Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Rapid Access to Thiolactone Derivatives through Radical-Mediated Acyl Thiol−Ene and Acyl Thiol−Yne Cyclization Ruairi O. McCourt,† Fabrice Dénès,‡ Goar Sanchez-Sanz,§ and Eoin M. Scanlan*,† †
Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, The University of Dublin, Dublin 2, Ireland Université de Nantes, CEISAM UMR CNRS 6230 UFR des Sciences et des Techniques -2 rue de la Houssinière, Nantes BP 92208-44322 Cedex 3, France § Irish Centre for High-End Computing, Floor 7, Tower Building, Trinity Technology & Enterprise Campus, Grand Canal Quay, Dublin 2, Ireland ‡
S Supporting Information *
ABSTRACT: A new synthetic approach to thiolactones that employs an efficient acyl thiol−ene (ATE) or acyl thiol−yne (ATY) cyclization to convert unsaturated thiocarboxylic acid derivatives into thiolactones under very mild conditions is described. The high overall yields, fast kinetics, high diastereoselectivity, excellent regiocontrol, and broad substrate scope of these reaction processes render this a very useful approach for diversity-oriented synthesis and drug discovery efforts. A detailed computational rationale is provided for the observed regiocontrol.
T
hiolactones represent a fascinating class of heterocyclic compounds with emerging applications in chemical biology,1,2 medicinal chemistry,3 drug discovery,4 and materials science.5,6 Hcy-thiolactone (Figure 1) is the most abundant thiolactone found in nature and is present in all human cells.7,8 Other thiolactone natural products include cyclic peptides constrained in a thiolactone ring that function as key signaling molecules in quorum-sensing regulation in bacteria.9,10 Thioester-containing proteins (TEPs), displaying a reactive thiolactone on the peptide backbone, are a superfamily of secreted proteins that play a critical role in the innate immune response of animals.11,12 Recently, δ-thiolactones were explored in preclinical animal studies as potential prodrugs of thiol-based Glutamate carboxypeptidase II (GCPII) inhibitors, used for the treatment of neurodegenerative diseases.3 However, widespread incorporation of thiolactone derivatives into chemical screening libraries or diversity-oriented synthesis (DOS) campaigns is hindered, as suitable methods for their de novo synthesis are limited to the often inefficient condensation reaction between a thiol and carboxylic acid.13 Generally, this approach requires multiple steps to introduce the thiol residue and often results in low yields of the thiolactone.14 Retrosynthetic analysis of thiolactones identified that a C−S bond disconnection could be made if a thiyl radical cyclization of a thioacid derivative onto an unsaturated moiety was realized (Figure 1). The radical nature of the cyclization would offer significant advantages over the traditional condensation approach due to the high reactivity of the thiyl radical, in particular, for the preparation of sterically hindered, polycyclic, or highly substituted thiolactones.14 © XXXX American Chemical Society
Herein, we demonstrate that the intramolecular reaction of an acyl-thiyl radical onto an alkene or alkyne moiety is a versatile approach for the synthesis of thiolactones. The utility of the methodology outlined in Figure 1 relies on the cyclization of an acyl-thiyl radical onto an unsaturated bond, a process that has not previously been reported in the scientific literature. An acid-catalyzed cyclization of an unsaturated thioacid substrate was reported by Korte and co-workers in the 1960s, but the desired thiolactone was only formed in low yield along with a polymeric byproduct.15 In order to study both the ATE and ATY reactions, we required access to a suitable range of unsaturated thioacid derivatives. Following a screening of suitable protecting groups for thioacids, the dimethoxytrityl (DMTrt) group was selected since the thioester can be readily cleaved under mild acidic conditions. The thioacid moiety was introduced in protected form using a modified version of the procedure reported by Crich and coworkers13 through coupling of the γ-unsaturated carboxylic acid with dimethoxytritylthiol (DMTrtSH) under Steglich coupling conditions (Scheme 1)14 or, alternatively, by reaction with suitable allylic bromide substrates. The synthesis of the first example in this class started from commercially available hexenoic acid. Steglich coupling of the carboxylic acid with DMTrtSH furnished the corresponding thioester in high yield. Treatment of the tritylthioester under mild acidic conditions for Received: March 28, 2018
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DOI: 10.1021/acs.orglett.8b00996 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Scheme 2. Acyl Thiol−Ene Cyclization of Unsaturated Thioacidsa
Figure 1. Synthetic therapeutics and naturally occurring thiolactones and retrosynthesis showing OC−S and C−S disconnections.
Scheme 1. General Route to Unsaturated Thioacids from Carboxylic Acids a dr determined by 1H NMR analysis. *Yield determined via combination of isolated yield and 1H NMR ratios.
resulted in very high yields of the γ-substituted thiolactones 1b and 1c. Introduction of an aromatic substituent on the alkene did not improve the overall yield of the cyclization, despite the process proceeding through a benzyl stabilized radical intermediate, giving 1d,e. A slightly lower yield was obtained for 1f, albeit with complete control of the regioselectivity despite the increased steric hindrance that could disfavor the 5exo process. Substitution at the β-position did not impact the overall yield of the cyclization, and the trans-products 1g−l were formed with >90% diastereoselectivity. Thiolactones 1i−k highlight the versatility of the cyclization, showing that halides and nitro groups are compatible with the radical reaction conditions. Methyl substitution at the γ-position led to 1m and 1n in 81% and 93% yields with moderate levels of stereoselectivity. The introduction of a gem-dimethyl group at the β-position furnished the cyclized product 1o in nearquantitative yield, likely due to the gem-dimethyl (Thorpe− Ingold) effect.16 Fused and spiro-bicyclic thiolactones 1p−q were prepared in good yields, highlighting the potential of this methodology toward the synthesis of polycyclic systems. Tricyclic norbornene derived thiolactone 1r was previously prepared by Koshland and co-workers through a condensation reaction in only 6% yield.17 Gratifyingly, thiolactone 1r was isolated in 84% using the mild reaction conditions developed for the ATE process. Compatibility with esters was shown by the high yield of 1s. Thiolactone 1u, prepared from the commercially available sorbic acid, is unique among the substrates screened due to the exclusive formation of the 6membered ring product. Interestingly, this example required longer reaction times (4 h) than the other ATE reactions,
25 min released the thioacid that was used directly, without purification, in the radical cyclization reaction, following the in vacuo removal of CF3CO2H and Me2EtSiH. The ATE process is analogous to thiol−ene ligation. In the ATE process, however, the presence of the acyl group was found to play a profound role in determining the regioselectivity of the cyclization reaction. Contrary to the classic thiol−ene process,18,19 the cyclization of acyl-thiyl radicals was found to be highly selective for the 5-exo mode, as supported by computational studies (see the Supporting Information (SI)). The ATY process is analogous to thiol−yne ligation, a process that usually results in dual-addition in ligation reactions but which can be carefully controlled to furnish the vinyl sulfide product in the intramolecular reaction.18 Photolysis of thiohexenoic acid in the presence of a radical initiator, 2,2-dimethoxy-2-phenylacetophenone (DPAP), and the photosensitizer 4-methoxyacetophenone (MAP) at 25 °C for 2 h furnished the 5-exo-trig γ-thiolactone product 1a in 88% isolated yield (Scheme 2). None of the competing 6-endo-trig product was observed. In order to evaluate the scope, we repeated the process with a broad range of unsaturated carboxylic derivatives. In general, the ATE cyclization reactions were found to proceed in high yield with complete control over regioselectivity. The full range of thiolactones prepared through the ATE approach is illustrated in Scheme 2. Substitution of the alkene with a methyl group or a phenyl terminated alkyl chain B
DOI: 10.1021/acs.orglett.8b00996 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
of the acyl-thiyl radical onto phenyl-substituted alkyne derivatives furnished 2a as an E/Z mixture of isomers. Monoor disubstitution at the β-position, as well as the use of terminal alkynes as precursors, did not have an appreciable effect on the overall yield of the cyclization, furnishing 2b and 2c in a similar yield. The introduction of disubstitution at the β-position resulted in a mixture of exo and endo products (2d exo and 2d endo, respectively), with the kinetically favored exo product afforded as the major product in 59% yield. Figure 2a shows the potential energy surface (PES) for the cyclization processes leading to the 5-exo-trig and 6-endo-trig products for compound 1a. The 5-exo-trig transition state lies almost 8 kJ·mol−1 lower than the 6-endo-trig transition state. Additionally, the 5-exo-trig product is 17.8 kJ·mol−1 more stable with respect to the 6-endo-trig product, indicating that 5-exo-trig is the kinetic and thermodynamic product. In case of the classic thiol−ene cyclization process (Figure 2b), the transition barriers that lead to 5-exo-trig and 6-endo-trig products are almost identical. However, the 6-endo-trig product is found to be almost 6 kJ·mol−1 more stable (thermodynamic product) than the 5-exo-trig product, which is in good agreement with the experimental results in the literature.18−20 Spin densities (SD) corresponding to the S atom in the reactants indicate that the radical is more stabilized in 1a (0.99 e) than in the direct thiol−ene (0.92 e). SD calculated for compound 1f (0.95 e) also show that in 1f the radical is less stabilized than in 1a but more than the thiol−ene compound, in agreement with the experimental results. This stabilization of the radical favors formation of the 5-exo product over the 6-endo product. Additionally, the SD on the O atom in 1a and 1f (−0.03 and −0.04 e) confirm that the radical is localized on the S atom (Figure S1 in the SI). Further discussions of structural parameters can be found in the SI.
probably due to the requirement for isomerization of the alkene stereochemistry prior to cyclization. In addition to the ATE reaction, we also investigated the related ATY process to access γ-unsaturated thiolactones. Suitable alkyne-containing DMTrt-protected thioesters were prepared following the procedure developed for the corresponding alkenes (see the SI). Deprotection and cyclization using conditions identical to those reported for the ATE process furnished the γ-unsaturated thiolactones derivatives through a 5-exo-dig cyclization.18 The full range of γunsaturated thiolactones prepared through the ATY approach is illustrated in Scheme 3. Scheme 3. Acyl Thiol−Yne Cyclization of Various Unsaturated Thioacid Derivativesa
dr determined by 1H NMR analysis. *Yield determined via combination of isolated yield and 1H NMR ratios. a
In general, yields for the ATY reaction were found to be lower than those reported for the ATE cyclization. Cyclization
Figure 2. (a) Potential energy surface (in kJ mol−1 and in kcal mol−1) corresponding to the intramolecular acyl thiol−ene (ATE) processes leading to the 5-exo-trig and 6-endo-trig products for compound 1a. (b) Potential energy surface (in kJ mol−1) corresponding to the cyclization processes leading to the 5-exo and 6-endo products for thiol−ene cyclization at the UMP2/6-311++G(d,p) computational level. C
DOI: 10.1021/acs.orglett.8b00996 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
(14) Langlais, M.; Kulai, I.; Coutelier, O.; Destarac, M. Macromolecules 2017, 50, 3524−3531. (15) Korte, F.; Christoph, H. Chem. Ber. 1961, 94, 1966−76. (16) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735−1766. (17) Storm, D. R.; Koshland, D. E., Jr J. Am. Chem. Soc. 1972, 94, 5815−25. (18) Denes, F.; Pichowicz, M.; Povie, G.; Renaud, P. Thiyl radicals in organic synthesis. Chem. Rev. 2014, 114, 2587−2693. (19) Crozet, M. P.; Surzur, J. M.; Dupuy, C. Tetrahedron Lett. 1971, 12, 2031−4. (20) Malone, A.; Scanlan, E. M. J. Org. Chem. 2013, 78, 10917− 10930.
In summary, a highly convergent synthesis of thiolactones has been developed. The application of this efficient process for the rapid synthesis of a diverse range of thiolactones under very mild conditions highlights its utility for the preparation of more structurally complex natural products and their analogues. Importantly, the excellent overall yields, fast reaction kinetics (the reactions are typically complete in
