Enantioselective synthesis of pseudotripeptides incorporating a γ-methylene derivative of 2,6-diaminopimelic acid: Part 6

Article abstract of DOI:10.1016/j.tetasy.2004.02.005

An efficient enantioselective synthesis of pseudotripeptides 5, 8a-d and 13a and b incorporating a 2,6-diamino-4-methylene-1,7-heptandioic acid residue, has been accomplished starting from the glycine derived chiral synthon 1 (from L-valine). The absolute configuration of the new stereocentres was assigned on the basis of ¹H NMR spectra. The geometry of derivative 4 was deduced on the basis of ¹H NMR parameters (δ_NH value, temperature coefficient, δ_NH change upon addition of DMSO or CD₃OD, NOE studies) and IR spectra.

Full text of DOI:10.1016/j.tetasy.2004.02.005

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1085–1093
Enantioselective synthesis of pseudotripeptides incorporating a
c-methylene derivative of 2,6-diaminopimelic acid: Part 6q
Daniele Balducci, Gianni Porzi* and Sergio Sandri*
Dipartimento di Chimica ÔG.CiamicianÕ, Universitꢀa di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 22 December 2003; revised 5 February 2004; accepted 11 February 2004
Abstract—An efficient enantioselective synthesis of pseudotripeptides 5, 8a–d and 13a and b incorporating a 2,6-diamino-4-meth-
ylene-1,7-heptandioic acid residue, has been accomplished starting from the glycine derived chiral synthon 1 (from L-valine). The
1
absolute configuration of the new stereocentres was assigned on the basis of H NMR spectra. The geometry of derivative 4 was
deduced on the basis of 1H NMR parameters (dNH value, temperature coefficient, dNH change upon addition of DMSO or CD3OD,
NOE studies) and IR spectra.
Ó 2004Elsevier Ltd. All rights reserved.
1. Introduction
(obtained from 2-chloromethyl-3-chloropropene and
NaI) afforded isomer 2 in good yield and with a high
diastereoselectivity (de P94%). The diastereomer
(30R,60S,300R,600S)-2 originated from a practically total
double 1,4-trans induction with respect to the isopropyl
group (Scheme 1) with the (30S,60S,300R,600S)-diastereo-
mer being recovered in a very small amount (2–3%).
However, the two diastereomers were easily separable
by silica gel chromatography and their stereochemistry
established on the basis of the 1H NMR spectra, as
already observed for a similar substrate.9 In fact, inter-
mediate 2 exhibited half the number of proton signals,
indicating the magnetic equivalence of symmetrical
protons and the existence of a C2 axis of symmetry. For
example, the signals for both iso-propyl groups (at 0.94
and 1.05 ppm) overlap as do the signals for the benzylic
protons (at 3.93 and 5.50 ppm), the (C-60)-H and (C-600)-
H (at 3.68 ppm), the (C-30)-H and (C-300)-H (at 4.3 ppm)
and the methyl protons of ethoxy group (at 1.22 ppm).
Our interest in the mimetics of 2,6-diamino-1,7-heptan-
dioic acid (2,6-DAP)1–5 is due to the fact that they can
function as inhibitors in the biosynthesis of L-lysine
(DAP/lysine pathway) and also have potential biological
activity both as antibacterial6 and herbicide agents.7
Recently, we reported an efficient enantioselective syn-
thesis of both the enantiomers of the 2,6-diamino-4-
methylene-1,7-heptanedioic acid5 since Jean-Marc
Girodeau et al.8 found that this c-methylene derivative
of 2,6-DAP is an inhibitor of bacterial growth (Esche-
richia coli). We also accomplished the synthesis both
enantiomerically pure forms of new structural analogues
of 2,6-diamino-4-methylene-1,7-heptanedioic acid start-
ing from a chiral dichetopiperazine derivative5 and of
uncommon tripeptides, structural variants of 2,6-DAP,
by using the chiral synthon 1, a mono-lactim ether,
easily synthesized from L
-valine.9;10
From the intermediate 2, submitted to a Birch reaction
to remove the benzyl groups, the aminoester 4 was ob-
tained, as a hydrochloride, after acid hydrolysis of 3
under mild conditions. Through a further acid hydro-
lysis, the intermediate 4 was converted into 5, a Ônon-
classical tripeptideÕ C-terminal at both ends of the chain,
which can be considered as a 2,6-DAP derivative.
2. Synthesis and stereochemical assignments
Herein we followed the strategy previously employed for
obtaining analogous derivatives of 2,6-DAP. Deproto-
nation of synthon 1 with LHMDS followed by alkyl-
ation with 0.5 equiv of 2-iodomethyl-3-iodopropene
Intermediate 2, after alkylation with various electro-
philes, gave 6 in good to very good chemical yields with
practically total regio- and diastereoselectivity (>98%)
(Scheme 2). The total 1,4-trans-stereoselection, induced
by the isopropyl group, was demonstrated by comparing
q Refs. 1–5 are considered to be Parts 1–5, respectively.
* Corresponding authors. E-mail: gianni.porzi@unibo.it
0957-4166/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.02.005

1086
D. Balducci et al. / Tetrahedron: Asymmetry 15 (2004) 1085–1093
OEt
OEt
OEt
OEt
OEt
N
N
6'
N
ii
i
6''
N
N
N
3''
3'
N
N
HN
NH
Ph
O
O
Ph
Ph
O
O
O
2
3
1
HOOC
COOH
NH3Cl
EtOOC
NH3Cl
COOEt
iv
iii
NH3Cl
NH3Cl
HN
NH
NH
HN
O
O
O
O
5
4
Scheme 1. Reagents and conditions: (i) 1 M LHMDS/THF, (ICH2)2C@CH2; (ii) Li/NH3; (iii) 0.5 M HCl at rt; (iv) 1 M HCl at 60 °C.
OEt
OEt
OEt
OEt
ii
i
N
N
N
N
2
N
N
HN
NH
R
R
Ph
O
O
Ph
O
O
6a-d
7a-d
HOOC
COOH
NH3Cl
iii
a) CH
b) CH32Ph
R =
NH3Cl
HN
NH
c) CH2CHCH2
d) CH3OCH2
R
O
O
8a-d
Scheme 2. Reagents and conditions: (i) LHMDS/THF, R–X; (ii) Li/NH3; (iii) 1 M HCl at 60 °C.
1
the H NMR spectra of 6a and 6b, on the basis of the
upfield shift induced on the H-60 by the phenyl shielding
of the benzyl group introduced on C-30. In fact, as al-
ready observed in analogous substrates,9;10 the phenyl
ring preferentially adopted the Ôaryl insideÕ arrangement
causing significant shielding on the cis-substituent at
C-60. The shielding of 0.53 ppm registered on 6b with
respect to 6a provided clear evidence of the cis-relation-
ship between (C-30)-CH2Ph and (C-60)-H. Consequently,
the absolute configuration of C-30 followed on from the
note (S)-configuration at the C-60 stereocentre.
giving 11 in very good chemical yield, as previously
observed for a similar substrate.10 From 11, submitted
to a Birch reaction to remove the benzyl groups, 12 was
obtained and after acid hydrolysis under mild condi-
tions, aminoester 13 was recovered as the hydrochloride.
In this strategy, 2-chloromethyl-3-chloropropene was
employed because by using 2-iodomethyl-3-iodopro-
pene, compound 14 could be obtained owing to the
intramolecular nucleophilic attack of the iminic nitrogen
on the iodoallyl group of the dialkylated intermediate,
which is not isolable as it quickly converts into the
bicyclic derivative (Scheme 4).
The intermediates 6, submitted to debenzylation, afford-
ed 7, in good chemical yields, and, after acid hydrolysis
the amino acids 8, were easily obtained as hydrochlor-
ides (Scheme 2).
1
Diastereomeric derivatives with opposite configurations
at the stereocentre C-30, in comparison to the com-
pounds described above, were obtained by using the
following alternative strategy. The protocol consisted of
an alkylation of the chiral synthon 1 to obtain 9, fol-
lowed by a second alkylation with 2-chloromethyl-3-
chloropropene to furnish 10.
3. H NMR and IR studies
1
First of all, it is noteworthy that the H NMR of the
Ônonclassical tripeptideÕ 4 is consistent with a symmet-
rical structure having a C2 axis. In fact, the signals for
both the iso-propyl groups overlap, as do the signals for
the methylene, methine and amide hydrogens, indicating
their magnetic equivalence (see Experimental). The
chemical shift of the magnetically equivalent amide
protons did not display concentration dependence,
suggesting that this pseudotripeptide did not exist in an
aggregate form, at least not in the concentration range
The intermediate 10 was then reacted with the Li-eno-
late of 1 to give 11, which is an epimer of 6 at the C-30
stereocentre (Scheme 3). The alkylation occurred with a
practically total regio- and diastereoselectivity (>98%)

D. Balducci et al. / Tetrahedron: Asymmetry 15 (2004) 1085–1093
OEt
1087
OEt
OEt
OEt
N
N
N
N
i
iii
ii
R
1
N
N
N
N
Cl
R
R
Ph
O
Ph
O
Ph
O
O
Ph
11
10
9
OEt
OEt
EtOOC
COOEt
NH3Cl
N
N
iv
v
NH3Cl
HN
NH
HN
NH
R
R
O
O
O
O
12
13
R = a) CH3, b) CH3CH=CH2
Scheme 3. Reagents and conditions: (i) LHMDS/THF, R–X; (ii) LHMDS/THF, (ClCH2)2C@CH2; (iii) Li-enolate of 1/THF; (iv) Li/NH3; (v) 0.5 M
HCl at rt.
O
OEt
OEt
I
N
N
N
+
I
I
N
N
N
CH3
CH3
CH3
Ph
O
Ph
O
Ph
O
9a
14
Scheme 4.
examined. The amide protons, which absorbed at
8.24ppm ( J ¼ 9:6 Hz) in 1.5 mM CDCl3, suffered a
downfield shift to 9.2 ppm in DMSO. Upon addition of
8% DMSO (a competitive solvent in the hydrogen bond
formation) to a solution of 4 in CDCl3 a downfield shift
of dNH of about 0.5 ppm was registered (Fig. 1). On
addition of DMSO, the allylic proton at 2.83 ppm re-
mained unchanged while that at 3.88 ppm underwent,
step by step, an upfield shift reaching 3.0 ppm upon
addition of about 10% DMSO (plot not reported). On
adding 10% of CD3OD to a solution of 4 in CDCl3, the
NH doublet at 8.24ppm shifted to 8.78 ppm, after
which, owing to proton–deuterium exchange, the signal
slowly decreased in intensity until it disappeared after
about 30 min.
The downfield shift of dNH induced by CD3OD or
DMSO was coherent with the presence of a hydrogen
bonded structure in CDCl3, which is disrupted by the
competitive solvent.11 Such an organized molecular
aggregation, presumably induced by two intramolecular
hydrogen bonds, was strengthened by the upfield shift
registered for the allylic protons on addition of DMSO.
The relatively slow H/D exchange rate of the amide
protons was probably due to the formation of a stronger
hydrogen bond between the amide protons of 4 and
methanol.11
Furthermore, from the linear dependence of dNH amide
protons on temperature, run on a 1.5 mM CDCl3 solu-
tion (plot not reported), a low value for the temperature
coefficient for the amide protons, DdNH=DT ¼ 0:4ppb/
°C, was found.
9.0
8.9
8.8
8.7
8.6
8.5
8.4
8.3
8.2
These findings (i.e., high dNH value, no concentration
dependence of dNH, low temperature coefficient and
DdNH ffi 0:5 ppm upon addition of a competitive solvent)
suggested the existence of a weak intramolecular
hydrogen bond between the –NH and C@O, giving rise
to a 10-membered ring (i.e., a Ônonclassical peptideÕ
mimetic b-turn structure), which was broken when a
competitive solvent (such as DMSO or CD3OD)
reached about 8–10% of concentration.12
0
2
4
6
8
10 12 14 16 18
% DMSO
Figure 1. Dependence of dNH amide protons on addition of DMSO to
a solution of 4 in CDCl3.

1088
D. Balducci et al. / Tetrahedron: Asymmetry 15 (2004) 1085–1093
Figure 2. Geometry assumed for 4 on the basis of the spectroscopic data described in Section 3.
Further support for the presence of an intramolecular
hydrogen bond came from IR spectra in CHCl3. In fact,
5. Experimental
both in 20 and in 2 mM solutions in CHCl3 a broad
band in the region þof 3160–3320 cmÀ1 ascribable to the
stretching of –NH3 and to the amide (–NH) hydrogen
bonded is displayed. Additionally, the absence of a
narrow adsorption at about 3420 cmÀ1, typical of free
–NH stretching, is indicative of the nonexistence of free
–NH.11
5.1. General information
1H and 13C NMR spectra were recorded on a Gemini
spectrometer at 300 MHz using CDCl3 as solvent, unless
otherwise stated. Chemical shifts are reported in ppm
relative to CDCl3. 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. Chromatographic
separations were performed by using silica gel 60 (230–
400 mesh).
Thus, we believe that compound 4 most probably exists
in a very compact conformation with two intramolecular
hydrogen bonds between the amide NHÕs and the
carbonyl groups producing a bicyclic 10-membered
structure. Figure 2 shows such a molecular structure,
which can be assumed as an inverse b-turn. Nevertheless,
the conformation drawn in Figure 2 is also supported by
NOE experiments. By irradiating the –NH a prevalent
NOE was registered on (C-2)-H while a minor NOE was
registered on the proton at C-3. The irradiation of –NH
gave a good NOE on the isopropyl group, but not on
the –COOEt. The NOE was also observed on both the
(C-2)-H and –NH by irradiating a proton bonded at C-3.
Conversely, irradiation of the other proton at C-3
registered only a NOE on the methylene protons.
5.2. 1-[(30R,60S)-10-Benzyl-30,60-dihydro-50-hetoxy-60-iso-
propyl-pirazin-30-yl-20-one]-3-[(300R,600S)-100-benzyl-300,600-
dihydro-500-hetoxy-600-isopropyl-pirazin-300-yl-200-one]-2-
methylenepropane, 2
To a stirred solution of 1 (5.48 g, 20 mmol) in dry THF
(50 mL) and cooled at )78 °C, a solution of LHMDS in
THF (1 M, 21 mL) was dropped under an inert atmo-
sphere. After about 1 h, 10 mmol of 2-iodomethyl-3-
iodopropene (obtained from 11 mmol of 2-chlorom-
ethyl-3-chloropropene and 20 mmol of NaI in acetone,
overnight at rt) was added and the reaction monitored
by TLC. When the reaction went to completion, the
mixture was allowed to warm up to room temperature
while 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 eluting with hexane/ethyl acetate
and the pure product obtained as an oil in 80% yield and
a de P94%. 1H NMR d 0.94(d, 6H, J ¼ 7); 1.05 (d, 6H,
J ¼ 7); 1.22 (t, 6H, J ¼ 7); 2.13–2.32 (m, 2H); 2.57 (dd,
2H, J ¼ 8:6, 14.2); 3.10 (dd, 2H, J ¼ 4, 14.2); 3.68 (dd,
2H, J ¼ 1:8, 4); 3.93 (d, 2H, J ¼ 15); 4.15 (m, 4H); 4.30
(ddd, 4H, J ¼ 1:4, 4, 8.6); 5 (s, 2H); 5.5 (d, 2H, J ¼ 15);
7.16–7.39 (m, 10ArH). 13C NMR d 13.7, 17.0, 19.5, 30.9,
39.9, 46.8, 57.3, 60.5, 61.3, 113.8, 126.9, 127.3, 127.4,
4. Conclusion
A simple stereoselective approach to Ônonclassical tri-
peptidesÕ C-terminal at both ends of the chain, con-
taining the 2,6-diaminoipimelic acid (2,6-DAP)
framework, was accomplished starting from L-valine.
The synthesis occurred in good chemical yields with high
stereocontrol.
1
From the analysis of both H NMR and IR data, it is
reasonable to deduce that compound 4 is aggregated
through the formation of two intramolecular hydrogen
bonds between the carbonyl oxygens and the amide
protons to form an inverse b-turn, that is the ÔU struc-
tureÕ schematized in Figure 2. Such a compact sym-
metrical conformation (having a C2 axis) is strengthened
by the NMR spectra where half signals were registered.
128.0, 128.1, 135.8, 144.0, 157.9, 169.6. ½aŠ ¼ +41.6
D
(c 1, CHCl3). IR (neat) mcmÀ1 : 1694(C @N), 1642 (C@O).

D. Balducci et al. / Tetrahedron: Asymmetry 15 (2004) 1085–1093
1089
Anal. Calcd for C36H48N4O4: C, 71.97; H, 8.05; N, 9.33.
Found: C, 72.15; H, 8.03; N, 9.35.
178.7, ½aŠ ¼ )47.2 (c 1.1, 1 M HCl). IR (CHCl3) mcmÀ1
:
D
1545 (N–C@O), 1685 (N–C@O), 1760 (COOH), 3100–
3350 (OH and NH3þ). Anal. Calcd for C18H34Cl2N4O6:
C, 45.67; H, 7.24; Cl, 14.98; N, 11.84. Found: C,45.75;
H, 7.26; Cl, 15.03 N, 11.8.
5.3. 1-[(30R,60S)-30,60-Dihydro-50-hetoxy-60-isopropyl-
pirazin-30-yl-20-one]-3-[(300R,600S)-300,600-dihydro-500-hetoxy-
600-isopropyl-pirazin-300-yl-200-one]-2-methylenepropane, 3
5.6. Alkylation of 2
To a stirred solution of Li (0.35 g, 50 mmol) dissolved in
liquid ammonia (ca. 50 mL), cooled at about )50 °C and
stirred under an inert atmosphere, was added a solution
of intermediate 2 (4.2 g, 7 mmol) in dry THF/tert-buta-
nol 9:1 (10 mL). After 5 min, the reaction was quenched
with 1 g of NH4Cl and the cooling bath removed
allowing complete removal of NH3. After the addition
of water, the aqueous solution was extracted with ethyl
acetate and the organic solution evaporated to dryness
under vacuum. The product was recovered as a wax in a
To a solution of 2 (0.6 g, 1 mmol), in dry THF (30 mL)
and cooled at )78 °C, 1 M LHMDS in THF (1.1 mL)
was added under stirring. After about 1 h, the appro-
priate alkylating reagent (1 mmol) was added and the
reaction monitored by TLC. When the reaction went to
completion, the mixture was allowed to warm up to
room temperature, after which water and ethyl acetate
were added. After separation, the organic solution was
dried and evaporated in vacuo. The residue was sub-
mitted to silica gel chromatography eluting with hexane/
ethyl acetate and the products, isolated as viscous oils,
obtained with a diastereoselectivity higher than 98%.
1
practically quantitative yield. H NMR d 0.88 (d, 6H,
J ¼ 7); 0.99 (d, 6H, J ¼ 7); 1.28 (t, 6H, J ¼ 7); 2.13–2.28
(m, 2H); 2.51 (dd, 2H, J ¼ 7:8, 14); 2.85 (dd, 2H,
J ¼ 4:4, 14); 3.9 (m, 2H); 4.16 (q, 4H, J ¼ 7); 4.23 (m,
2H); 4.96 (s, 2H); 5.83 (br s, 2H). 13C NMR d 14.1, 16.1,
18.1, 31.8, 40.4, 57.5, 58.0, 60.8, 114.8, 143.2, 157.8,
5.7. 1-[(30S,60S)-10-Benzyl-30-methyl-60-hydro-50-hetoxy-60-
isopropyl-pirazin-30-yl-20-one]-3-[(300R,600S)-100-benzyl-
300,600-dihydro-500-hetoxy-600-isopropyl-pirazin-300-yl-200-one]-
2-methylenepropane, 6a
172.1. ½aŠ ¼ +58.7 (c 1.1, CHCl3). IR (CHCl3) mcmÀ1
:
D
1672 (br, C@N and C@O). Anal. Calcd for C22H36N4O4:
C, 62.83; H, 8.63; N, 13.32. Found: C, 63.02; H, 8.65; N,
13.28.
Iodomethane was used as the alkylating reagent and the
pure product obtained in 90% yield. 1H NMR d 0.93 (d,
3H, J ¼ 7:2); 0.95 (d, 3H, J ¼ 7:2); 1.06 (d, 3H, J ¼ 7);
1.10 (d, 3H, J ¼ 7); 1.24(t, 3H, J ¼ 7); 1.26 (t, 3H,
J ¼ 7); 1.45 (s, 3H); 2.22 (m, 2H); 2.59 (dd, 2H, J ¼ 9:3,
14.1); 2.69 (d, 1H, J ¼ 13:2); 2.80 (d, 1H, J ¼ 13:2); 3.18
(dd, 1H, J ¼ 4:8, 14.1); 3.68 (dd, 1H, J ¼ 1:5, 4); 3.76 (d,
1H, J ¼ 2:7); 3.92 (d, 1H, J ¼ 15); 3.95 (d, 1H, J ¼ 15);
4.15 (m, 5H); 5.08 (s, 2H); 5.50 (d, 1H, J ¼ 15); 5.53 (d,
1H, J ¼ 15); 7.20–7.42 (m, 10ArH). 13C NMR d 14.2,
14.3, 17.4, 17.6, 20.0, 20.6, 29.4, 30.1, 31.5, 41.0, 46.8,
46.9, 47.3, 57.6, 60.7, 61.1, 61.3, 61.8, 116.9, 127.4, 127.8,
127.9, 128.6, 136.3, 136.4, 143.3, 154.7, 158.4, 170.3, 173.
5.4. Tripeptide [(
DAP-(
L
)-Val ethylester-4-methylene-(2R,6R)-
L
)-Val ethylester]Á2HCl, 4
To a solution of 3 (2.1 g, 5 mmol) in ethanol (50 mL) was
added 2.5 M HCl (5 mL) and the reaction mixture,
monitored by TLC and/or H NMR, stirred at room
1
temperature for about 12 h. The acid solution was
evaporated in vacuo and the pure product isolated as a
solid (mp 73–75 °C) in a practically quantitative yield.
1H NMR (CD3OD) d 1.02 (d, 6H, J ¼ 7:2); 1.06 (d, 6H,
J ¼ 7); 1.31 (t, 6H, J ¼ 7); 2.18–2.38 (m, 2H); 2.54(dd,
2H, J ¼ 10:8, 14.4); 2.96 (dd, 2H, J ¼ 4:8, 14.4); 4.22 (q,
4H, J ¼ 7); 4.32 (d, 2H, J ¼ 6:2); 4.54 (dd, 2H, J ¼ 4:8,
10.8); 5.33 (br s, 2H). 13C NMR (CD3OD) d 14.6, 19.0,
19.7, 31.5, 38.3, 51.9, 59.8, 62.3, 123.9, 137.3, 170.3,
½aŠ ¼ +29.4( c 1.6, CHCl3). IR (neat) mcmÀ1 : 1640 (C@O),
D
1699 (C@N). Anal. Calcd for C37H50N4O4: C, 72.28; H,
8.2; N, 9.11. Found: C, 72.46; H, 8.22; N, 9.07.
172.5. ½aŠ ¼ )23.5 (c 0.8, 1 M HCl). IR (CHCl3) mcmÀ1
:
D
1548 (N–C@O), 1689 (N–C@O), 1732 (ester), 3160–3320
(NH and NH3þ). Anal. Calcd for C22H42Cl2N4O6: C,
49.9; H, 8.0; Cl, 13.39; N, 10.58. Found: C, 49.8; H,
8.01; Cl, 13.42; N,10.55.
5.8. 1-[(30R,60S)-10,30-Dibenzyl-60-hydro-50-hetoxy-60-iso-
propyl-pirazin-30-yl-20-one]-3-[(300R,600S)-100-benzyl-300,600-
dihydro-500-hetoxy-600-isopropyl-pirazin-300-yl-200-one]-2-
methylenepropane, 6b
Benzylbromide was used as an alkylating reagent and the
1
product obtained in 88% yield. H NMR 0.84(d, 3H,
5.5. Tripeptide [(OH)-(
DAP-(
L
)-Val-4-methylene-(2R,6R)-
L
)-Val(OH)]Á2HCl, 5
J ¼ 7); 0.90 (d, 3H, J ¼ 7); 0.94(d, 3H, J ¼ 7); 1.07 (d,
3H, J ¼ 7); 1.27 (m, 6H); 2.02 (m, 1H); 2.25 (m, 1H); 2.65
(dd, 1H, J ¼ 9, 14.1); 2.84 (d, 1H, J ¼ 13:2); 2.99 (d, 1H,
J ¼ 13:2); 3.05 (d, 1H, J ¼ 12:6); 3.17 (d, 1H, J ¼ 2:4);
3.26 (dd, 1H, J ¼ 3:9, 14.1); 3.3 (d, 1H, J ¼ 12:6); 3.71
(dd, 1H, J ¼ 1:8, 3.9); 3.92 (d, 1H, J ¼ 15:3); 3.95 (d, 1H,
J ¼ 15:3); 4.11 (m, 5H); 5.14 (m, 2H); 5.18 (d, 1H,
J ¼ 15:3); 5.50 (d, 1H, J ¼ 15:3); 6.60 (m, 2ArH); 7.13–
7.38 (m, 13ArH). 13C NMR d 14.0, 14.3, 16.5, 17.4, 19.8,
20.2, 28.9, 31.3, 40.9, 46.3, 46.4, 47.2, 47.5, 57.3, 60.0,
A solution of 4 (0.53 g, 1 mmol) in 1 M HCl (10 mL) was
stirred for about 48 h at 60 °C and the reaction moni-
tored by TLC and/or H NMR. The acid solution was
1
evaporated in vacuo and the product, in a semisolid
state, isolated in a practically quantitative yield. 1H
NMR (D2O) d 1.15 (m, 12H); 2.2–2.5 (m, 2H); 2.85–3.0
(m, 4H); 4.4–4.7 (m, 5H); 5.53 (s, 2H). 13C NMR (D2O)
d 18.0, 19.7, 30.7, 38.3, 52.8, 61.8, 121.5, 136.9, 171.3,

1090
D. Balducci et al. / Tetrahedron: Asymmetry 15 (2004) 1085–1093
60.4, 60.9, 61.7, 65.6, 117.0, 125.8, 126.7, 127.2, 127.4,
127.6, 127.7, 128.0, 128.3, 130.5, 135.0, 136.1, 137.5,
J ¼ 6:6); 0.98 (d, 6H, J ¼ 7:2); 1.25 (t, 3H, J ¼ 7:4); 1.26
(t, 3H, J ¼ 7:2); 1.35 (s, 3H); 2.24(m, 2H); 2.44(dd, 1H,
J ¼ 8, 14); 2.49 (d, 1H, J ¼ 13:2); 2.76 (d, 1H, J ¼ 13:2);
2.83 (dd, 1H, J ¼ 4:4, 14); 3.85 (m, 1H); 3.93 (dd, 1H,
J ¼ 1:4, 2.8); 4.05–4.23 (m, 5H); 4.94 (m, 2H); 6.37 (br s,
1H); 6.61 (br s, 1H). 13C NMR d 14.3, 16.1, 16.3, 18.2,
18.4, 28.7, 29.6, 30.6, 31.8, 41.5, 46.3, 57.8, 58.0, 58.2,
143.0, 155.7, 158.3, 170.0, 170.3. ½aŠ ¼ )10.5 (c 1.6,
D
CHCl3). IR (neat) mcmÀ1 : 1645 (C@O), 1700 (C@N). Anal.
Calcd for C43H54N4O4: C, 74.75; H, 7.88; N, 8.11.
Found: C, 74.95; H, 7.91; N, 8.05.
5.9. 1-[(30S,60S)-10-Benzyl-30-allyl-60-hydro-50-hetoxy-60-
isopropyl-pirazin-30-yl-20-one]-3-[(300R,600S)-100-benzyl-
300,600-dihydro-500-hetoxy-600-isopropyl-pirazin-300-yl-200-
one]-2-methylenepropane, 6c
D
61.0, 61.1, 116.8, 142.7, 155.3, 157.8, 172.0, 174.3. ½aŠ ¼
+56 (c 1.7, CHCl3). IR (CHCl3) mcmÀ1 : 1670 (br, C@N
and C@O). Anal. Calcd for C23H38N4O4: C, 63.57; H,
8.81; N, 12.89. Found: C, 63.62; H, 8.84; N, 12.92.
Allylbromide was used as an alkylating reagent and the
1
5.12. 1-[(30R,60S)-30-Benzyl-60-hydro-50-hetoxy-60-isopro-
pyl-pirazin-30-yl-20-one]-3-[(300R,600S)-300,600-dihydro-500-
hetoxy-600-isopropyl-pirazin-300-yl-200-one]-2-methylene-
propane, 7b
product obtained in 92% yield. H NMR d 0.91 (d, 6H,
J ¼ 7); 1.04(d, 3H, J ¼ 7); 1.06 (d, 3H, J ¼ 7); 1.23 (t,
3H, J ¼ 7); 1.26 (t, 3H, J ¼ 7); 2.2 (m, 2H); 2.42–2.7 (m,
3H); 2.73 (d, 1H, J ¼ 13:2); 2.85 (d, 1H, J ¼ 13:2); 3.17
(dd, 1H, J ¼ 4, 14); 3.67 (dd, 1H, J ¼ 1:4, 4); 3.71 (d,
1H, J ¼ 2:6); 3.96 (d, 1H, J ¼ 15); 4.04–4.23 (m, 5H); 5–
5.17 (m, 4H); 5.47 (d, 1H, J ¼ 15); 5.49 (d, 1H, J ¼ 15);
5.44–5.62 (m, 1H); 7.17–7.4 (m, 10ArH). 13C NMR d
14.0, 14.2, 16.7, 17.3, 19.8, 20.4, 26.7, 29.3, 31.3, 40.8,
45.2, 46.5, 46.7, 47.1, 57.4, 60.6, 60.9 61.6, 64.3, 116.9,
117.9, 127.2, 127.5, 128.2, 128.3, 128.4, 133.8, 135.7,
Compound 7b was obtained as a wax in a practically
quantitative yield starting from 6b following the same
procedure used for 6a. 1H NMR d 0.70 (d, 3H, J ¼ 6:8);
0.77 (d, 3H, J ¼ 7:2); 0.87 (d, 3H, J ¼ 6:8); 1.0 (d, 3H,
J ¼ 7); 1.29 (t, 3H, J ¼ 7:2); 1.30 (t, 3H, J ¼ 7:2); 2.04
(m, 1H); 2.23 (m, 1H); 2.51 (dd, 1H, J ¼ 8:4, 14); 2.61
(d, 1H, J ¼ 13:2); 2.74(dd, 1H, J ¼ 1:2, 2.6); 2.79 (d,
1H, J ¼ 12:4); 2.82 (dd, 1H, J ¼ 4:4, 14); 3.03 (d, 1H,
J ¼ 13:2 Hz); 3.23 (d, 1H, J ¼ 12:4); 3.88 (m, 1H); 4.09–
4.33 (m, 5H); 5.0 (m, 2H); 5.51 (br s, 1H); 6.05 (br s,
1H); 7.03–7.38 (m, 5ArH). 13C NMR 14.2, 14.4, 15.7,
16.0, 18.0, 18.2, 29.7, 31.7, 41.6. 46.1, 47.2, 57.3, 58.0,
58.5, 61.1, 61.3, 117.2, 126.4, 127.7, 130.5, 136.7, 142.6,
156.8, 157.8, 171.8, 172.1. ½aŠ ¼ +10.2 (c 1, CHCl3). IR
(CHCl3) mcmÀ1 : 1673 (br, C@DN and C@O). Anal. Calcd
for C29H42N4O4: C, 68.21; H, 8.29; N, 10.97. Found: C,
68.38; H, 8.31; N, 10.99.
136.1, 143.0, 155.4, 158.2, 170.0, 170.8. ½aŠ ¼ +6.7 (c 1,
D
CHCl3). IR (neat) mcmÀ1 : 1640 (C@O), 1698 (C@N).
Anal. Calcd for C39H52N4O4: C, 73.09; H, 8.18; N, 8.74.
Found: C, 73.01; H, 8.16; N, 8.75.
5.10. 1-[(30R,60S)-10-Benzyl-30-methoxymethyl-60-hydro-
5000-hetoxy-60-isopropyl-pirazin-30-yl-20-one]-3-[(300R,600S)-
1 -benzyl-300,600-dihydro-500-hetoxy-600-isopropyl-pirazin-
300-yl-200-one]-2-methylenepropane, 6d
Methoxymethylbromide was used as an alkylating
reagent and the product obtained in 85% yield. 1H
NMR d 0.93 (d, 6H, J ¼ 6:9); 1.06 (d, 3H, J ¼ 6:8); 1.08
(d, 3H, J ¼ 6:8); 1.23 (t, 3H, J ¼ 7:5); 1.28 (t, 3H,
J ¼ 7:5); 2.22 (m, 2H); 2.59 (dd, 1H, J ¼ 9:0, 14.4); 2.66
(d, 1H, J ¼ 13:5); 2.67 (d, 1H, J ¼ 13:5); 3.22 (dd, 1H,
J ¼ 4:2, 14.4); 3.34 (s, 3H); 3.47 (d, 1H, J ¼ 8:1); 3.68
(m, 1H); 3.79 (d, 1H, J ¼ 2:1); 3.89 (d, 1H, J ¼ 8:1);
3.94(d, 1H, J ¼ 15:3); 3.97 (d, 1H, J ¼ 15:3); 4.00–4.28
(m, 5H); 5.04(m, 2H); 5.49 (d, 1H, J ¼ 15:3); 5.67 (d,
1H, J ¼ 15:3); 7.17–7.41 (m, 10ArH). 13C NMR d 14.0,
14.1, 17.0, 17.5, 19.9, 20.4, 29.5, 31.4, 40.7, 43.7, 46.5,
47.3, 57.5, 59.1, 60.4, 60.7, 61.0, 61.8, 64.9, 80.1, 116.6,
127.1, 127.4, 127.8, 128.0, 128.4, 128.6, 135.9, 136.3,
5.13. 1-[(30S,60S)-30-Allyl-60-hydro-50-hetoxy-60-isopropyl-
pirazin-30-yl-20-one]-3-[(300R,600S)-300,600-dihydro-500-het-
oxy-600-isopropyl-pirazin-300-yl-200-one]-2-methylenepro-
pane, 7c
Compound 7c was obtained as a wax in a practically
quantitative yield starting from 6c following the same
1
procedure used for 6a. H NMR d 0.82 (d, 3H, J ¼ 7);
0.84(d, 3H, J ¼ 6:6); 0.96 (d, 3H, J ¼ 7:4); 0.98 (d, 3H,
J ¼ 7); 1.26 (t, 3H, J ¼ 7); 1.27 (t, 3H, J ¼ 7); 2.10–2.85
(m, 6H); 2.47 (d, 1H, J ¼ 13); 2.81 (d, 1H, J ¼ 13); 3.85
(m, 2H); 4.10–4.26 (m, 5H); 4.9–5.1 (m, 4H); 5.5–5.77
(m, 1H); 6.33 (br s, 1H); 6.63 (br s, 1H). 13C NMR d
14.0, 14.2, 16.1, 16.2, 18.0, 18.2, 30.5, 31.8, 41.3, 45.5,
45.6, 57.7, 57.9, 58.0, 60.8, 64.4, 116.8, 118.2, 133.0,
142.8, 156.7, 158.5, 170.3, 170.5. ½aŠ ¼ +38 (c 0.6,
D
CHCl3). IR (neat) mcmÀ1 : 1646 (C@O), 1700 (C@N).
Anal. Calcd for C38H52N4O5: C, 70.78; H, 8.13; N, 8.69.
Found: C, 70.98; H, 8.15; N, 8.66.
142.4, 156.3, 157.8, 172.2, 172.8. ½aŠ ¼ +42.6 (c 0.8,
D
CHCl3). IR (CHCl3) mcmÀ1 : 1675 (br, C@N and C@O).
Anal. Calcd for C25H40N4O4: C, 65.19; H, 8.75; N,
12.16. Found: C, 65.25; H, 8.77; N, 12.2.
5.11. 1-[(30S,60S)-30-Methyl-60-hydro-50-hetoxy-60-isopro-
pyl-pirazin-30-yl-20-one]-2-[(300R,600S)-300,600-dihydro-500-
hetoxy-600-isopropyl-pirazin-300-yl-200-one]-3-methylene-
propane, 7a
5.14. 1-[(30R,60S)-30-Methoxymethyl-60-hydro-50-hetoxy-
60-isopropyl-pirazin-30-yl-20-one]-3-[(300R,600S)-300,600-dihy-
dro-500-hetoxy-600-isopropyl-pirazin-300-yl-200-one]-2-meth-
ylenepropane, 7d
Intermediate 6a was submitted to a Birch reaction fol-
lowing the procedure employed for preparing 3. The
product was obtained as a wax in a practically quanti-
tative yield. 1H NMR d 0.83 (d, 3H, J ¼ 7); 0.84(d, 3H,
Compound 7d was obtained as a wax in a practically
quantitative yield starting from 6d following the same

D. Balducci et al. / Tetrahedron: Asymmetry 15 (2004) 1085–1093
1091
1
procedure used for 6a H NMR d 0.81 (d, 3H, J ¼ 7);
0.84(d, 3H, J ¼ 7); 0.96 (d, 3H, J ¼ 7); 0.97 (d, 3H,
J ¼ 7:2); 1.25 (t, 3H, J ¼ 7); 1.26 (t, 3H, J ¼ 7:3); 2.17–
2.32 (m, 2H); 2.41 (d, 1H, J ¼ 13:2); 2.44 (dd, 1H,
J ¼ 4:8, 14); 2.69 (d, 1H, J ¼ 13:2); 2.82 (dd, 1H,
J ¼ 4:4, 14); 3.26 (d, 1H, J ¼ 8:4); 3.27 (s, 3H); 3.72 (d,
1H, J ¼ 8:4); 3.83 (m, 1H); 3.98 (dd, 1H, J ¼ 1, 2.6);
4.05–4.25 (m, 5H); 4.93 (m, 2H); 6.31 (br s, 1H); 6.77 (br
s, 1H). 13C NMR d 14.1, 16.0, 16.1, 18.1, 18.2, 30.1, 31.8,
41.4, 41.9, 57.6, 57.8, 58.2, 59.3, 61.0, 65.3, 79.8, 116.7,
175.3. ½aŠ ¼ )17.4( c 1.1, 1 M HCl). IR (CHCl3) mcmÀ1
:
D
1550 (N–C@O), 1690 (N–C@O), 1770 (COOH), 3100–
3300 (OH and NH3þ). Anal. Calcd for C21H38Cl2N4O6:
C, 49.12; H, 7.46; Cl, 13.81; N, 10.91. Found: C, 48.98;
H, 7.42; Cl, 13.85; N, 10.93.
5.18. Tripeptide [(OH)-(
ylene-(2R,6R)-DAP-(
L)-Val-2-metoxymethyl-4-meth-
)-Val(OH)]Á2HCl, 8d
L
The product, isolated in a semisolid state, was obtained
in a practically quantitative yield by submitting 7d to
141.8, 157.5, 157.8, 172.0, 172.1. ½aŠ ¼ +17.9 (c 2.5,
D
CHCl3). IR (CHCl3) mcmÀ1 : 1672 (br, C@N and C@O).
Anal. Calcd for C24H40N4O5: C, 62.04; H, 8.68; N,
12.06. Found: C, 61.81; H, 8.66; N, 12.1.
1
acid hydrolysis as described for 5. H NMR (D2O) d
0.75–0.93 (m, 12H); 1,97–2.2 (m, 2H); 2.44 (m, 2H); 2.65
(qAB, 2H, J ¼ 15); 3.29 (s, 3H); 3.61 (d, 1H, J ¼ 10:6);
3.82 (d, 1H, J ¼ 10:6); 4.09 (m, 1H); 4.11 (d, 1H,
J ¼ 5:8); 4.2 (d, 1H, J ¼ 6:2); 5.21 (m, 2H). 13C NMR
(D2O) d 18.1, 18.3, 19.1, 19.2, 30.3, 30.6, 38.0, 38.4, 52.2,
59.4, 59.7, 59.9, 63.9, 73.7, 124.2, 134.3, 169.8, 175.0,
5.15. Tripeptide [(OH)-(
L
L)-Val-2-methyl-4-methylene-
)-Val(OH)]Á2HCl, 8a
(2S,6R)-DAP-(
The product, isolated in a semisolid state, was obtained
in a practically quantitative yield by submitting 7a to
acid hydrolysis as described for 5. H NMR (D2O) d
0.84–0.90 (m, 12H); 1.64 (s, 3H); 2.02–2.33 (m, 2H);
2.44–2.60 (m, 2H); 2.67 (qAB, 2H, J ¼ 15); 4.1–4.3 (m,
3H); 5.24(m, 2H). 13C NMR (D2O) d 18.1, 18.6, 19.2,
23.2, 30.3, 30.4, 38.6, 42.3, 52.3, 59.4, 59.9, 60.7, 124.0,
175.3. ½aŠ ¼ )32.9 (c 0.55, 1 M HCl). IR (CHCl3) mcmÀ1
:
D
1548 (N–C@O), 1687 (N–C@O), 1765 (COOH), 3100–
3300 (OH and NH3þ). Anal. Calcd for C20H38Cl2N4O7:
C, 46.42; H, 7.4; Cl, 13.7; N, 10.83. Found: C, 46.52; H,
7.41; Cl, 13.72; N, 10.81.
1
5.19. (3R,6S)-1-Benzyl-5-hetoxy-6-isopropyl-3-methyl-6-
dihydropirazin-2-one, 9a
135.1, 169.7, 172.0, 175.0, 175.2. ½aŠ ¼ )25.5 (c 0.6, 1 M
D
HCl). IR (CHCl3) mcmÀ1 : 1545 (N–C@O), 1685 (N–C@O),
1750 (COOH), 3150–3350 (OH and NH3þ). Anal. Calcd
for C19H36Cl2N4O6: C, 46.82; H, 7.44; Cl, 14.55; N,
11.49. Found: C, 46.73; H, 7.42; Cl, 14.6; N, 11.51.
The pure product was obtained as an oil in 80% yield by
alkylating 1 with iodomethane and following the pro-
cedure as described for 2. 1H NMR d 0.95 (d, 3H,
J ¼ 7); 1.06 (d, 3H, J ¼ 7); 1.26 (t, 3H, J ¼ 7:2); 1.57 (d,
3H, J ¼ 7); 2.22 (m, 1H); 3.7 (dd, 1H, J ¼ 1:4, 4); 3.95
(d, 1H, J ¼ 15); 4.02–4.2 (m, 3H); 5.47 (d, 1H, J ¼ 15);
7.15–7.2 (m, 5ArH). 13C NMR d 14.2, 17.7, 20.1, 20.7,
31.6, 47.5, 53.9, 61.1, 62.4, 127.4, 127.7, 128.6, 136.3,
5.16. Tripeptide [(OH)-(
(2R,6R)-DAP-(
L)-Val-2-benzyl-4-methylene-
)-Val(OH)]Á2HCl, 8b
L
The product, isolated in a semisolid state, was obtained
in a practically quantitative yield by submitting 7b to
acid hydrolysis as described for 5. 1H NMR (D2O) d 0.53
(d, 3H, J ¼ 6:6); 0.66 (d, 3H, J ¼ 7); 0.86 (d, 3H,
J ¼ 6:8); 0.87 (d, 3H, J ¼ 6:8); 1.85–2 (m, 1H); 2.1–2.25
(m, 1H); 2.39 (d, 1H, J ¼ 14:2); 2.46–2.51 (m, 2H); 2.88
(qAB, 2H, J ¼ 14:6Þ; 3.16 (d, 1H, J ¼ 14:2); 4.13–4.27 (m,
3H); 5.16 (m, 2H); 7–7.2 (m, 5ArH). 13C NMR (D2O) d
16.0, 18.0, 18.3, 19.3, 30.6, 31.1, 39.9, 42.1, 48.0, 52.2,
59.0, 59.3, 65.1, 123.8, 128.4, 129.2, 131.2, 134.5, 136.5,
159.2, 171.3. ½aŠ ¼ +24.2 (c 1.7, CHCl3). IR (neat)
D
mcmÀ1 : 1690 (N–C@O), 1640 (C@O). Anal. Calcd for
C17H24N2O2: C, 70.8; H, 8.39; N, 9.71. Found: C, 70.92;
H, 8.38; N, 9.69.
5.20. (3R,6S)-3-Allyl-1-benzyl-5-hetoxy-6-isopropyl-6-
dihydropirazin-2-one, 9b
170.1, 170.7, 171.0, 175.2. ½aŠ ¼ +11.5 (c 2.4, 1 M HCl).
The pure product was obtained as an oil in 85% yield by
alkylating 1 with allylbromide and following the pro-
cedure as described for 2. 1H NMR d 0.92 (d, 3H,
J ¼ 6:6); 1.04(d, 3H, J ¼ 7); 1.24(t, 3H, J ¼ 7); 2.22
(m, 1H); 2.75 (m, 2H); 3.66 (m, 1H); 3.87 (d, 1H,
J ¼ 15); 4.13 (m, 3H); 5.11 (m, 2H); 5.5 (d, 1H, J ¼ 15);
5.87 (m, 1H); 7.35 (m, 5ArH). 13C NMR d 14.1, 17.4,
19.9, 31.5, 38.1, 47.1, 58.0, 61.0, 61.7, 117.1, 127.4,
D
IR (CHCl3) mcmÀ1 : 1548 (N–C@O), 1687 (N–C@O), 1765
(COOH), 3120–3330 (OH and NH3þ). Anal. Calcd for
C25H40Cl2N4O6: C, 53.28; H, 7.15; Cl, 12.58; N, 9.94.
Found: C, 53.37; H, 7.18; Cl, 12.62; N, 9.96.
5.17. Tripeptide [(OH)-(
L
L)-Val-2-allyl-4-methylene-
)-Val(OH)]Á2HCl, 8c
(2S,6R)-DAP-(
127.7, 128.5, 134.9, 136.0, 158.8, 169.7. ½aŠ ¼ +44.8 (c
D
2.1, CHCl3). IR (neat) mcmÀ1 : 1692 (N–C@O), 1645
(C@O). Anal. Calcd for C19H26N2O2: C, 72.58; H, 8.33;
N, 8.91. Found: C, 72.49; H, 8.31; N, 8.94.
The product, isolated in a semisolid state, was obtained
in a practically quantitative yield by submitting 7c to acid
hydrolysis as described for 5. 1H NMR (CD3OD) d 0.9–
1.07 (m, 12H); 2.08–2.29 (m, 5H); 2.41 (dd, 1H, J ¼ 4:4,
13.6); 2.62 (dd, 1H, J ¼ 4:4, 13.6); 2.82 (d, 1H, J ¼ 13:6);
3.6 (dd, 1H, J ¼ 4:8, 9.2); 4.22 (d, 1H, J ¼ 5:6); 4.36 (d,
1H, J ¼ 6); 5–5.21 (m, 4H); 5.7–5.93 (m, 1H). 13C NMR
(D2O) d 18.1, 18.8, 19.1, 30.3, 30.4, 38.6, 41.3, 52.3, 59.4,
60.3, 63.5, 124.0, 124.1, 128.8, 134.9, 169.7, 170.9, 175.0,
5.21. (3R,6S)-1-Benzyl-5-hetoxy-6-isopropyl-3-methyl-3-
(2-chloromethyl-2-propenyl)-6-hydro pirazin-2-one, 10a
The pure product was obtained as an oil in 88% yield by
alkylating 9a with 2-chloromethyl-3-chloropropene and

1092
D. Balducci et al. / Tetrahedron: Asymmetry 15 (2004) 1085–1093
1
following the procedure as described for 2. H NMR d
0.89 (d, 3H, J ¼ 7); 1.05 (d, 3H, J ¼ 7); 1.26 (t, 3H,
J ¼ 7); 1.49 (s, 3H); 2.2 (m, 1H); 2.53 (d, 1H, J ¼ 13:2);
2.72 (d, 1H, J ¼ 13:2); 3.72 (m, 1H); 3.91 (d, 1H,
J ¼ 15:3); 4.02 (qAB, 2H, J ¼ 11:7) 4–4.25 (m, 2H) 5.03
(s, 1H); 5.11 (s, 1H); 5.42 (d, 1H, J ¼ 15:3) 7.17–7.4(m,
5ArH). 13C NMR d 14.3, 17.4, 20.6, 29.1, 29.8, 45.5,
46.7, 49.7, 60.8, 61.2, 61.7, 118.4, 127.5, 128.3, 128.6,
NMR d 0.84(d, 3H, J ¼ 6:6); 0.92 (d, 3H, J ¼ 7); 1.01
(d, 3H, J ¼ 7); 1.04(d, 3H, J ¼ 7); 1.2 (t, 3H, J ¼ 7);
1.26 (t, 3H, J ¼ 7); 2.04–2.32 (m, 2H); 2.38–2.97 (m,
4H); 2.54 (d, 1H, J ¼ 13:2); 2.87 (d, 1H, J ¼ 13:2); 3.64
(dd, 1H, J ¼ 1:8, 3.6); 3.73 (d, 1H, J ¼ 2:6); 3.90 (d, 1H,
J ¼ 15); 3.99–4.37 (m, 6H); 4.9 (br s, 2H); 5.05–5.2 (m,
2H); 5.25 (d, 1H, J ¼ 15); 5.47 (d, 1H, J ¼ 15), 5.83–
6.11 (m, 1H); 7.13–7.43 (m, 10ArH). 13C NMR d 14.0,
14.1, 16.6, 17.4. 19.8, 20.6, 29.0, 31.3, 40.8, 46.1, 46.3,
47.1, 57.1, 60.4, 60.9, 61.5, 64.9, 115.9, 117.4 127.1
127.6, 128.2, 128.4, 134.1, 135.7, 136.0, 143.3, 155.6,
135.7, 141.7, 156.1, 171.3. ½aŠ ¼ )51.5 (c 1, CHCl3).
D
Anal. Calcd for C21H29ClN2O2: C,66.92; H, 7.76; Cl,
9.41; N, 7.43. IR (neat) mcmÀ1 : 1690 (N–C@O), 1642
(C@O). Found: C, 66.74; H, 7.72; Cl, 9.44; N, 7.42.
158.2, 170.0, 170.6. ½aŠ ¼ )31 (c 0.5, CHCl3). IR (neat)
D
mcmÀ1 : 1695 (C@N), 1640 (C@O). Anal. Calcd for
C39H52N4O4: C, 73.09; H, 8.18; N, 8.74. Found: C,
72.82; H, 8.13; N, 8.76.
5.22. (3R,6S)-3-Allyl-1-benzyl-5-hetoxy-6-isopropyl-3-(2-
chloromethyl-2-propenyl)-6-hydro pirazin-2-one, 10b
The pure product was obtained as an oil in 90% yield by
alkylating 9b with 2-chloromethyl-3-chloropropene and
following the procedure as described for 2. H NMR d
0.93 (d, 3H, J ¼ 7); 1.06 (d, 3H, J ¼ 7); 1.28 (t, 3H,
J ¼ 7); 2.09–2.24(m, 1H); 2.05 (d, 1H, J ¼ 13:2); 2.55–
2.65 (m, 2H); 2.85 (d, 1H, J ¼ 13:2); 3.73 (d, 1H,
J ¼ 2:6); 3.94–4.38 (m, 4H); 4.04 (d, 1H, J ¼ 15); 5–5.23
(m, 4H); 5.33 (d, 1H, J ¼ 15); 5.85–6.07 (m, 1H); 7.17–7.4
(m, 5ArH). 13C NMR d 14.0, 16.9, 20.5, 29.3, 42.7, 46.1,
46.7, 48.7, 60.5, 61.0, 64.0, 117.8, 118.0, 127.2, 127.9,
5.25. 1-[(30R,60S)-30-Methyl-60-hydro-50-hetoxy-60-iso-
propyl-pirazin-30-yl-2-one]-3-[(300R,600S)-600-dihydro-500-
hetoxy-600-isopropyl-pirazin-300-yl-200-one]-2-methylene-
propane, 12a
1
Compound 12a was obtained as a wax in 95% yield by
submitting 11a to a Birch reaction as described for 3.
The product was not obtained in a sufficiently pure form
to measure the specific rotation. 1H NMR d 0.85 (d, 3H,
J ¼ 7); 0.86 (d, 3H, J ¼ 7); 0.98 (d, 3H, J ¼ 7); 0.99 (d,
3H, J ¼ 7); 1.27 (t, 6H, J ¼ 7); 1.42 (s, 3H); 2.22 (m,
2H); 2.35 (d, 1H, J ¼ 13:2); 2.37 (dd, 1H, J ¼ 8, 14.4);
2.72 (dd, 1H, J ¼ 4:4, 14.4); 2.82 (d, 1H, J ¼ 13:2); 3.85
(m, 1H); 3.9 (dd, 1H, J ¼ 1:7, 2.6); 4.05–4.3 (m, 5H);
4.88 (m, 2H); 6.51 (br s, 1H); 6.7 (br s, 1H). 13C NMR d
14.3, 16, 16.1, 18.3, 29, 30.9, 31.8, 41.1, 47.9, 58.2, 58.3,
60.9, 61.1, 61.3, 116.1, 142.8, 155.9, 157.8, 171.9, 174. IR
(CHCl3) mcmÀ1 : 1670 (br, C@N and C@O).
128.2, 133.2, 135.4, 141.2, 156.2, 169.9. ½aŠ ¼ )36 (c 1.7,
D
CHCl3). IR (neat) mcmÀ1 : 1692 (N–C@O), 1642 (C@O).
Anal. Calcd for C23H31ClN2O2: C, 68.55; H, 7.75; Cl, 8.8;
N, 6.95. Found: C, 68.72; H, 7.77; Cl, 8.78; N, 6.93.
5.23. 1-[(30R,60S)-10-Benzyl-30-methyl-60-hydro-50-hetoxy-
60-isopropyl-pirazin-30-yl-2-one]-3-[(300R,600S)-100-benzyl-
300,600-dihydro-500-hetoxy-600-isopropyl-pirazin-300-yl-200-
one]-2-methylenepropane, 11a
5.26. 1-[(30R,60S)-30-Allyl-60-hydro-50-hetoxy-60-isoprop-
yl-pirazin-30-yl-2-one]-3-[(300R,600S)-300,600-dihydro-500-het-
oxy-600-isopropyl-pirazin-300-yl-200-one]-2-methylenepro-
pane, 12b
The pure product was obtained as a viscous oil in 85%
yield by alkylating the Li-enolate of 1 with 10a. 1H NMR
d 0.88 (d, 3H, J ¼ 7); 0.94(d, 3H, J ¼ 7); 1.02 (d, 3H, 7);
1.05 (d, 3H, J ¼ 7); 1.19 (t, 3H, J ¼ 7:2); 1.24(t, 3H,
J ¼ 7:2); 1.56 (s, 3H); 2.2 (m, 2H); 2.47 (m, 1H); 2.49 (d,
1H, J ¼ 13:2); 2.98 (m, 1H); 3 (d, 1H, J ¼ 13:2); 3.66 (dd,
1H, J ¼ 1:5, 4); 3.7 (d, 1H, J ¼ 2:4); 3.94 (d, 1H, J ¼ 15);
3.97 (d, 1H, J ¼ 15); 4.07 (m, 3H); 4.23 (m, 2H); 4.92 (s,
2H); 5.48 (d, 1H, J ¼ 15); 5.49 (d, 1H, J ¼ 15); 7.2 (m,
10ArH). 13C NMR d 13.8, 13.9, 16.7, 17.2, 19.7, 20.1,
28.9, 29.2, 31.1, 40.9, 46.2, 47.0, 48.3, 57.3, 60.2, 60.5,
60.6, 61.5, 62.0, 115.5, 127.2, 127.5, 127.9, 128.2, 128.3,
Compound 12b was obtained as a wax in 95% yield by
submitting 11b to a Birch reaction as described for 3.
The product was not obtained in a sufficiently pure form
to measure the specific rotation. 1H NMR d 0.83 (d, 3H,
J ¼ 7); 0.87 (d, 3H, J ¼ 7); 0.98 (d, 3H, J ¼ 7); 1.11 (d,
3H, J ¼ 7); 1.29 (t, 3H, J ¼ 7); 1.31 (t, 3H, J ¼ 7); 2.17–
2.45 (m, 3H); 2.36 (d, 1H, J ¼ 12:9); 2.67 (m, 1H); 2.78
(d, 1H, J ¼ 12:9); 3.87 (m, 1H); 3.91 (m, 1H); 4.1–4.35
(m, 5H); 4.89 (s, 1H); 4.93 (s, 1H); 5.06 (m, 2H); 5.7 (m,
1H); 6.77 (br s, 1H); 7.12 (br s, 1H). 13C NMR d 14.2,
16.1, 16.3, 18.2, 18.3, 30.3, 31.8, 40.9, 45.4, 47, 57.9,
58.2, 58.6, 61, 61.1, 64.2, 116.7, 117.8, 134.2, 142.6,
156.8, 158, 172, 172.9. IR (CHCl3) mcmÀ1 : 1670 (br, C@N
and C@O).
135.5, 136.1, 143.4, 155.1,158.2, 170.0, 171.4. ½aŠ ¼
D
)26.6 (c 1, CHCl3). IR (neat) mcmÀ1 : 1695 (C@N), 1640
(C@O). Anal. Calcd for C37H50N4O4: C, 72.28; H, 8.2;
N, 9.11. Found: C, 72.47; H, 8.21; N, 9.1.
5.24. 1-[(30R,60S)-30-Allyl-10-benzyl-60-hydro-50-hetoxy-60-
isopropyl-pirazin-30-yl-2-one]-3-[(300R,600S)-100-benzyl-
300,600-dihydro-500-hetoxy-600-isopropyl-pirazin-300-yl-200-
one]-2-methylenepropane, 11b
5.27. Tripeptide [(
ene-(2R,6R)-DAP-(
L
)-Val ethylester-2-methyl-4-methyl-
)-Val ethyl ester]Á2HCl, 13a
L
The pure product was obtained as a viscous oil in 87%
yield by alkylating the Li-enolate of 1 with 10b. 1H
The product, isolated in a semisolid state, was obtained
in 95% yield by submitting 12a to acid hydrolysis as

D. Balducci et al. / Tetrahedron: Asymmetry 15 (2004) 1085–1093
1093
described for 4. The product was not obtained in a
127.3, 128.4, 135.5, 140.1, 163.1, 169.3. IR (neat) mcmÀ1
1675 (N–C@O).
:
sufficiently pure form to measure the specific rotation.
1H NMR (CD3OD) d 0.97–1.1 (m, 12H), 1.28 (t, 3H,
J ¼ 7); 1.29 (t, 3H, J ¼ 7); 1.76 (s, 3H), 2.18–2.3 (m,
2H); 2.51 (dd, 1H, J ¼ 9:8, 14.2); 2.79 (dd, 1H, J ¼ 4:4,
14.2); 2.93 (qAB, 2H, J ¼ 14:8); 4.13–4.3 (m, 5H); 4.34
(d, 1H, J ¼ 6:8); 4.4 (dd, 1H, J ¼ 4:4, 7); 5.28 (s, 1H);
5.35 (s, 1H). 13C NMR (CD3OD) d 14.5, 18.8, 19.7, 20.0,
22.8, 30.9, 31.6, 40.8, 42.0, 52.4, 59.8, 61.1, 61.7, 62,2,
62.4, 123.7, 137.2, 142.2, 170.3, 172.7, 172.8. IR (CHCl3)
mcmÀ1 : 1545 (N–C@O), 1690 (N–C@O), 1730 (ester),
3150–3300 (NH and NH3þ).
Acknowledgements
Thanks are due to the MIUR (COFIN 2002) and to the
University of Bologna (ÔRicerca fondamentale orien-
tataÕ) for financial supports.
References and notes
5.28. Tripeptide [(
(2R,6R)-DAP-(
L)-Val ethylester-2-allyl-4-methylene-
)-Val ethyl ester]Á2HCl, 13b
L
1. Paradisi, F.; Porzi, G.; Rinaldi, S.; Sandri, S. Tetrahedron:
Asymmetry 2000, 11, 1259–1262.
2. Paradisi, F.; Porzi, G.; Rinaldi, S.; Sandri, S. Tetrahedron:
Asymmetry 2000, 11, 4617–4622.
3. Paradisi, F.; Piccinelli, F.; Porzi, G.; Sandri, S. Tetra-
hedron: Asymmetry 2002, 13, 497–502.
Compound 13b was obtained in 95% yield by submitting
12b to acid hydrolysis as described for 4. The product,
isolated in semisolid state, was not recovered in a suffi-
1
ciently pure form to measure the specific rotation. H
4. Ferioli, F.; Piccinelli, F.; Porzi, G.; Sandri, S. Tetrahedron:
Asymmetry 2002, 13, 1181–1187.
5. Piccinelli, F.; Porzi, G.; Sandri, M.; Sandri, S. Tetra-
hedron: Asymmetry 2003, 14, 393–398.
6. Williams, R. M.; Yuan, C. J. Org. Chem. 1992, 57, 6519.
7. Dereppe, C.; Bold, G.; Ghisalba, O.; Erbert, E.; Schar, H.
P. Plant Physiol. 1992, 98, 813.
8. Girodeau, J. M.; Agouridas, C.; Masson, M.; Pineaau, R.;
Le Goffic, F. J. Med. Chem. 1986, 29, 1023.
NMR (CD3OD) d 0.92–1.18 (m, 12H); 1.31 (t, 6H,
J ¼ 7:2); 2.23–2.57 (m, 3H); 2.44 (d, 1H, J ¼ 13:6); 2.72
(m, 1H); 2.7 (d, 1H, J ¼ 13:6); 3.82 (d, 1H, J ¼ 3); 4.15–
4.4 (m, 6H); 5.2 (m, 4H); 5.8 (m, 1H). 13C NMR (CD3OD)
d 14.5, 17.4, 18.7, 19, 19.6, 31.7, 32.9, 40.8, 45.4, 52.8,
59.7, 61.2, 62.4, 64.5, 120.7, 122.6, 133.2, 139, 169.7,
170.1, 171.2, 172.8. IR (CHCl3) mcmÀ1 : 1550 (N–C@O),
1685 (N–C@O), 1735 (ester), 3150–3300 (NH and NH3þ).
9. Paradisi, F.; Porzi, G.; Sandri, S. Tetrahedron: Asymmetry
2001, 12, 3319–3324.
10. Galeazzi, R.; Garavelli, M.; Grandi, A.; Monari, M.;
Porzi, G.; Sandri S. Tetrahedron: Asymmetry, 2003, 14,
2639–2649.
5.29. (3S,6R)-4-Benzyl-6-methyl-8-methylene-2,5-diketo-
3-isopropyl-1,4-diazabicyclo[4,3,0] nonane, 14
11. Fernandez, M. M.; Diez, A.; Rubiralta, M.; Montenegro,
E.; Casamitjana, N. J. Org. Chem. 2002, 67, 7587;
Trabocchi, A.; Occhiato, E. G.; Potenza, D.; Guarna, A.
J. Org. Chem. 2002, 67, 7483; Belvisi, L.; Bernardi, A.;
Manzoni, L.; Potenza, D.; Scolastico, C. Eur. J. Org.
Chem. 2000, 2563, and references cited therein.
12. Estiarte, M. A.; Rubiralta, M.; Diez, A. J. Org. Chem.
2000, 65, 6992–6999.
Compound 14 was obtained as an oil by following the
procedure used for preparing 2. 1H NMR d 1.07 (d, 3H,
J ¼ 6:9); 1.18 (d, 3H, J ¼ 6:9); 1.58 (s, 3H); 2.25 (m,
1H); 2.75 (br s, 2H); 3.72 (d, 1H, J ¼ 6:2); 3.92 (m, 1H);
3.94(d, 1H, J ¼ 14:8); 4.61 (m, 1H); 5.18 (m, 2H); 5.48
(d, 1H, J ¼ 14:8); 7.17–7.43 (m, 5ArH). 13C NMR d
18.6, 20, 24.5, 31.5, 45.6, 47.9, 48.4, 63.8, 65.6, 109.2,