Asymmetric synthesis of α,α-disubstituted amino acids by diastereoselective functionalization of enantiopure phenyloxazinones, derivatives of asymmetric Strecker reaction products of aldehydes

Article abstract of DOI:10.1016/S0040-4020(01)00502-6

Esterification of the asymmetric Strecker reaction products of a suitable aldehyde and (R)-phenylglycinol followed by lactonization and alkylation provides chiral oxazinones 5. Treatment of the enolates of 5 with active alkyl halides, or aldehydes provided the corresponding functionalization products with high diastereoselectivity. The configuration of newly created quaternary carbon is S for the products coupled with simple alkyl halides and aldehydes, and R for the products coupled with methyl bromoacetate. Deprotection of these products afforded the corresponding enantiopure α,α-dialkyl amino acids.

Full text of DOI:10.1016/S0040-4020(01)00502-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 6361±6366
Asymmetric synthesis of a,a-disubstituted amino acids by
diastereoselective functionalization of enantiopure
phenyloxazinones, derivatives of asymmetric Strecker reaction
products of aldehydes
Ke Dinga and Dawei Mab,p
aDepartment of Chemistry, Fudan University, Shanghai 200433, People's Republic of China
bState Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, 354 Fenglin Lu,
Chinese Academy of Sciences, Shanghai 200032, People's Republic of China
Received 24 January 2001; revised 23 February 2001; accepted 30 March 2001
AbstractÐEsteri®cation of the asymmetric Strecker reaction products of a suitable aldehyde and (R)-phenylglycinol followed by lactoniza-
tion and alkylation provides chiral oxazinones 5. Treatment of the enolates of 5 with active alkyl halides, or aldehydes provided the
corresponding functionalization products with high diastereoselectivity. The con®guration of newly created quaternary carbon is S for
the products coupled with simple alkyl halides and aldehydes, and R for the products coupled with methyl bromoacetate. Deprotection of
these products afforded the corresponding enantiopure a,a-dialkyl amino acids. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Owing to their remarkable pharmacological and conforma-
tional properties as either free amino acids or components of
bioactive peptides, enantiopure a,a-disubstituted amino
acids have attracted much synthetic attention.1 Among the
established methods, diastereolective functionalization of
an enantiopure a-amino acids via a nonracemic enolate is
one of the most popular ways.1 In order to achieve the high
diastereoselectivity, some cyclic derivatives of a-amino
acids were developed, which include Schollkopf's bis-
lactam ethers 1,2 Seebach's oxa- and imidazolidinones 2,3
and Williams' diphenyloxazinones 34 and oxazinones 45
Figure 1. Structures of chiral templates for the asymmetric synthesis of
a,a-dialkyl amino acids.
recently developed by Najera and coworkers. However,
most of them needed to take more reaction steps to build
their structures and acidic cleavage of a-functionalization
suitable aldehydes, as illustrated in Scheme 1. After treat-
ment of 5 with a suitable base, the nonracemic enolates
generated might react with various electrophiles to provide
functionalization products 6. If the diastereoselectivity in
this step was good we would be able to obtain enantiopure
a,a-disubstituted amino acids by deprotection. Thus, we
could synthesize either a-monosubstituted8 or a,a-disubsti-
tuted amino acids using the asymmetric Strecker reaction of
aldehyde. Herein, we wish to describe our results.7
products at high reaction temperature. In addition, some of
them were restricted by the source of enantiopure a-amino
acids. Thus, the discovery of new enantiopure cyclic
templates to overcome these drawbacks is still required
(Fig. 1).
Inspired from our studies on asymmetric Strecker reactions
starting with chiral amines,6 we developed a new method for
preparing chiral oxazinones 5,11 which took three steps and
started from the asymmetric Strecker reaction products of
2. Result and discussion
Keywords: amino acid; alkylation; diastereoselection.
Corresponding author. Tel.: 186-21-64163300; fax: 186-21-6416-6128;
e-mail: madw@pub.sioc.ac.cn
p
As shown in Scheme 1, the chiral oxazinones 5 were
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00502-6

6362
K. Ding, D. Ma / Tetrahedron 57 02001) 6361±6366
prepared from aldehyde by following steps: (1) asymmetric
Strecker reaction according to the known procedure8 except
for using NaCN instead of TMSCN; (2) esteri®cation of
nitrile moiety with methanolic hydrochloride; (3) cycliza-
tion in re¯uxing toluene catalyzed by TsOH; (4) alkylation
with benzyl bromide mediated by K2CO3 in DMF. The over-
all yields for preparing 5a±d from the corresponding
aldehyde were 33±48% and the diastereoselectivities were
66±80%.
Initially, we chose the coupling reaction of 5a with allyl
bromide as a model to explore the optimum reaction condi-
tions. It was found that the reaction was highly dependent on
the solvents used. From the results summarized in Table 1
we could see using DMEalone gave the highest yield in a
shorter time (entry 7), while THF, ether, and toluene were
the worst solvents for this reaction (entries 1±3). The
reaction could also be carried out in mixed solvents such
as THF/toluene, THF/DMEand THF/HMPA to give the
alkylation product in moderate yields (entries 4±6).
Scheme 1.
Table 1. Alkylation of 5a in different solvents
Under this optimized reaction condition other substrates and
electrophiles were tested and the results are listed in Table 2.
It was found that only active electrophiles could react with
the sodium enolates generated from oxazinones 5 to give the
corresponding products. For examples, apart from allyl
bromide, other active alkyl halides such as benzyl bromide
(entries 3, 5, 7, and 13), ethyl iodide (entry 8) and methyl
bromoacetate (entries 2, 4, 9 and 14) were also worked for
this reaction. However, less active alkyl halides such as
ethyl bromide (entry 11) could not be used as the coupling
reagents. In these cases, the corresponding oxazinone 5 was
completely recovered after quenching the reaction. The
aldol reaction of the sodium enolates generated from oxazi-
nones 5 with an aldehyde proceeds in a much faster manner
(entries 6 and 10). Two isomers were detected in this reac-
tion and their ratio was about 8:1. By recrystalization the
Entry
Solvent
THF
E 2O
Reaction time (h)
Yield (%)a
1
2
3
4
5
6
7
24
24
24
18
15
65
87
,10
,10
±
45
62
t
Toluene
THF/toluene
THF/HMPA
THF/DME12
DME8
Reaction conditions: see text.
Isolated yield.
a
Table 2. Diastereoselective functionalization of oxazinones 5
Entry
Substrate (R)
Electrophile
Reaction time (h)
Product (R0)
Yield (%)a
6
7
1
2
3
4
5
6
7
8
Bn (5a)
Bn (5a)
Bn (5a)
n-Pr (5b)
n-Pr (5b)
n-Pr (5b)
Me (5c)
Me (5c)
Me (5c)
Me (5c)
Me (5c)
Allyl bromide
BrCH2CO2Me
BnBr
BrCH2CO2Me
BnBr
CH3CHO
BnBr
EtI
BrCH2CO2Me
n-PrCHO
EtBr
8
9
8
12
8
0.1
8
24
12
0.1
12
6
Allyl (6a)
±
Bn (6b)
±
Bn (6c)
(S)-CH(OH)Me (6d)
Bn (6e)
Et (6f)
±
(S)-CH(OH)Pr-n(6g)
±
CH2CO2Me (7a)
87
79
83
76
85
85b
90
50
87
80b
±
CH2CO2Me (7b)
±
±
±
±
CH2CO2Me (7c)
-
±
±
9
10
11
12
13
14
±
BnO(CH2)2 (5d)
BnO(CH2)2 (5d)
BnO(CH2)2 (5d)
Allyl bromide
BnBr
BrCH2CO2Me
Allyl (6h)
Bn (6i)
±
90
89
83
6
8
±
CH2CO2Me (7d)
Reaction conditions: see text.
Isolated yield.
Based on 50% starting material recovery.
a
b

K. Ding, D. Ma / Tetrahedron 57 02001) 6361±6366
6363
Figure 2. X-ray structures of 7b (left) and 6g (right).
pure major isomer 6d or 6g was obtained and their
stereochemistry was assigned by X-ray structure analysis
(see below). The conversion of this reaction was about
2). This result implied that the quarternary carbon in 6a±c,
6e±f, and 6h±i might have S-form con®guration.
50% because
a
retro-aldol reaction might occur.
Taking the above investigations together, we concluded that
when sodium enolates of 5 reacted with aldehydes or some
simple alkyl halides, the (3R,5S)-products were provided.
This stereochemistry could be explained by Fig. 3. When 5
was used as a substrate, the generated enolate would prefer
the conformation A in which the N-benzyl group and the
phenyl group are trans each other. This enolate would attack
favorably the electrophile from the back side of the benzyl
group and give the (3R,5S)-product. However, as mentioned
above, when sodium enolates of 5 attacked methyl bromoa-
cetate, the coupling products had a (3R,5R)-con®guration.
The reason for this exception is not clear, but one possible
explanation is that this stereochemistry might come from
some chelation that formed between the ester moiety of
Prolonging the reaction time would result in the formation
of some side products. Although the reason for less
reactivity of enolates generated from oxazinones 5 was
not clear, one obvious explanation was because of their
steric hindrance. The side chain in oxazinone
substrates could be simple alkyl groups or some function-
alized alkyl groups (entries 12±14), which would allow the
preparation of more complicated a,a-disubstituted amino
acids.
The diastereoselectivity of these coupling reactions was
found to be very high. For example, HPLC analysis of the
reaction product of 5b with methyl bromoacetate indicated
the diastereoselectivity was over 250:1. In order to deter-
mine the stereochemistry of the present products, both
X-ray structure analysis and further conversion of the
products to known a,a-disubstituted amino acids were
undertaken. As shown in Fig. 2, the X-ray structure of 7b,
a coupling product of 5b with methyl bromoacetate, clearly
indicated that the 5-n-propyl group was cis to the 3-phenyl
group, which implied that the con®guration of 5-position
was R. However, the X-ray structure of 6g, an aldol reaction
product, demonstrated that its con®guration was 3R,5S,10S.
These surprising results prompted us to check the stereo-
chemistry of 6a±c, 6e±f, and 6h±i that were generated by
alkylation with simple alkyl halides. We decided to solve
this problem by conversion of 6e to the known amino acid 8.
Thus, 6e was treated with aqueous NaOH to open the
lactone ring, the generated sodium salt was neutralized
with HCl and then it was deprotected by Pd/C-catalyzed
hydrogenation (40 atm and 408C) to give the crude amino
acid, which was puri®ed with Dowex-50W to afford 8
([a]D ˆ222.2 (c 2.8, H2O), lit.9: [a]D ˆ222 (c 1.0,
19
25
H2O) for (S)-a-methylphenylalanine) in 62% yield (Scheme
Scheme 2.

6364
K. Ding, D. Ma / Tetrahedron 57 02001) 6361±6366
(2 mL/mmol). To this solution were added benzyl bromide
(1 equiv.) and anhydrous potassium carbonate (1 equiv.)
with stirring. The mixture was warmed to 60±658C slowly
and then the stirring was continued for 8 h. After the solvent
was evaporated in vacuo, the residue was puri®ed by chro-
matography to give 5.
Figure 3.
3.1.1. Compound 5a. 40% overall yield. 1H NMR
(300 MHz, CDCl3) d 7.52±7.02 (m, 15H), 4.30±4.14 (m,
2H), 3.97 (dd, Jˆ10.8, 3.7 Hz, 0.8H), 3.80±3.65 (m, 2.2H),
3.56 (d, Jˆ13.6 Hz, 0.3H), 3.48 (d, Jˆ13.6 Hz, 0.8H),
2.75±2.50 (m, 2H), 2.02±1.92 (m, 2H); EIMS m/z 371
(M1), 266, 91.
methyl bromoacetate and sodium enolates thereby giving
different stereochemistry. The predominant formation of
10S isomer of aldol reaction was explained by Fig. 3. The
conformation B is obviously more favorable than the
conformation C because of bigger steric hindrance between
R0 and R groups.
3.1.2. Compound 5b. 48% overall yield. 1H NMR
(300 MHz, CDCl3) d 7.54±7.17 (m, 10H), 4.31±4.14 (m,
2H), 3.97 (dd, Jˆ11.1, 3.6 Hz, 0.7H), 3.80 (d, Jˆ13.7 Hz,
0.7H), 3.67±3.63 (m, 1.6H), 3.51 (d, Jˆ13.7 Hz, 0.7H),
1.72±1.60 (m, 2H), 1.51±1.27 (m, 2H), 0.89 (t,
Jˆ7.2 Hz), 0.77 (t, Jˆ7.3 Hz, 2H); EIMS m/z 308
(M12H1), 266, 91.
Following the same reaction sequence from 6e to 8, the
lactones 7c and 7b were converted into (R)-a-methyl-
aspartic acid and (R)-a-propylaspartic acid in 72 and 75%
yields, respectively (Scheme 2). From the functionalization
products a,a-disubstituted amino acids could be obtained in
another manner that was demonstrated by the conversion of
6g to 10. Re¯uxing of 6g in 6N HCl to open the lactone ring
followed by Pd/C-catalyzed hydrogenation to cleavage the
benzyl groups afforded 10 in 80% yield.
1
3.1.3. Compound 5c. 33% overall yield. H NMR (300
MHz, CDCl3) d 7.54±7.20 (m, 10H), 4.33±4.14 (m, 2H),
3.96 (dd, Jˆ10.3, 3.8 Hz, 0.8H), 3.84±3.80 (m, 1H), 3.70±
3.63 (m, 1H), 3.54±3.50 (m, 1.2H), 1.39 (d. Jˆ7.1 Hz, 1H),
1.36 (d. Jˆ7.1 Hz, 2H); EIMS m/z 282 (M12H1), 132, 91.
3.1.4. Compound 5d. 38% overall yield. 1H NMR
(300 MHz, CDCl3) d 7.52±7.14 (M, 15H), 4.56±4.44 (m,
2H), 4.30±4.11 (m, 2H), 3.97±3.79 (m, 1.8H), 3.71±3.65
(m, 1.2H), 3.58±3.32 (m, 3H), 1.82±3.65 (m, 3H); EIMS
m/z 415 (M1), 324, 91.
As a summary, we have developed a new class of chiral
oxazinones that is suitable for preparing enantiopure a,a-
dialkyl amino acids, especially a-alkyl aspartic acids and
a,a-disubstituted analogues of serine and threine. These
chiral oxazinones could be easily synthesized from alde-
hydes and chiral phenylglycinol in three working-up steps
and the generated a,a-disubstituted amino acid precursors
could be deprotected in convenient manner. Further
optimization of the procedure and its application to prepare
biologically active a,a-disubstituted amino acids are in
progress.
3.2. General procedure of functionalization of 5
A solution (0.2 M) of 5 in DMEwas cooled to 2788C under
argon. To this solution was added NaHMDS (1.0 M in THF,
1.2 equiv.) over 15 min. After the stirring was continued for
1 h, a solution of a suitable electrophile (1.2 equiv.) in THF
was added at the same temperature. After the stirring was
continued for a time indicated in Table 1, saturated aqueous
ammonium chloride was added to quench the reaction. The
mixture was partitioned between ethyl acetate and brine,
and then the organic phase was separated and dried over
Na2SO4. After the solvent was evaporated in vacuo, the
residue was puri®ed by chromatography to give the
coupling product.
3. Experimental
3.1. General procedure of preparing oxazinones 5
To a solution of aldehyde (1.0 equiv.), (R)-phenylglycinol
(1.1 equiv.), ammonium chloride (1.3 equiv.) in MeOH±
H2O (1:1) was added sodium cyanide (1.0 equiv.) at 08C.
The solution was stirred at room temperature for 12 h and
then MeOH was evaporated in vacuo. The aqueous phase
was extracted with ethyl acetate three times, the combined
organic phase was washed with brine and dried over
Na2SO4. The solvent was evaporated by rotavapor and the
residue was dissolved in methanolic hydrochloride. The
resultant solution was stirred overnight before it was
concentrated. The residue was dissolved in water and the
solution was neutralized with aqueous NaHCO3 to pHˆ8.
After the solution was extracted with ethyl acetate three
times, the combined organic phase was washed with brine
and dried over Na2SO4. The solvent was removed to give
crude amino ester, which was dissolved in toluene (20 mL/
mmol) and then TsOH (0.2 equiv.) was added. The resultant
solution was re¯uxed for 2 days under argon. Removal of
the solvent followed by chromatography of the residue
afforded the lactone, which was dissolved in dry DMF
3.2.1.
-3S,5R)-3-Allyl-4-benzyl-3-phenethyl-5-phenyl-
26
1
morpholin-2-one 6a. [a]D ˆ126.2 (c 1.3, CHCl3). H
NMR (300 MHz, CDCl3) d 7.33±6.98 (m, 15H), 6.10 (m,
1H), 5.30 (dd, Jˆ15.8, 9.3 Hz, 2H), 4.56±4.43 (m, 2H), 4.29
(dd, Jˆ10.0, 2.0 Hz, 1H), 4.02 (d, Jˆ14.9 Hz, 1H), 3.80 (d,
Jˆ15.0 Hz, 1H), 3.12 (dt, Jˆ13.0, 4.5 Hz, 1H), 3.00 (dd,
Jˆ14.5, 7.0 Hz, 1H), 2.81 (dd, Jˆ14.5, 7.0 Hz, 1H), 2.50
(dt, Jˆ13.0, 4.3 Hz, 1H), 2.03 (dt, Jˆ13.3, 4.3 Hz, 1H), 1.69
(dt, Jˆ13.3, 4.2 Hz, 1H); EIMS m/z 412 (M11H1), 370.
HRMS found m/z 370.1760 (M12C3H5); C25H24NO2
requires 370.1794.
3.2.2. -3R,5R)--4-Benzyl-2-oxo-3-phenethyl-5-phenyl-
morpholin-3-yl)acetic acid, methyl ester 7a.

K. Ding, D. Ma / Tetrahedron 57 02001) 6361±6366
6365
[a]D ˆ121.6 (c 1.4, CHCl3); 1H NMR (300 MHz, CDCl3)
(300 MHz, CDCl3) d 7.53±7.09 (m, 10H), 4.78 (dd, Jˆ10.8,
3.7 Hz, 1H), 4.66 (dd, Jˆ10.8, 3.7 Hz, 1H), 4.00 (m, 1H),
3.90 (d, Jˆ14.8 Hz, 1H), 3.69 (d, Jˆ14.8 Hz, 1H), 2.00±
1.85 (m, 2H), 1.21±1.10 (m, 6H); EIMS m/z 309 (M1);
HRMS found m/z 309.1734 (M1); C20H23NO2 requires
309.1739.
26
d 7.53±7.03 (m, 15H), 4.63 (dd, Jˆ10.2, 2.9 Hz, 1H), 4.53
(t, Jˆ10.4 Hz, 1H), 4.34 (dd, Jˆ9.9, 3.0 Hz, 1H), 3.84 (d,
Jˆ15.1 Hz, 1H), 3.78 (s, 3H), 3.51 (d, Jˆ15.2 Hz, 1H), 3.25
(d, Jˆ17.3 Hz, 1H), 3.24 (m, 1H), 3.06 (d, Jˆ17.6 Hz, 1H),
2.53 (m, 1H), 1.73 (dt, Jˆ13.0, 4.3 Hz, 1H), 0.78 (m, 1H);
EIMS m/z 444 (M11H1), 370, 338; HRMS found m/z
443.2103 (M1); C28H29NO4 requires 443.2122.
3.2.9. -3R,5R)--4-Benzyl-3-methyl-2-oxo-5-phenylmor-
14
pholin-3-yl)acetic acid, methyl ester 7c. [a]D ˆ147.1
1
(c 4, CHCl3). H NMR (300 MHz, CDCl3) d 7.42±7.26
3.2.3. -3S,5R)-2,4-Dibenzyl-3-phenethyl-5-phenylmor-
26
1
(m, 10H), 4.87 (dd, Jˆ10.6, 3.5 Hz, 1H), 4.66 (dd,
Jˆ10.6, 3.5 Hz, 1H), 3.97 (m, 1H), 3.82 (s, 3H), 3.75 (d,
Jˆ8.8 Hz, 1H), 3.65 (d, Jˆ8.8 Hz, 1H), 3.18 (d, Jˆ16.4 Hz,
1H), 2.96 (d, Jˆ16.4 Hz, 1H), 1.21 (s, 3H); EIMS m/z 353
(M1); HRMS found m/z 353.1636 (M1); C21H23NO4
requires 353.1645.
pholin-2-one 6b. [a]D ˆ233.8 (c 1.0, CHCl3). H NMR
(300 MHz, CDCl3) d 7.45±6.85 (m, 20H), 4.47 (t,
Jˆ10.0 Hz, 1H), 4.21 (d, Jˆ15.4 Hz, 1H), 3.99 (dd,
Jˆ10.9, 3.0 Hz, 1H), 3.83 (d, Jˆ15.4 Hz, 1H), 3.66 (dd,
Jˆ10.6, 3.0 Hz, 1H), 3.49 (d, Jˆ14.2 Hz, 1H), 3.37 (d,
Jˆ14.2 Hz, 1H), 3.04 (dt, Jˆ12.9, 4.1 Hz, 1H), 2.59 (dt,
Jˆ13.0, 4.4 Hz, 1H), 2.21 (dt, Jˆ13.0, 4.5 Hz, 1H), 1.93
(dt, Jˆ13.3, 4.3 Hz, 1H); EIMS m/z 462 (M11H1), 370;
HRMS found m/z 461.2406 (M1); C32H31NO2 requires
461.2454.
3.2.10.
-10S,3S,5R)-4-Benzyl-3--10-hydroxybutyl)-3-
14
methyl-5-phenylmorpholin-2-one 6g. [a]D ˆ117.5 (c
2.5, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.38±6.92
(m, 10H), 4.59 (t, Jˆ10.7 Hz, 1H), 4.22±4.09 (m, 2H),
3.84 (d, Jˆ15.0 Hz, 1H), 3.77 (br s, 1H), 3.60 (d,
Jˆ15.0 Hz, 1H), 3.38±0.93 (m, 7H), 0.85 (dd, Jˆ13.1,
6.1 Hz, 3H). EIMS m/z 354 (M11H1), 280, 132; Anal.
calcd for C22H27NO3: C: 74.75, H: 7.69, N: 3.96, found C:
74.77, H: 7.39, N: 3.98.
3.2.4. -3S,5R)--4-Benzyl-2-oxo-5-phenyl-3-propylmor-
20
pholin-3-yl)acetic acid, methyl ester 7b. [a]D ˆ220.2
1
(c 0.5, CHCl3); H NMR (300 MHz, CDCl3) d 7.51±7.22
(m, 10H), 4.61 (dd, Jˆ10.3, 3.0 Hz, 1H), 4.47 (t,
Jˆ10.8 Hz, 1H), 4.28 (dd, Jˆ11.0, 3.2 Hz, 1H), 3.79 (s,
3H), 3.75 (d, Jˆ15.2 Hz, 1H), 3.40 (d, Jˆ15.2 Hz, 1H),
3.24 (d, Jˆ17.6 Hz, 1H), 3.03 (d, Jˆ17.6 Hz, 1H), 2.06
(m, 1H), 1.51±1.10 (m, 3H), 0.79 (t, Jˆ7.1 Hz, 3H);
EIMS m/z 381 (M1); HRMS found m/z 381.1917 (M1);
C23H27NO4 requires 381.1894.
3.2.11. -3S,5R)-3-Allyl-4-benzyl-3--3-benzyloxypropyl)-
26
5-phenylmorpholin-2-one 6h. [a]D ˆ18.2 (c 1.6,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.38±7.02 (m,
15H), 6.05 (m, 1H), 5.28 (dd, Jˆ15.5, 9.0 Hz, 2H), 4.46
(s, 1H), 4.43±4.38 (m, 2H), 4.21 (m, 1H), 3.97 (d,
Jˆ14.9 Hz, 1H), 3.72 (d, Jˆ14.9 Hz, 1H), 3.35±3.20 (m,
2H), 2.96 (dd, Jˆ14.4, 8.1 Hz, 1H), 2.77 (dd, Jˆ14.4,
6.9 Hz, 1H), 2.17 (m, 1H), 1.81±1.25 (m, 3H). EIMS m/z
456 (M11H1), 414, 308; HRMS found m/z 414.2043
(M12C3H5), C27H28NO3 requires 414.2069.
3.2.5. -3S,5R)-3,4-Dibenzyl-5-phenyl-3-propylmorpho-
lin-2-one 6c. [a]D ˆ253.6 (c 3.2, CHCl3); 1H NMR
25
(300 MHz, CDCl3) d 7.48±6.79 (m, 15H), 4.40 (t,
Jˆ10.3 Hz, 1H), 4.19 (d, Jˆ15.5 Hz, 1H) 3.94 (dd,
Jˆ10.8, 3.0 Hz, 1H), 3.77 (d, Jˆ15.5 Hz, 1H), 3.60 (dd,
Jˆ10.0, 2.9 Hz, 1H), 3.50 (d, Jˆ14.2 Hz, 1H), 3.34 (d,
Jˆ14.1 Hz, 1H), 1.98±1.84 (m, 2H), 1.53±1.36 (m, 2H),
0.81 (t, Jˆ7.1 Hz, 3H); EIMS m/z 308 (M12Bn); Anal.
calcd for C27H29NO2: C: 81.11, H 7.31, N 3.51, found C:
80.81, H: 7.08, N: 3.45.
3.2.12. -3S,5R)-3,4-Dibenzyl-3--3-benzyloxypropyl)-5-
26
phenylmorpholin-2-one 6i. [a]D ˆ222.0 (c 0.6,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.46±6.81 (m,
20H), 4.49 (s, 2H), 4.42 (t, Jˆ10.0 Hz, 1H), 4.18 (d,
Jˆ15.4 Hz, 1H), 3.94 (m, 1H), 3.78 (d, Jˆ15.4 Hz, 1H),
3.64 (dd, Jˆ9.6, 4.1 Hz, 1H), 3.49 (d, Jˆ14.3 Hz, 1H),
3.36 (d, Jˆ14.2 Hz, 1H), 3.31±3.12 (m, 2H), 2.16 (m,
1H), 1.98 (t, Jˆ10.7 Hz, 1H), 1.75±1.65 (m, 2H); EIMS
m/z 506 (M11H1), 414, 306; HRMS found m/z 414.2074
(M12Bn), C27H28NO3 requires 414.2089.
3.2.6. -10S,3S,5R)-4-Benzyl-3--1-hydroxyethyl)-5-phen-
14
yl-3-propylmorpholin-2-one 6d. [a]D ˆ120.5 (c 2.3,
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.41±7.16 (m,
10H), 4.53 (t, Jˆ9.7 Hz, 1H), 4.36±4.32 (m, 2H), 4.26±
4.21 (m, 1H), 3.88 (d, Jˆ11.2 Hz, 1H), 3.80 (m, 2H),
2.17±2.07 (m, 1H), 1.89±1.80 (m, 1H), 1.28±1.22 (m,
2H), 0.82 (t, Jˆ7.0 Hz, 3H); EIMS m/z 354 (M11H1),
308, 266, 91; Anal. calcd for C22H27NO3: C: 74.75, H:
7.69, N: 3.96, found C: 74.87, H: 7.75, N: 4.06.
3.2.13. -3R,5R)-[4-Benzyl-3--3-benzyloxypropyl)-2-oxo-
5-phenylmorpholin-3-yl]-acetic acid, methyl ester 7d.
26
1
[a]D ˆ14.4 (c 1.0, CHCl3). H NMR (300 MHz, CDCl3)
d 7.48±7.15 (m, 15H), 4.58 (dd, Jˆ10.3, 3.1 Hz, 1H), 4.47
(s, 2H), 4.51±4.43 (m, 1H), 4.28 (dd, Jˆ10.7, 3.0 Hz, 1H),
3.82 (s, 3H), 3.79±3.73 (m, 2H), 3.50 (d, Jˆ15.2 Hz, 1H),
3.31±3.20 (m, 2H), 3.03 (d, Jˆ15.5 Hz, 1H), 2.28 (m, 1H),
1.67±1.24 (m, 3H). EIMS m/z 488 (M11H1), 414, 338.
HRMS found m/z 487.2336, C30H33NO5 requires 487.2345.
3.2.7. -3S,5R)-3,4-Dibenzyl-3-methyl-5-phenylmorpho-
14
lin-2-one 6e. [a]D ˆ253.3 (c 2.9, CHCl3); 1H NMR
(300 MHz, CDCl3) d 7.39±7.07 (m, 15H), 4.40 (dd,
Jˆ10.7, 3.6 Hz, 1H). 4.11±4.04 (m, 2H), 3.85±3.80 (m,
2H), 3.30 (d, Jˆ13.9 Hz, 1H), 3.14 (d, Jˆ13.9 Hz, 1H),
1.32 (s, 3H); EIMS m/z 280 (M12Bn); HRMS found m/z
280.1355 (M12Bn); C18H18NO2 requires 280.1373.
3.3. General procedure for converting 6 or 7 to the
corresponding a,a-disubstituted amino acid
3.2.8. -3S,5R)-4-Benzyl-3-ethyl-3-methyl-5-phenylmor-
14
1
pholin-2-one 6f. [a]D ˆ265.3 (c 0.6, CHCl3); H NMR
Method A. The substrate was suspended in 6N HCl and the

6366
K. Ding, D. Ma / Tetrahedron 57 02001) 6361±6366
resultant mixture was re¯uxed for 24 h. The cooled solution
was concentrated and the residue was dissolved in mixture
of MeOH/H2O (v/v, 1:1). After 10% Pd/C was added,
the mixture was stirred under H2 (40 atm, 408C) for 36 h.
The catalyst was ®ltered off and the ®ltrate was concen-
trated, the residue was puri®ed by the residue was puri®ed
by Dowex-50W using water as eluent to give the product.
Natural Science Foundation of China (grant 29725205),
and Qiu Shi Science & Technologies Foundation for their
®nancial support.
References
1. For reviews, see: (a) Cativiela, M. D.; Diaz-De-Villegas, M. D.
Tetrahedron: Asymmetry 1998, 9, 3517. (b) Wirth, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 225. (c) Seebach, D.; Sting,
A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35,
2708. (d) Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992,
92, 889.
Method B. A solution of 6 or 7 in MeOH and 10% NaOH
(v/v, 1:1) was stirred at room temperature until no more
starting material was detected, as monitored by TLC. The
solution was added 2N HCl to adjust pHˆ4 before it was
evaporated in vacuo to dryness. After the residue was
dissolved in ethanol, 10% Pd/C was added. The mixture
was stirred under H2 (40 atm, 408C) for 36 h and then the
catalyst was ®ltered off. The ®ltrate was concentrated and
the residue was puri®ed by Dowex-50W using water as
eluent to give the product.
2. (a) Schollkopf, U. Tetrahedron 1983, 39, 2085. (b) Schollkopf,
U. Pure Appl. Chem. 1983, 55, 1799. (c) Schollkopf, U.; Busse,
U.; Kilger, R.; Lehr, P. Synthesis 1984, 271. (d) Schollkopf, U.;
Westphalen, K.-O.; Schroder, J.; Horn, K. Liebigs Ann. Chem.
1988, 781.
3. (a) Seebach, D.; Fadel, A. Helv. Chim. Acta 1985, 68, 1243.
(b) Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.;
Weber, T. Helv. Chim. Acta 1987, 70, 827. (c) Studer, A.;
Seebach, D. Liebigs Ann. Chem. 1995, 217. (d) Fadel, A.;
Salaun, J. Tetrahedron Lett. 1987, 28, 2243.
3.3.1. -S)-a-Methyl phenylalanine 8. 62% yield.
([a]D ˆ222.2 (c 2.8, H2O), lit.9: [a]D ˆ222 (c 1.0,
19
25
1
H2O); H NMR (300 MHz, D2O) d 7.36±7.240 (m, 5H),
3.32 (d, Jˆ14.5 Hz, 1H), 3.03 (d, Jˆ14.5 Hz, 1H), 1.58
(s, 3H); ESIMS m/z 179 (M1), 201, 224.
4. Williams, R. M. Aldrichim. Acta 1992, 25, 11.
5. (a) Chinchilla, R.; Falvello, L. R.; Galindo, N.; Najera, C.
Angew. Chem., Int. Ed. Engl. 1997, 36, 995. (b) Chinchilla,
R.; Galindo, N.; Najera, C. Tetrahedron: Asymmetry 1998, 9,
2769. (c) Abellan, T.; Najera, C.; Sansano, J. M. Tetrahedron:
Asymmetry 1998, 9, 2211.
3.3.2. -R)-a-Methyl aspartic acid 9a. 72% yield.
[a]D ˆ257.8 (c 0.41, H2O), (lit.10 [a]D ˆ252.9 (c 0.68,
17
20
1
H2O)); H NMR (300 MHz, D2O) d 3.17 (d, Jˆ18.2 Hz,
1H), 2.90 (d, Jˆ18.2 Hz, 1H), 1.56 (s, 3H); ESIMS m/z
148 (M11H1).
6. (a) Ma, D.; Tang, G.; Tian, H. Tetrahedron Lett. 1999, 40,
5753 (published erratum appeared in Tetrahedron Lett. 1999,
40, 9385). (b) Ma, D.; Tian, H.; Zou, G. J. Org. Chem. 1999,
64, 120.
3.3.3. -R)-a-Propyl aspartic acid 9b. 75% yield.
18
1
[a]D ˆ215.7 (c 0.6, H2O); H NMR (300 MHz, D2O) d
2.89 (d, Jˆ17.5 Hz, 1H), 2.64 (d, Jˆ17.5 Hz, 1H), 1.78±
1.63 (m, 2H), 1.41±1.14 (m, 2H), 0.89 (dd, Jˆ14.1, 6.9 Hz,
3H); ESIMS m/z 176 (M11H1).
7. Part of result was published as a communication. See: Ma, D.;
Ding, K. Org. Lett. 2000, 2, 2515.
8. (a) Chakraborty, T. K.; Reddy, G. V.; Hussain, K. A.
Tetrahedron Lett. 1991, 32, 7597. (b) Chakraborty, T. K.;
Hussain, K. A.; Reddy, G. V. Tetrahedron 1995, 51, 9179.
9. Bjokling, F.; Boutelje, J.; Gatenberck, S.; Hult, K.; Norin, T.;
Szmulik, P. Tetrahedron 1985, 41, 1347.
3.3.4.
-2S,3S)-2-Amino-3-hydroxy-2-methylpentanoic
25
1
acid 10. 80% yield. [a]D ˆ27.0 (c 1, MeOH). H NMR
(300 MHz, D2O) d 3.78 (m, 1H), 1.53±1.31 (m, 7H), 0.81 (t,
Jˆ6.9 Hz, 3H); ESIMS m/z 162 (M11H1).
10. Terashima, S.; Achiwa, K.; Yamada, S. Chem. Pharm. Bull.
1966, 14, 1138.
11. Dellaria, Jr., J. F.; Sautarsiero, B. D. J. Org. Chem. 1989, 54,
3916.
Acknowledgements
We thank the Chinese Academy of Sciences, National