiobenzoic and benzoic acid gave
the racemic benzamides 13 and 14, and the diastereoisomeric mixtures of the N-benzoyl dipeptides 15 and 16,
respectively (Scheme 3). The latter were separated chromatographically. The configurations and solid-state
conformations of all six benzamides were determined by X-ray crystallography. With the aim of examining the
use of the new synthons in peptide synthesis, the reactions of 7 with Z-Leu-Aib-OH to yield a tetrapeptide 17
(Scheme 4), and of 6 with Z-Ala-OH to give a dipeptide 18 (Scheme 5) were performed. The resulting
diastereoisomers were separated by means of MPLC or HPLC. NMR Studies of the solvent dependence of the
chemical shifts of the NH resonances indicate the presence of an intramolecular H-bond in 17. The dipeptides
(S,R)-18 and (S,S)-18 were deprotected at the N-terminus and were converted to the crystalline derivatives
(S,R)-19 and (S,S)-19, respectively, by reaction with 4-bromobenzoyl chloride (Scheme 5). Selective hydrolysis
of (S,R)-18 and (S,S)-18 gave the dipeptide acids (R,S)-20 and (S,S)-20, respectively. Coupling of a
diastereoisomeric mixture of 20 with H-Phe-OtBu led to the tripeptides 21 (Scheme 5). X-Ray crystal-structure
determinations of (S,R)-19 and (S,S)-19 allowed the determination of the absolute configurations of all
diastereoisomers isolated in this series.
1. Introduction. Peptides containing a,a-disubstituted a-amino acids are restricted
in their conformational freedom [1 12]. As a consequence of the rigidity of the
peptide backbone, secondary structures, such as b-turns and helices, are stabilized or
even promoted [13][14]. The synthesis of such conformationally restricted peptides is a
useful tool in the search for the biologically active conformation of a peptide. A useful
method for introducing a,a-disubstituted a-amino acids into peptides is the −azirine/
oxazolone method×, in which 2H-azirin-3-amines 1 are used as amino acid synthons
[15][16]. This method has been applied successfully in the synthesis of oligopeptides,
endothiopeptides, cyclic peptides, and cyclic depsipeptides [17] (and refs. cit. therein)
[18 21]. Thus, the reaction of 2 H-azirin-3-amines, e.g., the Aib synthon 2, with amino
or peptide acids leads to peptide amides, the terminal amide bonds of which can be
hydrolyzed selectively. Recently, the dipeptide synthon methyl N-(2,2-dimethyl-2H-
azirin-3-yl)-(S)-pr olinate (3) [22] has been prepared, and has found application in the
synthesis of the peptaibol antibiotics Trichovirin I 1B and I 4A [22][23]. Furthermore,
the heterospirocyclic N-methyl-N-phenyl-2H-azirin-3-amines 4 [24] and the hetero-
1
)
Diploma thesis of S. S., Universit‰t Z¸rich, 2002.

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Helvetica Chimica Acta Vol. 86 (2003)
spirocyclic dipeptide synthon N-(6-oxa-1-azaspiro[2.5]oct-1-en-2-yl)-(S)-proline meth-
yl ester (5) [18] have been synthesized.
R3
Me
R2
2
N
N
N
3
R4
Ph
R1
N
N
N
1
OMe
O
1
2
3
Me
N
O
X
X = O, S, N(Boc),
X = NCH2Ph
N
Ph
N
N
OMe
O
4
5
In the present paper, we report the synthesis of the amino acid synthon 6 (Thf
synthon) and the dipeptide synthon 7 (Thf-Pro synthon). In these new azirine
derivatives, a heterocycle is used for the first time as a stereogenic unit in a 2H-azirin-3-
amine, leading to racemic or diastereoisomeric building blocks 6 and 7, respectively.
Reactions with thiobenzoic and benzoic acid, with an a-amino acid, and with a
dipeptide confirmed that these new building blocks are suitable for peptide synthesis.
Me
O
O
N
N
Ph
N
N
CO2Me
6
7
2. Results and Discussion. 2.1. Synthesis of Heterospirocyclic 2H-Azirin-3-amines.
The starting material, 2,3,4,5-tetrahydrofuran-3-carboxylic acid (8), was prepared by
hydrogenation of commercially available furan-3-carboxylic acid. Consecutive treat-
ment with SOCl2 and methyl (S)-prolinate gave N-[(2,3,4,5-tetrahydrofuran-3-
yl)carbonyl]-(S)- proline methyl ester (9; Scheme 1). Since the method of Villalgordo
and Heimgartner [19][25], used by Str‰ssler [24] for the synthesis of 4, is limited to N-
alkyl-N-phenyl amides, 9 was converted to 10 by thionation with Lawesson reagent.
Analogously to the procedure described in [26] [27], consecutive treatment of a
solution of 10 and catalytic amounts of DMF in CH2Cl2 with COCl2, evaporation of the
solvent, dissolution of the residue in THF, addition of 1,4-diazabicyclo[2.2.2]octane
(DABCO), filtration, and reaction with NaN3 gave, after chromatographic workup,
azirine 7 in 63% yield as a pale-yellow oil. It is important that the SiO2 used for the
chromatographic separation of 7 is deactivated with Et3N, otherwise considerably less
product is obtained2).
2
)
The reaction conditions worked out for the synthesis of 6 (THF/DMF, 8d, r.t.; vide infra) were not optimal
in this case.

Helvetica Chimica Acta Vol. 86 (2003)
1373
Scheme 1
O
1. SOCl2, ↑↓
CO2H
N
O
O
2. Et3N, H-Pro-OMe · HCl,
2. CH2Cl2, 0° → r.t.
CO2Me
8
9
Lawesson reagent
Toluene, 95°
S
1. COCl2, Toluene,
1. DMF, 0°
O
N
N
O
2. DABCO, THF, r.t.
3. NaN3, THF, r.t.
N
CO2Me
CO2Me
7
10
The synthesis of 6 by the method of Villalgordo and Heimgartner [19][25] was
unsuccessful, even though 11 is an N-alkyl-N-phenyl amide (Scheme 2). Therefore,
after thionation of 11 to give 12, 6 was also synthesized according to the procedure
described in [26][27], which gives the product in 63% yield. However, after addition of
NaN3, it was necessary to change the solvent to DMF, otherwise not even traces of 6
could be detected by TLC. Wipf [26] has already shown that the rate of reaction of the
a-chloro enamine with NaN3 to give the 2H-azirin-3-amine is highly dependent on the
solvent. The reaction rate decreases in the order DMF > THF > Et2O, but, even in
DMF, a long reaction time of 8d was necessary in the case of 6, which is similar to the
reaction time in the synthesis of the carbocyclic N-methyl-N-phenyl-1-azaspiro[2.4]-
hept-1-en-2-am ine described by Sahebi et al. [28].
With the aim of showing that 6 and 7 are mixtures of enantiomers and
diastereoisomers, respectively, the isomers were separated on a chiral HPLC-column
(Chiracel-OD). It should also be possible to separate them on a preparative scale into
the enantiomerically pure amino acid synthons (R)-6 and (S)-6, and the diastereo-
isomerically pure dipeptide synthons (R,S)-7 and (S,S)-73).
2.2. Reactions with Thiobenzoic and Benzoic Acid. To examine the reactivity of the
new 2H-azirin-3-amines 6 and 7, they were reacted with PhCOSH and PhCOOH
(Scheme 3). All reactions gave the products in good to very good yields (87 99%).
The solid-state structures of products 13 and 14, obtained from the reactions with 6,
were established by X-ray crystallography (Fig. 1). The amide H-atom of 13 forms an
intermolecular H-bond with the O-atom of the tetrahydrofuran ring of a neighboring
3
)
All attempts to separate the mixture of diastereoisomers (R,S)-7 and (S,S)-7 on a nonchiral HPLC column
failed.

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Helvetica Chimica Acta Vol. 86 (2003)
Scheme 2
O
1. SOCl2, ↑↓
Me
CO2H
N
O
O
Ph
2. Et3N, HN(Me)Ph,
2. CH2Cl2, 0° → r.t.
8
11
Lawesson reagent,
Toluene, 95°
1. LDA, THF, 0°
2. DPPCl, THF, 0° → r.t.
3. NaN3, THF (/DMF), r.t.
S
Me
O
1. COCl2, Toluene,
1. CHCl2, DMF, 0°
Me
N
N
Ph
O
Ph
N
2. DABCO, THF, r.t.
3. NaN3, DMF, r.t.
6
12
LDA ˆ Lithium diisopropylamide; DPPCl ˆ diphenylphosphorochloridate; DABCO ˆ 1,4-diazabicyclo[2.2.2]-
octane.
Scheme 3
O
Me
O
Me
N
O
PhCOXH, CH2Cl2,
N
Ph
Ph
N
Ph
0° → r.t.
H
N
X
6
13 X = S
14 X = O
O
O
O
PhCOXH, CH2Cl2,
N
N
Ph
N
H
X
0° → r.t.
N
CO2Me
CO2Me
(R,S)-15, (S,S)-15 X = S
(R,S)-16, (S,S)-16 X = O
7
molecule (Table 1). This interaction links pairs of molecules across a center of inversion
into dimers, which have a graph-set motif [29] of R22(10) (Fig. 2). The conformations of
five-membered rings can be described by the puckering parameter f2 [30], where an
ideal envelope conformation has a value for f2 of 36n8 (n is an integer), and f2 ˆ
(36n ‡ 18)8 for an ideal half-chair or twist conformation. The heterocyclic five-
membered ring of 13 has an almost perfect envelope conformation (f2 ˆ 250.7(2)8)

Helvetica Chimica Acta Vol. 86 (2003)
1375
with C(3)4) as the envelope flap. In the case of 14, there are two symmetry-
independent molecules in the asymmetric unit. They differ primarily in the
conformation of the five-membered ring and in the orientations of the Ph rings. In
molecule B, the Ph rings of the benzamide and secondary amide groups are twisted by
ca. 308 and 118, respectively, compared with their orientations in molecule A. In the
five-membered ring of molecule B, the O-atom and the adjacent CH2 group most
distant from the spiro-C-atom are disordered over two approximately equally occupied
positions, which leads to two different conformations with f2 ˆ 298(1)8 and 264.5(5)8.
The former is halfway between a C(46) envelope and a half-chair twisted on
C(45a)ÀC(46), while the latter has
a half-chair conformation twisted on
O(44b)ÀC(45b) that is distorted towards an O(44b) envelope. The five-membered
ring of molecule A has f2 ˆ 224.2(4)8, which is a conformation that lies nearly halfway
between a C(13) envelope and a half-chair twisted on C(3)ÀC(13). The amide H-atom
of each molecule acts as a donor for intermolecular H-bonds (Table 1). In molecule A,
this interaction is with the secondary amide O-atom of a neighboring molecule B. The
NH group of molecule B, in turn, interacts with the primary amide O-atom of a
different molecule A. The combination of these interactions links the molecules into
infinite chains in which both symmetry-independent molecules are incorporated in an
alternating ¥¥¥A¥¥¥B¥¥¥A¥¥¥B¥¥¥ sequence. These chains run parallel to the x-axis and
have a binary graph-set motif of C22(9).
Table 1. H-Bonding parameters for 13, 14, (R,S)-15, (S,S)-15, (R, S)-16, (S,S)-16, (S,R)-19, and (S,S)-19
a
DÀH ¥¥¥ A
)
DÀH [ä]
H ¥¥¥ A [ä]
D ¥¥¥ A [ä]
DÀH ¥¥¥ A [8]
13
14
N(4)ÀH(4) ¥¥¥ O(14i)
N(4)ÀH(4) ¥¥¥ O(32ii)
N(34)ÀH(34) ¥¥¥ O(5)
N(7)ÀH(7) ¥¥¥ S(5iii)
N(7)ÀH(7) ¥¥¥ S(5iii)
N(7)ÀH(7) ¥¥¥ O(5iv)
N(7)ÀH(7) ¥¥¥ O(5v)
N(4)ÀH(4) ¥¥¥ O(28vi)
0.81(1)
0.84(2)
0.87(3)
0.82(2)
0.86(1)
0.86(2)
0.82(2)
0.79(3)
0.86(2)
0.91(4)
0.83(4)
0.81(2)
0.85(2)
0.95
2,37(1)
2.05(3)
2.24(3)
2.84(2)
2.76(1)
2.10(2)
2.17(2)
2.07(3)
2.21(2)
1.81(4)
1.87(4)
2.00(2)
2.22(2)
1.72
3.136(2)
2.877(3)
3.092(3)
3.628(1)
3.590(1)
2.933(2)
2.974(2)
2.847(2)
3.049(2)
2.723(2)
2.680(3)
2.810(2)
3.056(2)
2.664(2)
2.737(2)
160(1)
168(2)
163(2)
164(1)
161(1)
163(2)
167(2)
170(2)
168(2)
176(4)
162(3)
173(2)
169(2)
172
(R,S)-15
(S,S )-15
(R,S)-16
(S,S )-16
(S,R )-19
N(7)ÀH(7) ¥¥¥ O(2vii
)
O(27)ÀH(27) ¥¥¥ O(8)
O(28)ÀH(28) ¥¥¥ O(27)
(S,S )-19
N(4)ÀH(4) ¥¥¥ O(27viii
N(7)ÀH(7) ¥¥¥ O(2ix)
)
O(27)ÀH(27) ¥¥¥ O(28)
O(28)ÀH(28) ¥¥¥ O(8)
0.95
1.80
171
a) Symmetry operators: i 1Àx, 1Ày, 1Àz; ii À1 ‡ x, y, z; iii 1Àx, 1/2 ‡ y, 3/2Àz; iv 1Àx, À1/2 ‡ y, 1/2Àz; v 2Àx,
vii
ix
À1/2 ‡ y, 1Àz; vi Àx, À1/2 ‡ y, 1Àz; Àx, 1/2 ‡ y, Àz; viii 2Àx, À1/2 ‡ y, Àz; 2Àx, 1/2 ‡ y, 1Àz.
The reactions with 7 resulted in mixtures of diastereoisomers, i.e., (R,S)/(S,S)-15
and (R,S)/(S,S)-16, which could be separated by means of MPLC. The X-ray crystal-
structure determinations of all four compounds were carried out (Fig. 3), and the
absolute configurations of (R,S)-15, (S,S)-15, and (S,S)-16 were determined inde-
4
)
The atom numbering used in crystal-structure determinations was chosen arbitrarily.

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Helvetica Chimica Acta Vol. 86 (2003)
Fig. 1. ORTEP Plots [31] of the molecular structures of a) 13 and b) molecule Aof 14 (50% probability
ellipsoids; arbitrary numbering of atoms)
pendently by the diffraction experiment, whereas, for (R,S)-16, the (R)-configuration
at the spiro-C(6)-atom4) was determined relative to the known (S)-configuration of the
proline moiety. The pyrrolidine ring of (R,S)-15 has a half-chair conformation (f2 ˆ
97.2(2)8) twisted on C(10)ÀC(11), but distorted significantly towards a C(11) envelope,
while the tetrahydrofuran ring has a C(6) envelope conformation (f2 ˆ 258.8(2)8)
distorted towards a half-chair twisted on C(6)ÀC(16). The NH group forms an
intermolecular H-bond with the S-atom of a neighboring molecule (Table 1). This
interaction links the molecules into infinite chains that run parallel to the y-axis and
have a graph-set motif of C(5) (Fig. 4). Both five-membered rings of the diastereoiso-
meric (S,S)-15 have slightly distorted half-chair conformations. The pyrrolidine ring
(f2 ˆ 94.6(2)8) is twisted on C(10)ÀC(11), while the tetrahydrofuran ring (f2 ˆ
164.7(2)8) is twisted on O(14)ÀC(15). The intermolecular H-bonding pattern is
analogous to that of (R,S)-15 (Table 1).
The pyrrolidine rings of (R,S)-16 and (S,S)-16 have nearly ideal half-chair
conformations (f2 ˆ 91.4(3) and 92.9(3)8, resp.) twisted on C(10)ÀC(11)4). The
tetrahydrofuran rings also have half-chair conformations (f2 ˆ 270.1(3) and 168.5(3)8,
resp.) twisted on C(6)ÀC(16) and O(14)ÀC(15), respectively, although the latter is
somewhat distorted towards an O(14) envelope conformation. In both cases, the amide
NH group forms an intermolecular H-bond with the O(5)-atom of the central amide
group of a neighboring molecule (Table 1). These interactions link the molecules into
infinite chains that run parallel to the y-axis and have a graph-set motif of C(5) (Figs. 5
and 6). The asymmetric unit of (S,S)-16 contains one molecule of the peptide and one
CDCl3 molecule.
2.3. Reactions with Amino Acids and Peptides. To examine the use of the new
synthons in peptide synthesis, 7 was reacted with Z-Leu-Aib-OH to give the

Helvetica Chimica Acta Vol. 86 (2003)
1377
Fig. 2. Crystal packing of 13, projected down the a-axis showing the H-bonding interactions (uninvolved H-
atoms omitted for clarity)
tetrapeptides 17a and 17b (Scheme 4), while 6 was reacted with Z-Ala-OH to yield the
dipeptides (S,R)-18 and (S,S)-18 (Scheme 5). The resulting mixtures of diastereoisom-
ers were separated by means of MPLC ((S,R)-18 and (S,S)-18) and HPLC (17a and
17b).
In the case of the dipeptides (S,R)-18 and (S,S)-18, it was shown that both the N-
and the C-termini can be deprotected selectively by standard methods. After
hydrogenolysis of the dipeptides (S,R)-18 and (S,S)-18 and reaction with 4-bromo-
benzoyl chloride, the crystalline derivatives (S,R)-19 and (S,S)-19, respectively, were
obtained. Their structures were established by X-ray crystallography (Fig. 7), and the
absolute configurations of the two molecules were determined independently by the
diffraction experiment. This confirmed the expected (S)-configurations of the proline

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Helvetica Chimica Acta Vol. 86 (2003)
Fig. 3. ORTEP Plots [31] of the molecular structures of a) (R,S)-15, b) (S,S)-15, c) (R,S)-16, and d) (S,S)-16
(50% probability ellipsoids; arbitrary numbering of atoms; the CDCl3 molecule in (S,S)-16 is not shown)
Scheme 4
O
O
Z-Leu-Aib-OH,
O
N
H
Z
N
N
CH2Cl2, 0° → r.t.
N
N
N
CO2Me
H
H
CO2Me
O
O
17a; 17b
7
residue, and the (R)- and (S)-configurations, respectively, at C(6)4). The knowledge of
the absolute configurations of (S,R)-19 and (S,S)-19 allowed the assignment of the
absolute configurations of all diastereoisomers isolated in this series (Scheme 5).
The asymmetric units of both (S,R)-19 and (S,S)-19 contain one peptide molecule
plus two molecules of MeOH. In the five-membered ring of (S,R)-19, the O-atom and
the adjacent CH2 group most distant from the spiro-C-atom are disordered. Two
positions were defined for each of the disordered atoms, and the model was refined

Helvetica Chimica Acta Vol. 86 (2003)
1379
Scheme 5
O
Me
N
O
Me
N
Z-Ala-OH, CH2Cl2,
0° → r.t.
O
H
N
Ph
Z
N
Ph
H
N
O
6
(S,R)-18, (S,S)-18
1. H2, Pd (10%) / C, MeOH, r.t.
2. BrC6H4COCl, CH2Cl2,
2. 0° → r.t.
3 M HCl (H2O/MeCN 1:1), r.t.
O
Br
O
O
O
Me
N
H
H
N
OH
N
Z
N
N
Ph
H
H
O
O
O
(R,S)-20, (S,S)-20
(S,R)-19, (S,S)-19
H-Phe-OtBu, TBTU,
HOBt, CH2Cl2,
0° → r.t.
O
O
H
N
H
t
N
CO2 Bu
Z
N
H
O
Ph
21
successfully, although restraints were required in order to maintain sensible behavior of
the disordered region. The major conformation exists in ca. 68% of the molecules that
clearly have the (R)-configuration at C(3)4). However, from a purely crystallographic
point of view, it is not entirely unequivocal whether the minor conformation also has
the (R)-configuration, and the disorder is due simply to conformational disorder of the
ring, or whether the minor conformation actually has the (S)-configuration at C(3),
and the disorder is the result of there being a mixture of diastereoisomers in the crystal.
If the disordered model is refined as a mixture of diastereoisomers without bond-length
restraints, the resultant geometric parameters are slightly better than when the model is
treated as a single diastereoisomer. However, the anisotropic displacement parameters
for the disordered atoms are better in the latter case. The R-factors for the two models
are essentially identical. The crystallographic results probably favor the model
representing a single diastereoisomer very slightly, but the evidence is weak.
Nevertheless, this conclusion is in agreement with the NMR evidence obtained from

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Helvetica Chimica Acta Vol. 86 (2003)
Fig. 4. Crystal packing of (R,S)-15, projected down the a-axis showing the H-bonding interactions (uninvolved
H-atoms omitted for clarity)
a solution made from the crystalline material, which shows that the batch from which
the crystal was taken contains only a single diastereoisomer. The two conformations of
the disordered tetrahydrofuran ring in (S,R)-19 have C(18a) and C(19) envelope
conformations (f2 ˆ 329.9(6) and 332(2)8, resp.) that are distorted towards half-chair
conformations twisted on O(17a)ÀC(18a) and O(3)ÀC(19), respectively. The O-atom
of the tetrahydrofuran ring of (S,S)-19 is also disordered over two orientations with the
major conformation being occupied in ca. 80% of the molecules. This leads to two
conformations of the ring (f2 ˆ 150.6(3) and 222.4(6)8) that represent C(18) and C(16)
envelopes distorted towards half-chair conformations twisted on O(17a)ÀC(18) and
C(16)ÀO(17b), respectively.
In both diastereoisomers, the central amide NH group of the peptide molecule
forms an intermolecular H-bond with the O-atom of an adjacent MeOH molecule. The

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1381
Fig. 5. Crystal packing of (R,S)-16, projected down the a-axis showing the H-bonding interactions (uninvolved
H-atoms omitted for clarity)
latter then forms an intermolecular H-bond with the O-atom of the other symmetry-
independent MeOH molecule, which, in turn, forms another intermolecular H-bond
with the O-atom of the bromobenzamide group of a second peptide molecule
(Table 1). The combination of these interactions generates infinite zig-zag chains
containing the ¥¥¥peptide¥¥¥MeOH(1)¥¥¥MeOH(2) ¥¥¥ peptide¥¥¥ sequence (Fig. 8).
These chains run parallel to the [010] direction and have a ternary graph-set motif of
C33(11). An additional intermolecular H-bond between the bromobenzamide NH and
the O-atom at the opposite end of an adjacent peptide molecule links just the peptide
molecules into additional infinite chains, which also run parallel to the [010] direction
and have a graph-set motif of C(8). The combination of all H-bonding interactions
links the peptide and MeOH molecules together into an infinite two-dimensional

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Helvetica Chimica Acta Vol. 86 (2003)
Fig. 6. Crystal packing of (S,S)-16, projected down the a-axis showing the H-bonding interactions (uninvolved
H-atoms omitted for clarity)
Fig. 7. ORTEP Plots [31] of the molecular structures of a) (S,R)-19 and b) (S,S)-19 (50% probability ellipsoids;
arbitrary numbering of atoms; only one of the disordered conformations is shown; the MeOH molecules are not
shown)
network that lies parallel to the (100) plane. Overall, aside from the inverse
configuration at the spiro-C-atom, the structures of (S,R)-19 and (S,S)-19 are
extremely similar in terms of molecular conformation, crystal packing, H-bond
properties, and unit-cell dimensions.
Selective hydrolysis of (S,R)-18 and (S,S)-18 with 3m HCl in H2O/MeCN 1:1 at
room temperature gave the dipeptide acids (R,S)-20 and (S,S)-20, respectively, in 75
and 84% yield (Scheme 5). A mixture of these two diastereoisomers was coupled with
H-Phe-OtBu using TBTU/HOBt, which led to the tripeptide 21 as a mixture of
diastereoisomers.

Helvetica Chimica Acta Vol. 86 (2003)
1383
Fig. 8. Crystal packing of (S,S)-19, projected down the a-axis showing the H-bonding interactions (uninvolved
H-atoms omitted for clarity)
No crystals suitable for an X-ray crystal-structure determination were obtained
from 17a and 17b. Therefore, the conformations of 17a and 17b were examined in
solution by NMR methods. To determine which of the NH groups of 17a and 17b are
involved in intramolecular H-bonds, the chemical shifts of the NH resonances were
measured in different CDCl3/(D6)DMSO mixtures (solvent-titration experiment) and
at different temperatures (Fig. 9). The NH groups involved in intramolecular H-bonds
should show a very small dependence, whereas the chemical shifts of solvent-exposed
NH groups are influenced more significantly [32][33]. For the assignment of the NH
resonances, 2D-NMR experiments were performed. Surprisingly, no significant differ-
ences could be observed in the temperature dependence of the NH shifts. However,
significant differences were observed in the solvent-titration experiment: the very small
dependency of the NH(Thf) resonance on the CDCl3/(D6)DMSO ratio, compared with
the other NH resonances, strongly indicates the presence of an intramolecular H-bond.
Most likely, the acceptor is the O-atom of the urethane group, as this interaction leads
to the formation of a ten-membered ring, i.e., a b-turn (Fig. 9; cf. also [34][35]).

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Helvetica Chimica Acta Vol. 86 (2003)
Fig. 9. a) Solvent and b) temperature dependence of the NH shifts of 17a and 17b

Helvetica Chimica Acta Vol. 86 (2003)
1385
However, because all attempts to determine the crystal structure failed, and NOE
measurements concerning the configuration at the spiro-C-atom brought no clear
results, the configurations of 17a and 17b still remain in doubt.
2.4. Favored Torsion Angles of the Thf Residue. The torsion angles f, y, and w
(Fig. 10) of the synthesized peptides containing the Thf residue are listed in Table 2 ; the
data come from the X-ray crystal-structure determinations. The values of the torsion
angles fi and yi of 13, 14, (S,S)-16, (S,R)-19, and (S,S)-19, correspond to the values
expected for a b-turn of type I' or III' (I or III for molecule A of 14). In (R,S)-15, (S,S)-
15, and (R,S)-16, they correspond to the values expected for a left-handed a-helix. Such
short sequences containing proline as a −helix-breaking× amino acid do not allow exact
classifications. However, it is clear that the amino acid Thf prefers helical conforma-
tions (a b-turn of type III or III', respectively, corresponds to a part of a 310 helix), as
expected for a,a-disubstituted amino acids. The amide bonds are almost planar as the
torsion angles w show. As mentioned above, the formation of a b-turn has also been
observed for 17a and 17b in solution.
Fig. 10. Torsion angles of the Thf residue in a peptide backbone
Table 2. Torsion Angles [8] within the Backbone of 13, 14, (R,S)-15, (S,S)-15, (R,S)-16, (S,S)-16, (S,R)-19, and
(S,S)-19
fiÀ1
yiÀ1
wiÀ1
fi
yi
wi
fi‡1
yi‡1
13
14A
14B
(R,S)-15
(S,S)-15
(R,S)-16
(S,S)-16
58.4(2)
37.1(2)
174.6(1)a)
176.9(2)a)
174.0(2)a)
174.1(1)
175.5(1)
180.0(1)
À 61.7(3) À 24.9(3)
60.0(3)
63.5(2)
66.3(2)
54.8(2)
62.2(2)
56.4(2)
56.7(3)
37.3(3)
49.0(2)
47.4(2)
46.1(2)
37.5(3)
À 60.7(2) À 30.4(2)
À 60.6(2) À 32.2(2)
À 67.7(2) 156.9(1)
À 61.2(2) À 40.1(2)
176.0(2)
(S,R)-19 À 149.03(17) 151.11(15) 176.22(15)
29.2(2) À 178.66(16)a)
(S,S)-19 À 150.1(2) 147.5(2) 177.0(2)
30.9(3)
178.8(2)a)
a) Torsion angle C(3)ÀC(2)ÀN(1)À(Me).
3. Conclusions. We have shown that 2H-azirin-3-amines 6 and 7 can be prepared
and, in principle, separated into stereochemically pure compounds. These azirines are
Thf and Thf-Pro building blocks, which can be introduced conveniently into a peptide
chain by the −azirine/oxazolone method×. The conformational characteristics of Thf
within peptide backbones are comparable with those of other a,a-disubstituted a-
amino acids.

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Helvetica Chimica Acta Vol. 86 (2003)
We thank the analytical sections of our institute for spectra and elemental analyses, especially Miss Nadja
Walch for numerous NMR measurements, and Miss Jovita Cavegn for her assistance with the determination of
the crystal structures. Financial support of the Swiss National Science Foundation and F. Hoffmann-La Roche
AG, Basel, is gratefully acknowledged.
Experimental Part
1. General. Solvents were purified by standard procedures. TLC: Merck TLC aluminum sheets, silica gel 60
F254. Prep. TLC: Merck PLC plates (glass), silica gel 60 F254, 2 mm. Column chromatography (CC): Uetikon-
Chemie, silica gel C-560 (0.04 0.063 mm, 230 400 mesh). Medium-pressure liquid chromatography (MPLC):
Merck LiChroprep Si 60, 15 25 mm; column: Kron-Lab 4/98 PRO, 48 0Â 30 mm or Labomatic, 38 0Â 20 mm.
High-performance liquid chromatography (HPLC): column: Chiracel-OD, 250 Â 4.6 mm, 5 mm or Macherey-
Nagel Nucleosil 100-7, 250 Â 4.6 mm, 7 mm; or (reversed phase) Macherey-Nagel Nucleosil 100-7 C8, 250 Â
4.6 mm, 7 mm; detection (DAD) at l ˆ 220 nm. Prep. HPLC: column: Macherey-Nagel Nucleosil 100-7, 250 Â
21 mm, 7 mm; detection (DAD) at l ˆ 254 nm. M. p.: B¸chi Melting Point B-450 apparatus; uncorrected. IR
Spectra: Perkin-Elmer, Spectrum one FT-IR spectrophotometer; in KBr unless otherwise stated; absorptions in
cmÀ1. NMR Spectra: Bruker AC-300 (1H, 13C, DEPT) at 300 and 75 MHz, resp., or Bruker DRX-600 (1H, 13C,
HSQC, HMBC, COSY, NOESY) at 600 and 150 MHz, resp., in CDCl3 at 300 K unless otherwise stated; d in
ppm, coupling constants J in Hz; 13C-signal multiplicity from DEPT spectra. MS: Finnigan MAT-90 (EI, CI),
Finnigan SSQ-700 (EI, CI), or Finnigan TSQ-700 instrument (ESI); m/z (rel.%). GC/MS: Hewlett Packard HP-
5890 Series II (GC) / Hewlett Packard HP-5971 Series (EI-MS).
2. Synthesis of the 2H-Azirin-3-amines. 2.1. N-Methyl-N-phenyl-5-oxa-1-azaspiro[2.4]hept-1-en-2-amine
(6). 2,3,4,5-Tetrahydrofuran-3-carboxylic acid (8). To a soln. of furan-3-carboxylic acid (5.006 g, 44.67 mmol) in
100% AcOH (60 ml), Pd/C (10%, 0.308g) was added. The mixture was shaken for 1 d at r.t. in a hydrogenation
apparatus (3.5 atm H2), then left standing for additional 1.5 d. The suspension was filtered over Celite, and the
filtrate was concentrated. Short-path distillation yielded 8 (4.902 g, 95%). Colorless liquid. GC/MS: tR 4.29 min,
m/z 116. IR (film): 2984vs, 2884vs, 2647vs, 1956w, 1732vs, 1712vs, 1454s, 1417vs, 1371s, 1327vs, 1285vs, 1212vs,
1064vs, 965s, 904vs, 679s. 1H-NMR (300 MHz): 9.35 (br. s, COOH); 4.04 3.80 (m, 2 CH2O); 3.19 3.09 (m,
CH); 2.30 2.11 (m, CH2CH2O). 13C-NMR (75 MHz): 179.4 (s, CO2H); 70.0, 68.1 (2t, 2 CH2O); 43.5 (d, CH);
‡
29.3 (t, CH2CH2O). CI-MS (NH3): 135 (6), 134 (100, [M ‡ NH4] ).
2,3,4,5-Tetrahydro-N-methyl-N-phenylfuran-3-carboxamide (11). A mixture of 8 (2.003 g, 17.25 mmol) and
SOCl2 (1.9 ml, 26.11 mmol) was heated under reflux for 1 h. Then, excess SOCl2 was removed by distillation
(508/20 mbar). The residue was dissolved in CH2Cl2 (20 ml), and Et3N (2.7 ml, 19.34 mmol) and N-
methylaniline (2.1 ml, 19.30 mmol) were added at 08. The mixture was slowly warmed to r.t., stirred for 3 h,
and then concentrated. The residue was dispersed in Et2O, filtered, and the filtrate was concentrated. CC
(hexane/AcOEt 5 :1) yielded 11 (2.764 g, 78%). An almost colorless liquid. TLC (hexane/AcOEt 1:2): Rf 0.27
(UV254). GC/MS: tR 9.69 min, m/z 205. B.p. 1258/10À2 mbar. IR (film): 3563w, 3503w, 3296w, 3061m, 2977s, 2948s,
2869s, 1968w, 1734w, 1660vs, 1596vs, 1496vs, 1453s, 1424vs, 1391vs, 1336s, 1320m, 1290s, 1264s, 1210w, 1174w,
1125vs, 1068vs, 919s, 776s, 703vs. 1H-NMR (300 MHz): 7.47 7.34 (m, 3 arom. H); 7.19 7.15 (m, 2 arom. H);
3.91 3.69 (m, 2 CH2O); 3.28( s, Me); 2.93 (quint., J ˆ 8.1, CH); 2.27 2.16, 1.88 1.80 (2m, CH2CH2O).
13C-NMR (75 MHz): 173.2 (s, CO); 143.7 (s, 1 arom. C); 129.8, 127.9, 127.3 (3d, 5 arom. CH); 71.3, 68.5 (2t,
‡
2 CH2O); 42.0 (d, CH); 37.5 (q, Me); 30.9 (t, CH2CH2O). CI-MS (NH3): 207 (12), 206 (100, [M ‡ H] ). Anal.
calc. for C12H15NO2 (205.25): C 70.22, H 7.37, N 6.82; found: C 69.94, H 7.24, N 6.74.
2,3,4,5-Tetrahydro-N-methyl-N-phenylfuran-3-thiocarboxamide (12). A suspension of Lawesson reagent
(dried i.v., 1.780 g, 4.401 mmol) and 11 (1.502 g, 7.318mmol) in toluene (15 ml) was heated at 95 8 (oilbath) for
1 h. After cooling to r.t., the mixture was filtered, and the solvent was evaporated. CC (hexane/AcOEt 5 :1)
yielded 12 (1.356 g, 84%). Yellow oil. TLC (hexane/AcOEt 5 :1): Rf 0.18(UV 254, −Schlittler×). IR (film): 3055w,
2975w, 2867w, 1594w, 1493vs, 1469vs, 1385vs, 1364w, 1338w, 1317w, 1274w, 1215w, 1180w, 1171w, 1103m, 1073m,
1049m, 1002w, 8 06w, 912w, 774m, 701s. 1H-NMR (300 MHz): 7.51 7.39 (m, 3 arom. H); 7.16 7.14 (m, 2 arom.
H); 4.02 3.94, 3.94 3.69 (2m, 2 CH2O); 3.73 (s, Me); 3.23 (quint., J ˆ 8.3, CH); 2.50 2.39, 1.96 1.87 (2m,
CH2CH2O). 13C-NMR (75 MHz): 206.4 (s, CS); 145.6 (s, 1 arom. C); 130.1, 128.6, 125.5 (3d, 5 arom. CH); 75.8,
68.8 (2t, 2 CH2O); 49.3 (d, CH); 45.8( q, Me); 35.4 (t, CH2CH2O). CI-MS (NH3): 224 (6), 223 (15), 222 (100,
‡
[M ‡ H] ). Anal. calc. for C12H15NOS (221.32): C 65.12, H 6.83, N 6.33, S 14.49; found: C 65.42, H 6.88, N 6.59, S
14.27.

Helvetica Chimica Acta Vol. 86 (2003)
1387
Compound 6. A COCl2 soln. in toluene (20%, 7.5 ml, 14.18mmol) was added to a soln. of 12 (1.255 g,
5.671 mmol) and 3 drops of DMF in CH2Cl2 (20 ml) at 08, the mixture was stirred for 2 h at 08, then the volatiles
were removed under reduced pressure. The residue was dissolved in THF (15 ml), DABCO (0.640 g,
5.705 mmol) was added, and the mixture was stirred at r.t. for 20 min. The solid was removed by filtration under
N2 and washed with THF. To the filtrate, NaN3 (1.106 g, 17.01 mmol) and DMF (30 ml) were added, and the
THF was removed by distillation. The mixture was stirred at r.t. for 8d. After addition of Et 2O, the resulting
suspension was filtered over a Celite pad, and the solvent was removed i.v. CC (hexane/AcOEt 1:1) yielded a
mixture of 6 and 11 (11%). The yield of pure 6 (pale yellow oil), considering 11% 11, was 0.717 g (63%). Pure 6
for analysis was obtained by means of MPLC (hexane/AcOEt 1:2). TLC (hexane/AcOEt 1:1): Rf 0.18(UV 254
,
Ce(SO4)2). HPLC (Chiracel OD, hexane/i-PrOH 25 :1, 1 ml/min; enantiomers): tR(A) 13.9 min; tR(B) 15.4 min.
IR (film): 3480w, 3064w, 3046w, 2958m, 2921m, 2855s, 1761vs (n(C ˆ N)), 1647m, 1600s, 1502s, 1459m, 1421m,
1361w, 1333s, 1285s, 1221m, 1188m, 1156m, 1110s, 1078s, 1056s, 1034s, 1004s, 990m, 962m, 913m, 756s, 693s, 674s.
1H-NMR (300 MHz): 7.42 7.04 (m, 5 arom. H); 4.18 4.03 ( m, CH2CH2O); 3.83, 3.58 (AB, J ˆ 10.3, CH2O);
3.47 (s, Me); 2.26 2.16, 1.88 1.80 (2m, CH2CH2O). 13C-NMR (75 MHz): 158.6 (s, C(2)); 142.2 (s, 1 arom. C);
129.7, 123.6, 116.2 (3d, 5 arom. CH); 72.4, 68.3 (2t, 2 CH2O); ca. 52 (br., C(3)); 34.9 (t, CH2CH2O); ca. 34 (br.,
‡
Me). CI-MS (NH3): 204 (14), 203 (100, [M ‡ H] ). Anal. calc. for C12H14N2O (202.25): C 71.26, H 6.98, N 13.85;
found: C 70.99, H 6.75, N 13.87.
2.2. N-(5-Oxa-1-azaspiro[2.4]hept-1-en-2-yl)-(S)-proline Methyl Ester (7). N-[(2,3,4,5-Tetrahydrofuran-3-
yl)carbonyl]-(S)-proline Methyl Ester (9). A mixture of 8 (4.013 g, 34.55 mmol) and SOCl2 (3.8ml,
52.22 mmol) was heated under reflux for 75 min. Then, excess SOCl2 was removed by distillation (408/
20 mbar). The residue was dissolved in CH2Cl2 (30 ml), and Et3N (10.6 ml, 76.16 mmol) and H-Pro-OMe ¥ HCl
(6.314 g, 38.12 mmol) were added at 08. The mixture was slowly warmed to r.t., stirred for 18h, and then
concentrated. The residue was dispersed in Et2O, filtered, and the filtrate was concentrated. CC (AcOEt)
yielded 9 (5.558g, 71%). An almost colorless oil. TLC (AcOEt): Rf 0.17 (KMnO4). GC/MS: tR 10.69 min, m/z
227. IR (film): 3577w, 3488w, 2956s, 2876m, 1746vs, 1647vs, 1435vs, 1366m, 1339m, 1314m, 1281m, 1199vs, 1176vs,
1092m, 1066m, 1028w, 999w, 970w, 919m, 721w. 1H-NMR (300 MHz; diastereoisomers): 4.53 4.47 (m,
CH(a)(Pro)); 4.12 3.78( m, 2 CH2O(Thf)); 3.73, 3.72 (s, MeO); 3.71 3.53 (m, CH2(d)(Pro)); 3.22 3.15,
2.98 2.86 ( m, CH(Thf)); 2.29 1.91 (m, CH2(b)(Pro), CH2(g)(Pro), CH2CH2O(Thf)). 13C-NMR (75 MHz;
diastereoisomers): 172.8, 172.7, 172.0, 171.9 (4s, 2 CO); 70.4, 70.2, 68.6, 68.4 (4t, 2 CH2O(Thf)); 59.4, 58.9 (2d,
CH(a)(Pro)); 52.2 (q, MeO); 47.0 (t, CH2(d)(Pro)); 43.0 (d, CH(Thf)); 30.0, 29.6 (2t, CH2CH2O(Thf)); 29.1 (t,
‡
CH2(b)(Pro)); 24.8( t, CH2(g)(Pro)). CI-MS (NH3): 229 (13), 228(100, [ M ‡ H] ), 203 (12). Anal. calc. for
C11H17NO4, (227.26): C 58.14, H 7.54, N 6.16; found: C 58.44, H 7.42, N 6.29.
N-[(2,3,4,5-Tetrahydrofuran-3-yl)thiocarbonyl]-(S)-proline Methyl Ester (10). A suspension of Lawesson
reagent (dried i.v., 5.882 g, 14.54 mmol) and 9 (5.493 g, 24.17 mmol) in toluene (30 ml) was heated at 958 (oil-
bath) for 1 h. After cooling to r.t., the mixture was filtered, and the solvent was evaporated. CC (hexane/AcOEt
1:2) yielded 10 (4.910 g, 84%). Yellow oil. TLC (hexane/AcOEt 1:2; diastereoisomers): Rf(A) 0.28, Rf(B) 0.35
(−Schlittler×). GC/MS (diastereoisomers): tR(A) 12.99 min, m/z 243, tR(B) 12.95 min, m/z 243. IR (film): 3593w,
3470w, 2977s, 2953s, 2875s, 1744vs, 1465vs, 1445vs, 1350s, 1272vs, 1205vs, 1130m, 1087s, 1054s, 1002m, 973m,
914m, 8 8w5, 8 48w, 791w, 747w. 1H-NMR (300 MHz; diastereoisomers): 5.08 5.04, 4.81 4.72 (2 m, CH(a)-
(Pro)); 4.17 3.76 (m, CH2(d)(Pro), 2 CH2O(Thf)); 3.74, 3.73 (2s, MeO); 3.53 3.45, 3.30 3.18(2 m, CH(Thf));
2.54 2.03 (m, CH2(b)(Pro), CH2(g)(Pro), CH2CH2O(Thf)). 13C-NMR (75 MHz; diastereoisomers): 203.2 (s,
CS); 170.8( s, CO); 73.6, 73.2, 68.7, 68.4 (4t, 2 CH2O(Thf)); 65.4 (d, CH(a)(Pro)); 52.2 (q, MeO); 50.8( t,
CH2(d)(Pro)); 49.4, 49.3 (2d, CH(Thf)); 33.8, 33.4 (2t, CH2CH2O(Thf)); 28.7 (t, CH2(b)(Pro)); 24.6 (t,
‡
CH2(g)(Pro)). CI-MS (NH3): 246 (6), 245 (14), 244 (100, [M ‡ H] ), 225 (10). Anal. calc. for C11H17NO3S
(243.32): C 54.30, H 7.04, N 5.76, S 13.18; found: C 54.24, H 7.25, N 5.60, S 13.34.
Compound 7. A COCl2 soln. in toluene (20%, 6.5 ml, 12.29 mmol) was added to a soln. of 10 (1.196 g,
4.917 mmol) and 3 drops of DMF in CH2Cl2 (16 ml) at 08, the mixture was stirred for 45 min at 08, and then the
volatiles were removed under reduced pressure. The residue was dissolved in THF (15 ml), DABCO (0.562 g,
5.010 mmol) was added, and the mixture was stirred at r.t. for 20 min. The solid was removed by filtration under
N2 and washed with THF. To the filtrate, NaN3 (0.973 g, 14.97 mmol) was added, and the resulting mixture was
stirred at r.t. for 72 h. After addition of Et2O, the resulting suspension was filtered over a Celite pad, and the
solvent removed i.v. CC (SiO2; inactivated with Et3N, AcOEt/Et3N 100 :1) yielded 7 (0.697 g, 63%). Pale yellow
oil. TLC (AcOEt): Rf 0.16 (−Schlittler×). HPLC (Chiracel OD, hexane/i-PrOH 12 :1, 1 ml/min; diastereoisom-
ers): tR(A) 14.4 min; tR(B) 17.6 min; HPLC (normal phase, CH2Cl2/Et2O/MeOH 70 :30 :0.5, 1 ml/min;
diastereoisomers): tR(A) 11.3 min; tR(B) 11.7 min; HPLC (reversed phase, MeCN/H2O 10 :90, 1 ml/min;
diastereoisomers): tR(A) 23.5 min; tR(B) 24.2 min. IR (film): 3468w, 2955m, 2876m, 2856m, 1780vs, 1744vs,

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Helvetica Chimica Acta Vol. 86 (2003)
1665w, 1437m, 1418w, 1364m, 1346m, 1327w, 1282m, 1214vs, 1175vs, 1092w, 1077w, 1052s, 998w, 963w, 913m,
867w, 759w, 730w. 1H-NMR (300 MHz; diastereoisomers): 4.34 (br. s, CH(a)(Pro)); 4.10 4.02, 3.96 3.92 (2m,
2 H of CH2(d)(Pro), 2 CH2O(Thf)); 3.75 (s, MeO); 3.72 3.44 (m, 4 H of CH2(d)(Pro), 2 CH2O(Thf)); 2.37
2.00, 1.77 1.69 (2m, CH2(b)(Pro), CH2(g)(Pro), CH2CH2O (Thf)). 13C-NMR (75 MHz; diastereoisomers):
172.2 (s, CO), 156.7 (s, C(2)); 72.2, 68.3, 68.2 (3t, 2 CH2O(Thf)); 60.9 (d, CH(a)(Pro)); 52.5 (q, MeO); 48.2 (s,
C(3)); 47.1 (d, CH2(d)(Pro)); 34.6, 34.5 (2t, CH2CH2O (Thf)); 30.3 (t, CH2(b)(Pro)); 24.1 (t, CH2(g)(Pro)). EI-
.
‡
‡
‡
MS: 224 (22, M ), 195 (80, [M À CH2O ‡ H] ), 165 (41, [M À CO2Me] ), 122 (22), 70 (100, [pyrrolidine À
‡
H] ), 68(27), 55 (50), 41 (29). Anal. calc. for C 11H16N2O3 (224.26): C 58.91, H 7.19, N 12.49; found: C 59.06, H
7.33, N 12.40.
3. Reactions of 6 and 7 with PhCOSH and PhCOOH. 3.1. Reactions of 6. N-(2,3,4,5-Tetrahydro-3-
{[(methyl)(phenyl)amino]thiocarbonyl}furan-3-yl)benzamide (13). A soln. of PhCOSH (28mg, 0.203 mmol) in
CH2Cl2 (3 ml) was added to a soln. of 6 (36 mg, 0.176 mmol) in CH2Cl2 (2 ml) at 08. The mixture was stirred at
r.t. for 19 h, the solvent was evaporated, and the yellow, powdery crude product was purified by prep. TLC
(hexane/AcOEt 1:1). Recrystallization from CHCl3/Et2O yielded 13 (61 mg, 99%) as colorless prisms, which
were suitable for X-ray crystal-structure determination. TLC (hexane/AcOEt 1:1): Rf 0.29 (UV254, −Schlittler×).
M.p. 200 2018. IR: 3370s, 3057w, 2974w, 2921w, 2876w, 1657vs, 1593m, 1582m, 1526vs, 1490vs, 1466vs, 1432s,
1377vs, 1289s, 1248m, 1168w, 1129m, 1101vs, 1074m, 1051s, 1024w, 977w, 925w, 8 99w, 8 05w, 774m, 707vs, 691m.
1H-NMR (300 MHz): 7.50 7.04 (m, 10 arom. H); 5.71 (br. s, NH); 4.52 (part of AB, J ˆ 9.4, 1 H of CH2O);
4.04 3.86 (m, CH2CH2O, 1 H of CH2O); 3.72 (s, Me); 3.44 3.34, 2.36 2.04 (2m, CH2CH2O). 13C-NMR
(75 MHz): 202.7 (s, CS); 165.7 (s, CO); 147.0, 133.3 (2s, 2 arom. C); 131.7, 129.5, 128.3, 128.0, 126.8, 125.4 (6d,
10 arom. CH); 80.0 (t, CH2O); 71.8( s, C(a)(Thf)); 67.8( t, CH2O); 50.0 (q, Me); 42.9 (t, CH2CH2O). CI-MS
‡
‡
(NH3): 342 (23), 341 (100, [M ‡ H] ), 220 (26, [M À PhCONH] ), 139 (15). Anal. calc. for C19H20N2O2S
(340.44): C 67.03, H 5.92, N 8.23, S 9.42; found: C 67.07, H 5.91, N 8.08, S 9.47.
N-(2,3,4,5-Tetrahydro-3-{[(methyl)(phenyl)amino]carbonyl}furan-3-yl)benzamide (14).
A soln. of
PhCO2H (53 mg, 0.434 mmol) in CH2Cl2 (3 ml) was added to a soln. of 6 (71 mg, 0.352 mmol) in CH2Cl2
(2 ml) at 08. The mixture was stirred at r.t. overnight, and the solvent was evaporated. Prep. TLC (hexane/
AcOEt 1:2) yielded 14 (110 mg, 95%) as a colorless powder. Suitable crystals for the X-ray crystal-structure
determination were grown from CHCl3/Et2O. TLC (hexane/AcOEt 1:2): Rf 0.18(UV 254, Ce(SO4)2). M.p. 166
1678. IR: 3356w, 3280m, 3062w, 2971w, 2946w, 2862w, 1646vs, 1594vs, 1528vs, 1496vs, 1449m, 1380s, 1291m,
1220w, 1166w, 1100m, 1075m, 1065m, 1028w, 969w, 8 02w, 930w, 776w, 703s. 1H-NMR (300 MHz): 7.50 7.03 (m,
10 arom. H); 5.63 (br. s, NH); 4.26 (part of AB, J ˆ 9.5, 1 H of CH2O); 3.98 3.86 ( m, CH2CH2O, 1 H of CH2O);
3.28( s, Me); 3.11 3.01, 2.24 2.16 (2m, CH2CH2O). 13C-NMR (75 MHz): 169.3, 166.2 (2s, 2 CO); 144.0, 133.2
(2s, 2 arom. C); 131.7, 129.4, 128.2, 127.5, 126.9, 128.8 (6d, 10 arom. CH); 77.2, 67.5 (2t, 2 CH2O); 67.2 (s,
‡
C(a)(Thf)); 40.4 (q, Me); 38 .9 (t, CH2CH2O). CI-MS (NH3): 326 (22), 325 (100, [M ‡ H] ), 218(32, [ M À
‡
‡
N(Me)Ph] ), 108(35, [H 2N(Me)Ph] ). Anal. calc. for C19H20N2O3 (324.37): C 70.35, H 6.21, N 8.64; found: C
70.50, H 6.33, N 8.58.
3.2. Reactions of 7. N-{[(R)-3-(Benzoylamino)-2,3,4,5-tetrahydrofuran-3-yl]thiocarbonyl}-(S)-proline
Methyl Ester ((R,S)-15) and N-{[(S)-3-(Benzoylamino)-2,3,4,5-tetrahydrofuran-3-yl]thiocarbonyl}-(S)-proline
Methyl Ester ((S,S)-15). A soln. of PhCOSH (68mg, 0.492 mmol) in CH 2Cl2 (2 ml) was added to a soln. of 7
(101 mg, 0.450 mmol) in CH2Cl2 (3 ml) at 08. The mixture was stirred at r.t. for 52 h, and the solvent was
evaporated. Prep. TLC (AcOEt/Et3N 100 :3) yielded 15 (147 mg (90%) as
a colorless foam. The
diastereoisomers were separated by MPLC (CH2Cl2/MeOH 40 :1). Suitable crystals for the X-ray crystal-
structure determination of both diastereoisomers were grown from CH2Cl2/CHCl3/(i-Pr)2O.
Data of (R,S)-15. TLC (CH2Cl2/MeOH 40 :1): Rf 0.34 (UV254, −Schlittler×). M.p. 181 1838. IR: 3325m,
3056w, 2975m, 2951m, 2876m, 1742vs, 1643vs, 1602m, 1579m, 1524vs, 1487s, 1427vs, 1345s, 1287s, 1201vs, 1152s,
1086m, 1064s, 1001w, 970w, 927w, 914w, 8 04w, 717s, 695m. 1H-NMR (300 MHz): 7.83 7.81 (m, 2 arom. H); 7.55
7.41 (m, 3 arom. H, NH); 5.30 5.14 (m, CH(a)(Pro)); 4.33 4.10, 4.04 3.96 (2m, CH2(d)(Pro), 2 CH2O(Thf));
3.57 (s, MeO); 3.20 3.09, 2.67 2.59, 2.27 2.11, 2.07 1.99 (4m, CH2(b)(Pro), CH2(g)(Pro), CH2CH2O(Thf)).
13C-NMR (75 MHz): 200.3 (s, CS); 170.9 (s, OÀCˆO); 166.2 (s, PhÀCˆO); 133.8( s, 1 arom. C); 131.8, 128.6,
126.9 (3d, 5 arom. CH); 75.8( t, CH2O(Thf)); 71.4 (s, C(a)(Thf)); 68.5 (t, CH2O(Thf)); 68.4 (d, CH(a)(Pro));
52.6 (t, CH2(d)(Pro)); 52.1 (q, MeO); 40.3 (t, CH2CH2O(Thf)); 27.9 (t, CH2(b)(Pro)); 25.7 (CH2(g)(Pro)). ESI-
‡
‡
‡
MS: 747 (24, [2M ‡ Na] ), 390 (29), 385 (100, [M ‡ Na] ), 363 (27, [M ‡ H] ).
Data of (S,S)-15. TLC (CH2Cl2/MeOH 40 :1): Rf 0.29 (UV254, −Schlittler×). M.p. 132 1358. IR: 3316m,
2979m, 2952m, 2878m, 1742vs, 1643vs, 1602m, 1579m, 1524vs, 1488s, 1427vs, 1346s, 1289s, 1246s, 1201vs, 1151s,
1060s, 1027w, 1001m, 968m, 927w, 8 8 w9, 8 05w, 717m, 695m. 1H-NMR (300 MHz): 7.82 7.78 (m, 2 arom. H);
7.53 7.39 (m, 3 arom. H); 7.31 (br. s, NH); 5.30 5.10 (m, CH(a)(Pro)); 4.65, 4.29 (AB, J ˆ 9.7, CH2O(Thf));

Helvetica Chimica Acta Vol. 86 (2003)
1389
4.24 4.07, 4.01 3.95 (2m, CH2CH2O(Thf), CH2(d)(Pro)); 3.73 (s, MeO); 2.65 2.59, 2.25 2.14, 2.07 1.95
(3m, CH2(b)(Pro), CH2(g)(Pro), CH2CH2O(Thf)). 13C-NMR (75 MHz): 200.1 (s, CS); 170.9 (s, OÀCˆO);
166.3 (s, PhÀCˆO); 133.7 (s, 1 arom. C); 131.8, 128.6, 127.0 (3d, 5 arom. CH); 78.9 (t, CH2O(Thf)); 70.6 (s,
C(a)(Thf)); 68.0 (t, CH2O(Thf)); 67.8( d, CH(a)(Pro)); 52.9 (t, CH2(d)(Pro)); 52.1 (q, MeO); 37.8( t,
‡
CH2CH2O(Thf)); 27.9 (t, CH2(b)(Pro)); 25.7 (CH2(g)(Pro)). CI-MS (NH3): 364 (21), 363 (100, [M ‡ H] ), 331
‡
(34, [M À MeO] ).
N-{[(R)-3-(Benzoylamino)-2,3,4,5-tetrahydrofuran-3-yl]carbonyl}-(S)-proline Methyl Ester ((R,S)-16)
and N-{[(S)-3-(Benzoylamino)-2,3,4,5-tetrahydrofuran-3-y l]carbonyl}-(S)-proline Methyl Ester ((S,S)-16). A
soln. of PhCO2H (60 mg, 0.491 mmol) in CH2Cl2 (3 ml) was added to a soln. of 7 (98mg, 0.437 mmol) in CH 2Cl2
(3 ml) at 08. The mixture was stirred at r.t. for 16 h, and the solvent was evaporated. Then, AcOEt was added to
the residue, and the resulting precipitate was filtered, to yield 16 (132 mg, 87%). Colorless powder. The
diastereoisomers were separated by MPLC (CH2Cl2/MeOH 40 :1). Suitable crystals for the X-ray crystal-
structure determination of both diastereoisomers were grown from CHCl3/Et2O ((R,S)-16) and CDCl3 ((S,S)-
16), resp.
Data of (R,S)-16. TLC (AcOEt): Rf 0.18(UV 254, −Schlittler×). M.p. 223 2258. IR: 3324s, 3047w, 2980w,
2954m, 2885w, 2871m, 1745vs, 1654vs, 1620vs, 1579m, 1530vs, 1491s, 1433s, 1370m, 1297s, 1218s, 1204s, 1179s,
1157m, 1091w, 1059m, 1039w, 912w, 8 99w, 768w, 731m, 719m, 695m. 1H-NMR (300 MHz): 7.83 7.79 (m, 2 arom.
H); 7.53 7.39 (m, 3 arom. H, NH); 4.62 4.58( m, CH(a)(Pro)); 4.26 4.01, 3.78 3.57 (2 m, CH2(d)(Pro),
2 CH2O(Thf)); 3.71 (s, MeO); 3.03 2.93, 2.37 2.29, 2.14 1.90 (3m, CH2(b)(Pro), CH2(g)(Pro),
CH2CH2O(Thf)). 13C-NMR (75 MHz): 172.8, 169.3 (2s, 2 CO); 166.4 (s, PhCO); 133.5 (s, 1 arom. C); 131.8,
128.5, 127.0 (3d, 5 arom. CH); 74.1, 68.4 (2t, 2 CH2O(Thf)); 67.0 (s, C(a)(Thf)); 60.7 (d, CH(a)(Pro)); 52.0 (q,
MeO); 47.5 (t, CH2(d)(Pro)); 37.2 (t, CH2CH2O(Thf)); 27.8( t, CH2(b)(Pro)); 25.5 (t, CH2(g)(Pro)). ESI-MS:
‡
‡
‡
715 (11, [2M ‡ Na] ), 385 (10, [M ‡ K] ), 374 (91, [(M À Pro-OMe) ‡ (M À PhCONH(Thf))] ), 369 (100,
‡
‡
[M ‡ Na] ), 366 (41), 347 (48, [M ‡ H] ), 130 (31), 102 (38). Anal. calc. for C18H22N2O5 (346.38): C 62.42, H
6.40, N 8.09; found: C 62.45, H 6.57, N 8.08.
Data of (S,S)-16. TLC (AcOEt): Rf 0.16 (UV254, −Schlittler×). M.p. 225 2268. IR: 3324s, 3064w, 2983m,
2951m, 2876m, 2854m, 1748vs, 1659vs, 1615vs, 1580m, 1525vs, 1488s, 1447s, 1421vs, 1364s, 1307s, 1210vs, 1197s,
1178vs, 1067s, 936w, 927w, 747w, 731m, 696m. 1H-NMR (300 MHz): 7.84 7.81 (m, 2 arom. H); 7.56 7.38( m,
3 arom. H, NH); 4.59 4.54 (m, CH(a)(Pro), 1 H of CH2(b)(Pro), 2 CH2O(Thf)); 4.22 4.10, 4.09 3.95, 3.88
3.95 (3m, 4 H of CH2(d)(Pro), 2 CH2O(Thf)); 3.70 (s, MeO); 3.58 3.50 ( m, 1 H of CH2(d)(Pro),
2 CH2O(Thf)); 2.59 2.44, 2.09 1.86 (2m, CH2(b)(Pro), CH2(g)(Pro), CH2CH2O(Thf)). 13C-NMR
(75 MHz): 172.8, 169.8 (2s, 2 CO); 166.5 (s, PhCO); 133.3 (s, 1 arom. C); 131.8, 128.5, 127.1 (3d, 5 arom.
CH); 76.1, 67.7 (2t, 2 CH2O(Thf)); 66.0 (s, C(a)(Thf)); 60.5 (d, CH(a)(Pro)); 52.0 (q, MeO); 47.6 (t,
CH2(d)(Pro)); 36.2 (t, CH2CH2O(Thf)); 27.8( t, CH2(b)(Pro)); 25.3 (t, CH2(g)(Pro)). ESI-MS: 715 (6, [2M ‡
‡
‡
‡
Na] ), 374 (100, [(M À Pro-OMe) ‡ (M À P hCONH(Thf))] ), 369 (54, [M ‡ Na] ), 366 (17), 347 (16, [M ‡
‡
H] ), 130 (14), 102 (66). Anal. calc. for C18H22N2O5 (346.38): C 62.42, H 6.40, N 8.09; found: C 62.21, H 6.64, N
7.98.
4. Synthesis of Model Peptides. 4.1. Reactions of 6. Benzyl N-{(S)-2-[((R)-2,3,4,5-Tetrahydro-3-{[(meth-
yl)(phenyl)amino]carbonyl}furan-3-yl)amino]-1-methyl-2-oxoethyl}carbamate ((S,R)-18) and Benzyl N-{(S)-2-
[((S)-2,3,4,5-Tetrahydro-3-{[(methyl)(phenyl)amino]carbonyl}furan-3-yl)amino]-1-methyl-2-oxoethyl}carb-
amate ((S,S)-18). To a soln. of 6 (233 mg, 1.100 mmol) in CH2Cl2 (8ml) at 0 8, Z-Ala-OH (309 mg, 1.384 mmol)
in CH2Cl2 (7 ml) was added. The mixture was stirred at r.t. for 68h, and the solvent was evaporated. CC
(hexane/AcOEt 1:2) yielded 18 (465 mg, 97%). Colorless foam. A second CC separated the diastereoisomers,
with the exception of a small mixed fraction.
Data of (S,R)-18. TLC(hexane/AcOEt 1:2): Rf 0.15 (UV254, Ce(SO4)2). IR: 3295s, 3063m, 3034m, 2980m,
2939m, 2876m, 1963w, 1716vs, 1664vs, 1637vs, 1594vs, 1529vs, 1496vs, 1454vs, 1375s, 1287s, 1244vs, 1156m, 1098s,
1
1070vs, 1027s, 972w, 917w, 774m, 751m, 701vs. H-NMR (300 MHz): 7.39 7.27 (m, 8arom. H); 7.09 7.06 ( m,
2 arom. H); ca. 5.78(br. s, NH(Thf)); 5.20 (d, J ˆ 7.3, NH(Ala)); 5.09 (s, PhCH2); 4.11 4.08, 3.92 3.84, 3.78
3.67 (3m, CH(a)(Ala), 2 CH2O(Thf)); 3.25 (s, MeN); 2.97 2.87, 2.08 2.00 (2m, CH2CH2O(Thf)); 1.22 (d, J ˆ
7.0, Me(Ala)). 13C-NMR (75 MHz): 171.0, 169.0 (2s, 2 CO); 155.7 (s, CO(carbamate)); 144.0, 136.1 (2s, 2 arom.
C); 129.5, 128.5, 128.2, 127.9, 126.7 (5d, 10 arom. CH); 76.8, 67.4 (2t, 2 CH2O(Thf)); 66.9 (t, PhCH2 and
C(a)(Thf)); 49.9 (d, CH(a)(Ala)); 40.4 (q, MeN); 38.4 (t, CH2CH2O(Thf)); 18.0 (q, Me(Ala)). CI-MS (NH3):
‡
‡
‡
427 (27), 426 (100, [M ‡ H] ), 320 (9), 319 (50, [M À N(Me)Ph] ), 318(17, [ M À PhCH2O] ), 241 (13), 108
‡
(11, [H2N(Me)Ph] ). Anal. calc. for C23H27N3O5 (425.48): C 64.93, H 6.40, N 9.88; found: C 64.99, H 6.70, N
9.65.

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Helvetica Chimica Acta Vol. 86 (2003)
Data of (S,S)-18. TLC (hexane/AcOEt 1:2): Rf 0.10 (UV254, Ce(SO4)2). IR: 3311s, 3063m, 3035m, 2980m,
2940m, 2876m, 1958w, 1720vs, 1672vs, 1651vs, 1594vs, 1526vs, 1496vs, 1454vs, 1376vs, 1249vs, 1157m, 1098s,
1070vs, 1028s, 972w, 924w, 8 48w, 775m, 741m, 701vs. 1H-NMR (300 MHz): 7.39 7.27 (m, 8arom. H); 7.10 7.07
(m, 2 arom. H); ca. 5.97 (br. s, NH (Thf)); 5.25 (d, J ˆ 6.0, NH(Ala)); 5.10, 5.04 (AB, J ˆ 12.3, PhCH2); 4.24
(part of AB, J ˆ 9.5, 1 H of CH2O(Thf)); 4.12 3.70 (m, CH(a)(Ala), CH2CH2O(Thf), 1 H of CH2O(Thf)); 3.24
(s, MeN); 2.78 2.71, 1.96 1.92 (2 m, CH2CH2O(Thf)); 1.23 (d, J ˆ 7.0, Me(Ala)). 13C-NMR (75 MHz): 171.1,
169.3 (2s, 2 CO); 155.7 (s, CO (carbamate)); 144.0, 136.0 (2s, 2 arom. C); 129.5, 128.5, 128.2, 127.9, 127.8, 126.8
(6d, 10 arom. CH); 77.0, 67.2 (2t, 2 CH2O(Thf)); 66.9 (t, PhCH2); 66.6 (s, C(a)(Thf)); 49.9 (d, CH(a)(Ala)); 40.3
‡
(q, MeN); 38.9 (t, CH2CH2O(Thf)); 18.0 (q, Me(Ala)). CI-MS (NH3): 427 (27), 426 (100, [M ‡ H] ), 320 (7),
‡
‡
‡
319 (42, [M À N(Me)Ph] ), 318(42, [ M À PhCH2O] ), 108(6, [H 2N(Me)Ph] ). Anal. calc. for C23H27N3O5
(425.48): C 64.93, H 6.40, N 9.88; found: C 64.78, H 6.68, N 9.58.
4-Bromo-N-{(S)-2-[((R)-2,3,4,5-tetrahydro-3-{[(methyl)(phenyl)amino]carbonyl}furan-3-yl)amino]-2-oxo-
ethyl}benzamide ((S,R)-19). To a soln. of (S,R)-18 (100 mg, 0.235 mmol) in MeOH (5 ml), Pd/C (10%, 21 mg)
was added, and the mixture was stirred at r.t. under H2 for 20 h. The suspension was filtered through Celite, and
the filtrate was concentrated. The residue was dissolved in CH2Cl2 (2 ml), and an Et3N soln. (0.3 ml, 1.2m in
CH2Cl2) and 4-bromobenzoyl chloride (58mg, 0.289 mmol) were added at 0 8. The mixture was then stirred at
r.t. for 16 h, and the solvent was evaporated. CC (CH2Cl2/MeOH 50 :1) yielded (S,R)-19 (96 mg, 86%).
Colorless powder. Suitable crystals for the X-ray crystal-structure determination were grown from MeOH/Et2O.
TLC (CH2Cl2/MeOH 10 :1): Rf 0.48(UV 254, −Schlittler×). IR: 3297s, 3061w, 2979w, 2936w, 2873w, 1643vs, 1593vs,
1534vs, 1495vs, 1482vs, 1450s, 1376s, 1269m, 1170w, 1110m, 1070s, 1027w, 1011m, 970w, 938w, 8 45w, 774w, 756m,
703m. 1H-NMR (300 MHz): 7.67 7.59, 7.38 7.31, 7.09 7.06 (3 m, 9 arom. H); 6.82 (d, J ˆ 7.1, NH(Ala)); ca. 6.00
(br. s, NH(Thf)); 4.10 3.75 (m, CH(a)(Ala), 2 CH2O(Thf)); 3.27 (s, MeN); 3.02 2.95, 2.15 2.06 (2m,
CH2CH2O(Thf)); 1.32 (d, J ˆ 7.0, Me(Ala)). 13C-NMR (75 MHz): 171.3, 169.0, 165.7 (3s, 3 CO); 143.9, 132.4 (2s,
2 arom. C); 131.9, 129.5, 128.5, 127.9, 126.8 (5d, 9 arom. CH); 126.7 (s, 1 arom. CBr); 76.6, 67.4 (2t,
2 CH2O(Thf)); 67.0 (s, C(a)(Thf)); 48.8 (d, CH(a)(Ala)); 40.3 (q, MeN); 38.3 (t, CH2CH2O(Thf)); 18.5 (q,
‡
‡
Me(Ala)). CI-MS (NH3): 477 (25), 476 (100, [M(81Br) ‡ H] ), 475 (25), 474 (100, [M(79Br) ‡ H] ), 396 (11),
370 (14), 369 (82, [M(81Br) À N(Me)Ph] ), 368(14), 367 (83, [ M(79Br) À N(Me)Ph] ), 289 (12), 228 (19), 108
‡
‡
‡
(95, [H2N(Me)Ph] ). Anal. calc. for C22H24BrN3O4 ¥ 0.5 MeOH (490.37): C 55.11, H 5.34, N 8.57; found: C 55.11,
H 5.11, N 8.67.
4-Bromo-N-{(S)-2-[((S)-2,3,4,5-tetrahydro-3-{[(methyl)(phenyl)amino]carbonyl}furan-3-yl)amino]-2-oxo-
ethyl}benzamide ((S,S)-19). To a soln. of (S,S)-18 (60 mg, 0.141 mmol) in MeOH (5 ml), Pd/C (10%, 12 mg)
was added, and the mixture was stirred at r.t. under H2 for 8h. The suspension was filtered through Celite, and
the filtrate was concentrated. The residue was dissolved in CH2Cl2 (2 ml), and an Et3N soln. (0.3 ml, 0.8m in
CH2Cl2) and 4-bromobenzoyl chloride (37 mg, 0.184 mmol) were added at 08. The mixture was then stirred at
r.t. for 8h, and the solvent was evaporated. CC (CH 2Cl2/MeOH 50 :1) yielded (S,S)-19 (61 mg, 92%). Colorless
powder. Suitable crystals for the X-ray crystal-structure determination were grown from MeOH/CHCl3. TLC
(CH2Cl2/MeOH 10 :1): Rf 0.43 (UV254, −Schlittler×). IR: 3439w, 3326m, 3062w, 2978w, 2932w, 2857w, 1691s,
1657vs, 1641vs, 1593vs, 1523vs, 1496vs, 1481vs, 1448s, 1382s, 1359s, 1268m, 1166m, 1108m, 1072s, 1012m, 963w,
933w, 8 43m, 778w, 755m, 705m. 1H-NMR (300 MHz): 7.67 7.58, 7.38 7.25, 7.18 7.08(3 m, 9 arom. H); 6.94 (d,
J ˆ 7.3 NH(Ala)); ca. 6.32 (br. s, NH(Thf)); 4.31 (part of AB, J ˆ 9.5, 1 H of CH2O(Thf)); 4.22 4.13, 3.94 3.77
(2m, CH(a)(Ala), CH2CH2O(Thf), 1 H of CH2O(Thf)); 3.26 (s, MeN); 2.83 2.71, 2.02 1.94 (2m,
CH2CH2O(Thf)); 1.34 (d, J ˆ 6.9, Me(Ala)). 13C-NMR (75 MHz): 171.4, 169.4, 165.8(3 s, 3 CO); 143.9, 132.4
(2s, 2 arom. C); 131.8, 129.4, 128.6, 127.7, 126.9 (5d, 9 arom. CH); 126.6 (s, 1 arom. CBr); 76.9, 67.2 (2t,
2 CH2O(Thf)); 66.7 (s, C(a)(Thf)); 48.8 (d, CH(a)(Ala)); 40.2 (q, MeN); 38.8 (t, CH2CH2O(Thf)); 18.4 (q,
‡
‡
Me(Ala)). CI-MS (NH3): 493 (8, [M(81Br) ‡ NH4] ), 491 (8, [M(79Br) ‡ NH4] ), 477 (25), 476 (100,
[M(81Br) ‡ H] ), 475 (25), 474 (99, [M(79Br) ‡ H] ), 411 (10), 396 (26), 369 (12, [M(81Br) À N(Me)Ph] ), 367
‡
‡
‡
(13, [M(79Br) À N(Me)Ph] ), 108(13, [H 2N(Me)Ph] ). Anal. calc. for C22H24BrN3O4 (474.35): C 55.70, H 5.10,
‡
‡
N 8.86; found: C 55.41, H 5.12, N 8.80.
(R)-3-[((S)-2-{[(Benzyloxy)carbonyl]amino}-1-oxopropyl)amino]-2,3,4,5-tetrahydrofuran-3-carboxylic
Acid ((R,S)-20). A soln. of (S,R)-18 (106 mg, 0.249 mmol) and aq. HCl (2 ml, 6m) in MeCN (2 ml) was stirred at
r.t. for 88 h. After removal of the solvent, the crude product was purified by prep. TLC (CH2Cl2/MeOH 10 :1) to
yield (R,S)-20 (63 mg, 75%). Colorless powder. TLC (CH2Cl2/MeOH 10 :1): Rf stretched spot at the start,
yellow, with bromocresol green. IR: 3312s, 3065m, 3035m, 2980m, 2882m, 1707vs, 1664vs, 1607vs, 1517vs, 1454s,
1399vs, 1357s, 1342s, 1259vs, 1156w, 1072s, 1052s, 1029s, 973w, 917w, 8 26w, 777w, 740m, 698s. 1H-NMR (300 MHz,
CD3OD): 7.37 7.26 (m, 5 arom. H); 5.09 5.04 (m, PhCH2); 4.18 4.11 ( m, 2 H of CH(a)(Ala), 2 CH2O(Thf));
3.99 3.94 (m, 3 H of CH(a)(Ala), 2 CH2O(Thf)); 2.43 2.40, 2.26 2.22 (2m, CH2CH2O(Thf)); 1.34 (d, J ˆ 7.1,

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Me(Ala)). 13C-NMR (75 MHz, CD3OD): 178.8, 174.6 (2s, 2 CO); 158.2 (s, CO(carbamate)); 138.2 (s, 1 arom.
C); 129.4, 129.0, 128.8 (3d, 5 arom. CH); 77.2, 69.4, 67.7 (3t, 2 CH2O(Thf), PhCH2); 68.0 (s, C(a)(Thf)); 52.2 (d,
‡
CH(a)(Ala)); 38.5 (t, CH2CH2O(Thf)); 18.3 (Me(Ala)). ESI-MS: 739 (24), 717 (12), 359 (100, [M ‡ Na] ).
(S)-3-[((S)-2-{[(Benzyloxy)carbonyl]amino}-1-oxopropyl)amino]-2,3,4,5-tetrahydrofuran-3-carboxylic
Acid ((S,S)-20). A soln. of (S,S)-18 (101 mg, 0.237 mmol) and aq. HCl (2 ml, 6m) in MeCN (2 ml) was stirred at
r.t. for 88 h. After removal of the solvent, the crude product was purified by prep. TLC (CH2Cl2/MeOH 10 :1) to
yield (S,S)-20 (67 mg, 84%). Colorless powder. TLC (CH2Cl2/MeOH 10 :1): Rf: stretched spot at the start,
yellow, with bromocresol green. IR: 3394s, 3316s, 3064m, 3035m, 2980m, 2881m, 1707vs, 1659vs, 1597vs, 1536vs,
1514vs, 1454s, 1396vs, 1357s, 1259vs, 1154w, 1097m, 1070s, 1056s, 1029s, 973w, 917w, 8 27w, 774w, 737m, 698s.
1H-NMR (300 MHz, CD3OD): 7.37 7.26 (m, 5 arom. H); 5.09 (s, PhCH2); 4.19 4.11 (m, 2 H of CH(a)(Ala),
2 CH2O(Thf)); 3.98 3.85 ( m, 3 H of CH(a)(Ala), 2 CH2O(Thf)); 2.43 2.39, 2.26 2.15 (2m, CH2CH2O(Thf));
1.34 (d, J ˆ 7.1, Me(Ala)). 13C-NMR (75 MHz, CD3OD): 178.7, 174.8 (2s, 2 CO); 158.2 (s, CO (carbamate));
138.2 (s, 1 arom. C); 129.6, 129.1, 129.0 (3d, 5 arom. CH); 77.2, 69.4, 67.9 (3t, 2 CH2O(Thf), PhCH2); 67.7 (s,
C(a)(Thf)); 52.4 (d, CH(a)(Ala)); 38.5 (t, CH2CH2O(Thf)); 18.5 (q, Me(Ala)). ESI-MS: 739 (16), 717 (12), 359
‡
(100, [M ‡ Na] ), 209 (11).
tert-Butyl (S)-2-[({(R)- and (S)-3-[((S)-2-{[(Benzyloxy)carbonyl]amino}-1-oxopropyl)amino]-2,3,4,5-
tetrahydrofuran-3-yl}carbonyl)amino]-3-phenylpropanoate (21). At 08, EtN(i-Pr)2 (0.1 ml, 0.584 mmol) was
added to a mixture of (R,S)-20/(S,S)-2 0 (67 mg, 0.199 mmol, mixture of diastereoisomers), H-Phe-OtBu ¥ HCl
(57 mg, 0.221 mmol), TBTU (64 mg, 0.199 mmol), and HOBt hydrate (12% H2O, 31 mg, 0.202 mmol) in
CH2Cl2 (5 ml), whereupon the soln. turned clear for a short time. The mixture was stirred at r.t. for 5 d, and
washed twice with aq. 5% KHSO4 soln., aq. 5% NaHCO3 soln., and sat. aq. NaCl soln. The aq. layers were
extracted twice with CH2Cl2, then all combined org. layers were filtered through cotton and concentrated. CC
(hexane/AcOEt 2 :1) yielded 21 (80 mg, 74%). Colorless powder. TLC (hexane/AcOEt 2 :1): Rf 0.17 (UV254
,
−Schlittler×). M.p. 152 1588. IR: 3377m, 3308s, 3065w, 3035m, 2980m, 2936m, 2880w, 1726vs, 1707vs, 1682vs,
1651vs, 1546vs, 1456s, 1393m, 1367s, 1317s, 1257vs, 1227s, 1160vs, 1117m, 1074s, 1029s, 8 47w, 740m, 701s.
1H-NMR (300 MHz; diastereoisomers): 7.34 7.13 (m, 10 arom. H); 7.08, 7.06 (2s, NH); 6.91, 6.88 (2s, NH); 5.33,
5.30 (2s, NH); 5.13, 5.07 (AB, J ˆ 12.3, PhCH2(Z)); 4.69 4.66 (m, CH(a)(Phe)); 4.19 3.85 (m, CH(a)(Ala),
2 CH2O(Thf)); 3.15 3.01 (m, CH2(Phe)); 2.38 2.05 ( m, CH2CH2O(Thf)); 1.42, 1.41 (2s, Me3C); 1.34 (d, J ˆ
6.6, Me(Ala)). 13C-NMR (125 MHz; diastereoisomers): 172.4, 172.1, 172.1, 170.2 (4s, 3 CO); 156.0 (s,
CO(carbamate)); 136.2, 136.1, 136.0 (3s, 2 arom. C); 129.3, 129.3, 128.5, 128.4, 128.2, 128.0, 127.0 (7d, 10 arom.
CH); 82.4, 82.3 (2s, Me3C); 73.7, 73.4, 67.7, 67.6, 67.1 (5t, 2 CH2O(Thf), PhCH2); 64.8( s, C(a)(Thf)); 53.8, 53.8,
50.8(3 d, CH(a)(Ala), CH(a)(Phe)); 37.8, 37.7 (2t, CH2CH2O(Thf)); 36.1, 36.0 (2t, CH2(Phe)); 27.9 (q, Me3C);
‡
‡
18.2 (q, Me(Ala)). ESI-MS: 837 (27), 562 (100, [M ‡ Na] ), 540 (31, [M ‡ H] ), 484 (94). Anal. calc. for
C29H37N3O7 (539.62): C 64.55, H 6.91, N 7.79; found: C 64.33, H 7.03, N 7.68.
4.2. Reaction of 7. N-{[(R)- and (S)-3-({2-[((S)-2-{[(Benzyloxy)carbonyl]amino}- 4-methyl-1-oxopentyl)-
amino]-2-methyl-1-oxopropyl}amino)-2,3,4,5-tetrahydrofuran-3-yl]carbonyl}-(S)-proline Methyl Ester (17a and
17b, resp.). To a soln. of 7 (81 mg, 0.361 mmol) in CH2Cl2 (3 ml) at 08, Z-Leu-Aib-OH (138mg, 0.394 mmol) in
CH2Cl2 (3 ml) was added. The mixture was stirred at r.t. for 2 d, and the solvent was evaporated. Prep. TLC
(CH2Cl2/MeOH 10 :1) yielded 17 (172 mg (83%). Colorless foam. The diastereoisomers were separated by prep.
HPLC (CH2Cl2/MeOH 40 :1).
Data of 17a. TLC (CH2Cl2/MeOH 10 :1): Rf 0.31 (UV254, −Schlittler×). HPLC (normal phase, CH2Cl2/
MeOH 40 :1, 1 ml/min): tR 17.2 min. Prep. HPLC (normal phase, CH2Cl2/MeOH 40 :1, 12 ml/min): tR 44.2 min.
IR: 3319vs, 3033w, 2956s, 2873m, 1745vs, 1680vs, 1629vs, 1526vs, 1469s, 1454s, 1435vs, 1384s, 1363s, 1265vs,
1221vs, 1174vs, 1118m, 1092m, 1060s, 1044s, 923w, 741m, 699m. 1H-NMR (600 MHz): 7.57 (s, NH(Thf)); 7.37
7.31 (m, 5 arom. H); 6.44 (s, NH(Aib)); 5.45 (d, J ˆ 3.9, NH(Leu)); 5.12 (s, PhCH2); 4.54 (dd, J ˆ 8.9, J ˆ 3.5,
CH(a)(Pro)); 4.16 4.14 (m, 1 H of CH2O(Thf)); 3.98 3.90 ( m, CH(a)(Leu), 3 H of CH2O(Thf)); 3.69 (s,
MeO); 3.66 3.62 (m, 1 H of CH2(d)(Pro)); 3.43 (br. s, 1 H of CH2(d)(Pro)); 2.95 2.91 (m, 1 H of
CH2CH2O(Thf)); 2.12 2.04 (m, 1 H of CH2(b)(Pro), 1 H of CH2CH2O(Thf)); 1.95 1.89 (m, CH2(g)(Pro));
1.87 1.85 ( m, 1 H of CH2(b)(Pro)); 1.69 1.62 (m, 1 H of CH2(b)(Leu), CH(g)(Leu)); 1.55 1.49 (m, 1 H of
CH2(b)(Leu)); 1.52, 1.46 (2s, 2 Me(Aib)); 0.96 0.93 (m, 2 Me (Leu)). 13C-NMR (150 MHz): 173.5, 173.0, 171.9,
168.8 (4s, 4 CO); 156.7 (s, CO(carbamate)); 135.9 (s, 1 arom. C); 128.6, 128.4, 127.9 (3d, 5 arom. CH); 74.1, 68.1
(2t, 2 CH2O(Thf)); 67.2 (t, PhCH2); 66.9 (s, C(a)(Thf)); 60.3 (d, CH(a)(Pro)); 57.4 (s, C(a)(Aib)); 54.7 (d,
CH(a)(Leu)); 52.0 (q, MeO); 47.1 (t, CH2(d)(Pro)); 40.2 (t, CH2(b)(Leu)); 36.9 (t, CH2CH2O(Thf)); 28.0 (t,
(CH2(b)(Pro)); 26.2 (q, Me(Aib)); 25.4 (t, CH2(g)(Pro)); 24.7 (d, CH(g)(Leu)); 24.5 (q, Me(Aib)); 22.9, 21.8
‡
‡
‡
(2q, 2 Me(Leu)). ESI-MS: 597 (50, [M ‡ Na] ), 575 (10, [M ‡ H] ), 446 (100, [M À Pro-OMe] ), 333 (46,

1392
Helvetica Chimica Acta Vol. 86 (2003)
Table 3. Crystallographic Data of Compounds 13, 14, (R,S)-15, (S,S)-15, (R,S)-16, (S,S)-16, (S,R)-19, and
(S,S)-19
13
14
(R,S)-15
(S,S)-15
Crystallized from
CDCl3/Et2O
CHCl3/Et2O
i-Pr2O/CHCl3/
CH2Cl2
CHCl3/i-Pr2O
Empirical formula
Formula weight [g molÀ1
Crystal color, habit
C19H20N2O2S
340.44
C19H20N2O3
324.38362.44
C18H22N2O4S
362.44
C18H22N2O4S
]
colorless, prism colorless, needle colorless, needle colorless, prism
Crystal dimensions [mm]
Temp. [K]
Crystal system
Space group
Z
0.20 Â 0.25 Â 0.30 0.05 Â 0.05 Â 0.30 0.07 Â 0.10 Â 0.25 0.20 Â 0.25 Â 0.25
160(1)
monoclinic
P21/c
160(1)
monoclinic
P21/c
160(1)
160(1)
orthorhombic
P212121
orthorhombic
P212121
4
8
4
4
Reflections for cell determination 2711
5981
2378
2407
2q range for cell determination [8] 4 60
4
50
4
55
4 55
Unit-cell parameters a [ä]
9.6138(1)
10.9181(1)
29.1337(3)
10.9614(1)
108.2256(5)
3311.74(6)
1.301
7.4749(1)
10.8981(2)
21.9857(4)
90
1791.00(5)
1.344
7.5237(1)
10.9586(1)
21.9085(3)
90
1806.34(4)
1.333
b [ä]
c [ä]
b [8]
12.1775(2)
14.6489(2)
90.9387(6)
1714.75(4)
1.319
V [ä3]
Dx [g cmÀ3
m(MoKa) [mmÀ1
]
]
0.202
0.0887
0.206
0.204
Transmission factors [min; max]
Scan type
2q(max) [8]
0.844; 0.962
f and w
60
f and w
50
f and w
55
f and w
55
Total reflections measured
Symmetry-independent reflections 4999
Reflections with I > 2s(I)
Reflections used in refinement
Parameters refined
44650
50909
5850
4276
5845
37878
4092
3280
3280
38672
4151
3633
3633
232
3895
3895
222
463 (30 restraints) 232
0.05080.0374 0.0375
R (on F; I > 2 s(I) reflections)
0.0453
wR (on F; I > 2 s(I) reflections) 0.0446
0.0331
0.0375
0.007
wR (on F2; all indept. reflections)
0.1357
Weighting parameter [p]a)
Weighting parameters [a, b]b)
Goodness-of-fit
Secondary extinction coefficient
Final Dmax/s
D1 (max; min) [e äÀ3
0.005
0.010
0.0609; 1.9374
1.017
0.0053(8)
0.001
3.011
1.492
1.0(1) Â 10À6
0.0005
0.22; À0.22
2.240
1.8(3) Â 10À6
7(2) Â 10À7
0.0004
0.001
]
0.33; 0.23
0.47; À0.45
0.38; À0.24
b
a) wÀ1 ˆs2(Fo)‡(pFo)2. ) wÀ1 ˆs2(Fo2)‡(aP)2 ‡bP, where Pˆ(Fo2 ‡2 Fc2)/3.
‡
[M À Thf-Pro-OMe] ). Anal. calc. for C29H42N4O8 ¥ 0.4 H2O (581.88): C 59.86, H 7.41, N 9.63; found: C 59.96, H
7.33, N 9.56.
Data of 17b. TLC (CH2Cl2/MeOH 10 :1): Rf 0.31 (UV254, −Schlittler×). HPLC (normal phase, CH2Cl2/
MeOH 40 :1, 1 ml/min): tR 20.1 min. Prep. HPLC (normal phase, CH2Cl2/MeOH 40 :1, 12 ml/min): tR 52.5 min.
IR: 3320vs, 3033m, 2956vs, 2873m, 1745vs, 1692vs, 1665vs, 1628vs, 1525vs, 1453s, 1437s, 1384s, 1362s, 1264vs,
1
1221vs, 1173vs, 1119m, 1093w, 1062s, 973w, 924w, 741m, 698m. H-NMR (600 MHz): 7.59 (s, NH(Thf)); 7.38
7.31 (m, 5 arom. H); 6.41 (s, NH(Aib)); 5.43 (d, J ˆ 4.3, NH(Leu)); 5.13, 5.08( AB, J ˆ 12.3, PhCH2); 4.54 4.50

Helvetica Chimica Acta Vol. 86 (2003)
1393
Table 3 (cont.)
(R,S)-16
(S,S)-16
(S,R)-19
(S,S)-19
Crystallized from
Empirical formula
CHCl3/Et2O
C18H22N2O5
CDCl3
C18H22N2O5 ¥
CDCl3
MeOH/Et2O
C22H24BrN3O4 ¥
2 CH3OH
MeOH/CHCl3
C22H24BrN3O4 ¥
2 CH3OH
538.43
colorless, plate
Formula weight [g molÀ1
Crystal color, habit
]
346.38
466.76
538.43
colorless, needle colorless, needle colorless, plate
Crystal dimensions [mm]
Temp. [K]
Crystal system
Space group
Z
0.05 Â 0.07 Â 0.22 0.04 Â 0.05 Â 0.22 0.07 Â 0.22 Â 0.22 0.05 Â 0.15 Â 0.25
160(1)
orthorhombic
P212121
4
160(1)
monoclinic
P21
160(1)
monoclinic
P21
160(1)
monoclinic
P21
2
2
2
Reflections for cell determination 1829
2585
26729
22646
2q range for cell determination [8]
4
50
4
55
4
60
4 55
Unit-cell parameters a [ä]
7.8381(1)
10.8238(2)
20.8005(4)
90
1764.67(5)
1.304
9.3887(2)
11.5550(2)
9.8990(2)
94.3998(9)
1070.74(4)
1.445
9.3610(1)
10.5163(1)
13.3600(2)
102.8138(5)
1282.45(3)
1.394
9.1378(1)
10.6355(1)
13.3132(2)
100.6612(6)
1271.51(3)
1.406
b [ä]
c [ä]
b [8]
V [ä3]
Dx [g cmÀ3
m(MoKa) [mmÀ1
]
]
0.0956
0.460
1.650
1.664
Transmission factors [min; max]
Scan type
2q(max) [8]
0.671; 0.858
f and w
60
0.726; 0.920
f and w
55
w
f and w
55
50
Total reflections measured
Symmetry-independent reflections 3117
Reflections with I > 2s(I)
Reflections used in refinement
Parameters refined
19865
24423
4882
4040
4040
267
42259
7459
6091
7458
33790
5802
5076
5076
2806
2806
230
347
325
(30 restraints)
0.0330
R (on F; I > 2 s(I) reflections)
wR (on F; I > 2 s(I) reflections)
wR (on F2; all indept. reflections)
Weighting parameter [p]a)
Weighting parameters [a, b]b)
Goodness-of-fit
0.0371
0.0366
0.03780.0354
0.0368
0.0303
0.0762
0.005
2.124
0.013
0.005
0.0334; 0.2605
1.016
0.008(1)
0.002
1.370
1.625
Secondary extinction coefficient
Final Dmax/s
2.5(3) Â 10À6
2.3(1) Â 10À6
0.0003
0.16; À0.21
0.0005
0.0006
D1 (max; min) [e äÀ3
]
0.29; À0.32
0.26; À0.34
0.31; À0.31
b
a) wÀ1 ˆs2(Fo)‡(pFo)2. ) wÀ1 ˆs2(Fo2)‡(aP)2 ‡bP, where Pˆ(Fo2 ‡2 Fc2)/3.
(m, CH(a)(Pro), 1 H of CH2O(Thf)); 4.03 3.92 (m, 1 H of CH2CH2O(Thf)); 3.91 3.90 (m, CH(a)(Leu), 1 H
of CH2CH2O(Thf)); 3.85 3.84 (m, 1 H of CH2O(Thf)); 3.70 (s, MeO); 3.67-3.65 (m, 1 H of CH2(d)(Pro)); 3.51
(br. s, 1 H of CH2(d)(Pro)); 2.37 2.35 (m, CH2CH2O(Thf)); 2.08 2.04 ( m, 1 H of CH2(b)((Pro)); 1.95 1.93
(m, CH2(g)(Pro)); 1.87 1.85 (m, 1 H of CH2(b)(Pro)); 1.67 1.62 (m, 1 H of CH2(b)(Leu), CH(g)(Leu));
1.55 1.52 (m, 1 H of CH2(b)(Leu)); 1.54, 1.44 (2s, 2 Me(Aib)); 0.96 0.93 (m, 2 Me(Leu)). 13C-NMR
(150 MHz): 173.6, 173.2, 172.0, 169.4 (4s, 4 CO); 156.8( s, CO(carbamate)); 135.9 (s, 1 arom. C); 128.7, 128.4,
127.8(3 d, 5 arom. CH); 76.2 (t, CH2O(Thf)); 67.4 (t, CH2CH2O(Thf)); 67.2 (t, PhCH2); 65.8( s, C(a)(Thf)); 60.1
(d, CH(a)(Pro)); 57.5 (s, C(a)(Aib)); 54.8( d, CH(a)(Leu)); 52.0 (q, MeO); 47.2 (t, CH2(d)(Pro)); 40.2 (t,

1394
Helvetica Chimica Acta Vol. 86 (2003)
CH2(b)(Leu)); 35.7 (t, CH2CH2O(Thf)); 28.1 (t, (CH2(b)(Pro)); 26.7 (q, Me(Aib)); 25.4 (t, CH2(g)(Pro)); 24.8
‡
(d, CH(b)(Leu)); 24.2 (q, Me(Aib)); 22.9, 21.9 (2q, 2 Me(Leu)). ESI-MS: 597 (100, [M ‡ Na] ), 575 (26, [M ‡
‡
‡
‡
H] ), 446 (50, [M À Pro-OMe] ), 333 (7, [M À Thf-Pro-OMe] ). Anal. calc. for C29H42N4O8 ¥ 0.2 H2O (578.27):
C 60.23, H 7.39, N 9.73; found: C 60.17, H 7.20, N 9.62.
5. X-Ray Crystal-Structure Determination of 13, 14, (R,S)-15, (S,S)-15, (R,S)-16, (S,S)-16, (S,R)-19 and
(S,S)-19, (see Table 3 and Figs. 1 8)5). All measurements were made at low temp. on a Nonius Kappa CCD
area-detector diffractometer [36] with graphite-monochromated MoKa radiation (l 0.71073 ä) and an Oxford
Cryosystems Cryostream 700 cooler. The data collection and refinement parameters are given in Table 3, and
views of the molecules are shown in Figs. 1 8. Data reduction was performed with HKL Denzo and Scalepack
[37]. The intensities were corrected for Lorentz and polarization effects. In the case of 13, an absorption
correction based on the multi-scan method [38] was applied, while a numerical absorption correction [39] was
applied for (S,R)-19 and (S,S)-19. Each structure was solved by direct methods with SIR92 [40], which revealed
the positions of all non-H-atoms. The non-H-atoms were refined anisotropically. The amide H-atoms in each
structure, as well as the OH H-atoms of the MeOH molecules in (S,R)-19, were placed in the positions indicated
by difference-electron-density maps, and their positions were allowed to refine together with individual
isotropic displacement parameters. All remaining H-atoms were placed in geometrically calculated positions,
and each was assigned a fixed isotropic displacement parameter with a value equal to 1.2Ueq of its parent atom
(1.5Ueq for the Me groups of 14 and (S,R)-19). The orientations of the idealized OÀH vectors in the MeOH
molecules in (S,S)-19 were aligned to correspond with peaks in a difference electron-density map.
Except for 14 and (S,R)-19, each structure was refined on F using full-matrix least-squares procedures,
which minimized the function Sw(j Fo jÀj Fc j )2. For 14 and (S,R)-19, the refinement was carried out on F2 by
minimizing the corresponding function based on F2. Corrections for secondary extinction were applied, except
for (R,S)-16. Between one and five low-angle reflections were omitted from the final refinement of each
structure because their observed intensities were much lower than the calculated values as a result of being
partially obscured by the beam stop. Refinement of the absolute structure parameter [41] in the cases of (R,S)-
15, (S,S)-15, (S,S)-16, (S,R)-19, and (S,S)-19 yielded values of À 0.06(5), À0.08(4), À0.05(4), À0.017(5), and
À0.013(4), respectively, which confidently confirmed that the refined coordinates represent the true
enantiomorph.
The structure of 14 has two symmetry-independent molecules in the asymmetric unit, but significant
differences in their conformations preclude the possibility of a relationship from a higher-symmetry space group.
Two atoms in the five-membered ring of molecule B are disordered, and two equally occupied positions were
defined for each of these atoms. The disordered model could be refined satisfactorily, but only by applying quite
strong bond-length restraints to all bonds involving the disordered atoms, as well as strong approximate
isotropic restraints to the anisotropic atomic displacement parameters of the disordered atoms. In the structures
of (S,R)-19 and (S,S)-19, the asymmetric unit contains one peptide molecule plus two MeOH molecules. Two
atoms in the five-membered ring of (S,R)-19 are disordered, and two positions were defined for each of these
molecules. The disordered model was refined in an analogous way to that described for 14. The site occupation
factors of the two conformations refined to 0.68(2) and 0.32(2), resp. In the case of (S,S)-19, the O-atom of the
five-membered ring is disordered, and two positions were defined for this atom. The disordered model could be
refined satisfactorily without bond-length restraints, and the best results were obtained when the site-occupation
factors of the two conformations were set to 0.80 and 0.20, resp.
Neutral atom scattering factors for non-H-atoms were taken from [42a], and scattering factors for H-atoms
were taken from [43]. Anomalous dispersion effects were included in Fc [44]; the values for f ' and f '' were those
of [42b]. The values of the mass attenuation coefficients are those of [42c]. All calculations for 14 and (S,R)-19
were performed using SHELXL97 [45], while the teXsan crystallographic software package [46] was used for
the remaining structures.
5
)
CCDC-201305 201312 contain the supplementary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystal-
lographic Data Center, 12 Union Road, Cambridge CB2 1EZ, UK (fax: ‡44-(0)1223-336033; e-mail:
deposit@ccdc.cam.ac.uk)).

Helvetica Chimica Acta Vol. 86 (2003)
1395
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Received January 23, 2003