Enantioselective synthesis of β-amino acids. Part 11: Diastereoselective alkylation of chiral derivatives of β-aminopropionic acid containing the α-phenethyl group

Article abstract of DOI:10.1016/S0040-4020(01)00540-3

Several novel, chiral derivatives of β-aminopropionic acid were studied as potentially useful precursors of enantiopure α-substituted-β-amino acids. In particular, the diastereoselectivity of alkylation of (R,R)-2-Li enolate showed substantial stereoinduction by the bis[α-phenylethyl]amide auxiliary, leading to 80% ds in the methylation reaction. No appreciable effect upon diastereoselectivity was observed by the presence of additives (LiCl, HMPA, DMPU) in the reaction. On the other hand, stereoinduction by the α-phenylethylamino group in the methylation of ester enolate (S)-3-Li was lower (65% ds) under standard conditions (THF, -78°C) but improved to 81% ds in the presence of 3 equiv. of HMPA as cosolvent. 'Matched' and 'mismatched' derivatives, (R,R,S)-11 and (R,R,R)-11, respectively, were methylated via their corresponding lithium enolates. Observed diastereoselectivities generally followed the anticipated tendencies based on double stereoinduction. Thus diastereoselectivity reached 89% ds in the methylation of the matched isomer, (R,R,S)-11-Li.

Full text of DOI:10.1016/S0040-4020(01)00540-3

TETRAHEDRON
Pergamon
Tetrahedron 57 .2001) 6487±6496
Enantioselective synthesis of b-amino acids. Part 11:
Diastereoselective alkylation of chiral derivatives of
b-aminopropionic acid containing the a-phenethyl groupq
   Â
Võctor Manuel Gutierrez-Garcõa, Heraclio Lopez-Ruiz, Gloria Reyes-Rangel
and Eusebio Juaristip
  Â
Departamento de Quõmica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional,
Â
Apartado Postal 14-740, 07000 Mexico, DF, Mexico
Received 30 January 2001; revised 23 February 2001; accepted 2 March 2001
AbstractÐSeveral novel, chiral derivatives of b-aminopropionic acid were studied as potentially useful precursors of enantiopure a-substi-
tuted-b-amino acids. In particular, the diastereoselectivity of alkylation of .R,R)-2-Li enolate showed substantial stereoinduction by the
bis[a-phenylethyl]amide auxiliary, leading to 80% ds in the methylation reaction. No appreciable effect upon diastereoselectivity was
observed by the presence of additives .LiCl, HMPA, DMPU) in the reaction. On the other hand, stereoinduction by the a-phenylethylamino
group in the methylation of ester enolate .S)-3-Li was lower .65% ds) under standard conditions .THF, 2788C) but improved to 81% ds in the
presence of 3 equiv. of HMPA as cosolvent. `Matched' and `mismatched' derivatives, .R,R,S)-11 and .R,R,R)-11, respectively, were
methylated via their corresponding lithium enolates. Observed diastereoselectivities generally followed the anticipated tendencies based
on double stereoinduction. Thus diastereoselectivity reached 89% ds in the methylation of the matched isomer, .R,R,S)-11-Li. q 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
out, the groups of Lavielle8 and Lum9 described concep-
tually related studies with compounds M and N .Chart 1).10
The great importance of amino acids in physiological and
pharmacological events is well known. Furthermore, bio-
logical interactions are usually stereospeci®c2 and this has
led during the last two decades to an unprecedented amount
of research work directed to the enantioselective synthesis
of amino acids.3,4
2. Results and discussion
2.1. Stereoselectivity of alkylation of %R,R)-2
Chiral substrate .R,R)-2 was obtained in 44% overall yield
from b-alanine, following the synthetic route shown in
Scheme 2. Protection of the amino group with benzyl
chloroformate .CbzCl) was followed by treatment with
thionyl chloride to afford the corresponding acid chloride,
which was added to bis[.R)-a-phenylethyl]amine to give
chiral amide .R,R)-4, accompanied with varying amounts
of chiral dipeptide .R,R)-5.
Among the various methods developed for the preparation
of enantioenriched a-amino acids, those employing chiral
glycine derivatives5 .Fig. 1) have been particularly success-
ful. In this regard, chiral glycinamide .S,S)-1, incorporating
a-phenylethylamine as chiral auxiliary,6 was recently used
as convenient starting material for the preparation of
enantiopure a-substituted a-amino acids.7 .Scheme 1).
Our attention turned then to the potential of chiral deriva-
tives of b-aminopropionic acid, such as .R,R)-2 and .S)-3, as
precursors for the asymmetric synthesis of a-substituted
b-amino acids .Chart 1). While this work was being carried
q For Part 10, see Ref. 1.
N-Alkylation of .R,R)-4 with benzyl bromide proceeded
then in 81% yield to afford the desired chiral b-alanine
derivative .R,R)-2. .Scheme 2).
Keywords: alkylation; asymmetric induction; amino acids and derivatives;
diastereoselection; enolates; solvent effects.
p
Corresponding author. Tel.: 1525-747-3722; fax: 1525-747-7113;
e-mail: juaristi@relaq.mx
Alkylation of chiral amide .R,R)-2 was accomplished via
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020.01)00540-3

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V. M. Gutierrez-Garcõa et al. / Tetrahedron 57 12001) 6487±6496
6488
Figure 1. Pˆprotecting group; MOMˆmethoxymethyl.
Scheme 1.
enolate formation with lithium hexamethyldisilylamide
.LiHMDS) in the presence of the electrophile, in order to
minimize b-elimination reaction. Results are summarized in
Table 1.
Entries 1 and 5 in Table 1 show that under standard con-
ditions .THF, 2788C) the methylation reaction proceeds
with 4:1 diastereoselectivity, whereas the benzylation reac-
tion affords a 2:1 diastereomeric ratio of the products. In
contrast with alkylation reactions of chiral glycine deriva-
tive .S,S)-1, which are greatly in¯uenced by the presence of
Chart 1.

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V. M. Gutierrez-Garcõa et al. / Tetrahedron 57 12001) 6487±6496
6489
Table 1. Diastereoselectivity of enolate .R,R)-2-Li alkylations
hydrolysis to the known b-amino acid .R)-a-methyl-b-
alanine, .R)-811 .Scheme 3).
The stereochemical outcome of the alkylation reaction of
.R,R)-2 may be understood in terms of intermediate R in
Scheme 4. The Z-con®gurated enolate is anticipated to mini-
mize steric hindrance with the methylenic segment, and the
depicted conformation of the a-phenylethyl groups should
be favored by allylic A1,3 strain considerations.13 Therefore,
the phenyl and the methyl groups at the stereogenic centers
differentiate the prochiral CvC group, so that addition of
electrophile from the side of the less bulky methyl groups is
preferred .Scheme 4).
Entry
RX
CH3I
CH3I
CH3I
CH3I
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
Additive
dra
Yield .%)
1
2
3
4
5
6
7
8
±
80:20
79:21
76:24
80:20
66:34
67:33
56:44
60:40
65
60
65
49
50
28
50
43
LiClb
DMPUc
HMPAd
±
LiClb
DMPUc
HMPAd
2.2. Stereoselectivity of alkylation of %S)-3
Conjugate addition of .S)-a-phenylethylamine to methyl
acrylate proceeded in quantitative yield .CH3OH, re¯ux,
3 h) to give chiral ester .S)-9, which was N-benzylated in
86% yield .Scheme 5).
a
Diastereomeric ratio.
Lithium chloride, 6 equiv.
N,N-Dimethylpropylene urea, 6 equiv.
Hexamethylphosphoramide, 1 equiv.
b
c
d
LiCl salt or DMPU as cosolvent,6 the diastereoselectivity of
the alkylation reaction of chiral b-alanine derivative .R,R)-2
is essentially unaffected after incorporation of LiCl .entries
2 and 6 in Table 1) or polar aprotic solvents DMPU and
HMPA .entries 3,4,7, and 8 in Table 1).
Alkylation of chiral ester .S)-3 was accomplished via
enolate formation in THF solvent, with LiHMDS as the
base. Table 2 summarizes the results observed in the methyl-
ation reaction of .S)-3 with iodomethane.
In the absence of additives .THF solvent, 2788C; entry 1 in
Table 2), the methylation of enolate .S)-3-Li afforded a 2:1
mixture of the diastereomeric products 10, in 68% yield.
Nevertheless, both the diastereoselectivity and yield of the
reaction improved in the presence of HMPA or DMPU as
The absolute con®guration of the newly created stereogenic
center in the major diastereomeric product of methylation of
.R,R)-211 was ascertained by hydrogenolytic removal of the
N-benzyl and N-Cbz protecting groups, followed by acid
Scheme 2.
Scheme 3.

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V. M. Gutierrez-Garcõa et al. / Tetrahedron 57 12001) 6487±6496
6490
Scheme 4.
On the other hand, addition of `inert salt' lithium
chloride had a deleterious effect, both on diastereo-
selectivity and yield .entry 8 in Table 2). It is expected
that empirical observations on additive effects such as
those reported here will be understood when knowledge of
structure and aggregation state of Li enolates is more
advanced.14,15
The diastereomeric ratios reported in Table 2 were deter-
mined by integration of the 1H NMR spectra of crude
products 10, and the assignment of the con®guration at
the newly created center of chirality was established by
chemical correlation with known .R)-8 .Scheme 6).
Scheme 5.
In order to rationalize the observed stereoinduction by the
chiral a-phenylethyl auxiliary in enolate .S)-3-Li ..S)-
con®gurated auxiliary induces electrophile addition to the
Re face of the prochiral double bond; i.e. unlike stereo-
induction16), we resorted to molecular modeling studies by
means of PM3 semiempirical calculations.17 Fig. 2 presents
the conformation of minimum energy calculated for enolate
.S)-3-Li. Salient features are the `parallel' orientation of the
two phenyl rings, suggesting perhaps a p±p attractive inter-
action,18 and the steric hindrance that should inhibit electro-
philic addition on the Si face of the enolate. According to
this model, easier addition of the electrophile will lead
preferentially to the diastereomeric product of .S,R) con-
®gurationÐas experimentally observed.
Table 2. Diastereoselectivity of enolate .S)-3-Li methylation with iodo-
methane
Entry
Additive
dra
Yield .%)
1
2
3
4
5
6
7
8
±
65:35
72:28
81:19
70:30
71:29
77:23
75:25
60:40
68
77
87
95
68
91
95
64
1 equiv. HMPAb
3 equiv. HMPAb
6 equiv. HMPAb
1 equiv. DMPUc
3 equiv. DMPUc
6 equiv. DMPUc
6 equiv. LiCl
2.3. Double stereoinduction in the alkylation of %R,R,S)-
10, a derivative of b-alanine containing two chiral
auxiliaries
a
Diastereomeric ratio.
Hexamethylphosphoramide.
N,N-Dimethylpropylene urea.
b
c
Considering that stereoinduction in enolate .R,R)-2-Li
.Section 2.1) is of like stereoinduction .i.e. R-con®gurated
auxiliary favors reaction on the Re face16), whereas stereo-
induction in enolate .S)-3-Li .Section 2.2) corresponds to
unlike stereoinduction .i.e. S-con®gurated auxiliary favors
addition to the Re face16), we deemed it of interest to
determine the diastereoselectivity of alkylation reactions
in enolate .R,R,S)-11-Li .Scheme 7). According to
cosolvent. Best results were recorded when three molar
equivalents of these polar aprotic solvents were used
.entries 3 and 6 in Table 2), with diastereomeric product
ratios reaching 4:1, and chemical yields approaching the
90±95% range.
Scheme 6.

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V. M. Gutierrez-Garcõa et al. / Tetrahedron 57 12001) 6487±6496
6491
Table 3. Diastereoselectivity of enolate .R,R,S)-11-Li methylation
Entry
Additive
dra
Yield .%)
1
2
±
75:25
89:11
73
73
HMPAb
a
Diastereomeric ratio.
Hexamethylphosphoramide, 3 equiv.
b
methylation of .S)-3 .compare entry 1 in Table 3 with entry
1 in Tables 1 and 2).
As anticipated from the HMPA effect described in Section
2.2 .cf. entries 1 and 3 in Table 2), the diastereoselectivity in
the methylation of .R,R,S)-11-Li increased to 89:11 in the
presence of 3 equiv. of HMPA. That the major diastereo-
isomer corresponds to the product with .R) con®guration at
the newly created center of chirality was established by
Figure 2. Conformation of minimum energy calculated for enolate .S)-3-Li
by means of HyperChem's pm3 semiempirical program.17
Scheme 7.
Masamune's theory,19 this should be the `matched' combi-
nation of chiral auxiliaries, whereas an all .R)- or .S)-
con®gurated enolate would correspond to a `mismatched'
pair of auxiliaries.20
chemical correlation with .R)-2-methyl-3-aminopropionic
acid.
In the case of the methylation reaction of the mismatched
combination of chiral auxiliaries in .R,R,R)-11, the observed
The preparation of .R,R,S)-11 was accomplished according
to the route delineated in Scheme 7. Acryloyl chloride was
treated with bis[.R)-a-phenylethyl]amine to afford chiral
acrylamide .R,R)-12, which was the substrate for
conjugate addition of .S)-a-phenethylamine, providing
amide .R,R,S)-13 in 91% overall yield. Finally, N-benzyl-
ation afforded the desired substrate, .R,R,S)-11 in 94%
yield. .Scheme 7).
Table 4. Diastereoselectivity of enolate .R,R,R)-11-Li methylation
Entry
Additive
dra
Yield .%)
In the event, methylation of .R,R,S)-11 was accomplished
with n-BuLi as the base for enolate formation. The dia-
stereoselectivity observed in the absence of additive was
75:25, slightly lower than that found in the methylation of
.R,R)-2, but signi®cantly higher than that observed in the
1
2
±
66:34
36:64
89
47
HMPAb
a
Diastereomeric ratio.
Hexamethylphosphoramide, 3 equiv.
b

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V. M. Gutierrez-Garcõa et al. / Tetrahedron 57 12001) 6487±6496
6492
diastereoselectivity in the absence of additives was 66:34
.see entry 1 in Table 4), which is signi®cantly lower than the
one observed in the methylation of .R,R)-2-Li .see entry 1 in
Table 1). Interestingly, in the presence of 3 equiv. of
HMPA, stereoinduction in the methylation of .R,R,R)-11
is now dominated by the .R)-a-phenylethylamino auxiliary,
so that the product of .S) con®guration at C.2) is pre-
dominant .36:64 dr; see entry 2 in Table 4). In congruence
with Masamune's principle of double stereoinduction,19 this
diastereoselectivity is lower than that encountered in the
methylation of .S)-3-Li .entry 3 in Table 2).
temperature for 14 h. The solvent was removed in the rotary
evaporator and redissolved in diethyl ether, dried over anh.
Na2SO4, ®ltered, and concentrated to give an oil that was
puri®ed by ¯ash chromatography .hexane±EtOAc,
28
9:1!7:3) to afford 0.6 g .62% yield) of .R,R)-4, [a]D
ˆ
1111.5 .cˆ1, CHCl3). 1H NMR .DMSO-d6, 300 MHz,
1008C)26 d 1.70.d, Jˆ7.1 Hz, 3H), 1.71 .d, Jˆ7.1 Hz,
3H), 2.35±2.46 .m, 1H), 2.57±2.68 .m, 1H), 3.26±3.37
.b, 2H), 5.06 .,s, 2H), 5.13 .q, Jˆ7.1 Hz, 2H), 6.55±6.63
.b, 1H), 7.10±7.23 .m, 10H), 7.27±7.42 .m, 5H). 13C NMR
.DMSO-d6, 75 MHz, 10 08C) d 19.5, 36.2, 38.4, 54.0, 66.3,
127.5, 128.1, 128.3, 128.4, 128.6, 129.1, 138.2, 142.3,
156.8, 171.5. HRMS calcd for C27H30N2O3 .M111):
431.2335. Found: 431.2354.
3. Experimental
3.1. General
3.1.2. %R,R)-N0,N0-Bis%10-phenylethyl)-N-%N00-carbobenzyl-
oxyaminopropionyl)-N-carbobenzyloxypropionamide
[%R,R)-5]. This dipeptide was obtained as side product in the
Flasks, stirring bars, and hypodermic needles used for the
generation and reactions of organolithiums were dried for
ca. 12 h at 1208C and allowed to cool in a desiccator over
anhydrous CaSO4. Anhydrous solvents were obtained by
distillation from benzophenone ketyl.21 The n-butyllithium
employed was titrated according to the method of Juaristi
et al.22
28
1
preparation of .R,R)-4. [a]D ˆ182.6 .cˆ1, CHCl3). H
NMR .DMSO-d6, 400 MHz, 1008C) d 1.65 .d, Jˆ7.3 Hz,
6H), 2.46 .ddd < quintet, J1ˆ15.5 Hz, J2ˆ7.7 Hz, J3ˆ
7.6 Hz, 1H), 2.64 .ddd<quintet, J1ˆ15.5 Hz, J2ˆJ3ˆ
7.6 Hz, 1H), 3.03 .t, Jˆ6.8 Hz, 2H), 3.35 .dt, J1ˆJ2ˆ
6.6 Hz, 2H), 3.94 .dd, J1ˆJ2ˆ7.5 Hz, 2H), 5.01±5.18 .m,
4H), 5.21 .d, Jˆ12.5 Hz, 1H), 5.25 .d, Jˆ12.5 Hz, 1H), 6.78
.b, 1H), 7.06±7.55 .m, 20H). 13C NMR .DMSO-d6,
100 MHz, 1008C) d 19.0, 34.4, 37.4, 38.6, 41.5, 53.5,
53.5, 65.9, 68.6, 127.1, 127.8, 128.0, 128.1, 128.2,
128.2, 128.4, 128.7, 128.9, 136.0, 137.8, 141.8, 154.3,
156.5, 170.4, 173.8. MS .15 eV) m/z 636 .M111), 530,
422, 303, 259, 210, 120, 91. HRMS calcd for
C38H42N3O6:636.3074. Found: 636.3074.
TLC: Merck-DC-F254 plates, detection by UV light. Flash
column chromatography:23 Merck silica gel .0.040±
0.063 mm). Melting points: Mel Temp apparatus, not
1
corrected. H NMR spectra: Jeol Eclipse-400 .400 MHz),
Bruker Ultra Shield .300 MHz), and Jeol GSX-270
.270MHz) spectrometers. 13C NMR spectra: Jeol Eclipse-
400 .100 MHz), Bruker Ultra Shield .75 MHz), and Jeol
GSX-270.67.5 MHz). Chemical shifts . d) in ppm down-
®eld from internal TMS reference; the coupling constants
.J) are given in Hz. High-resolution mass spectra .HRMS)
3.1.3. %R,R)-N0,N0-Bis%10-phenylethyl)-N-benzyl-N-carbo-
benzyloxypropionamide [%R,R)-2]. To a suspension of
0.58 g .5.1 mmol) of 35% potassium hydride in 40 mL
of dry THF under nitrogen, was added 2.0g .4.6 mmol) of
chiral amide .R,R)-4 in 60mL of THF, at 0 8C. The resulting
mixture was treated with 0.6 mL .5.1 mmol) of benzyl bro-
mide .dropwise addition, still at 08C), the cooling bath was
removed, and the reaction mixture was stirred at ambient
temperature for 24 h. Work-up involved the addition of
15.0mL of saturated aqueous NaCl solution, and extraction
with three 20-mL portions of CH2Cl2. The combined
organic extracts were dried over anh. Na2SO4, ®ltered, and
concentrated in a rotary evaporator to give the crude
product, which was puri®ed by ¯ash chromatography
.hexane±EtOAc, 9:1). The pure product .1.96 g, 81%
 Â
were obtained at Instituto de Quõmica, UNAM, Mexico.
3.1.1. %R,R)-N0,N0-Bis%10-phenylethyl)-N-carbobenzyloxy-
propionamide [%R,R)-4]. A solution containing 10.0 g
.112.0mmol) of b-aminopropionic acid in 112.0mL of
1N NaOH was cooled in an ice bath and treated with
17.6 mL .21.0g, 0.12 mol) of benzylchloroformate,
followed by slow addition of 112.0mL of 1N NaOH. The
resulting mixture was allowed to warm up to ambient
temperature and stirred overnight. The crude product was
extracted with three 100 mL portions of diethyl ether, and
the aqueous phase was acidi®ed with 6N HCl to pH,4.0.
The precipitate that developed was dissolved in CH2Cl2,
dried over anh. Na2SO4 and concentrated in the rotary
evaporator. Recrystallization of the resulting residue from
ethyl acetate±ethanol .10:1) afforded 21.5 g .86%) of
the desired product .N-carbobenzyloxy-3-aminopropionic
acid), mp 103±1048C .lit.24 mp 103±1058C). This crystal-
line material .0.5 g, 2.2 mmol) was dissolved in 6.0 mL of
CH2Cl2 and three drops of dimethylformamide. The result-
ing solution was treated with 0.65 mL .9.0 mmol) of thionyl
chloride, and heated to re¯ux for 4 h. The solvent was
removed in the rotary evaporator and the residue was
washed three times with toluene, and then was redissolved
in 4.0mL of CH 2Cl2, and added to a solution of 1.0g
.4.4 mmol) of .R,R)-N,N-bis-.1-phenylethyl)amine25 in
4.0mL of toluene, under nitrogen at 0 8C. The reaction
mixture was allowed to warm up and stirred at ambient
28
1
yield) presented [a]D ˆ186.1 .cˆ1, CHCl3). H NMR
.DMSO-d6, 400 MHz, 1008C26) d 1.65 .d, Jˆ7.0Hz, 6H),
2.38 .ddd, J1ˆ14.8 Hz, J2ˆ8.2 Hz, J3ˆ6.4 Hz, 1H), 2.60
.ddd, J1ˆ14.8 Hz, J2ˆ8.2 Hz, J3ˆ6.4 Hz, 1H), 3.46 .ddd,
J1ˆ14.1 Hz, J2ˆ8.2 Hz, J3ˆ6.0Hz, 1H), 3.56 .ddd, J1ˆ
14.1 Hz, J2ˆ8.2 Hz, J3ˆ6.0Hz, 1H), 4.39 .d, Jˆ15.5 Hz,
1H), 4.48 .d, Jˆ15.5 Hz, 1H), 5.03±5.13 .b, 2H), 5.14 .s,
2H), 7.06±7.36 .m, 20H). 13C NMR .DMSO-d6, 100 MHz,
1008C) d 19.0, 34.7, 44.4, 51.1, 53.4, 67.0, 127.2, 127.5, 127.7,
128.0, 128.2, 128.3, 128.7, 128.8, 137.5, 138.7, 141.9, 156.1,
170.8. MS .70 eV) m/z 520.M 1), 415, 296, 181, 91. HRMS
calcd for C34H36N2O3 .M111): 521.2804. Found: 521.2816.
3.1.4. Methyl %S)-3-N-%10-phenylethyl)amino propionate
[%S)-9]. In a 100-mL round-bottom ¯ask ®tted with

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6493
condenser and magnetic stirrer, was placed 1.0g
.11.6 mmol) of methyl acrylate, 1.4 g .11.6 mmol) of .S)-
a-phenylethylamine and 30mL of methanol. The reaction
mixture was heated to re¯ux for 3 h, and then the solvent
was removed in a rotary evaporator. The desired product
.2.4 g, quantitative yield) was obtained as a colorless oil,
Jˆ15.7 Hz, 1H), 5.00±5.10 .m, 2H), 5.11 .s, 2H), 6.98±
7.35 .m, 20H). 13C NMR .DMSO-d6, 75 MHz, 10 08C) d
17.0, 19.8, 37.3, 51.3, 51.7, 54.2, 67.4, 127.5, 127.8,
128.0, 128.0, 128.4, 128.6, 128.6, 129.1, 129.2, 137.8,
138.9, 142.1, 156.8, 175.4. MS .20eV) m/z 534 .M1),
429, 385, 310, 181, 91. HRMS calcd for C35H38N2O3
.M111): 535.2961. Found: 535.2957.
[a]D ˆ242.0. cˆ1, CHCl3). 1H NMR .CDCl3, 400 MHz)
28
d 1.34 .d, Jˆ6.6 Hz, 3H), 2.47 .t, Jˆ6.6 Hz, 2H), 2.71 .m,
2H), 3.66 .s, 3H), 3.77 .q, Jˆ6.6 Hz, 1H), 7.30.b, 1H), 7.33
.m, 5H). 13C NMR .CDCl3, 100 MHz) d 24.5, 34.7, 42.9,
51.5, 58.2, 126.6, 126.9, 128.4, 145.5, 173.3. HRMS calcd
for C12H18NO2: 208.1338. Found: 208.1334.
3.2.2. %R,R)-N0,N0-Bis%10-phenylethyl)-N-benzyl-N-carbo-
benzyloxy-%2S)-2-methylpropionamide [%R,R,S)-6]. This
corresponds to the minor product of methylation of .R,R)-
28
2-Li .see Section 2.1 and Table 1). [a]D ˆ1181.0. cˆ1,
1
CHCl3). H NMR .DMSO-d6, 300 MHz, 1008C) d 0.65 .d,
Jˆ6.6 Hz, 3H), 1.68 .d, Jˆ7.1 Hz, 6H), 3.09 .ddd, J1ˆ
13.5 Hz, J2ˆ6.8 Hz, J3ˆ6.8 Hz, 1H), 3.25±3.40.m, 2H),
4.11 .d, Jˆ15.7 Hz, 1H), 4.54 .d, Jˆ15.7 Hz, 1H), 5.14
.d, J1ˆ12.6 Hz, 1H), 5.20.d, Jˆ12.6 Hz, 1H), 7.02±7.37
.m, 20H). 13C NMR .DMSO-d6, 75 MHz, 1008C) d 15.9,
19.3, 38.1, 51.9, 52.0, 53.7, 67.5, 127.6, 127.8, 128.0,
128.3, 128.4, 128.6, 129.1, 129.2, 137.7, 138.9, 142.2,
156.9, 175.6. MS .15 eV) m/z 534 .M1), 429, 385, 310,
181, 91.
3.1.5. Methyl %S)-3-[N-benzyl-N-%10-phenylethyl)]-amino-
propionate [%S)-3]. In a 100 mL round-bottom ¯ask ®tted
with a calcium chloride trap and magnetic stirrer was placed
5.3 g .25.6 mmol) of .S)-9, 50mL of CH 2Cl2, and 3.5 g
.25.6 mmol) of potassium carbonate in 20mL of water.
The ¯ask was submerged in an ice bath before the additon
of 4.4 g .25.6 mmol) of benzyl bromide, and then the reac-
tion mixture was stirred at ambient temperature overnight.
The solvents were removed at reduced pressure, the residue
was suspended in 15 mL of water, and the product was
extracted with three 50-mL portions of CH2Cl2. The organic
phase was dried over anh. Na2SO4, ®ltered, and concen-
trated to give the crude product, which was puri®ed by
3.2.3. %R,R)-N0,N0-Bis%10-phenylethyl)-N-benzyl-N-carbo-
benzyloxy-%2R)-2-benzylpropionamide [%R,R,R)-7]. This
corresponds to the major product of benzylation of .R,R)-
28
¯ash chromatography .hexane±EtOAc, 9:1) to provide
2-Li .see Section 2.1 and Table 1). [a]D ˆ119.7 .cˆ1,
28
1
CHCl3). H NMR .DMSO-d6, 300 MHz, 1008C26) d 1.53
5.7 g .89% yield) of .S)-3 as a colorless oil, [a]D
ˆ
1
.b, 3H), 1.70.b, 3H), 2.66 .dd, J1ˆ13.2 Hz, J2ˆ4.6 Hz,
1H), 2.95 .dd, J1ˆ13.2 Hz, J2ˆ9.1 Hz, 1H), 3.37 .dd,
J1ˆ13.8 Hz, J2ˆ7.5 Hz, 1H), 3.54 .dd, J1ˆ13.8 Hz, J2ˆ
6.4 Hz, 1H), 3.61±3.72 .m, 1H), 4.39 .d, Jˆ15.6 Hz, 1H),
4.45±4.61 .b, 1H), 4.66 .d, Jˆ15.6 Hz, 1H), 4.98±5.25 .m,
3H), 6.66±7.39 .m, 25H). 13C NMR .DMSO-d6, 75 MHz,
1008C) d 19.2, 19.7, 37.4, 44.8, 51.2, 52.4, 54.2, 55.7,
67.7, 126.6, 126.9, 128.0, 128.2, 128.4, 128.6, 128.7,
129.1, 129.1, 129.3, 130.0, 137.6, 138.8, 140.1, 156.9,
173.4. MS .20eV) m/z 610.M 1), 505, 461, 386, 371, 91.
HRMS calcd for C41H42N2O3 .M111): 611.3274. Found:
611.3264.
232.8 .cˆ1, CHCl3). H NMR .CDCl3, 400 MHz) d 1.42
.d, Jˆ6.6 Hz, 3H), 2.46 .t, Jˆ7.0Hz, 2H), 2.74 .m, 1H),
2.96 .m, 1H), 3.56 .d, Jˆ13.9 Hz, 1H), 3.64 .d, Jˆ13.9 Hz,
1H), 3.63 .s, 3H), 3.92 .q, Jˆ6.6 Hz, 1H), 7.24±7.39 .m,
10H). 13C NMR .CDCl3, 100 MHz) d 15.3, 33.3, 45.5, 51.4,
54.4, 58.1, 126.8, 127.9, 128.1, 128.2, 128.6, 140.3, 143.3,
173.1. HRMS calcd for C19H24NO2: 298.1807. Found:
298.1811.
3.2. General procedure for the reaction of b-alanin-
amide enolate [%R,R)-2-Li] with electrophiles
A solution of 0.2 g .0.38 mmol) of chiral amide .R,R)-2,
1.1 equiv. of alkylating agent, and the proper amount of
additive .HMPA, DMPU, or LiCl; see Table 1) in 10mL
of THF was cooled to 2788C and kept under nitrogen
atmosphere before the addition of 0.42 mL of 1.0 M
LiHMDS .1.1 equiv.). The reaction mixture was stirred at
2788C for 3 h, and then at ambient temperature for 0.5
additional hours. The reaction was quenched by the addition
of 3 mL satd. aqueous NH4Cl solution. The product was
extracted with three 15-mL portions of EtOAc, the
combined organic extracts were dried over anh. Na2SO4,
®ltered, and concentrated. Final puri®cation and simul-
taneous separation of diastereomeric products was
accomplished by ¯ash chromatography .hexane±EtOAc,
11:1).
3.2.4. %R,R)-N0,N0-Bis%10-phenylethyl)-N-benzyl-N-carbo-
benzyloxy-%2S)-2-benzylpropionamide [%R,R,S)-7]. This
corresponds to the minor product of benzylation of .R,R)-
28
2-Li .see Section 2.1 and Table 1). [a]D ˆ1174.4 .cˆ1,
1
CHCl3). H NMR .DMSO-d6, 300 MHz, 1008C) d 1.11±
1.28 .b, 3H), 1.55±1.75 .b, 3H), 2.56±2.74 .m, 2H), 3.36
.dd, J1ˆ13.6 Hz, J2ˆ8.4 Hz, 1H), 3.44±3.55 .m, 1H), 3.55±
3.64 .b, 1H), 3.92 .d, Jˆ15.7 Hz, 1H), 4.49 .d, Jˆ15.7 Hz,
1H), 4.72±4.85 .b, 1H), 4.93±5.07 .b, 1H), 5.11 .d, Jˆ
12.5 Hz, 1H), 6.93±7.37 .m, 25H). 13C NMR .DMSO-d6,
75 MHz, 1008C) d 18.8, 19.0, 38.0, 44.6, 50.8, 51.9, 54.1,
55.3, 67.6, 127.0, 127.8, 128.0, 128.5, 128.6, 128.7, 129.0,
129.1, 129.2, 130.0, 137.6, 138.8, 139.6, 141.3, 142.6,
156.8, 174.0. MS .15 eV) m/z 610.M 1), 505, 461, 386,
371, 91.
3.2.1. %R,R)-N0,N0-Bis%10-phenylethyl)-N-benzyl-N-carbo-
benzyloxy-%2R)-2-methylpropionamide [%R,R,R)-6]. This
corresponds to the major product of methylation of .R,R)-2-
3.2.5. %R)-2-Methyl-3-aminopropionic acid [%R)-8]. In a
250 mL hydrogenation ¯ask was placed 0.46 g .0.86
mmol) of .R,R,R)-6, 0.05 g of 20% Pd.OH)2 over charcoal,
and 25 mL of ethanol containing ®ve drops of acetic acid.
The ¯ask was pressurized to 33 atm of H2 and heated with
stirring to 658C for 12 h. The reaction mixture was ®ltered
28
Li .see Section 2.1 and Table 1). [a]D ˆ221.2 .cˆ1,
1
CHCl3). H NMR .DMSO-d6, 300 MHz, 1008C26) d 1.06
.d, Jˆ6.4 Hz, 3H), 1.66 .d, Jˆ7.0Hz, 6H), 3.10±3.25 .m,
2H), 3.37±3.50.m, 1H), 4.13 .d, Jˆ15.7 Hz, 1H), 4.48 .d,

 Â
V. M. Gutierrez-Garcõa et al. / Tetrahedron 57 12001) 6487±6496
6494
over Celite and concentrated in a rotary evaporator to afford
the deprotected amine in quantitative yield .0.27 g). This
product was transferred to a glass ampoule and dissolved
in 7.0mL of 6N HCl and heated to 90 8C for 12 h. The crude
product was washed with three 20-mL portions of CH2Cl2,
the aqueous phase was concentrated, and the residue was
adsorbed to acidic ion exchange resin Dowex 50W X4. The
resin was washed with distilled water until the washings
came out neutral, and then the free amino acid was
recovered with 0.1N aqueous NH4OH. Evaporation afforded
0.07 g .79% yield) of the chiral b-amino acid .R)-8.
was puri®ed by ¯ash chromatography .hexane±EtOAc,
8.5:1.5) to give 4.3 g .93% yield) of .R,R)-12 as a colorless
oil, [a]D ˆ1215.0. cˆ1, CHCl3). 1H NMR .CDCl3,
28
400 MHz) d 1.75 .s, 6H), 4.72±5.03 .b, 1H), 5.42 .dd,
J1ˆ10.3 Hz, J2ˆ2.2 Hz, 1H), 5.83±6.08 .b, 1H), 6.12 .dd,
J1ˆ16.8 Hz, J2ˆ10.3 Hz, 1H), 6.29 .dd, J1ˆ16.5 Hz, J2ˆ
2.2 Hz, 1H), 6.80±7.50 .m, 10H). 13C NMR .CDCl3,
100 MHz) d 17.6, 20.7, 52.5, 126.9, 127.3, 128.3, 130.6,
141.1, 166.8. MS .70eV) m/z 279 .M1), 174, 120, 106,
77. Anal. calcd for C19H21NO: C, 81.68; H, 7.58. Found:
C, 81.81; H, 7.81.
28
28
[a]D ˆ210.8 .cˆ1.3, 1N HCl), lit.12 [a]D ˆ211.8 .cˆ
1, 1N HCl).
3.3.3. %R)-N-%10-Phenylelthyl)-%R,R)-N0,N0-bis%10-phenyl-
ethyl)propionamide [%R,R,R)-13]. A mixture of 2.5 g
.9.0mmol) of chiral acrylamide . R,R)-12 and 1.6 g
.13.5 mmol) of .R)-a-phenylethylamine in 130mL of
ethanol was heated to re¯ux for 36 h. Solvent removal at
reduced pressure and ¯ash chromatography .hexane±
EtAOc, 7:3) .CH2Cl2±CH3OH±NH4OH, 9:0.5:0.05)
afforded 3.6 g .98% yield) of an oil identi®ed as .R,R,R)-
3.3. General procedure for the reaction of enolate %S)-3-
Li with electrophiles
In a 50-mL round-bottom ¯ask ®tted with magnetic bar
was placed 100 mg .0.34 mmol) of .S)-3 and 10mL of
dry THF, under nitrogen atm. The ¯ask was submerged in
a dry ice±acetone bath .2788C) and 1.3 equiv. of 1.0M
LiHMDS was added via syringe. The resulting solution
was allowed to react for 45 min before the addition of the
electrophile .dropwise addition) and the reaction mixture
was stirred at 2788C for 2 h. The reaction was quenched
with 3.0mL of aq. satd. NH 4Cl, and the product was
extracted with three 20-mL portions of diethyl ether, the
combined extracts were dried over anh. Na2SO4, and
concentrated. Final puri®cation was accomplished by ¯ash
chromatography.
28
1
13, [a]D ˆ1135.2 .cˆ1, CHCl3). H NMR .DMSO-d6,
300 MHz, 1008C26) d 1.27 .d, Jˆ6.5 Hz, 3H), 1.69 .d, Jˆ
7.0Hz, 6H), 2.35 .ddd, J1ˆ15.1 Hz, J2ùJ3ˆ6.8 Hz, 1H),
2.51 .ddd, J1ˆ15.2 Hz, J2ùJ3ˆ6.7 Hz, 1H), 2.59 .b, 1H),
2.67 .dd, J1ùJ2ˆ6.6 Hz, 2H), 3.71 .q, Jˆ6.6 Hz, 1H), 5.13
.q, Jˆ7.0Hz, 2H), 7.10±7.34 .m, 15H). 13C NMR .DMSO-
d6, 100 MHz, 1008C) d 19.5, 24.8, 36.6, 44.5, 53.9, 58.2,
127.2, 127.3, 127.4, 128.2, 128.3, 128.6, 128.9, 142.5,
147.1, 172.4. MS .20eV) m/z 401 .M111), 295, 191,
120, 105. HRMS calcd for C27H33N2O .M111): 401.2593.
Found: 401.2583.
3.3.1. Methyl N-benzyl-N-[%S)-%10-phenylethyl)]-%2R)-2-
methyl-3-aminopropionate [%S,R)-10]. The general pro-
cedure was followed with 0.5 g .1.7 mmol) of .S)-3 in
50mL of dry THF, 0.9 mL .5.1 mmol) of HMPA, and
3.3.4. %S)-N-%10-Phenylethyl)-%R,R)-N0,N0-bis%10-phenyl-
ethyl)propionamide [%R,R,S)-13]. Acrylamide .R,R)-12
.5.7 g, 20mmol) and 3.7 g .30.6 mmol) of . S)-a-phenyl-
ethylamine were handled as described above in the prepa-
ration of .R,R,R)-13. The isolated product .7.8 g, 98% yield,
1
0.14 mL .2.2 mmol) of methyl iodide. H NMR analysis
showed a mixture of two diastereomeric products in a
81:19 ratio. The major isomer was assigned the 2R con-
®guration by chemical correlation with .R)-8 .see text).
The diastereomeric product mixture proved inseparable in
our hands, but NMR spectroscopic analysis of the major
28
colorless oil) was identi®ed as .R,R,S)-13. [a]D ˆ198.5
1
.cˆ1, CHCl3). H NMR .DMSO-d6, 400 MHz, 1008C) d
1.24 .d, Jˆ6.7 Hz, 3H), 1.68 .d, Jˆ7.0Hz, 6H), 2.31
.ddd, J1ˆ15.1 Hz, J2ˆJ3ˆ6.7 Hz, 1H), 2.50.ddd, Jˆ
15.0Hz, J2ˆJ3ˆ6.6 Hz, 1H), 2.60.ddd, J1ˆ11.7 Hz, J2ˆ
J3ˆ6.6 Hz, 1H), 2.70.ddd, J1ˆ11.7 Hz, J2ˆJ3ˆ6.6 Hz,
1H), 3.66 .q, Jˆ6.5 Hz, 1H), 5.13 .q, Jˆ7.1 Hz, 2H),
7.11±7.32 .m, 15H). 13C NMR .DMSO-d6, 100 MHz,
1008C) d 19.2, 24.6, 36.2, 44.1, 53.4, 57.7, 126.8, 126.9,
127.1, 127.8, 128.2, 128.5, 142.1, 146.8, 172.0. MS .15 eV)
m/z 401 .M111), 295, 191, 120, 105. HRMS calcd for
C27H33N2O .M111): 401.2593. Found: 401.2602.
1
product was feasible. H NMR .CDCl3, 400 MHz) d 1.03
.d, Jˆ7.0Hz, 3H), 1.38 .d, Jˆ7.0Hz, 3H), 2.27 .dd, J1ˆ
12.8 Hz, J2ˆ6.6 Hz, 1H), 2.66 .m, 1H), 2.94 .dd, J1ˆ
12.8 Hz, J2ˆ8.4 Hz, 1H), 3.44 .d, Jˆ13.9 Hz, 1H), 3.65
.d, Jˆ13.9 Hz, 1H), 3.68 .s, 3H), 3.89 .q, Jˆ7.0Hz, 1H),
7.24±7.34 .m, 10H). 13C NMR .CDCl3, 100 MHz) d 14.7,
15.3, 39.1, 51.4, 53.4, 54.9, 57.4, 126.8, 127.9, 128.7, 128.8,
140.6, 142.8, 176.6.
3.3.5. %S)-N-%10-Phenylethyl)-N-benzyl-%R,R)-N0,N0-bis-
%10-phenylethyl)propionamide[%R,R,S)-11]. A solution of
3.0g .7.5 mmol) of . R,R,S)-13 in 70mL of CH 2Cl2 was
cooled to 08C and treated with 1.24 g .9.0mmol) of
K2CO3 in 45 mL of H2O. The resulting suspension was
stirred for 20min before the addition of 1.1 mL .1.5 g,
9 mmol) of benzyl bromide. The reaction mixture was
stirred at ambient temperature for 3 days, the organic
phase was separated and the aqueous phase was extracted
with three 25-mL portions of CH2Cl2. The organic
extracts were combined, dried over Na2SO4, ®ltered, and
concentrated in a rotary evaporator. The crude product
was puri®ed by ¯ash chromatography .hexane±EtOAc,
3.3.2. %R,R)-N,N-Bis%10-phenylethyl)acrylamide [%R,R)-
12]. To a solution of 1.5 g .16.6 mmol) of acryloyl chloride
in 25 mL of dry CH2Cl2 was added under nitrogen and at
08C, 3.7 g .16.6 mmol) of .R,R)-N,N-bis.10-phenylethyl)-
amine dissolved in 5 mL of dry CH2Cl2 .dropwise addition
via cannula). The resulting solution was stirred for 1 h at
08C before the addition of 2.3 mL .16.6 mmol) of triethyl-
amine. The reaction mixture was allowed to warm up and
stirring was continued at ambient temperature overnight.
Water .30mL) was added to the resulting suspension and
the mixture was extracted with three 20-mL portions of
CH2Cl2, the combined organic extracts were dried over
anh. Na2SO4, ®ltered, and concentrated. The crude product

 Â
V. M. Gutierrez-Garcõa et al. / Tetrahedron 57 12001) 6487±6496
6495
8.5:1.5) to give 3.5 g .94% yield) of .R,R,S)-11 as a
Acknowledgements
28
colorless oil, [a]D ˆ177.8 .cˆ1, CHCl3). 1H NMR
.DMSO-d6, 300 MHz, 1008C) d 1.25 .d, Jˆ6.8 Hz, 3H),
1.55 .d, Jˆ7.1 Hz, 6H), 2.24 .ddd, J1ˆJ2ˆ8.4 Hz,
J3ˆ6.9 Hz, 2H), 2.73 .dd, J1ùJ2ˆ7.4 Hz, 2H), 3.42 .d,
Jˆ14.3 Hz, 1H), 3.52 .d, Jˆ14.3 Hz, 1H), 3.76 .q,
Jˆ6.8 Hz, 1H), 5.02 .q, Jˆ6.9 Hz, 2H), 6.95±7.33 .m,
20H). 13C NMR .DMSO-d6, 75 MHz, 1008C) d 16.9, 19.5,
35.2, 47.5, 53.6, 55.4, 59.8, 127.3, 127.3, 127.5, 127.7,
128.0, 128.3, 128.6, 128.7, 128.8, 129.0, 141.6, 142.5,
144.9, 172.1. HRMS calcd for C34H39N2O .M111):
491.3062. Found: 491.3075.
We are indebted to Conacyt-Mexico for ®nancial support
Â
via grant L0006-E9607. We are also grateful to Võctor M.
Gonzalez and Marõa Luisa Rodrõguez for their assistance in
Â
Â
Â
the recording of NMR spectra.
References
  Â
1. Juaristi, E.; Balderas, M.; Lopez-Ruiz, H.; Jimenez-Perez,
 Â
V. M.; Kaiser-Carril, M. L.; Ramõrez-Quiros, Y. Tetrahedron:
Asymmetry 1999, 10, 3493.
3.3.6. %R)-N-%10-Phenylethyl)-N-benzyl-%R,R)-N0,N0-bis-
%10-phenylethyl)propionamide[%R,R,R)-11]. According to
the same procedure, 0.8 g .1.9 mmol) of .R,R,R)-13 was
benzylated with 0.28 mL .0.4 g, 2.3 mmol) of benzyl bro-
mide to give 0.6 g .60% yield) of .R,R,R)-11 as a colorless
2. See, for example: .a) Juaristi, E. Introduction to Stereo-
chemistry and Conformational Analysis; Wiley: New York,
1991. .b) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereo-
chemistry of Organic Compounds; Wiley: New York, 1994.
Â
.c) Juaristi, E. An. Quõm. Int. Ed. 1997, 93, 135.
28
1
oil, [a]D ˆ1128.8 .cˆ1, CHCl3). H NMR .DMSO-d6,
300 MHz, 1008C) d 1.29 .d, Jˆ6.8 Hz, 3H), 1.56 .d, Jˆ
7.1 Hz, 6H), 2.18 .ddd, J1ˆ15.0Hz, J2ˆ9.5 Hz, J3ˆ
5.6 Hz, 1H), 2.33 .ddd, J1ˆ15.0Hz, J2ˆ9.4 Hz, J3ˆ
5.6 Hz, 1H), 2.63 .ddd, J1ˆ13.5 Hz, J2ˆ9.3 Hz, J3ˆ
5.4 Hz, 1H), 2.87 .ddd, J1ˆ13.5 Hz, J2ˆ9.4 Hz, J3ˆ
5.6 Hz, 1H), 3.45 .d, Jˆ14.3 Hz, 1H), 3.53 .d, Jˆ14.3 Hz,
1H), 3.81 .q, Jˆ6.8 Hz, 1H), 5.00 .q, Jˆ7.0Hz, 2H), 6.97±
7.34 .m, 20H). 13C NMR .DMSO-d6, 75 MHz, 1008C) d
17.4, 19.5, 35.3, 47.7, 53.7, 55.5, 60.1, 127.3, 127.3,
127.5, 128.1, 128.3, 128.6, 128.7, 128.8, 129.0, 141.6,
142.5, 144.9, 172.1. HRMS calcd for C34H39N2O .M111):
491.3062. Found: 491.3069.
3. a-Amino acids: .a) O'Donnell, M. J. .Ed.) a-Amino acid
synthesis; TetrahedronÐSymposium-in-Print, 1988, 44,
5253 .b) Williams, R. M. Synthesis of Optically Active
a-Amino Acids; Pergamon: Oxford, 1989. .c) Duthaler, R. O.
Tetrahedron 1994, 50, 1539. .d) Calmes, M.; Daunis, J. Amino
Acids 1999, 16, 215.
4. b-Amino acids: .a) Juaristi, E.; Quintana, D.; Escalante, J.
Aldrichim. Acta 1994, 27, 3. .b) Cole, D. C. Tetrahedron
1994, 50, 9517. .c) Cardillo, G.; Tomasini, C. Chem. Soc.
Rev. 1996, 25, 117. .d) In Enantioselective Synthesis of
b-Amino Acids; Juaristi, E., Ed.; Wiley±VCH: New York,
Â
1997. .e) Juaristi, E.; Lopez-Ruiz, H. Curr. Med. Chem.
1999, 6, 983.
5. .a) Schoellkopf, U. Tetrahedron 1983, 39, 2085. .b) Seebach,
D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T. Helv.
3.4. General procedure for the reaction of enolates
%R,R,R)- and %R,R,S)-11
Â
Chim. Acta 1987, 70, 237. .c) Juaristi, E.; Leon-Romo, J. L.;
Â
Â
Ramõrez-Quiros, Y. J. Org. Chem. 1999, 64, 2914.
.d) Williams, R. M.; Sinclair, P. J.; Zhai, D.; Chen, D. J.
Am. Chem. Soc. 1988, 110, 1547. .e) Dellaria, J. F.; Santar-
siero, B. D. J. Org. Chem. 1989, 54, 3916. .f) Belokon, Y. N.;
Sagyan, A. S.; Djamgaryan, S. M.; Bakhmutov, V. I.; Belikov,
V. M. Tetrahedron 1988, 44, 5507. .g) Orena, M.; Porzi, G.;
Sandri, S. J. Org. Chem. 1992, 57, 6532. .h) Chinchilla, R.;
A solution of 0.2 g .0.4 mmol) of the chiral amide in 10 mL
of dry THF was cooled to 2788C .dry ice±acetone bath) and
¯ushed with nitrogen before the addition of 1.1 equiv. of
n-butyllithium in hexane solution. Stirring was continued
for 45 min before the addition of 1.1 equiv. of methyl
iodide. The reaction mixture was stirred at 2788C for 3 h,
and quenched with 3 mL of a satd. aqueous solution of
NH4Cl. The alkylated product was extracted with three
10-mL portions of ethyl acetate, the organic phases were
combined, dried over anh. Na2SO4, ®ltered, and concen-
trated in the rotary evaporator. Diastereomeric ratios in
Â
Falvello, L. R.; Galindo, N.; Najera, C. Angew. Chem., Int. Ed.
Engl. 1997, 36, 995. .i) Evans, D. A.; Weber, A. E. J. Am.
Chem. Soc. 1986, 108, 6757. .j) Ikegami, S.; Uchiyama, H.;
Hayama, T.; Katsuki, T.; Yamaguchi, M. Tetrahedron 1988,
44, 5333. .k) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason,
J. L. J. Am. Chem. Soc. 1994, 116, 9361. Myers, A. G.;
Gleason, J. L.; Yoon, T. J. Am. Chem. Soc. 1995, 117, 8489.
.l) Meyer, L.; Poirier, J. M.; Duhamel, P.; Duhamel, L. J. Org.
Chem. 1998, 63, 8094.
1
the product were determined from signal integration in H
NMR spectra.
3.4.1. %S)-N-%10-Phenylethyl)-N-benzyl-%R,R)-N0,N0-bis-
%10-phenylethyl)-%2R)-2-methylpropionamide [%R,R,S,R)-
6. For recent reviews on applications of a-phenylethylamine in
the preparation of enantiopure compounds, see: .a) Juaristi, E.;
Â
Escalante, J.; Leon-Romo, J. L.; Reyes, A. Tetrahedron:
1
14]. H NMR .DMSO-d6, 300 MHz, 1008C26) d 0.93 .d,
Jˆ6.5 Hz, 3H), 1.22 .d, Jˆ6.8 Hz, 3H), 1.68 .d, Jˆ
7.1 Hz, 6H), 2.42 .dd, J1ˆ12.9 Hz, J2ˆ8.6 Hz, 1H), 2.57
.dd, J1ˆ12.9 Hz, J2ˆ4.6 Hz, 1H), 2.62±2.70.m, 1H),
3.21 .d, Jˆ14.1 Hz, 1H), 3.33 .d, Jˆ14.1 Hz, 1H), 3.62
.q, Jˆ6.8 Hz, 1H), 5.00±5.21 .b, 2H), 7.02±7.38 .m,
20H). 13C NMR .DMSO-d6, 75 MHz, 1008C) d 13.2, 17.3,
19.9, 37.5, 53.6, 54.1, 55.5, 58.4, 127.2, 127.3, 127.5, 127.9,
128.6, 128.7, 128.8, 129.3, 141.4, 142.6, 144.4, 144.6,
176.5. HRMS calcd for C35H41N2O .M111): 505.3219.
Found: 505.3212.
Â
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10. In addition, analogs O and P were considered, but then

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V. M. Gutierrez-Garcõa et al. / Tetrahedron 57 12001) 6487±6496
6496
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12. Juaristi, E.; Quintana, D.; Balderas, M.; Garcõa-Perez, E.
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26. NMR spectra were recorded at 1008C in order to simplify their
appearance, since rotation around the N±CvO amide
segments is slow at ambient temperature, giving rise to a
complex mixture of signals.