Copper-Catalyzed Enantioselective Construction of Tertiary Propargylic Sulfones

Article abstract of DOI:10.1002/anie.201814242

Tertiary propargylic sulfones are of significant importance in organic synthesis and medicinal chemistry, but to date no general asymmetric synthesis approach has been developed. We disclose a versatile copper-catalyzed sulfonylation of propargylic cyclic carbonates using sodium sulfinates that allows the construction of propargylic sulfones featuring elusive quaternary stereocenters. This method provides the first successful example of such an enantioselective propargylic sulfonylation, features high asymmetric induction, wide functional group tolerance, and scalability, and enables attractive product diversification.

Full text of DOI:10.1002/anie.201814242

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Accepted Article
Title: Copper-Catalyzed Enantioselective Construction of Tertiary
Propargylic Sulfones
Authors: José Enrique Gómez, Alex Cristofol, and Arjan Willem Kleij
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814242
Angew. Chem. 10.1002/ange.201814242
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10.1002/anie.201814242
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Copper-Catalyzed Enantioselective Construction of Tertiary
Propargylic Sulfones
José Enrique Gómez,[a] Àlex Cristòfol,[a] and Arjan W. Kleij*,[a],[b]
Abstract: Tertiary propargylic sulfones are of significant importance
in organic synthesis and medicinal chemistry, but to date no general
asymmetric synthesis approach has been developed. Here we
disclose a versatile copper-catalyzed sulfonylation of propargylic
cyclic carbonates using sodium sulfinates allowing to construct
propargylic sulfones featuring elusive quaternary stereocenters. This
method provides the first successful example of enantioselective
propargylic sulfonylation, features high asymmetric induction, wide
functional group tolerance and scalability, and attractive product
diversification.
convert propargylic alcohol derivatives into enantioenriched
compounds,[9] with copper-allenylidenes acting as key
intermediates in these stereoconvergent transformations.[10]
Sulfur-containing quaternary stereocenters are ubiquitous motifs
in numerous natural products and are considered to be an integral
component in pharmaceuticals.[1] As a result, the pursuit of new
catalytic strategies that would allow to simultaneously forge a CS
bond while generating a sterically hindered stereocenter stand at
the forefront of modern synthetic organic chemistry.[2] In this
scenario, tertiary sulfones bearing a pendant propargyl group
represent an important class of structural diverse commodities,
which have been exploited in synthetic chemistry, drug design
and material sciences.[3,4a-b] Despite the versatile potential of
merging acetylenic and sulfur chemistry,[5] to the best of our
knowledge the asymmetric preparation of these synthons remains
to date elusive.
Traditional approaches leading to tertiary propargylic sulfones
rely on multistep synthetic sequences. These methods require the
C–S bond to be pre-installed prior to sulfone formation and they
have the intrinsic drawback of using more toxic thiols as
reagents.[4] In
a different approach, propargylic sulfones
containing a quaternary center can be prepared starting from the
corresponding sulfonylallenes, albeit with the limitation that a
highly specialized class of substrates are required.[6] Recently, the
advances in this field allowed the direct preparation of tertiary
propargylic sulfones via a one-step regioselective dehydrative
cross-coupling reaction of propargylic alcohols with sulfinic acids
(Scheme 1A).[7] Though attractive, this approach is limited to the
preparation of racemic sulfones even in the case when an
enantioenriched propargylic alcohol is utilized. Therefore, the
development of a general and practical strategy to access chiral
propargyl-substituted tertiary sulfones would be warranted to
further widen the synthetic potential of these scaffolds.[8]
Scheme 1. Reported strategy to construct propargylic sulfones (A), Copper-
catalyzed APS reactions (B), and the developed methodology towards
enantioenriched tertiary propargylic sulfones (C).
Whereas significant advances have been achieved in Cu-
catalyzed APS reactions with various reagents including N‒, O‒
and C‒based nucleophiles (Scheme 1B),[9,10] the employment of
sulfur-centered nucleophiles in these transformations has not yet
been achieved.[11] Additionally, extension of Cu-catalyzed APS
reactions to substrates that allow to construct quaternary centers
still remains limited.[9r-t] The apparent challenge in this domain is
to achieve a high degree of enantiofacial control upon substituting
a sterically hindered center[12a-c] with a potentially coordinating
nucleophile that easily leads to transition-metal (TM) catalyst
deactivation.[12d]
In this context, the copper-catalyzed asymmetric propargylic
substitution (APS) reaction has emerged as a powerful tool to
[a]
[b]
J. E. Gómez, À. Cristòfol, Prof. Dr. A. W. Kleij, Institute of Chemical
Research of Catalonia (ICIQ), the Barcelona Institute of Science and
Technology, Av. Països Catalans 16, 43007 - Tarragona, Spain. E-
mail: akleij@iciq.es
Inspired by these important limitations, our continuous interest
in the challenging synthesis of sterically congested quaternary
stereocenters,[13] and recognizing the high value of sulfones in
synthetic chemistry,[8] we set out to devise a catalytic approach
that would allow us to forge tertiary propargylic sulfones in an
enantioselective manner. Herein we report on a Cu-catalyzed
Prof. Dr. A. W. Kleij
Catalan Institute of Research and Advanced Studies (ICREA), Pg.
Lluís Companys 23, 08010 Barcelona, Spain
Supporting information for this article is given via a link at the end of
the document
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10.1002/anie.201814242
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APS reaction enabled by an efficient coupling of sulfinate salts[14]
and propargylic cyclic carbonates.[15] This practical methodology
is the first successful example of transition-metal-catalyzed
enantioselective propargylic substitution reactions with sulfur-
centered nucleophiles, and provides the targeted tertiary sulfones
under high enantiocontrol (Scheme 1C).
er).[16] Unfortunately, the evaluation of other PyBox ligands did not
provide any improvement of the enantioselectivity (see entry 2 in
Table 1 and the Supporting Information (SI): Table S1). By
switching to commercially available bis(oxazoline) (BOX) ligands
L3‒L7 (entries 3-7) slightly improved enantiocontrol was noted
with L4 (entry 4; 90% yield, 60:40 er) giving a lead for additional
optimization (see also Table S1). By further decreasing the
reaction temperature (entry 8), enantiocontrol slightly improved
(at ‒10 ºC: 72:28 er). Screening reactions performed under similar
conditions using different copper salts or bases did not show any
benefit towards the reaction outcome (see Tables S2 and S3).
The type of reaction medium turned out to be crucial for the
overall reaction efficiency. Whereas the reaction proceeded very
slowly in THF at ‒20 ºC (entry 9, <10% yield of 1), a combination
of THF and a protic solvent (MeOH) was able to promote the
formation of the propargylic target in good yield and appreciable
enantiomeric ratio (entries 10 and 11; er up to 92:8). The effect of
other protic solvents on the enantioselectivity was then
scrutinized (entries 12 and 13, see also Table S4). The Cu-
catalyzed APS reaction affording 1 gave the best result when a
3:1 mixture of THF/HFIP (HFIP = hexafluoroisopropanol) at -30 °C
was used, providing the desired product in 93% yield and 96.5:3.5
er (entry 13). The nature of the propargylic substrate in this Cu-
catalyzed APS reaction (entries 14‒16; E1‒E3, see also Table S5
and S6 for more details) proved to be decisive, as a propargylic
epoxide[17] and linear (O-protected) carbonates gave inferior
yields and/or levels of asymmetric induction under the optimized
conditions. Further to this, our method allows for the formation of
enantioenriched -hydroxysulfone fragments, which are
prominent motifs in bioactive compounds and versatile building
blocks in organic synthesis (Scheme 1C).[18]
Table 1. Selected optimization data for the synthesis of tertiary propargylic
sulfone 1 from propargylic cyclic carbonate A and sodium benzenesulfinate.[a]
Entry
L
Solvent
T [ºC]
Yield[b] [%]
er[c]
1
2
L1
L2
L3
L4
L5
L6
L7
L4
L4
L4
L4
L4
L4
L4
L4
L4
THF
THF
0
0
82
45
52:48
52:48
53:47
60:40
57:43
57:43
59:41
72:28

3
THF
0
46
4
THF
0
93
Having identified the optimized conditions for 1, we then
turned our attention to examine the generality of this Cu-catalyzed
asymmetric transformation (Scheme 2). The formation of
structurally diverse tertiary propargylic sulfones typically proceeds
with yields of up to 97%, and excellent enantiomeric ratios of up
to 98:2. The absolute configuration of propargylic sulfone 1 (S)
was unambiguously assigned by X-ray analysis (see the inset at
the right in Scheme 2).[19] With respect to the scope in propargylic
cyclic carbonates (Scheme 2, upper section), the developed
catalytic process tolerates a wide range of functionalities with
different steric and electronic effects present in the aryl
substituent of the substrate with little effect on the reaction
efficiency and enantiocontrol (cf., formation of compounds 1‒13).
Notably, under the optimized conditions, the introduction of a
bulky naphthyl and heteroaryl groups could also be easily
accomplished (formation of 10‒12). However, the catalytic
process was unsatisfactory with cyclic carbonates containing
aliphatic substituents even at higher temperatures and/or catalyst
loadings.[20] The catalytic transformation leading to sulfone 1 was
conveniently scaled up to gram quantities without any observable
erosion of the enantioinduction of the process (5 mmol scale: 1.13
g, 82% yield, 96.5:3.5 er).
5
THF
0
90
6
THF
0
80
7
THF
0
80
8
THF
-10
-20
-20
-30
-30
-30
-30
-30
-30
90
9
THF
<10
93
10[d]
11[d]
12[e]
13[f]
14[f,g]
15[f,g]
16[f,g]
THF/MeOH
THF/MeOH
THF/TFE
THF/HFIP
THF/HFIP
THF/HFIP
THF/HFIP
87:13
92:8
93
93
94:6
93
96.5:3.5

E1: 0
E2: 90
E3: 90
75:25
85:15
[a] Reaction conditions unless otherwise noted: cyclic carbonate A (0.20 mmol),
sodium benzenesulfinate (0.22 mmol, 1.1 equiv), solvent (200 L), i-Pr2NEt
(0.24 mmol, 1.2 equiv), Cu(OTf)2 (10 mol%), L (11 mol%). [b] Isolated yield. [c]
Determined by UPC2. [d] 24 h, THF/MeOH (3:1, 600 L). [e] 24 h, THF/TFE
(3:1, 600 L). [f] 24 h, THF/HFIP (3:1, 600 L). [g] An alternative propargylic
precursor (E1, E2 or E3) was used.
Our optimization studies (Table 1) began with the reaction
between racemic propargylic cyclic carbonate A and sodium
benzenesulfinate, as benchmark substrates in the presence of 10
mol% of Cu(OTf)2 and i-Pr2NEt in THF. In the presence of L1 at 0
ºC, the desired sulfone 1 was produced in good yield, though
virtually without any enantiocontrol (entry 1, 82% yield, 52:48
A variety of sulfinate salts were also assessed (Scheme 2,
lower section). The protocol is quite efficient for the coupling of
aryl sulfinate salts including those bearing aryl groups with para
(14‒20), meta (21 and 23), and ortho (22) substitutions. Both
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10.1002/anie.201814242
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electron-donating and electron-withdrawing aryl groups are
endorsed giving similar high levels of asymmetric induction. Bulky
naphthyl and heteroaryl sulfinates are also suitable reaction
partners demonstrated by the synthesis of 24-27.
cases that the targeted compounds can be obtained in excellent
yields and high er values.
Finally, to explore the synthetic value of tertiary propargylic
sulfones, 1 was transformed into a series of derivatives retaining
the chiral integrity from the starting propargylic sulfone (Scheme
3). For example, a Sonagoshira coupling reaction between
iodobenzene and 1 delivers compound 30 in 79% yield. A copper
catalyzed azide-alkyne cycloaddition (Cu-AAC) reaction of 1 with
benzyl azide affords the corresponding triazole 31 (89%). The
homopropargylic alcohol of sulfone 1 could be transformed
affording the mesylated derivative 32 (98%) and ester 33 (97%)
through simple procedures. Partial hydrogenation of the pendant
alkyne group in the presence of Pd/C using ambient pressure of
H2 delivers the allylic sulfone 34 in high yield (89%) and
enantiopurity. Notably, such types of allylic products are difficult
to access through conventional methodologies. The alkyne group
in 1 could also be conveniently brominated (35: 68%), and more
complex scaffolds such as optically pure cholesterol azide can be
used as coupling agents while preserving the chiral nature of the
tertiary sulfone (cf., 36: 96:4 dr).
Scheme 2. Tertiary propargylic sulfones 129 prepared from various
propargylic cyclic carbonates and sulfinate salts. Reactions performed under
the optimized conditions (Table 1, entry 13); The er values were determined by
UPC2. [a] Reaction time 36 h. [b] cyclic carbonate (0.22 mmol, 1.1 equiv.),
sulfinate salt (0.2 mmol). [c] The er value was determined from the
corresponding acetate.
Scheme 3. Elaboration of tertiary propargylic sulfone 1: (i) Iodobenzene (1.2
equiv), Pd(PPh3)4 (10 mol%), CuI (10 mol%), Et3N, toluene, rt, 8 h. (ii) BnN3 (1.2
equiv), CuTC (10 mol%), toluene, rt, 1 h. (iii) MsCl ( 1.5 equiv), Et3N (1.5 equiv),
CH2Cl2, 0 ºC, 8 h. (iv) Ac2O (1.5 equiv), Et3N (1.5 equiv), CH2Cl2, 0 ºC, 8 h. (v)
Pd/C (2 mol%), H2 (balloon), MeOH, rt, 2 h. (vi) AgNO3 (10 mol%), NBS (1.2
equiv), acetone, rt, 1 h. (vii) Cholesterol-azide (1.2 equiv), CuTC (10 mol%),
toluene, rt, 1 h. Further details are provided in the SI.
Notably, sulfinate salts equipped with 1,3-benzodioxole and
1,4-benzodioxane fragments were readily transformed into
tertiary propargylic sulfones 26 and 27. Such heteroaryl groups
are often encountered in APIs and therefore provide interesting
entries for pharmaceutical development programs. To highlight
the potential towards the use of alkyl sulfinates, the synthesis of
sulfone products 28 and 29 was probed, and revealed in both
According to previous mechanistic studies on related
propargylic substitution reactions[9g-t,10] and our experimental
observations,[21] a plausible mechanism is proposed in Scheme 4.
An in situ formed catalyst [Cu]* first activates the alkyne fragment
in A through a -complex (not shown). After base-assisted
deprotonation, a copper-acetylide species B is formed which
undergoes decarboxylation to furnish a copper-allenylidene
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intermediate C which is in resonance with copper-acetylide
intermediate C’. Subsequently, nucleophilic attack of the sulfinate
preferentially occurs at the Re-face of the Cu(allenylidene)
species, in line with the crystallographic analysis of sulfone
product (S)-1 (Scheme 2). Finally, protodemetalation renders the
sulfone target as the free alcohol species in the presence of HFIP
while regenerating the active copper catalyst.
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Scheme 4. Plausible mechanism towards the formation of sulfone (S)-1.
In summary, we have developed a general copper-catalyzed
asymmetric propargylic sulfonylation reaction enabling the
preparation of elusive scaffolds featuring quaternary
stereocenters. This protocol is characterized by good to high
yields, high enantiomeric ratios of up to 98:2 and appreciable
scope in reaction partners. It thus provides a new synthetic
approach targeting the construction of sulfur-containing
tetrasubstituted carbon stereocenters that could further enlarge
the potential of sulfone-based drug ingredients. The newly
prepared, formal propargylic -hydroxy sulfones serve as
versatile synthetic precursors to a variety of other enantioenriched
building blocks.
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Acknowledgements
We thank the CERCA Program/Generalitat de Catalunya, ICREA,
the Spanish MINECO (CTQ2017-88920-P), and AGAUR (2017-
SGR-232) for financial support. JEG thanks the MINECO for a
Severo Ochoa/FPI predoctoral fellowship. M. Serrano, M. Díaz
and S. Curreli are acknowledged for the UPC2 analyses.
Keywords: asymmetric synthesis • copper • homogeneous
catalysis • propargylic substitution • tertiary sulfones
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[10] a) K. Sakata, Y. Nishibayashi, Catal. Sci. Technol. 2018, 8, 12-25; b) G.
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[15] Propargylic carbonates were recently reported for Cu-catalyzed
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see: a) L. Tian, L. Gong, X. Zhang, Adv. Synth. Catal. 2018, 360, 2055-
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20, 7907−7911. However, as far as we know no report on the use of
challenging S-centered nucleophiles in Cu-catalyzed APS reactions exists
to date.
[11] Propargylic substitution reactions using thiols in the presence of various
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f) H.-H. Hui, Q. Zhao, M.-Y. Yang, D.-B. She, M. Chen, G.-S. Huang,
Synthesis 2008, 191-196.
[16] Note that parasitic, direct sulfonylation of the alkyne fragment in the
presence of copper has not been observed unlike in previous work: N.
Taniguchi, Tetrahedron, 2014, 70, 1984-1990. Further to this, a potential
retro-aldol/aldol of the -hydroxysulfones that could affect the ee of the
isolated products, was not detected.
[17] A propargylic ether product resulting from the nucleophilic attack of the
alcoholic solvent onto the copper-allenylidene intermediate was isolated in
86% yield under the optimized conditions, see also ref. 9k.
[12] a) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis, eds. J. Christoffers, A. Baro, Wiley-VCH, Weinheim, Germany
2005; b) K. W. Quasdorf, L. E. Overman, Nature 2014, 516, 181-191; c) J.
Feng, M. Holmes, M. J. Krische, Chem. Rev. 2017, 117, 12564-12580; d)
Catalyst Poisoning, eds. L. Hegedus, R. W. McCabe, Marcel Dekker, New
York 1984.
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Namiki, M. Ogawa, K. Maebashi, K. Ishida, M. Matsumoto, T. Asaoka,
Chem. Pharm. Bull. 2001, 49, 173-182; b) S. Oida, Y. Tajima, T. Konosu,
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[13] For a recent review see: a) W. Guo, J. E. Gómez, À. Cristòfol, J. Xie, A. W.
Kleij, Angew. Chem. Int. Ed. 2018, 57, 13735-13747; For recent
contributions see: a) J. E. Gꢀmez, W. Guo, S. Gaspa, A. W. Kleij, Angew.
Chem. Int. Ed. 2017, 56, 15035-15038; b) A. Cai, W. Guo, L. Martínez-
Rodríguez, A. W. Kleij, J. Am. Chem. Soc. 2016, 138, 14194-14197; c) W.
Guo, A. Cai, J. Xie, A. W. Kleij, Angew. Chem. Int. Ed. 2017, 56, 11797-
11801; d) J. Xie, W. Guo, A. Cai, E. C. Escudero-Adꢁn, A. W. Kleij, Org.
Lett. 2017, 19, 6388-6391; f) W. Guo, R. Kuniyil, J. E. Gómez, F. Maseras,
A. W. Kleij, J. Am. Chem. Soc. 2018, 140, 3981-3987.
[19] See the Supporting Information for more details, and CCDC 1574299.
[20] Quantitative recovery of the corresponding alkyl-substituted carbonate was
achieved.
[21] To gain further insight into the active catalytic species, we plotted the er
value of L4 against the er value of the produced propargylic sulfone 1 in
this sulfonylation reaction (Figure S1). A pronounced positive nonlinear
effect was clearly observed, which may indicate binuclear or higher order
species as key intermediates: T. Satyanarayana, S. Abraham, H. B. Kagan,
Angew. Chem. Int. Ed. 2009, 48, 456-494. However, the possibility of the
presence of mononuclear copper-allenylidene complexes ligated by more
than one L4 ligand cannot be ruled out.
[14] Sodium sulfinates are known to be versatile nucleophiles in transition-metal
catalyzed substitution reactions. For a review see: J. Aziz, S. Messaoudi,
M. Alami, A. Hamze, Org. Biomol. Chem. 2014, 12, 9743-9759 and
references therein.
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10.1002/anie.201814242
Angewandte Chemie International Edition
COMMUNICATION
TOC entry:
COMMUNICATION
Copper to the rescue: A general
José Enrique Gómez, Àlex
methodology for elusive propargylic
Cristòfol, and Arjan W. Kleij*
sulfones
featuring
quaternary
stereocenters has been developed.
The protocol relies on a copper-
catalyzed
sulfonylation
of
propargylic cyclic carbonates using
sodium sulfinates. Our protocol
provides the first successful
Page No. – Page No.
example of
a
transition-metal
catalyzed enantioselective propar-
gylic substitution reaction with
sulfur-centered nucleophiles giving
access to functionalized tertiary
sulfones.
Copper-Catalyzed
Enantioselective Construction of
Tertiary Propargylic Sulfones
This article is protected by copyright. All rights reserved.