A new synthesis of p-hydroxy phenylglycine and some analogues from p-benzoquinone

Article abstract of DOI:10.1021/ol9913183

(Formula presented) A new route to p-hydroxy phenylglycine and N-substituted analogues has been developed starting from p-benzoquinone. 1,2-Addition of methyl lithioacetate to p-benzoquinone and subsequent quenching of the oxygen anion with methyl chloroformate, followed by an elimination-addition reaction with an appropriate amine, resulted in the desired amino acid derivatives. A diastereoselectivity of 60% was achieved using 8-phenylmenthyl acetate as the chiral auxiliary.

Full text of DOI:10.1021/ol9913183

ORGANIC
LETTERS
2000
Vol. 2, No. 4
473-475
A New Synthesis of p-Hydroxy
Phenylglycine and Some Analogues
from p-Benzoquinone
Gerardus T. M. Titulaer, Jie Zhu, Antonius J. H. Klunder, and Binne Zwanenburg*
Department of Organic Chemistry, NSR Institute for Molecular Structure, Design and
Synthesis, UniVersity of Nijmegen, ToernooiVeld, 6525 ED Nijmegen, The Netherlands
zwanenb@sci.kun.nl
Received December 7, 1999
ABSTRACT
A new route to p-hydroxy phenylglycine and N-substituted analogues has been developed starting from p-benzoquinone. 1,2-Addition of
methyl lithioacetate to p-benzoquinone and subsequent quenching of the oxygen anion with methyl chloroformate, followed by an elimination−
addition reaction with an appropriate amine, resulted in the desired amino acid derivatives. A diastereoselectivity of 60% was achieved using
8-phenylmenthyl acetate as the chiral auxiliary.
D-(-)-2-(p-Hydroxyphenyl)glycine (HPG) is an important
intermediate in the synthesis of the life-saving semisynthetic
antibiotics amoxicillin and cefadroxil. The preparation of the
racemic compound has been achieved using different ap-
proaches involving the Strecker synthesis,1 the hydantoin
route2 and the ammonolysis of p-hydroxymandelic acid,
obtained by the condensation of phenol and glyoxilic acid.3
Both the hydantoin approach and the p-hydroxymandelic acid
route involve an electrophilic addition reaction on phenol.
A serious problem in this electrophilic addition reaction is
the formation of a mixture of ortho- and para-substituted
product due to the activation of both the ortho and the para
positions by the electron-donating effect of the OH group.
The Strecker approach has as drawback that it requires the
expensive p-hydroxy benzaldehyde as a starting material.
In this paper we report a new synthetic route to HPG,
starting from inexpensive p-benzoquinone. In this route the
ortho/para problem is circumvented, because the para
arrangement is already present in the starting material. Our
strategy involves functionalization of one carbonyl group in
p-benzoquinone, which then leads to exclusive formation of
para-substituted product.
The first step of this synthesis is a 1,2-addition of methyl
lithioacetate to benzoquinone4 and subsequent quenching of
the oxygen anion with methyl chloroformate to give 2 in
94% yield (Scheme 1).
Scheme 1. 1,2-Addition of Methyl Lithioacetate to
p-Benzoquinone and Quenching with Methyl Chloroformate
The key step is the base-induced â-elimination of the
carbonate group leading to intermediate 3, followed by a
nucleophilic addition to the R-carbon atom (Scheme 2).
Quinone methide compound 3 is a highly reactive species,
as it escapes isolation under the conditions of the reaction.
(1) Steiger, R. E. Organic Synthesis CollectiVe Volume 3; John Wiley
and Sons: New York, 1955; p 84.
(2) Greenstein, J. P.; Winitz, M. Chemistry of the Amino Acids; John
Wiley and Sons: New York, 1961; p 700.
(3) Powar, N. P.; Chandalia, S. B. J. Chem. Tech. Biotechnol. 1989, 46,
219.
(4) Fischer, A.; Henderson, G. N. Tetrahedron Lett. 1983, 24, 131.
10.1021/ol9913183 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/02/2000

“attacks” at the â-position with respect to the chiral auxiliary.
In our case, however, the nucleophile comes in at the
R-position, implying that the chiral auxiliary is even closer
to the reaction center (Scheme 3).
Scheme 2. Elimination-Addition Reaction
This anomalous behavior can be attributed to the electron-
withdrawing effect of the dienone functionality, resulting in
an electron deficiency at the R-carbon atom. A nucleophilic
attack at this carbon atom results in aromatization of the
dienone group, which explains the high reactivity of inter-
mediate 3. To study the diastereoselectivity, esters derived
from three different chiral alcohols have been investigated
as chiral auxiliaries (Scheme 4). The syntheses of 5a-c were
Even after the addition of a nonnucleophilic base and in the
absence of potential nucleophiles, 3 could not be isolated.
A one-pot approach in THF as the solvent, in which the
reactive intermediate 3 is trapped with an amine in an
elimination-addition reaction, proved to be very successful.
Six different amines have been introduced using this
procedure, as summarized in Table 1.
Scheme 4. Elimination-Addition Reaction Using Chiral
Auxiliaries
Table 1. Results of the One-Pot Elimination-Addition
Reaction Using Six Different Amines
entry
R1
R2
equiv
base
yield (%)
a
b
c
d
e
f
H
H
H
H
H
H
excess
10
10
10
10
NH3
DBU
DBU
DBU
DBU
DBU
80-90
95
100
99
92
87
CH2Ph
(CH2)3CH3
C6H11
C(CH3)3
piperidine
10
For the synthesis of HPG (entry a), 2 was dissolved in
THF and added to liquid ammonia at -30 °C. The presence
of THF appeared to be essential, because in its absence no
addition product was formed. Apparently, THF is beneficial
for the nucleophilicity of the amine. In the synthesis of 4a
no additional base was required to eliminate the carbonate
group. The reactions with benzylamine, n-butylamine, cy-
clohexylamine, tert-butylamine, and piperidine (entries b-f)
were performed at 0 °C with 10 equiv of the amines and
required a small amount of DBU (5-10 mol %) as a catalyst
to initiate the elimination of the carbonate group. These
elimination-addition reactions went to completion in a few
hours in very high yield. Using a lesser amount of amine,
e.g., 5 equiv, resulted in a minor decrease in the yield of the
corresponding addition products, whereas less than 3 equiv
resulted in a substantial decrease.
performed in a manner analogous to the sequence shown in
Scheme 1, using the corresponding acetate derived from the
chiral auxiliaries a-c in the 1,2-nucleophilic addition reaction
to p-benzoquinone (yields 80-90%). Two different nucleo-
philes have been studied in the elimination-addition reaction,
i.e., ammonia and benzylamine. The reactions were per-
formed under the same conditions as described above. The
reactions with ammonia, however, required considerable
longer reaction times, up to 10 h. The results are summarized
in Scheme 4. The bornyl group (a) did not show any
diastereoselectivity, which is in line with the rather poor
inducting capabilitiy of this group. The menthyl group (b),
however, gave a diastereoselectivity of 15-20%. In this
study, the best results were obtained using the 8-phenyl-
menthyl group (c) as a chiral auxiliary. The shielding effect
of the additional phenyl group apparently is quite effective,
resulting in a diastereoselectivity of 60%. Fine-tuning of the
chiral auxiliary might result in a further improvement of the
diastereoselectivity, which is currently under investigation.
In addition to the abovementioned synthesis of 4, we also
studied the diastereoselectivity in this elimination-addition
reaction using a chiral acetate ester. It should be noted that
this is a special case of the Michael addition reaction
(Scheme 3). In a regular Michael addition, the nucleophile
Scheme 3. R-Michael Addition vs â-Michael Addition
Benzylamine appeared to be a very effective nucleophile.
The yields of the addition products were in all cases very
high. However, the addition of ammonia was less effective
as a result of its poor nucleophilicity.
474
Org. Lett., Vol. 2, No. 4, 2000

In summary, a new synthesis of p-hydroxy phenylglycine
from the inexpensive p-benzoquinone has been developed,
in which the well-known ortho/para problem is circum-
vented. A de up to 60% was achieved using different kinds
of chiral auxiliaries.
try of Economical Affairs (Senter) for their financial sup-
port.
1
Supporting Information Available: H NMR spectra of
compounds 2, 4a-f, 5a-c, 6a-c, and 7a-c. This informa-
tion is available free of charge via the Internet at http://
pubs.acs.org.
Acknowledgment. The authors thank DSM Life Sciences
Group (Geleen, The Netherlands) and the Dutch Minis-
OL9913183
Org. Lett., Vol. 2, No. 4, 2000
475