Rapid Access to Thiolactone Derivatives through Radical-Mediated Acyl Thiol-Ene and Acyl Thiol-Yne Cyclization

Article abstract of DOI:10.1021/acs.orglett.8b00996

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.

Full text of DOI:10.1021/acs.orglett.8b00996

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rapid Access to Thiolactone Derivatives through Radical-Mediated
Acyl Thiol−Ene and Acyl Thiol−Yne Cyclization
Ruairi O. McCourt,† Fabrice Denes,‡ Goar Sanchez-Sanz,§ and Eoin M. Scanlan*,†
́
̀
†Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
‡Universite
de Nantes, CEISAM UMR CNRS 6230 UFR des Sciences et des Techniques -2 rue de la Houssiniere, 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.
hiolactones represent a fascinating class of heterocyclic
compounds with emerging applications in chemical
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 co-
workers13 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
T
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
Received: March 28, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b00996
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Letter
Scheme 2. Acyl Thiol−Ene Cyclization of Unsaturated
a
Thioacids
Figure 1. Synthetic therapeutics and naturally occurring thiolactones
and retrosynthesis showing OC−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
1
combination of isolated yield and H 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 5-
exo 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 near-
quantitative 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 6-
membered 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

Organic Letters
Letter
probably due to the requirement for isomerization of the alkene
stereochemistry prior to cyclization.
of the acyl-thiyl radical onto phenyl-substituted alkyne
derivatives furnished 2a as an E/Z mixture of isomers. Mono-
or 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.
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 corre-
sponding 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 γ-
unsaturated thiolactones prepared through the ATY approach
is illustrated in Scheme 3.
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.
Scheme 3. Acyl Thiol−Yne Cyclization of Various
a
Unsaturated Thioacid Derivatives
a
dr determined by 1H NMR analysis. *Yield determined via
1
combination of isolated yield and H NMR ratios.
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
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Letter
(14) Langlais, M.; Kulai, I.; Coutelier, O.; Destarac, M. Macro-
molecules 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 <2 h), regioselectivity,
and substrate diversity features render this process well suited
for the development of chemical screening libraries.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00996.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: eoin.scanlan@tcd.ie,
ORCID
Goar Sanchez-Sanz: 0000-0002-1390-4004
Eoin M. Scanlan: 0000-0001-5176-2310
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Science Foundation Ireland (SFI)
under Grant No. 15/CDA/3310 (E.M.S.) and by a
philanthropic donation to Trinity College Dublin by Beate
Schuler (R.O.M.) and an ANR grant (ANR Blanc 13 BS07-
0010-01 “UZFul-Chem”) (F.D.).
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DOI: 10.1021/acs.orglett.8b00996
Org. Lett. XXXX, XXX, XXX−XXX