Stereocontrolled synthesis of unnatural cyclic dipeptides containing an L-valine unit

Article abstract of DOI:10.1016/j.tetasy.2005.03.006

Stereoselective synthesis of unusual nonproteinogenic dipeptides 7a,b,d,e and h and 13b and i, containing an l-valine unit and a cyclic unnatural α-amino acid, has been accomplished starting from the l-valine derived chiral synthon 1. The absolute configu

Full text of DOI:10.1016/j.tetasy.2005.03.006

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1453–1462
Stereocontrolled synthesis of unnatural cyclic dipeptides
containing an L-valine unit
Daniele Balducci, Alessandro Grandi, Gianni Porzi* and Sergio Sandri*
`
Dipartimento di Chimica ‘G.Ciamician’, Universita di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 23 December 2004; revised 4 March2005; accepted 9 March2005
Abstract—Stereoselective synthesis of unusual nonproteinogenic dipeptides 7a,b,d,e and h and 13b and i, containing an L-valine
unit and a cyclic unnatural a-amino acid, has been accomplished starting from the L-valine derived chiral synthon 1. The absolute
configurations of the new stereocentres were assigned on the basis of H NMR spectra.
1
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Synthesis and stereochemical assignments
In continuation of our studies directed towards produc-
ing uncommon peptides1–5 we undertook the asymmet-
ric synthesis of new conformationally constrained
pseudodipeptides 7a,b,d,e and h and 13b and i contain-
ing the L-valine and a cyclic nonproteinogenic a-amino
acid.
Herein we have followed a strategy based on the use of
mono-lactim ether 1, a chiral synthon easily synthesized
starting from the L-valine.1–4 Deprotonation of 1 with
LHMDS at ꢀ78 °C, followed by the alkylation with
the appropriate dihaloderivative (3-chloro-2-chloro-
methylpropene, 1-chloro-4-iodobutane or a,a0-di-
bromo-o-xylene), generally afforded diastereomers 2a,d
and g witha 1,4- trans selectivity withat least a 98:2 ratio
withrespect to teh isopropyl group, as already ob-
served1–4 (Scheme 1). The alkylated products were gen-
erally obtained in good yield except for intermediate
2g, which was recovered in about 55% yield because it
competitively reacts withthe enolate of 1 to give the fol-
lowing product already described:3
Our interest in this field is twofold, firstly because some
natural products containing a cyclic system fused to the
diketopiperazine ring exhibit biological activity and sec-
ondly because the nonproteinogenic dipeptides could be
useful as components for preparing higher peptides or
act as starting materials in organic synthesis.
The strategy followed to accomplish the asymmetric
synthesis of these compounds is based on the experience
previously acquired on the stereoselective approach to
similar substrates.1–4 In fact, we have made use of chiral
synthon 1, a monolactim ether easily obtained starting
from L-valine, although our synthetic method differenti-
ates from that followed by Schollkopf. Actually, in an
asymmetric synthesis of nonproteinogenic dipeptides,
Schollkopf used the bislactim ether as a chiral synthon.6
Also Davies et al.,7 in an interesting investigation to
assign the correct structure of some diketopiperazines
derived from D-proline, described the synthetic
approachstarting from Schollkopf Õs auxiliary.
OEt
OEt
N
N
N
N
O
Ph
Ph
O
Intermediate 2a was easily converted into the bicyclic
derivative 3a by refluxing in acetone, in the presence
of NaI, while 2d and 2g were cyclized by heating in
DMF at 120 or 90 °C, respectively. Bicyclic compounds
3 were then converted into 4, withover 98% 1,4- trans
induction by alkylating withmethyl iodide or allyl bro-
mide. The removal of the benzyl group from bicyclic
compounds 3a and d and 4b,c,e,f,h and i through a
*
Corresponding authors. E-mail: gianni.porzi@unibo.it
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.03.006

1454
D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1453–1462
OEt
OEt
O
X
N
N
3
N
ii
6
i
Y
N
N
N
Y
55-90%Y
85-90%Y
H
H
Ph
O
Ph
O
Ph
O
1
3a,d,g
2a,d,g
80-90%Y
iii
iv
80%Y
O
N
Y
3
O
N
R
N
Ph
O
Y
Y
Y
HN
4b,c,e,f,h,i
O
5a,d
80-85%Y
iv
v
80%Y
O
N
O
Y
HN
N
R
O
N
5b,e,h
OEt
6a,d
v
80-90%Y
95%Y
vi
O
N
Y
O
N
R
N
OEt
NH3Cl
EtOOC
6b,e,h
7a,d
90%Y
vi
O
N
Y
NH3Cl
EtOOC
R
7b,e,h
a
b
c
d
e
f
g
h
i
>C=CH2 >C=CH2
-CH3
>C=CH2
CH2CH2 CH2CH2
-CH3
CH2CH2
CH2=CHCH2
o-C6H4 o-C6H4
o-C6H4
Y
R
H
CH2=CHCH2
H
H
-CH3 CH2=CHCH2
Scheme 1. Reagents and conditions: (i) 1 M LHMDS/THF, X–Y–X; (ii) heating in DMF, or refluxing in acetone/NaI; (iii) 1 M LHMDS/THF, R–X;
(iv) Li/NH3; (v) Et3OBF4/CH2Cl2; (vi) 0.5 M HCl at rt.
2
modified Birchreaction, furnished the intermediates 5,
which were converted into monolactims 6 following the
procedure already employed.8,9 Finally, the unusual
dipeptides 7a,b,d,e and h, incorporating the L-valine,
were quantitatively obtained by hydrolysis under mild
acid conditions.
The synthesis of diastereomeric pseudodipeptides 13b
and i withan opposite configuration at the C-2 stereo-
centre of the pyrrolidine or piperidine ring, with respect
to 7a,b,d,e and h, was accomplished on the basis of the
stereocontrolled trans-induction well tested in the alkyl-
ation reaction of the chiral synthon 1.1–4,8 Thus, non-

D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1453–1462
1455
OEt
OEt
O
O
X
N
3
N
N
i
6
ii
iii
Y
1
N
N
Y
N
80-90%Y
80-90%Y
R
R
R
Ph
O
Ph
O
O
Ph
9b,e,h,i
10b,e,h,i
8b,c
O
O
iv
85%Y
N
R
N
vi
N
v
Y
Y
Y
HN
N
NH3Cl
EtOOC
95%Y
80-85%Y
R
R
O
OEt
13b,i
12b,i
11b,i
b
a
c
d
e
f
g
h
i
>C=CH2 >C=CH2
-CH3
>C=CH2
CH2CH2 CH2CH2
-CH3
CH2CH2
CH2=CHCH2
o-C6H4 o-C6H4
-CH3 CH2=CHCH2
o-C6H4
Y
R
H
CH2=CHCH2
H
H
Scheme 2. Reagents and conditions: (i) 1 M LHMDS/THF, R–X; (ii) 1 M LHMDS/THF, X–Y–X; (iii) heating in DMF or refluxing in acetone/NaI;
(iv) Li/NH3; (v) Et3OBF4/CH2Cl2; (vi) 0.5 M HCl at rt.
proteinogenic dipeptides 13 were obtained simply by
changing the sequence of the alkylation at C-3 of the
chiral mono-lactim ether 1. In fact, as reported in
Scheme 2, chiral synthon 1 was alkylated firstly with
methyl iodide or allyl bromide and then successively
with the appropriate dihalo derivative (3-chloro-2-chlo-
romethylpropene, 1-chloro-4-iodobutane or a,a0-di-
bromo-o-xylene). The alkylation of 1 withbothmethyl
iodide and allyl bromide gave the trans diastereomers
8b and c, as already described,2 witha diastereoselectiv-
ity of ca. 75/25 and 85/15, respectively. However, in this
case the extent of the diastereoselection is not relevant
because the subsequent alkylation is performed on the
diastereomeric mixture.
ationally constrained unnatural dipeptides, which are
currently under study.
4. Experimental
4.1. General information
1H and 13C NMR spectra were recorded on a Gemini
spectrometer at 300 MHz using CDCl3 as solvent.
Chemical shifts are reported in ppm relative to CDCl3
withthe coupling constants ( J) given in Hz. Optical
rotation values were measured at 25 °C on a Perkin–
Elmer 343 polarimeter. Melting points are uncorrected.
The products isolated in not sufficiently pure form
for elemental analysis were submitted to HPLC-MS
analysis on a Hewlett-Packard Model 1100 liquid
chromatograph-single-quadrupole mass-selective detec-
tor system, with an Atmospheric Pressure Chemical
The absolute configuration of the new stereocentres in
substrates 2 and 9 was ascertained by measuring
the NOE between (C-6)-H and the substituents at the
C-3, the stereochemistry of C-6 being worthy of
note. In the case of substrate 4, the NOE was meas-
ured between (C-3)-H and the substituents at C-6 or
C-11a.
Ionisation–ElectroSpray interface, using
Eclipse XDB-C 8 column.
a Zorbax
Dry THF was distilled from sodium benzophenone
ketyl. Chromatographic separations were performed
withsilica gel 60 (230–400 mesh).
3. Conclusion
In conclusion, we have succeeded in synthesizing new
conformationally constrained nonproteinogenic dipep-
tides incorporating L-valine and unnatural a-amino
acids containing the pyrrolidine or piperidine ring. The
approach, accomplished in six steps starting from the
monolactim ether 1 easily obtained from L-valine,
allowed us to obtain pseudodipeptides, which differ in
the configuration of one stereogenic centre, that is, epi-
mers. We believe that our synthetic pathway represents
a useful complementary strategy to dipeptides and
might also provide a new and simple access to more
complex and unusual peptides incorporating conform-
4.2. Alkylation of 1
To a solution of 1 (2.74 g, 10 mmol) in dry THF (30 mL)
cooled at ꢀ78 °C were added 10 mmol of LHMDS (1 M
solution in THF). After about 1 hunder stirring, the
appropriate alkylating reagent (11 mmol) dissolved in
10 mL of dry THF was added dropwise and the reaction
monitored by TLC. When the reaction was complete,
water and ethyl acetate were then added, the organic ex-
tract dried over Na2SO4 and then evaporated to dryness
in vacuo. The crude reaction product was purified by the

1456
D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1453–1462
silica gel chromatography eluting with hexane/ethyl
acetate.
tography eluting with hexane/ethyl acetate. The product
was obtained pure as an oil in 90% yield. H NMR d:
1
1.02 (d, 1H, J = 7); 1.12 (d, 1H, J = 7); 2.17–2.36 (m,
1H); 2.74–2.92 (m, 1H); 3.04 (ddd, 1H, J = 1.6, 7.4,
15.8); 3.72 (d, 1H, J = 5.6); 3.93 (m, 1H); 3.95 (d, 1H,
J = 15); 5.30–5.54 (m, 2H); 5.09 (d, 1H, J = 1.6); 5.17
(d, 1H, J = 1.6); 5.4 (d, 1H, J = 15); 7.17–7.39 (m,
5ArH). 13C NMR d: 18.1, 19.9, 31.9, 36.8, 48.3, 49.9,
58.5, 66.6, 109.2, 127.9, 128.9, 135.7, 140.6, 164.1,
167.3. [a]D = +23.1 (c 1.3, CHCl3). Anal. Calcd for
C18H22N2O2: C, 72.46; H, 7.43; N, 9.39. Found: C,
72.5; H, 7.4; N, 9.36.
4.3. (3R,6S)-1-Benzyl-5-ethoxy-3-(2-chloromethyl-allyl)-
6-isopropyl-3,6-dihydro-1H-pyrazin-2-one, 2a
3-Chloro-2-chloromethylpropene was used as the alkyl-
ating reagent and the pure product was obtained as an
1
oil in 90% yield. H NMR d: 0.95 (d, 3H, J = 7); 1.07
(d, 3H, J = 7); 1.27 (t, 3H, J = 7); 2.18–2.30 (m, 1H);
2.69 (dd, 1H, J = 8.1, 14.1); 3.08 (dd, 1H, J = 4.2,
14.1); 3.71 (dd, 1H, J = 1.8, 4.2); 3.95 (d, 1H, J = 15);
4.03–4.28 (m, 5H); 5.17 (d, 1H, J = 0.9); 5.28 (d, 1H,
J = 0.9); 5.48 (d, 1H, J = 15); 7.19–7.40 (m, 5ArH).
13C NMR d: 13.8, 17.3, 19.7, 31.3, 36.3, 41.2, 48.9,
57.9, 61.0, 61.7, 116.4, 127.3, 127.5, 128.4, 135.9,
142.9, 159.1, 169.3. [a]D = +53.6 (c 1.4, CHCl3). Anal.
Calcd for C20H27ClN2O2: C, 66.19; H, 7.5; N, 7.72.
Found: C, 66.31; H, 7.48; N, 7.7.
4.7. (3S,6R)-4-Benzyl-3-isopropyl-1,4-diazabicyclo-
[4,4,0]decane-2,5-dione, 3d
A solution of intermediate 2d (9.12 g, 20 mmol) dis-
solved in 20 mL of DMF, was heated at 120 °C for
about 3 h. The organic solvent was evaporated, water
added to the residue and the reaction product extracted
withethyl acetate. After drying over Na 2SO4, the organ-
ic phase was evaporated in vacuo to dryness and the res-
idue purified by the silica gel chromatography eluting
with hexane/ethyl acetate. The product was obtained
4.4. (3R,6S)-1-Benzyl-5-ethoxy-3-(4-chlorobutyl)-6-iso-
propyl-3,6-dihydro-1H-pyrazin-2-one, 2d
1-Chloro-4-iodobutane was used as the alkylating re-
agent and the pure product was obtained as an oil in
75% yield. 1H NMR d: 0.92 (d, 3H, J = 7); 1.04 (d,
3H, J = 7); 1.25 (t, 3H, J = 7); 1.5 (m, 2H); 1.8–2.17
(m, 4H); 2.18–2.35 (m, 1H); 3.21 (t, 2H, J = 7); 3.69
(dd, 1H, J = 1.8, 4); 3.9 (d, 1H, J = 15); 4.02–4.22 (m,
3H); 5.48 (d, 1H, J = 15); 7.16–7.4 (m, 5ArH). 13C
NMR d: 7.2, 14.1, 17.5, 19.9, 26.2, 31.5, 32.5, 33.4,
47.2, 57.5, 61.1, 61.8, 127.5, 127.8, 128.7, 136.2, 159.1,
170.3. [a]D = +33.4 (c 1.1, CHCl3). Anal. Calcd for
C20H29ClN2O2: C, 65.83; H, 8.01; N, 7.68. Found: C,
66.1; H, 7.98; N, 7.7.
1
pure as a wax in 85% yield. H NMR d: 0.94 (d, 3H,
J = 7); 1.11 (d, 3H, J = 7); 1.4–1.82 (m, 4H); 2.04 (m,
1H); 2.32 (m, 1H); 2.53 (m, 2H); 3.76 (d, 1H, J = 3);
3.9 (d, 1H, J = 15); 3.92 (m, 1H); 4.7 (m, 1H); 7.18–7.4
(m, 5ArH). 13C NMR d: 16.4, 19.2, 23.3, 23.5, 30.9,
31.8, 40.9, 46.8, 56.9, 62.8, 127.1, 127.3, 128.2, 135.3,
163.6, 166.2. [a]D = ꢀ11.8 (c 0.8, CHCl3). Anal. Calcd
for C18H24N2O2: C, 71.97; H, 8.05; N, 9.33. Found: C,
72.11; H, 8.02; N, 9.29.
4.8. (3S,11aR)-2-Benzyl-3-isopropyl-2,3,11,11a-tetrahy-
dro-6H-pyrazino[1,2-b]isoquinoline-1,4-dione, 3g
4.5. (3R,6S)-1-Benzyl-5-ethoxy-3-(2-bromomethyl-
benzyl)-6-isopropyl-3,6-dihydro-1H-pyrazin-2-one, 2g
Intermediate 2g (9.16 g, 20 mmol) dissolved in 20 mL of
DMF was heated at 90 °C for about 3 hand the reaction
mixture worked up as above reported for 3d. The pure
product was isolated as a solid in 85% yield after purifi-
cation by the silica gel chromatography eluting with
a,a0-Dibromo-o-xylene was used as the alkylating re-
agent and the pure product was obtained as an oil in
1
55% yield. H NMR d: 0.9 (d, 3H, J = 7); 1.02 (d, 3H,
1
J = 7); 1.21 (t, 3H, J = 7); 2.19 (m, 1H); 3.37 (dd, 1H,
J = 7.2, 13.8); 3.57 (dd, 1H, J = 1.6, 4.2); 3.64 (dd, 1H,
J = 4.4, 13.8); 3.88 (d, 1H, J = 15); 3.9–4.2 (m, 2H);
4.4 (m, 1H); 4.84 (s, 2H); 5.48 (d, 1H, J = 15); 7.01
(m, 2ArH); 7.2–7.44 (m, 7ArH). 13C NMR d: 14.0,
17.4, 19.8, 31.4, 33.0, 35.0, 47.1, 59.1, 61, 61.7, 126.5,
127.3, 127.5, 128.2, 128.5, 130.1, 131.5, 135.8, 137.1,
138.1, 159.2, 169.4. [a]D = ꢀ50.5 (c 1.3, CHCl3). Anal.
Calcd for C24H29BrN2O2: C, 63.02; H, 6.39; N, 6.12.
Found: C, 63.11; H, 6.38; N, 6.1.
hexane/ethyl acetate. H NMR d: 0.99 (d, 3H, J = 7);
1.14 (d, 3H, J = 7); 2.3 (m, 1H); 2.99 (dd, 1H,
J = 11.8, 15.4); 3.63 (dd, 1H, J = 3.6, 15.4); 3.81 (d,
1H, J = 5.2); 3.99 (d, 1H, J = 15); 4.22 (dd, 1H,
J = 3.6, 11.8); 4.75 (qAB, 2H, J = 17.2); 5.5 (d, 1H,
J = 15); 7.17–7.42 (m, 5ArH). 13C NMR d: 17.7, 19.8,
31.9, 33.3, 44.6, 48.2, 54.3, 64.7, 126.9, 127.0, 127.7,
127.8, 128.6, 131.3, 133.4, 135.5, 165.1, 166.3. Mp
118–120 °C. [a]D = +91.4 (c 0.6, CHCl3). Anal. Calcd
for C22H24N2O2: C, 75.83; H, 6.94; N, 8.04. Found: C,
75.55; H, 6.96; N, 8.07.
4.6. (3S,6R)-4-Benzyl-3-isopropyl-8-methylene-1,4-diaza-
bicyclo[4,3,0]nonane-2,5-dione, 3a
4.9. (3S,6S)-4-Benzyl-3-isopropyl-6-methyl-8-methylene-
1,4-diazabicyclo[4,3,0]nonane-2,5-dione, 4b
A solution of intermediate 2a (7.24 g, 20 mmol) and
NaI (6 g, 40 mmol), dissolved in 50 mL of acetone,
was refluxed for about 18 h. The organic solvent was
evaporated, water added to the residue and the reaction
product extracted with ethyl acetate. The organic phase,
after drying over Na2SO4, was evaporated in vacuo to
dryness and the residue purified by the silica gel chroma-
To a solution of 3a (6 g, 20 mmol) in dry THF (60 mL)
cooled at ꢀ78 °C was added 20 mL (20 mmol) of
LHMDS (1 M solution in THF). After about 1 hunder
stirring, iodomethane (1.4 mL, 20 mmol) was dropped
and the reaction monitored by TLC. When the reaction
was complete, water and ethyl acetate were then added.

D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1453–1462
1457
The organic extract was dried over Na2SO4 and then
evaporated to dryness in vacuo. The crude reaction
product was purified by the silica gel chromatography
eluting with hexane/ethyl acetate and the pure product
74.08; H, 8.29; N, 8.23. Found: C, 73.83; H, 8.31; N,
8.26.
4.13. (3S,11aS)-2-Benzyl-3-isopropyl-11a-methyl-
2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-
1,4-dione, 4h
1
isolated as an oil in about 90% yield. H NMR d: 0.87
(d, 3H, J = 7); 1.16 (d, 3H, J = 7); 1.5 (s, 3H); 2.4 (m,
1H); 2.85 (m, 2H); 3.79 (d, 1H, J = 2.6); 3.97 (d, 1H,
J = 15); 4 (m, 1H); 4.47 (m, 1H); 5.19 (m, 2H); 5.55
(d, 1H, J = 15); 7.18–7.4 (m, 5ArH). 13C NMR d: 15.5,
19.8, 26.7 30.2, 43.4, 46.5, 48.4, 63.4, 63.8, 109.9,
127.8, 127.9, 128.7, 135.6, 140.6, 163.0, 169.9.
[a]D = +133.2 (c 0.9, CHCl3). Anal. Calcd for
C19H24N2O2: C, 73.05; H, 7.74; N, 8.97. Found: C,
72.89; H, 7.77; N, 8.98.
Compound 4h was obtained by alkylating 3g with
iodomethane and following the procedure used for 4b.
The pure product was isolated as a solid in about 85%
yield. 1H NMR d: 0.9 (d, 3H, J = 7); 1.13 (d, 3H,
J = 7); 1.6 (s, 3H); 2.36 (m, 1H); 3.3 (qAB, 2H,
J = 16.4); 3.89 (d, 1H, J = 3); 3.99 (d, 1H, J = 14.8);
4.25 (d, 1H, J = 18); 5.38 (d, 1H, J = 18); 5.56 (d, 1H,
J = 14.8); 7.10–7.44 (m, 9ArH). 13C NMR d: 16.8,
19.9, 24.7, 30.8, 38.9, 41.4, 47.1, 58.9, 63.2, 126.1,
126.7, 126.9, 128.0, 128.1, 128.9, 129.6, 130.5, 130.9,
162.9, 169.4. [a]D = ꢀ118.3 (c 0.7, CHCl3). Mp 161–
163 °C. Anal. Calcd for C23H26N2O2: C, 76.21; H,
7.23; N, 7.73. Found: C, 76.45; H, 7.22; N, 7.7.
4.10. (3S,6S)-6-Allyl-4-benzyl-3-isopropyl-8-methylene-
1,4-diazabicyclo[4,3,0]nonane-2,5-dione, 4c
Compound 4c was obtained by alkylating 3a withallyl
bromide and following the procedure used for 4b. Th e
pure product was isolated as an oil in about 85% yield.
1H NMR d: 0.81 (d, 3H, J = 7); 1.13 (d, 3H, J = 7); 2.38
(m, 1H); 2.39 (dd, 1H, J = 7.4, 14.4); 2.65 (dd, 1H,
J = 7.4, 13.6); 2.85 (m, 2H); 3.8 (d, 1H, J = 2.6); 3.88–
4.01 (m, 1H); 4.04 (d, 1H, J = 15); 5.04–5.24 (m, 4H);
5.39 (d, 1H, J = 15); 5.51 (m, 1H); 7.22–7.43 (m,
5ArH). 13C NMR d: 14.8, 19.4, 29.7, 42.2, 42.8, 46.6,
47.9, 63.4, 66.3, 109.4, 120.1, 127.4, 128.1, 128.4,
130.5, 134.8, 140.2, 163.0, 167.4. [a]D = ꢀ82.4 (c 1.2,
CHCl3). Anal. Calcd for C21H26N2O2: C, 74.52; H,
7.74; N, 8.28. Found: C, 74.77; H, 7.71; N, 8.26.
4.14. (3S,11aS)-11a-Allyl-2-benzyl-3-isopropyl-
2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-
1,4-dione, 4i
Compound 4i was obtained by alkylating 3g withallyl
bromide and following the procedure used for 4b. Th e
pure product was isolated as an oil in about 80% yield.
1H NMR d: 0.87 (d, 3H, J = 7); 1.11 (d, 3H, J = 7); 2.36
(m, 1H); 2.59 (dd, 1H, J = 7, 14.4); 2.73 (dd, 1H, J = 7.4,
14.4); 3.22 (br s, 2H); 3.89 (d, 1H, J = 2.8); 4.01 (d, 1H,
J = 14.2); 4.17 (d, 1H, J = 18); 5.05 (m, 2H); 5.35 (d, 1H,
J = 18); 5.48 (m, 2H); 7.17–7.42 (m, 9ArH). 13C NMR d:
16.4, 19.9, 30.4, 38.8, 40.2, 41.5, 47.2, 62.1, 62.8, 120.2,
126.2, 126.8, 126.9, 128.1, 128.7, 129.0, 129.5, 130.6,
130.9, 135.1, 163.8, 167.8. [a]D = ꢀ103.4 (c 1, CHCl3).
Anal. Calcd for C25H28N2O2: C, 77.29; H, 7.26; N,
7.21. Found: C, 77.45; H, 7.23; N, 7.2.
4.11. (3S,6S)-4-Benzyl-3-isopropyl-6-methyl-1,4-diazabi-
cyclo[4,4,0]decane-2,5-dione, 4e
Compound 4e was obtained by alkylating 3d with
iodomethane and following the procedure used for 4b.
The pure product was isolated as an oil in about 80%
yield. 1H NMR d: 0.85 (d, 3H, J = 7); 1.04 (d, 3H,
J = 7); 1.23 (m, 1H); 1.52 (s, 3H); 1.58–1.80 (m, 4H);
2.1–2.36 (m, 2H); 2.57–2.8 (m, 2H); 3.68 (d, 1H,
J = 2.6); 3.85 (d, 1H, J = 15); 4.5 (m, 1H); 5.36 (d, 1H,
J = 15); 7.08–7.3 (m, 5ArH). 13C NMR d: 16.6, 19.2,
19.7, 23.4, 24.9, 30.5, 33.8, 36.9, 46.7, 59.6, 62.5, 127.7,
128.4, 135.5, 162.1, 170.0. [a]D = ꢀ54.9 (c 0.9, CHCl3).
Anal. Calcd for C19H26N2O2: C, 72.58; H, 8.33; N,
8.91. Found: C, 72.8; H, 8.3; N, 8.89.
4.15. (3S,6R)-3-Isopropyl-8-methylene-1,4-diazabicyclo-
[4,3,0]nonane-2,5-dione, 5a
A solution of intermediate 3a (1.5 g, 5 mmol) in dry
THF/tert-butanol 9:1 (20 mL) was added to liquid
ammonia (ca. 50 mL) cooled at ꢀ50 °C. Then, Li
(0.07 g, 10 mmol), in small pieces, was added to the reac-
tion mixture under stirring. The addition of Li was con-
trolled by monitoring with TLC in the presence of the
starting material and stopped as soon as the reaction
mixture became blue. The reaction was then rapidly
quenched by the addition of NH4Cl (1 g) and the cool-
ing bathremoved allowing teh complete removal of
NH3. After addition of water, the aqueous solution
was extracted with ethyl acetate and the organic solution
evaporated to dryness under vacuum. The pure product
was recovered as a solid in 80% yield after silica gel
chromatography by eluting with hexane/ethyl acetate.1H
NMR d: 1.01 (d, 3H, J = 7); 1.07 (d, 3H, J = 7); 2.3 (m,
1H); 2.8 (m, 1H); 3.01 (m, 1H); 3.82 (dd, 1H, J = 4.6,
4.6); 3.99 (m, 1H); 4.29 (dd, 1H, J = 7, 11); 4.48 (m,
1H); 5.16 (m, 2H); 6.27 (br s, 1H). 13C NMR d: 17.3,
18.9, 33.4, 36.2, 50.0, 57.9, 63.0, 109.3, 140.1, 165.0,
4.12. (3S,6S)-6-Allyl-4-benzyl-3-isopropyl-1,4-diaza-
bicyclo[4,4,0]decan-2,5-dione, 4f
Compound 4f was obtained by alkylating 3d withallyl
bromide and following the procedure used for 4b. Th e
pure product was isolated as an oil in about 85% yield.
1H NMR d: 0.92 (d, 3H, J = 7); 1.12 (d, 3H, J = 7); 1.2
(m, 1H); 1.8 (m, 4H); 2.31 (m, 2H); 2.64 (m, 2H); 3.03
(dd, 1H, J = 7, 14.4); 3.78 (d, 1H, J = 3); 3.97 (d, 1H,
J = 15); 4.57 (m, 1H); 5.06 (m, 2H); 5.06 (m, 2H); 7.2–
7.4 (m, 5ArH). 13C NMR d: 16.3, 19.4, 19.9, 24.6,
30.2, 33.9, 36.8, 38.0, 47.0, 62.3, 62.8, 119.9, 127.6,
128.4, 128.7, 130.6, 135.0, 163.1, 168.3. [a]D = ꢀ51.6 (c
0.9, CHCl3). Anal. Calcd for C21H28N2O2: C,

1458
D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1453–1462
169.1. [a]D = +135 (c 0.4, CHCl3). Mp 156–157 °C.
Anal. Calcd for C11H16N2O2: C, 63.44; H, 7.74; N,
13.45. Found: C, 63.3; H, 7.77; N, 13.5.
4.20. (3S,6S)-3-Isopropyl-5-ethoxy-8-methylene-1,4-
diazabicyclo[4,3,0]-4-nonen-2-one, 6a
Intermediate 5a (2.08 g, 10 mmol) was treated with
Et3OBF4 (2.47 g, 13 mmol) dissolved in dry CH2Cl2
(15 mL) and the procedure already described was fol-
lowed.8,9 After the chromatographic elution with hex-
ane/ethyl acetate, the product was recovered as an oil
4.16. (3S,6S)-3-Isopropyl-6-methyl-8-methylene-1,4-
diazabicyclo[4,3,0]nonane-2,5-dione, 5b
Compound 5b was obtained starting from 4b and fol-
lowing the procedure previously described for 5a. Th e
product was recovered as a wax in 80% yield. 1H
NMR d: 0.9 (d, 3H, J = 7); 1.09 (d, 3H, J = 7); 1.45 (s,
3H); 2.65 (m, 1H); 2.96 (m, 1H); 3.97 (m, 1H); 4.04
(m, 1H); 4.38 (m, 1H); 5.17 (m, 2H); 6.11 (br s, 1H).
13C NMR d: 15.8, 19.0, 23.6, 28.9, 43.0, 48.9,
59.9, 110.2, 140.2, 164.3, 172.4. HPLC-MS: 223.3
(M++1), 245.3 (M++Na). The product was not isolated
in sufficiently pure form to measure the specific
rotation.
1
in 80% yield. H NMR d: 088 (d, 3H, J = 7); 1.06 (d,
3H, J = 7); 1.31 (t, 3H, J = 7); 2.27 (m, 1H); 2.58 (m,
1H); 2.87 (dd, 1H, J = 6.6, 15.4); 3.85 (m, 1H); 4.04–
4.27 (m, 4H); 4.52 (m, 1H); 5.11 (m, 2H). 13C NMR d:
13.2, 16.8, 18.4, 32.7, 36.2, 48.0, 55.4, 60.5, 65.7, 107.7,
140.5, 158.3, 167.1. HPLC-MS: 237.3 [M+1]+, 258.3
[M+Na]+. The product was not isolated in sufficiently
pure form to measure the specific rotation.
4.21. (3S,6S)-3-Isopropyl-6-methyl-5-ethoxy-8-methylene-
1,4-diazabicyclo[4,3,0]-4-nonen-2-one, 6b
4.17. (3S,6R)-3-Isopropyl-1,4-diazabicyclo[4,4,0]decane-
2,5-dione, 5d
Compound 6b was obtained starting from 5b and
following the procedure described for 6a. After the
chromatographic elution with hexane/ethyl acetate, the
The pure product was isolated as a wax in 80% yield
starting from 3d and following the procedure used for
5a. 1H NMR d: 0.89 (d, 3H, J = 7); 1.05 (d, 3H,
J = 7); 1.41–1.63 (m, 3H); 1.76 (m, 1H); 2.05 (m, 1H);
2.37–2.61 (m, 3H); 3.87 (m, 1H); 3.95 (m, 1H); 4.75
(m, 1H); 6.19 (br s, 1H). 13C NMR d: 15.7, 18.6, 24.2,
24.4, 31.1, 32.8, 42.4, 58.1, 59.9, 164.4, 168.5. HPLC-
MS: 211.3 [M+1]+, 233.3 [M+Na]+. The product was
not isolated in sufficiently pure form to measure the
specific rotation.
1
pure product was recovered as an oil in 85% yield. H
NMR d: 071 (d, 3H, J = 7); 1.1 (d, 3H, J = 7); 1.27 (t,
3H, J = 7); 2.48–2.79 (m, 3H), 3.79 (d, 1H, J = 2.6);
3.9 (m, 1H); 4.18 (m, 2H); 4.37 (m, 1H); 5.11 (m, 2H).
13C NMR d: 13.8, 16.0, 19.7, 22.8, 28.9, 43.0, 47.4,
60.9, 61.6, 62.8, 109.1, 141.2, 162.3, 167.5. HPLC-MS:
251.3 [M+1]+, 273.3 [M+Na]+. The product was not
isolated in sufficiently pure form to measure the specific
rotation.
4.22. (3S,6R)-3-Isopropyl-5-ethoxy-1,4-diazabicyclo-
[4,4,0]-4-decen-2-one, 6d
4.18. (3S,6S)-3-Isopropyl-6-methyl-1,4-diazabicyclo-
[4,4,0]decane-2,5-dione, 5e
Compound 6d was obtained as an oil in 80% yield start-
ing from 5d and following the procedure used for 6a. 1H
NMR d: 0.71 (d, 3H, J = 7); 1.11 (d, 3H, J = 7); 1.31 (t,
3H, J = 7); 1.37–1.76 (m, 4H); 1.95 (m, 1H); 2.25 (m,
1H); 2.33–2.6 (m, 2H); 3.82 (m, 1H); 3.97 (dd, 1H,
J = 2.4, 3); 4.05–4.25 (m, 2H); 4.78 (m, 1H). 13C NMR
d: 13.8, 15.8, 19.2, 23.7, 24.3, 30.6, 31.9, 41.2, 55.5,
60.4, 62.4, 157.4, 167.3. [a]D = ꢀ53.3 (c 1.1, CHCl3).
Anal. Calcd for C13H22N2O2: C, 65.51; H, 9.3; N,
11.75. Found: C, 65.23; H, 9.33; N, 11.8.
Compound 5e was obtained starting from 4e and follow-
ing the procedure previously described for 5a. The pure
product was recovered as an oil in 85% yield. H NMR
d: 0.77 (d, 3H, J = 7); 0.96 (d, 3H, J = 7); 1.18–1.8 (m,
5H); 1.46 (s, 3H); 2.1 (m, 1H); 2.47 (m, 1H); 2.59–2.8
(m, 1H); 3.83 (br s, 1H); 4.53 (m, 1H); 7.67 (br s, 1H).
13C NMR d: 15.5, 18.3, 19.1, 32.3, 24.6, 31.5, 34.2,
37.3, 58.8, 58.9, 164.6, 172.2. [a]D = ꢀ65 (c 1.1, CHCl3).
Anal. Calcd for C12H20N2O2: C, 64.26; H, 8.99; N,
12.49. Found: C, 64.03; H, 9.02; N, 12.53.
1
4.23. (3S,6S)-3-Isopropyl-6-methyl-5-ethoxy-1,4-diazabi-
cyclo[4,4,0]-4-decen-2-one, 6e
4.19. (3S,11aS)-3-Isopropyl-11a-methyl-2,3,11,11a-tetra-
hydro-6H-pyrazino[1,2-b]isoquinoline-1,4-dione, 5h
Compound 6e was obtained starting from 5e and follow-
ing the procedure described for 6a. After chromato-
graphic elution with hexane/ethyl acetate, the pure
product was recovered as an oil in 80% yield. 1H
NMR d: 0.7 (d, 3H, J = 7); 1.09 (d, 3H, J = 7); 1,26 (t,
3H, J = 7); 1.2–1.8 (m, 5H); 1.48 (s, 3H); 1.97–2.14 (m,
1H); 2.56 (m, 1H); 2.71 (m, 1H); 3.89 (dd, 1H, J = 1.2,
3.4); 3.98–4.28 (m, 2H); 4.65 (m, 1H). 13C NMR d:
14.1, 16.3, 19.4, 19.7, 21.1, 25.2, 31.8, 34.7, 36.3, 57.0,
60.6, 62.2, 161.1, 168.1. [a]D = ꢀ71.4 (c 0.8, CHCl3).
Anal. Calcd for C14H24N2O2: C, 66.63; H, 9.59; N,
11.1. Found: C, 66.75; H, 9.55; N, 11.07.
Compound 5h was obtained starting from 4h and fol-
lowing the procedure previously described for 5a. Th e
pure product was recovered as a solid in 80% yield. H
1
NMR d: 0.89 (d, 3H, J = 7); 1.09 (d, 3H, J = 7); 1.52
(s, 3H); 2.59 (m, 1H); 3.21 (qAB, 2H, J = 16); 4.06 (br
s, 1H); 4.36 (d, 1H, J = 18); 5.35 (d, 1H, J = 18); 6.61
(br s, 1H); 7.15–7.4 (m, 4ArH). 13C NMR d: 15.7,
18.7, 20.0, 31.7, 39.2, 42.3, 58.4, 59.7, 126.0, 126.9,
127.0, 129.4, 130.6, 130.8, 164.8, 171.3. [a]D = ꢀ164.4
(c 0.9, CHCl3). Mp 184–186 °C. Anal. Calcd for
C16H20N2O2: C, 70.56; H, 7.4; N, 10.29. Found: C,
70.74; H, 7.38; N, 10.25.

D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1453–1462
1459
4.24. (3S,11aS)-1-Ethoxy-3-isopropyl-11a-methyl-
3,6,11,11a-tetrahydro-pyrazino[1,2-b]isoquinolin-4-one,
6h
2H, J = 7); 4.4 (d, 1H, J = 4.4); 5.21 (m, 1H). 13C
NMR (CD3OD) d: 14.9, 17.3, 19.6, 22.0, 26.3, 28.0,
31.3, 45.3, 54.6, 56.8, 62.9, 170.2, 172.2. [a]D = +94.5
(c 1, CHCl3). Mp 151–152 °C. IR (CHCl3, cmꢀ1): 1653
(mNC@O), 1729 (mCOOEt), 2800–3000 (broad, mNH3+).
Anal. Calcd for C13H25ClN2O3: C, 53.33; H, 8.61; N,
9.57. Found: C, 53.5; H, 8.58; N, 9.55.
Compound 6h was obtained starting from 5h and fol-
lowing the procedure described for 6a. After chromato-
graphic elution with hexane/ethyl acetate, the pure
product was recovered as an oil in 90% yield. 1H
NMR d: 0.7 (d, 3H, J = 7); 1.13 (d, 3H, J = 7); 1.36 (t,
3H, J = 7); 1.43 (s, 3H); 2.58 (m, 1H); 3.11 (qAB, 2H,
J = 16.2); 4.04 (d, 1H, J = 2.8); 4.10–4.39 (m, 3H); 5.43
(d, 1H, J = 18); 7.1–7.3 (m, 4ArH). 13C NMR d: 14.2,
16.3, 19.6, 22.3, 31.9, 39.4, 40.7, 56.0, 61.0, 62.8, 126.1,
126.6, 129.2, 130.8, 131.0, 160.2, 168.3. [a]D = ꢀ162.8
(c 0.5, CHCl3). Anal. Calcd for C18H24N2O2: C, 71.97;
H, 8.05; N, 9.33. Found: C, 71.7; H, 8.07; N, 9.35.
4.28. (2S,20S)-1-(20-Amino-30-methyl-butyryl)-piperidine-
2-methyl-2-carboxylic acid ethyl ester hydrochloride, 7e
Compound 7e was obtained starting from 6e and follow-
ing the procedure used for 7a. The pure product was
1
isolated as an oil in 95% yield. H NMR d: 1.08 (d,
3H, J = 7); 1.16 (d, 3H, J = 7); 1.26 (t, 3H, J = 7); 1.5
(s, 3H); 1.58–1.97 (m, 6H); 2.23 (m, 1H); 3.33 (m, 1H);
3.8 (m, 1H); 3.98–4.27 (m, 2H); 4.29 (d, 1H, J = 5).
13C NMR d: 14.4, 17.2, 18.3, 18.8, 19.0, 24.5, 31.3,
35.2, 43.5, 56.8, 62.0, 62.2, 170.1, 175.4. [a]D = +70.6
(c 0.7, HCl 1 M). IR (CHCl3, cmꢀ1): 1652 (mNC@O),
1728 (mCOOEt), 2800–3000 (broad, mNH3+). Anal. Calcd
for C14H27ClN2O3: C, 54.8; H, 8.87; N, 9.13. Found:
C, 54.7; H, 8.9; N, 9.16.
4.25. (2R,20S)-1-(20-Amino-30-methyl-butyryl)-4-methyl-
ene-pyrrolidine-2-carboxylic acid ethyl ester hydrochlo-
ride, 7a
To a solution of 6a (1.18 g, 5 mmol) in ethanol (40 mL),
0.5 M HCl (20 mL) was added and the reaction mixture
stirred at room temperature for about 12 hmonitoring
by TLC. The hydroalcoholic solution was evaporated
in vacuo to dryness and the intermediate hydrochloride
4.29. (3S,20S)-2-(20-Amino-30-methyl-butyryl)-3-methyl-
1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid ethyl
ester hydrochloride, 7h
1
isolated as a wax in 95% yield. H NMR (CD3OD) d:
1.06 (d, 3H, J = 7); 1.14 (d, 3H, J = 7); 1.29 (t, 3H,
J = 7); 2.3 (m, 1H); 2.66 (m, 1H); 3.09 (m, 1H); 4.12–
4.26 (m, 3H); 4.38 (m, 2H); 4.68 (dd, 1H, J = 2.6, 10);
5.15 (m, 2H). 13C NMR (CD3OD) d: 14.4, 17.3, 19.2,
30.6, 36.1, 52.3, 57.8, 60.4, 62.6, 109.6, 143.2, 168.9,
172.9. IR (CHCl3, cmꢀ1): 1660 (mNC@O), 1732 (mCOOEt),
2800–3000 (broad, mNH3+). HPLC-MS: 291.8 [M+1]+,
313.8 [M+Na]+. The product was not isolated in suffi-
ciently pure form to measure the specific rotation.
Compound 7h was obtained starting from 6h and fol-
lowing the procedure used for 7a. The pure product
was isolated as a wax in 95% yield. H NMR d: 1.12
1
(t, 3H, J = 7); 1.13 (d, 3H, J = 7); 1.26 (d, 3H, J = 7);
1.35 (s, 3H); 2.4 (m, 1H); 2.98 (qAB, 2H, J = 15); 3.94–
4.37 (m, 2H); 4.62 (m, 1H); 4.73 (qAB, 2H, J = 14.6);
7.06–7.43 (m, 4ArH); 8.47 (br s, 3H). 13C NMR d:
13.9, 17.1, 19.2, 20.9, 29.4, 40.2, 46.4, 56.2, 61.1, 62.0,
126.3, 127.0, 127.2, 127.9, 133.2, 133.9, 167.4.
[a]D = ꢀ26.4 (c 1.2, CHCl3). IR (CHCl3, cmꢀ1): 1655
(mNC@O), 1730 (mCOOEt), 2800–3000 (broad, mNH3+).
Anal. Calcd for C18H27ClN2O3: C, 60.92; H, 7.67; N,
7.89. Found: C, 61.15; H, 7.65; N, 7.87.
4.26. (2S,20S)-1-(20-Amino-30-methyl-butyryl)-4-methyl-
ene-pyrrolidine-2-methyl-2-carboxylic acid ethyl ester
hydrochloride, 7b
Compound 7b was obtained starting from 6b and follow-
ing the procedure used for 7a. The product was isolated
as a wax in 95% yield. 1H NMR (CD3OD) d: 1.09 (d, 3H,
J = 7); 1.18 (d, 3H, J = 7); 1.27 (t, 3H, J = 7); 1.53 (s,
3H); 2.27 (m, 1H); 2.58 (d, 1H, J = 15); 2.94 (m, 1H);
3.99 (d, 1H, J = 5.6); 4.18 (m, 2H); 4.4 (m, 2H); 5.18
(m, 2H). 13C NMR (CD3OD) d: 14.7, 17.7, 19.4, 21.2,
31.1, 45.9, 53.1, 58.2, 62.9, 68.3, 110.2, 143.0, 168.6,
174.1. [a]D = ꢀ12.2 (c 0.4, CHCl3). IR (CHCl3, cmꢀ1):
1659 (mNC@O), 1735 (mCOOEt), 2800–3000 (broad,
mNH3+). Anal. Calcd for C14H25ClN2O3: C, 55.16; H,
8.27; N, 9.19. Found: C, 55.35; H, 8.24; N, 9.17.
4.30. (3R,6S)-1-Benzyl-5-ethoxy-6-isopropyl-3-methyl-
3,6-dihydro-1H-pyrazin-2-one, 8b
Synthesis and spectroscopic data are reported in Ref. 2.
4.31. (3R,6S)-3-Allyl-1-benzyl-5-ethoxy-6-isopropyl-3,6-
dihydro-1H-pyrazin-2-one, 8c
Synthesis and spectroscopic data are reported in Ref. 2.
4.32. (3R,6R)-1-Benzyl-5-ethoxy-3-methyl-6-isopropyl-3-
methyl-3,6-dihydro-1H-pyrazin-2-one, 9b
4.27. (2R,20S)-1-(20-Amino-30-methyl-butyryl)-piperidine-
2-carboxylic acid ethyl ester hydrochloride, 7d
Synthesis and spectroscopic data are reported in Ref. 2.
Compound 7d was obtained as a solid in 95% yield start-
ing from 6d and following the procedure used for 7a. 1H
NMR (CD3OD) d: 1.03 (d, 3H, J = 7); 1.16 (d, 3H,
J = 7); 1.31 (t, 3H, J = 7); 1.49 (m, 2H); 1.77 (m, 3H),
2.1–2.4 (m, 2H); 3.42 (m, 1H); 3.85 (m, 1H); 4.24 (q,
4.33. (3R,6S)-1-Benzyl-5-ethoxy-3-(4-chlorobutyl)-6-iso-
propyl-3-methyl-3,6-dihydro-1H-pyrazin-2-one, 9e
Compound 9e was obtained starting from 8b and
following the procedure employed to synthesize 2.

1460
D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1453–1462
1-Chloro-4-iodobuatane was used as the alkylating
reagent and the pure product was obtained as an oil in
80% yield. 1H NMR d: 0.95 (d, 3H, J = 7); 1.07 (d,
3H, J = 7); 1.16 (m, 1H); 1.26 (t, 3H, J = 7.4); 1.47 (s,
3H); 1.56 (m, 1H); 1.75 (m, 2H); 2.07 (m, 1H); 2.23
(m, 1H); 3.13 (t, 2H, J = 7); 3.78 (d, 1H, J = 2.6); 3.89
(d, 1H, J = 15); 4.1 (m, 2H); 5.53 (d, 1H, J = 15); 7.2–
7.42 (m, 5ArH). 13C NMR d: 7.0, 14.0, 17.1, 20.3,
28.7, 29.5, 33.2, 42.0, 46.3, 60.2, 60.5, 60.9, 127.4,
128.3, 128.5, 135.8, 155.8, 172.0. [a]D = ꢀ11.9 (c 0.9,
CHCl3). Anal. Calcd for C21H3IClN2O2: C, 66.56; H,
8.25; N, 7.39. Found: C, 66.33; H, 8.22; N, 7.42.
d: 1.07 (d, 3H, J = 6.9); 1.18 (d, 3H, J = 6.9); 1.58 (s,
3H); 2.25 (m, 1H); 2.75 (br s, 2H); 3.72 (d, 1H,
J = 6.2); 3.92 (m, 1H); 3.94 (d, 1H, J = 14.8); 4.61 (m,
1H); 5.13–5.23 (m, 2H); 5.48 (d, 1H, J = 14.8); 7.16–
7.42 (m, 5ArH). 13C NMR d: 18.6, 20.0, 24.5, 31.5,
45.6, 47.9, 48.4, 63.8, 65.6, 109.2, 127.3, 128.4, 135.5,
140.1, 163.1, 169.3. [a]D = ꢀ16.9 (c 1.6, CHCl3). Anal.
Calcd for C19H24N2O2: C, 73.05; H, 7.74; N, 8.97.
Found: C, 73.35; H, 7.72; N, 8.96.
4.37. (3S,6R)-4-Benzyl-3-isopropyl-6-methyl-1,4-
diazabicyclo[4,4,0]decane-2,5-dione, 10e
Compound 10e was obtained starting from 9e and fol-
lowing the procedure used to prepare 3d. The pure prod-
uct was obtained as an oil in 80% yield. 1H NMR d: 0.95
(d, 3H, J = 7); 1.12 (d, 3H, J = 7); 1.22–1.85 (m, 5H);
1.65 (s, 3H); 2.17–2.36 (m, 2H); 2.7 (m, 1H); 3.78 (d,
1H, J = 3.2); 3.9 (d, 1H, J = 15); 4.66 (m, 1H); 5.44 (d,
1H, J = 15); 7.18–7.42 (m, 5ArH). 13C NMR d: 17.7,
20.1, 21.1, 24.4, 31.0, 37.1, 37.5, 47.4, 59.7, 63.2, 127.6,
127.8, 128.7, 135.7, 162.8, 170.5. [a]D = ꢀ44.2 (c 0.9,
CHCl3). Anal. Calcd for C19H26N2O2: C, 72.58; H,
8.33; N, 8.91. Found: C, 72.32; H, 8.35; N, 8.92.
4.34. (3R,6S)-1-Benzyl-5-ethoxy-3-(2-bromomethyl-benz-
yl)-6-isopropyl-3-methyl-3,6-dihydro-1H-pyrazin-2-one,
9h
Compound 9h was obtained starting from 8b and fol-
lowing the procedure employed to synthesize 2. a,a0-
Dibromo-o-xylene was used as alkylating reagent and
the pure product was obtained as an oil in 90% yield.
1H NMR d: 0.87 (d, 3H, J = 7); 0.94 (d, 3H, J = 7);
1.27 (t, 3H, J = 7); 1.68 (s, 3H); 2.1 (m, 1H); 3.09 (d,
1H, J = 13.6); 3.34 (d, 1H, J = 2.4); 3.64 (d, 1H,
J = 13.6); 3.75 (d, 1H, J = 15); 3.9–4.4 (m, 2H); 4.83
(s, 2H); 5.43 (d, 1H, J = 15); 6.58 (m, 2ArH); 7.08–
7.18 (m, 7ArH). 13C NMR d: 14.0, 16.8, 20.0, 28.9,
29.8, 33.1, 43.6, 45.6, 59.8, 60.3, 62.0, 126.5, 127.0,
127.6, 127.9, 128.9, 130.2, 131.5, 134.7, 136.5, 137.3,
155.9, 170.9. [a]D = +12.2 (c 1.1, CHCl3). Anal. Calcd
for C25H3IBrN2O2: C, 63.69; H, 6.63; N, 5.94. Found:
C, 63.75; H, 6.61; N, 5.93.
4.38. (3S,11aR)-2-Benzyl-3-isopropyl-11a-methyl-
2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-
1,4-dione, 10h
Compound 10h was obtained starting from 9h and fol-
lowing the procedure used to prepare 3g. The pure prod-
uct was obtained as an oil in 80% yield. 1H NMR d: 1.05
(d, 3H, J = 7); 1.22 (d, 3H, J = 7); 1.61 (s, 3H); 2.37 (m,
1H); 3.1 (d, 1H, J = 15.9); 3.37 (d, 1H, J = 15.9); 3.89 (d,
1H, J = 3.3); 3.99 (d, 1H, J = 15); 4.25 (d, 1H, J = 18);
5.54 (d, 1H, J = 18); 5.58 (d, 1H, J = 15); 7.17–7.42
(m, 9ArH). 13C NMR d: 17.9, 20.2, 22.7, 31.4, 41.7,
47.6, 58.7, 63.5, 125.8, 126.8, 126.9, 128.0, 128.9,
129.4, 130.3, 131.2, 135.6, 163.5, 169.8. [a]D = +29.6
(c 0.8, CHCl3). Anal. Calcd for C23H26N2O2: C,
76.21; H, 7.23; N, 7.73. Found: C, 75.91; H, 7.26; N,
7.75.
4.35. (3R,6S)-3-Allyl-1-benzyl-5-ethoxy-3-(2-bromo-
methyl-benzyl)-6-isopropyl-3,6-dihydro-1H-pyrazin-2-
one, 9i
Compound 9i was obtained starting from 8c and follow-
ing the procedure employed to synthesize 2. a,a0-Di-
bromo-o-xylene was used as the alkylating reagent and
1
the product was obtained as an oil in 80% yield. H
NMR d: 0.87 (d, 3H, J = 7); 0.96 (d, 3H, J = 7); 1.29
(t, 3H, J = 7.2); 2.08 (m, 1H); 2.77 (dd, 1H, J = 6.9,
13.8); 2.87 (dd, 1H, J = 7.8, 13.8); 3.21 (d, 1H,
J = 13.5); 3.32 (d, 1H, J = 2.7); 3.58 (d, 1H, J = 13.8);
3.92 (d, 1H, J = 15); 4.02 (m, 1H); 4.29 (m, 1H); 4.82
(br s, 2H); 5.27 (m, 3H); 6.11 (m, 1H); 6.7 (m, 2ArH);
7.16–7.4 (m, 7ArH). 13C NMR d: 14.1, 16.8, 20.4,
29.1, 33.1, 41.1, 46.6, 46.7, 60.2, 60.6, 64.7, 118.4,
126.7, 127.1, 127.8, 128.1, 128.3, 130.4, 131.6, 133.5,
135.1, 136.6, 137.6, 156.5, 170.4. HPLC-MS: 497.2 and
499.2 [M+1]+, 519.2 and 521.2 [M+Na]+. The product
was not isolated in sufficiently pure form to measure
the specific rotation.
4.39. (3S,11aR)-2-Benzyl-3-isopropyl-11a-allyl-
2,3,11,11a-tetrahydro-6H-pyrazino[1,2-b]isoquinoline-
1,4-dione, 10i
Compound 10i was obtained starting from 9i and fol-
lowing the procedure used to prepare 3g. The pure prod-
1
uct was obtained as a solid in 85% yield. H NMR d:
1.06 (d, 3H, J = 7); 1.21 (d, 3H, J = 7); 2.35 (m, 1H);
2.56 (dd, 1H, J = 7.4, 14.2); 2.81 (dd, 1H, J = 7.6,
14.2); 3.04 (d, 1H, J = 16); 3.36 (d, 1H, J = 16); 3.84
(d, 1H, J = 3.6); 4.06 (d, 1H, J = 15); 4.2 (d, 1H,
J = 18); 5.09 (m, 2H); 5.51 (d, 1H, J = 15); 5.57 (d,
1H, J = 18); 5.9 (m, 1H); 7.15–7.43 (m, 9ArH). 13C
NMR d: 18.4, 20.7, 31.6, 39.4, 40.3, 41.5, 48.1, 61.9,
63.6, 119.4, 125.8, 126.9, 127.0, 127.8, 127.9, 128.9,
129.3, 130.8, 131.1, 132.4, 135.8, 164.4, 168.1.
[a]D = +16.4 (c 0.9, CHCl3). Mp 107–109 °C. Anal.
Calcd for C25H28N2O2: C, 77.29; H, 7.26; N, 7.21.
Found: C, 77.01; H, 7.28; N, 7.23.
4.36. (3S,6R)-4-Benzyl-3-isopropyl-6-methyl-8-methyl-
ene-1,4-diazabicyclo[4,3,0]nonane-2,5-dione, 10b
Compound 10b was obtained starting from 9b and
following the procedure used to prepare 3a. The pure
product was obtained as an oil in 90% yield. H NMR
1

D. Balducci et al. / Tetrahedron: Asymmetry 16 (2005) 1453–1462
1461
4.40. (3S,6R)-3-Isopropyl-6-methyl-8-methylene-1,4-
diazabicyclo[4,3,0]nonan-2,5-dione, 11b
131.2, 132.3, 158.1, 167.8. [a]D = +121.5 (c 0.7, CHCl3).
Anal. Calcd for C20H26N2O2: C, 73.59; H, 8.03; N, 8.58.
Found: C, 73.35; H, 8.06; N, 8.61.
Compound 11b was obtained starting from 10b and fol-
lowing the procedure used for 5b. The pure product was
isolated as a solid in 85% yield 1H NMR d: 1.03 (d, 3H,
J = 7); 1.1 (d, 3H, J = 7); 1.53 (s, 3H); 2.25 (m, 1H);
2.62–2.91 (m, 2H); 3.81 (dd, 1H, J = 3.2, 5.8); 3.95 (m,
1H); 4.6 (m, 1H); 5.22 (m, 2H); 6.3 (br s, 1H). 13C
NMR d: 18.1, 19.3, 25.6, 32.9, 44.4, 49.0, 62.6, 63.8,
109.8, 140.0, 164.1, 171.8, 184.4. [a]D = +100.9 (c 0.8,
CHCl3). Mp 148–150 °C. Anal. Calcd for C12H18N2O2:
C, 64.84; H, 8.16; N, 12.6. Found: C, 64.61; H, 8.18;
N, 12.63.
4.44. (2R,20S)-1-(20-Amino-30-methyl-butyryl)-4-methyl-
ene-pyrrolidin-2-methyl-2-carboxylic acid ethyl ester
hydrochloride, 13b
Compound 13b was obtained starting from 12b and
following the procedure used for 7b. The pure product
1
was isolated as a wax in 95% yield. H NMR d: 1.09
(d, 3H, J = 7); 1.17 (d, 3H, J = 7); 1.23 (t, 3H, J = 7);
1.53 (s, 3H); 2.3 (m, 1H); 2.53 (d, 1H, J = 15.2); 2.88
(d, 1H, J = 15.2); 4.21 (m, 4H); 4.66 (d, 1H, J = 13.6);
5.07 (d, 2H, J = 15.2); 8.45 (br s, 3H). 13C NMR d:
14.1, 17.3, 18.8, 21.3, 29.8, 44.5, 52.4, 56.5, 61.7, 66.6,
109.0, 140.9, 166.9, 172.7. [a]D = +47.5 (c 0.7, CHCl3).
IR (CHCl3, cmꢀ1): 1660 (mNC@O), 1735 (mCOOEt), 2800–
3000 (broad, mNH3+). Anal. Calcd for C14H25ClN2O3:
C, 55.16; H, 8.27; N, 9.19. Found: C, 54.91; H, 8.29;
N, 9.23.
4.41. (3S,11aR)-1-Ethoxy-3-isopropyl-11a-allyl-
3,6,11,11a-tetrahydro-pyrazino[1,2-b]isoquinolin-4-one,
11i
Compound 11i was obtained starting from 10i and fol-
lowing the procedure used for 5h. The pure product
1
was isolated as a solid in 85% yield. H NMR d: 0.97
4.45. (3R,20S)-2-(20-Amino-30-methyl-butyryl)-3-allyl-
1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid ethyl
ester hydrochloride, 13i
(d, 3H, J = 7); 1.11 (d, 3H, J = 7); 2.58 (dd, 1H,
J = 7.8, 14.4); 2.65 (m, 1H); 2.82 (dd, 1H, J = 6.9,
14.4); 3.22 (br s, 2H); 4.04 (m, 1H); 4.17 (d, 1H,
J = 18); 5.16 (m, 2H); 5.7 (d, 1H, J = 18); 5.73 (m,
1H); 6.7 (br s, 1H); 7.13–7.33 (m, 4ArH). 13C NMR d:
17.0, 19.0, 31.3, 38.6, 39.2, 41.1, 59.9, 62.1, 120.0,
126.0, 126.9, 127.0, 129.4, 130.6, 130.9, 131.8, 164.3,
169.3. [a]D = +84.7 (c 0.4, CHCl3). Mp 60–62 °C. Anal.
Calcd for C18H22N2O2: C, 72.46; H, 7.43; N, 9.39.
Found: C, 72.32; H, 7.45; N, 9.43.
Compound 13i was obtained starting from 12i and fol-
lowing the procedure used for 7h. The pure product
1
was isolated as a wax in 95% yield. H NMR d: 0.96 (t,
3H, J = 7); 1.1 (d, 3H, J = 7); 129 (d, 3H, J = 7); 2.37
(m, 1H); 2.83 (m, 2H); 3.09 (qAB, 2H, J = 15.4); 4 (m,
2H); 4.63 (qAB, 2H, J = 15); 4.79 (m, 1H); 5.03 (m,
2H); 5.72 (m, 1H); 7.01–7.43 (m, 4ArH). 13C NMR d:
13.9, 16.7, 19.3, 30.0, 36.9, 38.4, 47.6, 56.1, 61.3, 63.9,
119.5, 125.9, 127.4, 128.1, 132.7, 133.2, 133.8, 167.7,
172.6. [a]D = +21.4 (c 0.6, CHCl3). IR (CHCl3, cmꢀ1):
1653 (mNC@O and mC=C) 1729 (mCOOEt), 2800–3000 (broad,
mNH3+). Anal. Calcd for C20H29ClN2O3: C, 63.06; H,
7.67; N, 9.31. Found: C, 63.22; H, 7.65; N, 9.25.
4.42. (3S,6R)-3-Isopropyl-6-methyl-5-ethoxy-8-methyl-
ene-1,4-diazabicyclo[4,3,0]-4-nonen-2-one, 12b
Compound 12b was obtained starting from 11b and fol-
lowing the procedure used for 6b. The pure product was
1
isolated as an oil in 80% yield. H NMR d: 0.94 (d, 3H,
J = 7); 1.12 (d, 3H, J = 7); 1.31 (t, 3H, J = 7); 1.41 (s,
3H); 2.2 (m, 1H); 2.50–2.55 (m, 2H); 3.84 (m, 1H);
3.97 (d, 1H, J = 5.6); 4.05–4.35 (m, 2H); 4.64 (m, 1H);
5.15 (m, 2H). 13C NMR d: 14.1, 18.7, 20.0, 25.1, 33.0,
44.5, 47.9, 61.1, 62.0, 66.4, 109.2, 141.3, 161.2, 168.2.
[a]D = +104.9 (c 0.7, CHCl3). Anal. Calcd for
C14H22N2O2: C, 67.17; H, 8.86; N, 11.19. Found: C,
67.34; H, 8.83; N, 11.15.
Acknowledgements
Thanks are due to the University of Bologna for the
financial support (ÔRicerca fondamentale orientataÕ)
and we also thank Enrico Emer, undergraduate student,
for carrying out some reactions.
4.43. (3S,11aR)-1-Ethoxy-3-isopropyl-11a-allyl-
3,6,11,11a-tetrahydro-pyrazino[1,2-b]isoquinolin-4-one,
12i
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