A new stereoselective approach to β-hydroxy-α-aminoacids and dipeptides

Article abstract of DOI:10.1016/S0957-4166(99)00211-6

The chiral synthons 1, 2 and 1' were submitted to aldol condensation to achieve both β-hydroxy-α-aminoacids and dipeptides. The configuration of the new stereogenic centers was assigned on the basis of ¹H NMR spectroscopic data.

Full text of DOI:10.1016/S0957-4166(99)00211-6

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2191–2201
A new stereoselective approach to β-hydroxy-α-aminoacids and
dipeptides
Pina Di Felice, Gianni Porzi and Sergio Sandri ∗
Dipartimento di Chimica ‘G. Ciamician’, Università degli Studi di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 10 May 1999; accepted 24 May 1999
Abstract
The chiral synthons 1, 2 and 10 were submitted to aldol condensation to achieve both β-hydroxy-α-aminoacids
and dipeptides. The configuration of the new stereogenic centers was assigned on the basis of 1H NMR spectro-
scopic data. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
In a continuation of our studies directed to the stereoselective synthesis of common and uncommon
α-aminoacids1 and dipeptides,2 we focused our attention on the synthesis of enantiomerically pure
β-hydroxy-α-aminoacids and dipeptides. Previously, we have described the diastereoselective aldol
condensation of piperazine-2,5-dione derivatives3 as a possible approach to natural and unnatural β-
hydroxy-α-aminoacids. Now, we wish to report the results of the aldol condensation of the chiral
synthons (6R,10S)-5-ethoxy-6-methyl- 1 and (6R,10S)-5-ethoxy-6-benzyl-1-(10 -phenethyl)-3,6-dihydro-
1H-pyrazine-2-one 2 in order to investigate an alternative diastereoselective synthesis of both β-hydroxy-
α-aminoacids and dipeptides (see Scheme 1).
2. Results and discussion
The synthons 1 (obtained in high diastereomeric excesses as previously described2) and 2 (synthesized
starting from 10,1 as summarized in Scheme 2) were converted into the corresponding lithium enolates
and reacted with acetaldehyde and benzaldehyde (Scheme 1). The aldol condensations were complete
in a few minutes with a total conversion of the lactims and the stereochemical results are collected in
Table 1.
∗
Corresponding author. E-mail: porzi@ciam.unibo.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00211-6

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Scheme 1. (i) LHMDS (1.3 equiv.) 1 h at −50°C in dry THF; (ii) R0CHO (2 equiv.) at −78°C for 15 min; (iii) 0.5N HCl 2 h at
0°C; (iv) Li/NH3 at −60°C; (v) 5N HCl at reflux for 12 h; (vi) CH3OH/SOCl2
Scheme 2. (i) 5 M NH3 in i-PrOH at rt; (ii) ClCH2COCl/Et3N in CH2Cl2 at 0°C; (iii) 5 M NH3 in EtOH at rt; (iv) Et3OBF4 in
CH2Cl2
Table 1
Aldol condensation of 1, 2 and 10 with acetaldehyde and benzaldehyde
Comparing the entries 1 and 3 in Table 1, it appears that a bulkier substituent at C-6 induces both
greater trans induction and greater anti facial selectivity. This prompted us to also investigate the
influence of the chiral inductor configuration on the diastereoselectivity. Thus, we submitted the lactim
10 to a reaction in which the C-10 of the phenethyl group possesses the R- instead of the S-configuration
(entry 4). This substrate showed the same trans:cis ratio and a significant decrease in the anti:syn ratio
(compare entries 1 and 4). However, it is interesting to note that the facial selectivity was inverted: in fact,
with 10 the prevalent diastereomer was 30-(3S,100R) while with the lactim 1 it was 3-(3S,100S). Thus, it is
clear that the change in the inductor configuration produces an inversion of the facial diastereoselection,
while the steric bulkiness of the substituent at C-6 causes an increase in the trans induction on C-3.

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2193
Figure 1. C* represents the chiral inductor
This is a process that involves a prevalent 1,4-trans induction by the stereocenter C-6 and occurs with a
relative topicity lk in the addition of the two trigonal faces of enolate and aldehyde.
These preliminary experiments, which have, to date, shown only fairly good diastereoselectivity (entry
3), might open an interesting route to the synthesis of β-hydroxy-α-aminoacids and dipeptides. Thus, in
order to improve the diastereoselection, further investigations are in progress.
In order to find a reasonable explanation for the observed stereochemical results, a complete con-
formational analysis4 was performed for the lithium enolates of both 1 and 10. In the lowest energy
conformations the atoms N-1, C-2, C-3, N-4 and C-5 are substantially coplanar, while C-6 is about 20°
out of the plane. Furthermore, as already observed for similar compounds,5 the benzylic hydrogen of the
chiral inductor phenethyl preferentially lies syn-periplanar with respect to C-2. An important feature is
that, in the geometries corresponding to the energetic minima, the –O–Li bond, which is placed about
25° out of the plane (N1, C-2, C-3), lies trans with respect to the (C-6)-CH3 group. In fact, such a
conformation is 0.9 kcal/mol and 0.65 kcal/mol more stable than the cis conformation for the lithium
enolates of 1 and 10, respectively. These findings lead us to believe that the selection between the two
faces of the enolate double bond is governed by the ground state conformation of the lithium enolate
(Fig. 1) and the transition state is then reagent-like. This explanation agrees well with the observed
prevalent trans induction described by us independently of the chiral inductor configuration (see entries
1 and 4 in Table 1).
The configuration of the new stereocenters C-3 and C-100 introduced on 3, 4 and 5 was assigned
1
on the basis of H NMR spectroscopic data using the approaches previously employed for similar
compounds.1–3 The cis/trans relationship of 3 and 4 derivatives was established on the basis of NOE
registered on (C-3)-H by irradiating the (C-6)-CH3. However, when the doublet of (C-6)-CH3 could not
be selectively irradiated, as for example in the condensation product 30b-(3S,100R), the configuration
of the C-100 stereocenter was established on the piperazine-2,5-dione derivative 12 obtained as a minor
product (20–30%) by acid hydrolysis of 30b (Scheme 3).
Scheme 3.
As previously done for similar compounds,2,3 the cis/trans relationship for 5 was established on the
basis of the shielding effect induced by the phenyl ring of the (C-6)-CH2Ph (axially arranged) on the
substituent at C-3.

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The configuration of the stereocenter C-100 was assigned by the analysis of the coupling constants be-
tween the hydrogens of the cyclic derivatives 13 and 14, obtained from 3 and 4, respectively (Scheme 4).
In fact, the anti and the syn diastereomers of 3 and 4 can be converted into the cyclic cis and trans 2-
oxazolidones 13 and 14, respectively. Thus, consistent with literature reports,6 we assigned a cis Ha–Hb
relationship (corresponding to an anti configuration of 3 or 4) to the isomer with the greater Ja,b (7.7 or
7.9 Hz) and a trans Ha–Hb relationship (corresponding to a syn configuration of 3 or 4) to the isomer
with the lower Ja,b (3.3 or 5–5.5 Hz) (see Scheme 4).
Scheme 4. (i) 0.5N HCl in acetone; (ii) COCl2/Et3N in CH2Cl2 at −10°C, then chromatographic separation
In a model study, as summarized in Scheme 1, the cyclic intermediate (3S,100S)-3 was converted into
the corresponding dipeptides 6 and 8 and into the hydrochloride of (2S,3S)-threonine methyl ester 9.
Analogously, the intermediate (3S,100S)-4 was converted into the dipeptide 7. The concordance of the
specific rotation value ([α]D=8.5 (c 1, H2O)) of the L-allo-threonine, obtained from the hydrolysis of 9,
with that reported in the literature,7 validates the approach used to assign the absolute configuration of
the C-3 and C-100 stereocenters through the 1H NMR data.
3. Experimental
3.1. General information
1H NMR spectra were recorded at 300 MHz using CDCl3 as solvent, unless otherwise stated. Optical
rotation values were recorded on a Perkin–Elmer 343 polarimeter at 25°C. All reactions involving
organometallic reagents were carried out under an argon atmosphere in dry THF, distilled from sodium
benzophenone ketyl. Chromatographic separations were performed with silica gel 60 (230–400 mesh).
3.2. (6R,10S)-1 and (6R,10R)-5-Ethoxy-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 10
The products were synthesized following the procedure described in the literature.2
3.3. (6R,10S)-6-Benzyl-5-ethoxy-1-(10 -phenethyl)-3,6-dihydro-1H-pyrazine-2-one 2
The morpholin-2,5-dione derivative 10 (6.2 g, 20 mmol) (obtained as described in the literature1) was
dissolved in 100 mL of isopropanol saturated with NH3 at 0°C. The reaction flask was stoppered and kept
at rt for 24 h. The volatiles were evaporated in vacuo, to the residue was added water and the mixture

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was extracted with ethyl acetate. After complete evaporation of the organic solvent the crude reaction
product was dissolved in CH2Cl2 and N(C2H5)3 (3.5 mL) was added. Chloroacetylchloride (2 mL, 25
mmol) was added dropwise to the solution stirred at 0°C, and after 1 h the organic solution was washed
with dilute HCl, dried and then evaporated in vacuo. The intermediate 11 was isolated pure in 80% yield
after chromatographic separation eluting with hexane/ethyl acetate. 1H NMR: δ 1.67 (d, 3H, J=6.8 Hz),
3.0 (dd, 1H, J=6.6, 14 Hz), 3.39 (dd, 1H, J=8.8, 14 Hz), 3.81 (m, 1H), 4.23 (s, 2H), 5.17 (q, 1H, J=6.8
Hz), 5.47 (b s, 1H), 6.64 (d, 2H, J=6.1 Hz), 7.2 (m, 10ArH); 13C NMR: δ 17.4, 36.2, 42.4, 57.2, 62.6,
126.5, 127.4, 128.1, 128.5, 128.7, 128.8, 129.1, 129.5, 137.0, 137.7, 167.8, 173.5.
The intermediate 11 (3.45 g, 10 mmol) was dissolved in ethanol saturated with NH3 (about 7 M
solution) at 0°C. The reaction flask was stoppered and kept at rt for 24 h. After evaporation of NH3, the
intermediate (6R,10S)-6-benzyl-1-(10-phenethyl)-piperazine-2,5-dione was recovered pure as a solid in
1
85% yield. H NMR: δ 1.62 (d, 3H, J=7.2 Hz), 2.05 (dd, 1H, J=5.9, 13.8 Hz), 2.43 (d, 1H, J=17 Hz),
2.69 (dd, 1H, J=3.7, 13.8 Hz), 3.42 (dd, 1H, J=4.3, 17 Hz), 4.24 (dd, 1H, J=3.7, 5.9 Hz), 5.98 (q, 1H,
J=7.2 Hz), 6.85–7.7 (m, 10ArH); 13C NMR: δ 16.6, 38.1, 44.7, 52.3, 58.0, 127.5, 128.4, 128.7, 129.0,
130.0, 134.8, 139.1, 164.9, 169.2.
The piperazine-2,5-dione derivative intermediate (7.7 g, 25 mmol) was treated with Et3OBF4 (7.6
g, 40 mmol) dissolved in dry CH2Cl2 following the procedure described in the literature.2 After
1
chromatographic elution with hexane/ethyl acetate, the lactim 2 was recovered in 80% yield. H NMR:
δ 1.17 (t, 3H, J=7.1 Hz), 1.60 (d, 3H, J=7.1 Hz), 2.1 (dd, 1H, J=6.6, 13.5 Hz), 2.37 (dd, 1H, J=3.8, 13.5
Hz), 2.90 (dd, 1H, J=1.2, 19.8 Hz), 3.83 (d, 1H, J=19.8 Hz), 4.0 (m, 2H), 4.18 (m, 1H), 6.01 (q, 1H,
J=7.1 Hz), 7.1–7.6 (m, 10ArH); 13C NMR: δ 14.0, 16.4, 37.9, 50.7, 51.6, 54.8, 61.5, 127.0, 128.1, 128.3,
128.5, 128.7, 129.5, 135.1, 139.6, 161.7, 168.3.
3.4. Condensation of 1, 2 or 10 with aldehydes: general procedure
To 10 mmol of the lactim 1 (or 2 or 10) dissolved in dry THF cooled to −50°C under an inert
atmosphere, 10 mL of LHMDS (1 M solution in THF) were slowly added. After 1 h the reaction bath
was cooled to −78°C and 20 mmol of aldehyde were added. After a few minutes the reaction, followed
by TLC, was practically complete. Then the reaction was quenched with phosphate buffer (pH=7) and
extracted with ethyl acetate. The organic solution was evaporated in vacuo and the residue was submitted
to chromatographic separation by eluting with hexane/ethyl acetate.
3.4.1. (3S,6R,10S,100S)-5-Ethoxy-3-(100-hydroxyethyl)-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-
pyrazine-2-one 3a
1
This was obtained starting from 1 and acetaldehyde. H NMR: δ 0.70 (d, 3H, J=6.9 Hz), 1.27 (t, 3H,
J=7.1 Hz), 1.31 (d, 3H, J=6.2 Hz), 1.54 (d, 3H, J=7.1 Hz), 3.65 (dd, 1H, J=1.2, 7.9 Hz), 3.92 (dq, 1H,
J=1.2, 6.9 Hz), 4.12 (q, 2H, J=7.1 Hz), 4.19 (m, 1H), 4.76 (d, 1H, J=3 Hz), 5.91 (q, 1H, J=7.1 Hz), 7.35
(m, 5ArH); 13C NMR: δ 14.0, 15.9, 17.2, 19.2, 49.7, 50.8, 61.7, 62.1, 69.2, 127.9, 128.0, 128.6, 139.5,
164.1, 170.6. [α]D −214.2 (c 1.2, CCl4).
3.4.2. (3S,6R,10S,100R)-5-Ethoxy-3-(100-hydroxyethyl)-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-
pyrazine-2-one 3b
1
This was obtained starting from 1 and acetaldehyde. H NMR: δ 0.72 (d, 3H, J=6.9 Hz), 1.28 (t, 3H,
J=7.1 Hz), 1.30 (d, 3H, J=6.4 Hz), 1.55 (d, 3H, J=7.1 Hz), 3.88 (m, 2H), 3.94 (dq, 1H, J=1.2, 6.9 Hz),

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4.14 (m, 2H), 4.32 (m, 1H), 5.93 (q, 1H, J=7.1 Hz), 7.35 (m, 5ArH); 13C NMR: δ 14.0, 16.1, 17.9, 18.7,
49.6, 50.8, 60.8, 62.1, 68.9, 127.9, 128.0, 128.6, 139.7, 164.0, 169.5. [α]D −192.2 (c 0.5, CCl4).
3.4.3. (3R,6R,10S,100R)-5-Ethoxy-3-(100-hydroxyethyl)-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-
pyrazine-2-one 3c
1
This was obtained starting from 1 and acetaldehyde. H NMR: δ 0.96 (d, 3H, J=6.8 Hz), 1.28 (t, 3H,
J=7.1 Hz), 1.33 (d, 3H, J=6.1 Hz), 1.67 (d, 3H, J=7.2 Hz), 3.74 (d, 1H, 2.2 Hz), 3.9 (m, 1H), 4.1 (m, 4H),
5.74 (q, 1H, J=7.2 Hz), 7.35 (m, 5ArH); 13C NMR: δ 14.0, 15.9, 20.3, 21.7, 50.3, 51.8, 61.6, 65.0, 70.2,
127.3, 127.6, 128.5, 140.6, 161.5, 168.9. [α]D −152.4 (c 2.7, CCl4).
3.4.4. (3S,6R,10R,100S)-5-Ethoxy-3-(100-hydroxyethyl)-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-
pyrazine-2-one 30a
1
This was obtained starting from 10 and acetaldehyde. H NMR: δ 1.18 (t, 3H, J=7.2 Hz), 1.31 (d, 3H,
J=6.3 Hz), 1.38 (d, 3H, J=7 Hz), 1.64 (d, 3H, J=7.2 Hz), 3.62 (dq, 1H, J=1.2, 7 Hz), 3.83 (m, 1H), 3.96
(dd, 1H, J=1.2, 4.3 Hz), 4.08 (q, 2H, J=7.2 Hz), 4.31 (m, 1H), 5.85 (q, 1H, J=7.2 Hz), 7.25 (m, 5ArH);
13C NMR: δ 13.9, 17.7, 18.7, 19.3, 49.5, 51.4, 60.8, 61.7, 68.9, 126.9, 127.5, 128.6, 139.0, 163.5, 169.7.
3.4.5. (3S,6R,10R,100R)-5-Ethoxy-3-(100-hydroxyethyl)-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-
pyrazine-2-one 30b
1
This was obtained starting from 10 and acetaldehyde. H NMR: δ 1.18 (t, 3H, J=7.2 Hz), 1.32 (d, 3H,
J=6.2 Hz), 1.39 (d, 3H, J=7 Hz), 1.63 (d, 3H, J=7.2 Hz), 3.65 (dq, 1H, J=1.2, 7 Hz), 3.75 (dd, 1H, J=1.2,
7.6 Hz), 4.01 (q, 2H, J=7.2 Hz), 4.2 (m, 1H), 4.6 (b s, 1H), 5.87 (q, 1H, J=7.3 Hz), 7.15–7.4 (m, 5ArH);
13C NMR: δ 13.6, 17.4, 18.5, 19.0, 49.6, 51.1, 61.5, 61.6, 69.0, 126.6, 127.4, 128.4, 139.0, 163.7, 175.0.
3.4.6. (3R,6R,10R,100R)-5-Ethoxy-3-(100-hydroxyethyl)-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-
pyrazine-2-one 30c
1
This was obtained starting from 10 and acetaldehyde. H NMR: δ 1.20 (t, 3H, J=7.2 Hz), 1.31 (d, 3H,
J=6.3 Hz), 1.38 (d, 3H, J=6.9 Hz), 1.67 (d, 3H, J=7.2 Hz), 3.58 (dq, 1H, J=1.8, 6.9 Hz), 3.71 (m, 1H),
3.89 (m, 1H), 4.1 (m, 3H), 5.7 (q, 1H, J=7.2 Hz), 7.3 (m, 5ArH); 13C NMR: δ 13.9, 17.9, 20.1, 22.3,
49.8, 52.8, 61.4, 64.7, 70.1, 127.7, 127.8, 128.7, 138.0, 161.4, 168.6.
3.4.7. (3S,6R,10S,100S)-5-Ethoxy-3-(100-hydroxybenzyl)-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-
pyrazine-2-one 4a
1
This was obtained starting from 1 and benzaldehyde. H NMR: δ 0.66 (d, 3H, J=7 Hz), 1.19 (t, 3H,
J=7.1 Hz), 1.50 (d, 3H, J=7.1 Hz), 3.86 (dq, 1H, J=1.2, 7 Hz), 4.0 (m, 3H), 5.08 (dd, 1H, J=3.5, 8.9 Hz),
5.55 (d, 1H, J=3.5 Hz), 5.9 (q, 1H, J=7.1 Hz), 7.35 (m, 10ArH); 13C NMR: δ 13.8, 15.8, 17.4, 49.6, 51.0,
61.6, 62.1, 75.2, 127.1, 127.3, 127.7, 127.8, 128.0, 128.5, 139.4, 141.3, 163.6, 170.4. [α]D −102.9 (c
2.05, CCl4).
3.4.8. (3S,6R,10S,100R)-5-Ethoxy-3-(100-hydroxybenzyl)-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-
pyrazine-2-one 4b
This was obtained starting from 1 and benzaldehyde. 1H NMR: δ 0.71 (d, 3H, J=6.9 Hz), 1.26 (t, 3H,
J=7.1 Hz), 1.43 (d, 3H, J=7.1 Hz), 3.81 (dq, 1H, J=1.3, 6.9 Hz), 4.13 (m, 2H), 4.26 (dd, 1H, J=1.3, 3.9
Hz), 4.52 (d, 1H, J=8.7 Hz), 5.39 (dd, 1H, J=3.9, 8.7 Hz), 5.82 (q, 1H, J=7.1 Hz), 7.35 (m, 10ArH); 13
C

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NMR: δ 14.0, 15.9, 18.4, 49.6, 51.1, 61.7, 61.9, 73.9, 127.0, 127.3, 127.5, 127.6, 127.9, 128.2, 139.7,
141.6, 163.4, 169.0. [α]D −105.6 (c 2.3, CCl4).
3.4.9. (3R,6R,10S,100R)-5-Ethoxy-3-(100-hydroxybenzyl)-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-
pyrazine-2-one 4c
This was obtained starting from 1 and benzaldehyde. 1H NMR: δ 0.27 (d, 3H, J=6.9 Hz), 1.25 (t, 3H,
J=7.1 Hz), 1.62 (d, 3H, J=7.2 Hz), 3.91 (m, 2H), 4.15 (q, 2H, J=7.1 Hz), 4.55 (dd, 1H, J=1.8, 6 Hz), 5.24
(t, 1H, J=6 Hz), 5.40 (q, 1H, J=7.2 Hz), 7.35 (m, 10ArH); 13C NMR: δ 14.1, 16.1, 20.1, 51.0, 52.8, 61.7,
65.2, 75.0, 127.1, 127.3, 127.5, 127.8, 128.2, 140.2, 140.6, 161.6, 166.9.
3.4.10. (3R,6R,10S,100S)-5-Ethoxy-3-(100-hydroxybenzyl)-6-methyl-1-(10 -phenethyl)-3,6-dihydro-1H-
pyrazine-2-one 4d
This was obtained starting from 1 and benzaldehyde. 1H NMR: δ 0.22 (d, 3H, J=6.9 Hz), 1.29 (t, 3H,
J=7 Hz), 1.65 (d, 3H, J=7.2 Hz), 3.89 (dq, 1H, J=2, 6.9 Hz), 4.15 (m, 2H), 4.55 (dd, 1H, J=2, 3.6 Hz),
5.11 (m, 2H), 5.20 (q, 1H, J=7.2 Hz), 7.3 (m, 10ArH); 13C NMR: δ 14.3, 16.2, 19.3, 51.4, 53.5, 61.5,
63.7, 75.2, 127.0, 127.1, 127.4, 127.7, 127.8, 128.2, 140.5, 140.8, 160.8, 168.3. [α]D −55.8 (c 0.6, CCl4).
3.4.11. (3S,6R,10S,100S)-6-Benzyl-5-ethoxy-3-(100 -hydroxyethyl)-1-(10 -phenethyl)-3,6-dihydro-1H-
pyrazine-2-one 5a
1
This was obtained starting from 2 and acetaldehyde. H NMR: δ 1.09 (t, 3H, J=7 Hz), 1.17 (d, 3H,
J=6.2 Hz), 1.57 (d, 3H, J=7 Hz), 2.23 (m, 2H), 2.88 (d, 1H, J=7.8 Hz), 3.9–4.15 (m, 4H), 5.94 (q, 1H,
J=7 Hz), 6.73 (m, 2ArH), 7.1–7.6 (m, 8ArH); 13C NMR: δ 13.8, 16.4, 19.1, 37.5, 51.7, 55.5, 61.5, 61.7,
69.0, 127.0, 128.1, 128.4, 128.5, 128.8, 129.3, 135.2, 139.2, 161.9, 171.1.
3.4.12. (3S,6R,10S,100R)-6-Benzyl-5-ethoxy-3-(100 -hydroxyethyl)-1-(10 -phenethyl)-3,6-dihydro-1H-
pyrazine-2-one 5b
1
This was obtained starting from 2 and acetaldehyde. H NMR: δ 1.14 (t, 3H, J=7.1 Hz), 1.16 (d, 3H,
J=6.4 Hz), 1.59 (d, 3H, J=7.1 Hz), 2.14 (dd, 1H, J=6.2, 13.8 Hz), 2.32 (dd, 1H, J=4.2, 13.8 Hz), 2.91
(dd, 1H, J=1.1, 4.3 Hz), 3.9–4.2 (m, 4H), 5.98 (q, 1H, J=7.1 Hz), 6.75 (m, 2ArH), 7.1–7.6 (m, 8ArH);
13C NMR: δ 13.9, 16.7, 18.6, 37.8, 51.8, 55.3, 60.6, 61.7, 68.8, 127.1, 128.2, 128.4, 128.5, 128.8, 129.5,
135.2, 139.3, 161.7, 170.3.
3.4.13. (3R,6R,10S,100R)-6-Benzyl-5-ethoxy-3-(100 -hydroxyethyl)-1-(10 -phenethyl)-3,6-dihydro-1H-
pyrazine-2-one 5c
1
This was obtained starting from 2 and acetaldehyde. H NMR: δ 1.05 (d, 3H, J=6.1 Hz), 1.18 (t, 3H,
J=7.1 Hz), 1.76 (d, 3H, J=7.2 Hz), 2.34 (m, 1H), 2.45 (dd, 1H, J=6, 13.8 Hz), 2.73 (dd, 1H, J=4.3, 13.8
Hz), 3.72 (dd, 1H, J=1.5, 8.7 Hz), 4.02 (m, 3H), 4.33 (m, 1H), 5.7 (q, 1H, J=7.2 Hz), 6.7 (m, 2ArH),
7.15–7.6 (m, 8ArH); 13C NMR: δ 14.0, 17.1, 20.2, 39.4, 53.6, 55.9, 61.4, 64.9, 69.9, 127.2, 128.3, 128.5,
128.8, 129.6, 135.3, 140.1, 158.7, 170.6.
3.5. Hydrolysis of intermediate lactim 3, 30 and 4 to the corresponding dipeptide hydrochloride: general
procedure
To a solution of lactim 3, 30 or 4 (5 mmol) in acetone (50 mL), stirred at 0°C, 13 mL of 0.5N HCl were
added. After 2 h the acetone was evaporated in vacuo and the aqueous layer extracted with ethyl acetate.

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The aqueous solution was then evaporated in vacuo to dryness and the reaction product was obtained
as a solid in 70–80% yield. As reported in Scheme 3, the corresponding piperazine-2,5-dione can be
recovered from the organic solution (see later).
3.5.1. (2R,5S,6S,10S)-5-Amino-3-aza-6-hydroxy-2-methyl-4-oxo-3-(10 -phenethyl)-ethylheptanoate
hydrochloride 6a
This was obtained starting from the lactim 3a. 1H NMR: δ 0.88 (d, 3H, J=6.8 Hz), 1.25 (t, 3H, J=7.2
Hz), 1.26 (d, 3H, J=6.6 Hz), 1.75 (d, 3H, J=6.8 Hz), 3.88 (q, 1H, J=6.8 Hz), 4–4.25 (m, 2H), 4.46 (m,
1H), 4.91 (d, 1H, J=4.1 Hz), 5.45 (q, 1H, J=6.8 Hz), 7.45 (m, 5ArH); 13C NMR (D2O, dioxane as internal
standard): δ 13.3, 13.7, 15.8, 16.3, 52.8, 55.5, 56.4, 62.5, 63.9, 127.9, 128.7, 128.9, 137.6, 165.3, 173.0.
[α]D −14.5 (c 1.6, CH3OH).
3.5.2. (2R,5S,6R,10S)-5-Amino-3-aza-6-hydroxy-2-methyl-4-oxo-3-(10 -phenethyl)-ethylheptanoate
hydrochloride 6b
This was obtained starting from the lactim 3b. 1H NMR (CD3OD): δ 0.91 (d, 3H, J=6.8 Hz), 1.24 (t,
3H, J=7.1 Hz), 1.43 (d, 3H, J=6.5 Hz), 1.76 (d, 3H, J=6.8 Hz), 3.96 (q, 1H, J=6.8 Hz), 4.13 (m, 3H), 4.69
(d, 1H, J=5.8 Hz), 5.50 (q, 1H, J=6.8 Hz), 7.3–7.55 (m, 5ArH); 13C NMR (CD3OD): δ 14.4, 15.1, 17.0,
20.2, 53.9, 56.8, 57.0, 62.3, 68.0, 129.0, 129.4, 129.6, 129.7, 129.8, 140.2, 167.4, 172.8. [α]D −12.0 (c
2.3, CH3OH).
3.5.3. (2R,5R,6R,10R)-5-Amino-3-aza-6-hydroxy-2-methyl-4-oxo-3-(10 -phenethyl)-ethylheptanoate
hydrochloride 60c
This was obtained starting from the lactim 30c. 1H NMR (D2O): δ 0.97 (t, 3H, J=7.2 Hz), 1.23 (d, 3H,
J=6.5 Hz), 1.44 (d, 3H, J=6.8 Hz), 1.71 (d, 3H, J=7 Hz), 3.85 (m, 3H), 4.43 (m, 1H), 4.99 (d, 1H, J=4.8
Hz), 5.39 (q, 1H, J=7 Hz), 7.45 (m, 5ArH); 13C NMR (D2O, dioxane as internal standard): δ 13.1, 14.7,
16.1, 17.0, 52.2, 55.9, 62.0, 64.2, 128.1, 128.3, 128.4, 128.7, 137.3, 165.4, 172.4.
3.5.4. (2R,5S,6S,10S)-5-Amino-3-aza-6-hydroxy-2-methyl-4-oxo-6-phenyl-3-(10 -phenethyl)-
ethylhexanoate hydrochloride 7a
This was obtained starting from the lactim 4a. 1H NMR (D2O): δ 0.84 (d, 3H, J=6.6 Hz), 1.28 (t, 3H,
J=7 Hz), 1.64 (d, 3H, J=6.6 Hz), 3.97 (q, 1H, J=6.6 Hz), 4.2 (m, 2H), 5.14 (d, 1H, J=5.3 Hz), 5.23 (d, 1H,
J=5.3 Hz), 5.45 (q, 1H, J=6.6 Hz), 7.5 (m, 10ArH); 13C NMR (CD3OD): δ 14.5, 15.0, 17.4, 54.0, 57.0,
57.7, 62.4, 73.5, 128.6, 129.0, 129.4, 129.8, 130.0, 138.8, 140.1, 166.7, 172.7. [α]D −31 (c 0.9, CH3OH).
3.5.5. (2R,5S,6R,10S)-5-Amino-3-aza-6-hydroxy-2-methyl-4-oxo-6-phenyl-3-(10 -phenethyl)-
ethylhexanoate hydrochloride 7b
1
This was obtained starting from the lactim 4b. H NMR (D2O): δ 0.81 (d, 3H, J=6.7 Hz), 0.86 (d,
3H, J=6.6 Hz), 1.27 (t, 3H, J=7 Hz), 3.77 (q, 1H, J=6.7 Hz), 4–4.3 (m, 2H), 5.09 (m, 3H), 7.3–7.6 (m,
10ArH).
3.6. (2R,5S,6S)-5-Amino-3-aza-6-hydroxy-2-methyl-4-oxo-ethylheptanoate hydrochloride 8
To a stirred solution of Li (0.64 g, 28 mmol) in liquid NH3 (100 mL) at −60°C, 3a (1.04 g, 4 mmol)
in dry THF (25 mL) and ethanol (2.5 mL) was added under an inert atmosphere. After 5 min the
reaction was quenched with NH4Cl (1.48 g, 28 mmol) and the cooling bath was removed to completely
eliminate NH3. Water was added to the residue and the solution was extracted with ethyl acetate. Then the

P. Di Felice et al. / Tetrahedron: Asymmetry 10 (1999) 2191–2201
2199
organic solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting
with hexane/ethyl acetate. The intermediate (3S,6R,100S)-5-ethoxy-3-(100 -hydroxyethyl)-6-methyl-3,6-
dihydro-1H-pyrazine-2-one was submitted to acid hydrolysis following the procedure reported to obtain
6 and 7. The reaction product 8 was not isolated pure enough to measure the optical rotation. 1H NMR:
δ 1.21 (d, 3H, J=6.4 Hz), 1.28 (t, 3H, J=6.7 Hz), 1.43 (d, 3H, J=7.2 Hz), 3.94 (d, 1H, J=4.5 Hz), 4.2 (m,
3H), 4.44 (q, 1H, J=7.2 Hz); 13C NMR: δ 14.4, 17.5, 17.8, 59.3, 62.6, 66.5, 167.6, 173.9.
3.7. Conversion of the lactim 3(a–c) into the threonine methyl ester 9: general procedure
The intermediate lactims 3(a–c) (1.3 g, 5 mmol) were refluxed for 12 h in 50 mL of 5N HCl. Then
the solution was evaporated in vacuo to dryness and the residue was submitted to esterification by the
usual procedure8 (SOCl2 and CH3OH). The crude reaction product was concentrated under vacuum then
dissolved in water. The aqueous layer was neutralized by adding 1N NaOH, extracted with CH2Cl2 and
the organic solution was dried. The organic solvent and the (R)-alanine methyl ester were removed under
reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate).
(2S,3S)-Threonine methyl ester 9a. 1H NMR: δ 1.10 (d, 3H, J=6.9 Hz), 2.1 (b s, 3H), 3.55 (b s, 1H),
3.74 (s, 3H), 4.12 (m, 1H).
1
(2S,3R)-Threonine methyl ester 9b. H NMR: δ 1.23 (d, 3H, J=6.3 Hz), 2.1 (m, 3H), 3.28 (d, 1H,
J=4.8 Hz), 3.73 (s, 3H), 3.88 (m, 1H).
3.8. Conversion of lactim 30 into the piperazine-2,5-dione derivative 12
The lactims 30(a,b) were hydrolyzed following the procedure previously described to obtain the
corresponding dipeptide hydrochloride 6 and 7. The piperazine-2,5-dione derivative was extracted with
ethyl acetate.
3.8.1. (3S,6R,10R,100S)-3-(100-Hydroxyethyl)-6-methyl-1-N-(10 -phenethyl)-piperazine-2,5-dione 12a
This was obtained starting from 30a. 1H NMR: δ 1.34 (d, 3H, J=6.6 Hz), 1.5 (d, 3H, J=7 Hz), 1.65 (d,
3H, J=7.2 Hz), 3.67 (q, 1H, J=7 Hz), 4.02 (d, 1H, J=3.7 Hz), 4.28 (m, 1H), 5.84 (q, 1H, J=7.2 Hz), 6.8 (b
s, 1H), 7.3 (m, 5ArH).
3.8.2. (3S,6R,10R,100R)-3-(100-Hydroxyethyl)-6-methyl-1-N-(10 -phenethyl)-piperazine-2,5-dione 12b
This was obtained starting from 30b. 1H NMR: δ 1.26 (d, 3H, J=6.3 Hz), 1.5 (d, 3H, J=7.2 Hz), 1.64
(d, 3H, J=7.2 Hz), 3.69 (q, 1H, J=7.2 Hz), 4.09 (d, 1H, J=5.1 Hz), 4.46 (m, 1H), 5.82 (q, 1H, J=7.2 Hz),
6.5 (b s, 1H), 7.3 (m, 5ArH).
3.9. Conversion of lactims 3 and 4 into the corresponding 2-oxazolidones 13 and 14
The lactim 3 (or 4) was converted into the corresponding dipeptide hydrochloride 6 (or 7) as previously
reported. To 2 mmol of 6 (or 7), dissolved in CH2Cl2 at −10°C, 3 mL (6 mmol) of phosgene (20% in
toluene), then pyridine (0.44 mL, 6.6 mmol) were added. After stirring for about 2 h the reaction mixture
was acidified with dilute HCl and extracted with CH2Cl2. The organic layer was dried, evaporated to
dryness and the residue purified by silica gel chromatography (hexane/ethyl acetate).

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3.9.1. (4S,5S,10R,100S)-4-[N-(10-Ethoxycarbonylethyl)-N-(100 -phenethyl)-carboxamido]-5-methyl-
2-oxazolidone 13a
1
This was obtained starting from 3a. H NMR: δ 1.10 (d, 3H, J=6.8 Hz), 1.25 (t, 3H, J=7.1 Hz), 1.5
(d, 3H, J=6.3 Hz), 1.74 (d, 3H, 6.9 Hz), 3.67 (q, 1H, J=6.8 Hz), 4.2 (m, 2H), 4.98 (m, 2H), 5.11 (d, 1H,
J=7.9 Hz), 5.45 (b s, 1H), 7.2–7.45 (m, 5ArH); 13C NMR: δ 13.9, 14.6, 16.4, 17.1, 52.7, 54.6, 56.9, 61.1,
74.3, 127.1, 127.7, 127.8, 128.4, 128.5, 128.6, 128.8, 138.2, 158.5, 166.3, 170.7.
3.9.2. (4S,5R,10R,100S)-4-[N-(10-Ethoxycarbonylethyl)-N-(100 -phenethyl)-carboxamido]-5-methyl-
2-oxazolidone 13b
This was obtained starting from 3b. 1H NMR: δ 1.09 (d, 3H, J=6.9 Hz), 1.25 (t, 3H, J=7.2 Hz), 1.53
(d, 3H, J=6.4 Hz), 1.72 (d, 3H, J=7 Hz), 3.59 (q, 1H, J=6.9 Hz), 4.15 (m, 2H), 4.59 (dq, 1H, J=3.3, 6.4
Hz), 4.98 (d, 1H, J=3.3 Hz), 5.23 (q, 1H, J=7 Hz), 7.45 (m, 5ArH).
3.9.3. (4S,5S,10R,100S)-4-[N-(10-Ethoxycarbonylethyl)-N-(100 -phenethyl)-carboxamido]-5-methyl-
2-oxazolidone 14a
This was obtained starting from 4a. 1H NMR: δ 1.0 (d, 3H, J=7.5 Hz), 1.3 (m, 6H), 3.64 (q, 1H, J=7.5
Hz), 4.2 (m, 2H), 4.4 (d, 1H, J=7.7 Hz), 5.3 (b s, 1H), 5.58 (q, 1H, 6.8 Hz), 5.75 (d, 1H, J=7.7 Hz), 6.4
(m, 2ArH), 7.3 (m, 8ArH).
3.9.4. (4S,5R,10R,100S)-4-[N-(10-Ethoxycarbonylethyl)-N-(100 -phenethyl)-carboxamido]-5-methyl-
2-oxazolidone 14b
This was obtained starting from 4b. 1H NMR: δ 1.09 (d, 3H, J=6.9 Hz), 1.25 (t, 3H, J=7 Hz), 1.53 (d,
3H, J=6.7 Hz), 3.6 (q, 1H, J=6.9 Hz), 4.14 (q, 2H, J=7 Hz), 4.82 (q, 1H, J=6.7 Hz), 4.9 (d, 1H, J=5 Hz),
5.64 (d, 1H, J=5 Hz), 7.25 (m, 10ArH).
3.9.5. (4R,5S,10R,100S)-4-[N-(10-Ethoxycarbonylethyl)-N-(100 -phenethyl)-carboxamido]-5-methyl-
2-oxazolidone 14d
This was obtained starting from 4d. 1H NMR: δ 1.15 (d, 3H, J=6.8 Hz), 1.26 (t, 3H, J=7 Hz), 1.62 (d,
3H, J=7 Hz), 3.61 (q, 1H, J=6.8 Hz), 4.12 (q, 2H, J=7 Hz), 4.71 (d, 1H, J=5.5 Hz), 4.9 (q, 1H, J=7 Hz),
5.88 (d, 1H, J=5.5 Hz), 7.25 (m, 10ArH).
Acknowledgements
This investigation was supported by the University of Bologna (funds for selected research topics) and
by COFIN 1998–2000 of MURST.
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