Asymmetric PTC C-Alkylation Catalyzed by Chiral Derivatives of Tartaric Acid and Aminophenols. Synthesis of (R)- and (S)-α-Methyl Amino Acids

Article abstract of DOI:10.1021/jo000719p

A new type of efficient chiral catalyst has been elaborated for asymmetric C-alkylation of CH acids under PTC conditions. Sodium alkoxides formed from chiral derivatives of tartaric acid and aminophenols (TADDOL's 2a-e and NOBIN's 3a-h) can be used as chiral catalysts in the enantioselective alkylation, as exemplified by the reaction of Schiffs bases la-e derived from alanine esters and benzaldehydes with active alkyl halides. Acid-catalyzed hydrolysis of the products formed in the reaction afforded (R)-α-methylphenylalanine, (R)-α-naphthylmethylalanine, and (R)-α-allylalanine in 61-93% yields and with ee 69-93%. The procedure could be successfully scaled up to 6 g of substrate 1b. When (S,S)-TADDOL or (R)-NOBIN are used, the (S)-amino acids are formed. A mechanism rationalizing the observed features of the reaction has been suggested.

Full text of DOI:10.1021/jo000719p

J . Org. Chem. 2000, 65, 7041-7048
7041
Asym m etr ic P TC C-Alk yla tion Ca ta lyzed by Ch ir a l Der iva tives of
Ta r ta r ic Acid a n d Am in op h en ols. Syn th esis of (R)- a n d
(S)-r-Meth yl Am in o Acid s
Yuri N. Belokon,*,† Konstantin A. Kochetkov,† Tatiana D. Churkina,† Nikolai S. Ikonnikov,†
Alexey A. Chesnokov,‡ Oleg V. Larionov,‡ Ishwar Singh,§ Virinder S. Parmar,§
Sˇtˇepa´n Vyskocˇil,*,| and Henri B. Kagan*,
A. N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, 117813,
Moscow, Vavilov 28, Russian Federation, Higher Chemical College, Russian Academy of Sciences, 125820
Moscow, Russian Federation, Department of Chemistry, University of Delhi, Delhi-110007, India, Charles
University, Faculty of Science, Department of Organic Chemistry, 12840, Prague 2, Hlavova 2030, Czech
Republic, and Universite de Paris Sud, Institut de Chimie Moleculaire d’Orsay, Laboratoire de Synthese
Asymmetrique, 91405 Orsay Cedex, France
yubel@ineos.ac.ru
Received May 12, 2000
A new type of efficient chiral catalyst has been elaborated for asymmetric C-alkylation of CH acids
under PTC conditions. Sodium alkoxides formed from chiral derivatives of tartaric acid and
aminophenols (TADDOL’s 2a -e and NOBIN’s 3a -h ) can be used as chiral catalysts in the
enantioselective alkylation, as exemplified by the reaction of Schiff’s bases 1a -e derived from
alanine esters and benzaldehydes with active alkyl halides. Acid-catalyzed hydrolysis of the products
formed in the reaction afforded (R)-R-methylphenylalanine, (R)-R-naphthylmethylalanine, and (R)-
R-allylalanine in 61-93% yields and with ee 69-93%. The procedure could be successfully scaled
up to 6 g of substrate 1b. When (S,S)-TADDOL or (R)-NOBIN are used, the (S)-amino acids are
formed. A mechanism rationalizing the observed features of the reaction has been suggested.
In tr od u ction
bases,5 and Maruoka reported new serC2-symmetric
chiral ammonium salts.6 However, all the chiral catalysts
of the quaternary ammonium type, with a possible
exception in the last case, are efficient only at low
temperatures.2-5 The catalysts are also unstable in the
presence of alkali decomposing to give achiral derivatives,
whose competition with homochiral catalysts results in
the formation of racemic products decreasing the enan-
tioselectivity of the process.2a Chiral crown ethers were
suggested by Cram as potent catalysts of asymmetric
formation of C-C bonds.7 Unfortunately, chiral crown
ethers are expensive and their synthesis is tedious. Thus,
the search for novel, active, stable, simple, and cheap
chiral PTC-catalysts is still continuing.8
Ion-pair-mediated reactions under phase-transfer con-
ditions have been increasingly useful in organic synthesis
since their introduction.1 Until recently, there have been
no successful applications of PTC conversions to catalytic
asymmetric synthesis, except for a few cases, involving
the use of cinchona alkaloid-derived quaternary am-
monium salts, where however, the enantioselectivity is
normally relatively low.2 A significant improvement (ee
higher than 90%) of the asymmetric alkylation of a
glycine Schiff’s base under PTC conditions using N-(9-
anthracenylmethyl)-modified cinchonidinium salt as a
catalyst and aqueous (aq) CsOH or aq KOH as a base
has been reported by two independent groups.3,4 Recently,
O’Donnell introduced neutral, nonionic phosphazene
At the same time, asymmetric reactions of C-H acids
carried out under the effects of chiral bases constitute
an important class of organic transformations.9 Asym-
metric C-alkylations of achiral Li-enolates using chiral
* To whom correspondence should be addressed. (Y.N.B.) Fax: 007
(095) 135 5085.
† A. N. Nesmeyanov Institute of Organo-Element Compounds,
Russian Academy of Sciences.
(4) (a) Lygo, B.; Crosby, J .; Lowdon, T. R.; Wainwright, P. G.
Tetrahedron Lett. 1997, 38, 2343. (b) Lygo, B.; Wainwright, P. G.
Tetrahedron Lett. 1997, 38, 8595. (c) Lygo, B.; Wainwright, P. G.
Tetrahedron Lett. 1998, 39, 1599. (d) Lygo, B.; Crosby, J .; Peterson, J .
A. Tetrahedron Lett. 1999, 40, 8671.
‡ Higher Chemical College, Russian Academy of Sciences.
§ University of Delhi.
| Charles University.
Universite de Paris Sud.
(1) Makosza, M. Pure Appl. Chem. 1975, 43, 439.
(2) (a) Dolling, U.; Hughes, D.; Bhattacharya, A.; Ryan, K.; Karady,
S.; Weinstock, L.; Grabowski, E. In Phase Transfer Catalysis, New
Chemistry, Catalysts, and Applications; Starks, M., Ed.; ACS Sympo-
sium Series No. 326; American Chemical Society: Washington, DC,
1987; Vol. 326, p 67. (b) O’Donnell, M. J .; Bennett, W.; Wu, S. J . Am.
Chem. Soc. 1989, 111, 2353. (c) O’Donnell, M. J .; Wu, S. Tetrahedron:
Asymmetry 1992, 3, 591. (d) O’Donnell, M. J .; Wu, S.; Huffman, J . C.
Tetrahedron 1994, 50, 4507. (e) Arai, S.; Shioiri, T. Tetrahedron Lett.
1998, 39, 2145. (f) Arai, S.; Ishida, T.; Shioiri, T. Tetrahedron Lett.
1998, 39, 8299.
(5) O’Donnell, M. J .; Delgano, F.; Hostettler, C.; Schwesinger, R.
Tetrahedron Lett. 1998, 39, 8775.
(6) Ooi, T.; Kameda, M.; Maruoka, K. J . Am. Chem. Soc. 1999, 121,
66519.
(7) Cram, D.; Sogah, G. D. Y. J . Chem. Soc., Chem. Commun. 1981,
625.
(8) Nelson, A. Angew. Chem., Int. Ed. Engl. 1999, 38, 1583.
(9) (a) Duhamel, L.; Fouquay, S.; Plaquevent, J . C. Tetrahedron Lett.
1986, 27, 4875. (b) Cox, P.; Simpkins, N. Tetrahedron: Asymmetry
1991, 2, 1. (c) Koga, K.; Shindo, M. J . Synth. Org. Chem. J pn. 1995,
53, 1021. (d) Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga,
K. J . Am. Chem. Soc. 1994, 116, 8829. (e) Vadecard, J .; Plaquevent, J .
C.; Duhamel, L.; Duhamel, P.; Toupet, L. J . Org. Chem. 1994, 59, 2285.
(f) Amadji, M.; Vadecard, J .; Plaquevent, J . C.; Duhamel, L.; Duhamel,
P. J . Am. Chem. Soc. 1996, 118, 12483.
(3) (a) Corey, E.; Xu, F.; Noe, M. J . Am. Chem. Soc. 1997, 119, 12414.
(b) Corey, E.; Noe, M.; Xu, F. Tetrahedron Lett. 1998, 39, 5347. (c)
Corey, E.; Bo, Y.; Busch-Petersen, J . J . Am. Chem. Soc. 1998, 120,
13000.
10.1021/jo000719p CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/22/2000

7042 J . Org. Chem., Vol. 65, No. 21, 2000
Sch em e 1. Alk yla tion of Su bstr a tes 1 u n d er P TC Con d ition sa
Belokon et al.
ligands represents another important development.9d In
all these cases, chiral ion pairs or chiral Li-organic
compounds are formed and become the intermediates in
the alkylation reactions of the carbanionic particles.
Recently, a pioneering work of L. Duhamel disclosed
the first reported use of chiral alkoxides (derived from
chiral â-amino alcohols) either as stoichiometric bases9e
or basic catalysts9f to effect an asymmetric dehydrobro-
mination reaction.
1). The catalysts were either derivatives of tartaric acid
(2a -e), such as easily available 1,4-chiral diol, (4R,5R)-
2,2-dimethyl-1,3-dioxolane-4,5-bis(diphenylmethanol)
(TADDOL, catalyst 2b)15-17 or 1,4-aminophenols, 2,2′-
disubstituted binaphthyls (3a -h ), such as (S)-2-amino-
2′-hydroxy-1,1′-binaphthyl (NOBIN, catalyst 3a ).18 Pre-
liminary results of this work were reported by us
earlier.19
We supposed that another important class of organic
reactions, C-alkylation of CH-acids with alkyl halides
carried under PTC conditions, could be performed asym-
metrically by use of dioles or other chiral hydrophobic,
chelating agents - amino alcohols. We suggested that
such dioles and amino alcohols would function in the
reaction as chelating agents for the alkali ions and thus
make the ion-pairs (formed by the corresponding carban-
ion and alkali ions) soluble in organic solvents. We
believed that this modification could combine the syn-
thetic simplicity of the PTC-approach2-4 with the rigidity
of the mutual orientations of the chiral ligand and the
substrate in the transition state of the reaction, similar
to the case of transition metal complex catalysis.10,11
This paper reports the results of the application of the
PTC approach to the elaboration of asymmetric synthesis
of R-methyl-R-amino acids (R-Me-AA), important syn-
thetic targets.12-14 For instance, R-allyl-R-alanine (R-All-
Ala), R-methyl-R-naphthylalanine (R-Me-Napht-Ala) are
valuable nonproteinogenic R-Me-AA.2c-d,13,14 (S)-R-Methyl-
phenylalanine (R-Me-Phe) is a very important compound
for the synthesis of a new generation of solution stable
aspartam derivatives.12 Modern analysis of the pathways
leading to R-Me-AA sets development of catalytic meth-
ods as a primary synthetic challenge.12a
Resu lts
Substrates 1 derived from benzaldehyde and racemic
alanine esters Schiff’s bases were suggested by O’Donnell
as substrates for the synthesis of racemic amino acids
with quaternary carbon atoms.20 CH acidity of the
substrates (pKa ∼20, DMSO)21 was sufficient for them
to be alkylated in the presence of alkali hydroxides under
PTC conditions.2,20
The alkylations of a substrate 1b with benzyl bromide
(BnBr) (see Scheme 1) were conducted in dry organic
solvents at ambient temperature using solid NaOH
(ground under argon) as base. Derivatives of tartaric acid,
mostly TADDOL and its derivatives 2a -e, 2,2′-dihy-
(15) J uaristi, E.; Beck, A. K.; Hansen, J .; Matt, T.; Mukhopadhyay,
T.; Simson, M.; Seebach, D. Synthesis 1993, 1271.
(16) Beck, A. K.; Bastani, B.; Plattner, D. A.; Petter, W.; Seebach,
D.; Braunschweiger, H.; Gysi, P.; Vecchia, L. L. Chimia 1991, 45, 238.
(17) (a) Belokon, Yu. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Orlova, S. A.; Smirnov, V. V.; Chesnokov, A. A.
Mendeleev Commun. 1997, 137. (b) Belokon, Yu. N.; Kochetkov, K. A.;
Churkina, T. D.; Ikonnikov, N. S.; Orlova, S. A.; Smirnov, V. V.;
Chesnokov, A. A. Izv. Ross. Akad. Nauk, Ser. Khim. 1998, 47, 76 (Bull.
Rus. Acad. Sci., Div. Chem. Sci. 1998, 47, 74).
(18) (a) Smrcina, M.; Polakova, J .; Vyskocil, S.; Kocovsky, P. J . Org.
Chem. 1993, 58, 4534. (b) Smrcina, M.; Vyskocil, S.; Maca, B.; Polasek,
M.; Claxton, T. A.; Abbott, A. P.; Kocovsky, P. J . Org. Chem. 1994, 59,
2156. (c) Smrcina, M.; Vyskocil, S.; Polivkova, J .; Polakova, J .;
Kocovsky, P. Collect. Czech. Chem. Commun. 1996, 61, 1520. (d)
Smrcina, M.; Vyskocil, S.; Polivkova, J .; Polakova, J .; Sejbal, J .; Hanus,
V.; Polasek, M.; Verrier, H.; Kocovsky, P. Tetrahedron: Asymmetry
1997, 8, 537. (e) Vyskocil, S.; J aracz, S.; Smrcina, M.; Sticha, M.;
Hanus, V.; Polasek, M.; Kocovsky, P. J . Org. Chem. 1998, 63, 7727.
(19) (a) Belokon, Yu. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S.; Chesnokov, A. A.; Larionov, O. A.; Parmar, V. S.;
Kumar, R.; Kagan, H. B. Tetrahedron: Asymmetry 1998, 9, 851. (b)
Belokon, Yu. N.; Kochetkov, K. A.; Churkina, T. D.; Ikonnikov, N. S.;
Chesnokov, A. A.; Larionov, O. A.; Kagan, H. B. Izv. Ross. Akad. Nauk,
Ser. Khim. 1999, 48, 926 (Bull. Rus. Acad. Sci., Div. Chem. Sci. 1999,
48, 917). (c) Belokon, Yu. N.; Kochetkov, K. A.; Churkina, T. D.;
Ikonnikov, N. S., Vyskocil, S., Kagan, H. B. Tetrahedron: Asymmetry
1999, 10, 1723.
In the present study, we propose a new class of phase
transfer catalysts for the asymmetric PTC C-alkylation
of Schiff’s bases derived from esters of (()-Ala (substrates
(10) Genet, J . P.; Kopola, N.; J uge, S.; Ruiz-Montes, J .; Antunes, O.
A. C.; Tanier, S. Tetrahedron Lett. 1990, 31, 3133.
(11) (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 258. (b)
Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New
York, 1993.
(12) (a) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225. (b)
Chinchilla, R.; Falvello, L.; Galindo, N.; Najera, C. Angew. Chem., Int.
Ed. Engl. 1997, 36, 995. (c) Cativiela, C.; Diaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 1998, 9, 3517. (d) Alonso, F.; Davies, S. G.;
Elend, A. S.; Haggitt, J . L. J . Chem. Soc., Perkin Trans. 1 1998, 257.
(13) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32,
1244.
(20) O’Donnell, M. J .; Wojciechowski, K.; Ghosez, L.; Navarro, M.;
Sainte, F.; Antoine, J .-P. Synthesis 1984, 313.
(21) O’Donnell, M. J .; Bennett, W.; Bruder, W.; J acobsen, W.; Knuth,
K.; LeClef, B.; Polt, R.; Bordwell, F.; Mrozack, S.; Cripe, T. J . Am.
Chem. Soc. 1988, 110, 8520.
(14) Burgess, K.; Ho, K.-K.; Pal, B. J . Am. Chem. Soc. 1995, 117,
3808.

Synthesis of (R)- and (S)-R-Methyl Amino Acids
J . Org. Chem., Vol. 65, No. 21, 2000 7043
Ch a r t 1
Ta ble 1. Asym m etr ic Syn th esis of r-Me-P h e by
C-Ben zyla tion of Su bstr a te 1b P r om oted w ith Differ en t
Typ es of Ca ta lysts u n d er P TC Con d ition sa
Ta ble 2. Asym m etr ic Syn th esis of r-Me-P h e by
Ben zyla tion of Com p ou n d 1b Med ia ted by NOBIN a n d Its
Der iva tives 3a -h a
run
catalyst
c.y. (%)
ee (%) (confign)
run
catalyst 3a -h
base
c.y.b (%)
ee (%) (confign)c
1
2
3
4
5
6
7
8
9
diethyl tartrate
(R)-BINOL
(R)-2a
(R)-2b,(R,R)-TADDOL
(S)-2b,(S,S)-TADDOL
(R)-2c
(R)-2d
(R)-2e
(R)-3a , (R)-NOBIN
(S)-3a , (S)-NOBIN
0
0
0
0
1
2
3
4
5
6
7
8
9
(S)-3a
(S)-3a
(S)-3b
(S)-3c
(R)-3d
(R)-3e
(R)-3f
(S)-3g
(R)-3h
(S)-3a
(S)-3a
NaOH
KOH
>90
>90
>90
90
>90
>90
>90
>90
>90
60
62 (R)
43 (R)
31 (R)
15 (R)
8 (S)
11 (S)
10 (S)
3 (R)
40
90
80
60
58
90
90
90
15 (R)
80 (R)
82 (S)
3 (R)
3 (R)
59 (R)
60 (S)
62 (R)
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaH
17 (S)
68 (R)d
22 (S)
10
10
11e
NaH
80
a
The reaction conditions: toluene, ambient temperature, the
concentration of the substrate was 0.2 M, the reaction was
conducted for 15-24 h with the ratio of 1b/BnBr/catalyst/NaOH
) 1.0:1.2:0.1:4.0-5.0.
a
Concentration of the substrate was 0.4 M; the reactions were
conducted at 20 °C over 12 h in toluene with a molar ratio of 1b/
b
BnBr/3a -h /NaOH (NaH) ) 1.0:1.2:0.1:4.0 (1.0). Determined by
1H NMR, using leucine as an internal standard. c Chiral GLC
d
analysis. After crystallization, (R)-R-Me-Phe was obtained in 40%
droxy-1,1′-binaphthyl (BINOL) or 2-hydroxy-2′-amino-
1,1′-binaphthyl (NOBIN) and its derivatives 3a -h (Chart
1) were taken in catalytic amounts (10 mol %) as chiral
promoters. After 12 h, the reaction product was decom-
posed under mild conditions to give R-Me-Phe hydrochlo-
ride which was analyzed, after derivatization by GLC on
a chiral stationary phase (Table 1). Toluene was found
to be the solvent of choice to get maximum ee of the final
product.
We chose benzylation of Schiff’s base formed from (()-
Ala and benzaldehyde as a model reaction for testing the
efficiency of ligands (Table 1). Thus, BINOL and diethyl
tartarate proved to be inefficient as both catalysts and
asymmetry-inducing agents (see Table 1, runs 1 and 2).
Another derivative of tartaric acid, (+)-2,3-O-isopropyl-
idene-L-threitol, 2a , was a more efficient promoter of the
reaction with c.y. of R-Me-Phe as high as 40% and 15%
ee (Table 1, run 3). (S,S)- and (R,R)-TADDOL, 2b proved
to be even more successful furnishing relatively high
enantiomeric and chemical yields of R-Me-Phe (see Table
1, runs 4 and 5). In this case (S,S)-TADDOL gave (S)-R-
Me-Phe. Mono and di-O-alkylation of TADDOL led to
compounds 2c and 2d that retained some catalytic
activity but failed to induce any asymmetry into the final
product (Table 1, runs 6 and 7). (+)-2,3-O-Isopropylidene-
yield with >98% ee. e Substrate 4 (see Chart 2) was used.
1,1,4,4-tetra(2-naphthyl)-L-threitol, 2e, likewise (S)- and
(R)-NOBIN, 3a , were catalytically active and capable of
mediating moderate asymmetric induction into the final
product of C-alkylation (Table 1, runs 9 and 10; (S)-
NOBIN furnished (R)-R-Me-Phe.
The analysis of the catalytic activities of tartaric acid
derivatives (Table 1, runs 1 and 3-8) testified that high
hydrophobicity and the presence of free 1,4-hydroxyl
groups were necessary features for the catalytic activity
and asymmetric inducing power of this class of catalysts
to be observed. Inactivity of BINOL might be traced to
its higher OH acidity, as compared to TADDOL, and the
formation of the insoluble disodium salt of the former
under the reaction conditions, removing it from the
reaction media. The asymmetric induction observed with
NOBIN as a catalyst (Table 1, runs 9 and 10) showed
that OH group could be substituted by a less acidic NH
group and the asymmetric inducing power of the catalyst
finally revealed.
The data summarized in Table 2 showed that the
nature of base was important as the substitution of
NaOH by KOH significantly decreased the ee of the

7044 J . Org. Chem., Vol. 65, No. 21, 2000
Belokon et al.
Ta ble 3. Asym m etr ic Ben zyla tion of Ala n in e Der iva tives
tive 2e was much less efficient asymmetric catalyst with
ee of only 59%, as compared to 2b under the same
experimental conditions (Table 1, runs 8 and 4).
Hexane was found to be a good medium for the reaction
with chemical yields and asymmetric induction of the
reaction being on the same level as those in toluene
(Table 3, runs 8 and 12). Use of more polar solvents, such
as CH3CN, CHCl3, and CH2Cl2 resulted in almost racemic
product of the alkylation.
The leaving group in the alkylating agent seemed to
influence the asymmetric induction in the reaction, as
the switch from BnBr to BnCl improved the ee of the
product from 80% to almost 93% (Table 3, runs 8 and 9)
although the reaction became sluggish and the chemical
yields dropped.
Any possible enrichment of the final alkylation product
by a complex formation with 2b during the product
isolation was excluded by a control experiment where
(S,S)-TADDOL and the racemic final product of the
reaction (a Schiff’s base of benzaldehyde and i-Pr ester
of racemic R-methylphenylalanine) were mixed and
treated in the conditions of workup, and no ee enrichment
was found for the final R-methylphenylalanine.
The structure of the substrate was important to secure
both high chemical yields of the product and its ee. The
alkylation of 1a in the presence of NaOH was not
successful as the substrate was effectively hydrolyzed
under the reaction conditions (Table 3, run 1) but use of
NaH as a base was productive to give (R)-R-Me-Phe with
70% ee (Table 3, run 2). Naturally, t-Bu ester derivative,
1e, was much more stable to the base catalyzed hydroly-
sis, but ee of the reaction was only 22% (Table 3, run 3).
It seems that the introduction of different substituents
into the aromatic moiety of the Schiff’s base of alanine
i-Pr ester had no effect on the ee of benzylation (Table 3,
runs 10 and 11).
The type of base was vital, as there was no alkylation
with LiOH (Table 3, run 5) and ee of the reaction dropped
from 80 to 82% to 24% on substituting NaOH by KOH
(Table 3, run 4 and 7). Similarly, no asymmetric induc-
tion was observed in the case of CsOH × H2O (run 6)
application. The addition of 50% of Na2CO3 to NaOH
resulted in a diminished ee of the reaction (Table 3, run
16). Use of 50% aqueous NaOH led to complete disap-
pearance of the asymmetric induction of 1b benzylation
(Table 3, run 15) and significant increase in the amount
of the hydrolyzed product.
The addition of competitive PTC agents, such as Et4-
NBr or chelating agents such as TMEDA to the reaction
mixture either diminished or completely suppressed any
asymmetric induction in the reaction (Table 3, runs 13
and 14).
TADDOL or NOBIN could be used to bring about the
alkylation of 1b with other active alkylating agents, as
Table 4 (runs 1-5) illustrated. Aliphatic alkyl halides
were either not active or asymmetric induction and
chemical yields of the products were unsatisfactory (Table
4, run 6). Methylation of the Schiff’s base formed from
the isopropyl ester of D,L-Phe and benzaldehyde by MeI,
catalyzed by TADDOL under the standard conditions
resulted in a lower yield of (R)-R-Me-Phe with ee ∼4%
(Table 3, run 24).
1, Med ia ted by (R,R)-Ta d d ol, (R)-2ba
(R)-R-
(R)-R-
catalyst
run substrate (equiv)
Me-Phe, Me-Phe,
base
NaOH
NaH
NaOH
KOH
LiOH
CsOHxH2O
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH +
0.1 equiv
of TMEDA
NaOH +
0.1 equiv
of Et4NBr
50% aq NaOH
NaOH +
0.1 equiv
of Na2CO3
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaOH
c.y.b (%)
eec (%)
1
2
1a
1a
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.1
0.1
0.1
0.1
0.1
0.1
0
90
90
31
0
94
80
92
65
89
91
54
78
0
70
22
24
-
3d 1e
4
5
6
1b
1b
1b
0
7e 1b
82
80
93
83
83
77
30
8f
9g 1b
1b
10
11
1c
1d
12h 1b
13
1b
14
1b
0.1
83
0
15
16
1b
1b
0.1
0.1
79
65
0
21
17
18
19
20i
21j
1b
1b
4
1b
1b
1.0
0.1
1.0
1.0
1.0
1.0
1.0
0.1
95
90
85
90
20
40
70
80
93
40
10
70
71
93
87
4
22k 1b
23l
1b
m
24m
a
The concentration of the substrates in PhMe was 0.2 M; the
reaction time was 12 h; T ) 15-20 °C; the ratio of 1 or 4/BnBr/
b
2/NaOH (NaH) ) 1.0:1.2:0.1-1.0:4.0-5.0 (2.0). Determined by
1H NMR, using leucine as an internal standard. c Chiral GLC
d
analysis. The initial alanine moiety was of (S)-configuration; the
reaction time was 168 h. e (S,S)-TADDOL gave (S)-R-Me-Phe. After
crystallization (S)-R-Me-Phe was recovered in 40% yield with ee
greater than 99%.19 f The reaction was conducted in hexane.
g
h
Using BnCl as an alkylating agent. Scale-up experiment (see
i
j
below). 4 equiv of NaH was used. 0.25 equiv of NaH was used.
k
l
m
0.5 equiv of NaH was used. 1 equiv of NaH was used.
A
Schiff’s base derived from benzaldehyde and racemic i-Pr ester of
phenylalanine was alkylated with MeJ .
reaction (Table 2, runs 1 and 2). Any substitution of the
NH bond by alkyl groups invariably decreased the
asymmetric inducing power of NOBIN (Table 2, runs 1,
3-7, and 9). The effect was even more pronounced when
a phenyl group was introduced into this position (Table
2, run 8). NaH was shown to be a superior base relative
to NaOH (Table 2, run 10).
As our attempts on improving performance of the
catalyst by modifications of NOBIN failed, further re-
search efforts were concentrated on studying TADDOL,
which showed greater synthetic potential (Table 1,
compare run 4 with runs 8-10).
TADDOL, 2b, at a ratio of 1/1 or 1/10 to the substrates
effectively catalyzed asymmetric C-benzylation of all the
substrates 1a -e (see Table 3, runs 1-18, 20-23) with
ee’s ranging from 20% to 93% with NaOH or NaH used
as bases. Surprisingly, the ee of the product did not fall
below 40% in the case of NaH-promoted reaction even
when the ratio of NaH/2b was decreased from 1/1 to 1/0.1
(Table 3, runs 17 and 18). (R,R)-2b furnished invariably
(R)-R-Me-Phe, whereas (S,S)-2b gave (S)-R-Me-Phe (Table
3, run 7). TADDOL can be recovered from the reaction
mixture and repeatedly used after crystallization without
any loss of catalytic activity. A more hydrophobic deriva-
The CH acidity of the substrate (4, Chart 2) (pKa ∼19,
DMSO)22 was also sufficient to enable the alkylation in
the presence of alkali hydroxides under PTC condi-

Synthesis of (R)- and (S)-R-Methyl Amino Acids
J . Org. Chem., Vol. 65, No. 21, 2000 7045
Ta ble 4. Asym m etr ic Alk yla tion of 1b Accor d in g to
Sch em e 1 Med ia ted by TADDOL 2b or NOBIN 3a a
son of the solid NaOH and KOH (Table 2, runs 1 and 2).
Thus, the chelating properties of the catalyst seemed to
be indispensable with the NOBIN better fit for Na rather
than K ions. Finally, an intermolecular hydrogen bond
between the ionized substrate and -OH or/and -NH
groups of the catalyst may stabilize the complex of the
enolate ion pair with the catalyst, as the substitution at
NH moiety invariably diminished ee of the reaction
(Table 2, runs 3-9). In fact, the structure of the complex
would be the same, regardless whether the sodium salt
of NOBIN served initially as a hydrophobic base or the
neutral catalyst functioned as a chelating agent in the
same manner as disclosed for another chiral catalyst of
Li-enolate alkylations.9c,d In our case, the unreactive
aggregates of the sodium enolates28 generated from 1 may
be activated for the C-alkylation by the complexation
with catalyst.
R-Me-AA,
ee (%)
(equiv) catalyst c.y.,b (%) (confign)c
catalyst
R-Me-AA,
run
RX
1
2
3
4
5
6
allylBr
allylBr
allylBr
1-naphthylCH2Cl
1-NaphthylCH2Cl
PriBr
1.0
0.1
0.1
0.1
0.1
0.1
(R)-2b
(S)-2b
(S)-3a
(R)-2b
(S)-3a
(R)-2b
91
89
90
86
60
25
73 (R)
70 (S)
67 (R)
71 (R)
18 (R)
12 (R)
a
The concentration of the substrates in PhMe was 0.2 M; the
reaction time was 12 h; T ) 15-20 °C; the ratio of 1b/BnBr/
b
catalyst/NaOH ) 1.0:1.2:0.1-1.0:4.0-5.0. Determined by 1H
NMR, using leucine, as an internal standard. c Chiral GLC
analysis.
Ch a r t 2
It was more difficult to ascribe the same kind of
mechanism to TADDOL as pKa of tertiary alcohols had
been found to be close to 30 in the same solvent27 where
pKa of class 1 substrates was determined.
The absence or presence of minute amounts of the
products of O-alkylation of TADDOL in the reaction
mixture, despite the presence of its alcoholate in the
solution, can be attributed to the steric hindrance pre-
venting the alkylation reaction. The difficulty of TAD-
DOL alkylation was confirmed by the blank experiment;
even prolonged refluxing of TADDOL with excess of
NaOH and BnBr in MeCN resulted only in formation of
R-monoalkylated derivative of TADDOL, i.e., 2c. Very low
asymmetric induction observed for the 2c-catalyzed reac-
tion proved that it is TADDOL and not its O-alkylated
products (that might eventually be formed in the reaction
media), which is the real catalyst of the reaction.
tions.23,24 Thus, TADDOL- and NOBIN-promoted asym-
metric benzylation of substrate 4 (Table 2, run 11, and
Table 3, run 19) but the asymmetric induction was low
(10 and 24% ee, respectively).
Discu ssion
The products of alkylation of substrates 1 and 4 cannot
undergo epimerization; therefore, the ratio of enanti-
omers obtained in the reactions reflected the actual
kinetic stereoselectivity of the process.
To elucidate the mechanism, a series of experiments
was carried out differing from our standard procedure19
as the order of addition of the components was concerned.
TADDOL and NaOH in toluene were placed in a dry flask
filled with argon and stirred for several hours. Then, the
resulting heterogeneous mixture was filtered in a flow
of argon to remove the excess of solid alkali. Substrate
1b and BnBr were added successively in a flow of argon
to the homogeneous filtrate, which could contain only
TADDOL and/or the alcoholate of TADDOL. After stir-
ring and the standard workup, (R)-R-Me-Phe was isolated
in a 33% yield and ee 79%. This meant that it was
alcoholate of TADDOL (contained in the filtrate), which
actually catalyzed enantioselective alkylation of the
substrate. Thus, under the experimental conditions, the
alkali metal alcoholates of TADDOL functioned as chiral
hydrophobic bases soluble in toluene in the same way as
NOBIN. Similarly, the rigid structure of TADDOL was
favorable for the chelate formation with the sodium ions
and much less complementary for Li, K, and Cs ions
(Table 3, runs 4-6). Finally, an intramolecular hydrogen
bond between the ionized substrate and TADDOL can
stabilize the complex formed by the enolate, alkali ion
and TADDOL, as any substitution of its OH groups by
OR drastically decreased ee of the reaction (see Table 1,
runs 4-7). Water and any chelating competitors natu-
It seems likely that NOBIN and its derivatives 3a -h
functioned in the reaction as bases, ionizing the sub-
strate. The pKa of 1e, determined in DMSO, is in the
range of 17-20,21 whereas that of NOBIN is most likely
about 18 (the measured pKa value of phenol in DMSO is
18,25 whereas the value for aniline is 3026 (so as the value
for tertiary aliphatic alcohols had been found close to 30
in the same solvent).27 Hence, the catalyst is likely to be
first ionized at its OH-group in an aprotic solvent in order
to function as a base. On the other hand, the rigid
structure of NOBIN could provide the necessary features
to make it a hydrophobic complexing agent for cations.
The transition state of the alkylation should involve both
catalyst and alkali metal ion as revealed by the compari-
(22) Terekhova, M. I.; Belokon’, Yu. N.; Maleev, V. I.; Chernoglazova,
N. I.; Kochetkov, K. A.; Belikov, V. M.; Petrov, E. S. Izv. Akad. Nauk,
Ser. Khim. SSSR. 1986, 905. (Bull. Acad. Sci. USSR, Div. Chem. Sci.
1986, 35, 824).
(23) Belokon’, Yu. N.; Maleev, V. I.; Savel’eva, T. F.; Garbalinskaya,
N. S.; Saporovskaya, M. B.; Bakhmutov, V. I.; Belikov, V. M. Izv. Akad.
Nauk SSSR, Ser. Khim. 1989, 631. (Bull. Acad. Sci. USSR, Div. Chem.
Sci. 1989, 38, 557.)
(24) Belokon’, Yu. N.; Maleev, V. I.; Videnskaya, S. O.; Sapor-
ovskaya, M. B.; Tsyryapkin, V. A.; Belikov, V. M. Izv. Akad. Nauk
SSSR, Ser. Khim. 1991, 126. (Bull. Acad. Sci. USSR, Div. Chem. Sci.,
1991, 40, 110).
(25) Bordwell, F. G.; McCallum, R. J .; Olmstead, W. N. J . Org. Chem.
1984, 49, 1424.
(26) Bordwell, F. G.; Algrim, D. J . J . Am. Chem. Soc. 1988, 110,
2964.
(27) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J . Org. Chem.
1980, 45, 3295.
(28) (a) Solladie-Cavallo, A.;. Simon-Wermeister, M.; Schwarz, J .
Organometallics 1993, 12, 3743. (b) Streitwieser, A.; Krom, J . A.;
Kilway, K. V.; Abbotto, A. J . Am. Chem. Soc. 1998, 120, 10801. (c)
Abbotto, A.; Leung, S. Sh.-W.; Streitwieser, A.; Kilway, K. V. J . Am.
Chem. Soc. 1998, 120, 10807.

7046 J . Org. Chem., Vol. 65, No. 21, 2000
Belokon et al.
Sch em e 2. P ossible Mech a n ism of
TADDOL-Med ia ted Asym m etr ic P TC Alk yla tion of
1
Ta ble 5. Th e Dep en d en ce of th e En a n tiom er ic P u r ity of
th e P r od u ct of 1b Ben zyla tion [(R)-r-Me-P h e] on th e
En a n tiom er ic P u r ity of Ca ta lyzin g (R,R)-Ta d d ola
run
ee of (R)-R-MePhe
ee of (R,R)-TADDOL
1
2
3
4
42
42
85
80
50
61
80
82
a
The reaction conditions and methods of analysis are the same
as in the reference to Table 3.
rally ruined the asymmetry inducing performance of the
catalyst (Table 3, runs 13-15).
It is difficult to estimate if it was one or two OH groups
of TADDOL that were ionized under the experimental
conditions without any kinetic experiments, and if it was
mono- or bis-alcoholate which constituted the real cata-
lyst. Still there is a broad maximum of the asymmetric
induction of the reaction centered at a 1:1 NaH/TADDOL
ratio. Also the analogy with NOBIN could support a
notion that the mono-alcoholate of TADDOL functioned
as the real catalytic particle in the PTC C-alkylation
reaction.
Finally, the question of the number of TADDOL
molecules in the catalytic complex has to be addressed.
A very rough linear correlation between the ee of TAD-
DOL and that of the product (R-Me-Phe) of 1b benzyla-
tion was observed (see Table 5, runs 1-4), indicating that
most likely only one molecule of TADDOL was present
in the catalytic complex (for a discussion of nonlinear
effects, see ref 29).
As data collected in Table 2 (run 11) and Table 3 (run
19) indicated, substrate 4 was invariably inferior sub-
strate relative to 1b (Table 2, runs 10 and 11; Table 3,
runs 20 and 19) or even 1a (Table 3, run 2) in terms of
asymmetric induction under the identical conditions.
Obviously, the carbanion of 4 was functioning as a
monodentate ligand with too many degrees of freedom
of rotation in the chiral ion pair. The obvious reason for
the better performance of the substrates 1a -d , as
compared to 4, lies in the ability of their carbanion to
chelate sodium ions in a mixed chiral complex with
TADDOL (see Scheme 2). Compound 1e proved to be a
slowly reacting substrate, giving low ee of the final
product (Table 3, run 3). In this case the sterically
demanding substrate preventing formation of the com-
plex between the enolate ion pair and TADDOL together
with spontaneous alkylation of the hydrophobic (and thus
more soluble in toluene) sodium salt of 1e might be the
underlying reason for this obvious deviation.
The highly hypophetical mechanism of the catalytic
action of TADDOL or NOBIN is depicted in Scheme 2,
as applied to the TADDOL case. At the surface of solid
NaOH, TADDOL becomes ionized, the alcoholate thus
formed acts as a chiral base in an organic solvent,
ionising 1b. The chiral ion pair, consisting of the sub-
strate enolate and TADDOL complexed with the metal
ion, is the intermediate species that undergoes alkylation.
After the complex had been alkylated, TADDOL (or
NOBIN) is released to participate in a new catalytic cycle.
PTC conditions. The conditions for the alkylation were
not optimized and higher ee of the alkylation could be
expected when lower temperatures, improved catalysts,
etc. were employed. The procedure could be successfully
scaled up to 6 g of substrate 1b (see the Experimental
Section). Our results compare favorably with other
methods of asymmetric PTC alkylations, employing
chiral derivatives of alkaloids,2-5 in terms of the catalyst
stability and recovery, and the ambient temperature of
the reaction. Thus, new asymmetric alkylations of vari-
ous C-H acids can be envisaged, using our approach with
chelates tailor-made for each particular application. We
believe that further increase in the number of chelating
catalysts would allow the enantioselectivity of this reac-
tion to be increased.
Exp er im en ta l Section
Gen er a l Meth od s. The IR-spectra were taken in KBr
plates. All chemical shifts are reported as δ values (ppm)
relative to C6D6 as an external standard. The optical rotations
were measured at 25 ( 0.2 °C in CHCl3 unless otherwise
stated. The electronic absorption spectra were carried out with
matched pair of quarts cells. Melting points are uncorrected.
The reactions were monitored by TLC on Silufol plates; for
TLC silicagel 60 F254 (Merck) was employed. Enantiomeric
GLC analyses30 of (a) R-Me-Phe, (b) R-All-Ala, and (c) R-Me-
Napht-Ala were performed on a Chirasil-L-Val type phase, by
using n-propyl esters of N-trifluoroacetyl derivatives of amino
acids. Fused silica capillary column 40m × 0.23 mm i.d. Phase
film thickness 0.12 µm. Column temperature: (a) 125 °C, (b)
75 °C, (c) 160 °C. Carrier-gas He: 1.80 bar.
All reactions were performed under a dry argon atmosphere.
Hexane and toluene were distilled over Na prior to the reaction
(the water content was e0.01%; determined by the Fischer
method). Granules of NaOH (Reakhim or Merck) were pow-
dered in a glovebox filled with Ar immediately prior to the
reaction. For preparation of aminonaphthols 3a -g see ref 18.
Compound 3h was prepared by reaction of 3a with ethylene
oxide.31 Commercial diols 2a (Merck) and (-)-2,3-O-isopropyl-
idene-1,1,4,4-tetra(2-naphthyl)-L-threitol (2e) (Fluka) were
t
used. Butyl ester of L-alanine was received from Aldrich. All
the synthesized compounds had the appropriate physical and
chemical data.
(4R,5R)-2,2-Dim et h yl-1,3-d ioxola n e-4,5-b is(d ip h en yl-
m eth a n ol) [(R,R)-TADDOL (2b)] were synthesized by previ-
Con clu sion s
In summary, we propose a new type of efficient chiral
catalysts for asymmetric C-alkylation of CH acids under
(30) Saporovskaya, M. B.; Volkova, L. M.; Pavlov, V. A. Zh. Anal.
Khim. 1989, 44, 425 [J . Anal. Chem. USSR, 1989, 44 (Engl. Transl.)]
(31) Weber, L. M. J . Med. Chem. 1963, 6, 637.
(29) Girard, C., Kagan, H. B. Angew. Chem., Int. Ed. Engl. 1998,
37, 2922.

Synthesis of (R)- and (S)-R-Methyl Amino Acids
J . Org. Chem., Vol. 65, No. 21, 2000 7047
ously described procedures:15,16 mp 196-198 °C; [R]20 -61.5°
Hz), 3.25 (m, 2H, CH2), 4.15 (m, 1H, CH), 5.07 (m, 1H, OCH),
7.21-7.69 (m, 10H, 2Ph), 7.98 (s, 1H, CHdN).
D
1
(c 1, CHCl3); H NMR (200 MHz, CDCl3) δ 1.05 (s, 6H, 2Me);
4.01 (s, 2H, 2CH); 7.30-7.50 (m, 20H, 4Ph) (lit.15 mp 193-
Alk yla tion of Sch iff’s Ba ses 1a -f (Typ ica l P r oced u r e).
A solution of compound 2b (0.047 g, 0.1 mmol) or 3a (0.0285
g, 0.1 mmol) in 3 mL of anhydrous PhMe was placed in a dry
flask containing a stirring bar and filled with Ar (the reaction
flask had been twice evacuated and heated in a flame of a
burner followed by filling with Ar). NaOH (0.16 g, 4 mmol)
(powdered under Ar immediately prior to the experiment) or
NaH (oil covered) was added, and the suspension was stirred
for 5 min. Then, a solution of the Schiff’s base 1 (0.219 g, 1
mmol) (distilled in vacuo in an Ar flow) in 2 mL of dry PhMe
and benzyl bromide (0.14 mL, 1.2 mmol) were added succes-
sively in a flow of Ar. The mixture was stirred at room
temperature (15-20 °C) for 12 h, and 6 N HCl (6 mL) was
added. The stirring was continued for an additional 15 min at
the ambient temperature, the aqueous layer was separated,
the organic layer was washed with 6 N HCl, and the aqueous
layers were combined. Catalyst was recovered by concentration
of the organic layer and crystallization of the residue. The
aqueous extract was refluxed for 1 h (to determine the
chemical yield, an aliquot portion of a standard solution of Leu
in 6 N HCl was added; the yield was found by integrating the
signals of the Me groups in Leu and the CH2 groups in Me-
Phe in the 1H NMR spectra), concentrated, and passed through
a column with DOWEX-50W resin (in the H+ form). (R)-R-Me-
Phe (0.145 g, yield 81%) was eluted with 5% ammonia, and
the eluate was concentrated and analyzed by GLC for enantio-
meric composition (ee 82%). The crude amino acid thus
produced could be recrystallized from an i-PrOH-H2O mixture
to give the enantiomerically pure (R)-R-Me-Phe: yield 40%;
195 °C; [R]20 -66.7 (c 1, CHCl3)). (4S,5S)-TADDOL (S,S)-
D
2b) was synthesized by analogy.
1-O-Ben zyl-2,3-isop r op ylid en e-1,1,4,4-t et r a p h en yl-L-
tr eitol (2c) was prepared by benzylation of compound 2b with
excess BnBr (3 equiv) and NaH (2.5 equiv) in MeCN on
refluxing of the reaction mixture during 18h (see ref 15 and
16) and crystallized from hexane/CH2Cl2: mp 224 °C; [R]20
D
1
-25.7 (c 1, CHCl3); H NMR (200 MHz, CDCl3) δ 0.76, 0.95
(both s, both 3H, 2Me), 3.60 (d, 1H, CH, J ) 10.0 Hz), 4.05
(AB system, 2H, CH2, ∆ν ) 20 Hz, J ) 15.0 Hz), 4.30 (d, 1H,
CH, J ) 10.0 Hz), 5.66 (s, 1H, OH), 6.80-7.40 (m, 25H, 5Ph);
IR (KBr) 1019, 1034, 1042, 1057, 1082 (O-C-O), 3350 (Bn-
O‚‚‚H) cm-1. Anal. Calcd for C38H36O4: C, 81.98; Η, 6.52.
Found: C, 81.97; H 6.45.
2,3-Isopr opyliden e-1,4-di-O-m eth yl-1,1,4,4-tetr aph en yl-
L-tr eitol (2d ) was synthesized by alkylation of compound 2b
with excess MeI (4 equiv) in DMF in the presence of NaH (3
1
equiv) at 50 °C during 24 h: [R]20 -89.90 (c 1, CHCl3); H
578
NMR (200 MHz, CDCl3) δ 0.86 (s, 6H, 2Me), 3.00 (s, 6H, 2Me),
4.88 (s, 2H, 2CH), 7.10-7.60 (m, 20 H, 4 Ph). Anal. Calcd for
C
33H34O4: C, 80.12; H 6.93. Found: C, 80.17; H 7.02.
Ni(II) com p lex of th e Sch iff ba se of D,L-Ala a n d N-(2-
p yr r id ylca r bon yl)-o-a m in oben za ld eh yd e (4) was prepared
by a previously described procedure:23 mp 286 °C dec (lit.23 mp
286°C dec). Anal. Calcd for C16H13N3NiO3: C, 54.29; H, 3.70;,
N, 11.87. Found: C, 53.83; H, 3.57; N, 11.85.
Schiff’s bases 1a -f were synthesized by standard proce-
dures32 from benzaldehydes and the corresponding Ala ester.
N-Ben zylid en e-D,L-a la n in e m eth yl ester (1a ): yield 66%;
mp 288-290 °C dec; [R]25 +17.8 (c 0.2, H2O), ee >99%
D
according to GLC (lit.34 for (S)-R-Me-Phe [R]25 -17.8 (c 0.2,
D
colorless oil; bp 112-113 °C (2.5 Torr) (lit.32 mp 105-107 °C
H2O), ee >99% according to GLC); 1H NMR (200 MHz, CDCl3)
δ 1.31 (s, 3H, Me); 2.90 (AB system, 2H, CH2, J ) 14.0 Hz),
6.90-7.20 (m, 5H, Ph); UV λmax/nm (ꢀ) 252 (139), 258 (178),
264 (135). Anal. Calcd for C10H13NO2: C, 67.02; H 7.31; N,
7.82. Found: C, 67.12; H 7.50; N, 7.87.
1
(2 Torr)); nD 1.5378; H NMR (200 MHz, CDCl3) δ 1.08 (d,
15
3H, Me, J ) 7.0 Hz), 3.29 (s, 3H, OMe), 3.80 (q, 1H, CH, J )
7.0 Hz), 6.60-7.30 (m, 5H, Ph), 7.86 (s, 1H, CHdN); IR (KBr)
1451, 1581, 1643 (CdN), 1742 (CdO), 2952 cm-1. Anal. Calcd
for C11H13NO2: C, 68.30; H, 6.85, N 7.32. Found: C, 68.30; H,
6.82, N 8.19.
A similar procedure involving allyl bromide gave (R)-R-
allylalanine ((R)-R-All-Ala); the use R-naphthylmethyl chloride
led to (R)-R-(1-naphthylmethyl)alanine ((R)-R-Me-Napht-Ala,
and the reaction with isopropyliodide gave (R)-R-Me-Val. The
enantiomeric purities of these products were also estimated
by GLC based on a comparison with authentic samples of the
amino acids.34
Alk yla tion of 4 w ith Ben zyl Br om id e. The alkylation
was performed as described for the alkylation of Schiff’s bases
1a -f (see above). The recovery and enantiomeric analysis of
R-Me-Phe was carried out as described in ref 23.
Alk yla tion of Sch iff’s Ba ses 1b w ith Ben zyl Br om id e
(Sca le-Up P r oced u r e). A solution of (S,S)-TADDOL 2b (1.34
g, 2.88 mmol) in 110 mL of anhydrous hexane was placed in a
dry flask, containing a stirring bar, and Ar (see above) and
NaOH (4.6 g, 115 mmol) (powdered under Ar immediately
prior to the experiment) were added and the suspension was
stirred for 15 min. Then, a solution of the Schiff’s base 1b (6.3
g, 28.8 mmol) (distilled in vacuo in an Ar flow) in 10 mL of
dry hexane and benzyl bromide (0.14 mL, 1.2 mmol) were
added successively in a flow of Ar. The mixture was stirred at
20 °C for 20 h, and hexane was evaporated. Then benzene (100
mL) and 6 N HCl (100 mL) were added. The stirring was
continued for an additional 15 min, the aqueous layer was
separated, the organic layer was washed with 6 N HCl, and
the aqueous layers were combined. The catalyst was recovered
from organic layer. The aqueous extracts were refluxed for 6
h and evaporated, a fresh portion of 2 N HCl was added, and
the solution was passed through a column with DOWEX-50W
resin (in the H+ form). (R)-R-Me-Phe (2,8 g, 15.6 mmol, yield
54.3%) was eluted with 5% ammonia, and the eluate was
concentrated and analyzed by enantiomeric GLC (ee 77.3%).
The crude amino acid thus produced was recrystallized from
N-Ben zylid en e-D,L-a la n in e isop r op yl ester (1b): yield
71%; bp 120-121 °C (2 Torr); nD15 1.5168; 1H NMR (200 MHz,
CDCl3) δ 1.23, 1.27 (both d, both 3H, 2Me, J ) 6.2 Hz), 1.51
(d, 3H, Me, J ) 7.1 Hz), 3.80 (m, 1H, OCH), 3.29 (q, 1H, CH,
J ) 7.1 Hz), 6.60-7.30 (m, 5H, Ph), 7.86 (s, 1H, CHdN); IR
(KBr) 1451, 1581, 1644 (CdN), 1735 (CdO) cm-1. Anal. Calcd
for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C, 71.18;
H, 7.82; N, 6.55.
N-4-Ch lor oben zyliden e-D,L-alan in e isopr opyl ester (1c):
yield 85%; 1H NMR (200 MHz, CDCl3) δ 1.17, 1.21 (both d,
both 3H, 2Me, both J ) 6.0 Hz), 1.45 (d, 3H, Me, J ) 7.1 Hz),
4.00 (q, 1H, CH, J ) 7.1 Hz), 4.95 (m, 1H, OCH), 7.30-7.50
(m, 4H, Ar), 8.26 (s, 1H, CHdN); IR (KBr) 1451, 1581, 1644
(CdN), 1735 (CdO) cm-1
.
N-4-Flu or oben zyliden e-D,L-alan in e isopr opyl ester (1d):
yield 83%; 1H NMR (200 MHz, CDCl3) δ 1.19, 1.23 (both d,
both 3H, 2Me, J ) 6.1 Hz), 1.48 (d, 3H, Me, J ) 7.1 Hz), 4.10
(q, 1H, CH, J ) 7.1 Hz), 5.05 (m, 1H, OCH), 7.20-7.40 (m,
4H, Ar), 8.59 (s, 1H, CHdN).
N-Ben zylid en e-L-a la n in e ter t-bu tyl ester (1e): yield
51%; colorless oil; bp 105-107 °C (1.5 Torr); nD15 1.5119; [R]20
D
1
-36° (c 1, CHCl3); H NMR (200 MHz, CDCl3) δ 1.48 (s, 9H,
3Me), 1.50 (d, 3H, Me, J ) 6.3 Hz), 4.02 (q, 1H, CH, J ) 6.3
Hz), 7.34-7.86 (m, 5H, Ph), 8.30 (s, 1H, CHdN), IR (KBr)
2979, 1735 (CdO), 1644 (CdN) 1451 cm-1 (lit.33 IR (KBr) 1740
(CdO), 1650 (CdN) cm-1). Anal. Calcd for C14H19NO2: C,
72.07; H, 8.21; N, 6.00. Found: C, 71.97; H, 8.27; N, 6.02.
N-Ben zylid en e-D,L-p h en yla la n in e isop r op yl ester (1f):
yield 75%; bp 169-170 °C (2 Torr); nD 1.5538; 1H NMR (200
16
MHz, CDCl3) δ 1.23, 1.25 (both d, both 3H, 2Me, both J ) 6.1
(32) Grigg, R.; Gunaratne, H. Q. N.; Kemp, J . J . Chem. Soc., Perkin
Trans. 1 1984, 41.
(33) Ojima, I.; Nakahashi, K.; Brandstadter, S. M.; Hatanaka, N.
J . Am. Chem. Soc. 1987, 109, 1798.
(34) Belokon, Yu. N.; Bakhmutov, V. I.; Chernoglazova, N. I.;
Kochetkov, K. A.; Vitt, S. V.; Garbalinskaya, N. S.; Belikov, V. M. J .
Chem. Soc., Perkin Trans. 1 1988, 305.

7048 J . Org. Chem., Vol. 65, No. 21, 2000
Belokon et al.
an PriOH-H2O mixture to give (R)-R-Me-Phe (1.8 g, yield
Grant Agency of the Czech Republic (Grant No. 203/
00/0601), Grant Agency of Charles University (Grant
No. 18/98), Department Science and Technology (DST)
Government of India.
34.8%, ee 98.1%).
Ack n ow led gm en t. The work was supported by
European Foundation INCO-Copernicus (Grant No.
IC15-CT96-0722), Russian Fund for Fundamental Sci-
ences (Project No. 99-03-32970), ISTC Grant No. A-356,
J O000719P