Enantioselective synthesis of α,β-substituted β-amino acids

Article abstract of DOI:10.1016/S0040-4020(00)00997-2

Chiral derivative 3 was shown to be a precursor of α and β-substituted β-amino acids as well as α,β-disubstituted β-amino acids. The key steps of the procedure are a diastereoselective alkylation of synthon 3 by organocuprates reagents and a diastereoselective alkylation of the alkylated adduct.

Full text of DOI:10.1016/S0040-4020(00)00997-2

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 195±200
Enantioselective synthesis of a,b-substituted b-amino acids
*
Claude Agami, Sandrine Cheramy, Luc Dechoux and Mohand Melaimi
Á Â Â
Laboratoire de Synthese Asymetrique (UMR 7611), Universite P. et M. Curie, 4 place Jussieu, 75005 Paris, France
Received 24 July 2000; revised 5 October 2000; accepted 23 October 2000
AbstractÐChiral derivative 3 was shown to be a precursor of a and b-substituted b-amino acids as well as a,b-disubstituted b-amino acids.
The key steps of the procedure are a diastereoselective alkylation of synthon 3 by organocuprates reagents and a diastereoselective alkylation
of the alkylated adduct. q 2000 Elsevier Science Ltd. All rights reserved.
b-Amino acids have attracted much attention in recent
years, whether as analogues of a-amino acids to increase
the resistance of peptides to enzymatic degradation1 or as
building blocks for the synthesis of b-lactam antibiotics.2 In
addition, b-amino acids derivatives are crucial structural
components of numerous biologically active natural
products.3 Although many methods for synthesizing
enantiomerically pure b-amino acids have been reported,
great effort continues to be devoted towards more ef®cient
enantioselective methods.4 The most obvious strategy
consists on directed conjugate addition of chiral amines to
a,b-unsaturated esters.5 Another strategy is based on stereo-
selective alkylation en route to enantiopure b-amino acids.
Cardillo and Konopelski used substituted perhydropyrimi-
din-4-ones6 I an II whose stereoselective alkylation and
subsequent hydrolysis afforded substituted b-amino acids.
Juaristi and Seebach showed the usefulness of chiral
derivatives of 3-aminopropionic acids III (Scheme 1).7
Moreover Juaristi alkylated heterocyclic compounds
derived from aspartic acid8 and Seebach made use of
lithiated hydropyrimidines in order to synthesize
a-branched b-amino acids.9
We have reported a new synthetic method that starts from
chiral synthon 3 and allows to synthesize substituted
enantiopure b-amino acids.10 The key steps of this method
consist in conjugate additions of different organocuprate
reagents to this chiral Michael acceptor followed by
a-alkylation of the resulting adduct with methyl iodide.
Herein we report full details of our study concerning these
reactions.
1. Results and discussion
Preparation of the chiral auxiliary: compound 3 was
prepared in two steps. The reaction between (S)-phenyl-
glycinol and cyanogen bromide afforded amino-oxazolidine
211 and the condensation of this heterocycle with methyl
propiolate gave bicyclic heterocycle 3 (Scheme 2).
Scheme 1.
Scheme 2. (a) BrCN, EtOH, re¯ux 12 h then NaOH, 98%. (b) Ethyl propiolate, EtOH, re¯ux, 12 h, 66%.
Keywords: asymmetric synthesis; conjugate addition; b-amino acids.
* Corresponding author. Tel.: 133-1-44-27-26-20; fax: 133-1-44-27-26-20; e-mail: dechoux@ccr.jussieu.fr
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00997-2

196
C. Agami et al. / Tetrahedron 57 (2001) 195±200
Table 1. Organocuprates addition to cyclic compound 3
mixture was stirred for 2 h at this temperature and further
hydrolyzed with a saturated aqueous ammonium chloride
solution (Table 2).
The overall yields of alkylation range from 88 to 96% when
the reactions were conducted at 2108C. At 2508C the
yields drop due incomplete conversion. The results reported
in Table 2 show that electrophiles attack the chiral enolates
derived from compounds 4 from the b-face, i.e. in a syn
relationship with respect to the phenyl group. This stereo-
chemical course is surprising since this alkylation takes
place on the apparently most hindered b side of the enolate
intermediate. The presence of a methyl or a n-butyl sub-
stituent on the a-face produces an enhancement of the
stereoselectivity (compare entries 2, 3 and 5). In order to
rationalize this stereoselectivity, specially when no sub-
stituent is present on the a-side (i.e. in substrate 4e), the
geometry of the enolate derived from susbstrate 4e, shown
in Fig. 1, was optimized by AM1 calculations.13
R
Yield (%)
de (%)
4a
4b
4c
4d
Me
86
93
75
81
.95
.95
.95
.95
n-Bu
Vinyl
Ph
It is worth noting that the b-nitrogen atom is pyramidal and
that the electron lone pair is located on the a-side of the
enolate. An unfavorable ®eld interaction occurs between
this lone pair and the enolate b-electrons on the a-face.14
Scheme 3.
Scheme 4. (a) Methyl acrylate, MeOH, re¯ux, 12 h, 76%. (b) Ethyl crotonate, EtOH, re¯ux 12 h, 25%.
Bicyclic compound 3 was used in Michael additions with
different organocuprate reagents. In all cases, these reac-
tions afforded compounds 4a±d as pure diastereoisomers
in high yields (Table 1).
This electronic effect may account for the observed stereo-
selectivity. The S absolute con®guration of the a center in
adducts 6 was established by NOE 1H NMR experiments in
the case of the a,b-dialkylated compounds 6a, b, f. Adduct
6e and 6b led, respectively to the known (S)-3-amino-2-
methylpropanoic acid 8b and to (2S, 3S)-3-amino-2-methyl-
heptanoic acid 8c. The absolute con®guration of the created
stereocenter of compound 4a was con®rmed by synthesizing
the already described (S)-3-aminobutanoic acid 8a starting
The observed stereoselectivity corresponds to an attack of
the nucleophile in an anti orientation with respect to the
phenyl group. It is interesting to note that, in order to
achieve Michael addition, the use of trimethylsilylchloride
is necessary. The utility of TMSCl in similar 1,4-addition on
enone using organocuprate reagents is well established.12
Thus, in the absence of TMSCl, product 5 was formed via
a b-elimination process that involves the abstraction of the
benzylic hydrogen (Scheme 3). Pyrimidine 5 could also be
obtained quantitatively by treatment of product 3 with an
equimolar quantity of sodium hydride.
Table 2. a-Alkylation of intermediates 4
Chiral intermediates 4 were used in asymmetric a-alkyl-
ation processes. Condensation of the aminooxazolidine 2
with methylacrylate and ethyl crotonate afforded respec-
tively compound 4e and a 70/30 mixture of compounds 4a
and 4f (Scheme 4).
Entry Product
R1
R2
Temp (8C) Yield (%)a Ratio (%)b
1
2
3
4
5
6e
6e
6a
6f
H
H
Me
H
n-Bu
H
H
H
Me
H
250
210
210
210
210
30
95
88
93
96
80:20
74:24
.97:3
57:43
.97:3
6b
Enolates derived from product 4 were generated by reaction
with LiHMDS for 15 min at 2108C in THF. The electro-
phile was added at 2108C or at 2508C and the reaction
a Combined yields of the two diastereoisomers.
b Determined by 1H NMR of the crude reaction mixture.

C. Agami et al. / Tetrahedron 57 (2001) 195±200
197
currently used in the asymmetric synthesis of 1,3-diamines,
tetrahydropyrimidinones.
2. Experimental
2.1. General comments
1H and 13C Spectra were respectively recorded on a Bruker
ARX 250 spectrometer at 250 MHz and 62.9 MHz;
chemical shifts are reported in ppm from TMS. Column
Figure 1. AM1 modelization of enolate derived from compound 4e.
Scheme 5.
from compound 4e. As depicted on Scheme 5, the chemical
sequence used for this synthesis involved two steps
(Tables 3 and 4).
chromatography were performed on silica gel, 230±400.
TLC were run on Merck Kieselgel 60F254 plates. THF was
distilled from sodium/benzophenone ketyl.
2.1.1. (4S)-4-Phenyl oxazolidin-2-ylidene amine 2. To a
solution of (S)-phenylglycinol 1 (2 g; 14.6 mmol) in EtOH
(20 mL) was added, at room temperature, cyanogen
bromide (1.77 g; 16.7 mmol). After 12 h at re¯ux, ethanol
was evaporated under reduced pressure and the residue was
dissolved in a 1 M aqueous solution of NaOH (30 mL) and
extracted with dichloromethane (3£20 mL). The organic
phase was concentrated at reduced pressure to afford quan-
titatively compound 2 as a white solid. Mp: 1148C.
[a]2D0ˆ111 (c 1.0, CHCl3). MS-CI/NH3: 163 (M1H1,
100). IR n (cm21): 3425±1682. NMR 1H (CDCl3,
250 MHz): 4.17 (dd, 1H, Jˆ7.3±8.0 Hz,), 4.74 (dd, 1H,
Jˆ8.0±9.0 Hz), 4.95 (ls, 2H), 5.13 (dd, 1H, Jˆ7.3±
9.0 Hz), 7.22 (m, 5H). NMR 13C (CDCl3, 65.2 MHz):
65.7, 75.6, 126.3, 127.7, 128.7, 142.2, 162.1.
The ®rst step is a selective hydrogenolysis of the homo-
benzylic C±O bond.15 Reaction with hydrogen in presence
of palladium on carbon, platinum oxide or palladium
hydroxyde in acidic, basic or neutral medium gave products
7a±d. The experimental conditions of base-catalysed
hydrolysis16 could be used in the case of the synthesis of
b-substituted b-amino acid. Thus, (S)-3-aminobutanoic acid
8a17 was obtained in two steps from 7a (i.e. hydrolysis of
pyrimidinone 7a followed by hydrogenolysis of the benzylic
C±N bond). In contrast, compounds 7b and 7c, submitted to
the base-catalysed conditions which were used in the
hydrolysis of b-substituted b-amino acids, gave rise, in
the present case, to epimerization of the created stereocenter
of compound 7b and 7c which is in these cases a to carbonyl
group. However, strong acidic conditions afforded optically
pure (S)-3-amino-2-methylpropanoic acid 8b18 and (2S, 3S)-
3-amino-2-methylheptanoic acid 8c after chromatography
on an acidic cation exchanger.
2.1.2. (3S)-3-Phenyl-2,3-dihydro oxazolo [3,2-a] pyrimi-
din-7-one 3. To a solution of 2 (800 mg; 4.94 mmol) in
ethanol (15 mL) was added, at room temperature, ethyl
propiolate (0.88 mL; 9.88 mmol). After 12 h at re¯ux, eth-
anol was evaporated under reduced pressure and the residue
was chromatographed on silica gel (MeOH/EtOAc: 10/90)
to afford product 3 as a white solid (0.7 g; 3.27 mmol, yield
66%). Mp: 1868C. [a]2D0ˆ218 (c 0.4, MeOH). HRMS: calc
for C12H10O2N21H1ˆ215.0821, obsˆ215.0816. IR n
In conclusion, we have developed a novel and highly dia-
stereoselective method for the asymmetric synthesis of a-,
b- and a,b-substituted b-amino acids starting from chiral
synthon 3. Heterocycles derived from compound 3 are
Table 3. Hydrogenolysis of compounds 6
1
(cm21): 1632±1528±1477. NMR H (CDCl3, 250 MHz):
R1
R2
Yield (%)
4.49 (dd, 1H, Jˆ7.8±9.2 Hz), 5.01 (t, 1H, Jˆ9.2 Hz), 5.23
(dd, 1H, Jˆ7.8±9.2 Hz), 5.95 (d, 1H, Jˆ7.5 Hz), 6.90 (d,
1H, Jˆ7.5 Hz), 7.27 (m, 5H). NMR 13C (CDCl3,
62.5 MHz): 61.9, 74.0, 109.8, 127.1, 129.7, 130.0, 135.0,
135.8, 161.0, 175.0.
7a
7b
7c
7d
Me
H
n-Bu
n-Bu
H
93
98
95
95
Me
Me
H
Table 4. Hydrolysis of compounds 7
2.2. General procedure for Michael addition
R1
R2
Yield (%)
To a solution of compound 3 (0.93 mmol) in THF (10 mL)
were successively added, at 2788C, trimethylsilylchloride
(0.93 mmol) and a solution of alkyl organocuprate
(1.4 mmol, 0.15 M in diethyl ether, prepared by addition,
8a
8b
8c
Me
H
n-Bu
H
Me
Me
61
68
81

198
C. Agami et al. / Tetrahedron 57 (2001) 195±200
at 2108C, of a solution of commercially organolithium
(2.8 mmol) to a suspension of CuI (1.4 mmol) in diethyl
ether). The reaction was allowed to reach room temperature
within 1 h and the mixture was stirred at rt for 2 h. An
aqueous solution saturated with ammonium chloride
(15 mL) was added and the reaction mixture was extracted
with CH2Cl2 (2£20 mL). After evaporation the residue was
chromatographed (EtOAc/MeOH).
2-one 4f. To a solution of 2 (1 g; 6.21 mmol) in methanol
(60 mL) was added, at room temperature, ethyl crotonate
(3.54 mL; 31 mmol). After 12 h at re¯ux, ethanol was
evaporated under reduced pressure and the residue is chro-
matographed on silica gel (MeOH/EtOAc: 10/90) to afford
product 4f as a white solid (0.357 g; 1.55 mmol, yield 25%).
[a]2D0ˆ183 (c 1.0, CHCl3). MS-CI/NH3: 231 (M1H1, 100).
Mp: 1628C. NMR 1H (CDCl3, 250 MHz): 0.74 (d, 3H,
Jˆ6.6 Hz), 2.30 (dd, 1H, Jˆ8.75±15.9 Hz), 2.59 (dd, 1H,
Jˆ6.5±15.9 Hz), 3.71 (m, 1H), 4.11 (m, 1H), 4.28 (m, 1H),
4.90 (m, 1H), 7.37 (m, 5H). NMR 13C (CDCl3, 62.5 MHz):
20.2, 38.4, 49.5, 62.9, 73.6, 126.8, 128.5, 129.5, 137.7,
168.7, 178.5.
2.2.1. (4S,40S)-4-(2-Imino-4-phenyl oxazolidin-3-yl)-
pentan-2-one 4a. (86%). [a]2D0ˆ1119 (c1, CHCl3). MS-
1
CI/NH3: 231 (M1H1, 100). H NMR (250 MHz, CDCl3):
1.20 (d, Jˆ6.4 Hz, 3H), 2.35 (dd, Jˆ15.9, 6.6 Hz, 1H), 2.59
(dd, Jˆ15.9, 6.9 Hz, 1H), 3.39±3.44 (m, 1H), 4.32 (dd,
Jˆ8.9, 6.3 Hz, 1H), 4.81 (t, Jˆ8.9 Hz, 1H), 5.03 (dd,
Jˆ8.6, 6.2 Hz, 1H), 7.22±7.39 (m, 5H). 13C NMR
(63 MHz, CDCl3): 17.2, 37.1, 45.5, 60.3, 73.2, 126.9,
128.6, 129.7, 135.5, 167.2, 178.1.
2.3. General procedure for the a-alkylation
To a solution of compound 4 (1 mmol) in THF (10 mL) was
added, at 2108C, LiHMDS (1.1 mL of a 1 M solution in
THF, 1.1 mmol) and after 15 min, at 2108C, methyl iodide
(0.09 mL, 1.5 mmol) was added. The reaction mixture was
stirred 2 h at 2108C and further quenched by a saturated
NH4Cl aqueous solution and extracted with CH2Cl2
(2£20 mL). After evaporation, the residue was chromato-
graphed (EtOAc/MeOH).
2.2.2. (3S,5R)-5-Butyl-3-phenyl-2,3,5,6-tetrahydro oxazolo
[3,2-a] pyrimidin-7-one 4b. (93%). [a]2D0ˆ1109 (c 0.5,
CHCl3). MS-CI/NH3: 273 (M1H1, 100). NMR 1H (CDCl3,
250 MHz): 0.69 (t, 3H, Jˆ7.0 Hz), 1.10 (m, 2H), 1.39 (m,
2H), 1.69 (m, 2H), 2.33 (dd, 1H, Jˆ5.5±16.0 Hz), 2.50 (dd,
1H, Jˆ7.0±16.0 Hz), 3.21 (m, 1H), 4.26 (dd, 1H, Jˆ6.0±
9.0 Hz), 4.75 (t, 1H, Jˆ9.0 Hz), 4.90 (dd, 1H, Jˆ6.0±
9.0 Hz), 7.14±7.34 (m, 5H). NMR 13C (CDCl3, 62.5 MHz):
13.7, 22.3, 26.5, 30.8, 34.4, 49.3, 60.6, 73.2, 126.7, 129.7,
135.8, 167.3, 178.1.
2.3.1. (3S,5S,6S)-5,6-Dimethyl-3-phenyl-2,3,5,6-tetrahy-
dro oxazolo [3,2-a] pyrimidin-7-one 6a. (88%). [a]D20
ˆ162 (c 0.8, CHCl3). HRMS: calc for C14H16O2N2
1H1ˆ245.1290, obsˆ245.1290. NMR 1H (CDCl3,
250 MHz): 1.14 (d,3H, Jˆ6.6 Hz), 1.19 (d, 3H,
Jˆ6.6 Hz), 2.29 (quint, 1H, Jˆ6.6 Hz), 3.03 (quint, 1H,
Jˆ6.6 Hz), 4.33 (q, 1H, Jˆ6.3±8.9 Hz), 4.84 (t, 1H,
Jˆ8.9), 5.02 (q, 1H, Jˆ6.3±8.9 Hz), 7.31 (m, 5H). NMR
13C (CDCl3, 62.5 MHz): 14.8, 16.7, 40.9, 51.7, 60.2, 73.0,
126.8, 128.4, 129.5, 135.5, 165.9, 181.4.
2.2.3. (3S,5S)-5-Vinyl-3-phenyl-2,3,5,6-tetrahydro oxazolo
[3,2-a] pyrimidin-7-one 4c. (75%). NMR 1H (CDCl3,
250 MHz): 2.55 (dd, 1H, Jˆ5.7±16.0 Hz), 2.73 (dd, 1H,
Jˆ7.0±16.0 Hz), 3.80 (m, 1H), 4.90 (m, 1H), 4.92 (m,
1H), 5.03 (dd, 1H, Jˆ17.1±1.2 Hz), 5.28 (dd, 1H,
Jˆ10.0±1.2 Hz), 5.70 (m, 1H), 3.35 (m, 5H).
2.2.4. (3S,5R)-3,5-Diphenyl-2,3,5,6-tetrahydro oxazolo
[3,2-a] pyrimidin-7-one 4d. (81%). Mp: 908C [a]D20
ˆ196 (c 0.5, CHCl3). MS-CI/NH3: 293 (M1H1, 100).
NMR 1H (250 MHz, CDCl3): 2.67 (dd, 1H, Jˆ7.4±
16.2 Hz), 2.85 (dd, 1H, Jˆ7.1±16.2 Hz), 4.25 (dd, 1H,
Jˆ7.1±7.4 Hz), 4.40 (dd, 1H, Jˆ5.8±8.8 Hz), 4.59 (dd,
1H, Jˆ5.8±8.8 Hz), 4.80 (t, 1H, Jˆ8.8 Hz), 7.03 (m, 5H),
7.32 (m, 5H). NMR 13C (62.5 MHz, CDCl3): 37.6, 54.4,
60.7, 73.1, 126.8, 127.1, 129.1, 129.4, 129.6, 129.8, 135.4,
137.0, 167.7, 177.4.
2.3.2. (3S,5S,6S)-5-butyl-6-methyl-3-phenyl-2,3,5,6-
tetrahydro oxazolo [3,2-a] pyrimidin-7-one 6b. (96%).
[a]2D0ˆ195 (c 0.2, CHCl3). MS-CI/NH3: 287 (M1H1,
100). NMR 1H (CDCl3, 250 MHz): 0.81 (t, 3H,
Jˆ6.7 Hz), 1.08 (d, 3H, Jˆ7.2 Hz), 1.22 (m, 4H), 1.50
(m, 2H), 2.46 (qd, 1H, Jˆ3.5±7.2 Hz), 2.90 (m, 1H), 4.36
(dd, 1H, Jˆ6.9±8.9 Hz); 4.88 (t, 1H, Jˆ8.9 Hz), 5.01 (dd,
1H, Jˆ6.9±8.9 Hz), 7.32 (m, 5H). NMR 13C (CDCl3,
62.5 MHz): 13.6, 16.5, 22.4, 26.1, 29.8, 38.1, 55.6, 60.4,
73.1, 127.1, 129.4, 129.6, 135.4, 165.8, 182.0.
2.2.5. (3S)-3-Phenyl-2,3,5,6-tetrahydro oxazolo [3,2-a]
pyrimidin-7-one 4e. To a solution of 2 (1 g; 6.21 mmol)
in ethanol (60 mL) was added, at room temperature, methyl
acrylate (0.87 mL; 9.3 mmol). After 12 h at re¯ux, ethanol
was evaporated under reduced pressure and the residue is
chromatographed on silica gel (MeOH/EtOAc: 10/90) to
afford product 4e as a white solid (1.02 g; 4.71 mmol,
yield 76%). [a]2D0ˆ193 (c 0.6, CHCl3). Mp: 1838C. MS-
2.3.3. (3S,6S)-6-Methyl-3-phenyl-2,3,5,6-tetrahydro oxazolo
[3,2-a] pyrimidin-7-one 6e. (35%). [a]2D0ˆ160 (c 0.6, CHCl3).
HRMS: calc for C13H14O2N21H1ˆ231.1134, obsˆ231.1128.
NMR 1H (CDCl3, 250 MHz): 1.23 (d, 3H, Jˆ6.9 Hz), 2.84 (m,
1H), 2.88(dd, 1H, Jˆ9.2±11.7 Hz), 3.36(dd, 1H), 4.46(m, 1H,),
4.91 (m, 2H), 7.35 (m, 5H). NMR13C (CDCl3, 62.5M Hz): 14.6,
33.5, 45.5, 62.9, 73.5, 127.0, 129.6, 129.7, 135.3, 167.2, 181.4.
1
CI/NH3: 217 (M1H1, 100). NMR H (250 MHz, CDCl3):
2.3.4. (3S,5R,6R)-5,6-Dimethyl-3-phenyl-2,3,5,6-tetrahy-
dro oxazolo [3,2-a] pyrimidin-7-one 6f. (35%).
[a]2D0ˆ134 (c 0.2, CHCl3). MS-CI/NH3: 245 (M1H1,
100). NMR 1H (CDCl3, 250 MHz): 0.78 (d, 3H,
Jˆ7.2 Hz), 1.18 (d, 3H, Jˆ7.2 Hz), 2.27 (quint, 1H,
Jˆ7.2 Hz), 3.33 (quint, 1H, Jˆ7.2 Hz), 4.33 (m, 1H,),
4.84 (m, 2H,), 7.29 (m, 5H,). NMR 13C (CDCl3,
2.57 (t, 2H, Jˆ8.3 Hz), 3.16 (m, 1H), 3.27 (m, 1H), 4.33 (m,
1H), 4.86 (m, 2H), 7.33 (m, 5H). NMR 13C (62.5 MHz,
CDCl3): 29.4, 39.3, 63.2, 73.5, 127.0, 129.6, 129.8, 135.1,
168.3, 178.1.
2.2.6. (4R,40S)-4-(2-Imino-4-phenyl oxazolidin-3-yl)-pentan-

C. Agami et al. / Tetrahedron 57 (2001) 195±200
199
62.5 MHz): 14.6, 19.5, 42.3, 55.6, 63.5, 73.5, 127.2, 129.4,
129.7, 137.8, 167.3, 181.4.
137.2 (c0.3, H2O)]. Mp: 2108C. NMR 1H (D2O, 250 MHz):
1.26 (d, 3H, Jˆ6.9 Hz), 2.25 (dd, 1H, Jˆ8.4±16.6H), 2.39
(dd, 1H, Jˆ4.7±16.6 Hz), 3.40 (m, 1H). NMR 13C (CD3OD,
62.5 MHz): 18.7, 41.2, 46.6, 177.5.
2.4. General procedure for hydrogenolysis of
compounds 6
2.5.2. (2S,3S)-3-Amino-2-methylpropanoic acid 8b. (68%).
[a]D25ˆ111 (c 0.3, 1N HCl); [lit.19: [a]2D9ˆ111.6 (c1, 1N
To a solution of compound 6 (1 mmol) in ethanol (10 mL)
and under hydrogen atmosphere was added 0.75 equiv. of
Pd/C. The reaction mixture was stirred 6 h at room tempera-
ture and then ®ltered over celite and after evaporation
compounds 7 were obtained and used, without puri®cation,
for the next step.
1
HCl). H NMR (250 MHz, D2O): 1.15 (d, Jˆ7.3 Hz, 3H),
2.57 (m, 1H), 2.98 (dd, Jˆ12.8, 5.3 Hz, 1H), 3.08 (dd,
Jˆ12.8±8.4 Hz, 1H). 13C NMR (63 MHz, D2O): 14.0, 38.1,
41.3, 180.3.
2.5.3. (S)-3-Amino-2-methylheptanoic acid 8c. (81%).
[a]2D0ˆ112 (c 0.15, MeOH). NMR 1H (MeOD,
250 MHz): 1.03 (t, 3H, Jˆ7 Hz), 1.35 (d, 3H, Jˆ7 Hz),
1.46 (m, 4H), 1.73 (m, 2H), 2.72 (m, 1H), 3.44 (m, 1H).
NMR 13C (MeOD, 62.5 MHz): 12.7, 13.6, 22.8, 26.8, 30.0,
41.8, 53.2, 175.5.
2.4.1. (10R,6S)-6-Methyl-1-(10-phenyl ethyl) dihydro
pyrimidine-2,4-dione 7a. (93%). [a]2D0ˆ169 (c 0.5,
CHCl3). MS-CI/NH3: 250 (M1NH14 , 100). NMR 1H
(CDCl3, 250 MHz): 0.47 (d, 3H; Jˆ6.7 Hz), 1.45 (d, 3H,
Jˆ7.1 Hz), 2.24 (m, 1H), 2.55 (dd, 1H, Jˆ6.0±16.4 Hz),
3.52 (m, 1H), 5.70 (q, 1H, Jˆ7.1 Hz), 7.22 (m, 5H), 8.76
(ls, 1H). NMR 13C (CDCl3, 62.5 MHz): 16.5, 18.8, 38.8,
43.9, 51.5, 127.8, 127.9, 128.4, 139.2, 151.9, 169.8.
Acknowledgements
2.4.2. (10R,5S)-1-(10-Phenyl ethyl)-5-methyl dihydro
pyrimidine-2,4,dione 7b. (98%). [a]2D0ˆ190 (c 0.3,
CHCl3) HRMS: calc pour C13H16O2N21H1ˆ233.1290,
We thank Dr Louis Hamon for AM1 calculations and Mr
Alain Valleix for MS measurements.
1
obsˆ233.1287. NMR H (CDCl3, 250 MHz): 1.18 (d, 3H,
Jˆ7.0 Hz), 1.60 (d, 3H, Jˆ7.3 Hz), 2.48 (m, 1H), 3.02 (m,
2H), 5.83 (q, 1H, Jˆ7.3 Hz), 7.36 (m, 5H). NMR 13C
(CDCl3, 62.5 MHz): 12.6, 15.4, 35.2, 43.1, 51.3, 127.1,
127.8, 128.7, 139.6, 153.6, 172.5.
References
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2.4.3. (10S,5S,6S)-6-Butyl-5-methyl-1-(1-phenyl-ethyl)-
dihydro-pyrimidin-2,4-dione 7c. (95%). NMR 1H
(CDCl3, 250 MHz): 0.54 (t, 3H, Jˆ7.2 Hz), 1.21 (d, 3H,
Jˆ4.9 Hz), 1.50 (d, 3H, Jˆ7.1 Hz), 1.90 (m, 6H), 2.51
(m, 1H), 2.97 (m, 1H), 5.81 (q, 1H, Jˆ7.1 Hz), 7.36 (m,
5H). NMR 13C (CDCl3, 62.5 MHz): 15.1, 17.9, 18.2, 23.6,
29.5, 34.3, 40.5, 53.1, 56.8, 129.7,130.2, 140.9, 152.9,
175.0.
3. See for example: Spatola, A. F. In Chemistry and Biochemis-
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4. Juaristi, E. Enantioselective Synthesis of b-Amino Acids;
Wiley-VCH: New York, 1997.
5. (a) Hawkins, J. M.; Fu, G. C. J. Org. Chem. 1986, 51, 2820±
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2.4.4. (10S,6S)-6-Butyl-1-(1-phenyl-ethyl)-dihydro-pyri-
din-2,4-dione 7d. (95%). [a]2D0ˆ169 (c 0.5, CHCl3). MS-
CI/NH3: 292 (M1NH41, 100). NMR 1H (CDCl3, 250 MHz):
0.56 (t, 3H, Jˆ7.2 Hz), 0.86 (m, 4H), 1.12 (m, 2H), 1.52 (d,
3H, Jˆ7.2 Hz), 2.51 (m, 2H), 3.32 (m, 1H), 5.73 (q, 1H,
Jˆ7.2 Hz), 7.36 (m, 5H), 2.51 (ls, 1H). NMR 13C (CDCl3,
62.5 MHz): 14.0, 17.2, 22.4, 28.4, 32.5, 35.9, 49.0, 52.7,
128.6, 129.5, 139.6, 152.1, 169.9.
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2.5. General procedure for the hydrolysis of the
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A suspension of adduct 7 (180 mg, 0.870 mmol) in 10 mL
of 8N HCl was heated at re¯ux for 96 h. The aqueous phase
was concentrated at reduced pressure and the amino acid
hydrochloride was adsorbed to acidic ion exchange resin
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2.5.1. (S)-3-Aminobutanoic acid 8a. (61%): [a]2D0ˆ134 (c
0.6, H2O); [lit.7a: [a]D28ˆ132.2 (c0.9, H2O); lit.18: [a]2D3ˆ
13. AM1 calculations were performed using the ampac version

200
C. Agami et al. / Tetrahedron 57 (2001) 195±200
2.14 package. The geometry of the enolate intermediate was 15. Agami, C.; Dechoux, L.; Melaimi, M. Org. Lett. 2000, 2, 633±
optimized by using the Davidson±Fletcher±Powell algorithm
(FLEPO procedure), minimising the energy with respect to all
internal coordinates. Further re®nement by minimizing the
energy gradient (NLLSQ procedure) gives no improvement
in energies with insigni®cant differences in geometrical para-
meters.
634.
16. Rachina, V.; Blagoeva, I. Synthesis 1982, 967±968.
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(c 0.6, H2O); [lit.7a: [a]D28ˆ132.2 (c 0.9, H2O); lit.19:
[a]2D3ˆ137.2 (c 0.3, H2O)].
18. Selected data for ent-8b: [a]2D5ˆ210 (c 0.35, 1N HCl); [lit.20:
[a]2D9ˆ211.8 (c 1,1, 1N HCl).
14. Similar electronic effect on the facial alkylation of the p CvC
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Â
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