Stereoselective alkylation of C2-symmetric chiral N- phthaloylglycinamides in the preparation of enantiopure α-amino acids

Article abstract of DOI:10.1016/S0957-4166(00)00066-5

The novel, chiral glycinamides (S,S)-3 and (S,S)-4 were prepared in good yields from C₂-symmetric chiral amines (S,S)-1 and (S,S)-2, respectively. Enolate formation and addition to methyl iodide and benzyl bromide proceeded in good yield and high diastereoselectivity, especially in the presence of LiCl or DMPU. Removal of the phthaloyl protecting group with hydrazine, followed by hydrolysis with 6N HCl, converted the benzylated product (S,S,S)- 7 to enantiopure (S)-phenylalanine. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00066-5

Tetrahedron: Asymmetry 11 (2000) 1411±1423
Stereoselective alkylation of C2-symmetric chiral
N-phthaloylglycinamides in the preparation of
enantiopure a-amino acids1
Adelfo Reyes and Eusebio Juaristi*
Â
Departamento de Quõmica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional,
Â
Apartado Postal 14-740, 07000 Mexico City, D.F., Mexico
Â
Received 9 February 2000; accepted 10 February 2000
Abstract
The novel, chiral glycinamides (S,S)-3 and (S,S)-4 were prepared in good yields from C2-symmetric
chiral amines (S,S)-1 and (S,S)-2, respectively. Enolate formation and addition to methyl iodide and
benzyl bromide proceeded in good yield and high diastereoselectivity, especially in the presence of LiCl or
DMPU. Removal of the phthaloyl protecting group with hydrazine, followed by hydrolysis with 6N HCl,
converted the benzylated product (S,S,S)-7 to enantiopure (S)-phenylalanine. # 2000 Elsevier Science Ltd.
All rights reserved.
1. Introduction
Because of the great importance of amino acids in physiological and pharmacological events,
and because biological interactions are usually stereospeci®c,2 during the last two decades we
have witnessed an unprecedented amount of research work directed to the enantioselective
synthesis of chiral amino acids.3
Among the various methods available for the preparation of enantioenriched a-amino acids,
those employing chiral glycine derivatives4 15 (Fig. 1) have been particularly successful, and
among these, `open-chain' glycine substrates I±L are attractive from the point of view of simplicity
and relative low cost.
Motivated in great measure by the work of Katsuki and co-workers,13 who demonstrated
the eciency of C2-symmetric chiral auxiliaries16 in glycinamide J (Fig. 1), and encouraged by the
accessibility of C2-symmetric chiral amines (S,S)-117 and (S,S)-2,18,19 we decided to explore the
* Corresponding author. Fax: (525) 747-7113; e-mail: juaristi@relaq.mx
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00066-5

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A. Reyes, E. Juaristi / Tetrahedron: Asymmetry 11 (2000) 1411±1423
Figure 1.
potential of N-phthaloylglycinamides (S,S)-3 and (S,S)-4 (Fig. 2) for the enantioselective synthesis
of chiral a-amino acids.
2. Stereoselectivity of alkylation of (S,S)-3
Preliminary experiments showed poor diastereoselectivity in the alkylation reaction of enolates
derived from chiral glycine derivatives M and N. Nevertheless, promising results were observed
with N-phthaloyl protected20 glycinamide (S,S)-3.

A. Reyes, E. Juaristi / Tetrahedron: Asymmetry 11 (2000) 1411±1423
1413
Figure 2.
Chiral glycinamide (S,S)-3 was obtained in 74.2% overall yield according to the synthetic route
depicted in Scheme 1.
The results of alkyl halide addition (at ^78ꢀC) to enolate (S,S)-3-Li, generated by metallation
of the corresponding glycinamide with LDA or LHMDS, are summarized in Table 1. Examina-
tion of entries 1±4 reveals that better results (higher yields and diastereoselectivities) are achieved
when LDA base is used for enolate formation; indeed, methylation takes place with 81% ds and
benzylation proceeds with 95% ds.
Recently,21 addition of `inert' salts to reaction media has been found to a€ect the stereo-
selectivity of alkylation reactions. Thus, Table 1 includes data obtained in the presence of six
equivalents of lithium chloride. As can be appreciated in entries 5 and 10, diastereoselectivities do
seem to improve with LiCl as additive.22
In this context, use of dimethylpropylene urea (DMPU) is known to activate the reaction of
lithium carbanions with electrophiles.23 In the present study, the diastereoselectivity of the
benzylation reaction (entries 3 versus 11±14, Table 1) did improve in the presence of one to six
equivalents of DMPU,24 so that a single diastereomeric product was observed (ds >97%).
Nevertheless, the diastereoselectivity of the methylation reaction (entries 1 versus 6±9) was erratic.

1414
A. Reyes, E. Juaristi / Tetrahedron: Asymmetry 11 (2000) 1411±1423
Scheme 1.
It is expected that seemingly contrasting observations such as those reported here will be under-
stood as knowledge of structure and aggregation state of Li enolates is more advanced.22,25
3. Stereoselectivity of alkylation of (S,S)-4
Chiral glycinamide (S,S)-4 was obtained in 82.3% yield according to the synthetic procedure
shown in Scheme 2. Diphenylaziridine (S,S)-2 has proven an ecient chiral auxiliary, most
notably in the work of Tanner et al.26
The results of alkyl halide addition (at ^78ꢀC) to enolate (S,S)-4-Li, generated by metallation
of the corresponding glycinamide with LDA or LHMDS, are summarized in Table 2.
As was observed in the alkylation of (S,S)-3 (see above), LDA proved a more convenient base
than LHMDS (entries 1±4 in Table 2), a€ording higher diastereoselectivities (65% ds in the
methylation reaction and 83% ds in the benzylation reaction). The moderate yields achieved in
these reactions are ascribed to decomposition products whose structure could not be established.
Addition of LiCl (6 equiv.) to the reaction mixture led to decomposition products, probably via
Li+-catalyzed aziridine ring opening processes.27 In contrast, use of DMPU as cosolvent (6 equiv.)
proved quite bene®cial in the case of the benzylation reaction, improving the observed diastereo-
selectivity from 83% in THF to higher than 97% ds in THF±DMPU (entries 4 and 8 in Table 2).
The potential of (S,S)-4 in the preparation of a,a-disubstituted a-amino acids was then
explored. Treatment of enolate 9-Li (R=CH3) with benzyl bromide in the presence of 6 equiv. of
DMPU a€orded a 67:33 diastereomeric mixture of dialkylated derivative 11 (Scheme 3). By the
same token, methylation of enolate 10-Li (R=CH2Ph) gave a 40:60 mixture of 11 (Scheme 3).
The low diastereoselectivity in the alkylation of 9 and 10 is probably due in part to the higher
temperature (^20ꢀC instead of ^78ꢀC) required for this reaction to proceed.

A. Reyes, E. Juaristi / Tetrahedron: Asymmetry 11 (2000) 1411±1423
1415
Table 1
Diastereoselectivity of enolate (S,S)-3-Li alkylations
4. Assignment of con®guration of the diastereoisomeric products 6, 7, 9 and 10
The absolute con®guration of the newly created stereogenic center in the major diastereomeric
product of benzylation of (S,S)-3 was ascertained by removal of the N-phthaloyl protecting
group,28 followed by acid hydrolysis to the known a-amino acid (S)-phenylalanine, (S)-1329
(Scheme 4).

1416
A. Reyes, E. Juaristi / Tetrahedron: Asymmetry 11 (2000) 1411±1423
Direct hydrolysis (6N HCl, 100ꢀC, 18 h) of product mixtures containing (S,S,S)-6 and (S,S,S)-
9 as the major component a€orded (S)-alanine. Similarly, a sample enriched in the benzylated
aziridine derivative (S,S,S)-10 was hydrolyzed to give (S)-phenylalanine. Thus, enolate alkylation
takes place on the Si face of both (S,S)-3-Li and (S,S)-4-Li.
Table 2
Diastereoselectivity of enolate (S,S)-4-Li alkylations
Scheme 2.

A. Reyes, E. Juaristi / Tetrahedron: Asymmetry 11 (2000) 1411±1423
1417
Examination of molecular models suggests that conformer O in the (Z)-diastereoisomer of
enolate (S,S)-3-Li should correspond to an energy minimum, which is predicted to react on the Si
face since the bulky phenyl rings inhibit electrophile addition on the Re face (Fig. 3a). By the
Scheme 3.
Scheme 4.
Figure 3.

1418
A. Reyes, E. Juaristi / Tetrahedron: Asymmetry 11 (2000) 1411±1423
same token, conformation P of aziridine-containing enolate (S,S)-4-Li should represent the
energy minimum; it can be appreciated that the Re face of the enolate is prevented by the three-
membered ring from reacting with the electrophile, so that reaction takes place on the Si face
(Fig. 3b).
In summary, chiral N-phthaloylglycinamides (S,S)-3 and (S,S)-4 were prepared in good yields
from C2-symmetric amines (S,S)-1 and (S,S)-2, respectively. Enolates (S,S)-3-Li and (S,S)-4-Li
were alkylated with good to excellent diastereoselectivity, especially in the presence of LiCl or
DMPU as additive or cosolvent. Hydrolysis of the main product (S,S,S)-7 with 6N HCl a€orded
enantiopure (S)-phenylalanine in good yield.
5. Experimental30
5.1. (S,S)-N,N-Bis-(1-phenylethyl)amine (S,S)-1
This chiral amine was prepared according to the procedure described in the literature.17
‰ꢀŠD28=^205.3 (c=4.92, C6H6) {lit.17 ‰ꢀŠ ^197.3 (c=3.65, C6H6)}.
D
5.2. (2S,3S)-2,3-Diphenylaziridine (S,S)-2
This chiral amine was prepared according to the recently reported procedure.19 ‰ꢀŠD28=^334.3
(c=1.02, CHCl3) {lit.31 ‰ꢀŠD28=^341.0 (c=0.83, CHCl3)}.
5.3. (S,S)-2-Bromo-N,N-bis(10-phenylethyl)acetamide (S,S)-5
A solution of 11.25 g (50.0 mmol) of chiral amine (S,S)-1 in 125 mL of CH2Cl2 was cooled to
0ꢀC under nitrogen atmosphere before the dropwise addition of 4.4 mL (10.1 g, 50.0 mmol) of
bromoacetyl bromide. The resulting suspension was then treated with 7.6 mL (5.55 g, 55.0 mmol)
of triethylamine, and stirring at 0ꢀC was continued for 3 h. The reaction mixture was washed with
50 mL of cold water, 25 mL of aqueous 5% NaOH, and ®nally with two 50 mL portions of cold
water. The organic phase was dried over anhyd. Na2SO4, ®ltered, and concentrated to give the
crude product that was puri®ed by ¯ash chromatography (hexane:EtOAc, 8:2). The desired pro-
duct (15.3 g, 88.6% yield) was obtained as a white solid, mp 94±95ꢀC. ‰ꢀŠD28=^125.0 (c=3.8,
CHCl3). H NMR (CDCl3, 60ꢀC, 400 MHz) ꢁ 1.78 (d, J=7.0 Hz, 6H), 3.69 (d, J=11.2 Hz, 1H),
1
3.75 (d, J=11.2 Hz, 1H), 5.05±5.30 (br s, 2H), 7.05±7.25 (m, 10H). 13C NMR (CDCl3, 60ꢀC, 100
MHz) ꢁ 18.6, 28.6, 54.0, 127.5, 128.3, 140.4, 166.7. Anal. calcd for C18H20BrNO: C, 62.43; H,
5.82. Found: C, 62.61; H, 5.81.
5.4. (S,S)-N0,N0-Bis(10-phenylethyl)-N-phthaloylglycinamide (S,S)-3
To a suspension of 4.34 g (29.5 mmol) of phthalimide in 80 mL of THF was added dropwise
4.5 mL (4.5 g, 29.5 mmol) of DBU, and the resulting mixture was stirred at ambient temperature
for 0.5 h. Bromide (S,S)-5 (10.25 g, 29.5 mmol) in 20 mL of THF was added, and the reaction
mixture was stirred for an additional hour. The solvent was then removed in the rotary evap-
orator and the residue was suspended in 100 mL of water, to be extracted with two 50 mL
portions of CH2Cl2. The organic extracts were dried over anhyd. Na2SO4 and concentrated in the

A. Reyes, E. Juaristi / Tetrahedron: Asymmetry 11 (2000) 1411±1423
1419
rotary evaporator. The residue was crystallized from hexane:EtOAc (1:1) to a€ord 7.6 g of pro-
duct. An additional amount of the desired product was obtained by evaporation of the mother
liquor followed by puri®cation by ¯ash chromatography (hexane:EtOAc, 8:2), bringing the total
28
ꢀ
1
amount of product to 10.2 g (83.8% yield), mp 167±168 C. ‰ꢀŠD =^90.1 (c=3.2, CHCl3). H
NMR (DMSO-d6, 100ꢀC, 270 MHz) ꢁ 1.71 (d, J=7.1 Hz, 6H), 4.23 (d, J=16.3 Hz, 1H), 4.52 (d,
J=16.3 Hz, 1H), 5.10 (q, J=7.1 Hz, 2H), 7.05±7.20 (br s, 10H), 7.80±7.90 (br s, 4H). 13C NMR
(CDCl3, 22.49 MHz) ꢁ 18.3, 41.0, 52.7, 123.3, 127.4, 128.4, 132.1, 133.8, 140.2, 166.2, 167.9. Anal.
calcd for C26H24N2O3: C, 75.71; H, 5.86. Found: C, 76.09; H, 5.92.
5.5. N-Phthaloylglycine 8
A suspension of 3.7 g (25.0 mmol) of phthalic anhydride, 2.25 g (30.0 mmol) of glycine, and 5
mL of pyridine was heated to 95ꢀC for 20 h. The reaction mixture was then allowed to cool to
ambient temperature before the sequential addition of 50 mL of water and 5 mL of concd HCl.
The resulting mixture was extracted with three 15 mL portions of EtOAc and the combined
organic extract was dried over anhyd. Na2SO4, and concentrated in the rotary evaporator. The
residue was crystallized from benzene to give 4.2 g (82.3% yield) of 8, mp 194±196ꢀC (lit.32 mp
ꢀ
1
191±192 C). H NMR (CDCl3, 400 MHz) ꢁ 4.44 (s, 2H), 7.72±7.75 (m, 2H), 7.86±7.90 (m, 2H),
10.9±11.0 (br s, 1H). 13C NMR (CDCl3, 100 MHz) ꢁ 39.1, 123.6, 132.1, 134.1, 167.6, 170.9.
5.6. (S,S)-(2,3-Diphenylaziridinyl)-N-phthaloylglycinamide (S,S)-4
To a solution of 4.1 g (20.0 mmol) of N-phthaloylglycine 8, 4.13 g (20.0 mmol) of N,N0-1,3-
dicyclohexylcarbodiimide (DCC), and 50 mL of CH2Cl2 was added, at 0ꢀC, 3.9 g (20.0 mmol) of
chiral aziridine (S,S)-2 in 25 mL of CH2Cl2. The reaction mixture was stirred at 0ꢀC for 3 h, the
precipitate (N,N0-dicyclohexylurea) was removed by ®ltration, the ®ltrate was washed with three
25 mL portions of cold 5% AcOH and three 25 mL portions of water, dried over anhyd. Na2SO4,
and concentrated in a rotary evaporator. The crude product was puri®ed by ¯ash chromato-
graphy (hexane:EtOAc, 8:2) to give 6.3 g (82.3% yield) of (S,S)-4, mp 127±130ꢀC. ‰ꢀŠD28=^56.9
1
(c=1.6, CHCl3). H NMR (CDCl3, 270 MHz) ꢁ 3.79 (s, 2H), 4.10 (d, J=17.1 Hz, 1H), 4.53 (d,
J=17.1 Hz, 1H), 7.20±7.40 (m, 10H), 7.65±7.68 (m, 2H), 7.76±7.78 (m, 2H). 13C NMR (CDCl3,
67.8 MHz) ꢁ=42.1, 48.6, 123.5, 126.5, 128.6, 128.9, 132.0, 134.1, 134.6, 167.5, 174.1. MS m/z 382
(M+), 276, 194, 160. HRMS calcd for C24H19N2O3 (M++1): 383.1396. Found: 383.1388.
5.7. General procedure for the reaction of glycinamide enolates [(S,S)-3-Li or (S,S)-4-Li] with
electrophiles
A solution of diisopropylamine (0.15 mL, 1.1 mmol) in 15 mL of dry THF and under nitrogen
atmosphere was cooled to ^78ꢀC before the slow addition of 0.45 mL (1.1 mmol) of 2.4 M n-BuLi
in hexane. The resulting solution was stirred at ^78ꢀC for 0.5 h before the dropwise addition of
1.0 mmol of the glycinamide and 1.1 mmol of the electrophile in 20 mL of dry THF (when LiCl
or DMPU additives were used, they were added at this point). Stirring was continued for 7 h at
^78ꢀC, and then the reaction was quenched by the addition of 15 mL of water. The product was
extracted with three 15 mL portions of CH2Cl2, the combined organic extracts were washed
with 15 mL of brine solution, dried over anhyd. Na2SO4, and concentrated. Final puri®cation
was accomplished by ¯ash chromatography.

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A. Reyes, E. Juaristi / Tetrahedron: Asymmetry 11 (2000) 1411±1423
5.8. (10S,10S,2S)-N0,N0-Bis-(10-phenylethyl)-N-phthaloylalanilamide (S,S,S)-6
The general procedure was followed with 0.43 g (1.0 mmol) of (S,S)-3, 0.73 mL of DMPU (6.0
mmol), and 0.07 mL (0.15 g, 1.1 mmol) of methyl iodide. The isolated product (0.31 g, 71% yield)
consisted of an 83:17 mixture of (S,S,S)-6 and (S,S,R)-6 diastereomeric products, which could
not be separated by ¯ash column chromatography, but allowed spectroscopic characterization of
the major product. 1H NMR (CDCl3, 270 MHz) ꢁ 1.60 (d, J=6.95 Hz, 3H), 1.76 (m, 6H), 4.30 (s,
1H), 5.10 (s, 1H), 5.37 (q, J=6.95 Hz, 1H), 6.72±7.36 (m, 10H), 7.62±7.65 (m, 2H), 7.75±7.79 (m,
2H). 13C NMR (CDCl3, 67.8 MHz) ꢁ 15.0, 49.6, 53.7, 54.2, 123.2, 123.5, 127.8, 128.1, 128.6,
131.9, 133.9, 168.4, 169.9.
5.9. (10S,10S,2S)-N0,N0-Bis-(10-phenylethyl)-N-phthaloylphenylalanilamide (S,S,S)-7
The general procedure was followed with 0.43 g (1.0 mmol) of (S,S)-3 and 0.13 mL (0.19 g, 1.1
mmol) of benzyl bromide. The isolated product (0.47 g, 90% yield) consisted of a 95:5 mixture
of (S,S,S)-7 and (S,S,R)-7 diastereomeric products, from which the major isomer was separated
by ¯ash chromatography (CH2Cl2:EtOAc:hexane, 10:10:1) to give 0.40 g (78.0% yield) of the
28
ꢀ
1
major product, (S,S,S)-7, mp 84±85 C. ‰ꢀŠD =^82.9 (c=0.41, CHCl3). H NMR (CDCl3, 270
MHz) ꢁ 1.75 (br, 3H), 1.85 (br, 3H), 2.95 (dd, J1=14.3 Hz, J2=4.6 Hz, 1H), 3.93 (dd, J1=14.3
Hz, J2=11.6 Hz, 1H), 5.50 (dd, J1=11.6 Hz, J2=4.6 Hz, 1H), 6.93±7.22 (m, 15H), 7.57±7.63 (m,
2H), 7.66±7.72 (m, 2H). 13C NMR (CDCl3, 67.8 MHz) ꢁ 18.7, 34.4, 54.3, 55.0, 123.3, 126.8,
127.0, 128.0, 128.5, 128.8, 129.0, 131.6, 134.0, 137.1, 139.9, 141.2, 168.4, 169.3. MS (20 eV)
m/z 503 (M++1), 397, 250, 105. HRMS calcd for C33H31N2O3 (M++1): 503.2335. Found:
503.2327.
5.10. (2S,3S,20S)- and (2S,3S,20R)-N0-Phthaloylalanil-2,3-diphenylaziridine (S,S,S)- and (S,S,R)-9
The general procedure was followed with 0.38 g (1.0 mmol) of (S,S)-4 and 0.07 mL (0.15 g, 1.1
mmol) of methyl iodide. The isolated product (0.22 g, 57% yield) consisted of a 65:35 mixture of
(S,S,S)-9 and (S,S,R)-9 diastereomeric products, which proved inseparable by column chroma-
tography, but yielded their relevant NMR spectroscopic characteristics.
1
(S,S,S)-9: H NMR (CDCl3, 400 MHz) ꢁ 1.64 (d, J=7.3 Hz, 3H), 3.70 (s, 2H), 4.62 (q, J=7.3
Hz, 1H), 7.13±7.36 (m, 10H), 7.70±7.74 (m, 2H), 7.78±7.84 (m, 2H). 13C NMR (CDCl3, 100
MHz) ꢁ 14.8, 48.6, 50.4, 123.4, 126.3, 128.4, 128.7, 131.9, 134.0, 134.9, 167.3, 177.1.
(S,S,R)-9: 1H NMR (CDCl3, 400 MHz) ꢁ 1.73 (d, J=7.3 Hz, 3H), 3.69 (s, 2H), 4.74 (q, J=7.3
Hz, 1H), 7.13±7.36 (m, 10H), 7.53±7.71 (m, 4H). 13C NMR (CDCl3, 100 MHz) ꢁ 14.8, 48.6, 50.0,
123.1, 126.4, 128.3, 128.6, 131.8, 133.6, 134.4, 167.3, 176.0. HRMS (for the diastereomeric mix-
ture) calcd for C25H21N2O3 (M++1): 397.1552. Found: 397.1540.
5.11. (2S,3S,20S)- and (2S,3S,20R)-N0-Phthaloylphenylalanil-2,3-diphenylaziridine (S,S,S)- and
(S,S,R)-10
The general procedure was followed with 0.38 g (1.0 mmol) of (S,S)-4 and 0.13 mL (0.19 g, 1.1
mmol) of benzyl bromide. The isolated product (0.28 g, 59% yield) consisted of an 83:17 mixture
of (S,S,S)-10 and (S,S,R)-10 diastereomeric products, which could not be separated by column
chromatography, but yielded the following spectroscopic data.

A. Reyes, E. Juaristi / Tetrahedron: Asymmetry 11 (2000) 1411±1423
1421
1
(S,S,S)-10: H NMR (CDCl3, 270 MHz) ꢁ 3.60±3.78 (m, 2H), 3.74 (s, 2H), 4.84 (dd, J1=10.4
Hz, J2=5.9 Hz, 1H), 7.00±7.30 (m, 19H). 13C NMR (CDCl3, 100 MHz) ꢁ 34.6, 48.7, 56.0, 123.0,
126.4, 126.7, 128.4, 128.5, 128.7, 131.4, 133.5, 134.3, 137.1, 167.3, 175.3.
(S,S,R)-10: 1H NMR (CDCl3, 270 MHz) ꢁ 3.4±3.8 (m, 2H), 3.71 (s, 2H), 4.80 (dd, J1=10.4 Hz,
J2=5.9 Hz, 1H), 6.94±7.32 (m, 15H), 7.61±7.71 (m, 4H). 13C NMR (CDCl3, 100 MHz) ꢁ 34.4,
48.7, 56.3, 123.3, 126.3, 126.6, 128.4, 128.8, 131.5, 133.9, 134.9, 136.9, 167.3, 176.3.
HRMS (for the diastereomeric mixture) calcd for C31H25N2O3 (M++1): 473.2103. Found:
473.2103.
5.12. (2S,3S,20S)-
and
(2S,3S,20R)-20-Methyl-N-phthaloylphenylalanil-2,3-diphenylaziridine
(2S,3S,20S)- and (2S,3S,20R)-11
The general procedure was followed with 0.39 g (1.0 mmol) of 9 (dr=50:50) and 0.13 mL (0.19
g, 1.1 mmol) of benzyl bromide. The reaction temperature was ^20ꢀC (7 h) and then 25ꢀC
(overnight). The isolated product (0.30 g, 61.7% yield) was shown by H NMR to consist of a
1
67:33 diastereomeric mixture of the expected doubly alkylated 11 [a 40:60 mixture of these dia-
stereomeric products was obtained in 57.6% yield (0.28 g) when 0.47 g (1.0 mmol) of 10
(dr=50:50) was treated with 0.15 g (1.1 mmol) of methyl iodide under the same reaction condi-
tions]. Dialkylated (S,S,S)- and (S,S,R)-11 proved inseparable in our hands.
1
Diastereomer 1: H NMR (CDCl3, 400 MHz) ꢁ 2.20 (s, 3H), 3.43 (d, J=13.8 Hz, 1H), 4.05
(d, J=13.8 Hz, 1H), 5.09 (d, J=9.1 Hz, 1H), 5.24 (d, J=9.1 Hz, 1H), 7.13±7.43 (m, 15H),
7.68±7.83 (m, 4H). 13C NMR (CDCl3, 100 MHz) ꢁ 23.5, 42.3, 60.5, 79.3, 90.1, 123.1, 125.9,
126.6, 127.1, 127.3, 127.8, 128.2, 128.4, 128.8, 130.7, 131.6, 134.0, 135.9, 139.8, 141.6, 168.5,
169.3.
Diastereomer 2: 1H NMR (CDCl3, 400 MHz) ꢁ 2.13 (s, 3H), 3.47 (d, J=13.8 Hz, 1H), 4.15 (d,
J=13.8 Hz, 1H), 5.14 (d, J=9.4 Hz, 1H), 5.28 (d, J=9.4 Hz, 1H), 7.13±7.43 (m, 15H), 7.68±7.83
(m, 4H). 13C NMR (CDCl3, 100 MHz) ꢁ 23.6, 41.8, 60.8, 78.6, 90.8, 123.1, 125.9, 126.6, 127.1,
127.3, 127.8, 128.2, 128.5, 128.9, 130.6, 131.7, 134.0, 135.8, 139.3, 141.5, 168.6, 169.1.
5.13. (10S,10S,2S)-N0,N0-Bis-(10-phenylethyl)phenylalanilamide (S,S,S)-12
A solution of 2.56 g (5.2 mmol) of (S,S,S)-7 in 50 mL of abs. EtOH was treated under nitrogen
atmosphere with 0.17 mL (176 mg, 5.5 mmol) of anhyd. hydrazine, and heated to re¯ux for 3 h.
The resulting suspension was ®ltered and the ®ltrate concentrated in the rotary evaporator. The
residue was dissolved in 50 mL of hot EtOAc, cooled to 4ꢀC, and left standing overnight at this
temperature. The precipitate that formed at this stage was removed by ®ltration, and the ®ltrate
was concentrated in the rotary evaporator to give the crude product that was puri®ed by ¯ash
chromatography (hexane:EtOAc, 1:1) to a€ord 1.4 g (72.2% yield) of the desired deprotected
28
amine product, mp 142±144ꢀC. ‰ꢀŠD =^27.3 (c=2.85, CHCl3). H NMR (CDCl3, 270 MHz) ꢁ
1.46 (br s, 2H), 1.68 (d, J=6.9 Hz, 3H), 1.71 (d, J=6.9 Hz, 3H), 2.47±2.66 (m, 2H), 3.50 (br s,
1H), 4.87 (q, J=6.9 Hz, 1H), 5.87 (br s, 1H), 6.64 (br d, J=5.7 Hz, 2H), 6.99 (br s, 2H), 7.13±7.34
(m, 11H). 13C NMR (CDCl3, 67.8 MHz) ꢁ 17.5, 19.7, 42.2, 51.8, 52.6, 55.2, 126.2, 126.7, 127.5,
127.6, 128.4, 128.7, 129.7, 138.2, 141.0, 141.8, 176.0. Anal. calcd for C25H28N2O: C, 80.60; H,
7.52. Found: C, 80.82; H, 7.61.
1

1422
A. Reyes, E. Juaristi / Tetrahedron: Asymmetry 11 (2000) 1411±1423
5.14. (S)-Phenylalamine (S)-13
A solution of 400 mg (1.1 mmol) of (S,S,S)-12, 5 mL of 6 N HCl, and 1 mL of 1,4-dioxane was
heated in a sealed ampoule to 100ꢀC for 18 h. The solution was then allowed to cool to ambient
temperature and extracted with two 15 mL portions of CH2Cl2. The aqueous phase was evapo-
rated to a€ord the amino acid hydrochloride, which was dissolved in 2 mL of water and adsorbed
to acidic ion exchange resin Dowex 50 WÂ4. The resin was washed with distilled water until the
washings came out neutral, and then the free amino acid was recovered with 1N aqueous NH3.
Evaporation a€orded 146.2 mg (82.4% yield) of (S)-13, mp 269±273ꢀC (decomp.) [lit.33 mp 270±
275ꢀC (decomp.)]. ‰ꢀŠ2D8=^31.7 (c=2.1, H2O) {lit.33 ‰ꢀŠD=^32.7 (c=2, H2O)}.
Acknowledgements
We are grateful to L. Velasco-Ibarra, Instituto de Quõmica-UNAM, for the high resolution
mass spectra, and to CONACYT for ®nancial support via grant L0006-E9607.
References
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a
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