A Sequential Acyl Thiol-Ene and Thiolactonization Approach for the Synthesis of δ-Thiolactones

Article abstract of DOI:10.1021/acs.orglett.9b01271

A novel strategy for the synthesis of δ-thiolactones from inexpensive and readily available ?-unsaturated esters has been developed. This strategy incorporates a radical acyl thiol-ene reaction as the key C-S bond forming step. Cyclization is achieved via a Steglich-type thiolactonization of 5-mercaptopentanoic acids. We report the facile and scalable synthesis of δ-thiolactones in moderate to good yield under mild reaction conditions with tolerance for a range of functional groups.

Full text of DOI:10.1021/acs.orglett.9b01271

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Sequential Acyl Thiol−Ene and Thiolactonization Approach for the
Synthesis of δ‑Thiolactones
Ruairí O. McCourt and Eoin M. Scanlan*
Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
S
* Supporting Information
ABSTRACT: A novel strategy for the synthesis of δ-thiolactones from inexpensive and readily available γ-unsaturated esters
has been developed. This strategy incorporates a radical acyl thiol−ene reaction as the key C−S bond forming step. Cyclization
is achieved via a Steglich-type thiolactonization of 5-mercaptopentanoic acids. We report the facile and scalable synthesis of δ-
thiolactones in moderate to good yield under mild reaction conditions with tolerance for a range of functional groups.
hiolactones represent an underexploited class of sulfur-
containing heterocyclic compounds with potential
and preventing disulfide formation, ultimately increasing
potential storage times, a common problem associated with
thiol-containing therapeutics. Furthermore, a subclass of
aromatic δ-thiolactones, isothiochroman-3-ones, have been
utilized as aminopeptidase inhibitors, agrochemical fungicides,
and herbicides.14,15 However, only few preparative methods for
these structural motifs have been reported and a novel strategy
for their synthesis is therefore highly desirable. Traditional
strategies for the synthesis of thiolactones focused on oxygen−
sulfur exchange of more readily available lactones,16,17 or
isomerization of thionolactones18 prepared by the treatment of
lactones with thionating reagents, such as phosphorus
pentasulfide19 or Lawesson’s reagent.18
T
application in numerous fields, although of late they have
garnered increased interest. β-thiolactones, although somewhat
unstable,1 have drawn considerable attention for their ability to
mediate the coupling of sterically demanding peptides by
native chemical ligation.2 γ-Thiolactones have proven useful in
chemical biology,3,4 medicinal chemistry,5 drug discovery,6 and
materials science,7,8 with the γ-thiolactones derivatives of
homocysteine thiolactone (Hcy-thiolactone), the product of
homocysteine metabolism,9 of particular interest (Figure 1).
Recently, we have focused on the development of new
methods for the efficient synthesis of thiolactones. For γ-
thiolactones, radical processes, in particular radical cyclizations,
were identified and validated as a successful approach to this
structural motif. First a low-yielding nBu3SnH mediated
cyclization of an α-bromo-allylic thioester was reported.20
Furthermore, it was demonstrated that an α-xanthate-allylic
thioester could also undergo cyclization in slightly improved
yields, though the scope remained unexplored and the yield
remained modest. A more robust approach focused on
formation of the C−S bond of the thiolactone via 5-exo-trig
(Scheme 1a) and 5-exo-dig (Scheme 1b) radical acyl thiol−ene
and acyl thiol−yne cyclization of unsaturated thioacids,
respectively.21 This strategy proved highly effective with a
range of thiolactones being prepared in good yield, together
with considerable control over diastereoselectivity. The
substrates for the acyl thiol−ene (ATE) cyclization were
Figure 1. Examples of bioactive thiolactones.
For example, the liver therapeutic citiolone10 and the
mucolytic erdosteine11 are simple derivatives of Hcy-
thiolactone in which the amino group is acylated. δ-
Thiolactones also possess interesting biological effects, with
potential applications as flavor or aroma compounds12 and as
prospective prodrugs for glutamate carboxypeptidase II
(GCPII) inhibition,13 masking the thiol moiety as a thioester
Received: April 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01271
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Organic Letters
Letter
group tolerance. This process has also proven to be scalable to
gram quantity synthesis of thiolactones.
Scheme 1. Recent Advances in the Synthesis of
Thiolactones
We commenced our studies by preparing a structurally
diverse family of thioesters by subjecting γ-unsaturated esters
(1a−w) to radical acyl thiol−ene reaction with 3 equiv of
thioacetic acid (AcSH). A synergistic photosensitizer−photo-
initiator pairing of MAP (4′-methoxyacetophenone) and
DPAP (2,2-dimethoxy-2-phenylacetophenone), respectively,
in degassed ethyl acetate (EtOAc) was employed, irradiating
at 350 nm. Only 0.1 equiv of each reagent was required to
drive all of the acyl thiol−ene reactions to complete conversion
within 1 h. With these previously optimized conditions in
hand,29 the scope of the acyl thiol−ene reaction for thioester
synthesis was investigated with γ-unsaturated esters (1a−w).
Simple unsubstituted ester 1a afforded thioester 2a in near-
quantitative yield (Scheme 2). The anti-Markovnikov hydro-
thiolation product was formed exclusively, as expected, due to
the relative stability of the of the 2° carbon-centered radical
generated.31 Monosubstitution at the α- and β-position relative
to the ethyl ester moiety was well tolerated (2b−2d). Higher
Scheme 2. Acyl Thiol−Ene Reaction of γ-Unsaturated
Esters and Thioacetic Acid (AcSH) To Afford Thioesters
a
synthesized from the corresponding γ-unsaturated esters in
only three steps. Other groups have reported novel strategies
for thiolactone synthesis. Most recently, a modular approach
based on the radical addition of xanthates onto alkenes
followed by Chugaev elimination and condensation of the free
thiol onto a pendant ester in a 5-exo-trig cyclization has also
been developed; however, the conditions require elevated
temperatures (Scheme 1c).22 New methods for the synthesis of
δ-thiolactones remain scant; however, in 2018 a strategy for
the synthesis of isothiochroman-3-ones was developed utilizing
a Brønsted acid catalyzed N-oxide oxidative C−H functional-
ization of alkynyl thioethers (Scheme 1d).14 Although highly
novel and good-yielding, this approach is limited in that all
thiolactones formed must incorporate an aromatic moiety.
In this letter we report the synthesis of δ-thiolactones
starting from γ-unsaturated esters (Scheme 1e). The key C−S
bond forming step in this strategy involves an acyl thiol−ene
reaction employing thioacetic acid as a reagent for introducing
the thiol in a protected form (thioester). The thiol−ene
reaction has long been established as a highly efficient method
for the formation of C−S bonds23 and has seen broad
application from polymer production24 to the functionalization
of proteins25 and the synthesis of thiosugars.26,27 There are
numerous strategies for the initiation of thiol−ene reactions28
with this field still attracting much attention to enable cleaner
and more procedurally simple methods.29,30 Following acyl
thiol−ene reaction the thiol and carboxylic acid are
concomitantly deprotected under basic conditions, furnishing
5-mercaptopentanoic acids. Steglich coupling conditions are
utilized to induce cyclization (Steglich thiolactonization) using
N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide hydro-
chloride (EDC·HCl) as a coupling reagent, affording δ-
thiolactones in moderate to good yield with broad functional
a
AcSH (3.0 equiv), γ-unsaturated esters (1) (1.0 equiv) DPAP (0.1
equiv), MAP (0.1 equiv) in degassed EtOAc (5 mL/mmol), at 25 °C,
under UV irradiation (350 nm) for 1 h. Reactions ran on 1.5−5.0
1
mmol scale. Isolated yield reported. dr determined by H NMR.
B
DOI: 10.1021/acs.orglett.9b01271
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Letter
functionalized alkenes also proved compatible with the acyl
thiol−ene reaction, with a range of aryl halide containing esters
affording the corresponding thioesters in very good yield (2e−
2g). Nitro compound 2h was afforded in good yield (87%).
Gem-disubstituted alkene 1i underwent smooth thiol−ene
reaction giving 2i in good yield. Following this, disubstitution
of the carbon skeleton was investigated. First, gem-
disubstitution at the α-position afforded 2j in excellent yield.
Aryl-ether containing thioester 2k was furnished in 93% yield.
Trifluoromethyl compound 1l yielded 2l as a compound in
90% yield. Heterocycles such as furans and aryl ethers proved
tolerant of the reaction conditions as exemplified by the
preparation of 2m in 87% yield. Similar results were obtained
upon disubstitution at the β-position (2n−2p). Vicinal
disubstitution also proved successful (2q−2r), the observed
dr being a direct result of the preparation of the γ-unsaturated
esters (1q−1r). Acyl thiol−ene addition onto a gem-
disubstituted alkene in which there is a substituent at the β-
position (1s) yielded 2s in excellent yield, although only
modest diastereoselectivity was induced (dr 1.4:1). Following
this, the acyl thiol−ene reaction of internal alkenes was
examined. Trisubstituted alkenes 1t−1v proved compatible
with the reaction conditions giving the anti-Markovnikov
products in good yield, through formation of the more
stabilized 3° radical intermediates, with essentially no
diastereoselectivity observed.32−34 However, slight traces of
the regioisomer of 2u were observed, likely due to the relative
stability of the generated benzylic radical competing with the
steric hindrance of the alkene. Further terminal alkenes were
subsequently examined. 2-Vinyl benzoic acid ester (1w)
proved a good substrate for radical addition, likely due to
the stability of the intermediate benzyl radical formed.
Trisubstitution along the carbon backbone was well-tolerated
(2x). Finally, gem-disubstitution both on the alkene and at the
α-position was also tolerated, giving 2y in 88% yield.
With a diverse range of thioesters available, we next
examined the viability of affording δ-thiolactones. Previous
reports have shown that under intense heating for extended
periods thiols can be condensed onto a carboxylic acid in an
intramolecular manner to afford δ-thiolactones, albeit in low
yield,35,36 or esters, which afford improved yields.22 Encour-
aged by this, thioester 2a was hydrolyzed to deprotect the thiol
and carboxylic acid moiety, furnishing 5-mercaptopentanoic
acid. The free thiol was then immediately subjected to Steglich
cyclization conditions, modified slightly from conditions
previously reported for the synthesis of β-thiolactones.1 To
the thiol in anhydrous CH2Cl2 under dilute conditions were
added 2 equiv of the carbodiimide coupling reagent EDC·HCl
and 1.2 equiv of the nucleophilic catalyst 4-(dimethylamino)-
pyridine (DMAP). Gratifyingly, simple thiolactone 3a was
afforded in good yield (71%) over two synthetic steps,
following the Steglich thiolactonization approach (Scheme 3).
Applying these conditions to the thioesters (2a−y) previously
prepared furnished a plethora of novel thiolactones (3a−y).
Monosubstituted thiolactones (3b−3i) were prepared in
moderate to good yield from the corresponding thioesters
via the corresponding 5-mercaptopentanoic acid derivatives.
Thiolactones 3e−3h highlight the versatility and scope of the
methodology. Aryl halide containing thioesters proved
compatible with the conditions affording the aryl fluoride
(3e), aryl chloride (3f), and aryl bromide (3g) containing
thiolactones in yields of 73%, 70%, and 74%, respectively.
Nitro group containing thioester 2h also proved compatible
Scheme 3. Steglich Thiolactonization of 5-
Mercaptopentanoic Acids
a
a
Thioester (2) (1.0 equiv), heated in 1 M NaOH solution for 45 min,
then EDC·HCl (2.0 equiv), DMAP (1.2 equiv) in dry CH2Cl2 (6.5
mL/mmol), at rt, under argon for 8−14 h. Reactions ran on 0.4−0.9
1
mmol scale. Isolated yield reported. dr determined by H NMR.
with the conditions, furnishing thiolactone 3h in 76% yield.
Geminal disubstitution on the carbon skeleton of the thioesters
only proved to have a minor effect on the observed yield (3j−
3n), likely due to the Thorpe−Ingold effect.37 Thiolactones 3k
and 3m demonstrated that this methodology is compatible
with the synthesis of ether containing thiolactones (aryl and
alkyl, respectively). Fluorinated compound 3l of potential
interest in medicinal chemistry was prepared in 71% yield.
Incorporation of a furan motif (3m) appeared to have no
detrimental effect on the cyclization process. This approach
allowed for the synthesis of spiro-bicyclic system 3p. A
diminished yield was obtained due to difficulty during
purification. Vicinal-disubstituted thiolactones were also
prepared in good yield (3q−3v) with no change in dr being
observed from the thioester starting materials. 2w was
converted to isothiochroman-1-one (3w) in a comparable
yield to that reported in the recent synthesis of isothiochro-
man-3-one,14 highlighting that the current strategy could also
be utilized for the preparation of this class of compound.
Trisubstituted thioesters also furnished the desired thiolac-
tones in good yield (3x−3y).
To test the practicality, employability, and robustness of our
developed approach, we set out to test our reaction on large-
scale (Scheme 4). Cheap and commercially available cinnamyl
C
DOI: 10.1021/acs.orglett.9b01271
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Letter
of thioesters in excellent yield with broad functional group
compatibility, albeit with little to no diastereoselectivity. The
ester and thioester moieties are readily hydrolyzed to afford 5-
mercaptopentanoic acids which undergo thiolactonization in
good yield under Steglich coupling conditions to afford δ-
thiolactones in good yield. The methodology is robust and
regioselective, allowing rapid access to thiolactone derivatives
with high yields under mild conditions. The investigation of
the scope and potential of this process in addition to the
development of routes to the corresponding thioester natural
product derivatives is underway.
Scheme 4. Gram-Scale Synthesis of δ-Thiolactone
alcohol (2.01 g, 15 mmol) was subjected to Johnson−Claisen
rearrangement with triethyl orthoacetate, with purification by
distillation to furnish γ-unsaturated ester 1c in 87% yield. 1c
(13 mmol) underwent acyl thiol−ene reaction with AcSH
without special precautions to degas or dry the solvent (i.e.,
used directly from the bottle, HPLC grade). We were pleased
to see that 2c could be afforded in 94% yield (3.42 g).
Thioester 2c was hydrolyzed to the corresponding 5-
mercaptopentanoic acid. Steglich thiolactonization conditions
were applied to the free thiol, again, without special
precautions being employed (solvent and reagents direct
from the bottle, reaction open to air) furnishing thiolactone 3c
in a slightly diminished yield of 59% (1.38 g).
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.9b01271.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: eoin.scanlan@tcd.ie.
ORCID
Increasing the attractiveness of our approach is the synthetic
divergence made possible by this strategy. Depending on the
iteration of the steps used, either γ- or δ-thiolactones can be
afforded from the same starting material (Scheme 5). Recently
Eoin M. Scanlan: 0000-0001-5176-2310
Notes
Scheme 5. Divergent Approach To Access δ- or γ-
Thiolactones
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.).
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