Nucleophilic Trifluoromethylthiolation of Cyclic Sulfamidates: Access

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,†,‡ Hélène Chachignon,† Jun-An Ma,*,‡ and Dominique Cahard*,† †

UMR 6014 CNRS COBRA, Normandie Université, INSA Rouen, 1 rue Tesnière, 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 αAmino Esters and Outline of This Work

nnatural fluorinated amino acids have emerged as privileged labels for probing the structure and function of peptides and proteins, particularly by 19F NMR spectroscopy.1 While several reports have addressed the preparation and use of structurally relevant monofluorinated and trifluoromethylated 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 wellestablished 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 trifluoromethylthiolation of amino acid derivatives, it appeared relevant to orient our research toward the development of a new and efficient approach. Sulfamidates are important synthetic intermediates that outperform aziridines and azetidines in terms of reactivity

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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 threeand four-membered nitrogen rings featuring different substituents. 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 Received: February 18, 2017 Published: April 5, 2017 1974

DOI: 10.1021/acs.orglett.7b00501 Org. Lett. 2017, 19, 1974−1977

Letter

Organic Letters Table 2. Synthesis of β- and γ-SCF3 Aminesa

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 Lphenylalanine (Table 1). Table 1. Optimization of the Reaction Parametersa

entry

CF3S− donor

solvent

1 2 3 4 5 6 7 8 9 10

CuSCF3 CuSCF3 AgSCF3 AgSCF3, NaI AgSCF3, Me4NF S8, CF3SiMe3, KF Me4NSCF3 (1.2 equiv) Me4NSCF3 (1.5 equiv) Me4NSCF3 (2 equiv) Me4NSCF3 (2 equiv)

CH3CN DMF CH3CN CH3CN CH3CN DMF CH3CN CH3CN CH3CN DMF

temp (°C), time (h) 25, 60, 25, 25, 25, 25, 25, 25, 25, 25,

10 8 18 18 18 18 14 14 18 18

yieldb (%) 0 0 trace 20 0 15 73 92 92 87

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. a

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 tetramethylammonium 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 1,3sulfamidates (Table 2) and second the ester-substituted sulfamidates to access SCF3 α-amino esters (Table 3). Fivemembered 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 complements the trifluoromethylthioamination of alkenes reported by

a

Reaction conditions: 1 (0.1 mmol), Me4NSCF3 (1.5 equiv), CH3CN (2 mL), 25 °C, 12 h); then, 20% aq H2SO4/DCM (1:1). bYields 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 4methoxybenzyl (PMB) protecting groups gave high yields of 2g−i in the range 86−96% (Table 2, entries 7−9); nevertheless, 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. 1975


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Organic Letters

2). Diastereomers that would result from partial racemization at either chiral center could not be detected by 19F and 1H NMR

Table 3. Synthesis of Trifluoromethylthiolated Amino Acidsa

Scheme 2. Further Syntheses of Trifluoromethylthiolated Diand 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). 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. Remarkably, 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 18 F-labeled peptides.

a

Reaction conditions: 1 (0.1 mmol), Me4NSCF3 (1.5 equiv), CH3CN (2 mL), 25 °C, 12 h); then, 20% aq H2SO4/DCM (1:1). bYields of isolated pure products. cYield of the reaction performed on a 1 mmol scale.

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 Lthreonine 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 hydrochloride (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

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00501. Experimental procedures and NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Jun-An Ma: 0000-0002-3902-6799 Dominique Cahard: 0000-0002-8510-1315 Notes

The authors declare no competing financial interest.

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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 Founda1976


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Organic Letters

(16) (a) Tyrra, W.; Naumann, D.; Hoge, B.; Yagupolskii, Y. L. J. Fluorine Chem. 2003, 119, 101. (b) Yin, G.; Kalvet, I.; Schoenebeck, F. Angew. Chem., Int. Ed. 2015, 54, 6809. (17) Tavener, S. J.; Adams, D. J.; Clark, J. H. J. Fluorine Chem. 1999, 95, 171. (18) Preservation of chiral integrity is claimed based on measurement of optical rotations of chiral products (see the SI) and comparison with literature data (ref 21). Accurate optical rotation for known compound 2o was measured with a variance of ±2% compared to ref 21. Accordingly, we assume that optical rotations measured for all new single-enantiomer products 2a−f and 2n−q are indicative of enantiopurity. (19) Luo, J.; Zhu, Z.; Liu, Y.; Zhao, X. Org. Lett. 2015, 17, 3620. (20) For stereospecific ring opening, see, for example, ref 14a, b and: (a) Mata, L.; Jiménez-Osés, G.; Avenoza, A.; Busto, J. H.; Peregrina, J. M. J. Org. Chem. 2011, 76, 4034. For a racemizing process, see: (b) Wei, L.; Lubell, W. D. Org. Lett. 2000, 2, 2595. (c) Wei, L.; Lubell, W. D. Can. J. Chem. 2001, 79, 94. The assigned trans stereochemical relationship in 2r is based on the assumed inversion of configuration at the β-carbon. (21) Tripeptides featuring internal S-(trifluoromethyl)-L-cysteine or L-trifluoromethionine were recently prepared by using Langlois’ procedure (ref 8) or Togni’s reagent (ref 6). Gadais, C.; SaraivaRosa, N.; Chelain, E.; Pytkowicz, J.; Brigaud, T. Eur. J. Org. Chem. 2017, 2017, 246.

tion of China (Nos. 21225208, 21472137, and 21532008), and the National Basic Research Program of China (973 Program: 2014CB745100). H.C. thanks the French “Ministère de la Recherche et de l’Enseignement Supérieur” for a doctoral fellowship.

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Nucleophilic Trifluoromethylthiolation of Cyclic Sulfamidates: Access

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