Regio- and Enantioselective Preparation of Chiral Allylic Sulfones Featuring Elusive Quaternary Stereocenters

Article abstract of DOI:10.1002/anie.201908318

We describe here the first general asymmetric synthesis of sterically encumbered α,α-disubstituted allylic sulfones via Pd-catalyzed allylic substitution. The design and application of a new and highly efficient phosphoramidite ligand (L10) proved to be crucial, and a wide variety of challenging allylic sulfones featuring quaternary stereocenters could be obtained in good yields and with good to excellent levels of regio- and enantioselectivities under attractive process conditions. The developed methodology employs easily accessible chemical feedstock including racemic allylic precursors and sodium sulfinates. The utility of the method is further demonstrated by the synthesis of the sesquiterpene (?)-Agelasidine A.

Full text of DOI:10.1002/anie.201908318

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Accepted Article
Title: Regio- and Enantioselective Preparation of Chiral Allylic Sulfones
Featuring Elusive Quaternary Stereocenters
Authors: Aijie Cai and Arjan Willem Kleij
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201908318
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Regio- and Enantioselective Preparation of Chiral Allylic Sulfones
Featuring Elusive Quaternary Stereocenters
Aijie Cai[a] and Arjan W. Kleij*[a][b]
Abstract: We describe here the first general asymmetric synthesis
of sterically encumbered -disubstituted allylic sulfones via Pd-
catalyzed allylic substitution. The design and application of a new
and highly efficient phosphoramidite ligand (L10) proved to be
crucial, and a wide variety of challenging allylic sulfones featuring
quaternary stereocenters could be obtained in good yields and with
good to excellent levels of regio- and enantioselectivities under
attractive process conditions. The developed methodology employs
easily accessible chemical feedstock including racemic allylic
precursors and sodium sulfinates. The utility of the method is further
demonstrated by the synthesis of the sesquiterpene ()-Agelasidine
A.
disubstituted allylic sulfones continues to be an unsolved yet
inspiring synthetic problem.
Allylic sulfones serve as versatile building blocks in modern
organic
synthesis[1]
and
pharmaceutical
chemistry.[2]
Furthermore, chiral allylic sulfones are important motifs in
biological research that strives towards the discovery of new
anticancer agents,[2g] antibacterial agents[2e] and TSH receptor
antagonists.[2j] Approximately 20% of all FDA approved drugs
are organosulfur compounds[3] and their preparation is thus of
high significance.[1-3] Despite the massive attention that has been
paid to the synthesis of allylic sulfones in the past decade,[4] the
catalytic asymmetric synthesis of -disubstituted allylic
sulfones featuring a quaternary stereocenter remains extremely
challenging and underdeveloped. In this context, only a few
examples of enantioselective synthesis of sterically less
hindered -monofunctionalized allylic sulfones by traditional
allylic substitution reactions (i.e., Tsuji−Trost reactions, Scheme
1a) have been reported.[5]
Scheme 1. Different known strategies towards chiral allylic sulfones (a-c), and
the current approach towards -disubstituted allylic sulfones (d).
Breit and co-workers pioneered Rh-catalyzed asymmetric
hydrothiolation of allenes, which after oxidation provides access
to branched allylic sulfones in a two-step process (Scheme
1b).[6] Recently, Zhang and co-workers developed an intriguing
approach involving the regio- and enantioselective semi-
reduction of allenes for the generation of chiral -
monosubstituted allylic sulfones (Scheme 1c).[7] In spite of
significant progress in this area, the catalytic formation of
sterically even more challenging chiral -disubstituted allylic
sulfones incorporating tetrasubstituted tertiary carbons has
proven to be elusive. Despite scarce examples of such
syntheses,[8] to the best of our knowledge a general asymmetric
method for the regio- and enantioselective preparation of -
Forging chiral branched allylic derivatives from simple and
readily available racemic starting materials continues to be an
important task in synthetic chemistry, due to the potential of the
allylic moiety for further elaboration and asymmetric synthesis.[9]
In this respect, significant progress has been achieved by
transition-metal mediated allylic substitution of primary and
secondary allylic precursors, with iridium catalysis being
prevalent.[10] However, the regio- and enantioselective synthesis
of -disubstituted allylic targets via substitution of tertiary
allylic precursors by TM in general and for palladium in particular
is rather rare and embodies a largely unexplored landscape in
synthetic chemistry.[9,11] A major obstacle is the propensity of
nucleophiles to attack at the less hindered terminus of the -allyl
palladium intermediate, which leads to
a
linear allylic
product.[5b,12]
[a]
[b]
A. Cai, Prof. Dr. A. W. Kleij, Institute of Chemical Research of
Catalonia (ICIQ), Barcelona Institute of Science & Technology
(BIST), Av. Països Catalans 16, 43007 Tarragona, Spain.
E-mail: akleij@iciq.es
A further requisite for the successful synthesis of chiral -
disubstituted allylic compounds is the ease of isomerization of
the intermediate -allyl palladium species via 
interconversion (Scheme 1d). When such isomerization is faster
relative to subsequent nucleophilic attack, a dynamic kinetic
resolution of the -allyl palladium complex allows for kinetic
discrimination of the two forward-going allylic substitution
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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Table 1. Selected data for the optimization of the reaction conditions towards
the formation of allylic sulfone product 2a.[a]
pathways and thus efficient asymmetric induction (Scheme
1d).[9a,12a] In this context, we recently communicated a Pd-
catalyzed allylic substitution process allowing for the preparation
of enantioenriched -disubstituted allylic amines and ethers,
respectively.[13] Such an approach using more nucleophilic
sulfur-centered species has intrinsically the challenge of being
limited in scope and causing catalyst poisoning. Herein we show
that by careful ligand and process design allylic sulfonylation of
racemic tertiary allylic carbonates can be accomplished under
Pd catalysis using sodium sulfinates as nucleophilic reaction
partners. This process illustrates a combination of high regio-
and enantiocontrol providing the first general route to elusive
chiral -disubstituted branched allylic sulfones.
Initially the reaction of racemic tertiary allylic carbonate 1a
and sodium benzylsulfinate was selected as a model system
(see Supporting Information, SI, for more details). We set out to
explore the effects of the chiral phosphoramidite ligands L1L4
(Table 1) on the regio- and enantioselectivity in this sulfonylation
reaction. To our delight, the use of Feringa-type ligand L1[14]
(entry 1) and ligand L2 (entry 2) provided good NMR yields of
the branched allylic sulfone with excellent regiocontrol, though
with low enantioinduction. Use of ligands L3 and L4 (entries 3
and 4) gave lower levels of regiocontrol and similar moderate
enantioinduction. These results helped to assess that the
bulkiness of the nitrogen substituent of the phosphoramidite
ligand exerts an important influence on the regio- and
enantioselectivity in the allylic sulfonylation reaction.
Yield
Entry
L
Solvent
T
[ºC]
2a/3a[b]
er[d]
2a
[%][b]
1
2
3
4
L1
L2
L3
L4
THF
THF
THF
THF
0
0
0
0
99:1
96:4
67
83
27
78
76:24
67:33
32:68
70:30
35:65
88:12
5[e]
6[e]
L5
L6
THF
THF
rt
rt
99:1
99:1
71
36
79
65
74
80
50
82
0
59:41
60:40
Therefore, we next varied the steric nature of the
substituents of the amine unit in the phosphoramidite ligand
(L5L10). The presence of tetramethymorpholine or piperidine-
7[f]
L7
THF
0
87:13
71:29
83:17
87:13
57:43
88:12
1:99
82.5:17.5
86:14
derived ligands L5 and L6 led to
a decrease in the
8
L8
THF
0
enantioselectivity, and importantly also a deceleration of the
reaction progress was observed (entries 5 and 6; rt required). By
switching the methyl substituents to the β-position in the amine
moiety (L7), both the rate of the reaction and the
enantioselectivity improved giving the branched allylic sulfone 2a
in 79% yield and 82.5:17.5 er (entry 7). Evaluation of other more
bulky alkyl/aryl groups (ethyl and phenyl) at the same position of
the phosphoramidite ligand (i.e., L8 and L9; entries 8 and 9) did
not significantly change the reaction outcome. The presence of a
chiral center in the amine module of the ligand L10 slightly
increased the enantioselectivity while maintaining the
regioselectivity compared to L7 utilized under similar conditions
(entry 10).
9
L9
THF
0
87:13
10[f]
L10
L10
L10
L10
L10
L10
L10
L10
L10
L10
L10
THF
0
85.5:14.5
53.5:46.5
86:14
11
CH3CN
2-Me-THF
DCM
0
12
0
13
0

14
Toluene
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
THF
0
40:60
87:13
88:12
88:12
99:1
30
81
81
79
80[c]
78
82[c]

15[g]
16[h]
17[h,i]
18[e,h,i]
19[e,h,i]
20[e,h-j]
0
86.5:13.5
89.5:10.5
90.5:9.5
93.5:6.5
92.5:7.5
95:5
0
-10
-20
-20
-20
91:9
Subsequently, the exploration of various solvents revealed
that 2-Me-THF is the best medium for this reaction (entries
1114). Remarkably, complete linear regioselectivity was
observed in DCM (entry 13). An increase in the amount of
solvent (entries 15 and 16) and a decrease of the amount of
nucleophile at lower reaction temperature (entries 1719)
significantly improved both regio- and enantioselectivity. The
reaction was further optimized by changing the palladium
precursor loading. These subtle changes finally furnished allylic
sulfone 2a in 82% isolated yield and 95:5 er, with an excellent
regioselectivity (entry 20; 2a/3a = 99:1). Notably, this synthetic
method can be performed in the absence of additives and under
air adding to the practicality of this asymmetric methodology.
2-Me-THF
99:1
[a] 1a (0.15 mmol), BnSO2Na (0.165 mmol, 1.1 equiv), solvent (300 L),
Pd2(dba)3·CHCl3 (2.5 mol %), L (10 mol %). [b] Determined by 1H NMR
analysis of the crude reaction mixture using toluene as internal standard. [c]
Isolated yield. [d] er determined by SFC. [e] 48 h. [f] 8 h. [g] Solvent (500 L).
[h] Solvent (1.0 mL). [i] BnSO2Na (0.10 mmol), 1a (0.15 mmol, 1.5 equiv). [j]
Pd2(dba)3·CHCl3 (3.5 mol %).
Having established these optimized conditions (Table 1,
entry 20), the scope of the allylic substitution reaction was
evaluated first focusing on the variation of the sodium
alkylsulfinate
nucleophile
(Figure
1;
117).
Various
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benzylsulfinates (15, 7 and 8) were tolerated, giving rise to -
disubstituted allylic sulfones in good yields and with high
enantioselectivity including those bearing aryl groups with para
(15), meta (7) and ortho (8) substitutions. Importantly, various
alkylsulfinate salts showed effective reactivity and provided the
desired branched allylic sulfone products with high er values (6,
917) unlike in previous reports.[5] The allylic sulfone products
containing ester and trifluoromethyl groups (6 and 16) were also
analysis (see insert).[15] The reaction leading to product 2a could
be scaled up to 3.0 mmol without any significant erosion of the
process outcome (647 mg, 75% yield, 95:5 er). The protocol
proved to be rather efficient for various other reaction partners,
and the use of a wide range of allylic carbonates was feasible
providing access to enantioenriched -disubstituted allylic
sulfones 1835 in moderate to good yields along with high levels
of regio- and enantioselectivities. Substrates exerting different
obtained in good yields with 93.5:6.5 er and 92.8 er, respectively. steric and electronic effects were tolerated with the use of meta-
Substrates with methyl (10), ethyl (11), n-butyl (19), isobutyl (17)
and longer alkyl chains (13) were also productive reaction
partners and afforded the chiral allylic sulfone products with high
levels of enantioinduction. The installation of three-, five-, and
six-membered rings (12, 14 and 15) was easily accomplished
without eroding the overall reactivity/enantioinduction. Notably,
all the reactions proceeded with excellent regioselectivity
typically being >95:5 in favor of the branched product.
substituted -aryl allylic precursors providing typically better
enantio-control. The presence of a bulky naphthyl or heterocyclic
groups did not reduce the efficiency of the catalytic protocol (20,
34 and 35), while the installation of a 1,3-benzodioxole fragment
(22; 85% yield, 93:7 er) of importance in pharmaceutical
development[16] was also endorsed.
Figure 1. Scope in sodium sulfinates; reactions were performed under the
optimized conditions (Table 1, entry 20). Isolated yields are reported, and er
values were determined by SFC (supercritical fluid chromatography). [a] 72 h.
[b] 60 h. [c] [Pd] (2.5 mol %), L10 (10 mol %), THF (1.0 mL). [d] 96 h. [e] [Pd]
(4 mol %), L10 (12 mol %), 2-Me-THF (0.80 mL). [f] [Pd] (5.0 mol %), L10 (20
mol %), 2-Me-THF (0.80 mL).
Figure 2. Scope in tertiary allylic carbonates; reactions were performed under
the optimized conditions (Table 1, entry 20). Isolated yields are reported, and
er values were determined by SFC. [a] 72 h. [b] 60 h. [c] 96 h.
We then focused on investigating the scope of the tertiary
allylic precursors (Figure 2). The absolute configuration of chiral
allylic sulfone 2a (S) was unambiguously confirmed by X-ray
The developed method was unsatisfactory with tertiary allylic
carbonates bearing ortho-substituents on the aryl group even at
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higher reaction temperatures, indicating some (steric) limitation
of the present methodology. Alkyl substituted carbonates also
seem to be suitable reaction partners as demonstrated by the
preparation of 24 (67%) although with substantial lower
enantioselectivity (64.5:35.5 er). When the Me substituent in the
allylic precursor was replaced by an Et or iPr group, exclusive
In summary, we present herein the first general regio- and
enantioselective synthesis of ,-allylic sulfones featuring
quaternary stereocenters based on Pd-catalyzed allylic
sulfonylation. Crucial in the developed protocol is the presence
of a new phosphoramidite ligand L10 that is able to overcome
simultaneously the intrinsic challenge of achieving both high
formation of a linear allylic sulfone product in 47% and 34% yield, regio- and enantio-control. The ligand optimization studies
respectively, was noted (see the SI for details).
illustrate the delicate balance between the location of the steric
impediment and its influence on the reaction outcome. Our
methodology is characterized by a wide scope of chiral allylic
sulfone scaffolds, excellent regio-selectivity and high enantio-
induction, and user-friendly conditions. The formal synthesis of
(−)-Agelasidine A supports the view that these chiral allylic
sulfones hold great promise as synthetic building blocks,
amplifying the repertoire of nucleophiles in challenging allylic
substitution reactions.
To further challenge this new asymmetric protocol, the regio-
and enantioselective synthesis of -disubstituted aryl allylic
sulfones was probed (Figure 3). By re-optimization of the
reaction conditions (SI: see Table S2 for details), a series of
arylsulfinate nucleophiles and tertiary allylic carbonates were
successfully employed in our process by using phosphoramidite
ligand L4 giving access to allylic sulfones 3643. Notably, the
introduction of bulky naphthyl and heteroaryl groups could be
accomplished (39, 41 and 43) and the chiral sulfones were
isolated in good yields and with appreciable enantioselectivity.
Figure 3. Scope of products obtained by combining different allylic precursors
and arylsulfinates. Conditions: allylic precursor (0.15 mmol), arylsulfinate (0.18
mmol, 1.2 equiv), [Pd] (2.5 mol %), L4 (10 mol %), THF (0.4 mL), 0 ºC, open
to air, 12 h. Isolated yields are reported, and er values were determined by
SFC. [a] arylsulfinate (0.23 mmol, 1.5 equiv), [Pd] (4 mol %), L4 (16 mol %).
Scheme 2. Additional synthetic transformations from 2a/1b: (i) m-CPBA (4.0
equiv), DCM. (ii) 9-BBN (3.0 equiv), THF, 60 oC to rt, then EtOH, NaOH, H2O2
(30%), rt. (iii) PhI(OAc)2 (2.0 equiv), TEMPO (30 mol %), CH3CN/H2O (1:1).
(iv) NaH, EtOH, NH2C(=NH)NH2·HCl, 1,4-dioxane, rt; see the SI for more
details.
Synthetic transformations of allylic sulfone 2a were
performed to demonstrate the utility of the newly developed
building blocks. Oxidation of 2a with 3-chloroperbenzoic acid
smoothly led to epoxide 4a in 93% yield while retaining the
enantiopurity (Scheme 2a). Hydroboration of 2a with 9-
borabiclo-(3.3.1)nonane (9-BBN) and oxidative work-up
furnished -sulfonyl alcohol 5a, which upon oxidation by
PhI(OAc)2 and TEMPO gave -sulfonyl acid 6a in 67% yield
(Scheme 2b, 95.5:4.5 er). In addition, we focused on the formal
synthesis of ()-Agelasidine A, which is a natural sesquiterpene
that was isolated from marine sponges of the genus Agelas and
has antifungal and antimicrobial activity.[8c,17] To achieve the
synthesis of this target molecule using allylic sulfonylation as a
key step, treatment of allylic carbonate 1b with alkylsulfinate 1c
under the optimized reaction conditions (Table 1, entry 20) was
performed. The enantioenriched allylic sulfone 1d was isolated
in 62% yield (82:12 er, Scheme 2c). Following a previous
report,[18] ()-Agelasidine A could be obtained in 65% yield from
sulfone 1d in the presence of excess guanidine.
Acknowledgements
We thank the CERCA Program/Generalitat de Catalunya,
ICREA, and the Spanish MINECO (CTQ-2014–60419-R) and
AGAUR (2017-SGR-232) for financial support. Dr. Eduardo C.
Escudero-Adán is thanked for measuring the X-ray molecular
structure of 2a. A.C. thanks MINECO for a FPI predoctoral
fellowship. We also acknowledge Prof. Baoguo Zhao and Prof.
Yian Shi for providing the procedure for the preparation of L5
and L6.
Keywords: allylic sulfones • enantioselectivity • homogeneous
catalysis • palladium • regioselectivity
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10.1002/anie.201908318
Angewandte Chemie International Edition
COMMUNICATION
Ichikawa, T. Kashiwagi, N. Urano, A. J. Chem. Soc., Perkin Trans. 1
1992, 1, 1497.
This article is protected by copyright. All rights reserved.

10.1002/anie.201908318
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents:
COMMUNICATION
Chiral sulfones moving forward:
Aijie Cai and Arjan W. Kleij*
The
first
general,
Pd-catalyzed
asymmetric synthesis of elusive -
disubstituted allylic sulfones has been
realized. This process is based on a
Tsuji-Trost allylic alkylation using both
Page No. – Page No.
alkyl-
and
arylsulfinate
and
based
new
nucleophiles
a
phosphoramidite ligand. The new
protocol features ample scope in
sulfone products, good yields and high
enantioinduction with er´s of up to
95:5. The developed protocol was
successfully applied to the formal
synthesis of the sesquiterpene ()-
Agelasidine A.
Regio- and Enantioselective
Preparation of Chiral Allylic
Sulfones Featuring Elusive
Quaternary Stereocenters
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