Organic Process Research & Development 2003, 7, 164−167
Reductions of Aromatic Amino Acids and Derivatives
David J. Ager*,† and Indra Prakash*,‡
The NutraSweet Company, 601 East Kensington Road, Mount Prospect, Illinois 60056, U.S.A.
Abstract:
alkyl derivatives with Rh-Al2O3 has been reported for this
Catalytic reduction of phenylalanine and phenylglycine deriva-
tives can be achieved with rhodium on carbon or alumina to
give good yields of the corresponding cyclohexyl derivatives.
The procedure can be scaled.
amino alcohol but with moderate yield.7 We now report a
simple method for the reduction of aromatic amino acid
derivatives to corresponding cyclohexyl compounds with
hydrogen at low pressure and rhodium as the catalyst under
conditions used in “conventional” equipment and without
racemization of the amino acids.
The reduction of aromatic amino acids leads to unnatural
amino acids that have been incorporated into a number of
pharmaceutical candidates. For example, L-cyclohexylalanine
(1), L-cyclohexylalaninol (2), and their derivatives are used
for the construction of peptide isosteres related to the renin-
angiotensin system. These have been utilized by several
research groups involved in the design and synthesis of
peptidomimetic therapeutic agents.1 L-Cyclohexylalanine
amide (3) has been used in the synthesis of tetrapeptide
analogues of pentagastrin and cholecystokinin drugs.2
Previous reported methods for the synthesis of L-cyclo-
hexylalanine (1) involve the reduction of L-phenylalanine
(4) using platinum oxide or platinum on carbon in acetic
acid.3 Rhodium in the presence of acid has been used for
the reduction of phenylglycine (vide infra).4 Synthesis of
L-cyclohexylalanine amide (3) is reported in a patent without
any experimental detail.2 L-Cyclohexylalaninol (2)5 was
prepared by the sodium or calcium borohydride reduction
of the L-Boc-cyclohexylalanine methyl ester (6),6 followed
by hydrolysis of the Boc group (Scheme 1). A method for
the hydrogenation of aromatic amines to their corresponding
Catalytic reduction of L-phenylalanine (4) over rhodium
on carbon under acidic conditions (hydrochloric, sulfuric,
or phosphoric acids) gave 1 in good yields. The reduction
could not be achieved under neutral conditions. Interestingly,
when the Rh-C was replaced with Rh-Al2O3 catalyst, no
acid was required to achieve the reduction, and high yields
of the saturated compound were obtained. Alternatively, 1
could also prepared by the reduction of L-Boc-phenylalanine
methyl ester (7) followed by acidic treatment to remove the
protecting group and hydrolysis of the ester (8) (Scheme 1)
in a manner similar to that previously reported.6 The less
direct route was used to illustrate that derivatives of the
parent amino acid 1 are also available by reduction of the
appropriate substrate rather than by performing reactions or
protection/deprotection chemistry on 1.
For either reaction pathway, no racemization of the amino
acid was observed. The product 1 was isolated by standard
precipitation techniques near the isoelectric point. For the
more polar amino acids, water was used as the solvent, while
methanol had to be employed for the N-protected ester 7. In
a similar manner, the reduction was then extended to the
synthesis of L-cyclohexylalanine amide (3) from L-phenyl-
alanine amide (9) (Scheme 2).
The procedure can also be applied to L-phenylglycine (10)
in addition to the D-isomer. Again, no racemization was
observed in the product 11. As well as acidic conditions,
the sodium salt of the amino acid can be used to enhance
solubility in water (Scheme 3). This methodology is also
available for other arylamino acids. In our hands, the basic
method performed better than those with acidic conditions,4
and this approach is more amenable to scale-up as reactor
compatibility problems with the acidic conditions are avoided.
In addition to R-amino acids, the amino alcohol 2 was
prepared by the reduction of L-phenylalaninol (12) over
Rh-C under acidic conditions (Scheme 4). Again, the
reaction did not proceed under neutral conditions with either
Rh-C or Rh-Al2O3 although a wide range of catalysts of
these types was screened. The yield obtained was higher
(97%) than that previously reported (47%).7
* Authors for correspondence. Telephone: (919) 844-2985. Fax: (919) 870-
7902. E-mail: scribusted@aol.com and indra.prakash@nutrasweet.com.
† Current address: RCCorp, 805 Darfield Drive, Raleigh, NC 27615.
‡ Current address: NutraSweet, 699 Wheeling Road, Mount Prospect, IL
60056.
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(6) Reduction of 7 to 6 by the use of Rh-Al2O3 at 30-55 psi has been reported
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Alternatively, 2 was also prepared from L-Boc-phenyl-
alaninol (13) by catalytic reduction followed by acidic
(7) Strotmann, M.; Butenscho¨n, H. Synth. Commun. 2000, 30, 4173.
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Vol. 7, No. 2, 2003 / Organic Process Research & Development
10.1021/op0200773 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/12/2003