Catalytic asymmetric synthesis of thiols

Article abstract of DOI:10.1021/ja510069w

The synthesis of enantiopure thiols is of significant interest for industrial and academic applications. However, direct asymmetric approaches to free thiols have previously been unknown. Here we describe a novel organocascade that is catalyzed by a confined chiral phosphoric acid and furnishes O-protected β-hydroxythiols with excellent enantioselectivities. The method relies on an asymmetric thiocarboxylysis of meso-epoxides, followed by an intramolecular trans-esterification reaction. By varying the reaction conditions, the intermediate thioesters can also be obtained chemoselectively and enantioselectively.

Full text of DOI:10.1021/ja510069w

Communication
pubs.acs.org/JACS
Catalytic Asymmetric Synthesis of Thiols
Mattia Riccardo Monaco, Sebastien Prevost, and Benjamin List*
́
́
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm Platz 1, 45470 Mulheim an der Ruhr, Germany
̈
̈
S
* Supporting Information
untapped, and most investigated routes rely on the thiolysis
of epoxides. Much progress has recently been made in this area
using metal-based Lewis acid catalysis and, very recently, also
organocatalysis.5,6 Despite such efforts, all these methodologies
suffer the difficulty of satisfying both substrate generality and
stereoselectivity. Moreover, thioether products are delivered in
all cases, and their conversion into the desired free thiols
generally requires additional steps and typically harsh
conditions.5c,6
Very recently, we introduced a novel activation mode for
carboxylic acids using Brønsted acid catalysis.7 We reported the
self-assembly between chiral phosphoric acid catalysts and
carboxylic acids to exhibit a twofold beneficial effect: the
enhancement of the nucleophilicity of the carboxylic acid
molecule and a concurrent increase of the acidity of the
heterodimer.8 Presumably, the increased acidity observed is
important for the activation of the electrophilic reaction partner
in Brønsted acid organocatalysis. Broadening this activation
mode to thiocarboxylic acids, a general and highly selective
thiocarboxylysis of epoxides would be expected. Moreover, this
reactivity should be extendable into an organocascade process,9
in which the initially generated β-hydroxythioester undergoes
an in situ Brønsted acid-catalyzed intramolecular trans-
esterification reaction.10 This sequence would give direct access
to the free thiol moiety upon epoxide ring opening and
represents an effective equivalent to the sulfhydrolysis reaction
(Scheme 1).
ABSTRACT: The synthesis of enantiopure thiols is of
significant interest for industrial and academic applications.
However, direct asymmetric approaches to free thiols have
previously been unknown. Here we describe a novel
organocascade that is catalyzed by a confined chiral
phosphoric acid and furnishes O-protected β-hydroxythiols
with excellent enantioselectivities. The method relies on an
asymmetric thiocarboxylysis of meso-epoxides, followed by
an intramolecular trans-esterification reaction. By varying
the reaction conditions, the intermediate thioesters can
also be obtained chemoselectively and enantioselectively.
ulfur is a frequent constituent of pharmaceuticals, and its
Sselective incorporation into complex molecular frameworks
is highly relevant in medicinal chemistry.1 Common approaches
to the synthesis of sulfurous bioactive molecules rely on the
nucleophilicity of thiol derivatives.2 Remarkably, though,
despite the value of enantiopure free thiols as building blocks,
direct asymmetric approaches toward their preparation have
been entirely elusive to date.3 We now report an asymmetric
organocascade that is catalyzed by a confined chiral phosphoric
acid and delivers O-protected β-hydroxythiols in excellent
enantioselectivities.
Developing enantioselective routes to β-hydroxythiols should
be particularly rewarding, since they are often associated with
privileged bioactivity, as illustrated with dihydrobenzoxathiins,
cysteinyl leukotrienes, or the marketed drugs diltiazem and
cevimeline (Figure 1).4
At the outset of our investigation, we studied the proposed
self-assembly between phosphoric acid 4a (TRIP) and
thiobenzoic acid (2a). NMR spectroscopic analysis indeed
supported our speculations, confirming that in mixtures of the
two acids in nonpolar media, an equilibrium toward hetero-
dimer formation exists.11 We therefore focused our attention
An asymmetric sulfhydrolysis of epoxides with hydrogen
sulfide (H2S) would arguably represent the most straightfor-
ward approach to β-hydroxythiols. However, due to the
difficulties in exploiting H2S, this transformation is still
Scheme 1. Organocascade Catalysis to β-Hydroxythiols
Figure 1. Bioactive molecules that incorporate a β-hydroxythiol
framework.
Received: September 30, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja510069w | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
on developing the proposed methodology, choosing cyclo-
hexene oxide 1a as model substrate. Indeed, the reaction
catalyzed by TRIP (4a) gave full conversion of the starting
material into ring-opened product 3a with promising enantio-
selectivity, yet the expected acyl-transfer product was not
observed under these conditions (entry 1, Table 1). A
screening of various reaction parameters was next performed
to identify suitable conditions for the epoxide-opening reaction
(Table 1).
With the optimal conditions in hand, we next began
investigating the substrate scope of this organocatalytic
thiocarboxylysis of epoxides.
As shown in Chart 1, the transformation is rather general,
and a large variety of meso-epoxides 1a−k reacted with high
ab
,
Chart 1. Thiocarboxylysis Reaction Scope
a
Table 1. Establishing Suitable Reaction Conditions
b
c
entry
catalyst
solvent
yield (%)
er
1
2
3
4
5
6
TRIP, 4a (4 mol %)
4b (4 mol %)
4c (4 mol %)
4c (4 mol %)
4c (4 mol %)
4c (4 mol %)
4c (4 mol %)
4c (4 mol %)
4c (2 mol %)
4c (1 mol %)
4c (0.1 mol %)
4c (0.01 mol %)
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
C6H6
>95
>95
>95
>95
>95
>95
>95
>95
>95
89
19.5:80.5
14.5:85.5
86:14
85:15
87.5:12.5
90:10
toluene
toluene
toluene
toluene
toluene
toluene
toluene
d
7
95:5
eg
,
8
eg
,
98:2
9
98:2
eg
,
10
11
12
97.5:2.5
89.5:10.5
85:15
g
a
>95
48
Isolated yields (%) and enantiomeric ratio (er); see Supporting
g
b
Information for experimental details. Enantiomeric ratio determined
c
by HPLC on chiral stationary phase. Product ratio determined by 1H
a
Unless otherwise indicated, all reactions were carried out with
NMR analysis.
substrate 1a (0.05 mmol) and thiobenzoic acid 2 (0.08 mmol, 1.6
b
equiv) in 0.4 mL of solvent at room temperature. Determined by 1H
c
NMR analysis. Determined by HPLC on chiral stationary phase.
levels of stereocontrol. Six-membered-ring substrates 1a−c
delivered the corresponding β-hydroxythioesters 3a−c in good
to outstanding yields and excellent enantioselectivities. It is
noteworthy that the reaction outcome is essentially unaffected
by the ring size of the starting material, as proven by the high
yields and optical purity of products 3d,e. The presence of
heteroatoms in the substrate scaffold is well tolerated (products
3f,g), albeit with a small influence on the reactivity.14 Acyclic
substrates also reacted smoothly, providing syn-hydroxy-
thioesters 3h−j with excellent stereoselectivity. Notably,
substrate 1h gave product 3h in outstanding yield (99%) and
enantioselectivity (97:3 er), further confirming the potential of
a confined catalysts in enantioselective transformations of very
small substrates.15 Furthermore, the challenging cis-stilbene
oxide 1k could be reacted under mild conditions, giving the
product 3k together with a minor amount of its thiol isomer 5k
in good yield and moderate optical purities (3k, 89:11 er; 5k,
87:13 er).16 Moreover, the asymmetric thiocarboxylysis could
also be performed using thioacetic acid 2b. Under similar
reaction conditions, products 3l,m were obtained with high
levels of stereocontrol, albeit with slightly diminished reactivity.
The detection of significant amounts of thiol isomers 5k,l (as
shown in Chart 1) was important in our investigation since it
d
e
Reaction performed at −40 °C in 16 h. Reaction performed at −78
g
°C. Reaction time 2 days.
The enantioselectivity of the transformation was found to be
affected by the steric hindrance of the catalyst pocket. In fact,
confined chiral phosphoric acids bearing polycyclic substituents
on the BINOL backbone, recently introduced by our group,8b
were found to again outperform TRIP (entry 2, Table 1).
Catalyst 4c, with the hydrogenated BINOL-scaffold, promoted
the reaction at room temperature, delivering the desired
product in 86:14 enantiomeric ratio (er), and was selected for
further optimization (entry 3, Table 1).12 Extensive screening
of the solvent and temperature revealed that full conversion and
an excellent level of enantioselectivity can be achieved in
toluene under cryogenic conditions (entry 8, Table 1).
Remarkably, the reaction could be promoted by 1 mol % of
catalyst 4c, yielding the product in 89% yield and 97.5:2.5 er
(entry 10, Table 1), while at room temperature, 100 ppm of
catalyst loading was found to be the threshold for this activity
(entry 12, Table 1).13
B
dx.doi.org/10.1021/ja510069w | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
confirmed the feasibility of our originally designed organo-
cascade. Apparently, the in situ sequence had been hampered
with other substrates by a slow and rate-determing acyl-transfer
step.
efficiently obtained in good yields and remarkable selectivity. In
some cases, the optical purity of thiols 5 was found to be
slightly lower than that of isolated alcohols 3, shown above.
This may be due to the conversion of a residual amount of
epoxide starting material at higher temperature during the
second step. A single recrystallization significantly improved the
enantioenrichement of thiol 5k, which was initially obtained in
nearly quantitative yield but in only moderate enantioselectivity
(entry 8, Table 2).
It is noteworthy that our transformation either can directly
deliver organocascade products 5 or can be interrupted, giving
intermediates 3. This reaction control enables isolation of the
same 1,2-hydroxythiol scaffold protected either on sulfur or on
oxygen. Further, the initially formed products can also be
deprotected in situ under mild conditions, yielding enantiopure
1,2-hydroxythiols. The overall methodology constitutes an
equivalent of the long sought after asymmetric sulfhydrolysis
reaction (eq 1).
Consequently, we reinvestigated the reactions of all the
previously tested substrates by simply elevating the reaction
temperature upon consumption of the epoxide. Indeed, these
conditions proved to be suitable for the catalytic activation of
the thioester moiety, and the free thiol products were
selectively obtained (Table 2).17 Six- and seven-membered
ring substrates smoothly underwent the cascade transformation
(entries 1−5, Table 2), while the requirement for a trans-fused
bicyclooctane intermediate prevented the formation of five-
membered-ring products.18 Linear products 5h−j were also
a
Table 2. Organocascade Reaction Scope
In summary, we have developed a direct asymmetric
approach to enantiopure free thiols. Expanding the concept
of the organocatalytic activation of carboxylic acids, we disclose
a catalytic organocascade that furnishes protected β-hydroxy-
thiols. Employing a chiral confined phosphoric acid catalyst,
this methodology shows wide substrate generality and high
levels of stereoselectivity. Synthetic applicability is predicted,
due to the possibility to control the position of the acyl
protecting group. Further exploration in the field of carboxylic
acids activation is currently in progress in our laboratories,
especially regarding the use of thiocarboxylic acids as masked
synthons of hydrogen sulfide in Brønsted acid catalysis.
ASSOCIATED CONTENT
* Supporting Information
Additional screening tables, detailed synthetic procedures,
spectra, and HPLC traces for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
list@kofo.mpg.de
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous support by the Max-Planck-Society and the European
Research Council (Advanced Grant “High Performance Lewis
Acid Organocatalysis, HIPOCAT”) is gratefully acknowledged.
We thank the members of our mass spectrometry department
for their excellent service.
a
Unless otherwise indicated, all reactions were carried out with
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Journal of the American Chemical Society
Communication
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dx.doi.org/10.1021/ja510069w | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX