Enantioselective alkylation and protonation of prochiral enolates in the asymmetric synthesis of β-amino acids

Article abstract of DOI:10.1016/S0040-4020(03)00578-7

Achiral 1-benzoyl-3-methylperhydropyrimidin-4-one (1) was deemed a useful, potential precursor for the enantioselective synthesis of α-substituted β-amino acids. Pyrimidinone 1 was prepared from inexpensive β-aminopropanoic acid in 62% overall yield. Prochiral enolate derivative 1 -Li was alkylated in good yield and moderate enantioselectivity in the presence of chiral amines (S)-8, (S,S)-9, (S,S)-10, or (-)-sparteine. The enantioselectivity of the alkylation process is highest in toluene as the solvent and in the presence of lithium bromide as additive. The racemic alkylated derivatives 2 and 3 were readily metallated with LDA to give prochiral enolates 2-Li and 3-Li, that were reprotonated with novel chiral phenolic acids (S)-11, (S,S)-12, (S)-13, and (S,S)-14 in moderate enantioselectivity in the case of 2-Li and good enantioselectivity in the case of 3-Li. The acid (6N HCl) hydrolysis of enantioenriched 2 and 3 proceeded in good yield and without racemization to afford α-alkyl-β-amino acids 4 and 5, respectively.

Full text of DOI:10.1016/S0040-4020(03)00578-7

Tetrahedron 59 (2003) 4223–4229
Enantioselective alkylation and protonation of prochiral enolates
in the asymmetric synthesis of b-amino acidsq
*
Omar Mun˜oz-Mun˜iz and Eusebio Juaristi
´ ´ ´
Departamento de Quımica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Apartado Postal 14-740,
´
07000 Mexico, D.F., Mexico
Received 30 January 2003; revised 6 March 2003; accepted 6 March 2003
Abstract—Achiral 1-benzoyl-3-methylperhydropyrimidin-4-one (1) was deemed a useful, potential precursor for the enantioselective
synthesis of a-substituted b-amino acids. Pyrimidinone 1 was prepared from inexpensive b-aminopropanoic acid in 62% overall yield.
Prochiral enolate derivative 1 -Li was alkylated in good yield and moderate enantioselectivity in the presence of chiral amines (S)-8, (S,S)-9,
(S,S)-10, or (2)-sparteine. The enantioselectivity of the alkylation process is highest in toluene as the solvent and in the presence of lithium
bromide as additive. The racemic alkylated derivatives 2 and 3 were readily metallated with LDA to give prochiral enolates 2-Li and 3-Li,
that were reprotonated with novel chiral phenolic acids (S)-11, (S,S)-12, (S)-13, and (S,S)-14 in moderate enantioselectivity in the case of 2-Li
and good enantioselectivity in the case of 3-Li. The acid (6N HCl) hydrolysis of enantioenriched 2 and 3 proceeded in good yield and without
racemization to afford a-alkyl-b-amino acids 4 and 5, respectively. q 2003 Published by Elsevier Science Ltd.
1. Introduction
reagents to give enantiomerically enriched products.3 The
potential of this approach has been exploited by several
research groups.4
The development of highly diastereoselective a-alkylation
reactions of carbonyl and related compounds is one of the
most important methods in asymmetric synthesis.2 Accord-
ing to Scheme 1, it is possible to develop enantioselective
alkylation reactions in which, instead of binding covalently
a chiral auxiliary (which requires a removal later on) a chiral
amine concomitantly generated with the lithium enolate
from a carbonyl compound and Rp2N2Liþ is temporarily
joined through a complexation that causes two achiral
Achiral enolate A can in principle be protonated enantio-
selectively by reaction with chiral proton sources, to afford
non-racemic derivatives (Scheme 2). This conceptually
simple approach (enantiotopic faces being distinguished by
chiral reagents5) has been confirmed by Duhamel,6 Fehr,7
Vedejs,8 and others.9
With the above information at hand, we undertook the
studies reported herein: (1) enantioselective alkylation of
prochiral enolate 1-Li (Scheme 3(a)) and (2) enantio-
selective protonation of enolates 2-Li and 3-Li
(Scheme 3(b)). Enantiomerically pure alkylated pyrimi-
dinones 2 and 3 should afford the desired a-substituted
b-amino acids 4 and 5 (Scheme 3).10
Scheme 1.
q See Ref. 1.
Keywords: amino acids and derivatives; stereoselective alkylations;
enantioselective protonations; chiral bases; solvent and salt effects.
*
Corresponding author. Tel.: þ52-55-57473722; fax: þ52-55-57477113;
e-mail: juaristi@relaq.mx
Scheme 2.
0040–4020/03/$ - see front matter q 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4020(03)00578-7

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O. Mun˜oz-Mun˜iz, E. Juaristi / Tetrahedron 59 (2003) 4223–4229
Table 1. Solvent effect on the alkylation reaction of pyrimidinone 1 with
methyl iodide and benzyl bromide
Entry
Solvent
EX
CH3I
CH3I
CH3I
CH3I
PhCH2Br
PhCH2Br
PhCH2Br
PhCH2Br
Yield (%)
1
2
3
4
5
6
7
8
THF
87
84
42
69
91
90
56
65
Toluene
MTBEa
CH2Cl2
THF
Toluene
MTBEa
CH2Cl2
Scheme 3.
2. Results and discussion
a
MTBE¼methyl tert-butyl ether.
2.1. Synthesis of 1-benzoyl-3-methylperhydropyrimidin-
4-one, 1
2.3. Enantioselective alkylation of prochiral
pyrimidinone enolate 1-Li in the presence of chiral
amines
The heterocycle 1 was prepared from b-alanine by initial
conversion of its methyl ester to the corresponding
N-methylamide 6,11 which formed a Schiff base with
paraformaldehyde.12 Imine 7 was then treated with benzoyl
chloride in the presence of 4-dimethylaminopyridine
(DMAP) to give the desired perhydropyrimidinone 1 in
good yield overall (Scheme 4).13
Chiral amines 8–10 (Chart 1) incorporating the (S)-a-
phenylethylamino group16 – 19 were chosen to explore
potential stereoinduction in the alkylation of enolate 1-Li,
according to the working hypothesis advanced in Scheme 1.
In the event, lithium amides (S)-8-Li, (S,S)-9-Li, and (S,S)-
10-Li were prepared by metallation of the corresponding
secondary amine with one equivalent of butyllithium. The
required pyrimidinone enolate 1-Li was then obtained upon
treatment of heterocycle 1 with chiral bases 8–10-Li in
2.2. Solvent effect on the alkylation reaction, 1-Li!2 or 3
We first established the efficiency of the alkylation reaction
of pyrimidinone enolate 1-Li (obtained by metallation of 1
with lithium diisopropylamide, LDA, as base) with methyl
iodide and benzyl bromide as electrophiles. Particularly
interesting is the comparison of poorly coordinating
solvents such as toluene, methylene chloride, and methyl
tert-butyl ether14 with the good coordinating THF. Our
observations are collected in Table 1, and it can be
appreciated that the alkylation reaction proceeds in very
good yields both in THF and toluene. This latter solvent was
then selected for the subsequent studies, since THF can
compete with amine ligands for lithium cation coordination,
and this could prevent asymmetric induction.15
Chart 1.
Table 2. Enantioselective alkylation of enolate 1-Li in the presence of
chiral amines 8–10 and (2)-sparteine
Entry Chiral amine
EX
CH3I
CH3I
CH3I
Yield (%) e.r. Major enantiomer
1
2
3
4
5
6
7
8
(S)-8
70
85
75
90
81
92
86
88
47:53 (R)
41:59 (R)
63:37 (S)
67:33 (S)
46:54 (R)
39:61 (R)
64:36 (S)
70:30 (S)
(S,S)-9
(S,S)-10
(2)-Sparteine CH3I
(S)-8
PhCH2Br
PhCH2Br
PhCH2Br
(S,S)-9
(S,S)-10
(2)-Sparteine PhCH2Br
Molar concentration of 1: 4.6–7.6£1023 M. A 1:1 chiral diamine–
butyllithium complex was used.
Scheme 4.

O. Mun˜oz-Mun˜iz, E. Juaristi / Tetrahedron 59 (2003) 4223–4229
4225
this study. Although moderately, it is seen that enantio-
selectivities did improve when the alkylation reaction is
carried out in the presence of LiBr (26–41% ee without salt,
34–50% ee with salt).
2.5. Enantioselective protonation of prochiral enolates
2-Li and 3-Li
Chart 2.
toluene solvent. The alkylation reactions were carried out at
2788C and enantiomeric ratios were determined by
comparison of optical rotations with those of enantiopure
standards (see below).
Racemic alkylated pyrimidinones (^)-2 and (^)-3 (Table 1)
were treated with the achiral base LDA to give prochiral
enolates 2-Li and 3-Li, which were then reprotonated with
novel chiral Bronsted acids 11–14 (Chart 3).
Table 2 collects the results of alkylation of enolate 1-Li in
the presence of chiral amines 8–10. For comparison
purposes, Table 2 also includes the results of methylation
and benzylation in the presence of (2)-sparteine (Chart 2), a
chiral diamine that has received considerable attention in
the area of enantioselective alkylations.20
Salient observations are the opposite stereoinductions
encountered with monodentate ligands (S)-8 and (S,S)-9
versus bidentate diamine ligands (S,S)-10 and (2)-spar-
teine. Indeed, low and unlike21 enantioinduction is found
with the former whereas higher, like21 enantioinduction is
seen with the latter. Among the two monoamines (S)-8 and
(S,S)-9, the latter induces higher enantioselectivities (com-
pare entries 2 and 6 with entries 1 and 5 in Table 2),
probably as consequence of the presence of C2 symmetry in
(S,S)-9.22 Nevertheless, asymmetric (2)-sparteine afforded
better enantioselectivities than C2-symmetric (S,S)-10, as
can be appreciated from comparison of entries 4 and 8 with
entries 3 and 7 in Table 2.
Chart 3.
As anticipated,5–9 enantiomerically enriched heterocycles 2
and 3 were produced in good yields (Table 4). Highest
enantioselectivities (53–68% ee) were observed in the
protonation of benzylated 3-Li relative to 2-Li (compare
entries 5–8 with entries 1–4 in Table 4), with best results
arising from protonation with chiral phenolic amides (S)-11
and (S,S)-12.
2.4. Salt (lithium bromide) effects on the enantioselective
alkylation of enolate 1-Li
The higher degree of enantioselectivity achieved in the
protonation of benzylated 3-Li relative to methylated 2-Li
may originate from increased rigidity present in the former
enolate, as evidenced from molecular modeling studies at
the ab initio level and within the frame of density
functional theory (DFT) at the B3LYP/6-31G(d) level.25
Figure 1 presents the geometry-optimised structure for
Evidence has accumulated in the last decade or so, that the
presence of ‘inert’ salts can have a remarkable effect on the
stereochemical outcome of enolate alkylation reactions.3,4d,
9c,22–24 Thus, it was deemed of interest to examine the effect
of LiBr addition to the reaction of enolate 1-Li with methyl
iodide or benzyl bromide, in the presence of chiral ligands
(S,S)-10 and (2)-sparteine. Table 3 collects the results of
Table 3. Salt (lithium bromide) effect on the enantioselective alkylation of enolate 1-Li
Entry
Ligand
(S,S)-10
(S,S)-10
(S,S)-10
(S,S)-10
(2)-Sparteine
(2)-Sparteine
(2)-Sparteine
(2)-Sparteine
LiBr (equiv.)
EX
CH3I
Yield (%)
e.r.
Major enantiomer
1
2
3
4
5
6
7
8
1
6
1
6
1
6
1
6
79
77
82
80
71
76
81
75
69:31
70:30
69:31
73:27
70:30
74:26
67:33
75:25
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
CH3I
PhCH2Br
PhCH2Br
CH3I
CH3I
PhCH2Br
PhCH2Br

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O. Mun˜oz-Mun˜iz, E. Juaristi / Tetrahedron 59 (2003) 4223–4229
Table 4. Enantioselective protonation of prochiral enolates 2-Li and 3-Li
with chiral acids
Scheme 5.
Entry
E
Ap–H
Yield (%)
e.r.
Major enantiomer
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
PhCH2
PhCH2
PhCH2
PhCH2
(S)-11
(S,S)-12
(S)-13
(S,S)-14
(S)-11
(S,S)-12
(S)-13
(S,S)-14
88
80
90
84
90
89
87
92
64:36
68:32
60:40
63:35
81:19
84:16
77:23
80:20
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
Scheme 6.
Alternatively, a-substituted b-amino acids 4 and 5 of
known configuration2g were converted into enantiopure
standards (R)-2 and (R)-3, according to the synthetic route
outlined in Scheme 6.11–13
3. Conclusions
b-Alanine, an inexpensive b-amino acid, was converted
into achiral 1-benzoyl-3-methylperhydropyrimidin-4-one,
1, in 62% overall yield.
In the presence of chiral amines 8–10 or (2)-sparteine,
prochiral enolate 1-Li was alkylated in good yields and
moderate enantioselectivities. Higher enantioinduction
was exhibited by bidentate diamine ligands (S,S)-10 and
(2)-sparteine, especially in the presence of LiBr salt.
Figure 1. Global energy minimum geometry of enolate 3-Li at B3LYP/6-
31G(d) level.
enolate (S)-3-Li. The most interesting finding is that the
global minimum shows that lithium is bridged both to the
enolate oxygen and to the phenyl ring in a bridged structure
that resembles allyllithium.24a,26 It is plausible that this
conformationally rigid enolate affords a more defined
transition structure favoring protonation on the Re face of
the enolate, and providing (S)-3 as the major enantiomeric
product. By contrast, the lithium cation in enolate 2-Li is
expected to be more mobile, leading to several transition
structures during protonation, and therefore to lower
enantioselectivity.
Racemic alkylated pyrimidinones 2 and 3 were readily
metallated with LDA, and the resulting prochiral enolates
2-Li and 3-Li were reprotonated with novel chiral proton
sources 11–14. Good enantioselectivities were observed in
this protonation protocol, especially with enolate 3-Li.
Hydrolysis of enantioenriched alkylated heterocycles 2 and
3 proceeds in good yield and without racemization to afford
the corresponding a-substituted b-amino acids of interest.
2.6. Assignment of absolute configuration in alkylated
products 2 and 3
4. Experimental
4.1. General experimental procedures
Hydrolysis of alkylated pyrimidinones 2 and 3 required
exposure to 6N HCl with heating to 958C for 12–24 h
(Scheme 5). Isolation of the free a-alkyl-b-aminopropanoic
acid 4 or 5 in ion-exchange resin permitted comparison of
optical rotation data,2g and thus correlation of configuration.
Flasks, stirring bars, and hypodermic needles used for the
reactions with organolithium compounds were dried for ca.
12 h at 1208C and allowed to cool in a desiccator over anh.
CaSO4. Anh. toluene, tetrahydrofuran (THF) and methyl

O. Mun˜oz-Mun˜iz, E. Juaristi / Tetrahedron 59 (2003) 4223–4229
4227
tert-butyl ether (MTBE) were obtained by distillation from
benzophenone ketyl. Methylene chloride was dried over
CaH2 and then distilled at reduced pressure. Lithium
bromide was dried at 1508C for 5 days. The BuLi employed
was titrated according to the method we developed.27 TLC:
DC-F254 Plate, detection by UV light and iodine. Flash
column chromatography: silica gel (0.040–0.063 mm).
Optical rotations were measured in a polarimeter using
the sodium D-line (589 nm). Melting points are not
2788C before the dropwise addition of pyrimidinone 1 in
the solvent used. Stirring was continued for 1 h at 2788C in
order to secure the complete formation of the corresponding
enolate. The alkylating agent (1.2 mmol) was then added
dropwise via syringe, and the reaction mixture was stirred at
2788C for 2 h and at ambient temperature for 20 min, and
finally was cooled at 2788C for 1 additional hour. At this
point the reaction was quenched by the addition of saturated
aqueous NH4Cl solution and extracted with CH2Cl2
(3£20 mL). The combined extracts were washed with
water, brine and dried over anhydrous Na2SO4, filtered
and concentrated at reduced pressure. The residue was
purified by flash chromatography using hexanes–ethyl
acetate (7:3) as eluent.
1
corrected. H NMR spectra: 400 MHz. 13C NMR spectra:
100 MHz. Chemical shifts (d) in ppm downfield from
internal TMS reference; the coupling constants (J) are given
in Hz.
4.1.1. General procedure for the preparation of 1-ben-
zoyl-3-methyl-tetrahydro-pyrimidin-4-one, 1. A 100 mL
three-necked flask provided with a magnetic stirrer and
addition funnel was loaded with 3-amino-propanoic acid
(8.9 g, 0.1 mol) in 45 mL of methanol at 08C. Freshly
distilled chlorotrimethylsilane (14 mL, 0.2 mol) was added
slowly, and the resulting solution was stirred for 8 h at room
temperature and at 08C overnight. Concentration in a rotary
evaporator afforded the crude product that was recrystal-
lized from MeOH to give 11.2 g (90% yield) of 3-amino-
propionic acid methyl ester hydrochloride mp 89–908C
(lit.11 mp 89–908C). This intermediate (10 g, 7.2 mmol)
was placed in a 100 mL three-necked flask provided with a
magnetic stirrer, addition funnel and condenser, and then
dissolved in 50 mL of methanol. The resulting solution was
cooled to 08C before the slow addition of aqueous 40%
methylamine (16 mL, 0.22 mol) with continued stirring for
36 h. The solvent was removed at reduced pressure to give
9.5 g (95% yield) of 6 as a pale yellow oil. The crude
product was placed in a 100 mL flask dissolved in 50 mL of
CHCl3 and Et3N (19 mL, 0.14 mol), and the resulting
mixture was heated to reflux with removal of water in an
inverted Dean–Stark tramp during 2 h. Then, p-formal-
dehyde (6.12 g, 0.2 mol) was added and the reflux continued
for 4 additional hours. The precipitate that formed was
filtered, and the solvent was removed at reduced pressure to
give 7.8 g of 7 (quantitative yield). This crude product was
redissolved in 150 mL of toluene before the addition of
4-DMAP (4.72 g, 0.04 mol) and benzoyl chloride (5.5 mL,
0.05 mol). The reaction mixture was refluxed 4 h, then
cooled to room temperature, and filtered. The filtrate was
evaporated at reduced pressure to give a yellow oil residue,
which was purified by flash chromatography (hexanes–
ethyl acetate, 80:20) to afford a colorless oil of the desired
product, 1.29 (7.4 g, 82% yield). 1H NMR (400 MHz,
DMSO-d6, 1008C): d 2.41 (t, J¼6.6 Hz, 2H), 2.79 (s, 3H),
3.69 (t, J¼6.6 Hz, 2H), 4.82 (s, 2H), 7.46 (s, 5H). 13C NMR
(100 MHz, DMSO-d6, 1008C): d 31.9, 32.2, 42.2, 60.9,
126.9, 128.5, 130.5, 130.7, 167.6, 170.3. Anal. calcd for
C12H14O2N2: C, 66.05; H, 6.42. Found: C, 66.12; H, 6.51.
4.3. General procedure for the alkylation of 1 via enolate
formation with (2)-sparteine/BuLi
To a solution of (2)-sparteine (0.6 mL, 1.1 mmol) in the
selected solvent (toluene, TBME or CH2Cl2) at 2788C was
added BuLi (1.8 M in hexane, 1.1 mmol). The reaction was
stirred for 20 min at 2788C, and a solution of pyrimidinone
1 (0.22 g, 1 mmol) in the same solvent (15 mL) was added
at 2788C. The resulting mixture reaction was stirred for 4 h,
and then the alkylating agent (1.2 mmol) was added
dropwise via syringe. The reaction mixture was stirred for
1 additional hour at 2788C and quenched with MeOH
(1 mL) before the mixture was allowed to warm to room
temperature. The workup procedure was similar to that
described in Section 4.2.
4.4. General procedure for the alkylation of 1 in the
presence of LiBr
The general procedure for enolate formation was followed
as described above. Lithium bromide (1.1 or 6.1 mmol) was
added before the addition of alkylating agent in 10 mL of
solvent, with continued stirring for 30 min. The reaction
was quenched according to the general procedure.
4.5. General procedure for the enantioselective
protonation of a-alkylated pyrimidinone 2 and 3 with
chiral proton sources (S)-11, (S,S)-12, (S)-13, and
(S,S)-14
The general procedure for enolate formation with LDA
(Section 4.2) was followed. The protonating agent (1 mmol)
in 10 mL of toluene was then added dropwise via syringe,
and the reaction mixture was stirred at 2788C for 1 h and
quenched with MeOH (1 mL) before the mixture was
allowed to warm to room temperature. The workup
procedure was similar to that described above, and the
residue was purified by flash chromatography using
hexanes–ethyl acetate (100:0!70:30) gradient.
4.2. General procedure for the alkylation of 1 via enolate
formation with LDA or chiral lithium amides
4.6. Preparation of enantiopure standards (R)-2 and
(R)-3
A solution of the appropriate amine [(i-Pr)2NH, (S)-8, (S,S)-
9, or (S,S)-10)] (1.1 mmol) in the selected solvent (THF,
toluene, TBME, or CH2Cl2) was cooled to 08C before the
slow addition of BuLi (1.1 mmol, ca. 1.8 M in hexane). The
resulting solution was stirred for 30 min and then cooled to
Enantiopure a-alkylated-b-amino acids (R)-4 and (R)-5
were prepared according to the methodology described by
Juaristi et al.2g The corresponding enantiomerically pure
pyrimidinone (R)-2 and (R)-3 were then obtained following
the synthetic procedure described in Section 4.1.1.

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O. Mun˜oz-Mun˜iz, E. Juaristi / Tetrahedron 59 (2003) 4223–4229
4.6.1. 1-Benzoyl-3,5R-dimethyl-tetrahydro-pyrimidin-4-
1
one, (R)-4. H NMR (400 MHz, CDCl3, 608C): d 1.18 (d,
J¼7.2 Hz, 1H), 3.70 (dd, J¼11.9, 6.9 Hz, 2H) 4.21 (q,
J¼7.1 Hz, 1H), 7.11–7.55 (m, 14H), 9.37 (bs, 1H). 13C
NMR (100 MHz, CDCl3): d 21.9, 22.1, 40.6, 40.8, 49.9,
50.2, 117.6, 120.4, 121.9, 127.5, 129.1, 129.2, 130.4, 142.6,
155.9, 179.8. [a]2D8¼275.4 (c¼1.0 CHCl3), oil. Anal. calcd
for C16H20ONCl: C, 66.92; H, 7.22. Found: C, 66.62; H,
7.26.
J¼7.0 Hz, 3H), 2.64 (m, 1H), 2.97 (s, 3H), 3.33 (m, 1H),
3.95 (m, 1H), 4.75 (s, 2H), 7.42 (m, 5H). 13C NMR
(100 MHz, CDCl3, 608C): d 16.1, 31.5, 42.1, 59.3, 61.1,
126.1, 128.3, 129.2, 134.4, 168.9, 170.8. [a]2D8¼249.5
(c¼1.0, CHCl3), oil. Anal. calcd for C13H16O2N2: C, 67.52;
H, 6.42. Found: C, 67.82; H, 6.67.
4.8.3. 2-[2-(1-Phenyl-ethylamino)-ethyl]-phenol, (S)-13.
1H NMR (400 MHz, CDCl3): d 1.47 (d, J¼6.9 Hz, 3H),
2.71–2.83 (m, 4H), 3.84 (q, J¼6.9 Hz, 1H), 6.95–7.39 (m,
9H). 13C NMR (100 MHz, CDCl3): d 22.9, 34.4, 47.7, 58.1,
117.6, 118.9, 119.0, 126.3, 126.5, 127.3, 127.6, 128.2,
128.8, 130.9, 143.2, 156.9. [a]2D8¼256.9 (c¼1.5, CHCl3),
wax. Anal. calcd for C24H25O2N: C, 80.19; H, 7.01. Found:
C, 80.31; H, 7.18.
4.6.2. 1-Benzoyl-5R-benzyl-3-methyl-tetrahydro-pyrimi-
din-4-one, (R)-5. 1H NMR (400 MHz, CDCl3, 608C): d 2.47
(m, 1H), 2.73 (m, 1H), 2.90 (s, 3H), 3.22 (m, 1H), 4.23 (m,
2H), 4.88 (s, 2H), 7.12–7.46 (m, 10H). 13C NMR
(100 MHz, CDCl3, 608C): d 31.4, 36.3, 47.5, 49.7, 57.1,
124.9, 126.1, 127.7, 128.0, 128.5, 129.6, 134.1, 138.2,
168.9, 170.1. [a]2D8¼þ68.1 (c¼1.3, CHCl3), wax. Anal.
calcd for C19H20O2N2: C, 74.00; H, 6.54. Found: C, 74.17;
H, 6.63.
4.8.4. 2-{[2-Bis(1-phenyl-ethyl)-amino]-ethyl}-phenol,
(S,S)-14. 1H NMR (400 MHz, CDCl3): d 1.34 (d,
J¼6.9 Hz, 3H), 1.42 (d, J¼6.9 Hz, 3H), 2.69–2.80 (m,
4H), 3.79 (q, J¼6.9 Hz, 1H), 3.93 (q, J¼6.9 Hz, 1H), 7.11–
7.62 (m, 14H). 13C NMR (100 MHz, CDCl3): d 21.7, 22.8,
33.7, 39.6, 46.1, 48.3, 56.5, 57.3, 116.3, 116.9, 117.7, 118.2,
118.9, 119.3, 120.1, 125.4, 126.1, 126.8, 127.5, 129.8,
133.4, 142.9, 147.3, 157.3. [a]2D8¼295.0 (c¼1.1, CHCl3),
oil. Anal. calcd for C24H27ON: C, 83.44; H, 7.88. Found: C,
83.59; H, 7.63.
4.7. General procedure for the hydrolysis of alkylated
pyrimidinones, (R)-4 and (R)-5
A suspension of approximately 1 mmol of a-alkylated
pyrimidinone in 10 mL of 6N HCl was heated in a sealed
ampule at 958C. The solution was then allowed to cool to
ambient temperature and was extracted three times with
CH2Cl2. The aqueous phase was evaporated to afford the
crude amino acid hydrochloride, which was adsorbed to
acid ion-exchange resin Dowex 50W X 8. The resin was
washed with distilled H2O until the washings came out
neutral, and then the free amino acid was recovered with 1N
aqueous NH3. Evaporation afforded the crystalline amino
acid, which was dried under vacuum at 408C.
Acknowledgements
We are indebted to Dr Jaime Escalante for the preparation of
´
pyrimidinone 1, Q. Fred Garcıa Flores for the elemental
analysis and to Conacyt-Mexico for financial support via
´
4.8. Synthesis of chiral proton sources (S)-11, (S,S)-12,
(S)-13, and (S,S)-14
grant 33023-E.
To a 100 mL flask provided with Dean–Stark tramp and
magnetic stirrer was added (2-hydroxy-phenyl)-acetic acid
(4.4 g, 29 mmol) in 60 mL of toluene and catalytic amounts
of p-TsOH. The mixture was refluxed for 4 h with removal
of water and then the residual solvent was removed at
reduced pressure to give 3H-benzofuran-2-one in quanti-
tative yield (3.9 g), mp 528C (lit.28 mp 50–518C).
Acetamides (S)-11 and (S,S)-12 were obtained by refluxing
of 3H-benzofuran-2-one and (S)-phenylethyl-amine or
(S,S)-bis-phenylethylamine (equimolar amounts) in toluene.
Aminoalcohols (S)-13 and (S,S)-14 were prepared by
refluxing of the corresponding acetamides with LiAlH4
(3.3 equiv.) in THF for 24–48 h.
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