Stereoselective synthesis of uncommon α,α'-dialkyl-α- aminoacids. Part 1

Article abstract of DOI:10.1016/S0957-4166(98)00272-9

The alkylation of the diastereomeric mixture of chiral morpholinone derivatives 4 and 5 occurs with good yield and trans induction. Cleavage of the alkylated products 6a,b,c,e gives enantiomerically pure uncommon (and sterically constrained) α,α'-dialkyl-α-aminoacids. The absolute configuration of the new stereocentres of 4, 5, 6 and 7 has been assigned on the basis of the ¹H-NMR spectra and NOE measurements.

Full text of DOI:10.1016/S0957-4166(98)00272-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2987–2998
Stereoselective synthesis of uncommon α,α0-dialkyl-α-
aminoacids. Part 1
Armando Carloni, Gianni Porzi and Sergio Sandri ∗
Dipartimento di Chimica ‘G.Ciamician’, Via Selmi 2, Università degli Studi di Bologna, Bologna, Italy
Received 1 June 1998; accepted 7 July 1998
Abstract
The alkylation of the diastereomeric mixture of chiral morpholinone derivatives 4 and 5 occurs with good yield
and trans induction. Cleavage of the alkylated products 6a,b,c,e gives enantiomerically pure uncommon (and
sterically constrained) α,α0-dialkyl-α-aminoacids. The absolute configuration of the new stereocentres of 4, 5,
6 and 7 has been assigned on the basis of the 1H-NMR spectra and NOE measurements. © 1998 Elsevier Science
Ltd. All rights reserved.
1. Introduction
In recent years, optically active non-proteinogenic and rigidified α-amino acids have gained relevance
because of their potential biological activity.1 In fact, several molecules with therapeutic effects contain
unnatural amino acids which can also act as enzyme inhibitors. For instance, α,α0-dialkyl-α-aminoacids
are able to influence remarkably the peptides into which they can be incorporated by reducing the
conformational freedom.
In a previous paper2 we reported a new approach to the enantioselective synthesis of uncommon
α-amino acids through the stereoselective alkylation of (6S)- and (6R)-6-methyl-morpholine-2,5-dione
derivatives. Therefore, as a continuation of our studies, we have directed our interest to investigating the
mono and dialkylation of the chiral synthon (3R,6S)-4-N-((S)-1-phenethyl)-3,6-dimethyl-1,4-morpholin-
2,5-dione 3, our aim being the accomplishment of a new strategy to the stereoselective synthesis of
uncommon α,α0-dialkyl-α-aminoacids. The starting synthon 3 we used was synthesized in satisfactory
yield as previously reported2 or starting from methansulfonate of (S)-ethyl lactate and (2S)-2-acethoxy-
propanoylchloride (Scheme 1).
∗
Corresponding author. E-mail: porzi@ciam.unibo.it
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00272-9
tetasy 2421 Article

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Scheme 1.
2. Results and discussion
The alkylation of 3 with both allyl iodide and benzyl bromide occurs in very good chemical yield ex-
clusively at C-6 and with total trans stereoselection, the new stereocentre C-6 having the S configuration.
In fact, the diastereomer 5, isolated in only 20–30% yield, was produced owing to the isomerization of the
stereocentre C-3 of the prevalent cis isomer 4 (see Scheme 2). A very good alkylation of 3 (yield>95%)
was achieved by using 1.6 equivalents of LHMDS, 1 equivalent of alkylating agent and performing the
reaction at −78°C for 6 hours. Employing one equivalent of LHMDS the reaction occurred in lower yield
(about 60%). The alkylation of the chiral synthon 3 at C-6 was probed with NOE measurements on the
reaction products. In fact, by irradiating both the CH3 and the hydrogen of the chiral auxiliary, NOEs
were exclusively registered on the (C-3)–H and the (C-3)–CH3 both at 4 and at 5.
Scheme 2.
The absolute configurations of stereocentres C-3 and C-6 in 4 and 5 were assigned by 1H-NMR data
(see the following stereochemical assignments): however, we confirmed that 4 and 5 are diastereomers
with opposite configuration to the C-3, because, after metallation followed by water addition, both 4b
and 5b gave a mixture of 4b and 5b (see Scheme 3).
Scheme 3.
The second alkylation, performed at −40°C directly on the diastereomeric mixture (4+5) (Scheme 4),
occurs with a good chemical yield (>90%) and diastereoselectivity, as it appears in the data collected in
Table 1. It is interesting to emphasize that by using the same alkylating reagent (entry c and e, Table 1) for

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2989
either of the alkylation processes it is posssible to do both steps in one-pot, i.e. avoiding the purification
of the monoalkylated diastereomers.
Scheme 4.
The trans-3,6-dimethyl derivative 6 was obtained in large proportion with respect to the cis isomer 7
in all cases investigated regardless of the alkylating reagent used. The data collected in Table 1 show that
the reaction occurs with good trans induction with respect to (C-6)–R, i.e. the bulkier substituent at C-6.
Thus, the prevalent trans stereocontrol observed could be ascribed mainly to the configuration of the C-6
stereocentre that causes a different steric hindrance between the diastereotopic faces of the enolate ion
of 4 or 5. In fact, better diastereoselection is achieved when both the alkylating reagent and the alkyl
substituent at C-6 are rather sterically hindered. Nevertheless, further studies are in progress in order to
investigate the influence of the chiral auxiliary (phenethyl group) on the stereochemical outcome of this
alkylation.
Finally, in a model study, the intermediates 6a, 6b and 6e were converted into the corresponding α,α0-
dialkyl-α-aminoacids whose specific rotation values are reported in the literature (Scheme 5). Thus,
1
the correct absolute configuration assigned to the stereocentre C-3 through the H-NMR data was also
confirmed.
Starting from derivative 6c the unnatural α-aminoacid 13, that to our knowledge is not reported in the
literature, was obtained. The one step conversion of 6e into the (2R)-2-benzylalanine hydrochloride 11
refluxing with 57% HI, as previously described for similar compounds,2 occurred in a low yield (∼30%).
In conclusion, the stereocontrolled double alkylation of the chiral synthon 3, described in this
report, gives access to a variety of enantiomerically pure unusual α,α0-dialkyl-α-aminoacids (sterically
constrained) which are an interesting class of products that can exhibit important and diverse biological
functions.
Table 1
Diastereoselectivity on the alkylation of (4+5) mixture

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Scheme 5.
3. Stereochemical assignments
The configuration of the stereocentres in the derivatives 4 and 5 was deduced on the basis of NOE
1
experiments and H-NMR spectra using the approach previously employed for similar molecules.2,3
In previous papers we showed that: (a) the favoured geometry of the morpholindione derivative 3
is a quasiboat (or sofa) conformation in which the (C-3)–CH3 preferentially lies in the pseudo-axial
arrangement;2 (b) the configuration of C-3 can be easily assigned by means of the different shielding
induced by the phenyl ring of the adjacent chiral auxiliary.3,4 Thus, on the basis of the registered chemical
shifts, we could assign the R and the S configuration to the C-3 stereocentre of 4 and 5, respectively. In
fact, in 4a the (C-3)–CH3 doublet lies at higher field (0.95 ppm) than in 5a (1.65 ppm), whereas the
(C-3)–H resonates at a lower field (4.25 ppm) in the former than in the latter isomer (3.87 ppm). Besides,
the significant NOE observed between the methyls bonded at C-3 and C-6 stereocentres allowed us
to assign the 6S configuration to 4a (Fig. 1). By irradiating the CH3 of the chiral auxiliary in 4b the
NOE was exclusively registered on (C-3)–H, while in 5b a largely prevalent NOE was observed on (C-
3)–CH3. Thus, we assigned the 3R configuration to 4b and the 3S one to 5b. In addition, the significant
NOE registered between the (C-3)–CH3 and (C-6)–CH3 (in analogy to 4a) allowed us to ascribe the
6S configuration to 4b. The S configuration of the C-6 centre was confirmed by the greater shielding
observed for both (C-3)–H (3.57 ppm) and (C-3)–CH3 (0.41 ppm) in 5b in comparison to 4b (3.79 and
0.87 ppm, respectively). In fact, the high field resonance of the (C-3)–CH3 doublet observed in 5b is
diagnostic for a cis diaxial relationship between the methyl and the (C-6)–CH2Ph which can actually
adopt the ‘aryl inside’ arrangement3 (Fig. 1).
The stereochemistry at C-3 of the diastereomers 6 and 7 was ascertained by NOE experiments, the
C-6 configuration being established, or through the shielding effects induced by the phenyl ring of the

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2991
Fig. 1. NOE registered on 4a, 4b, 5b (curved arrows) and phenyl shielding of (C-3)–CH3 observed on 5b
Fig. 2. Representative NOEs (curved arrows) and shielding effects
Ph–CH2 substituent. For instance, the representative NOE registered between the (C-6)–CH3 and the
methyl group of (C-3)–C2H5 allowed us to assign the 3R configuration to 6d. Analogously, it was possible
to confirm the 3S configuration of 7d owing to the NOE observed on the (C-6)–CH2–CH_CH2 vinylic
protons, by irradiating the CH3 of (C-3)–C2H5. Besides, the 3R configuration of 6a was inferred through
the NOEs registered on the vinylic protons of cinnamyl substituent by irradiating the (C-6)–CH3 (see
Fig. 2).
It is interesting to point out that a conformational analysis performed by semiempirical quantomechan-
ical calculations5 on tetra-substituted morpholindione 6b showed that: (a) the morpholine ring becomes
quasi planar (O-1, C-2, C-3, N-4, and C-5 being practically coplanar, while C-6 is ∼23° out of the plane);
(b) the benzylic hydrogen of the (S)-phenethyl group is preferentially arranged in the antiperiplanar
conformation with respect to the adjacent carbonyl (this conformer being 2.3 kcal/mol more stable than
the synperiplanar one), as evidenced by the NOE measurements. In fact, by irradiating the (C-3)–CH3 of
6b a NOE was observed on the benzylic proton of the chiral auxiliary, but not on the CH3 (see Fig. 2).
In addition, the irradiation of the CH3 of (S)-phenethyl group in 6a gave NOEs on the vinylic protons of
the cinnamyl substituent, but not on the (C-3)–CH3 (see Fig. 2).
In the compounds having the Ph–CH2 as a substituent, the configuration at C-3 was assigned on the
basis of the shielding effect3 suffered by the group that lies in front of the Ph–CH2 and exerted by the
phenyl ring. For instance, the (C-6)–CH3 resonates at a higher field on 6b (0.86 ppm) than in 7b (1.54
ppm) and conversely the vinylic protons at C-6 absorb at lower field (5.1 and 5.6 ppm) on the former

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A. Carloni et al. / Tetrahedron: Asymmetry 9 (1998) 2987–2998
diastereomer than in the latter one (4.95 and 5.35 ppm). Therefore, these findings, confirmed by the
NOEs registered on the vinylic protons of (C-6)–CH2–CH_CH2 by irradiating the (C-3)–CH3 (as shown
in Fig. 2), indicated that the (C-3)–CH2–Ph lies trans to (C-6)–CH3 in 7b and cis in 6b.
The 3R configuration of 6e was established considering that the (C-3)–CH3 and (C-6)–CH3 substan-
tially show the same chemical shift (1.0 and 1.06 ppm), i.e. both methyls are shielded in the same manner.
On the other hand, in 7e these methyls resonate at different fields (1.6 and 1.8 ppm) and, furthermore,
are strongly deshielded with respect to 6e. These findings suggested a trans relationship between the
(C-3)–CH3 and (C-6)–CH3 in 6e, both methyls being equally shielded by the phenyl ring of both PhCH2
groups bonded at C-3 and C-6 (see Fig. 2). Thus, it allowed us to assign the 3S configuration to the
diastereomer 7e.
4. Experimental
1
General information: H- and 13C-NMR were recorded on a Gemini spectrometer at 300 MHz using
CDCl3 as solvent, unless otherwise stated, and the 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 benzophe-
none ketyl.
4.1. (2R,4S)-3-Aza-2-methyl-4-phenyl-ethylpentanoate 1
(2S)-Ethyl lactate (9.3 g, 47.4 mmol), triethylamine (7 ml, 50 mmol) and (S)-1-phenethylamine (6.45
ml, 50 mmol) dissolved in benzene (60 ml) and DMF (30 ml) were stirred at 80°C. After 24 h the
reaction was cooled at r.t. then water was added and the solution extracted with ethyl acetate. The organic
layer was extracted with diluted HCl, then the aqueous solution was made alkaline with NaOH and
extracted with ethyl acetate. After removal of the organic solvent the residue was purified by silica gel
chromatography eluting with hexane/ethyl acetate and the pure product was isolated in 90% yield. The
NMR data and the [α]D25 value are indentical to those previously reported.4
4.2. (2R,3S,4S)-3-Aza-3-acetoxypropanoyl-2-methyl-4-phenyl-ethylpentanoate 2
(2S)-2-Acetoxy-propanoylchloride (6.7 ml, 53.7 mmol) was dropped into a solution of 1 (11.9 g, 52.7
mmol) and triethylamine (8.75 ml, 58 mmol) and stirred at 0°C. After 1 h, the reaction was slowly
warmed to r.t. and dilute HCl and CH2Cl2 were added. The organic extract was dried, evaporated in
vacuo and the residue was purified by silica gel chromatography eluting with hexane/ethyl acetate. The
pure product was isolated in 85% yield. 1H-NMR δ 0.97 (d, 2H, J=6.9 Hz), 1.21 (t, 3H, J=7 Hz), 1.53 (d,
1H, J=6.8 Hz), 1.67 (d, 1H, J=6 Hz), 2.13 (s, 3H), 3.43 (q, 1H, J=6.9 Hz), 4.1 (m, 2H), 5.21 (q, 1H, 6.8
Hz), 5.54 (q, 1H, J=6.8 Hz), 7.38 (m, 5ArH); 13C-NMR δ 14.0, 14.7, 16.7, 18.8, 20.7, 52.8, 54.5, 60.1,
67.0, 127.9, 128.2, 128.6, 138.1, 169.0, 170.8, 171.2. Anal. calcd for C18H25NO5: C, 64.46; H, 7.51; N,
4.18. Found: C, 64.7; H, 7.49; N, 4.2.
4.3. (3R,6S,10S)-3,6-Dimethyl-4-N-(10-phenethyl)-1,4-morpholin-2,5-dione 3
2 N NaOH (60 ml) was added to the intermediate 2 (6.7 g, 20 mmol) dissolved in ethanol (60 ml) and
the reaction mixture was stirred at r.t. After about 3 h the reaction mixture was concentrated in vacuo,

A. Carloni et al. / Tetrahedron: Asymmetry 9 (1998) 2987–2998
2993
acidified with 2 N HCl then extracted with ethyl acetate. The organic layer was dried and evaporated
in vacuo. The pure product was isolated in 80% yield after purification by silica gel chromatography
eluting with hexane/ethyl acetate. The NMR data and the [α]D25 value are indentical to those previously
reported.2
4.4. Alkylation of 3: general procedure
A quantity (8 ml) of LHMDS (1 M solution in THF) was dropped into a stirred solution of 3 (1.24 g,
5 mmol) in dry THF (50 ml) and cooled at −78°C under an inert atmosphere. After 1 h, 5 mmol of the
appropriate alkyl halide was added and the reaction mixture was stirred for 6 h. The reaction mixture,
was slowly warmed to r.t., and was quenched with water and extracted with ethyl acetate. The organic
layer was dried, evaporated under reduced presssure and the diastereomers were separated by silica gel
chromatography (hexane/ethyl acetate as eluant) and recovered as oil.
4.5. (3R,6S,10S)-6-Allyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 4a
1H-NMR δ 0.95 (d, 3H, J=7.1 Hz), 1.6 (d, 3H, J=7.1 Hz), 1.65 (s, 3H), 2.5 (dd, 1H, J=7.4, 13.9 Hz),
2.9 (dd, 1H, J=6.9, 13.9 Hz), 4.25 (q, 1H, J=7.1 Hz), 5.17 (m, 2H), 5.7 (m, 1H), 5.80 (q, 1H, J=7.1 Hz),
7.36 (m, 5ArH); 13C-NMR δ 16.4, 21.2, 26.2, 44.4, 51.8, 52.1, 84.4, 120.7, 127.7, 128.2, 128.7, 131,
139.6, 167.1, 168.0. Anal. calcd for C17H21NO3: C, 71.06; H, 7.37; N, 4.87. Found: C, 71.26; H, 7.4; N,
4.85.
4.6. (3S,6S,10S)-6-Allyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 5a
1H-NMR δ 1.52 (d, 3H, J=7.2 Hz), 1.65 (d, 3H, J=7.2 Hz), 1.67 (s, 3H), 2.58 (dd, 1H, J=7.5, 13.8 Hz),
2.75 (dd, 1H, J=7.2, 13.8 Hz), 3.87 (q, 1H, J=7.2 Hz), 5.2 (m, 2H), 5.7 (q, 1H, J=7.2 Hz), 5.8 (m, 1H),
7.37 (m, 5ArH); 13C-NMR δ 17.5, 22, 25.6, 44.5, 51.6, 53.2, 83.9, 120.8, 120.1, 128, 130.4, 137.5, 167,
167.7.
4.7. (3R,6S,10S)-6-Benzyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 4b
1H-NMR δ 0.87 (d, 3H, J=7.1 Hz), 1.14 (d, 3H, J=7.2 Hz), 1.8 (s, 3H), 3.03 (d, 1H, J=13.4 Hz), 3.45
(d, 1H, J=13.4 Hz), 3.79 (q, 1H, J=7.1 Hz), 5.68 (q, 1H, J=7.2 Hz), 7.28 (m, 10ArH); 13C-NMR δ 15.3,
21.2, 26.4, 46.2, 51.0, 51.3, 85.1, 127.0, 127.2, 127.7, 128.0, 128.4, 130.7, 134.5, 139.5, 166.5, 167.0.
Anal. calcd for C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.9; H, 6.9; N, 4.14.
4.8. (3S,6S,10S)-6-Benzyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 5b
1H-NMR δ 0.41 (d, 3H, J=7.2 Hz), 1.53 (d, 3H, J=7.2 Hz), 1.8 (s, 3H), 2.97 (d, 1H, J=13.5 Hz), 3.45
(d, 1H, J=13.5 Hz), 3.57 (q, 1H, J=7.2 Hz), 5.61 (q, 1H, J=7.2 Hz), 7.2 (m, 10ArH); 13CNMR δ 17.1,
20.2, 28.0, 46.1, 51.7, 53.4, 85.4, 127.0, 127.5, 127.8, 128.1, 128.5, 128.7, 130.9, 134.6, 136.9, 166.2,
167.2.

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4.9. Alkylation of diastereomeric mixture 4+5: general procedure
The diastereomeric mixture of 4 and 5 (2 mmol) in dry THF (20 ml) was metallated with 2 ml of
LHMDS (1 M solution in THF) at −40°C, then submitted to alkylation with the appropriate halide (3
mmol). The reaction mixture was slowly warmed to 0°C, then quenched with water and extracted with
ethyl acetate. After removal of the organic solvent, from the crude reaction product the diastereomers
were separated by silica gel chromatography using hexane/ethyl acetate as eluant. All the products are
oil-like
4.10. (3R,6S,10S)-6-Allyl-3,6-dimethyl-4-N-(10 -phenethyl)-3-[(E)-3-phenyl-2-propenyl]-1,4-
morpholin-2,5-dione 6a
Cinnamyl bromide was used as the alkylating reagent. The reaction occurred in 4 h and the pure
product was isolated in 81% yield. 1H-NMR δ 1.41 (s, 3H), 1.70 (s, 3H), 1.95 (d, 3H, J=7 Hz), 2.34 (dd,
1H, J=6.6, 13.9 Hz), 2.68 (dd, 1H, J=7.3, 13.9 Hz), 2.87 (m, 2H), 4.52 (q, 1H, J=7.0 Hz), 5.02 (m, 2H),
5.50 (m, 1H), 6.09 (m, 1H), 6.51 (d, 1H, J=15.9 Hz), 7.27 (m, 10ArH); 13CNMR δ 19.5, 26.9, 27.0, 43.0,
45.1, 55.3, 66.9, 83.4, 121.3, 121.7, 126.1, 126.9, 127.0, 127.9, 128.5, 130.5, 136.0, 136.1, 140.9, 166.6,
168.6. [α]D=−46.0 (c=0.2, CHCl3). Anal. Calcd for C26H29NO3: C, 77.39; H, 7.24; N, 3.47. Found: C,
77.19; H, 7.27; N, 3.46.
4.11. (3S,6S,10S)-6-Allyl-3,6-dimethyl-4-N-(10 -phenethyl)-3-[(E)-3-phenyl-2-propenyl]-1,4-morpholin-
2,5-dione 7a
1
The pure product was isolated in 13% yield. H-NMR δ 1.63 (s, 3H), 1.85 (s, 3H), 1.92 (d, 3H, J=7
Hz), 2.39 (dd, 1H, J=6.6, 13.9 Hz), 2.83 (m, 3H), 4.57 (q, 1H, J=7 Hz), 4.72 (m, 1H), 5.02 (m, 1H), 5.5
(m, 1H), 5.68 (m, 1H), 6.05 (d, 1H, J=15.1 Hz), 7.25 (m, 10ArH); 13C-NMR δ 21.4, 26.5, 27.4, 42.2,
43.9, 57.1, 67.0, 83.4, 120.1, 122.5, 126.2, 127.2, 127.5, 127.8, 128.2, 128.3, 131.0, 135.2, 136.5, 141.3,
167.3, 169.0. [α]D=165.8 (c=0.5, CHCl3).
4.12. (3R,6S,10S)-6-Allyl-3-benzyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 6b
Benzyl bromide was used as the alkylating reagent. The reaction occurred over 5 h and the pure product
was isolated in 81% yield. 1H-NMR δ 0.86 (s, 3H), 1.69 (s, 3H), 2.05 (d, 3H, J=7), 2.32 (dd, 1H, J=7.3,
13.8 Hz), 2.7 (dd, 1H, J=7.2, 13.8 Hz), 3.28 (qAB, 2H, J=14.3 Hz), 4.68 (q, 1H, J=7 Hz), 5.12 (m, 2H),
5.6 (m, 1H), 7.25–7.5 (m, 10 ArH); 13C-NMR δ 22.2, 25.8, 28.0, 45.4, 56.7, 68.1, 83.5, 121.3, 127.0,
127.1, 127.8, 128.2, 128.7, 130.5, 130.7, 134.3, 142.2, 167.4, 168.5. [α]D=3.9 (c=1.0, CHCl3). Anal.
calcd for C24H27NO3: C, 76.36; H, 7.21; N, 3.71. Found: C, 76.16; H, 7.2; N, 3.7.
4.13. (3S,6S,10S)-6-Allyl-3-benzyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 7b
1
The product was isolated in 13% yield. H-NMR δ 1.54 (s, 3H), 1.93 (s, 3H), 1.94 (d, 3H, J=7 Hz),
2.18 (m, 2H), 3.3 (qAB, 2H, J=14.4 Hz), 4.7 (q, 1H, J=7 Hz), 4.95 (m, 2H), 5.35 (m, 1H), 6.7 (m, 2H),
7.25 (m, 8ArH); 13C-NMR δ 21.0, 26.6, 27.3, 43.7, 45.0, 57.1, 67.6, 83.1, 119.8, 127.2, 128.1, 128.4,
130.6, 130.9, 134.2, 141.1, 167.4, 168.5.

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2995
4.14. (3R,6S,10S)-3,6-Diallyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 6c
Allyl iodide was used as the alkylating reagent. The reaction occurred over 4 h and the pure product
1
was isolated in 79% yield. H-NMR δ 1.63 (s, 3H), 1.72 (s, 3H), 1.95 (d, 3H, J=7 Hz), 2.41 (dd, 1H,
J=7.5, 13.8 Hz), 2.75 (dd, 1H, J=7.2, 13.8 Hz), 2.78 (m, 2H), 4.52 (q, 1H, J=7 Hz), 5.1 (m, 2H), 5.3 (m,
2H), 5.6 (m, 1H), 5.8 (m, 1H), 7.35 (m, 5ArH); 13C-NMR δ 18.5, 25.6, 26.2, 42.9, 44.4, 54.2, 66.0, 82.5,
116.6, 120.2, 125.9, 126.3, 127.3, 130.6, 131.3, 141.1, 165.8, 167.8. [α]D=−52.0 (c=1.4, CHCl3). Anal.
calcd for C20H25NO3: C, 73.37; H, 7.7; N, 4.28. Found: C, 73.29; H, 7.68; N, 4.3.
4.15. (3S,6S,10S)-3,6-Diallyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 7c
The product was isolated in 16% yield. 1H-NMR δ 1.62 (s, 3H), 1.8 (s, 3H), 1.91 (d, 3H, J=6.8 Hz),
2.51 (dd, 1H, J=7.1, 14.6 Hz), 2.73 (m, 2H), 2.87 (dd, 1H, J=7.4, 14.6 Hz), 4.54 (q, 1H, J=6.8 Hz), 4.94
(m, 2H), 5.18 (m, 2H), 5.42 (m, 1H), 5.76 (m, 1H), 7.35 (m, 5ArH); 13C-NMR δ 20.9, 26.5, 27.2, 43.3,
44.1, 56.7, 66.8, 83.5, 120.5, 120.8, 127.1, 127.7, 128.1, 131.3, 140.6, 167.1, 168.0.
4.16. (3R,6S,10S)-6-Allyl-3-ethyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 6d
Ethyl iodide was used as the alkylating reagent. The reaction occurred over 8 h and the pure product
was isolated in 74% yield. 1H-NMR δ 1.02 (t, 3H, J=7.2 Hz), 1.62 (s, 3H), 1.75 (s, 3H), 1.87 (d, 3H, J=7
Hz), 2.03 (m, 2H), 2.47 (dd, 1H, J=7.5, 13.7 Hz), 2.69 (dd, 1H, J=7.2, 13.7 Hz), 4.45 (q, 1H, J=7 Hz),
5.05 (m, 2H), 5.50 (m, 1H), 7.32 (m, 5ArH); 13C-NMR δ 9.1, 20.8, 26.4, 27.1, 32.2, 43.7, 56.3, 66.9,
82.9, 120.2, 126.9, 127.4, 127.6, 127.9, 131.0, 141.2, 167.3, 169.3. [α]D=−48.7 (c=1.2, CHCl3). Anal.
calcd for C19H25NO3: C, 72.35; H, 7.99; N, 4.44. Found: C, 72.64; H, 7.97; N, 4.43.
4.17. (3S,6S,10S)-6-Allyl-3-ethyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 7d
The product was isolated in 16% yield. 1H-NMR δ 0.63 (t, 3H, J=7.3 Hz), 1.63 (s, 3H), 1.77 (s, 3H),
1.87 (d, 3H, J=7 Hz), 1.83–2.15 (m, 2H), 2.49 (dd, 1H, J=7.3, 14 Hz), 2.89 (dd, 1H, J=7.1, 13.8 Hz),
4.43 (q, 1H, J=7 Hz), 5.2 (m, 2H), 5.75 (m, 1H), 7.35 (m, 5ArH); 13C-NMR δ 9.2, 18.7, 26.8, 27.1, 32.8,
45.3, 54.8, 66.7, 83.1, 121.2, 126.7, 127.0, 127.7, 130.4, 140.7, 166.6, 168.9.
4.18. (3R,6S,10S)-3,6-Dibenzyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 6e
Benzyl bromide was used as the alkylating reagent. The reaction occurred over 5 h and the pure product
was obtained in 85% yield. 1H-NMR δ 1.0 (s, 3H), 1.06 (s, 3H), 1.93 (d, 3H, J=7 Hz), 2.85 (d, 1H, J=13.7
Hz), 3.2 (qAB, 2H, J=14.3 Hz), 3.25 (d, 1H, J=13.7 Hz), 4.49 (q, 1H, J=7 Hz), 7.24 (m, 15ArH); 13C-NMR
δ 21.7, 26.8, 27.1, 45.1, 46.5, 56.4, 67.9, 84.2, 126.8, 126.9, 127.6, 127.7, 127.9, 128.1, 128.4, 130.3,
131.0, 134.3, 134.4, 141.4, 166.5, 168.1. [α]D=−50.2 (c=1.1, CHCl3). Anal. calcd for C28H29NO3: C,
78.66; H, 6.84; N, 3.28. Found: C, 78.45; H, 6.87; N, 3.27.
4.19. (3S,6S,10S)-3,6-Dibenzyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 7e
1
The pure product was isolated in 9% yield. H-NMR δ 1.60 (s, 3H), 1.80 (s, 3H), 1.90 (d, 3H, J=7
Hz), 2.59 (d, 1H, J=14.2 Hz), 2.59 (d, 1H, J=14.1 Hz), 2.85 (qAB, 2H, J=13.8 Hz), 3.18 (d, 1H, J=14.1
Hz), 4.63 (q, 1H, J=7 Hz), 6.72 (m, 2H), 7.17 (m, 13ArH); 13C-NMR δ 19.8, 26.0, 27.5, 45.0, 45.2, 56.2,

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A. Carloni et al. / Tetrahedron: Asymmetry 9 (1998) 2987–2998
66.6, 83.7, 126.9, 127.1, 127.9, 128.1, 130.4, 131.0, 134.4, 134.6, 140.3, 167.0, 168.2. [α]D=2.9 (c=0.8,
CHCl3).
4.20. (3R,6S,10S)-6-Benzyl-3,6-dimethyl-4-N-(10 -phenethyl)-3-[(E)-3-phenyl-2-propenyl]-1,4-
morpholin-2,5-dione 6f
Cinnamyl bromide was used as the alkylating reagent. The reaction occurred over 5 h and the pure
1
product was isolated in 83% yield. H-NMR δ 1.0 (s, 3H), 1.6 (s, 3H), 1.93 (d, 3H, J=6.9 Hz), 2.77
(m, 2H), 2.9 (d, 1H, J=13.6 Hz), 3.26 (d, 1H, 13.6 Hz), 4.38 (q, 1H, J=6.9 Hz), 6.12 (m, 1H), 6.55
(d, 1H, J=15 Hz), 7.15 (m, 15ArH); 13C-NMR δ 19.1, 26.0, 27.8, 42.8, 46.5, 55.5, 66.7, 84.0, 121.7,
126.0, 126.8, 126.9, 127.7, 127.8, 128.1, 128.3, 128.5, 130.9, 134.0, 135.9, 136.0, 139.9, 165.9, 168.1.
[α]D=−63.7 (c=1.0, CHCl3). Anal. calcd for C30H31NO3: C, 79.44; H, 6.89; N, 3.09. Found: C, 79.65;
H, 6.85; N, 3.1.
4.21. (3S,6S,10S)-6-Benzyl-3,6-dimethyl-4-N-(10 -phenethyl)-3-[(E)-3-phenyl-2-propenyl]-1,4-
morpholin-2,5-dione 7f
The pure product was isolated in 12% yield. 1H-NMR δ 1.71 (s, 3H), 1.73 (s, 3H), 1.88 (d, 3H, J=6.9
Hz), 2.38 (dd, 1H, J=6.3, 14.9 Hz), 2.74 (dd, 1H, J=8.2, 14.9 Hz), 2.98 (d, 1H, J=13.8 Hz), 3.37 (d, 1H,
J=13.8 Hz), 4.5 (q, 1H, J=6.9 Hz), 5.35 (m, 1H), 6.0 (d, 1H, J=15.6 Hz), 6.9–7.45 (m, 15ArH); 13C-NMR
δ 20.7, 26.4, 28.0, 42.7, 45.1, 56.0, 66.2, 84.1, 122.4, 126.6, 126.7, 127.1, 127.2, 127.4, 127.9, 128.0,
128.2, 131.0, 134.5, 134.9, 136.6, 140.5, 166.9, 169.0. [α]D=77.5 (c=0.6, CHCl3).
4.22. (3R,6S,10S)-6-Benzyl-3-allyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 6g
Allyl iodide was used as the alkylating reagent. The reaction occurred over 4 h and the pure product
1
was isolated in 81% yield. H-NMR δ 0.9 (s, 3H), 1.75 (s, 3H), 1.87 (d, 3H, J=7 Hz), 2.62 (m, 2H),
2.9 (d, 1H, J=13.6 Hz), 3.28 (d, 1H, J=13.6 Hz), 4.29 (q, 1H, J=7 Hz), 5.25 (m, 2H), 5.76 (m, 1H),
7.15 (m, 10ArH); 13C-NMR δ 18.8, 26.0, 28.1, 43.5, 46.5, 55.4, 66.4, 83.8, 121.3, 126.8, 126.9, 127.6,
128.1, 128.3, 130.8, 130.9, 133.9, 139.8, 165.7, 168.0. [α]D=−88.7 (c=1.2, CHCl3). Anal. calcd for
C24H27NO3: C, 76.36; H, 7.21; N, 3.71. Found: C, 76.65; H, 7.19; N, 3.7.
4.23. (3S,6S,10S)-6-Benzyl-3-allyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 7g
The product was isolated in 14% yield. 1H-NMR δ 1.7 (s, 3H), 1.72 (s, 3H), 1.84 (d, 3H, J=6.9 Hz),
2.25–2.55 (m, 2H), 2.9 (d, 1H, J=13.5 Hz), 3.48 (d, 1H, J=13.5 Hz), 4.4 (q, 1H, J=6.9 Hz), 4.5–4.75 (m,
3H), 7.2 (m, 10ArH).
4.24. (3R,6S,10S)-6-Benzyl-3-ethyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 6h
Ethyl iodide was used as the alkylating reagent. The reaction occurred over 8 h and the pure product
1
was isolated in 70% yield. H-NMR δ 0.9 (s, 3H), 0.95 (t, 3H, J=7 Hz), 1.76 (s, 3H), 1.81 (d, 3H, J=7
Hz), 1.9 (m, 2H), 2.9 (d, 1H, J=13.6 Hz), 3.26 (d, 1H, J=13.6 Hz), 4.21 (q, 1H, J=7 Hz), 6.85 (m, 2H),
7.2 (m, 8ArH); 13C-NMR δ 9.3, 18.3, 26.3, 28.0, 32.6, 46.7, 55.2, 66.7, 83.8, 126.9, 127.0, 127.6, 128.2,
128.7, 131.0, 134.0, 139.8, 166.0, 168.6. [α]D=−100.7 (c=1.0, CHCl3). Anal. calcd for C23H27NO3: C,
75.59; H, 7.45; N, 3.83. Found: C, 75.75; H, 7.44; N, 3.82.

A. Carloni et al. / Tetrahedron: Asymmetry 9 (1998) 2987–2998
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4.25. (3S,6S,10S)-6-Benzyl-3-ethyl-3,6-dimethyl-4-N-(10 -phenethyl)-1,4-morpholin-2,5-dione 7h
1
The product was isolated in 20% yield. H-NMR δ −0.1 (t, 3H, J=7 Hz), 1.67 (s, 3H), 1.75 (s, 3H),
1.8 (m, 2H), 1.86 (d, 3H, J=7 Hz), 2.9 (d, 1H, J=13.6 Hz), 3.5 (d, 1H, J=13.6 Hz), 4.3 (q, 1H, J=7 Hz),
7.2 (m, 10ArH).
4.26. (2R,4S)-3-Aza-2-[(E)-30-phenyl-20-propenyl]-2-methyl-4-phenyl-pentanoic acid hydrochloride 8
1 M LiOH (20 ml) was added to 6a (0.8 g, 2 mmol) dissolved in ethanol (20 ml) and the solution
was refluxed for 40 h. After complete evaporation of ethanol in vacuo, the residue was acidified with
10% HCl and evaporated to dryness under reduced pressure. The residue was dissolved in water and the
solution was adsorbed on an ion exchange resin Amberlist H-15. The resin was washed with distilled
water then eluted with 5 M NH4OH. After evaporation to dryness of the eluted solution, the aminoacid
was recovered in practically quantitative yield and converted into the hydrochloride by refluxing for 1
1
h in 2 N HCl. H-NMR (CD3OD) δ 1.62 (s, 3H), 1.74 (d, 3H, J=6.6 Hz), 2.85 (m, 2H), 3.3 (m, 1H),
4.64 (q, 1H, J=6.6 Hz), 6 (m, 1H), 6.5 (d, 1H, J=15.9 Hz), 7.35 (m, 10ArH); 13C-NMR δ (CD3OD)
19.8, 22.0, 41.3, 58.2, 67.2, 121.5, 127.5, 129.0, 129.6, 130.2, 130.8, 137.3, 137.9, 171.7. [α]D=−52.2
(c=0.42, CH3OH). Anal. calcd for C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 77.95; H, 7.47; N,
4.52.
4.27. (2R)-2-(30-Phenylpropyl)alanine hydrochloride 9
The sodium salt of 8 (0.66 g, 2 mmol), dissolved in ethanol (20 ml), was hydrogenated at 50 psi for 12
h in the presence of Pd(OH)2 (0.04 g, 0.3 mmol). The catalyst was removed by filtration through Celite,
the ethanol was evaporated in vacuo and the residue dissolved in 2 N HCl. The product, isolated in 85%
yield after treatment with the ion exchange resin Amberlist H-15, was converted into the hydrochloride.
After evaporation to dryness the residue was triturated with diethyl ether. [α]D=−8 (c=0.2, H2O), [lit.6
8.1 (c=0.2, H2O)].
4.28. (2R,4S)-3-Aza-2-benzyl-2-methyl-4-phenyl-pentanoic acid hydrochloride 10
The product was recovered in practically quantitative yield starting from 6b and following the same
1
procedure used to obtain 8. H-NMR (CD3OD) δ 1.52 (s, 3H), 1.76 (d, 3H, J=6.9 Hz), 3.15 (d, 1H,
J=13.2 Hz), 3.35 (d, 1H, J=13.2 Hz), 4.55 (q, 1H, J=6.9 Hz), 7.2 (m, 10ArH); 13C-NMR (D2O) δ 16.4,
20.4, 43.7, 56.8, 66.3, 128.1, 128.7, 128.9, 129, 130, 130.4, 132.6, 134.7, 171. [α]D=−79.9 (c=0.9, 1 N
HCl). Anal. calcd for C18H21NO2: C, 76.3; H, 7.47; N, 4.94. Found: C, 76.6; H, 7.5; N, 4.92.
4.29. (2R)-2-Benzylalanine hydrochloride 11
The product, obtained in 90% yield by hydrogenation of the sodium salt of 10, in the same conditions
employed for 8, was then converted into the hydrochloride. After evaporation to dryness the residue was
triturated with diethyl ether. [α]D=9.5 (c=0.2, H2O), [lit.6 9.6 (c=0.2, H2O)].

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A. Carloni et al. / Tetrahedron: Asymmetry 9 (1998) 2987–2998
4.30. (2R,4S)-3-Aza-2-allyl-2-methyl-4-phenyl-pentanoic acid hydrochloride 12
The product was obtained in practically quantitative yield by refluxing 6c for 60 h with LiOH and
following the same procedure used to prepare 8. 1H-NMR (D2O) δ 1.52 (s, 3H), 1.70 (d, 3H, J=6.9 Hz),
2.4 (m, 2H), 4.42 (q, 1H, J=6.9 Hz), 5 (m, 2H), 5.35 (m, 1H), 7.25 (m, 5ArH). [α]D=−19.5 (c=0.7, 1 N
HCl). Anal. calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 72.3; H, 8.2; N, 6.02.
4.31. (2R)-2-Propylalanine 13
The product was obtained by hydrogenation of the sodium salt of 12, as reported for 9, and it was
recovered pure in 90% yield after treatment with the ion exchange resin Amberlist H-15. 1H-NMR (D2O)
δ 0.88 (t, 3H, J=7.2 Hz), 1.22 (m, 2H), 1.41 (s, 3H), 1.9 (m, 2H); 13C-NMR (D2O) δ 13.8, 17.2, 24.3,
41.3, 60.2, 181.0. [α]D=−1.4 (c=0.86, 1 N HCl). Anal. calcd for C6H13NO2: C, 54.94; H, 9.99; N, 10.68.
Found: C, 55.14; H, 10.02; N, 10.65.
Acknowledgements
Investigation supported by University of Bologna (funds selected research topics) and by Fondi Ricerca
Istituzionale (ex quota 60%).
References
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2. Porzi, G.; Sandri, S. Tetrahedron: Asymmetry 1996, 7, 189 and references therein.
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5. Energy calculations have been performed by the AM1 method (HyperChem programme, 1994) by using the ‘Polak-Ribiere
algorithm (conjugate gradient)’ with a RMS gradient 0.01 kcal.
6. Williams, R.; Im, M.-N. J. Am. Chem. Soc. 1991, 113, 9276.