α-Methylphenacyl thioesters as convenient thioacid precursors

Article abstract of DOI:10.1039/c6ob02256a

α-Methylphenacyl (Mpa) thioesters are described as precursors of thioacids. Mpa thioesters are accessible via the condensation of carboxylic acids and phenacyl thiol, which is easily prepared without column chromatography. The Mpa thioesters are selectively deprotected by reduction with zinc dust in the presence of conventional thioacid protecting groups. In addition, the Mpa group exhibits orthogonal reactivity to the Boc group. These features are expected to facilitate the preparation of complex thioacids, including those in peptides.

Full text of DOI:10.1039/c6ob02256a

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-Methylphenacyl thioesters as convenient thioacid precursors
Toru Hatanaka,a Ryosuke Yuki,a Ryota Saitoa,b and Kaname Sasaki*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
-Methylphenacyl (Mpa) thioesters are described as precursors of precursor that has, notably, reactivity orthogonal to the Boc
thioacids. Mpa thioesters are accessible via the condensation of group. As thioesters are not generally stable to nucleophilic
carboxylic acids and phenacyl thiol, which is easily prepared amines such as piperidine, Boc-based elongation would be the
without column chromatography. The Mpa thioesters are first choice for preparing thioacid-bearing peptides. Therefore,
selectively deprotected by reduction with zinc dust in the thioacid precursors with reactivity orthogonal to the Boc group
presence of conventional thioacid protecting groups. In addition, could be useful for the preparation of peptide thioacids. In this
the Mpa group exhibits orthogonal reactivity to the Boc group. context, we focused on phenacyl groups. As a protective group
These features are expected to facilitate the preparation of for carboxylic acids, phenacyl esters have been used due to
complex thioacids, including those in peptides.
their stability under acidic conditions and removal by one-
electron reduction in mildly acidic media.20 However, phenacyl
esters are known to be relatively electrophilic and susceptible
to undesired transesterification. Therefore, we prepared
phenacyl thiols 3a–c, which vary in bulkiness (Scheme 1), to
examine the stabilities of their thioesters. Each variant was
prepared from the commercially available phenacyl bromides
The thioacid functional group, due to its unique reactivity, can
be an expedient handle by which to convergently and
chemoselectively install modification modules, particularly in
peptides.1 For example, thioacid-based amide ligation
reactions relying on unprotected aziridines,2 electron-deficient
azides,3 electron-deficient arylsulfonamides,4 isonitriles,5 and
isocyanates6 have been reported. Furthermore, condensation
reactions between thioacids and amines have also been
described recently, employing the Sanger and Mukaiyama
reagents,7 HOBt,8 organonitrite,9 Cu(II),10 HOBt-Cu(OAc)2,11 and
N,O-bis(trimethylsilyl)acetamide as activators.12
1a
to give 2a
scalable spot-to-spot reactions, and afford phenacylthiol 3a
methylphenacylthiol 3b, and -dimethylphenacylthiol 3c
–
c
by a two-step sequence of substitution with thioacetate
–
c
, followed by deacetylation. These are all easily
, -
,
quantitatively, without the need for column chromatography.
A promising approach to preparing peptide thioacids is to carry
thioesters through the peptide elongation sequence and then
release the thioacids by reliable and simple reactions.
Currently, several thioesters are available as thioacid
precursors, including 2,4,6-trimethoxybenzyl (Tmob),3 9-
fluorenylmethyl (Fm),13 trityl (Trt),14 and 2-cyanoethyl,15 which
release thioacids under either basic or acidic conditions. As for
C-terminal peptide thioacids, another approaches were
reported, which utilize N-S acyl transfer16-18 or acyl
hydrazines.19 We were interested in a different type of
precursor that would permit a wider range of applications for
thioacid chemistry, and herein, report a novel thioacid
a.Department of Chemistry, Toho University, 2-2-1 Miyama, Funabashi 274-8510
Japan. b.Research Center for Materials with Integrated Properties, Toho
University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan. *Email:
kaname.sasaki@sci.toho-u.ac.jp
Scheme 1. Preparation of thiols 3a-c and thioesters 4a-c.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Each thiol was efficiently coupled with Boc-protected
tryptophan using standard coupling procedures in the
presence of DMAP.21 The lower yield in the preparation of 4a is
due to the partial loss of 3a observed during silica gel column
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DOI: 10.1039/C6OB02256A
Table 2. Substrate scope of thioacid preparation via Mpa thioesters.
chromatography. Thioesters 4a–c were subjected to reducing
conditions using zinc dust in aqueous acetic acid as a
benchmark (Table 1). The efficiency in liberating the thioacid
was evaluated after conversion to the corresponding benzyl
thioester 5, because thioacids generally have two tautomeric
Entry
R2-COOH
PhCOOH (6a)
Yield of 7a-i /%a
Yield of 8a-i /%a
forms (O- and S-acids) that complicate spectroscopic analysis.22
All three substrates were deprotected to give the
corresponding thioacid. The reaction rate clearly depended on
the bulkiness of the phenacyl moiety. The bulkier thioester 4c
required a longer reaction time than 4a and 4b, even though
the intermediate phenacyl radical of 4c would presumably be
more stable than those of the others. Elevating the reaction
temperature shortened the reaction time and improved the
1
2
3
4
5
6
7
8
9
90
92
94
95
98
94
98
74
77
-
80
91
83
83
78
73
85
78
81
77b
nC9H19COOH (6b)
Boc-Phe-OH (6c)
Boc-Gly-OH (6d)
Boc-Ser(OBn)-OH (6e)
Boc-Thr(OBn)-OH (6f)
Fmoc-Trp-OH (6g)
Boc-Glu(SFm)-OH (6h)
Fmoc-Glu(STmob)-OH (6i)
6i
yield. We considered the
-methylphenacyl group,
10
abbreviated as Mpa, to be a good entry as a precursor for
thioacids.23
aIsolated yields. b3-Bromopropionitrile was used instead of BnBr, which afforded
2-cyanoethyl thioester 8i’.
Table 1. Deprotection of phenacyl thioesters 4a–c.
Next, we examined the orthogonality of the Mpa thioesters
and Boc groups. As shown in Scheme 2, Boc-protected
thioglycinate 7d was employed as the C-terminus, and peptide
elongation based on Boc-TFA chemistry was conducted. In the
presence of the Mpa thioester, the Boc group was successfully
deprotected in 40% TFA/CH2Cl2. The subsequent coupling
reaction afforded dipeptidyl thioester
performed better than DIPEA as a base. Another deprotection-
coupling sequence was performed with lysine having a Boc
9, where NMM
Entry
Thioester 4a-c
Temp./ °C
Time
1 h
20 min
3 h
1 h
26 h
6 h
Yield of 5 /%a
1
2
3
4
5
6
4a
4a
4b
4b
4c
4c
25
40
25
40
25
40
92
88
86
86
50
83
group at the
problems. In the presence of the

-amine to give tripeptide 10 without any
-Boc group, Mpa was

cleanly removed using zinc at 40 °C to afford the peptidyl
thioacid in good yield, which was confirmed by derivatization
to the benzyl thioester 11
.
aIsolated yields.
Table 2 summarizes the scope of this thioacid preparation
procedure. Each of the aromatic, aliphatic, and amino acids 6a-
i
was converted to the Mpa thioester 7a-i using EDCI and
DMAP in excellent isolated yields. These precursors afforded
the corresponding thioacids smoothly when treated with zinc
at ambient temperature. Excess zinc dust was removed by
filtration through a silica gel pad, and then the solvent was
evaporated to effectively give the thioacid, according to the
yield after benzylation. It is noteworthy that no diastereomeric
benzyl thioester of 8f was observed, which excludes the
possibility of racemization in the reaction sequence. The
present transformation was also applicable to Fmoc-protected
amino acid 6g. Furthermore, carboxylic acids having additional
thioester groups such as 6h and 6i could be converted to the
bisthioesters, and the Mpa group could be removed in the
presence of either an Fm- or Tmob-thioester. The thioacids
could be also captured by 3-bromopropionitrile instead of
benzyl bromide to give the 2-cyanoethyl thioester 8i′
.
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Scheme 2. Synthesis of oligopeptide -thioacid.
Finally, we prepared
glutamate 12 by protecting group manipulation, i.e., allylation
of the -carboxylic acid, deprotection of the -9-
-Mpa thioglutamate 16 from the known


fluorenylmethyl ester, thioesterification using MpaSH, and
deallylation using a Pd catalyst. This glutamate residue could
be incorporated into a peptide by Boc-TFA chemistry without
loss of the Mpa group to afford tripeptide 18. Again, the Mpa
group could be removed in the presence of the Boc group, and
benzyl thioester 19 was obtained after treatment with benzyl
bromide. This orthogonality permits the preparation of
peptidyl thioacids at either the C-terminus or the side-chain.
Scheme 3. Synthesis of oligopeptide having thioacid on its side-chain.
Conclusions
-Methylphenacyl (Mpa) thioesters were developed as
precursors for thioacids. MpaSH is easily accessible from
commercially available, low-cost materials and readily
introduced to carboxylic acids. Mpa thioesters can facilitate
the preparation of peptides bearing a thioacid either at the C-
terminus or on the side chain. The orthogonal reactivity to the
Boc-group and chemoselectivity over Tmob- and Fm-thioesters
are expected to enable the preparation of complex thioacids
such as peptide thioacids. We are now applying this chemistry
to the preparation of oligo- and polypeptides.
Acknowledgments
This work was financially in part supported by a JSPS Grant-in-
Aid for Young Scientists B (JP26810062) to KS and the MEXT-
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Supported Program for the Strategic Research Foundation at
Private Universities (2012-2016) to RS. We also thank Prof.
Hidemasa Hikawa, Toho University, for help with FABHRMS
experiments.
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DOI: 10.1039/C6OB02256A
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