Direct synthesis of α-thio aromatic acids from aromatic amino acids

Article abstract of DOI:10.1016/j.tetlet.2018.02.030

Modified amino acids are useful synthetic components in both chemistry and biology. Here we describe a simple, scalable two-step procedure to generate α-thio aromatic acids from aromatic amino acids with yields of up to 96%. Diazotization and α-lactone me

Full text of DOI:10.1016/j.tetlet.2018.02.030

Accepted Manuscript
Direct Synthesis of α-Thio Aromatic Acids from Aromatic Amino Acids
Eric R. Samuels, Irina Sevrioukova
PII:
S0040-4039(18)30200-4
https://doi.org/10.1016/j.tetlet.2018.02.030
TETL 49715
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 January 2018
5 February 2018
12 February 2018
Please cite this article as: Samuels, E.R., Sevrioukova, I., Direct Synthesis of α-Thio Aromatic Acids from Aromatic
Amino Acids, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.030
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Direct Synthesis of α-Thio Aromatic Acids from Aromatic Amino Acids
Eric R. Samuels†* and Irina Sevrioukova‡
Departments of †Pharmaceutical Sciences and ‡Molecular Biology and Biochemistry,
University of California, Irvine, California 92697-3900
Abstract:
Modified amino acids are useful synthetic components in both chemistry and biology.
Here we describe a simple, scalable two-step procedure to generate α-thio aromatic acids
from aromatic amino acids with yields of up to 96%. Diazotization and α-lactone
mediated bromination efficiently form the α-bromo acid with retention of configuration.
Thiol substitution with mild reagents such as sodium hydrosulfide or sodium
trithiocarbonate provides the inverted, free α-thio acid. The mildly acidic soft nucleophile
can then be utilized in many synthetic applications.
Keywords: thiol synthesis; α-thio acid; diazonium compound; α-bromo acid; aromatic
amino acids
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Ar = Phenyl, Indole, Naphthyl
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Introduction:
Modified amino acids are valuable synthetic tools in numerous fields from total
synthesis, chemical and synthetic biology, and medicinal chemistry. One such method of
modification involves transformation of the α-amine to bromine, which can be utilized as
an electrophile in a range of synthetic applications1,2. Notwithstanding, little has been
reported on the direct synthesis of free α-thio acids, particularly from α-bromo acids.
In general, free thiols are useful moieties involved in an assortment of reactions
from conjugate addition to polymer cross-linking. The soft, reactive nucleophile is
frequently involved in click chemistry, bioconjugation, and materials chemistry3,4.
Moreover, α-thio acids can be utilized in a variety of proteomic techniques beyond
cysteine conjugation and even peptidomimetic chemistry. For our purposes, α-thio
aromatic acids are useful backbone thioether intermediates in the synthesis of ritonavir
like CYP3A4 inhibitors5.
Previous synthetic methods to generate free α-thio acids from α-bromo acids
typically involve protected thiol nucleophiles, such as 1,1-diphenylmethanethiol, which
must be subsequently deprotected6. Here we describe a simple and effective two-step
synthesis of free α-thio aromatic acids through diazotization, bromination, and
nucleophilic substitution that has been optimized accordingly.
α-Bromination of amino acids was initially reported by Izumiya and Nagamatsu,
who diazotized the α-amine with sodium nitrite and brominated with KBr in the presence
7
of H2SO4 . The resulting α-bromo acids maintained retention of configuration. Since
then several adjustments have been reported to generate a variety of α-bromo acids1,2,8,9
.
We discovered that HBr alone was a sufficient bromine source for phenylalanine,

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whereas KBr was required for bromination of tryptophan and 1-naphthylalanine. α-
Bromo phenylalanine was easily converted into α-thio phenylalanine in the presence of
aqueous sodium hydrosulfide10. However, the more nucleophilic sodium trithiocarbonate
was necessary to thiolate tryptophan and 1-naphthylalanine (Scheme 1). Conveniently,
both reagents were able to form the free thio acid in a one-pot manner. Due to the
retentive nature of α-bromination, thiolation resulted in an inversion of configuration.
Therefore, an opposite aromatic amino acid enantiomer should be utilized to produce the
desired α-thio aromatic amino acid.
The optimized syntheses of the aforementioned α-bromo and α-thio acids were
found to be not only straightforward, but also highly robust. Aside from α-bromo
tryptophan and naphthylalanine, liquid-liquid extraction was sufficient to obtain the pure
α-bromo or α-thio acid in excellent yields. Another advantage is that all reagents - with
the exception of sodium trithiocarbonate, which needs to be freshly prepared - are
commonly found in most organic chemistry laboratories.
Scheme 1. Synthesis of α-thio acids from aromatic amino acids

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Results and Discussion:
Diazotization of aromatic amines commonly occurs through a radical SRN1 or
standard SN1 fashion, with a free radical or aryl cation intermediate respectively11,12,13
.
However, few mechanical examples of diazotization of aliphatic amines exist. Previous
studies with amino acids have shown that halide substitution of a formed alpha
diazonium compound results in retention of configuration. Despite this, little has been
postulated regarding the mechanism. We presume that the reaction occurs via a double
inversion, with an alpha lactone intermediate (Scheme 2). The mechanism is comparable
to that of γ-butyrolactone-γ-carboxylic acid synthesis from glutamic acid14,15. Following
diazotization, the carboxylic acid displaces the nitrogen to form an alpha lactone with an
inversion of configuration. The second inversion occurs when aqueous hydrogen halide
(with or without a metal halide) protonates the lactone while haloginating the alpha
carbon in a SN2 fashion. Lactone formation is presumably more stable than tertiary
carbocation or alpha radical formation - as with other diazonium compounds - because
the product retains stereochemistry, rather than forming a racemic mixture.
Scheme 2. Proposed mechanism of α-halogenation of amino acids via α-lactone
intermediate

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D- or L-phenylalanine were the only amino acids in the series that a) effectively
brominated with HBr alone, and b) substituted more efficiently with NaSH than sodium
trithiocarbonate. For bromination, addition of KBr did produce the desired product,
however, higher yields were obtained with salt-free, aqueous HBr9. The resulting α-
bromo-acid was then treated with aqueous NaSH, heated, and acidified10 to produce the
thiol with typical yields of around 75%. Interestingly, large-scale synthesis (40 mmol) of
D-α-thio-phenylalanine produced the highest yield, 92% overall, denoting that the
synthesis is highly efficient.
Reactions with unprotected L-tryptophan were unsuccessful, presumably due to
the semi-reactive indole ring. Boc protection of the indole however, allowed for synthesis
of the bromide and subsequent thiol. As reported previously, a mixture of KBr with
aqueous HBr was more effective than HBr alone or with NaBr1. This was also the case
for DL-1-naphthylalanine, despite the similarity to phenylalanine. Likewise, NaSH failed
to produce the final thiol of tryptophan and naphthylalanine, so the more sensitive sodium
trithiocarbante was prepared as described previously, and used as the thiol
nucleophile16,17 . The synthesis was highly robust, with yields ≥90% achieved in both
small and large scale.
For tryptophan, the thiol product was expediently a mixture of Boc protected and
free amine. In an effort to deprotect the Boc product in one pot, longer exposure to H2SO4
during wash was attempted. However, protected product still remained. Lingering Boc
product was simply deprotected with HCl in dioxane to form the unprotected D-α-thio-
tryptophan.
In summary, a simple and effective method for the production of α-thio acids

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from several aromatic amino acids has been developed. For other aromatic amino acids
with different R-functionalities, i.e. tyrosine and histidine, the bromination and thiolation
process developed for tryptophan could be applicable, but Boc protection of the histidine
imidazole would be necessary. The final thiol can be used in numerous applications: as a
starting material in thioether/thioester synthesis, to conjugate addition in click chemistry.
Moreover, an alternate soft nucleophile at the α-carbon can be very useful in the synthesis
of new peptide-like pharmaceuticals, or humbly as a modified amino acid in
chemical/synthetic biology.
Acknowledgements:
This work was supported by National Institute of Health grant ES025767. The authors
thank A. R. Chamberlin, T. L. Poulos, and D. J. Hogenkamp for materials, discussion and
advice.
Supporting Information:
Experimental details, optical rotation data, and 1H NMR, 13C NMR, and HRMS spectra
are provided in the supporting information.
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Highlights
 Two-step procedure to produce α-thio aromatic acids from aromatic amino acids.
 Stereospecific synthesis that results in free thiols, with yields above 90%.
 The free thiol can be used in numerous applications.