Enantiomerically enriched (R)- and (S)-α-methylphenylalanine via asymmetric PTC C-alkylation catalysed by NOBIN

Article abstract of DOI:10.1016/S0957-4166(99)00185-8

Enantiopure 2-hydroxy-2'-amino-1,1'-binaphthyl (NOBIN) is shown to catalyse C-alkylation of aldimine Schiff's bases of alanine ester under phase-transfer catalysis conditions (solid NaOH or NaH, toluene, ambient temperature, 10% NOBIN). Using (R)-NOBIN, t

Full text of DOI:10.1016/S0957-4166(99)00185-8

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1723–1728
Enantiomerically enriched (R)- and (S)-α-methylphenylalanine
via asymmetric PTC C-alkylation catalysed by NOBIN
Yuri N. Belokon’,a,∗ Konstantin A. Kochetkov,a Tatiana D. Churkina,a Nikolai S. Ikonnikov,a
Stepan Vyskocil b,∗ and Henri B. Kagan c,∗
aA.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, 117813, Moscow, Vavilov 28,
Russia
bCharles University, Faculty of Science, Department of Organic Chemistry, 12840, Prague 2, Hlavova 2030, Czech Republic
cUniversité de Paris Sud. 91405, Orsay Cedex, Institut de Chimie Moléculaire d’Orsay, Laboratoire de Synthèse Asymétrique,
Associated to CNRS, Paris, France
Received 24 March 1999; accepted 12 May 1999
Abstract
Enantiopure 2-hydroxy-20-amino-1,10-binaphthyl (NOBIN) is shown to catalyse C-alkylation of aldimine
Schiff’s bases of alanine ester under phase-transfer catalysis conditions (solid NaOH or NaH, toluene, ambient
temperature, 10% NOBIN). Using (R)-NOBIN, the final (S)-α-methylphenylalaninewas obtained in up to 68% ee.
© 1999 Published by Elsevier Science Ltd. All rights reserved.
1. Introduction
Ion-pair-mediated reactions under phase-transfer conditions (phase-transfer catalysis, PTC) 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 ammonium salts.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 CsOH as a base has been
reported by two independent groups.3,4 Recently, O’Donnell introduced neutral, non-ionic phosphazene
bases.5 However, all the chiral catalysts of the quaternary ammonium-type are efficient only at low
temperatures.2–5 Thus, the search for novel, active and stable chiral phase-transfer catalysts continues.
Recently, we have found that a mixture of NaH and (4R,5R)-2,2-dimethyl-α,α,α0,α0-tetraphenyl-1,3-
dioxolane-4,5-dimethanol (TADDOL), a chiral, hydrophobic, chelating diol, served as a chiral base
∗
Corresponding authors. E-mail: yubel@ineos.ac.ru
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00185-8

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Figure 1.
to induce asymmetry in Michael addition reaction of an achiral glycine derivative, resulting in the
enantiomerically enriched (28% ee) γ-substituted glutamic acid.6 Furthermore, we have shown that
TADDOL can function as a chiral phase-transfer catalyst in the enantioselective alkylation. Thus, reaction
of Schiff’s bases 1, derived from alanine esters and benzaldehyde, with active alkyl halides at ambient
temperatures gave (after hydrolysis) α-methyl-α-amino acids 2 in good chemical yields and with ee
reaching 93%.7 TADDOL functioned in the reaction as a chelating agent for the alkali ions and thus
made the ion-pair (formed by the corresponding carbanion and alkali ions) soluble in organic solvents.
This modification combined the synthetic simplicity of the PTC-approach2 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.8 We reasoned that another important class of organic chelating
agents, for example 2,20-disubstituted-1,10 -binaphthyls, might function in the same way, activating the
ion-pair by the complexation of an alkali ion. To this end, we set out to use BINOL and NOBIN 3 and
its derivatives 4–10.9 Herein, we report on the application of these ligands in a catalytic asymmetric
synthesis of α-methyl substituted α-amino acids, that represent an important class of nonproteinogenic
amino acids.2b,10
2. Results and discussion
The alkylation of the Schiff’s base 1, formed from benzaldehyde and racemic alanine isopropyl ester,
served as a model reaction. The alkylations of the substrate with active alkyl bromides were conducted in
toluene (rigorously dried before use) at ambient temperature (20°C) using NaH or solid NaOH (ground
under argon) as bases. BINOL and NOBIN or NOBIN derivatives 4–10 (Fig. 1) were used as chiral
promoters of the reaction. After 12 h the reaction was quenched with HCl (aq.) and the liberated amino
ester was hydrolysed (see Scheme 1). The ee of the resulting amino acids 2 was established by chiral
GLC.
Scheme 1. (i) NOBIN (0.1–1.0 equiv.), NaOH (4 equiv.) or NaH (2 equiv.), toluene, Ar, 20°C, 4 h; (ii) 6 N HCl (aq.): (1) 20°C,
15 min, extraction of NOBIN; (2) reflux
While BINOL proved to be inefficient as both the catalyst and asymmetry-inducing agent, compounds
3–10 proved to be more successful. The results are shown in Table 1.

Y. N. Belokon’ et al. / Tetrahedron: Asymmetry 10 (1999) 1723–1728
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Table 1
The asymmetric alkylation of alanine ester 1 mediated by aminonaphthols 3–10 [a]
As can be seen from the data, enantiopure NOBIN was efficient as an asymmetric promoter of the
alkylation reactions (ee in the range of 48–68%) with both types of bases and active alkylating agents (see
Table 1, runs 1–5). (S)-NOBIN furnished (R)-α-methylphenylalanine (α-MePhe) 2a, (R)-α-allylalanine
2b and (R)-α-(1-naphthylmethyl)alanine 2c (runs 1–3, 5–7) whereas (R)-NOBIN gave (S)-2a (run 4).
The reaction occurs readily and does not give any side products under the standard conditions. The
chemical yields were very high; toluene was found to be the best solvent for the reaction to proceed with
good yield and ee. In hexane, the reaction was very slow and both ee of the product and its chemical yield
were below several percents. The ee of the product depended strongly on the structure of the catalyst.
The unsubstituted NOBIN gave 2a with up to 68% ee (run 2). The enantiomeric purity of 2a could then
be increased substantially by crystallisation, as demonstrated previously.7,11 The asymmetric allylation
of the substrate with allyl bromide mediated by (S)-3 under the standard PTC-conditions gave (R)-2b in
good chemical yield and 67% ee (run 5), whereas reaction with 1-(chloromethyl)naphthalene gave (R)-2c

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with 18% ee (run 6). The increase of the reaction temperature to 65°C resulted in the decrease of ee of
the product (R)-2a (run 7).
The choice of the cation of the base employed also proved to be of importance. Thus, for example,
LiOH was completely inactive, while with KOH the ee of the final (R)-2a dropped to 43% (run 8).
Addition of 1 mmol of CuBr (run 9) to the reaction mixture also led to a decrease in ee of the product,
while the addition of MgSO4 had no effect.
The introduction of sterically demanding alkyl groups at the nitrogen of NOBIN brought a decrease
in the ee of the final product 2a. Thus, when (S)-4, the N-methyl derivative of NOBIN, was used (R)-2a
was obtained with 31% ee (run 10). With the N,N-dimethyl derivative (S)-5, the product (R)-2a obtained
was of 15% ee (run 11). N-Isopropyl (R)-6, N-cyclohexyl (R)-7, N-(2-adamantyl) (R)-8 and N-phenyl
(S)-9 derivatives gave (R)- or (S)-2a in even lower enantioselectivities (runs 12–15). Catalyst (R)-10 with
an additional hydroxyethyl group gave (S)-2a of 17% ee (run 16). Thus, the introduction of substituents
at the N-atom of NOBIN (4–10) invariably decreased the ee of the reaction (Table 1, runs 10–16). In all
cases, catalysts 3–10 could be easily recovered from the reaction media and repeatedly used.
We believe that under the experimental conditions NOBIN functioned as a chiral base, ionising the
substrate. The pKa of 1, determined in DMSO, is in the range of 17–20,12 whereas that of NOBIN is
most likely about 18 (the measured pKa value of phenol in DMSO is 18,13 whereas the value for aniline is
3014). Hence, NOBIN is likely to be first ionised 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
NOBIN derivatives 3–10 and the alkali metal ion as revealed by the comparison of the solid NaOH and
KOH (runs 2 and 8). Finally, an intermolecular hydrogen bond between the ionised substrate and NOBIN
may stabilise the complex of the enolate ion pair with NOBIN. In fact, the structure of the complex would
be the same, regardless of whether the sodium salt of NOBIN served initially as a hydrophobic base or the
neutral NOBIN functioned as a chelating agent in the same manner as disclosed for another chiral catalyst
of Li-enolate alkylations.15 In our case, the unreactive aggregates of the sodium enolates generated from
116 may be activated for the C-alkylation by the complexation with NOBIN (Scheme 2).
Apparently, the good performance of the substrate 1 stems from the ability of the carbanion to chelate
the sodium ion in the mixed chiral complex with NOBIN (see Scheme 2). The latter effect provides a
rigid structure where the Si-face of the carbanion is effectively shielded from the electrophilic attack.
However, the mixed complex of the catalyst and the substrate or its enolate might have a much more
complicated structure.
In summary, our results offer a useful addition to the development of a new generation of efficient
chiral catalysts for asymmetric C-alkylation of C–H-acids, under PTC conditions. The conditions for the
alkylation were not optimised and higher ee of the alkylation could be expected when lower temperatures,
improved catalysts, etc. are employed. Our results compare favourably with other methods of asymmetric
PTC alkylations, employing chiral derivatives of alkaloids,2–5 in terms of the catalysts’ stability and
recovery and the ambient temperature of the reaction. Thus, a host of new asymmetric alkylations
of various C–H-acids can be envisaged, using our approach, with chelates tailored for each particular
application.
3. Experimental
Synthesis of 1 was performed as described earlier.7 For preparation of aminonaphthols 3–9 see the
literature.9 Compound 10 was prepared by reaction of 3 with ethylene oxide.17 Toluene was distilled

Y. N. Belokon’ et al. / Tetrahedron: Asymmetry 10 (1999) 1723–1728
1727
Scheme 2. Possible mechanism of NOBIN’s mediated asymmetric PTC-alkylation of 1
from sodium prior to use. All the synthesised compounds had the appropriate physical and chemical
data. GLC enantiomeric analyses of (a) α-methylphenylalanine 2a, (b) α-allylalanine 2b, and (c)
α-(1-naphthylmethyl)alanine 2c were performed on a Chirasil-L-Val type phase, by using their N-
trifluoroacetyl n-propyl esters. Fused silica capillary column 40 m×0.23 mm ID. Film 0.12 µm. Col.
temp.: (a) 125°C, (b) 75°C, (c) 160°C. Carrier gas He: 1.80 bar.
The alkylation of the substrate 1 was carried out as follows: a 25 mL flask containing a stirring bar
was flame dried in vacuo and filled with Ar. (S)-NOBIN 3 (0.0285 g, 0.1 mmol) and NaOH (0.16 g, 4
mmol, ground under Ar before use) (or NaH, oil covered) was added and mixed during 30 min. Then,
a solution of the Schiff’s base 1 (0.22 g, 1 mmol, distilled in vacuo under Ar) in dry toluene (2 mL)
and benzyl bromide (0.14 mL, 1.2 mmol) were added to the flask. The mixture was stirred at room
temperature (20°C) for 12 h and then aq. HCl (6 N, 6 mL) was added. The stirring was continued for
an additional 15 min at the ambient temperature. The aqueous layer was separated, the toluene layer
was washed with 6 N HCl and the aqueous layers were combined. The aqueous solution was refluxed
for 1 h and (R)-2a was purified by the ion-exchange technique (DOWEX-50, H+ form). The yield was
determined using 1H NMR analysis of the reaction mixture with (S)-leucine as an internal standard, and
the ee was determined by chiral GLC. The crude amino acid thus produced could be recrystallised from a
PriOH–H2O mixture to give the enantiomerically pure 2a: [α]25 +17.8 (c 0.2, H2O), ee >99% by GLC;
D
(the data for the sample of (S)-2a obtained by an earlier developed method:11 [α]25 −17.8 (c 0.2, H2O)).
D
α-Allylalanine 2b and α-(1-naphthylmethyl)alanine 2c also were checked with samples of the amino
acids.7 Pure NOBIN could be recovered from the toluene layer after its evaporation in vacuo, followed
by crystallisation from toluene.

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Y. N. Belokon’ et al. / Tetrahedron: Asymmetry 10 (1999) 1723–1728
Acknowledgements
The work was supported by the EU through INCO-Copernicus grant IC15-CT96-0722, the Russian
Fund for Fundamental Sciences (Grant No. 99-03-32970), the Grant Agency of the Czech Republic
(Grant No. 203/98/1185), and the Grant Agency of Charles University (Grant No. 18/98).
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