Stereoselective synthesis of sterically constrained dipeptides. Part 2

Article abstract of DOI:10.1016/S0957-4166(97)00609-5

The alkylation of the diastereomeric mixture of lactims 2 and 3 occurs in total regioselectivity and good to high facial stereoselectivity (d.s. ranging from 82 to 97%). Cleavage of the lactim 4e gives enantiomerically pure dipeptide 12, sterically constrained at the α-carbon. The absolute configuration of the new stereocentres has been assigned on the basis of ¹H- NMR data and NOE measurements.

Full text of DOI:10.1016/S0957-4166(97)00609-5

Pergamon
Tetrahedron: Asymmetry 9 (1998) 119–132
Stereoselective synthesis of sterically constrained dipeptides.
Part 2 †
Gianni Porzi, Sergio Sandri ∗ and Piera Verrocchio
Dipartimento di Chimica ‘G. Ciamician’, Via Selmi 2, Università degli Studi di Bologna, Bologna, Italy
Received 28 October 1997; accepted 21 November 1997
Abstract
The alkylation of the diastereomeric mixture of lactims 2 and 3 occurs in total regioselectivity and good to
high facial stereoselectivity (d.s. ranging from 82 to 97%). Cleavage of the lactim 4e gives enantiomerically pure
dipeptide 12, sterically constrained at the α-carbon. The absolute configuration of the new stereocentres has been
assigned on the basis of 1H-NMR data and NOE measurements. © 1998 Elsevier Science Ltd. All rights reserved.
In a previous paper we reported a new approach to the stereoselective synthesis of uncommon
dipeptides monoalkylated at the α-carbon.1 Our current aim is the developement of a new stereoselective
synthesis to obtain conformationally constrained dipeptides C-αα0 dialkylated in good enantiomeric
excess. This is because in recent years this class of compound has received considerable attention
(particularly in the medical field) owing to its peptidomimetic properties for receptor ligands, i.e.
agents that can imitate (agonists) or block (antagonists) the biological functions of bioactive peptides.2
Therefore, in a continuation of our studies in this field, we accomplished an extension of the previously
reported diastereoselective synthesis of dipeptides.1 The procedure followed consists of a double alkyla-
tion of the chiral synthon (6R,10S)-5-ethoxy-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one
1 synthesized starting from the methansulfonate of naturally occurring (S)-ethyl lactate and following the
same protocol reported for (ꢀ)-2-bromopropionate.1
In the previous paper1 we described the conversion of lactim 1 into the trans-2 and cis-3 diastereomers
which occurs with moderate to good trans stereoselectivity. We report herein the stereochemical results
concerning the alkylation of the diastereomeric mixture of 2 and 3 (Scheme 1). The reaction was carried
out with good to high diastereoselectivity and chemical yield, demonstrating a new synthetic route to
enantiomerically pure uncommon C-αα0 dialkyl dipeptides. This second alkylation, totally regioselective
at C-3, was performed directly on the diastereomeric mixture of the lactims 2 (trans) and 3 (cis) thereby
avoiding their separation. The stereochemical outcome of such alkylations thus represents the most
salient feature of this approach to the synthesis of C-αα.
∗
†
Corresponding author. E-mail: porzi@ciamserv.unibo.it
Ref. 1 is considered to be Part 1.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(97)00609-5

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Scheme 1. R and R1 are reported in Table 1
Table 1
Diastereoselectivity of the alkylation
The results summarized in Table 1 indicate that, regardless of the alkylating reagent used, the alkylation
of the diastereomeric mixture (3S,6R)-2 and (3R,6R)-3 yields the isomer 4 in large predominance with
respect to 5. It can therefore be asserted that the reaction occurs with a good 1,4-trans induction with
respect to (C-6)-CH3.3
To investigate the influence of the chiral auxiliary configuration on the stereochemical outcome of the
alkylation, the reaction was also performed on the lactim 6 in which the (N-1)-phenethyl group possessed
the R instead of the S configuration. By comparing the stereochemical results, reported in Scheme 2, to

G. Porzi et al. / Tetrahedron: Asymmetry 9 (1998) 119–132
121
those previously obtained in the alkylation of 1,1 it is evident that the change of the auxiliary configuration
produces an appreciable decrease of the diastereoselection comparable to that already observed1 when
the (S)-1-phenethyl group was substituted by the sterically similar achiral benzyl group.
Scheme 2.
These findings prompted us to also investigate the influence of the (R)-phenethyl group on the
alkylation of the diastereomeric mixture of 7 and 8 (Scheme 3) in order to compare the stereochemical
results with those observed for the (2 and 3) diastereomeric mixture.
Scheme 3. R and R1 are reported in Table 1
The data collected in Table 1 reveal that, in this case as well, the second alkylation proceeds with a
prevalent trans induction, although an overall slight decrease of the diastereoselectivity was registered,
particularly for entry 6.
In summary, the data described in this paper and those previously reported,1 allow us to make the
following conclusions: (a) the first alkylation is evidence that the trans diastereoselection is prevalently,
but not exclusively, influenced by the C-6 center; (b) both the first and the second alkylation reactions
occur with better trans diastereoselection if the (S)-phenethyl group is employed and the (C-6) stereo-
centre has the R configuration, i.e. the stereocentres are of opposite configuration. Assuming that in the
enolate ion the atoms N-1, C-2, C-3, N-4 and C-5 are substantially coplanar, while the C-6 is out of the
plane and that the benzylic hydrogen preferentially lies syn-periplanar with respect to the carbonyl group
(as can be seen from the NOE experiments illustrated in Figs 2 and 3), a reasonable explanation of the
observed diastereoselection could be the result of differences in steric hindrance of the lithium enolate
diastereotopic faces during the approach of the achiral electrophile (Fig. 1).
Actually, in the syn-periplanar conformer the phenyl ring could increase the steric hindrance on the re
face (hindered as well by the (C-6)-CH3) thereby favouring the attack on the si face of the enolate anion
(model A in Fig. 1). Conversely, in the model B enolate the phenyl ring produces steric interactions on
the face opposite where the (C-6)-CH3 lies, leading to a lower facial discrimination which is significant
for entry 6 (Table 1).

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Thus, it can be deduced that in both the first and second alkylations of the synthon 1 the best
stereoselection is achieved when the two stereocentres have opposite configurations, since the si face is
sterically less hindered than the re one (A enolate). In addition, as previously observed,1 the alkylation of
a synthon without the chiral auxiliary gives lower diastereoselection; however, the results are comparable
to those observed when the two stereocentres have the same configuration (B enolate).
Finally, in a model study, the lactim 4e was debenzylated and easily converted into the corresponding
dipeptide 12 (following the procedure previously reported for a similar substrate1) which was then
functionalized as acetamido derivative 13 (Scheme 4).
In conclusion, we can assert that the above reported double alkylation of the chiral synthon 1 provides
a good synthetic route to enantiomerically pure uncommon and conformationally constrained C-αα0
dialkylated dipeptides.
1. Stereochemical assignments
The configuration of the introduced stereocentre (C-3) was deduced on the basis of 1H-NMR spectro-
scopic data using the approach previously employed for similar molecules.1 We previously reported1 that
the preferred geometry of the lactims 1, 2 and 3 is the boat-like conformation in which the (C-6)-CH3
preferentially lies in an axial-like arrangement. Thus, the relative configuration of the C-3 stereocentre
both of 4 and 5 has been assigned on the basis of the NOE measurements and the shielding effects
registered. In fact, for the derivatives 4 upon irradiation of (C-6)-CH3 the NOE was exclusively observed
on the (C-3)-R, while the lactims 5 displayed a significant NOE between (C-6)-CH3 and (C-3)-R1. It is
important to underline that neither in 4 nor in 5 were any NOEs registered between (C-6)-H and (C-3)-R
or (C-3)-R1. For both the isomers, in addition to a meaningful NOE between (C-6)-H and the methyl
of the chiral auxiliary,4 a characteristic shielding effect of about 0.4 ppm, induced by the phenyl ring of
the phenethyl group,1 was observed on the (C-6)-CH3. These findings were evidence that for both the
isomers, the preferred geometry is the boat-like conformation in which the (C-6)-CH3 is axially arranged
and the (S)-phenethyl group preferentially lies in the syn periplanar conformation. As examples, the
NOEs recorded for 4b and 5b are schematized in Fig. 2.
Furthermore, the high field resonance (0.16 ppm) of the (C-6)-CH3 doublet in the spectrum of the cis
isomer 3 (when R=CH2Ph) is diagnostically very useful in assigning the relative configuration of C-3, in
contrast to the value of 0.69 ppm registered for the corresponding trans isomer 2.1 In fact, this upfield
shift is induced by the shielding effect of the phenyl ring of the (C-3)-CH2Ph group which lies in the
axial-like position, thus adopting the preferential ‘aryl inside’ arrangement. As previously observed in
analogous substrates,4,5 such a conformation causes significant shielding of the axial-like (C-6)-CH3 that
we registered both in 4(l,m,n) and 5(c,f,i), this shielding of about 0.8 ppm providing clear evidence that
both the (C-6)-CH3 and (C-3)-CH2Ph are axially arranged (Fig. 3). The trans relationship between the
Fig. 1. Models proposed for the enolate anions: A (6R,10S) and B (6R,10R)

G. Porzi et al. / Tetrahedron: Asymmetry 9 (1998) 119–132
123
Scheme 4. (i) Na/NH3; (ii) 0.5 N HCl/acetone at 0°C; (iii) CH3COCl/Et3N in CH2Cl2 at 0°C
Fig. 2. Representative NOE registered for 4b and 5b
(C-3)-CH2Ph and the (C-6)-CH3 in 4(c,f,i) and 5(l,m,n) was ascertained by both the absence of the above
mentioned shielding effect and the significant NOE registered between the (C-6)-CH3 and the alkyl group
at C-3 (Fig. 3).
Fig. 3. Shielding induced by the (C-3)-CH2Ph on (C-6)-CH3 and significant NOE registered on 4 and 5
The relative configuration of the C-3 stereocentre of 7 and 8 was determined as described in the
previous paper,1 but considering that since in this case the chiral auxiliary possesses the R-configuration,
the phenyl ring of the R-phenethyl group shields the (C-6)-H rather than the (C-6)-CH3.
Finally, the relative configuration of the C-3 stereocentre of 9 and 10 was assigned on the basis of
1H-NMR data and NOE measurements as described above for 4 and 5.
2. Experimental
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 the solvent. Optical
rotation values were measured on a Perkin–Elmer 343 polarimeter. Chromatographic separations were
performed with silica gel 60 (230–400 mesh). Dry THF was distilled from sodium benzophenone ketyl.

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2.1. Alkylation of diastereomeric mixture 2 and 3: general procedure
3 ml of LHMDS (1M solution in THF) were dropped into a stirred solution of 3 mmol of diastereomeric
mixture (2 and 3) in dry THF (30 ml), cooled at −78°C under an inert atmosphere. After 1 h, 4.5 mmol
of the appropriate alkyl halide were added and the reaction mixture was stirred for 3 h. The reaction
mixture, slowly warmed up to r.t., was quenched with water and extracted with ethyl acetate. The organic
extract was dried, evaporated under reduced pressure and the diastereomers were sperarated by silica gel
chromatography (hexane:ethyl acetate as eluent).
2.2. (3S,6R,10S)-5-Ethoxy-3-ethyl-3,6-dimethyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 4a or
5d
1
Iodoethane was used as the alkylating reagent. H-NMR δ 0.7 (t, 3H, J=7.3 Hz), 0.89 (d, 3H, J=6.8
Hz), 1.26 (t, 3H, J=7.1 Hz), 1.39 (s, 3H), 1.55 (m, 1H), 1.62 (d, 3H, J=7.1 Hz), 2.18 (m, 1H), 4.05 (q,
1H, J=6.8 Hz), 4.11 (m, 2H), 5.78 (q, 1H, J=7.1 Hz), 7.32 (m, 5ArH); 13C-NMR δ 8.8, 14, 16.3, 21.1,
28.6, 34.9, 50.4, 51.5, 60.9, 61.4, 127.26, 127.33, 128.2, 141.1, 159.7, 171.9. The pure 4a was isolated
in 70% yield: [α]D=−195.5 (c=2.9, CHCl3). Anal. Calcd for C18H26N2O2: C, 71.49; H, 8.67; N, 9.26.
Found: C, 71.72; H, 8.7; N, 9.23.
2.3. (3S,6R,10S)-3-Allyl-5-ethoxy-3,6-dimethyl-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 4b or 5g
1
3-Iodopropene was used as the alkylating reagent. H-NMR δ 0.87 (d, 3H, J=6.8 Hz), 1.25 (t, 3H,
J=7.1 Hz), 1.4 (s, 3H), 1.59 (d, 3H, J=7.2 Hz), 2.33 (dd, 1H, J=7.3, 13.1 Hz), 2.82 (dd, 1H, J=7.3, 13.1
Hz), 3.99 (q, 1H, J=6.8 Hz), 4.07 (m, 2H), 5.02 (m, 2H), 5.63 (m, 1H), 5.75 (q, 1H, J=7.2 Hz), 7.3 (m,
5ArH); 13C-NMR δ 14, 16.3, 21.1, 28.2, 46.1, 50.3, 51.5, 61, 61.1, 117.5, 127.3, 127.4, 128.2, 134.4,
141, 159.4, 171.6. The pure 4b was isolated in 80% yield: [α]D=−168.9 (c=3.5, CHCl3). Anal. Calcd for
C19H26N2O2: C, 72.58; H, 8.34, N; 8.91. Found: C, 72.45; H, 8.35; N, 8.95.
2.4. (3S,6R,10S)-3-Benzyl-5-ethoxy-3,6-dimethyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 4c
or 5l
1
Benzyl bromide was used as the alkylating reagent. H-NMR δ 0.81 (d, 3H, J=6.8 Hz), 1.25 (t, 3H,
J=7.1 Hz), 1.29 (d, 3H, J=7.1 Hz), 1.54 (s, 3H), 2.83 (d, 1H, J=2.5 Hz), 3.47 (d, 1H, J=12.5 Hz), 3.65
(q, 1H, J=6.8 Hz), 4.12 (m, 2H), 5.66 (q, 1H, J=7.1 Hz), 7.22 (m, 10ArH); 13C-NMR δ 14.1, 15.7, 21.1,
28.9, 47.5, 50, 51.2, 60.9, 62.3, 125.9, 127.1, 127.2, 128.2, 130.7, 137.9, 141.1, 158.9, 171.1. The pure
4c was isolated in 81% yield: [α]D=−107.9 (c=3.6, CHCl3). Anal. Calcd for C23H28N2O2: C, 72.79; H,
7.74; N, 7.69. Found: C, 76.02; H, 7.72; N, 7.67.
2.5. (3R,6R,10S)-5-Ethoxy-3-ethyl-3,6-dimethyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 4d or
5a
Iodomethane was used as the alkylating reagent. 1H-NMR δ 0.9 (t, 3H, J=7.5 Hz), 1.01 (d, 3H, J=6.8
Hz), 1.26 (t, 3H, J=7.1 Hz), 1.41 (s, 3H), 1.65 (d, 3H, J=7.2 Hz), 1.66 (m, 1H), 1.92 (m, 1H), 4.08 (m,
3H), 5.68 (q, 1H, J=7.2 Hz), 7.31 (m, 5ArH); 13C-NMR δ 9.1, 14.1, 16.1, 21.1, 28.2, 34.8, 51, 51.7, 61.1,
61.7, 127.1, 127.2, 128.3, 141.9, 158.4, 171. The pure 4d was isolated in 72% yield: [α]D=−149 (c=0.4,
CHCl3). Anal. Calcd for C18H26N2O2: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.61; H, 8.65; N, 9.22.

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2.6. (3S,6R,10S)-3-Allyl-5-ethoxy-3-ethyl-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 4e
or 5h
1
3-Iodopropene was used as the alkylating reagent. H-NMR δ 0.85 (t, 3H, J=7.5 Hz), 1.02 (d, 3H,
J=6.8 Hz), 1.27 (t, 3H, J=7 Hz), 1.65 (d, 3H, J=7.2 Hz), 1.63 (m, 1H), 2 (m, 1H), 2.3 (dd, 1H, J=7.2, 12.8
Hz), 2.73 (dd, 1H, J=7.2, 12.8 Hz), 4.1 (m, 3H), 4.95 (m, 2H), 5.51 (m, 1H), 5.6 (q, 1H, J=7.2 Hz), 7.31
(m, 5ArH); 13C-NMR δ 9.1, 14.1, 16.2, 21.1, 33.5, 45.5, 51.1, 52.1, 60.9, 65.1, 117.8, 127, 128.1, 133.8,
141.5, 158.6, 170.6. The pure 4e was isolated in 92% yield: [α]D=−161.6 (c=2.4, CHCl3). Anal. Calcd
for C20H28N2O2: C, 73.14; H, 8.59; N, 8.53. Found: C, 73.43; H, 8.57; N, 8.5.
2.7. (3S,6R,10S)-3-Benzyl-5-ethoxy-3-ethyl-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one
4f or 5m
1
Benzyl bromide was used as the alkylating reagent. H-NMR δ 0.84 (d, 3H, J=6.8 Hz), 0.89 (t, 3H,
J=7.5 Hz), 1.22 (d, 3H, J=7.3 Hz), 1.26 (t, 3H, J=7.1 Hz), 1.75 (m, 1H), 2.24 (m, 1H), 2.79 (d, 1H,
J=12.4 Hz), 3.36 (d, 1H, J=12.4 Hz), 3.55 (q, 1H, J=6.8 Hz), 4.17 (m, 2H), 5.65 (q, 1H, J=7.3 Hz), 7.25
(m, 10ArH); 13C-NMR δ 9.4, 14.3, 15, 21.1, 34, 47.5, 49.9, 50.6, 60.8, 66.6, 126, 126.9, 127, 127.4,
128.1, 130.5, 137.5, 142.2, 158.6, 170. The pure 4f was isolated in 90% yield: [α]D=−107.7 (c=6.6,
CHCl3). Anal. Calcd for C24H30N2O2: C, 76.16; H, 7.99; N, 7.4. Found: C, 76.23; H, 8.02; N, 7.42.
2.8. (3R,6R,10S)-3-Allyl-5-ethoxy-3,6-dimethyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 4g or
5b
1
Iodomethane was used as the alkylating reagent. H-NMR δ 1.0 (d, 3H, J=6.8 Hz), 1.25 (t, 3H, J=7
Hz), 1.43 (s, 3H), 1.65 (d, 3H, J=7.2 Hz), 2.38 (dd, 1H, J=7.4, 12.8 Hz), 2.64 (dd, 1H, J=7.4, 12.8 Hz),
4.1 (q, 2H, J=7 Hz), 4.1 (q, 1H, J=6.8 Hz), 5.1 (m, 2H), 5.7 (q, 1H, J=7.2 Hz), 5.77 (m, 1H), 7.31 (m,
5ArH); 13C-NMR δ 13.9, 15.9, 21.1, 28.4, 46.2, 50.8, 51.5, 60.9, 61.2, 118.2, 126.9, 127, 127.3, 128.1,
133.8, 141.5, 158.4, 171.5. The pure 4g was isolated in 78% yield: [α]D=−134.2 (c=0.96, CHCl3). Anal.
Calcd for C19H26N2O2: C, 72.58; H, 8.34; N, 8.91. Found: C, 72.65; H, 8.32; N, 8.88.
2.9. (3R,6R,10S)-3-Allyl-5-ethoxy-3-ethyl-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one
4h or 5e
Iodomethane was used as the alkylating reagent. 1H-NMR δ 0.64 (t, 3H, J=7.3 Hz), 1.03 (d, 3H, J=6.8
Hz), 1.28 (t, 3H, J=7.1 Hz), 1.56 (m, 1H), 1.66 (d, 3H, J=7.2 Hz), 2.11 (m, 1H), 2.36 (dd, 1H, J=7.1,
13.4 Hz), 2.67 (dd, 1H, J=7.1, 13.4 Hz), 4.3 (m, 3H), 5.1 (m, 2H), 5.62 (q, 1H, J=7.2 Hz), 5.73 (m, 1H),
7.31 (m, 5ArH); 13C-NMR δ 8.5, 14.2, 16.2, 21.5, 34.4, 45.7, 51.2, 52.1, 61.1, 65.1, 118.3, 127.2, 127.3,
128.1, 134.1, 141.7, 159.2, 170.5. The pure 4h was isolated in 93% yield: [α]D=−168.6 (c=3, CHCl3).
Anal. Calcd for C20H28N2O2: C, 73.14; H, 8.59; N, 8.53. Found: C, 73.03; H, 8.62; N, 8.55.
2.10. (3S,6R,10S)-3-Allyl-3-benzyl-5-ethoxy-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one
4i or 5n
1
Benzyl bromide was used as the alkylating reagent. H-NMR δ 0.83 (d, 3H, J=6.8 Hz), 1.24 (d, 3H,
J=7.1 Hz), 1.26 (t, 3H, J=7.1 Hz), 2.5 (dd, 1H, J=6.9, 13.1 Hz), 2.82 (d, 1H, J=12.6 Hz), 2.94 (dd, 1H,
J=7.7, 13.1 Hz), 3.42 (d, 1H, J=12.6 Hz), 3.55 (q, 1H, J=6.8 Hz), 4.16 (m, 2H), 5.16 (m, 2H), 5.6 (q, 1H,

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J=7.1 Hz), 5.75 (m, 1H), 7.24 (m, 10ArH); 13C-NMR δ 14.2, 15.1, 21.3, 45.6, 47.3, 50.1, 50.9, 60.9, 66,
118.5, 126.1, 126.9, 127.1, 127.5, 128, 128.7, 129, 130.5, 134, 137.3, 141.9, 158.7, 169.5. The pure 4i
was isolated in 92% yield: [α]D=−113 (c=1.7, CHCl3). Anal. Calcd for C25H30N2O2: C, 76.89; H, 7.74;
N, 7.17. Found: C, 76.98; H, 7.77; N, 7.2.
2.11. (3R,6R,10S)-3-Benzyl-5-ethoxy-3,6-dimethyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 4l
or 5c
Iodomethane was used as the alkylating reagent. 1H-NMR δ 0.07 (d, 3H, J=6.8 Hz), 1.28 (t, 3H, J=7.1
Hz), 1.51 (s, 3H), 1.62 (d, 3H, J=7.2 Hz), 2.82 (d, 1H, J=12.8 Hz), 3.39 (d, 1H, J=12.8 Hz), 3.88 (q,
1H, J=6.8 Hz), 4.16 (q, 2H, J=7.1 Hz), 5.19 (q, 1H, J=7.2 Hz), 7.22 (m, 10ArH); 13C-NMR δ 14.1,
16.2, 19.2, 30.2, 47.1, 52, 53.2, 60.7, 62.9, 126.3, 126.7, 127.1, 127.3, 127.5, 127.8, 130.6, 137.3, 141.2,
157.9, 170.6. The pure 4l was isolated in 79% yield: [α]D=−109.7 (c=1.7, CHCl3). Anal. Calcd for
C23H28N2O2: C, 72.79; H, 7.74; N, 7.69. Found: C, 75.97; H, 7.77; N, 7.71.
2.12. (3R,6R,10S)-3-Benzyl-5-ethoxy-3-ethyl-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-
2-one 4m or 5f
1
Iodoethane was used as the alkylating reagent. H-NMR δ 0.07 (d, 3H, J=6.8 Hz), 0.6 (t, 3H, J=7.3
Hz), 1.3 (t, 3H, J=7.2 Hz), 1.65 (m, 1H), 1.62 (d, 3H, J=7.2 Hz), 2.2 (m, 1H), 2.78 (d, 1H, J=12.7 Hz),
3.35 (d, 1H, J=12.7 Hz), 3.9 (q, 1H, J=6.8 Hz), 4.2 (m, 2H), 5.12 (q, 1H, J=7.2 Hz), 7.24 (m, 10ArH); 13C-
NMR δ 8.3, 14.2, 16.1, 19.2, 35.6, 46.7, 52.2, 53.5, 60.7, 66.6, 126.3, 126.8, 127, 127.5, 127.6, 130.7,
137.4, 141.1, 158.8, 169.5. The pure 4m was isolated in 92% yield: [α]D=−101.2 (c=2.5, CHCl3). Anal.
Calcd for C24H30N2O2: C, 76.16; H, 7.99; N, 7.4. Found: C, 76.3; H, 7.97; N, 7.38.
2.13. (3R,6R,10S)-3-Allyl-3-benzyl-5-ethoxy-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one
4n or 5i
3-Iodopropene was used as the alkylating reagent. 1H-NMR δ 0.05 (d, 3H, J=6.8 Hz), 1.27 (t, 3H, J=7
Hz), 1.6 (d, 3H, J=7.2 Hz), 2.38 (dd, 1H, J=7.4, 12.8 Hz), 2.8 (d, 1H, J=12.6 Hz), 2.85 (dd, 1H, J=7.4,
12.8 Hz), 3.4 (d, 1H, J=12.6 Hz), 3.85 (q, 1H, J=6.8 Hz), 4.17 (m, 2H), 4.85–5.05 (m, 2H), 5.1 (q, 1H,
J=7.2 Hz), 5.49 (m, 1H), 7.23 (m, 10ArH); 13C-NMR δ 14.1, 16, 19.2, 46.1, 46.7, 52, 53.4, 60.6, 66.1,
117.9, 126.3, 126.7, 126.9, 127.5, 130.6, 133.2, 137, 140.9, 158.5, 169. The pure 4n was isolated in 93%
yield: [α]D=−89.5 (c=1.7, CHCl3). Anal. Calcd for C25H30N2O2: C, 76.89; H, 7.74; N, 7.17. Found: C,
76.78; H, 7.72; N, 7.15.
2.14. (6R,10R)-5-Ethoxy-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 6
The product was prepared starting from the methansulfonate of naturally occurring (S)-ethyl lactate
and (R)-1-phenylethylamine by following the procedure employed for 1.1 1H-NMR δ 1.18 (t, 3H, J=7
Hz), 1.38 (d, 3H, J=6.9 Hz), 1.64 (d, 3H, J=7.2 Hz), 3.61 (dq, 1H, J=1, 6.9 Hz), 4.03 (q, 2H, J=7 Hz),
4.09 (dd, 1H, J=1, 19.7 Hz), 4.27 (d, 1H, J=19.7 Hz), 5.87 (q, 1H, J=7.2 Hz), 7.3 (m, 5ArH); 13C-NMR
δ 13.5, 17.4, 19.2, 49, 50.4, 51.1, 61.2, 126.8, 127.3, 128.2, 138.8, 163.5, 167.5. [α]D=−37.5 (c=2.1,
CHCl3). Anal. Calcd for C15H20N2O2: C, 69.2; H, 7.74; N, 10.76. Found: C, 69.45; H, 7.71; N, 10.8.

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127
2.15. Alkylation of 6 to the diastereomeric mixture 7(a–d) and 8(a–d).
The reaction was performed by following the procedure used for the alkylation of the compound 1.1
2.16. (3S,6R,10R)-5-Ethoxy-3,6-dimethyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 7a
1
After 4 h of reaction, the pure product was isolated in 23% yield. H-NMR δ 1.18 (t, 3H, J=7.1 Hz),
1.37 (d, 3H, J=6.9 Hz), 1.58 (d, 3H, J=7.1 Hz), 1.62 (d, 3H, J=7.3 Hz), 3.65 (dq, 1H, J=1.1, 6.9 Hz),
4.05 (dq, 1H, J=1.1, 7.1 Hz), 4.1 (q, 2H, J=7.1 Hz), 5.85 (q, 1H, J=7.3 Hz), 7.3 (m, 5ArH); 13C-NMR δ
14, 17.8, 18.7, 19.5, 50.1, 51.6, 53.7, 61.6, 127.1, 127.6, 128.6, 139.7, 163.3, 171. [α]D=−18.2 (c=0.9,
CHCl3). Anal. Calcd for C16H22N2O2: C, 70.04; H, 8.08; N, 10.21. Found: C, 70.3; H, 8.11; N, 10.18.
2.17. (3S,6R,10R)-3-Benzyl-5-ethoxy-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 7b
After 12 h of reaction, the pure product was isolated in 52% yield. 1H-NMR δ 1.17 (t, 3H, J=7.1 Hz),
1.29 (d, 3H, J=6.9 Hz), 1.61 (d, 3H, J=7.2 Hz), 3.26 (dd, 1H, J=7, 13.3 Hz), 3.42 (dd, 1H, J=4.2, 13.3 Hz),
3.44 (dq, 1H, J=1.4, 6.9 Hz), 4.05 (m, 2H), 4.27 (ddd, 1H, J=1.4, 4.2, 7 Hz), 5.78 (q, 1H, J=7.2 Hz), 6.95
(m, 2ArH), 7.3 (m, 8ArH); 13C-NMR δ 14, 17.7, 19.8, 39, 49.7, 51.7, 59.2, 61.4, 125.9, 127.1, 127.7,
128.4, 130.4, 138.9, 139.2, 162, 169.2. [α]D=−156.8 (c=1.5, CHCl3). Anal. Calcd for C22H26N2O2: C,
75.4; H, 7.48; N, 7.99. Found: C, 75.6; H, 7.5; N, 8.01.
2.18. (3S,6R,10R)-5-Ethoxy-3-ethyl-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 7c
1
After 5 h of reaction, the pure product was isolated in 63% yield. H-NMR δ 0.98 (t, 3H, J=7.2 Hz),
1.36 (d, 3H, J=6.9 Hz), 1.63 (d, 3H, J=7.2 Hz), 1.9 (t, 3H, J=7.2 Hz), 2.05 (m, 2H), 3.62 (dq, 1H, J=1.2,
6.9 Hz), 3.95 (m, 1H), 4.09 (m, 2H), 5.88 (q, 1H, J=7.2 Hz), 7.3 (m, 5ArH); 13C-NMR δ 9.2, 13.6, 17.5,
18.9, 25.6, 49.4, 51.2, 58, 61, 126.7, 127.1, 128.2, 139.3, 162.4, 169.6. [α]D=−32.1 (c=8.4, CHCl3).
Anal. Calcd for C17H24N2O2: C, 70.8; H, 8.39; N, 9.71. Found: C, 71.1; H, 8.37; N, 9.75.
2.19. (3S,6R)-3-Allyl-5-ethoxy-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 7d
1
After 2 h of reaction the pure product was isolated in 76% yield. H-NMR δ 0.8 (t, 3H, J=7.2 Hz),
1.36 (d, 3H, J=6.9 Hz), 1.63 (d, 3H, J=7.3 Hz), 2.75 (m, 2H), 3.61 (dq, 1H, J=1.3, 6.9 Hz), 4.05 (m, 3H),
5.12 (m, 2H), 5.85 (q, 1H, J=7.3 Hz), 6 (m, 1H), 7.3 (m, 5ArH); 13C-NMR δ 13.9, 17.7, 19.3, 37.2, 49.8,
51.6, 57.7, 61.4, 116.8, 127.1, 127.4, 128.5, 135.4, 139.4, 162.7, 169.5. [α]D=−17.1 (c=3.7, CHCl3).
Anal. Calcd for C18H24N2O2: C, 71.97; H, 8.05; N, 9.33. Found: C, 72.16; H, 8.06; N, 9.3.
2.20. (3R,6R,10R)-5-Ethoxy-3,6-dimethyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 8a
After 4 h of reaction, the pure product was isolated in 67% yield. 1H-NMR δ 1.2 (t, 3H, J=7 Hz), 1.42
(d, 3H, J=6.8 Hz), 1.49 (d, 3H, J=7.3 Hz), 1.65 (d, 3H, J=7.2 Hz), 3.57 (dq, 1H, J=0.8, 6.8 Hz), 4.07 (m,
2H), 4.28 (dq, 1H, J=0.8, 7.3 Hz), 5.85 (q, 1H, J=7.2 Hz), 7.4 (m, 5ArH); 13C-NMR δ 13.8, 17.8, 21.7,
22.3, 49.3, 51.9, 56.2, 61.2, 127.4, 127.6, 128.5, 138.6, 161.5, 170.6. [α]D=20.3 (c=2.2, CHCl3). Anal.
Calcd for C16H22N2O2: C, 70.04; H, 8.08; N, 10.21. Found: C, 70.23; H, 8.05; N, 10.17.

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2.21. (3R,6R,10R)-3-Benzyl-5-ethoxy-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 8b
After 12 h of reaction, the pure product was isolated in 43% yield. 1H-NMR δ 0.35 (d, 3H, J=6.9 Hz),
1.2 (t, 3H, J=7.1 Hz), 1.52 (d, 3H, J=7.2 Hz), 3.11 (dd, 1H, J=4.5, 13.1 Hz), 3.3 (dq, 1H, J=6.9, 13.1
Hz), 3.43 (dd, 1H, J=5.2, 13.1 Hz), 4.05 (m, 2H), 4.53 (ddd, 1H, J=1.8, 4.5, 5.2 Hz), 5.75 (q, 1H J=7.2
Hz), 7.3 (m, 10ArH); 13C-NMR δ 14.1, 17.6, 20.2, 40.3, 49.7, 52.5, 60.9, 61.1, 126.6, 127.7, 127.9, 128,
128.5, 130.5, 137.2, 138, 160.6, 168.1. [α]D=−5.5 (c=1, CHCl3). Anal. Calcd for C22H26N2O2: C, 75.4;
H, 7.48; N, 7.99. Found: C, 75.3; H, 7.45; N, 7.97.
2.22. (3R,6R,10R)-5-Ethoxy-3-ethyl-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 8c
1
After 5 h of reaction, the pure product was isolated in 27% yield. H-NMR δ 1.05 (t, 3H, J=7.4 Hz),
1.19 (t, 3H, J=7.2 Hz), 1.38 (d, 3H, J=6.9 Hz), 1.63 (d, 3H, J=7.2 Hz), 1.7 (m, 1H), 1.95 (m, 1H), 3.56 (q,
1H, J=6.9 Hz), 4.04 (m, 3H), 5.82 (q, 1H, J=7.2 Hz), 7.3 (m, 5ArH); 13C-NMR δ 10.7, 13.9, 17.9, 22.1,
29.3, 49.4, 52.1, 61.2, 61.5, 127.6, 128.6, 138.6, 160.9, 169.8. [α]D=40.1 (c=2.1, CHCl3). Anal. Calcd
for C17H24N2O2: C, 70.8; H, 8.39; N, 9.71. Found: C, 70.6; H, 8.36; N, 9.68.
2.23. (3R,6R,10R)-3-Allyl-5-ethoxy-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 8d
After 2 h of reaction, the pure product was isolated in 19% yield 1H-NMR δ 1.2 (t, 3H, J=7.1 Hz), 1.39
(d, 3H, J=6.9 Hz), 1.65 (d, 3H, J=7.1 Hz), 2.6 (m, 2H), 3.55 (dq, 1H, J=1.2, 6.9 Hz), 4.02 (m, 2H), 4.28
(m, 1H), 5.13 (m, 2H), 5.8 (q, 1H, J=7.1 Hz), 5.9 (m, 1H), 7.35 (m, 5ArH); 13C-NMR δ 14, 18.1, 22.3,
40.1, 49.7, 52.4, 60.2, 61.4, 117.8, 127.8, 128.7, 134.3, 138.5, 161.6, 169. [α]D=14.3 (c=0.5, CHCl3).
Anal. Calcd for C18H24N2O2: C, 71.97; H, 8.05; N, 9.33. Found: C, 71.69; H, 8.08; N, 9.31.
2.24. Alkylation of diastereomeric mixture 7 and 8
The reaction was performed following the general procedure and the same alkylating reagents used for
the alkylation of diastereomeric mixture (2 and 3) above described.
2.25. (3S,6R,10R)-5-Ethoxy-3,6-dimethyl-3-ethyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 9a
or 10d
1H-NMR δ 0.78 (t, 3H, J=7.1 Hz), 1.2 (t, 3H, J=7 Hz), 1.38 (d, 3H, J=6.7 Hz), 1.4 (s, 3H), 1.55 (m,
1H), 1.66 (d, 3H, J=7.2 Hz), 2.2 (m, 1H), 3.58 (q, 1H, J=6.7 Hz), 4.05 (q, 2H, J=7 Hz), 5.76 (q, 1H,
J=7.2 Hz), 7.3 (m, 5ArH); 13C-NMR δ 9.1, 14, 17.9, 22.1, 28.9, 34.9, 50, 52.5, 61, 61.5, 127.6, 128.6,
139.1, 159.7, 172. The pure 9a was isolated in 81% yield: [α]D=15.9 (c=0.8, CHCl3). Anal. Calcd for
C18H26N2O2: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.68; H, 8.7; N, 9.23.
2.26. (3S,6R,10R)-3-Allyl-5-ethoxy-3,6-dimethyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 9b
or 10g
1H-NMR δ 1.2 (t, 3H, J=7.1 Hz), 1.37 (d, 3H, J=6.8 Hz), 1.42 (s, 3H), 1.65 (d, 3H, J=7.2 Hz), 2.37
(dd, 1H, J=7.1, 13 Hz), 2.87 (dd, 1H, J=7.1, 13 Hz), 3.55 (q, 1H, J=6.8 Hz), 4.3 (q, 2H, J=7.1 Hz), 5.08
(m, 2H), 5.7 (m, 2H), 7.3 (m, 5ArH); 13C-NMR δ 14, 17.9, 22.1, 28.5, 46.1, 50, 52.5, 61, 61.4, 117.6,

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127.5, 127.6, 128.5, 134.6, 139, 159.4, 171.5. The pure 9b was isolated in 66% yield: [α]D=43.8 (c=0.8,
CHCl3). Anal. Calcd for C19H26N2O2: C, 72.58; H, 8.34; N, 8.91. Found: C, 72.85; H, 8.36; N, 8.95.
2.27. (3S,6R,10R)-3-Benzyl-5-ethoxy-3,6-dimethyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 9c
or 10l
The product 9c was obtained in 68% yield. 1H-NMR δ 1.2 (t, 3H, J=7.1 Hz), 1.27 (d, 3H, J=6.8 Hz),
1.57 (s, 3H), 1.59 (d, 3H, J=6.8 Hz), 2.87 (d, 1H, J=12.4 Hz), 3.19 (q, 1H, J=7.1 Hz), 3.49 (d, 1H, J=12.4
Hz), 4.12 (m, 2H), 5.57 (q, 1H, J=7.1 Hz), 6.65 (m, 2ArH), 7.3 (m, 8ArH); 13C-NMR δ 14, 17.6, 22.1,
29, 47.5, 49.4, 51.8, 60.7, 62.6, 125.9, 127.1, 127.2, 127.4, 127.7, 127.8, 128.2, 128.3, 130.8, 137.9,
138.4, 159, 170.7.
2.28. (3R,6R,10R)-5-Ethoxy-3-ethyl-3,6-dimethyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 9d
or 10a
1H-NMR δ 0.87 (t, 3H, J=7.2 Hz), 1.2 (t, 3H, J=7.2 Hz), 1.37 (d, 3H, J=6.8 Hz), 1.47 (s, 3H), 1.67 (d,
3H, J=7 Hz), 1.67 (m, 1H), 1.95 (m, 1H), 3.61 (q, 1H, J=6.8 Hz), 4.06 (m, 2H), 5.73 (q, 1H, J=7 Hz),
7.33 (m, 5ArH); 13C-NMR δ 9.2, 14.1, 18, 21.9, 28.7, 34.8, 50.4, 52.7, 60.9, 61.7, 127.6, 127.8, 128.6,
138.9, 158.3, 172.1. The pure 9d was isolated in 60% yield: [α]D=21.4 (c=0.6, CHCl3). Anal. Calcd for
C18H26N2O2: C, 71.49; H, 8.67; N, 9.26. Found: C, 71.28; H, 8.65; N, 9.22.
2.29. (3S,6R,10R)-3-Allyl-5-ethoxy-3-ethyl-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one
9e or 10h
The product 9e was obtained in 78% yield. 1H-NMR δ 0.83 (t, 3H, J=7.3 Hz), 1.2 (t, 3H, J=7 Hz), 1.33
(d, 3H, J=6.8 Hz), 1.66 (d, 3H, J=7.1 Hz), 1.63 (m, 1H), 2.05 (m, 1H), 2.35 (dd, 1H, J=6.7, 12.8 Hz),
2.8 (dd, 1H, J=7.7, 12.8 Hz), 3.56 (q, 1H, J=6.8 Hz), 4.07 (m, 2H), 5.09 (m, 2H), 5.71 (m, 2H), 7.31 (m,
5ArH); 13C-NMR δ 9.1, 14.1, 17.9, 21.9, 33.7, 45.7, 50.2, 52.8, 60.9, 65.5, 117.8, 127.5, 127.9, 128.5,
134.3, 138.5, 158.7, 170.1.
2.30. (3S,6R,10R)-3-Benzyl-5-ethoxy-3-ethyl-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-
2-one 9f or 10m
1H-NMR δ 0.86 (t, 3H, J=7.4 Hz), 1.17 (d, 3H, J=6.8 Hz), 1.23 (t, 3H, J=7.2 Hz), 1.56 (d, 3H, J=7.1
Hz), 1.75 (m, 1H), 2.25 (m, 1H), 2.87 (d, 1H, J=12.4 Hz), 3.08 (q, 1H, J=6.8 Hz), 3.39 (d, 1H, J=12.4
Hz), 4.14 (m, 2H), 5.5 (q, 1H, J=7.1 Hz), 6.65 (m, 2ArH), 7.21 (m, 8ArH); 13C-NMR δ 9.3, 14.2, 17.7,
21.7, 34.2, 47.5, 49.7, 52.1, 60.7, 66.9, 126, 127.2, 127.7, 128.2, 130.7, 137.9, 158.8, 169.3. The pure 9f
was isolated in 50% yield: [α]D=12.5 (c=9.8, CHCl3). Anal. Calcd for C24H30N2O2: C, 76.16; H, 7.99;
N, 7.4. Found: C, 76.25; H, 8.02; N, 7.42.
2.31. (3R,6R,10R)-3-Allyl-5-ethoxy-3,6-dimethyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 9g
or 10b
1H-NMR δ 1.19 (t, 3H, J=7.1 Hz), 1.35 (d, 3H, J=6.8 Hz), 1.48 (s, 3H), 1.64 (d, 3H, J=7.2 Hz), 2.36
(dd, 1H, J=7.5, 13.2 Hz), 2.65 (dd, 1H, J=7.5, 13.2 Hz), 3.58 (q, 1H, J=6.8 Hz), 4.04 (m, 2H), 5.08 (m,
2H), 5.73 (m, 2H), 7.33 (m, 5ArH); 13C-NMR δ 14, 17.9, 22, 28.9, 46.3, 50.4, 52.8, 61, 61.4, 118.4,

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127.6, 127.8, 128.6, 134, 138.7, 158.5, 171.4. The pure 9g was isolated in 68% yield: [α]D=−3.2 (c=1.7,
CHCl3). Anal. Calcd for C19H26N2O2: C, 72.58; H, 8.34; N, 8.91. Found: C, 72.45; H, 8.32; N, 8.9.
2.32. (3R,6R,10R)-3-Allyl-5-ethoxy-3-ethyl-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one
9h or 10e
1H-NMR δ 0.7 (t, 3H, J=7.3 Hz), 1.21 (t, 3H, J=7 Hz), 1.33 (d, 3H, J=6.8 Hz), 1.6 (m, 1H), 1.65 (d,
3H, J=7.1 Hz), 2.18 (m, 1H), 2.33 (dd, 1H, J=7.4, 13.1 Hz), 2.7 (dd, 1H, J=7.4, 13.1 Hz), 3.57 (q, 1H,
J=6.8 Hz), 4.05 (m, 2H), 5.1 (m, 2H), 5.71 (m, 2H), 7.32 (m, 5ArH); 13C-NMR δ 8.7, 14, 17.8, 22.1,
34.2, 45.6, 50.2, 52.8, 60.8, 65.1, 118.2, 127.5, 127.7, 127.8, 128.5, 134, 138.5, 159, 170.1. The pure 9h
was isolated in 80% yield: [α]D=2.3 (c=1.1, CHCl3). Anal. Calcd for C20H28N2O2: C, 73.14; H, 8.59;
N, 8.53. Found: C, 73.25; H, 8.62; N, 8.5.
2.33. (3S,6R,10R)-3-Allyl-3-benzyl-5-ethoxy-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one
9i or 10n
1H-NMR δ 1.16 (d, 3H, J=6.9 Hz), 1.22 (t, 3H, J=7 Hz), 1.53 (d, 3H, J=7.1 Hz), 2.48 (dd, 1H, J=7.5,
12.8 Hz), 2.88 (d, 1H, J=12.6 Hz), 2.92 (dd, 1H, J=7.5, 12.8 Hz), 3.43 (d, 1H, J=12.6 Hz), 4.17 (m,
2H), 5.12 (m, 2H), 5.46 (q, 1H, J=7.1 Hz), 5.72 (m, 1H), 6.65 (m, 2ArH), 7.2 (m, 8ArH); 13C-NMR δ
14.2, 17.6, 21.9, 45.7, 47.2, 49.6, 52.2, 60.8, 66.3, 118.6, 126.1, 127.2, 127.7, 128.2, 130.7, 133.9, 137.6,
137.9, 158.8, 168.8. The pure 9i was isolated in 65% yield: [α]D=56.2 (c=2.2, CHCl3). Anal. Calcd for
C25H30N2O2: C, 76.89; H, 7.74; N, 7.17. Found: C, 76.65; H, 7.72; N, 7.2.
2.34. (3R,6R,10R)-3-Benzyl-5-ethoxy-3,6-dimethyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 9l
or 10c
The product 9l was obtained in 50% yield. 1H-NMR δ 0.2 (d, 3H, J=6.8 Hz), 1.21 (t, 3H, J=7.1 Hz),
1.52 (d, 3H, J=7.1 Hz), 1.62 (s, 3H), 2.84 (d, 1H, J=12.1 Hz), 3.29 (q, 1H, J=6.8 Hz), 3.42 (d, 1H, J=12.1
Hz), 4.1 (m, 2H), 5.62 (q, 1H, J=7.1 Hz), 7.3 (m, 10ArH); 13C-NMR δ 14.2, 17.4, 19.9, 30.6, 47.6, 50.2,
52.7, 60.8, 62.9, 126.5, 127.3, 127.5, 127.6, 127.8, 128, 128.2, 128.3, 128.4, 130.8, 137.7, 138.3, 158.3,
170.8.
2.35. (3R,6R,10R)-3-Benzyl-5-ethoxy-3-ethyl-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-
2-one 9m or 10f
1
The product 9m was obtained in 84% yield. H-NMR δ 0.18 (d, 3H, J=6.8 Hz), 0.81 (t, 3H, J=7.4
Hz), 1.22 (t, 3H, J=7.1 Hz), 1.51 (d, 3H, J=7.1 Hz), 1.7 (m, 1H), 2.33 (m, 1H), 2.78 (d, 1H, J=12.6 Hz),
3.26 (q, 1H, J=6.8 Hz), 3.4 (d, 1H, J=12.6 Hz), 4.11 (q, 2H, J=7.1 Hz), 5.64 (q, 1H, J=7.1 Hz), 7.23
(m, 10ArH); 13C-NMR δ 8.9, 14.3, 17.3, 20, 35.4, 47.1, 50.2, 52.7, 60.8, 66.8, 126.4, 127.5, 127.7, 128,
128.2, 128.5, 130.9, 137.6, 138.3, 159.1, 169.6.
2.36. (3R,6R,10R)-3-Allyl-3-benzyl-5-ethoxy-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-
2-one 9n or 10i
1H-NMR δ 0.19 (d, 3H, J=6.9 Hz), 1.22 (t, 3H, J=7.3 Hz), 1.5 (d, 3H, J=7.2 Hz), 2.48 (dd, 1H, J=6.9,
12.8 Hz), 2.8 (d, 1H, J=12.5 Hz), 3 (dd, 1H, J=7.7, 12.8 Hz), 3.23 (q, 1H, J=6.9 Hz), 3.44 (d, 1H, J=12.5

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Hz), 4.01 (q, 2H, J=7.3 Hz), 5.14 (m, 2H), 5.6 (q, 1H, J=7.2 Hz), 5.71 (m, 1H), 7.23 (10ArH); 13C-NMR
δ 14.2, 17.3, 20, 46.6, 46.7, 50.1, 52.7, 60.8, 66.6, 118.1, 126.5, 127.5, 127.8, 128.1, 128.2, 128.4, 130.9,
134, 137.4, 138.2, 158.9, 169. The pure 9n was isolated in 87% yield: [α]D=9.5 (c=2.7, CHCl3). Anal.
Calcd for C25H30N2O2: C, 76.89; H, 7.74; N, 7.17. Found: C, 76.76; H, 7.76; N, 7.15.
2.37. (3S,6R)-3-Allyl-5-ethoxy-3-ethyl-6-methyl-3,6-dihydro-1H-pyrazine-2-one 11
To a stirred solution of Na (0.6 g, 26 mmol) dissolved in about 100 ml of liquid ammonia, cooled
at −60°C, was added 4e (1.2 g, 3.7 mmol) in dry THF (25 ml) and ethanol (2.5 ml) under an inert
atmosphere. After 5 minutes the reaction was quenched with 1.4 g of NH4Cl and the cooling bath was
removed allowing the complete removal of NH3. Then, water was added and the solution extracted with
ethyl acetate. After removal of the organic solvent the crude reaction product was purified by silica gel
chromatography eluting with hexane:ethyl acetate. The pure product was isolated in 85% yield. 1H-NMR
δ 0.78 (t, 3H, J=7.4 Hz), 1.28 (t, 3H, J=7.1 Hz), 1.38 (d, 3H, J=6.8 Hz), 1.51–1.65 (m, 1H), 2.02 (m, 1H),
2.3 (dd, 1H, J=7.4, 13.1 Hz), 2.64 (dd, 1H, J=7.4, 13.1 Hz), 4.1 (m, 3H), 5.05 (m, 2H), 5.61 (m, 1H), 6.33
(bs, 1H); 13C-NMR δ 8.8, 14.4, 21.3, 32.8, 45.4, 48.7, 61, 64.7, 118.2, 133.4, 158.6, 172.7. [α]D=−25.5
(c=5, CHCl3). Anal. Calcd for C12H20N2O2: C, 64.26; H, 8.99; N, 12.49. Found: C, 64.47; H, 9.02; N,
12.5.
2.38. (2R,5S)-5-Amino-3-aza-5-ethyl-2-methyl-4-oxo-ethyl-7-octenoate hydrochloride 12
4.4 ml of 0.5 M HCl were dropped to 11 (0.5 gr, 2.2 mmol) dissolved in 50 ml of acetone and the
solution was stirred at r.t. After about 3 h the acetone was evaporated and to the residue was added water
then ethyl acetate. The product was recovered as an oil in practically quantitative yield by evaporation
of the aqueous solution in vacuo. 1H-NMR δ 0.95 (t, 3H, J=7.4 Hz), 1.26 (t, 3H, J=7.1 Hz), 1.4 (d, 3H,
J=7.3 Hz), 1.72 (m, 1H), 1.96 (m, 1H), 2.37 (dd, 1H, J=8.8, 13.7 Hz), 2.76 (dd, 1H, J=6, 13.7 Hz), 4.17
(q, 2H, J=7.1 Hz), 4.49 (dq, 1H, J=7.2, 7.3 Hz), 4.7 (bs, 3H), 5.18 (m, 2H), 5.77 (m, 1H), 7.8 (d, 1H,
J=7.2 Hz); 13C-NMR (CD3OD) δ 8, 14.5, 17.3, 31.7, 43.4, 49.8, 62.4, 63.4, 121.2, 132.4, 173.8, 174.5.
2.39. (2R,5S)-5-Acetamido-3-aza-5-ethyl-2-methyl-4-oxo-ethyl-7-octenoate 13
The dipeptide 12 was easily acetylated in CH2Cl2 at 0°C with acetyl chloride in the presence of triethyl
amine. After chromatographic elution with hexane:ethyl acetate, the pure product was obtained in 90%
1
yield. H-NMR δ 0.8 (t, 3H, J=7.4 Hz), 1.29 (t, 3H, J=7.1 Hz), 1.41 (d, 3H, J=7.1 Hz), 1.7 (m, 1H), 2
(s, 3H), 2.41 (dd, 1H, J=6.9, 14.3 Hz), 2.57 (m, 1H), 3.2 (dd, 1H, J=7.5, 14.3 Hz), 4.21 (m, 2H), 4.5
(dq, 1H, J=7.1, 6.4 Hz), 5.08 (m, 2H), 5.64 (m, 1H), 6.54 (d, 1H, J=6.4 Hz), 6.62 (bs, 1H); 13C-NMR δ
7.8, 13.9, 17.9, 24, 28.1, 39.4, 48.3, 61.4, 64, 118.7, 132.3, 169.2, 172.1, 172.5. [α]D=7 (c=3.3, CHCl3).
Anal. Calcd for C14H24N2O4: C, 59.14; H, 8.51; N, 9.85. Found: C, 59.37; H, 8.5; N, 9.8.
Acknowledgements
Investigation supported by University of Bologna (funds selected research topics).

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References
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[4]. Subsequent esterification by SOCl2/CH3OH and chromatographic purification led to the pure (R)-alanine methyl ester.
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