Stereoselective approach to uncommon tripeptides incorporating a 2,6-diaminopimelic acid framework: X-ray analysis and conformational studies. Part 4

Article abstract of DOI:10.1016/j.tetasy.2005.01.047

Stereoselective synthesis of pseudopeptides 4, 5, 8, 9, 13 and 14, incorporating 2,6-diamino-4-methylen-1,7-heptanedioic acid residue, has been accomplished starting from the l-valine derived chiral synthon 1. The absolute configuration of new stereocentr

Full text of DOI:10.1016/j.tetasy.2005.01.047

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1103–1112
Stereoselective approach to uncommon tripeptides incorporating
a 2,6-diaminopimelic acid framework: X-ray analysis
and conformational studies. Part 4I
Daniele Balducci,a Sara Crupi,a Roberta Galeazzi,b Fabio Piccinelli,a
Gianni Porzia,* and Sergio Sandria,*
a
`
Dipartimento di Chimica ‘G.Ciamician’, Universita di Bologna, Via Selmi 2, 40126 Bologna, Italy
`
Dipartimento di Scienze dei Materiali e della Terra, Universita di Ancona, Via Brecce Bianche, 60131 Ancona, Italy
b
Received 15 November 2004; revised 20 January 2005; accepted 31 January 2005
Abstract—Stereoselective synthesis of pseudopeptides 4, 5, 8, 9, 13 and 14, incorporating 2,6-diamino-4-methylen-1,7-heptanedioic
acid residue, has been accomplished starting from the L-valine derived chiral synthon 1. The absolute configuration of new stereo-
centres was assigned on the basis of 1H NMR spectra. The geometry of these unnatural tripeptides was deduced on the basis of 1H
NMR parameters and IR spectra. X-ray analysis of the unusual peptide 18 and conformational studies of 5, 9 and 14 are also
reported.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
show biological activity as immuno-adjuvants.8 The
strategy followed to accomplish the synthesis of these
unusual tripeptides is based on the experience previously
acquired on the stereoselective approach to similar sub-
strates.1–4
The present article is a continuation of our program
directed towards producing uncommon tripeptides C-
terminal at both ends of the chain.1–4 For this purpose,
we undertook the stereoselective synthesis of new and
complex pseudopeptides, as 5, 9 and 14, incorporating
the 4-methylen-derivative of the 2,6-diaminopimelic acid
(pointed out in red in Schemes 1 and 2) and the L-valine
units at the ends of the chain.
2. Synthesis and stereochemical assignments
The stereoselective synthesis, makes use of chiral syn-
thon 1, a mono-lactim ether easily synthesised starting
from L-valine, as reported previously.1–4 Deprotonation
of 1 with LHMDS followed by the alkylation with
0.5 equiv of 2-iodomethyl-3-iodopropene (obtained
from 2-chloromethyl-3-chloropropene and NaI) afford-
ed the diastereomer (30R,60S,300R,600S)-2 in good yield
and with a practically total double 1,4-trans induction
with respect to the isopropyl group (ds P96%).1–4
Our interest in these ÔunnaturalÕ tripeptides arises from
their potential biological activity as antibacterial5 and/
or herbicide agents.6 In fact, it can be supposed that
mimetics of 2,6-diaminopimelic acid (2,6-DAP) can
function as inhibitors of biosynthetic formation or
metabolism of L-lysine and meso-2,6-DAP. Further-
more, short peptides, able to mimic some important
aspect of protein structure or their function, can behave
as bioactive molecules.7 Finally, such compounds are
interesting because in the literature it has been reported
that some tri- and tetrapeptides incorporating the 2,6-
DAP skeleton, conjugated with lauric or palmitic acid,
Isomer 2, which has a C2-symmetry axis, was obtained
pure by silica gel chromatography with its stereochemis-
try well established on the basis of the 1H NMR spectra,
as already reported.1,3,4 Intermediate 2, submitted to the
Birch reduction to remove the benzyl groups and to the
acid hydrolysis in mild conditions, was converted into
hydrochloride 3 and then into aminoester 4. The acyl-
ation of 4 gave the Ônon-classical tripeptideÕ 5, C-terminal
q Refs. 1–3 are considered to be Parts 1–3.
*
Corresponding authors. E-mail: gianni.porzi@unibo.it
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.047

1104
D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1103–1112
OEt
OEt
OEt
OEt
OEt
N
N
3'
N
3''
N
N
i
6'
N
6''
vi
N
N
N
N
H3C
ii
CH3
Ph
O
Ph
O
O
Ph
Ph
O
O
Ph
2
6
1
ii, iii
OEt
O
OEt
EtOOC
NH3Cl
COOEt
N
N
NH3Cl
HN
NH
NH
HN
CH3
H3C
O
O
O
3
7
iv
iii, iv
EtOOC
NH2
COOEt
NH2
COOEt
NH2
EtOOC
NH2
HN
NH
HN
NH
H3C
CH3
O
O
8
4
O
O
v
v
EtOOC
NH2Ac
COOEt
COOEt
EtOOC
NH2Ac
NH2Ac
NH2Ac
NH1
NH1
NH1
NH1
H3C
CH3
O
5
9
O
O
O
Scheme 1. Reagents and conditions: (i) 1 M LHMDS/THF, then 0.5 equiv of (CH2I)2C@CH2; (ii) Li/NH3; (iii) 0.5 M HCl at rt; (iv) 1 M K2CO3; (v)
CH3COCl/Et3N, CH2Cl2; (vi) 1 M LHMDS/THF, then 2 equiv of CH3I.
OEt
OEt
OEt
OEt
OEt
N
N
N
N
ii
N
iii
i
N
1
NH
HN
N
N
CH3
H3C
H3C
CH3
CH3
Ph
O
O
O
O
Ph
Ph
O
12
11
10
COOEt
NH2
EtOOC
NH2
COOEt
EtOOC
NH2Ac
NH2Ac
iv
v
HN
NH
NH1
NH1
CH3
CH3
H3C
H3C
O
O
13
14
O
O
Scheme 2. Reagents and conditions: (i) LHMDS/THF, then CH3I; (ii) LHMDS/THF, then 0.5 equiv of (ICH2)2C@CH2; (iii) Li/NH3; (iv) 0.5 M HCl
at rt, then 1 M K2CO3; (v) CH3COCl/Et3N, CH2Cl2.
at both ends of the chain, which can also be considered
as a 2,6-DAP derivative (Scheme 1). Intermediate 2,
alkylated with CH3I at both positions 30 and 300, gave
6 in good yield and with a practically total trans-induc-
tion (de P96%) induced by the isopropyl group, as pre-
viously observed for similar substrates1 (Scheme 1). The
trans-stereoselection was evident from the 1H NMR and
13C NMR spectra, which showed the molecules possess-
ing a C2-axis of symmetry. In fact, in compound 6 the
signals for both methyl and isopropyl groups overlap
as do the signals for benzylic protons indicating their
magnetic equivalence. The overlapping signals also
occurred between (C-30)-H and (C-300)-H, (C-60)-H and
(C-600)-H and between (C-50)-OC2H5 and (C-500)-
OC2H5 protons. However, the stereochemistry of 6
was confirmed by the NOE registered between the (C-
30)-CH3 and (C-60)-H, the absolute configuration of ste-
reocentre C-60 being known. Intermediate 6 was then
converted into 9 following the same procedure used to
obtain 5 (Scheme 1).

D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1103–1112
1105
1
Table 1. Meaningful H NMR and IR data of substrates 5, 9, 14, 15,
16, 17 and 18
The synthesis of diastereomeric derivatives 12, 13 and
14, with an opposite configuration at the stereocentres
C-30 and C-300, in comparison to 6, 7 and 9, respectively,
was accomplished on the basis of the practically total
stereocontrolled trans-induction observed in the alkyl-
ation reaction. Thus, the strategy described in Scheme
2 was followed, starting from 10 synthesised as previ-
ously reported.1,3
Product
d
NH (ppm) dNH (ppm)
(in 2 mM
CDCl3)
DdNH/DT
(ppb/ꢁC)
IR (cmꢀ1
(2 mM
(in CDCl3) CHCl3)
)
(in 2 mM
CDCl3/
DMSO)
H1
H2
7.0
H1
H2
H1 H2
5
7.5
8.1
7.4
6.6
7.9a
7.4a ꢀ2.0 ꢀ2.1 3415 (sharp)
3303 (broad)
8.0a
7.2a ꢀ3.8 ꢀ1.0 3370 (broad)
3425 (sharp)
7.5a ꢀ1.9 ꢀ2.2 3376 (broad)
3281 (broad)
1
3. H NMR and IR studies
9
7.1
14
6.95 7.5a
Firstly, it is important to underline that Ôno classicalÕ
tripeptides 5, 9 and 14 possess a symmetry element, that
is, a C2-axis. In fact, as previously observed for similar
derivatives,1,3,4 the 1H NMR and 13C NMR spectra
show half of the expected signals (see above).
15
16
6.1
7.25b 6.9b ꢀ2.1 ꢀ2.1 3428 (sharp)
6.95 6.3
7.4c
7.0c ꢀ0.9 ꢀ1.5 3429 (sharp)
3387 (sharp)
d
17
17
6.6
8.5
5.9
6.2
8.4f
8.5f
7.9f ꢀ1.5 ꢀ1.5 3430 (sharp)
The simple peptides 15, 16 and 17, 18, synthesised start-
ing from 10 and 1, respectively, (Scheme 2) have been
investigated as models in order to acquire spectroscopic
data useful for deducing the geometry of the more com-
e
8.0f ꢀ6.0 ꢀ1.5 3299 (broad)
18
6.9
6.4
7.3g
7.0g ꢀ0.4 ꢀ1.9 3437 (sharp)
3388 (sharp)
1
plex tripeptides 5, 9 and 14 through H NMR and IR
a In CDCl3/DMSO = 80/20.
b In CDCl3/DMSO = 96/4.
c In CDCl3/DMSO = 88/12.
d More abundant conformer.
e Less abundant conformer.
f In 100% DMSO.
informations. In fact, unnatural peptides 16, 17 and 18
can be considered as monomeric structures of 14, 5
and 9, respectively. To determine the structural features
of the uncommon peptides synthesised, we performed
conformational investigations by both 1H NMR and
IR spectroscopies, as well as by molecular modelling
studies.2–4,9
g In CDCl3/DMSO = 92/8.
The meaningful 1H NMR and IR data of substrates sub-
mitted to the investigation are listed in Table 1 and, for
clarity their amide protons are labelled as H1 and H2
(see Schemes 1–3).
NHs. These data and the small temperature coefficient,
DdNH/DT, suggest that dipeptide 15 most probably
forms intermolecular hydrogen bonds, which are broken
by the addition of just 4% of DMSO. This hypothesis is
strengthened by the spectroscopic data of peptide 17,
which exists in two conformations in a ratio of ꢁ1/3,
as evidenced by the 1H NMR spectrum. In CDCl3 solu-
tion, the H1 and the H2 of the less abundant conformer
resonate at 8.5 and at 6.2 ppm, respectively, while in the
more abundant one they resonate at 6.6 and at 5.9 ppm,
respectively. In DMSO, the H1 doublet of the minor
conformer does not change while the H2 undergoes a rele-
vant downfield shift. In addition, the less abundant
conformer shows a temperature coefficient value of
In a 20 mM CDCl3 solution of 15, H1 and H2 protons
resonate at 6.9 and 6.35 ppm, respectively, and in a
2 mM solution they are shifted upfield to 6.6 and
6.1 ppm, respectively. By adding only 4% of DMSO (a
competitive solvent in the formation of hydrogen
bonds), both protons suffer a significant downshift to
7.25 and 6.9 ppm, respectively. Besides, the IR spectrum
in the 2 mM CHCl3 solution shows only one intense
sharp band at 3428 cmꢀ1, ascribable to the free amidic
COOEt
COOEt
NH2COCH3
CH3
CH3
iv, i, ii, iii
i, ii, iii
NH1
NH1
10
N
H2
O
CH3
O
O
15
16
COOEt
COOEt
NH1
iv, v, i, ii, iii
NH2COCH3
iv, i, ii, iii
1
NH1
COCH3
N
H2
CH3
O
O
18
17
Scheme 3. Reagents and conditions: (i) Li/NH3; (ii) 0.5 M HCl at rt, then 1 M Na2CO3; (iii) CH3COCl/Et3N in CH2Cl2; (iv) LHMDS/THF, then
CH2@C(CH3)CH2Cl; (v) LHMDS/THF, then CH3I.

1106
D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1103–1112
ꢀ6.0 ppb/ꢁC for H1 and ꢀ1.5 ppb/ꢁC for H2. Con-
versely, both H1 and H2 of the prevalent conformer suf-
fer a large downfield shift in DMSO and show the same
small value of the temperature coefficient. The IR spec-
trum in 2 mM CHCl3 solution shows one sharp band at
3430 cmꢀ1, attributable to the free amidic NH, and the
less intense broad band at 3299 cmꢀ1 attributable to a
hydrogen bonding structure. These findings lead us to
believe that the minor conformer most probably forms
an intramolecular hydrogen bond between H1 and the
acetamidic carbonyl oxygen giving rise to a cyclic
seven-membered structure, while in the major conformer
any hydrogen bond is present, analogous to that ob-
served for 15. We believe that the value of ꢀ6.0 ppb/
ꢁC, calculated for the H1 in the less abundant con-
former, is probably due to the existence of a dynamic
equilibrium between the intramolecularly hydrogen-
bonded and non-hydrogen-bonded structure, the latter
increasing with the temperature.
addition, the IR spectrum of 9 shows a very broad band
centred at 3370 cmꢀ1 attributable to the hydrogen
bonded NHÕs amide. These findings suggest that both
H1 and H2 probably form intramolecular hydrogen
bonds. Thus, it is possible to infer that the presence of
CH3 at C-5 and C-9 positions favours the formation
of intramolecular hydrogen bonds between the amide
NHs and the carbonyl groups, making the structure very
compact.
In tripeptide 16, the H1 protons resonate at 6.95 and
6.3 ppm, respectively, which are shifted to a lower field
after addition of 12% DMSO, and show a temperature
coefficient of ꢀ0.9 ppb/ꢁC and ꢀ1.5 ppb/ꢁC, respec-
tively. The IR spectrum shows two sharp bands of com-
parable intensity at 3429 and 3387 cmꢀ1 ascribable to
free amidic NHs. Thus, it is reasonable to deduce that
16, analogously to 15, does not form hydrogen bonds.
The H2 protons of the tripeptide 14 absorb as a singlet
at 6.95 ppm, in 2 mM CDCl3 solution, which is shifted
downfield to 7.5 ppm after addition of 20% DMSO;
their temperature coefficient in CDCl3 solution is
ꢀ2.2 ppb/ꢁC. Neither H1 protons (doublet at 7.4 ppm,
DdNH/DT = ꢀ1.9 ppb/ꢁC) display concentration depen-
dence in CDCl3 nor do they undergo an appreciable
shift downfield by adding 20% of DMSO
(dNH = 7.5 ppm). The IR spectrum exhibits two broad
bands at 3281 and 3376 cmꢀ1, ascribable to the two dif-
ferent hydrogen bonded –NHs amide, and one sharp
band at 3425 cmꢀ1 characteristic of a free –NH amide.
From these data it can be believed that H1 probably
forms a strong intramolecular hydrogen bond, while
H2 a weaker one. Therefore, from the comparison be-
tween 9 and 14, it is possible deduce that the absolute
configurations of C-5 and C-9 affect the conformation
of the tripeptide. In fact, from the spectroscopic data
we can deduce that, owing to the formation of the two
strong intramolecular hydrogen bonds, tripeptide 9 pos-
sesses a more organised structure than 14.
In tripeptide 5, which can be considered a dimeric struc-
ture of 17, both H2 protons, which do not display con-
centration dependence, absorb as a doublet at 7 ppm
in CDCl3 (DdNH/DT = ꢀ2.1 ppb/ꢁC) and the signal
shifted to 7.4 ppm by adding 20% DMSO. The H1 pro-
tons, which absorb as doublet at 7.5 ppm (DdNH/DT =
ꢀ2 ppb/ꢁC) and display no concentration dependence,
are downfield shifted by 0.4 ppm on the addition of
20% DMSO, as exhibited by the H2 protons. Besides,
the IR spectrum shows a broad band at 3303 cmꢀ1
,
ascribable to a hydrogen bonded NH amide, and a
sharp band at 3415 cmꢀ1 characteristic of a free NH
amide.
By comparing these data with those reported for 17 and
15, it is possible to argue that tripeptide 5 exists in a con-
formation in which both H1 and H2 are engaged in
intramolecular hydrogen bonds.
Dipeptide 18 in CDCl3 shows a doublet at 6.9 ppm for
H1 and a singlet at 6.4 ppm for H2, which suffer a signif-
icant downfield shift by adding only 8% of DMSO and
show a temperature coefficient of ꢀ0.4 and ꢀ1.9 ppb/
ꢁC, respectively. The IR spectrum shows two sharp
bands at 3437 and 3388 cmꢀ1 of comparable intensity
ascribable to two different free NHs amide. In fact, the
structure resolved by X-ray crystallography (see later)
shows the presence of an intermolecular hydrogen bond
between H1 and the acetamidic carbonyl oxygen and a
weak intramolecular hydrogen bond between H2 and
(C-4)@O which gives rise to a five-membered cyclic
structure.
4. Molecular modelling: conformational analysis
A complete, extensive unconstrained conformational
analysis of 5, 9 and 14 was performed by using AM-
BER* force field10 and the Monte Carlo conformational
search11 (MC/EM), all degrees of freedom being varied.
A relative nonpolar solvent, such as CHCl3, was chosen
in order to not interfere in hydrogen bonding of the
amide protons and to compare these results with the
1H NMR data. All the conformers within the energy
gap of 6 kcal/mol were kept and subsequently only the
ones below 3.6 kcal/mol were fully analysed.
In tripeptide 9, the magnetically equivalent H2 protons
absorb as a singlet at 7.1 ppm in 2 mM CDCl3 solution
and are shifted to 7.2 ppm by adding 20% of DMSO.
Additionally, these protons show no concentration
The investigated compounds show a preference to
assume very compact conformations in which both ami-
dic protons H1 and H2 form intramolecular hydrogen
bonds, according to that deduced from spectroscopic
data. Among the conformers significantly populated,
that is, population >3.0%, at 298 K (Tables 2–4) a rele-
vant role is played by the two most populated
conformations.
dependence and a small temperature coefficient (DdNH
/
DT = ꢀ1 ppb/ꢁC). The H1 protons, which do not display
concentration dependence, absorb as a doublet at
8.1 ppm, are shifted to 8.0 ppm after the addition of
20% DMSO and exhibit a temperature coefficient
DdNH/DT = ꢀ3.8 ppb/ꢁC in 2 mM CDCl3 solution. In

D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1103–1112
Table 2. Most significant low energy conformers of 5 (438 within
6 kcal/mol, 14 within 2.0 kcal/mol)
1107
COOEt
EtOOC
NHAc (C=O63)
H33 NHAc (C=O64)
27 HN
NH 37
O
O
5
34
Conformers
Energy
(kcal/mol)
Number of H-bonds
Population
(%)
1
2
3
4
5
6
7
0.0
3
3
3
3
3
3
3
37.0
14.8
8.9
0.54
0.84
0.87
0.90
0.95
1.46
8.5
8.1
7.0
3.0
Figure 1. Lowest energy conformation for compound 5 (the arrows
point out the hydrogen bonds).
Table 3. Most significant low energy conformers of 9 (399 within
6 kcal/mol, 15 within 2.0 kcal/mol)
In molecule 5, all conformers show the existence of
intramolecular amidic hydrogen bonds. In particular,
in the lowest energy conformers (1 and 2 in Table 2)
the two strongest intramolecular hydrogen bonds
COOEt
NHAc (C=O68)
EtOOC
H71 NHAc (C=O78)
52 HN
NH 27
˚
˚
(1.81 A H33ꢂ ꢂ ꢂO63 and 1.93 A H27ꢂ ꢂ ꢂO34) form two rings
˚
of 10 terms (Fig. 1), while the third one (1.86 A
H C
3
CH
3
O
34
O
H37ꢂ ꢂ ꢂO64) gives rise to a seven-membered ring. It is
noteworthy that the major difference among the most
populated conformations lies in the orientation of the
lateral chains.
9
Conformers
Energy
(kcal/mol)
Number of H-bonds
Population
(%)
1
2
3
4
5
6
7
8
0.0
3
3
3
3
3
3
3
2
36.6
11.0
9.6
8.4
6.2
5.9
5.1
4.4
From the examination of the lowest energy conforma-
tions of 9 (Table 3), it can be observed that conformer
1 shows three intramolecular amidic hydrogen bonds
(1.80 A H52ꢂ ꢂ ꢂO68, 1.86 A H27ꢂ ꢂ ꢂO78 and 1.73 A
H71ꢂ ꢂ ꢂO34) forming two seven-membered rings and a
nine-membered one (Fig. 2). In conformations 2 and 3
both H52 and H71 form hydrogen bonds with the
carbonyl oxygen O68 giving rise to both a seven- and a
0.71
0.79
0.88
1.06
1.08
1.11
1.25
˚
˚
˚
˚
˚
ten-membered ring (1.78 A H71ꢂ ꢂ ꢂO68 and 1.86 A
H52ꢂ ꢂ ꢂO68), the third one being the same of conformer 1
Table 4. Most significant low energy conformers of 14 (291 within
6 kcal/mol, 14 within 2.0 kcal/mol)
˚
(1.86 A H27ꢂ ꢂ ꢂO78).
In the lowest energy conformation the molecule 14
(Table 4) shows three amidic intramolecular hydrogen
EtOOC
COOEt
˚
˚
˚
bonds (1.86 A H27ꢂ ꢂ ꢂO71, 1.73 A H52ꢂ ꢂ ꢂO73 and 1.80 A
H51ꢂ ꢂ ꢂO12), which give rise to two seven-membered rings
and one of 9 terms (Fig. 3). Also in conformers 2 and 3,
the hydrogen bonds produce two seven-membered rings
and one of 9 terms. Conformer 4, analogously to 1,
H76 NHAc (C=O71)
NHAc (C=O73)
H51
HN
52
NH
27
CH
H C
3
3
14
O
34
O
12
˚
shows the existence of three hydrogen bonds (1.73 A
˚
˚
Conformers
Energy
(kcal/mol)
Number of H-bonds
Population
(%)
H27ꢂ ꢂ ꢂO71, 1.80 A H52ꢂ ꢂ ꢂO73 and 1.73 A H76ꢂ ꢂ ꢂO34)
forming two seven-membered rings and a nine-mem-
bered one.
1
2
3
4
5
6
7
0.0
3
3
3
3
2
2
3
45.3
19.5
6.8
0.55
1.13
1.43
1.51
1.53
1.57
In the conformation with reduced hydrogen bonds, we
can observe the presence of two rings, one of 10 and
4.1
3.6
˚
˚
one of 7 terms (1.82 A H51ꢂ ꢂ ꢂO71, 1.82 A H52ꢂ ꢂ ꢂO73), con-
firming the importance of the configuration of C-5 and
C-9 stereocentres, as suggested by the 1H NMR data.
3.6
3.2

1108
D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1103–1112
Figure 3. Lowest energy conformation for compound 14 (the arrows
point out the hydrogen bonds).
5. X-ray analysis
In the solid state, two conformers of 18 are present in
the asymmetric unit, but only one is shown in Figure 4
because the sole difference between them is in the orien-
tation of the C2H5 group belonging to the ester moiety
Figure 2. Lowest energy conformation for compound 9 (the arrows
point out the hydrogen bonds).
Figure 4. Molecular structure (SCHAKAL drawing) of 18, the intramolecular N(2)–H(2n)ꢂ ꢂ ꢂO(3) hydrogen bond being outlined in purple.
Figure 5. Crystal packing of 18 (hydrogen bonds are outlined in purple).

D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1103–1112
1109
[the angles O(1)C(3)O(2) and O(1)C(2)C(1) being
43.7(8)ꢁ and 6.0(6)ꢁ, respectively]. A weak intramolecu-
lar hydrogen bond connects the carbonyl oxygen O(3)
with the amidic hydrogen H(2n): N(2)–H(2n)ꢂ ꢂ ꢂO(3),
stirring. After about 2 h, 2 M HCl (5 mL) was added
and the reaction product extracted by ethyl acetate.
The organic solution was dried over Na2SO4 and the
solvent completely evaporated under vacuum. The resi-
due was then submitted to purification by silica gel chro-
matography eluting with hexane/ethyl acetate. The pure
product was recovered as a solid (mp 144.5–146 ꢁC) in
˚
112(2)ꢁ, H(2n)ꢂ ꢂ ꢂO(3) 2.22(3) A.
The two conformers are linked together through an
intermolecular hydrogen bond between the amidic
hydrogen and the carbonyl oxygen of the amidic
units not engaged in the intramolecular hydrogen bond
1
80% yield. H NMR d 0.97 (d, 6H, J = 6.6); 1 (d, 6H,
J = 6.6); 1.31 (t, 6H, J = 6.9); 2.05 (s, 6H); 2.24 (m,
2H); 2.46 (dd, 2H, J = 8.1, 14.7); 2.61 (dd, 2H, J = 5.4,
14.7); 4.23 (q, 4H, J = 6.9); 4.47 (dd, 2H, J = 5.1, 8.4);
4.85 (s, 2H); 4.93 (m, 2H); 7.05 (d, 2H, J = 7.8); 7.54
(d, 2H, J = 8.4). 13C NMR d 14.1, 17.6, 19, 22.8, 30.7,
40.5, 51.3, 57.5, 61, 115.3, 140.4, 170.6, 171.4, 172.
[a]D = +40.7 (c 0.7, CHCl3). Anal. Calcd for
C26H44N4O8: C, 57.76; H, 8.2; N, 10.36. Found: C,
57.88; H, 8.2; N, 10.35.
˚
˚
[N(1)–H(1N)ꢂ ꢂ ꢂO(4a), 162(2)ꢁ, H(1N)ꢂ ꢂ ꢂO(4a) 2.24(3) A,
N(1a)–H(1N1)ꢂꢂꢂO(4), 177(3)ꢁ, H(1N1)ꢂꢂꢂO(4) 2.11(3) A].
In the crystal packing (Fig. 5), each conformer is
engaged in two intermolecular hydrogen bonds using
both the amidic NHs and the carbonyl oxygen, thus
generating a zig-zag chain.
6. Experimental
6.4. 1-[(30S,300S,60S,600S)-10Benzyl-60-hydro-50-hetoxy-60-
isopropyl-pirazin-30-methyl-30-yl-20-one]-3-[100-benzyl-
300,600-dihydro-500-hetoxy-600-isopropyl-300-methyl-pirazin-
300-yl-200one]-2-methylenpropane, 6
6.1. General information
Melting points are uncorrected. 1H and 13C NMR spec-
tra were recorded on a Gemini spectrometer at 300 MHz
using CDCl3 as the solvent. Chemical shifts are reported
in ppm relative to CDCl3 and the coupling constants (J)
are in Hz. IR spectra were recorded on a Nicolet 210
spectrometer. Optical rotation values were measured at
25 ꢁC on a Perkin–Elmer 343 polarimeter. Dry THF
was distilled from sodium benzophenone ketyl. Chro-
matographic separations were performed with silica gel
60 (230–400 mesh). Synthesis and spectroscopic data
of compounds 1, 2, 3 and 10 are reported in Refs. 1
and 3.
To a stirred solution of 2 (1.2 g, 2 mmol) in dry THF
(50 mL) and cooled at ꢀ78 ꢁC, a solution of LHMDS
in THF (1 M, 4 mL) was added under an inert atmo-
sphere. After about 1 h, CH3I (0.25 mL, 4 mmol) was
added and the reaction monitored by TLC. When the
reaction reached completion, the mixture was allowed
to warm up to room temperature under stirring. Water
and ethyl acetate were added and after separation, the
organic solvent was completely removed in vacuo. The
residue was submitted to silica gel chromatography elut-
ing with hexane/ethyl acetate and the pure product ob-
1
tained as an oil in 85% yield. H NMR d 0.93 (d, 6H,
6.2. (2S,5R,9R,12S)-5,9-Diamino-3,11-diaza-2,12-diiso-
propyl-4,10-dioxa-7-methylentridecane-1,13-dicarboxylic
acid diethylester, 4
J = 6.6); 1.01 (d, 6H, J = 7.2); 1.28 (t, 6H, J = 6.9);
1.43 (s, 6H); 2.2 (m, 2H); 2.64 (d, 2H, J = 12.9); 2.79
(d, 2H, J = 12.9); 3.73 (d, 2H, J = 3); 3.97 (d, 2H,
J = 15); 4.14 (m, 4H); 5.12 (s, 2H); 5.49 (d, 2H,
J = 15); 7.23–7.36 (m, 10ArH). 13C NMR d 14.2, 17.2,
20.6, 29.9, 30.7, 46.8, 47.3, 60.5, 61.1, 61.8, 119.9,
127.4, 128.0, 128.6, 136.6, 141.7, 155.0, 172.5.
[a]D = +38 (c 1, CHCl3). Anal. Calcd for C38H52N4O4:
C, 72.58; H, 8.33; N, 8.91. Found: C, 72.55; H, 8.3; N,
8.9.
A solution of 3 (2.65 g, 5 mmol) and K2CO3 (1.4 g,
10 mmol) in water (20 mL) was stirred for 1 h, the reac-
tion product was then extracted with ethyl acetate and
the organic solution washed with water. After complete
removal of the organic solvent in vacuo, the product was
purified by silica gel chromatography eluting with hex-
ane/ethyl acetate and the pure product was isolated in
1
95% yield. H NMR d 0.90 (d, 6H, J = 6.6); 0.93 (d,
6.5. 1-[(30S,300S,60S,6000S)-60-Hydro-50-hetoxy-60-isoprop-
yl-pirazin-30-methyl-3 -yl-20-one]-3- [300,600-dihydro-500-
hetoxy-600-isopropyl-300-methyl-pirazin-300-yl-200one]-2-
methylenpropane, 7
6H, J = 6.6); 1.26 (t, 6H, J = 7); 1.62 (br s, 4H); 2.15
(m, 4H); 2.73 (dd, 2H, J = 3.4, 14.2); 3.58 (dd, 2H,
J = 3.6, 11); 4.18 (m, 4H); 4.44 (dd, 2H, J = 5.2, 9.2);
4.99 (s, 2H); 7.94 (d, 2H, J = 9.2). 13C NMR d 14.2,
17.7, 19, 31, 40.2, 52.3, 56.9, 61.1, 117.8, 142.1, 171.9,
176.6. [a]D = +22.5 (c 1, CHCl3). Anal. Calcd for
C22H40N4O6: C, 57.87; H, 8.83; N, 12.27. Found: C,
57.94; H, 8.85; N, 12.25.
Intermediate 6 (3.14 g, 5 mmol), dissolved in dry THF/
tert-butanol 9:1 (20 mL), was added to a solution of Li
(0.07 g, 10 mmol) in liquid ammonia (ca. 50 mL), cooled
at about ꢀ50 ꢁC and stirred under an inert atmosphere.
After 5 min, the reaction mixture was quenched with 1 g
of NH4Cl and the cooling bath removed allowing the
complete removal of NH3. After addition of water, the
aqueous solution was extracted with ethyl acetate and
the organic solution evaporated to dryness under vac-
uum. The pure product was recovered as an oil in 80%
yield after silica gel chromatography by eluting with
6.3. (2S,5R,9R,12S)-5,9-Diacetyldiamino-3,11-diaza-
2,12-diisopropyl-4,10-dioxa-7-methylentridecane-1,13-
dicarboxylic acid diethylester, 5
To a solution of 4 (2.28 g, 5 mmol) and triethylamine
(2.8 mL, 20 mmol) in CH2Cl2 (20 mL) cooled at 0–
5 ꢁC was added acetyl chloride (1.1 mL, 15 mmol) under
1
hexane/ethyl acetate. H NMR d 0.82 (d, 6H, J = 6.6);

1110
D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1103–1112
0.97 (d, 6H, J = 7.4); 1.29 (t, 6H, J = 7.4); 1.35 (s, 6H);
2.15 (m, 2H); 2.43 (d, 2H, J = 12.8); 2.76 (d, 2H,
J = 12.8); 3.92 (dd, 2H, J = 1.4, 3.2); 4.17 (q, 4H,
J = 7.4); 4.96 (s, 2H); 6 (s, 2H). 13C NMR d 14.5, 16.2,
18.6, 29.6, 30.5, 47.3, 58.2, 61.1, 62.2, 119.0, 142.2,
155.4, 173.9. [a]D = +93.2 (c 0.5, CHCl3). Anal. Calcd
for C24H40N4O4: C, 64.26; H, 8.99; N, 12.49. Found:
C, 64.48; H, 8.98; N, 12.5.
60.3, 60.6, 62.5, 117.5, 127.3, 128.3, 128.4, 135.5,
142.8, 155.0, 171.5. [a]D = ꢀ107.6 (c 1.1, CHCl3). Mp
237–240 ꢁC (dec.). Anal. Calcd for C38H52N4O4: C,
72.58; H, 8.33; N, 8.91. Found: C, 72.35; H, 8.35; N,
8.92.
6.9. 1-[(30R,300R,60S,600S)-60-Hydro-50-hetoxy-60-isoprop-
yl-pirazin-30-methyl-30-yl-20-one]-3-[300,600-dihydro-500-
hetoxy-600-isopropyl-300-methyl-pirazin-300-yl-200one]-2-
methylenpropane, 12
6.6. (2S,5S,9S,12S)-5,9-Diamino-5,9-dimethyl-3,11-di-
aza-2,12-diisopropyl-4,10-dioxa-7-methylentridecane-
1,13-dicarboxylic acid diethylester, 8
It was obtained in 80% yield following the procedure
1
used for the preparation of 7. H NMR d 0.83 (d, 6H,
To a solution of 7 (2.24 g, 5 mmol) in ethanol (40 mL)
was added 0.5 M HCl (20 mL) and the reaction mixture,
monitored by TLC, stirred at room temperature for
about 12 h. The acid solution was evaporated in vacuo
and the crude product stirred for 2 h with K2CO3
(2.1 g, 15 mmol) in water (5 mL). The reaction product
was extracted with ethyl acetate and the organic solution
washed with water. The organic solvent was then evap-
orated in vacuo and the product was purified by silica
gel chromatography eluting with hexane/ethyl acetate.
The product was isolated as an oil in 90% yield 1H
NMR d 0.92 (d, 12H, J = 7); 1.27 (t, 6H, J = 7); 1.29
(s, 6H); 2.18 (m, 2H); 2.19 (d, 2H, J = 13.8); 2.75 (d,
2H, J = 13.8); 4.17 (m, 4H); 4.38 (dd, 2H, J = 5.2, 9.2);
5 (s, 2H); 8.32 (d, 2H, J = 9.2). 13C NMR d 13.9, 17.5,
18.8, 27.7, 30.4, 45.9, 56.9, 57, 60.7, 119, 141.5, 171.6,
177.1. [a]D = ꢀ43.7 (c 1.6, CHCl3). Anal. Calcd for
C24H44N4O6: C, 59.48; H, 9.15; N, 11.56. Found: C,
59.62; H, 9.17; N, 11.52.
J = 6.6); 0.96 (d, 6H, J = 7.4); 1.28 (t, 6H, J = 7.2);
1.28 (s, 6H); 2.25 (m, 2H); 2.27 (d, 2H, J = 13.2); 2.73
(d, 2H, J = 13.2); 3.87 (dd, 2H, J = 1.8, 2.4); 4.16 (m,
4H); 4.83 (s, 2H); 6.1 (br s, 2H). 13C NMR d 14.3,
16.0, 18.2, 28.9, 30.8, 48.3, 58.4, 60.9, 61.8, 116.7,
142.5, 155.9, 173.9. [a]D = ꢀ95.5 (c 1.1, CHCl3). Anal.
Calcd for C24H40N4O4: C, 64.26; H, 8.99; N, 12.49.
Found: C, 64.24; H, 9.02; N, 12.47.
6.10. (2S,5R,9R,12S)-5,9-Diamino-5,9-dimethyl-3,11-
diaza-2,12-diisopropyl-4,10-dioxa-7-methylentridecane-
1,13-dicarboxylic acid diethylester, 13
It was obtained in 85% yield following the procedure
1
used for the preparation of 8. H NMR d 0.91 (d, 6H,
J = 7.2); 0.94 (d, 6H, J = 7.2); 1.26 (t, 6H, J = 7); 1.30
(s, 6H); 1.70 (br s, 4H); 2.08 (d, 2H, J = 14.7); 2.21
(m, 2H); 2.83 (d, 2H, J = 14.7); 4.20 (m, 4H); 4.42 (dd,
2H, J = 4.8, 9.3); 4.93 (s, 2H); 8.29 (d, 2H, J = 9.3).13C
NMR d 14.1, 17.4, 18.9, 28.9, 30.9, 46.7, 56.5,
56.7, 60.8, 117.1, 141.9, 171.8, 176.9. [a]D = +17.2
(c 1, CHCl3). Anal. Calcd for C24H44N4O6: C,
59.48; H, 9.15; N, 11.56. Found: C, 59.7; H, 9.12; N,
11.59.
6.7. (2S,5S,9S,12S)-5,9-Diacetyldiamino-5,9-dimethyl-
3,11-diaza-2,12-diisopropyl-4,10-dioxa-7-methylentri-
decan-1,13-dicarboxylic acid diethylester, 9
It was obtained in 80% yield following the procedure
1
used for the preparation of 5. H NMR d 0.92 (d, 6H,
J = 7); 0.98 (d, 6H, J = 7); 1.34 (t, 6H, J = 7); 1.75 (s,
6H); 1.97 (s, 6H); 2.28 (d, 2H, J = 14); 2.3 (m, 2H);
3.18 (d, 2H, J = 14); 4.26 (q, 4H, J = 7); 4.85 (m, 4H);
7.05 (s, 2H); 8.08 (d, 2H, J = 9.6). 13C NMR d 14,
17.3, 19.1, 24.1, 24.6, 31.3, 39.4, 57.2, 60.1, 61.9, 120.3,
137.9, 169.1, 173.8, 174.2. [a]D = +21.6 (c 0.4, CHCl3).
Mp 195.5–197 ꢁC. Anal. Calcd for C28H48N4O8: C,
59.13; H, 8.51; N, 9.85. Found: C, 59.25; H, 8.5; N, 9.88.
6.11. (2S,5R,9R,12S)-5,9-Diacetyldiamino-5,9-dimethyl-
3,11-diaza-2,12-diisopropyl-4,10-dioxa-7-methylentride-
cane-1,13-dicarboxylic acid diethylester, 14
It was obtained in 85% yield following the procedure
1
used for the preparation of 9. H NMR d 0.94 (d, 6H,
J = 7); 0.99 (d, 6H, J = 7); 1.3 (t, 6H, J = 7.4); 1.61 (s,
6H); 2.08 (s, 6H); 2.22 (m, 2H); 2.67 (qAB, 4H,
J = 14.6); 4.21 (m, 4H); 4.46 (dd, 2H, J = 4.8, 8.2);
5.06 (s, 2H); 6.98 (s, 2H); 7.44 (d, 2H, J = 8.2). 13C
NMR d 14.1, 17.7, 18.9, 23.9, 31.0, 43.4, 57.7, 59.6,
61.1, 121.1, 139.9, 170.9, 171.8, 174.2. [a]D = +69.7
(c 0.9, CHCl3). Anal. Calcd for C28H48N4O8: C,
59.13; H, 8.51; N, 9.85. Found: C, 59.05; H, 8.52; N,
9.85.
6.8. 1-[(30R,300R,60S,600S)-10Benzyl-60-hydro-50-hetoxy-60-
isopropyl-pirazin-30-methyl-30-yl-20-one]-3-[100-benzyl-
300,600-dihydro-500-hetoxy-600-isopropyl-300-methyl-pirazin-
300-yl-200one]-2-methylenpropane, 11
It was obtained as a solid in 85% yield by alkylation of
101 with 2-chloromethyl-3-chloropropene and following
the procedure already reported for an analogous deriva-
tive.1 1H NMR d 0.84 (d, 6H, J = 6.6); 1 (d, 6H, J = 6.9);
1.25 (t, 6H, J = 7.2); 1.44 (s, 6H); 2.17 (m, 2H); 2.41 (d,
2H, J = 12.6); 2.79 (d, 2H, J = 12.6); 3.65 (d, 2H,
J = 2.4); 3.93 (d, 2H, J = 15.3); 4.04–4.3 (m, 4H); 4.81
(s, 2H); 5.42 (d, 2H, J = 15.3); 7.18–7.38 (m, 10ArH).
13C NMR d 14.1, 16.8, 20.2, 29.1, 29.2, 46.4, 49.2,
6.12. (2S,5R)-5-Acetylamino-3-aza-2-isopropyl-5-methyl-
4-oxa-hexanoic acid ethyl ester, 15
The product was obtained starting from 10 and follow-
ing the procedure reported in Scheme 3. 1H NMR d 0.94
(d, 3H, J = 6.9); 0,98 (d, 3H, J = 6.9); 1.3 (t, 3H,
J = 7.2); 1.42 (d, 3H, J = 6.9); 2.04 (s, 3H); 2.22 (m,

D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1103–1112
1111
1H); 4.22 (m, 2H); 4.55 (dd, 1H, J = 5.1, 9); 4.6 (m, 1H);
6.1 (d, 1H, J = 6.9); 6.6 (d, 1H, J = 10.2). 13C NMR d
14, 17.5, 18.6, 18.8, 22.7, 30.9, 48.6, 57.2, 61, 170.4,
171.5, 173.1. The product was not isolated in sufficiently
pure form to measure the specific rotation.
structures for each variable torsion angle was generated
and minimised until the gradient was less than 0.05 kJ/
A mol. The cyclic moieties containing the amide bonds
were also included into the search. Duplicate conforma-
tions and those with an energy in excess of 6 kcal/mol
above the global minimum were discarded.
6.13. (2S,5R)-5-Acetylamino-3-aza-2-isopropyl-5,7-
dimethyl-4-oxa-7-octenoic acid ethyl ester, 16
6.17. Crystallographic data
Single crystal X-ray diffraction data of 18: C16H28N2O4,
Fw 312.40, colourless parallelepiped, size: 0.35 ·
The product was obtained starting from 10 and follow-
ing the procedure reported in Scheme 3. 1H NMR d 0.92
(d, 3H, J = 6.9); 0.96 (d, 3H, J = 6.9); 1.28 (t, 3H,
J = 7.5); 1.65 (s, 3H); 1.71 (s, 3H); 2.01 (s, 3H); 2.21
(m, 1H); 2.76 (qAB, 2H, J = 14.4); 4.19 (m, 2H); 4.47
(dd, 1H, J = 4.5, 8.4); 4.78 (s, 1H); 4.93 (s, 1H); 6.3 (s,
1H); 6.95 (d, 1H, J = 8.4). 13C NMR d 14.2, 17.7,
18.9, 23.3, 24.2, 24.5, 31.1, 45, 57.6, 59.7, 61.2, 115.8,
141.4, 170.1, 171.8, 173.8. [a]D = +42.9 (c 1.4, CHCl3).
Anal. Calcd for C16H28N2O4: C, 61.5; H, 9.03; N,
8.97. Found: C, 61.31; H, 8.98; N, 8.94.
0.27 · 0.20 mm,
Orthorhombic,
˚
space
group
C2221, a = 12.446 (1) A, b = 15.880(1) A, c =
˚
3
˚
˚
36.796(3) A, V = 7272.5(9) A , theta range for data col-
lection 1.11–30.04ꢁ, Z = 16, F(000) = 2720, Dx =
1.141 mg/m3, l =0.082 mmꢀ1, data collected on a
Bruker AXS CCD diffractometer (Mo-Ka radiation,
˚
k = 0.71073 A) at 293(2) K, total of 47,712 reflections,
of which 10,643 unique [R(int) = 0.0675]. Empirical
absorption correction was applied, initial structure model
by direct methods. Anisotropic full-matrix least-squares
refinement on F2 for all non-hydrogen atoms yielded
R1 = 0.0508 and wR2 = 0.1265 for [I > 2r(I)] and
R1 = 0.1158 and wR2 = 0.1511 for all intensity data. All
hydrogen atoms were added in calculated position except
the amidic hydrogens that were located in the Fourier
map. Goodness-of-fit = 0.911. CCDC number is 252649.
6.14. (2S,5R)-5-Acetylamino-3-aza-2-isopropyl-7-methyl-
4-oxa-7-octenoic acid ethyl ester, 17
The product was obtained starting from 1 and following
the procedure reported in Scheme 3. H NMR (mixture
1
of conformers A+B) d 0.96 (m, 6H); 1.31 (m, 3H); 1.8 (s,
3H); 2.04 (m, 3H); 2.2 (m, 1H); 2.5 (m, 2H); 4.2 (m, 2H);
4.48 (m, 1H); 4.61 and 5.34 (m, 1H); 4.88 (m, 2H); 5.9
(d, HA, J = 6.9); 6.2 (d, HB, J = 9); 6.6 (d, HA,
J = 7.8); 8.5 (d, HB, J = 10.2). 13C NMR d 14, 17.6,
18.8, 21.9, 22.7, 30.8, 40.3, 51.2, 57.2, 60.9, 113.8,
140.8, 170.3, 171.5, 171.8. [a]D = +30 (c 1.1, CHCl3).
Anal. Calcd for C15H26N2O4: C, 60.38; H, 8.78; N,
9.39. Found: C, 60.12; H, 8.8; N, 9.42.
Acknowledgements
Thanks are due to the University of Bologna (ÔRicerca
fondamentale orientataÕ) for financial supports.
References
6.15. (2S,5S)-5-Acetylamino-3-aza-2-isopropyl-5,7-di-
methyl-4-oxa-7-octenoic acid ethyl ester, 18
1. Paradisi, F.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry
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The product was obtained starting from 1 and following
the procedure reported in Scheme 3. 1H NMR d 0.93 (d,
3H, J = 6.9); 0.96 (d, 3H, J = 6.9); 1.31 (t, 3H, J = 7.2);
1.66 (s, 3H); 1.7 (s, 3H); 2.02 (s, 3H); 2.2 (m, 1H), 2.83
(qAB, 2H, J = 14); 4.22 (m, 2H); 4.5 (dd, 1H, J = 4.6,
8.4); 4.76 (s, 1H); 4.9 (s, 1H); 6.4 (s, 1H); 6.9 (d, 1H,
J = 9.2). 13C NMR d 14.1, 17.6, 18.9, 23.3, 24, 24.1,
31.2, 43.7, 57.4, 59.9, 61.2, 115.7, 140.9, 170.2, 171.7,
174. Mp: 109–110 ꢁC. [a]D = ꢀ4.2 (c 0.8, CHCl3). Anal.
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C, 61.71; H, 9.05; N, 8.95.
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each molecule was randomly varied with the usage-di-
rected Monte Carlo conformational search of Chang–
Guida–Still. For each search, at least 1000 starting
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