Nucleophilic Trifluoromethylthiolation of Cyclic Sulfamidates: Access to Chiral β- And γ-SCF3 Amines and α-Amino Esters

Article abstract of DOI:10.1021/acs.orglett.7b00501

The regio- and stereoselective ring opening of 1,2- and 1,3-sulfamidates with trifluoromethanethiolate anion is reported. This direct introduction of the whole SCF₃ motif is a straightforward synthetic route toward β- and γ-SCF₃ amines and α-amino acid derivatives. The utility of this reaction was further illustrated by incorporation of Cys(S-CF₃) into di- and tripeptides.

Full text of DOI:10.1021/acs.orglett.7b00501

Letter
pubs.acs.org/OrgLett
Nucleophilic Trifluoromethylthiolation of Cyclic Sulfamidates: Access
to Chiral β- and γ‑SCF3 Amines and α‑Amino Esters
Jun-Liang Zeng,†,‡ Helene Chachignon,† Jun-An Ma,*,‡ and Dominique Cahard*,†
́
̀
†UMR 6014 CNRS COBRA, Normandie Universite,
́ ̀
INSA Rouen, 1 rue Tesniere, 76821 Mont Saint Aignan, France
‡Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Collaborative Innovation Center of
Chemical Science and Engineering, Tianjin University, Tianjin 300072, China
S
* Supporting Information
ABSTRACT: The regio- and stereoselective ring opening of
1,2- and 1,3-sulfamidates with trifluoromethanethiolate anion
is reported. This direct introduction of the whole SCF3 motif is
a straightforward synthetic route toward β- and γ-SCF3 amines
and α-amino acid derivatives. The utility of this reaction was
further illustrated by incorporation of Cys(S-CF3) into di- and
tripeptides.
Scheme 1. Summary of Synthetic Routes to β- and γ-SCF3 α-
Amino Esters and Outline of This Work
nnatural fluorinated amino acids have emerged as
Uprivileged labels for probing the structure and function
of peptides and proteins, particularly by 19F NMR spectrosco-
py.1 While several reports have addressed the preparation and
use of structurally relevant monofluorinated and trifluorome-
thylated amino acids,2 in sharp contrast, methods for the
incorporation of the emergent fluorine chemotype SCF3 into
amino acids remain limited. Molecules featuring the highly
lipophilic SCF3 group have high potential in medicinal
chemistry, but challenges associated with their synthesis are
manifold.3 Current approaches to obtain trifluoromethionine
and S-trifluoromethyl cysteine are based on electrophilic or
radical trifluoromethylation of thiols and disulfides (Scheme
1a). The thiol group in cysteine derivatives reacted with CF3I in
liquid ammonia under UV irradiation4 or using visible light and
Ru(bpy)3Cl2 as photocatalyst5 to give the corresponding SCF3
derivatives. Togni’s electrophilic trifluoromethylating reagent
was also suitable for the S-trifluoromethylation of cysteine side
chains in peptides.6 Starting from disulfides in cystine
derivatives, several reagents were employed such as Umemoto’s
N-(trifluoromethyl)-N-nitrosotrifluoromethane−sulfonamide
(TNS-Tf),7 sodium trifluoromethanesulfinate,8 and CF3I to
deliver S-CF3 cysteine derivatives.9 In addition to the well-
established trifluoromethylation of sulfur reactants, an isolated
example of photolytic decarbonylation of a trifluorothioacetate
was reported (Scheme 1b).10 Lastly, two recent articles dealing
with the direct trifluoromethylthiolation of unactivated C−H
bonds provided the same single example of transformation of
an amino ester with high regioselectivity (Scheme 1c).11,12
Faced with the lack of generality for the direct trifluorome-
thylthiolation of amino acid derivatives, it appeared relevant to
orient our research toward the development of a new and
efficient approach.
and selectivity in ring-opening reactions. Indeed, the C−O
bond is preferentially the site of ring-opening, whereas
regioselectivity issues were raised in the opening of three-
and four-membered nitrogen rings featuring different sub-
stituents. In addition, the nitrogen protecting group has little or
no impact on the reactivity.13 We envisioned that direct
nucleophilic trifluoromethylthiolation of sulfamidates would
provide a simple access to β- and γ-SCF3 α-amino acid
Sulfamidates are important synthetic intermediates that
Received: February 18, 2017
outperform aziridines and azetidines in terms of reactivity
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00501
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
derivatives (Scheme 1d).14 The sulfamidates used in our study
were readily prepared from amino alcohols, a number of which
were derived from natural amino acids. In a first series of
experiments, we sought an effective nucleophilic SCF3 source in
the reaction involving 1,2-sulfamidate 1a derived from L-
phenylalanine (Table 1).
a
Table 2. Synthesis of β- and γ-SCF3 Amines
a
Table 1. Optimization of the Reaction Parameters
b
temp (°C),
time (h)
yield
(%)
entry
CF3S− donor
CuSCF3
solvent
1
2
CH3CN
DMF
25, 10
60, 8
0
CuSCF3
0
trace
20
3
AgSCF3
CH3CN
CH3CN
CH3CN
DMF
25, 18
25, 18
25, 18
25, 18
25, 14
25, 14
25, 18
25, 18
4
AgSCF3, NaI
AgSCF3, Me4NF
S8, CF3SiMe3, KF
5
0
6
15
7
Me4NSCF3 (1.2 equiv) CH3CN
Me4NSCF3 (1.5 equiv) CH3CN
73
8
92
9
Me4NSCF3 (2 equiv)
Me4NSCF3 (2 equiv)
CH3CN
DMF
92
10
87
a
Reaction conditions: 1a (0.1 mmol), CF3S− donor (1.5 equiv unless
otherwise noted), solvent (2 mL); then, 20% aq H2SO4/DCM (1:1).
b
Yields were determined by 19F NMR using trifluorotoluene as an
internal standard.
We anticipated that the nucleophilic displacement of the
sulfamidate would be effective by metal−SCF3 reagents such as
CuSCF3 and AgSCF3; however, the expected reaction did not
occur with these organometallic reagents (Table 1, entries 1−
3). The use of additives to help the in situ generation of ionic
trifluoromethanethiolate salts was encouraging (Table 1, entry
4 vs entry 3). We next investigated a transition-metal-free
approach to generate the CF3S anion by means of the
combination of CF3SiMe3/S8/KF/DMF, but the yield of
product 2a was only 15% (Table 1, entry 6).15 Among the
sources of CF3S anion, we next considered the tetramethy-
lammonium trifluoromethylthiolate Me4NSCF3, which is
conveniently prepared from anhydrous Me4NF, S8, and
Ruppert−Prakash reagent (CF3SiMe3).16 Me4NSCF3 is a
moisture-sensitive solid that can be stored for months in a
freezer. Gratifyingly, Me4NSCF3 appeared as the reagent of
choice to give the β-SCF3 amino product 2a in high yields
without a fluorination side reaction that would have occurred as
a result of its decomposition into thiocarbonyl fluoride (F2CS)
and fluoride, which is sometimes observed in the handling of
this reagent.17 The nucleophilic trifluoromethylthiolation by
means of 1.5 equiv of Me4NSCF3 proceeded smoothly at room
temperature in acetonitrile leading to the intermediate sulfamic
acid, which was hydrolyzed by a 20% aqueous H2SO4 solution
in DCM (1:1) to give 2a in 92% yield (Table 1, entries 8−10).
With the optimized conditions in hand, we first explored the
substrate scope for alkyl- and aryl-substituted 1,2- and 1,3-
sulfamidates (Table 2) and second the ester-substituted
sulfamidates to access SCF3 α-amino esters (Table 3). Five-
membered cyclic 1,2-sulfamidates derived from natural amino
acids and unnatural D-phenylglycine led to the desired optically
pure β-SCF3 amines 2a−f in high yields, 84−99% (Table 2,
entries 1−6).18 Our approach toward β-SCF3 amines comple-
ments the trifluoromethylthioamination of alkenes reported by
a
Reaction conditions: 1 (0.1 mmol), Me4NSCF3 (1.5 equiv), CH3CN
b
(2 mL), 25 °C, 12 h); then, 20% aq H2SO4/DCM (1:1). Yields of
isolated pure products.
Zhao et al. with the distinct advantage of providing enantiopure
amines.19 As anticipated, the nature of the nitrogen-protecting
group has little impact on the nucleophilic substitution since
tert-butoxycarbonyl (Boc), carboxybenzyl (Cbz), and 4-
methoxybenzyl (PMB) protecting groups gave high yields of
2g−i in the range 86−96% (Table 2, entries 7−9); never-
theless, we preferred to use the Boc group for its easy and
selective removal. Six-membered cyclic 1,3-sulfamidates with
lower ring strain are also suitable substrates for the ring opening
with the trifluoromethanethiolate anion to produce γ-SCF3
amines 2j−m in 66−92% yields (Table 2, entries 10−13).
From the aniline derivative 1m, we obtained the benzyl
trifluoromethyl sulfide 2m as a new aniline-based building
block.
B
DOI: 10.1021/acs.orglett.7b00501
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2). Diastereomers that would result from partial racemization at
Table 3. Synthesis of Trifluoromethylthiolated Amino
Acids
a
1
either chiral center could not be detected by 19F and H NMR
Scheme 2. Further Syntheses of Trifluoromethylthiolated Di-
and Tripeptides
(see the SI). Likewise, the dipeptide Boc-Ser-Phe-OH reacted
with 3 to end up with the tripeptide Boc-Ser-Phe-Cys(S-CF3)-
OEt 5 in 50% yield (Scheme 2).
a
In summary, we have established a new synthetic strategy for
the construction of trifluoromethylthiolated amines and amino
acid derivatives by direct nucleophilic substitution of cyclic
sulfamidates with the trifluoromethanethiolate anion. Remark-
ably, a range of novel attractive SCF3 products were obtained
with emphasis on β- and γ-SCF3 α-amino esters as illustrated in
the incorporation of S-(trifluoromethyl)-L-cysteine into di- and
tripeptides. This work contributes to a greater synthetic
accessibility of fluorinated peptides and opens a new route to
18F-labeled peptides.
Reaction conditions: 1 (0.1 mmol), Me4NSCF3 (1.5 equiv), CH3CN
b
(2 mL), 25 °C, 12 h); then, 20% aq H2SO4/DCM (1:1). Yields of
isolated pure products. Yield of the reaction performed on a 1 mmol
scale.
c
As central piece of this work, we explored the reaction of
sulfamidates featuring an ester function for a straighforward
synthetic route to β- and γ-SCF3 α-amino esters. Starting from
L-serine ethyl ester, the corresponding 1,2-sulfamidate 1n was
easily obtained and used as substrate for the nucleophilic
displacement by means of Me4NSCF3 that gave N-Boc-S-
(trifluoromethyl)-L-cysteine ethyl ester 2n in 91% yield and
even in 98% yield when the reaction was scaled up to 1 mmol
(Table 3, entry 1). Analogues featuring a benzyl and a methyl
ester or a Fmoc protecting group were also prepared (Table 3,
entries 2 and 3).18 Likewise, L-homoserine methyl ester led to
S-(trifluoromethyl)-L-homocysteine (or L-trifluoromethionine)
methyl ester 2q (Table 3, entry 4). With the less reactive L-
threonine sulfamidate derivative 1r bearing a secondary alcohol,
some decomposition of the trifluoromethanethiolate anion
occurred, resulting in a moderate 58% yield for the
trifluoromethylthiolation (Table 3, entry 5). The nucleophilic
substitution took place with high stereoselectivity (dr 17:1),
and the main diastereomer was isolated pure by silica gel
column chromatography.20
To highlight the synthetic value of our approach, the
incorporation of S-(trifluoromethyl)-L-cysteine ethyl ester into
a di- and a tripeptide was carried out.21 After selective
deprotection of the Boc group in 2n using HCl/dioxane (4 M),
the corresponding hydrochloride 3 was engaged in the coupling
with Boc-Ser-OH in triethylamine−dichloromethane in the
presence of equimolar quantities of the acid-activating agent N-
(3-(dimethylamino)propyl)-N-ethylcarbodiimide hydrochlor-
ide (EDC) and 1-hydroxybenzotriazole (HOBt). The dipeptide
Boc-Ser-Cys(S-CF3)-OEt (4) was obtained in 68% yield with
retention of the chiral integrity of each stereocenter (Scheme
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00501.
Experimental procedures and NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: majun_an68@tju.edu.cn.
*E-mail: dominique.cahard@univ-rouen.fr.
ORCID
Jun-An Ma: 0000-0002-3902-6799
Dominique Cahard: 0000-0002-8510-1315
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the China Scholarship Council
and Hubert Curien Partnership Sino−French Cai Yuanpei
programme, the Centre National de la Recherche Scientifique
(CNRS), University of Rouen, INSA Rouen, Labex SynOrg
(ANR-11-LABX-0029), the National Natural Science Founda-
C
DOI: 10.1021/acs.orglett.7b00501
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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2014CB745100). H.C. thanks the French “Minister
Recherche et de l’Enseignement Superieur” for a doctoral
fellowship.
̀
e de la
́
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