Biosci. Biotechnol. Biochem., 75 (2), 352–354, 2011
Note
Novel Synthesis of Optically Active Bishomotyrosine Derivatives
Using the Friedel-Crafts Reaction in Triflic Acid
y
Yuta MURAI, Yasuyuki HASHIDOKO, and Makoto HASHIMOTO
Division of Applied Science, Graduate School of Agriculture, Hokkaido University,
Kita 9, Nishi 9, Kita-ku, Sapporo 060-8589, Japan
Received August 18, 2010; Accepted October 29, 2010; Online Publication, February 7, 2011
We report here a novel synthesis of optically active
bishomotyrosine. The bishomotyrosine skeleton was
constructed by using a Friedel-Crafts reaction between
phenol and optically active N-Tfa-Glu(Cl)-OMe in triflic
acid under the mild condition. Reduction and subse-
quent deprotection then afforded bishomotyrosine
derivatives without any loss of optical purity.
acid, TfOH), and a novel synthesis of the optically
active regioisomer, 2-amino-5-(2-hydroxyphenyl)penta-
noic acid (ortho-bishomotyrosine, o-bhTyr).
One of the retrosynthetic methods for of bhTyr is
presented in Scheme 1. The reduction of the benzyl
carbonyl group and deprotection of compound I would
afford bhTyr. Compound I could be prepared by two
methods: first, by the Friedel-Crafts acylation of phenol
II and protected glutamic acid ꢀ-acid chloride III:
second, by Fries rearrangement of IV. The synthesis of
IV follows from the same precursors as those for the
direct synthesis of compound I. Although these retro-
synthetic methods are very simple, the actual synthesis
of bhTyr in this way has not been previously reported.
One of the most important drawbacks is the solubility of
ꢁ-amino acid derivatives in an organic solvent. The
Friedel-Crafts reaction has generally proceeds by com-
bined use of a Lewis acid and such organic solvents as
CH2Cl2, CH3NO2 and nitrobenzene. Since the ꢁ-amino
acid equivalents become insoluble in these organic
solvents in the presence of a Lewis acid, the reaction
mixture forms a suspension. The reaction has to be set
up with excess aromatics as the reagents and solvent,
and heated to improve the yield.12) It is very difficult to
apply a stoichiometric reaction with an acyl donor and
acyl acceptor by using the previous method.
TfOH is known to be a super-acid and has been used
as a catalyst in Friedel-Crafts acylation13) and alkyla-
tion.14) The reactions is most likely to proceed by the
formation of trifluoromethanesulfonic–carboxylic anhy-
drides as an active species for the origin of acyl
chloride,15,16) and this anhydride then reacts to form
aromatics. On the other hand, TfOH also has high
solubility for ꢁ-amino acid derivatives at room temper-
ature.17–19) We therefore planned to apply a Friedel-
Crafts reaction for the synthesis of bhTyr from phenol
by using the this favorable reaction. It is noteworthy that
the phenol has several reactions with acyl halides under
acidic conditions. Several requirements were necessary
for a successful reaction. O-Acylation and subsequently
Fries rearrangement and Friedel-Crafts C-acylation has
to be maintained for successful bhTyr synthesis. The
protective groups of glutamic acid also have to be stable
under acidic conditions. Trifluoroacetamide and a
methyl ester were therefore respectively selected for
N- and C-terminal protection.
Key words: bishomotyrosine; phenol; Friedel-Crafts
reaction; Fries rearrangement; triflic acid
We developed on developing the synthesis of bisho-
motyrosine (bhTyr, 2-amino-5-(4-hydroxyphenyl)penta-
noic acid), which has an elongated two-carbon chain, as
we considered that this compound may have versatile
use in enzyme structure-activity studies. bhTyr has been
found in the active components of AM-toxin III,1) which
is a host-specific phytotoxic metabolite produced by
Alternaria mali, that causes leaf spot disease in
apples.2–4) The bhTyr skeleton has also recently been
found as a constituent in Largamides C, an unusual
cyclic peptide from the marine cyanobacterium of
Oscillatoria sp.5) The synthesis of bhTyr was reported
by Izumiya et al. over three decades ago6) using a
classical diethyl acetoamidomalonate amino acid
method and enzymatic resolution to afford an optically
pure (S)-form. However, the phenol hydroxyl group has
to be protected by a methyl group to construct the amino
acid skeleton, and then deprotected under acidic con-
ditions in the last synthetic step. The enzyme resolution
of acetyl-protected bhTyr afforded an optically pure (S)-
form, but few reports of the synthesis and analysis of the
(R)-form have been published. There are many reports
of the synthesis of natural and unnatural amino acid
derivatives; these methods include enzymatic resolu-
tion,7) Suzuki coupling,8) diastereoselective Michael
addition9) and catalytic asymmetric hydrogenation.10)
These methods require special reagents or precursors
and the phenolic hydroxyl groups would not be expected
to tolerate the synthetic conditions. Little success has
been reported for the synthesis of elongated carbon in
the side chain of Tyr without protecting the phenolic
hydroxyl groups.11) The establishments of synthetic
methods for unprotected phenolics for amino acid
derivatives could be very useful. We report in this
paper the first synthetic methods for optically active
bhTyr featuring the Friedel-Crafts reaction or Fries
rearrangement with trifluoromethanesulfonic acid (triflic
O-Acylation of the phenol: N-Tfa-Glu(Cl)OMe 2 was
prepared in an optically active form by using to the same
y
To whom correspondence should be addressed. Tel/Fax: +81-11-706-3849; E-mail: hasimoto@abs.agr.hokudai.ac.jp