Enantioselective synthesis of β-amino acids. Part 10: Preparation of novel α,α- and β,β-disubstituted β-amino acids from (S)-asparagine

Article abstract of DOI:10.1016/S0957-4166(99)00328-6

Perhydropyrimidinone (S)-1 is alkylated with very high diastereoselectivity to give trans products (2S,5R)-3, (2S,5R)-4 and (2S,5R)- 5. Dialkylation of (S)-1 also proceeds with complete stereoselectivity to afford adducts (2S,5R)-6, (2S,5S)-6, (2S,5R)-7 a

Full text of DOI:10.1016/S0957-4166(99)00328-6

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3493–3505
Enantioselective synthesis of β-amino acids. Part 10: Preparation
of novel α,α- and β,β-disubstituted β-amino acids from
(S)-asparagine1
Eusebio Juaristi,∗ Margarita Balderas, Heraclio López-Ruiz, Víctor Manuel Jiménez-Pérez,
María Luisa Kaiser-Carril and Yara Ramírez-Quirós
Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional,
Apartado Postal 14-740, 07000 Mexico, D.F., Mexico
Received 7 July 1999; accepted 29 July 1999
Abstract
Perhydropyrimidinone (S)-1 is alkylated with very high diastereoselectivity to give trans products (2S,5R)-3,
(2S,5R)–4 and (2S,5R)-5. Dialkylation of (S)-1 also proceeds with complete stereoselectivity to afford adducts
(2S,5R)-6, (2S,5S)-6, (2S,5R)-7 and (2S,5S)-7. Hydrolysis (6N HCl, 100°C) of monoalkylated derivative (2S,5R)-3
gives enantiopure α-substituted β-amino acid (R)-8. Hydrolysis of dialkylated adducts 6 and 7 affords enantiopure
α,α-disubstituted β-amino acids (R)- or (S)-9 and (R)- or (S)-10. Related iminoester (2S,6S)-2 is alkylated with
complete diastereoselectivity to give products (2S,6S)-11–13whose hydrolysis under relatively mild conditions (2N
CF3CO2H, CH3OH, 100°C) affords enantiopure N-benzoylated β,β-disubstituted β-amino acid esters (S)-14–16,
with intact double bonds in the olefinic substituents. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
In recent years, the preparation of enantiopure α,α-dialkylated α-amino acids has deserved substantial
attention owing to the interesting chemical and biological properties exhibited by these compounds.2–6 It
can be anticipated that analogous α,α- and β,β-disubstituted β-amino acids will also exhibit interesting
chemical properties.7 Furthermore, incorporation of such gem-branched β-amino acids into unnatural
peptides is likely to confer peculiar conformational properties to the macromolecule.8,9
Aspartic acid derivatives are also interesting subjects for study in view of their relevant role in
physiological events. In particular, α-alkylated aspartic acids are a relevant class of β,β-disubstituted
β-amino acids, whose enantioselective synthesis has been reported by several groups.10
∗
Corresponding author. Fax: (525) 747-7113; e-mail: ejuarist@mail.cinvestav.mx
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00328-6

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Very recently, we described the conversion of (S)-asparagine into chiral heterocycles (S)-1 and (2S,6S)-
2, which proved to be convenient precursors of α,α- (Scheme 1a) and β,β-disubstituted β-amino acids
(Scheme 1b).1,10a
Scheme 1.
In the present paper, application of pyrimidinone (S)-1 to the preparation of four novel α,α-
disubstituted β-amino acids is reported. Furthermore, iminoester (2S,6S)-2 was alkylated with three
olefinic electrophiles to give the expected products, which were hydrolyzed under mild conditions to
afford the desired unsaturated β,β-disubstituted β-amino acids.
2. Results and discussion
2.1. Diastereoselective alkylation of (S)-1
Pyrimidinone (S)-1 was prepared as described in the literature,11 and enolate (S)-1-Li was generated
upon treatment of the heterocycle with lithium diisopropylamide (LDA), in THF solvent and under
nitrogen atmosphere. The electrophile (ethyl iodide, benzyl bromide or n-hexyl iodide) was then added
at −78°C to afford the trans alkylated products in 95% or higher diastereoselectivity (Table 1).
The high stereoselectivity achieved in the addition of (S)-1-Li to electrophiles is explained in terms of
a reactive enolate conformation with the tert-butyl group occupying the axial position,12 which sterically
hinders one enolate face (the syn face, relative to the tert-butyl group) for reaction with electrophiles.
The alkylated products (2S,5R)-3–5 are all solids. Stereochemically pure materials were readily obtained
by recrystallization.
2.2. Stereoselective alkylation of (2S,5R)-3,-4 and -5
Enolates (2S)-3-Li, (2S)-4-Li and (2S)-5-Li were generated upon treatment of the appropriate hetero-
cycle with LDA, in THF solvent and under nitrogen atmosphere. The electrophile (benzyl bromide, n-
hexyl iodide or ethyl iodide) in solvent N,N0-dimethylpropyleneurea (DMPU) was then added at −78°C
to afford the dialkylated products in high diastereoselectivity (no NMR spectroscopic evidence for minor
diastereomeric product was recorded13) and good to excellent yields (Table 2). The use of DMPU as
co-solvent was necessary to achieve the dialkylation in high yield.14 That addition of the electrophile
takes place from the face opposite to the tert-butyl group was confirmed by X-ray crystallography [see,
for example, Fig. 1 for (2S,5S)-6] and by chemical correlation.1

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Table 1
Diastereoselectivity of enolate (S)-1-Li alkylations
Table 2
Diastereoselectivity of enolate (2S)-3-Li, (2S)-4-Li and (2S)-5-Li alkylations
2.3. Hydrolysis of the C(5) alkylated pyrimidinone derivatives 3, 6 and 7 to give enantiopure α-alkylated
and α,α-dialkylated β-amino acids
The final step of the overall conversion of (S)-asparagine to 2-ethyl-3-aminopropionic acid, the
hydrolysis of the heterocycle (2S,5R)-3, was achieved by heating during 12 h with 6N HCl in a sealed
tube at 100°C (Scheme 2).
Hydrolysis of (2S,5S)-6, (2S,5R)-6, (2S,5R)-7 and (2S,5S)-7 required heating with 6N HCl in a sealed
tube at 100°C for two days. p-Dioxane was used as co-solvent in order to improve the solubility of
the substrate in the aqueous medium. While the drastic conditions employed for hydrolysis may not be

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Figure 1. Structure and solid-state conformation of (2S,5S)-1-benzoyl-2-tert-butyl-3-methyl-5-benzyl-5-ethylperhydropyrimid-
in-4-one [(2S,5S)-6]
Scheme 2.
tolerated by sensitive amino acids,15 they proved harmless to the α,α-disubstituted β-amino acids 9 and
10. Enantiopure (S)-9, (R)-9, (R)-10 and (S)-10 were purified by chromatography on an ion-exchange
column (Table 3 and Experimental).
In summary, monoalkylation and double alkylation of chiral β-aminopropionic acid derivative (S)-1
proceeds with very high stereoselectivity. Acid hydrolysis of the alkylated adducts affords enantiopure
alkylated β-amino acids in good yields.
2.4. Diastereoselective alkylation of iminoester (2S,6S)-2
Enantiopure (2S,6S)-2 was prepared according to the procedure recently described in the literature.10a
Enolate (2S,6S)-2-Li was then generated by treatment of the heterocycle with LDA, in THF solvent
and under nitrogen atmosphere. The olefinic electrophile (allyl bromide, 4-bromo-2-methyl-2-butene or
trans-1-bromo-2-pentene) was then added at −78°C to afford the trans-alkylated products, apparently
with complete diastereoselectivity.16 The trans configuration of the alkylated products (Table 4) was
assigned by chemical correlation to the known α-methyl and α-benzyl aspartic acids.10a Furthermore,
an X-ray crystallographic structure of allylic derivative (2S,6S)-11 (Fig. 2) confirms the trans relative
configuration between the allyl and isopropyl groups. Table 4 summarizes the chemical yields and
diastereoselectivities observed in the alkylation reaction, as well as some physical properties of the
isolated products.
It is interesting that addition of (2S,6S)-2-Li, with an axial isopropyl group at the stereoinducing C(2)
center, proceeds with stereoselectivities comparable with those obtained when a bulkier tert-butyl group
is present. Thus, at least in this system, inexpensive isobutyraldehyde can efficiently replace the much
costlier pivalaldehyde in the preparation of the chiral heterocycles.

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Table 3
Hydrolysis of C(5) dialkylated products 6 and 7
Table 4
Diastereoselectivity of enolate (2S,6S)-2-Li alkylations
2.5. Hydrolysis of olefinic adducts (2S,6S)-11–13
The hydrolysis of the alkylated heterocycles (2S,6S)-11–13 was achieved under relatively mild
conditions (2N CF3CO2H, 100°C, 72 h). This was important, as more drastic conditions would probably
result in intramolecular amino group addition to the olefin.15 The N-benzoylated amino acid esters (S)-
14–16 were purified by flash chromatography (Table 5).
Sections 2.4 and 2.5 demonstrate that (S)-asparagine is efficiently converted to enantiopure pyrimi-

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Figure 2. Structure and solid-state conformation of 1-benzoyl-2(S)-isopropyl-4-methoxy-6(S)-(2-propenyl)-6(S)-carbometh-
oxy-(1,2),(5,6)-tetrahydropyrimidin-4-one [(2S,6S)-11]
Table 5
Hydrolysis of products (2S,6S)-11–13 to give N-benzoylated amino acid esters (S)-14–16
dinone iminoester (2S,6S)-2, which is alkylated with very high diastereoselectivity. Hydrolysis of the
olefinic derivatives (2S,6S)-11–13 proceeds under mild conditions to afford enantiopure β,β-disubstituted
β-amino acid esters (S)-14–16, with preservation of the olefinic double bond.
3. Experimental17
3.1. 1-Benzoyl-2(S)-tert-butyl-3-methylperhydropyrimidin-4-one [(S)-1]
The procedure described by Juaristi et al.11 was followed.
3.2. 1-Benzoyl-2(S)-isopropyl-4-methoxy-6(S)-carbomethoxy-(1,2),(5,6)-tetrahydro-1,3-pyrimidine
[(2S,6S)-2]
The procedure described by Juaristi et al.10a was followed.

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3.3. General procedure for the alkylation of perhydropyrimidinone (S)-1
In a dry two-necked round-bottom flask provided with addition funnel, rubber septa and thermometer
was placed under nitrogen diisopropylamine (4.4 mmol) in 50 mL of THF, which was then cooled to
−20°C before the slow addition of 4.8 mmol of n-BuLi (ca. 1.8 M in n-hexane). The resulting solution
was stirred at −20°C for 20 min and then cooled to −78°C before the dropwise addition of 4.0 mmol of
the heterocycle in 30 mL of THF. Stirring was continued for 1 h at −78°C in order to secure the complete
formation of the enolate. The alkylating agent (4.6 mmol, 15% excess) was then added dropwise via
syringe and the reaction mixture was stirred at −78°C until no further changes were detected by TLC
(silica gel 60 F254, 2–3 h). At this point the reaction was quenched by the addition of saturated aqueous
NH4Cl solution, allowed to warm to ambient temperature and extracted with two portions of CH2Cl2.
The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in a rotary
evaporator.
3.4. 1-Benzoyl-2(S)-tert-butyl-3-methyl-5(R)-ethylperhydropyrimidin-4-one [(2S,5R)-3]
The general procedure (Section 3.3) was followed for the alkylation of 1.0 g (3.6 mmol) of (S)-1 with
0.31 mL (4.36 mmol) of ethyl iodide. Purification of the crude product by flash chromatography on silica
gel, 230–400 mesh (n-hexane:ethyl acetate 7:3) (TLC: n-hexane:ethyl acetate 2:3, Rf=0.33) afforded 0.89
28
1
g (80% yield) of (2S,5R)-3, mp 85–86°C. [α] =+27.5 (c=1, CHCl3). H NMR (CDCl3, 400 MHz) δ
D
0.60 (t, J=6.2 Hz, 3H), 1.15 (s, 9H), 1.35 (m, 1H), 1.72 (m, 1H), 2.29 (br, 1H), 3.10 (s, 3H), 3.50 (d,
J=13.8 Hz, 1H), 3.75 (dd, J1=13.8 Hz, J2=6.4 Hz, 1H), 5.78 (s, 1H), 7.43 (m, 5H). 13C NMR (CDCl3,
67.8 MHz) δ 11.2, 24.8, 28.4, 37.7, 39.2, 41.3, 45.7, 73.7, 126.6, 128.6, 130.1, 135.0, 167.5, 170.4. Anal.
calcd for C18H26N2O2: C, 71.49; H, 8.67. Found: C, 71.47; H, 8.81.
3.5. 1-Benzoyl-2(S)-tert-butyl-3-methyl-5(R)-n-hexylperhydropyrimidin-4-one [(2S,5R)-4]
The procedure described by Juaristi et al.11 was followed.
3.6. 1-Benzoyl-2(S)-tert-butyl-3-methyl-5(R)-benzylperhydropyrimidin-4-one [(2S,5R)-5]
The procedure described by Juaristi et al.11 was followed.
3.7. General procedure for the alkylation of α-substituted perhydropyrimidinones
In a dry two-necked round-bottom flask equipped with an addition funnel, rubber septa and thermo-
meter was placed, under nitrogen, diisopropylamine (1.1 mmol) in 15 mL of THF. This was then cooled
to −20°C before the slow addition of 1.1 mmol of n-BuLi (ca. 2.3 M in n-hexane). The resulting solution
was stirred at −20°C for 30 min before the dropwise addition of 1.0 mmol of monoalkylated heterocycle
in 10 mL of THF. Stirring was continued for 1 h at −20°C in order to secure the complete formation
of the enolate, before the reaction temperature was lowered to −78°C. The alkylating agent (1.1 mmol,
10% excess) and DMPU (1.1 mmol) was then added dropwise via syringe, and the reaction mixture was
stirred at −78°C until no further changes were detected by TLC (silica gel 60 F254). At this point the
reaction was quenched by the addition of saturated aqueous NH4Cl solution, allowed to warm to ambient
temperature and extracted with two portions of CH2Cl2. The combined organic extracts were dried over
anhydrous Na2SO4, filtered and concentrated in a rotary evaporator.

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3.8. (2S,5R)-1-Benzoyl-2-tert-butyl-3-methyl-5-benzyl-5-ethylperhydropyrimidin-4-one [(2S,5R)-6]
The general procedure was followed for the alkylation of 0.97 g (3.2 mmol) of (2S,5R)-3 with 0.42
mL (3.5 mmol, 1.1 equiv.) of benzyl bromide. Purification of the crude product by flash chromatography
(n-hexane:ethyl acetate 9:1) (TLC: n-hexane:ethyl acetate 1:1, Rf=0.42) afforded 1.2 g (95.3% yield) of
(2S,5R)-6 as a yellowish oil. [α]28=−11.6 (c=1, CHCl3). 1H NMR (CDCl3, 400 MHz) δ 0.80 (t, J=7.5
D
Hz, 3H), 0.86 (s, 9H), 1.84 (m, 2H), 2.50 (d, J=13.2 Hz, 1H), 2.73 (d, J=13.2 Hz, 1H), 2.95 (s, 3H), 3.81
(dd, J=14.3 Hz, 2H), 5.78 (s, 1H), 7.20 (m, 10H). 13C NMR (CDCl3, 100 MHz), δ 8.4, 27.4, 28.8, 37.4,
38.0, 38.8, 43.7, 45.3, 74.0, 126.6, 127.6, 128.2, 128.5, 130.2, 130.6, 134.7, 137.3, 170.0, 173.4. HRMS
calcd m/z for C25H33N2O2 (M+ +1): 393.2542. Found: 393.2551.
3.9. (2S,5S)-1-Benzoyl-2-tert-butyl-3-methyl-5-benzyl-5-ethylperhydropyrimidin-4-one [(2S,5S)-6]
The general procedure was followed for the alkylation of 0.80 g (2.38 mmol) of (2S,5R)-5 with 0.21
mL (2.62 mmol, 1.1 equiv.) of ethyl iodide. Purification of the crude product by flash chromatography
(n-hexane:ethyl acetate 9:1) (TLC: n-hexane:ethyl acetate 1:1, Rf=0.43) afforded 1.1 g (76% yield) of
(2S,5S)-6 as white crystals, mp 106–107°C. [α]28=−35.3 (c=1, CHCl3). 1H NMR (CDCl3, 400 MHz) δ
D
0.50 (t, J=7.5 Hz, 3H), 0.70 (s, 9H), 1.41 (m, 1H), 1.65 (m, 1H), 2.14 (d, J=13.4 Hz, 1H), 3.20 (s, 3H),
3.35 (d, J=13.4 Hz, 1H), 3.61 (dd, J=14.3 Hz, 2H), 5.78 (s, 1H), 7.32 (m, 10H). 13C NMR (CDCl3, 100
MHz) δ 8.4, 28.0, 31.3, 37.7, 38.2, 38.8, 47.3, 47.4, 73.7, 126.7, 127.3, 128.3, 128.7, 130.2, 131.2, 134.9,
137.2, 170.7, 172.1. Anal. calcd for C25H32N2O2: C, 76.49; H, 8.21. Found: C, 76.39; H, 8.36. X-Ray
crystallographic structure, see Fig. 1.
3.10. (2S,5R)-1-Benzoyl-2-tert-butyl-3-methyl-5-benzyl-5-n-hexylperhydropyrimidin-4-one [(2S,5R)-7]
The general procedure was followed for the alkylation of 0.87 g (2.43 mmol) of (2S,5R)-4 with 0.38
mL (2.9 mmol, 1.1 equiv.) of n-hexyl iodide. Purification of the crude product by flash chromatography
(n-hexane:ethyl acetate 9:1) (TLC: n-hexane:ethyl acetate 1:1, Rf=0.50) afforded 0.80 g (80% yield) of
(2S,5R)-7 as colorless oil. [α]28=−29.0 (c=1.1 CHCl3). 1H NMR (CDCl3, 400 MHz) δ 0.83 (t, J=7.3 Hz,
D
3H), 1.17 (s, 9H), 1.29 (m, 8H), 1.73 (m, 2H), 2.54 (d, J=13.3 Hz, 1H), 2.73 (d, J=13.4 Hz, 1H), 2.92 (s,
3H), 3.90 (dd, J=14.3 Hz, 2H), 5.98 (s, 1H), 7.25 (m, 10H). 13C NMR (CDCl3, 100 MHz) δ 14.0, 22.5,
23.8, 24.2, 28.8, 29.9, 31.7, 37.9, 39.8, 40.3, 44.0, 45.2, 74.2, 126.5, 127.4, 128.2, 128.6, 130.2, 130.5,
134.6, 136.2, 169.9, 173.5. HRMS calcd m/z for C29H40N2O2: 449.3168. Found: 449.3168.
3.11. (2S,5S)-1-Benzoyl-2-tert-butyl-3-methyl-5-benzyl-5-n-hexylperhydropyrimidin-4-one [(2S,5S)-7]
The general procedure was followed for the alkylation of 1.0 g (2.97 mmol) of (2S,5R)-5 with 0.48
mL (3.26 mmol, 1.1 equiv.) of n-hexyl iodide. Purification of the crude product by flash chromatography
(n-hexane:ethyl acetate 9:1) (TLC: n-hexane:ethyl acetate 1:1, Rf=0.52) afforded 0.82 g (63% yield) of
(2S,5S)-7 as a colorless oil. [α]28=−11.3 (c=1 CHCl3). 1H NMR (CDCl3, 270 MHz) δ 0.63 (s, 9H), 0.84
D
(t, J=6.9 Hz, 3H), 1.20 (m, 10H), 2.15 (d, J=13.3 Hz, 1H), 2.90 (s, 3H), 3.33 (d, J=13.3 Hz, 1H), 3.61 (dd,
J=14.3 Hz, 2H), 5.75 (s, 1H), 7.10 (m, 5H), 7.40 (m, 5H). 13C NMR (CDCl3, 67.8 MHz) δ 14.1, 22.7,
23.6, 25.0, 28.0, 29.9, 31.7, 37.3, 38.0, 39.4, 40.0, 47.3, 73.7, 126.7, 127.4, 128.2, 128.6, 130.2, 131.2,
134.9, 137.2, 170.6, 172.2. HRMS calcd m/z for C29H40N2O2: 449.3168. Found: 449.3150.

E. Juaristi et al. / Tetrahedron: Asymmetry 10 (1999) 3493–3505
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3.12. General procedure for the hydrolysis of monoalkylated pyrimidinone 3 and dialkylated pyrimidi-
nones 6 and 7
A suspension of 0.8 mmol of adduct 3 in 20 mL of 6N HCl was heated in a sealed ampoule to 100°C
until complete reaction (see Sections 3.14–3.19). The solution was then allowed to cool to ambient
temperature and the precipitate of benzoic acid was removed by filtration. The filtrate was extracted with
three 20 mL portions of EtOAc and the aqueous phase was concentrated at reduced pressure to afford a
1:1 mixture of the amino acid hydrochloride and methylammonium chloride, which was adsorbed onto
acidic ion-exchange resin Dowex 50WX8. The resin was washed with distilled water until the washings
emerged neutral, and then the free amino acid was recovered with 1N ammonium hydroxide. Evaporation
afforded the free amino acid, which was dried under high vacuum at 40°C.
3.13. (R)-(+)-2-Ethyl-3-aminopropionic acid [(R)-8]
Derivative (2S,5R)-3 (0.21 g, 0.71 mmol) was hydrolyzed according to the general procedure (100°C,
12 h) to afford 74 mg (89.3% yield) of pure, free amino acid (R)-8, mp 206–207°C. [α]28=+4.6 (c=1,
D
H2O). 1H NMR (D2O, 270 MHz) δ 0.83 (t, J=7.6 Hz, 3H), 1.52 (m, 2H), 2.4 (m, 1H), 2.95 (dd, J1=12.7
Hz, J2=5.2 Hz, 1H), 3.04 (dd, J1=12.7 Hz, J2=8.7 Hz, 1H). 13C NMR (D2O, 67.8 MHz) δ 10.7, 23.2,
40.9, 47.0, 181.1.
3.14. (R)-(−)-α-Benzyl-α-ethyl-β-aminopropionic acid [(R)-9]
erivative (2S,5R)-6 (0.12 g, 0.305 mmol) was hydrolyzed according to the general procedure (100°C,
48 h) to afford 63 mg (85% yield) of pure, free amino acid (R)-9, mp 240–242°C. [α]28=−11.5 (c=1, 1
D
N HCl). 1H NMR (D2O, 300 MHz) δ 0.65 (t, J=7.5 Hz, 3H), 1.43 (m, 2H), 2.62 (d, J=13.8 Hz, 1H), 2.73
(d, J=13.8 Hz, 1H), 2.83 (dd, J1=13.8 Hz, J2=16.15 Hz, 2H), 7.0 (m, 5H). 13C NMR (D2O, 75.5 MHz) δ
7.7, 25.9, 39.8, 41.9, 49.4, 127.5, 128.7, 130.2, 135.8, 177.8.
3.15. (S)-(+)-α-Benzyl-α-ethyl-β-aminopropionic acid [(S)-9]
erivative (2S,5S)-6 (0.12 g, 0.305 mmol) was hydrolyzed according to the general procedure (100°C,
48 h) to afford 58 mg (88% yield) of pure, free amino acid (S)-9, mp 240–242°C. [α]28=+11.5 (c=1, 1
D
N HCl). 1H and 13C NMR spectra were similar to those reported for (R)-9.
3.16. (R)-(−)-α-Benzyl-α-n-hexyl-β-aminopropionic acid [(R)-10]
erivative (2S,5R)-7 (0.20 g, 0.447 mmol) was hydrolyzed according to the general procedure (100°C,
48 h) to afford 0.10 g (87% yield) of pure, free amino acid (R)-10, mp 173–175°C. [α]28=−8.0 (c=1, 1
D
N HCl). 1H NMR (D2O, 270 MHz) δ 0.5 (t, J=7.2 Hz, 3H), 0.52 (m, 8H), 0.90 (m, 2H), 2.27 (dd, J=13.8
Hz, 2H), 2.90 (dd, J=6.9 Hz, 2H), 6.90 (m, 5H). 13C NMR (D2O, 75.5 MHz) δ 13.6, 22.2, 23.3, 29.0,
31.1, 33.1, 40.2, 42.6, 49.2, 127.7, 128.9, 130.3, 135.9, 178.0.

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3.17. (S)-(+)-α-Benzyl-α-n-hexyl-β-aminopropionic acid [(S)-10]
erivative (2S,5S)-7 (0.11 g, 0.248 mmol) was hydrolyzed according to the general procedure (100°C,
48 h) to afford 56 mg (86.5% yield) of pure, free amino acid (S)-10, mp 173–175°C. [α]28=+8.0 (c=1, 1
D
N HCl). 1H and 13C NMR spectra were similar to those reported for (R)-10.
3.18. General procedure for the reaction of pyrimidine enolate [(2S,6S)-2-Li] with electrophiles
ithium chloride (6 equiv.) was placed in a 100 mL round-bottom flask provided with stirring bar and
under nitrogen. Diisopropylamine (1.0 equiv.) in THF was added, and the resulting mixture was cooled to
−20°C before the slow addition of 1.0 equiv. of n-BuLi (ca. 1.8 M in hexane). The resulting solution was
stirred at −20°C for 20 min and then cooled to −78°C before the dropwise addition of 1.0 equiv. of imino
ester (2S,6S)-2 in THF. Stirring was continued for 1 h at −78°C in order to secure the complete formation
of the enolate. The alkylating agent (1.15 equiv.) was then added dropwise via syringe, and the reaction
mixture was stirred at −78°C for 2 h and at ambient temperature overnight. At this point the reaction
was quenched by the addition of saturated aqueous NH4Cl solution and extracted with three portions of
CH2Cl2. The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated at reduced
pressure, maintaining the temperature below 30°C.
3.19. 1-Benzoyl-2(S)-isopropyl-4-methoxy-6(S)-carbomethoxy-6(S)-(2-propenyl)-(1,2),(5,6)-tetra-
hydro-1,3-pyrimidine [(2S,6S)-11]
he general procedure was followed with 1.30 g (4.09 mmol) of iminoester (2S,6S)-2 in 40 mL of
THF and 0.42 mL (4.90 mmol) of allyl bromide. The crude product was purified by flash column
chromatography (n-hexane:ethyl acetate 9:1) (TLC: n-hexane:ethyl acetate 3:1; Rf=0.43) to give 1.46
g (90% yield) of (2S,6S)-11 as a white, crystalline solid, mp 151–152°C. [α]28=−21.5 (c=1, CHCl3). 1H
D
NMR (CDCl3, 400 MHz) δ 0.78 (d, J=6.6 Hz, 6H), 1.96 (m, 1H), 2.50 (d, J=16.1 Hz, 1H), 2.62 (dd,
J1=14.5 Hz, J2=7.7 Hz, 1H), 2.84 (d, J=16.1 Hz, 1H), 3.33 (dd, J1=14.5 Hz, J2=7.7 Hz, 1H), 3.69 (s,
3H), 3.80 (s, 3H), 5.07 (s, 1H), 5.10 (d, J=10.6 Hz, 1H), 5.33 (d, J=9.2 Hz, 1H), 5.75 (m, 1H), 7.40 (m,
5H). 13C NMR (CDCl3, 100 MHz) δ 19.3, 19.9, 34.0, 35.6, 40.0, 52.6, 53.1, 62.1, 77.7, 119.3, 128.1,
128.4, 129.9, 132.3, 136.4, 163.3, 170.9, 173.3. Anal. calcd for C20H26N2O4: C, 67.01; H, 7.31. Found:
C, 67.15; H, 7.44.
3.20. 1-Benzoyl-2(S)-isopropyl-4-methoxy-6(S)-carbomethoxy-6(S)-(3-methyl-2-butenyl)-(1,2),(5,6)-
tetrahydro-1,3-pyrimidine [(2S,6S)-12]
The general procedure was followed with 0.61 g (1.90 mmol) of iminoester (2S,6S)-2 in 40 mL of
THF and 0.28 mL (2.40 mmol) of 1-bromo-3-methyl-2-butene. The crude product was purified by flash
chromatography (n-hexane:ethyl acetate 9:1) (TLC: n-hexane:ethyl acetate 3:1; Rf=0.45) to give 0.48 g
(54% yield) of (2S,6S)-12 as a viscous oil. [α]28=+24.0 (c=1, CHCl3). 1H NMR (CDCl3, 400 MHz) δ
D
0.69 (d, J=6.6 Hz, 3H), 0.70 (d, J=6.6 Hz, 3H), 1.47 (s, 3H), 1.61 (s, 3H), 1.88 (m, 1H), 2.32 (d, J=15.9
Hz, 1H), 2.53 (dd, J1=14.9 Hz, J2=8.2 Hz, 1H), 2.70 (d, J=15.9 Hz, 1H), 3.19 (dd, J1=14.9 Hz, J2=7.5
Hz, 1H), 3.59 (s, 3H), 3.70 (s, 3H), 4.98 (t, J=8.1 Hz, 1H), 5.24 (d, J=9.4 Hz, 1H), 7.30 (m, 5H). 13C
NMR (CDCl3, 100 MHz) δ 17.9, 19.4, 19.9, 26.3, 33.8, 34.0, 35.5, 52.5, 53.1, 62.8, 77.7, 118.5, 128.1,
128.3, 129.9, 135.5, 136.5, 163.7, 170.8, 173.7. HRMS calcd m/z for C22H30N2O4: 387.2271. Found:
387.2284.

E. Juaristi et al. / Tetrahedron: Asymmetry 10 (1999) 3493–3505
3503
3.21. 1-Benzoyl-2(S)-isopropyl-4-methoxy-6(S)-carbomethoxy-6(S)-(2(E)-pentenyl)-(1,2),(5,6)-tetra-
hydro-1,3-pyrimidine [(2S,6S)-13]
The general procedure was followed with 0.55 g (1.73 mmol) of iminoester (2S,6S)-2 in 40 mL of THF
and 0.24 mL (2.07 mmol) of 1-bromo-2(E)-pentene. The crude product was purified by flash column
chromatography (n-hexane:ethyl acetate 9:1) (TLC: n-hexane:ethyl acetate 3:1; Rf=0.44) to give 0.47 g
(58% yield) of (2S,6S)-13 as a viscous oil. [α]28 =+16.0 (c=1, CHCl3). 1H NMR (CDCl3, 400 MHz) δ
D
0.77 (d, J=6.6 Hz, 6H), 0.88 (t, J=7.3 Hz, 3H), 1.97 (m, 1H), 2.01 (m, 2H), 2.40 (d, J=15.7 Hz, 1H), 2.68
(dd, J1=15.0 Hz, J2=8.4 Hz, 1H), 2.80 (d, J=15.7 Hz, 1H), 3.28 (dd, J1=13.2 Hz, J2=7.3 Hz, 1H), 3.66 (s,
3H), 3.78 (s, 3H), 5.27 (m, 1H), 5.32 (d, J=9.2 Hz, 1H), 5.48 (m, 1H), 7.40 (m, 5H). 13C NMR (CDCl3,
100 MHz) δ 14.0, 19.3, 19.9, 20.6, 32.9, 34.0, 35.6, 52.5, 52.9, 62.4, 77.7, 122.4, 128.1, 128.3, 129.8,
135.4, 136.4, 163.4, 170.8, 172.5.
3.22. General procedure for the hydrolysis of the alkylated pyrimidines 11–13
A solution of 1 mmol of adduct in 10 mL of methanolic 2 N CF3CO2H was heated in a sealed ampoule
to 100°C for 72 h. The solution was then allowed to cool to ambient temperature, and was concentrated
in a rotary evaporator. The residue was dissolved in 200 mL of CH2Cl2, washed three times with H2O,
dried over anh. Na2SO4 and concentrated in the rotary evaporator to afford the crude product that was
purified by flash chromatography (n-hexane:ethyl acetate 9:1).
3.23. N-Benzoyl dimethyl ester of (S)-α-(2-propenyl)-aspartic acid [(S)-14]
Derivative (2S,6S)-11 (200 mg, 0.55 mmol) was hydrolyzed according to the general procedure to
afford 145 mg (96% yield) of (S)-14 as a viscous oil (TLC: n-hexane:ethyl acetate 3:1; Rf=0.36).
[α]28=−29.4 (c=1, CHCl3). 1H NMR (CDCl3, 400 MHz) δ 2.54 (dd, J1=13.8 Hz, J2=7.5 Hz, 1H), 3.01
D
(d, J=16.7 Hz, 1H), 3.40 (ddt, J1=13.9 Hz, J2=7.3 Hz, J3=1.1 Hz, 1H), 3.60 (s, 3H), 3.81 (d, J=16.7
Hz, 1H), 3.82 (s, 3H), 5.10 (m, 2H), 5.60 (m, 1H), 7.36 (br, 1H), 7.46 (m, 3H), 7.76 (m, 2H). 13C NMR
(CDCl3, 100 MHz) δ 39.3, 51.8, 53.1, 61.8, 119.7, 126.9, 128.6, 131.3, 131.7, 134.6, 166.6, 171.0, 172.9.
3.24. N-Benzoyl dimethyl ester of (S)-α-(3-methyl-2-butenyl)-aspartic acid [(S)-15]
Derivative (2S,6S)-12 (418 mg, 1.08 mmol) was hydrolyzed according to the general procedure to
afford 193 mg (62% yield) of (S)-15 as a viscous oil (TLC: n-hexane:ethyl acetate 3:1; Rf=0.34).
[α]28=−37.5 (c=1, CHCl3). 1H NMR (CDCl3, 400 MHz) δ 1.52 (s, 3H), 1.60 (s, 3H), 2.53 (dd, J1=14.5
D
Hz, J2=7.7 Hz, 1H), 3.00 (d, J=16.5 Hz, 1H), 3.26 (dd, J1=14.3 Hz, J2=7.7 Hz, 1H), 3.55 (s, 3H), 3.77
(s, 3H), 3.80 (d, J=16.5 Hz, 1H), 4.91 (t, J=7.7 Hz, 1H), 7.33 (br, 1H), 7.40 (m, 3H), 7.72 (m, 2H). 13
C
NMR (CDCl3, 100 MHz) δ 17.8, 25.9, 33.9, 39.1, 51.6, 52.9, 61.8, 116.8, 126.9, 128.5, 131.5, 134.8,
136.6, 166.6, 171.0, 173.1. HRMS calcd m/z for C18H23NO5: 334.1654. Found: 334.1666.
3.25. N-Benzoyl dimethyl ester of (S)-α-[(E)-2-pentenyl]-aspartic acid [(S)-16]
Derivative (2S,6S)-13 (102 mg, 0.26 mmol) was hydrolyzed according to the general procedure
to afford 65 mg (86% yield) of (S)-16 as a viscous oil (TLC: n-hexane:ethyl acetate 3:1; Rf=0.40).
28
1
[α] =−24.0 (c=1, CHCl3). H NMR (CDCl3, 400 MHz) δ 0.86 (t, J=7.7 Hz, 3H), 1.98 (m, 2H), 2.59
D
(dd, J1=14.3 Hz, J2=7.7 Hz, 1H), 3.03 (d, J=16.5 Hz, 1H, 3.36 (dd, J1=14.3 Hz, J2=7.7 Hz, 1H), 3.59 (s,

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E. Juaristi et al. / Tetrahedron: Asymmetry 10 (1999) 3493–3505
3H), 3.80 (s, 3H), 3.85 (d, J=16.5 Hz, 1H), 5.13 (m, 1H), 5.50 (m, 1H), 7.36 (br, 1H), 7.40 (m, 3H), 7.76
(m, 2H). 13C NMR (CDCl3, 100 MHz) δ 14.1, 20.6, 32.9, 39.2, 51.7, 53.1, 61.7, 120.9, 126.9, 128.5,
131.6, 134.7, 136.5, 166.6, 171.0, 173.0. HRMS calcd m/z for C18H23NO5: 334.1654. Found: 334.1653.
Acknowledgements
We are indebted to Mr. L. Velasco (Instituto de Química, UNAM) for the high-resolution mass spectra,
and to CONACYT for financial support via grant L0006-9608.
References
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E. Juaristi et al. / Tetrahedron: Asymmetry 10 (1999) 3493–3505
3505
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13. Slow rotation around the N-benzoyl group in the disubstituted heterocyclic products gives rise to two sets of signals for
the corresponding isomers. A single set of signals is observed at T=145°C (DMSO-d6).
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16. A single product was detected by both 1H and 13C NMR spectroscopy (400 and 100 MHz, respectively).
17. For a description of general experimental procedures, see Ref. 1.