An asymmetric allylic alkylation-smiles rearrangement-sulfinate addition sequence to construct chiral cyclic sulfones

Article abstract of DOI:10.1021/ol402158u

An asymmetric allylic alkylation of Morita-Baylis-Hillman carbonates and β-keto sulfones was investigated by the catalysis of modified cinchona alkaloids, whose products underwent a Smiles rearrangement-sulfinate addition cascade to furnish highly functionalized five-membered cyclic sulfones in moderate to excellent enantioselectivity and good diastereoselectivity after treatment with DBU.

Full text of DOI:10.1021/ol402158u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
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An Asymmetric Allylic AlkylationꢀSmiles
RearrangementꢀSulfinate Addition
Sequence to Construct Chiral Cyclic Sulfones
Quan-Gang Wang,† Qing-Qing Zhou,† Jin-Gen Deng,† and Ying-Chun Chen*,†,‡
Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of
Education, West China School of Pharmacy, and State Key Laboratory of Biotherapy,
West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China, and College
of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China
ycchen@scu.edu.cn
Received July 30, 2013
ABSTRACT
An asymmetric allylic alkylation of MoritaꢀBaylisꢀHillman carbonates and β-keto sulfones was investigated by the catalysis of modified
cinchona alkaloids, whose products underwent a Smiles rearrangementꢀsulfinate addition cascade to furnish highly functionalized
five-membered cyclic sulfones in moderate to excellent enantioselectivity and good diastereoselectivity after treatment with DBU.
Chiral cyclic sulfones are the key scaffolds in a number
of pharmaceutically important compounds and natural
products as those exemplified in Figure 1,1 which exhibit
broad biological activities such as inhibiting HIV-1 pro-
tease, hepatitis C virus, influenza neuraminidase, and
human carbonic anhydrase II, etc. They have also been
to chiral olefins.3 Although an array of catalytic protocols
have been developed for the construction of acyclic chiral
sulfones,4 production of chiral cyclic sulfones remains a
challenging problem, and most reported methodologies rely
on utilizing chiral starting materials.5 To the best of our
knowledge, the catalytic versions of chiral cyclic sulfones are
very limited up to date, except that a notable example was
presented by Anderson and co-workers through Ir-catalyzed
asymmetric hydrogenation of prochiral unsaturated cyclic
sulfones.6
Recently, an asymmetric allylic alkylation (AAA) reac-
tion with racemic MoritaꢀBaylisꢀHillman (MBH) carbo-
nates or acetates catalyzed by a chiral tertiary amine or
phosphine has provided an efficient approach to produce
multifunctional chiral compounds, which could be further
applied to synthesize diverse cyclic frameworks.7 In our
utilized as versatile intermediates in diverse synthetic
2
€
transformations, suchasRambergꢀBacklund rearrangement
† Sichuan University
‡ Third Military Medical University
(1) (a) Ghosh, A. K.; Thompson, W. J.; Fitzgerald, P. M. D.;
Culberson, J. C.; Axel, M. G.; McKee, S. P.; Huff, J. R.; Anderson, P. S.
J. Med. Chem. 1994, 37, 2506. (b) Kim, C. U.; McGee, L. R.; Krawczyk,
S. H.; Harwood, E.; Harada, Y.; Swaminathan, S.; Bischofberger, N.;
Chen, M. S.; Cherrington, J. M.; Xiong, S. F.; Griffin, L.; Cundy, K. C.;
Lee, A.; Yu, B.; Gulnik, S.; Erickson, J. W. J. Med. Chem. 1996, 39, 3431. (c)
ꢀ
Velazquez, F.; Sannigrahi, M.; Bennett, F.; Lovey, R. G.; Arasappan, A.;
Bogen, S.; Nair, L.; Venkatraman, S.;Blackman, M.; Hendrata, S.; Huang,
Y.; Huelgas, R.; Pinto, P.; Cheng, K.-C.; Tong, X.; McPhail, A. T.;
Njoroge, F. G. J. Med. Chem. 2010, 53, 3075. (d) Brant, M. G.; Wulff,
J. E. Org. Lett. 2012, 14, 5876.
(5) For selected examples, see: (a) Ghosh, A. K.; Liu, W. J. Org. Chem.
€
1995, 60, 6198. (b) Otten, S.; Frohlich, R.; Haufe, G. Tetrahedron:
(2) (a) Prilezhaeva, E. N. Russ. Chem. Rev. 2000, 69, 367. (b)
Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(3) (a) Paquette, L. A. Org. React. 1977, 25, 1. (b) Paquette, L. A. Acc.
Chem. Res. 1968, 1, 209.
Asymmetry 1998, 9, 189. (c) Waser, M.; Haunschmidt, M.; Himmelsbach,
ꢁ
M. Monatsh. Chem. 2010, 141, 1347. (d) Cere, V.; Peri, F.; Pollicino, S.
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Tetrahedron Lett. 1997, 38, 7797. (e) Cere, V.; Mantovani, G.; Peri, F.;
Pollicino, S.; Rici, A. Tetrahedron 2000, 56, 1225.
(6) Zhou, T.-G.; Peters, B.; Maldonado, M. F.; Govender, T.;
Andersson, P. G. J. Am. Chem. Soc. 2012, 134, 13592.
(7) For reviews, see: (a) Liu, T.-Y.; Xie, M.; Chen, Y.-C. Chem. Soc.
Rev. 2012, 41, 4101. (b) Rios, R. Catal. Sci. Technol. 2012, 2, 267.
(4) For reviews, see: (a) Nielsen, M.; Jacobsen, C. B.; Holub, N.;
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Paixao, M. W.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2010, 49, 2668.
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(b) Alba, A. N. R.; Companyo, X.; Rios, R. Chem. Soc. Rev. 2010, 39,
2018.
r
10.1021/ol402158u
XXXX American Chemical Society

cyclic sulfones in a quite straightforward and efficient
manner, as outlined in Scheme 1.
Scheme 1. Allylic AlkylationꢀSmiles Rearrange-
mentꢀSulfinate Addition Sequence to Cyclic Sulfones
Figure 1. Biologically active compounds containing a cyclic
sulfone motif.
continuing efforts to expand this catalytic strategy,8 we are
interested in the assembly of MBH carbonates 1 and
nucleophilic β-keto sulfones 2 containing a benzothiazol-
2-yl moiety.9 It was revealed that the alkylation intermedi-
ate 3 from the catalysis of DABCO (1,4-diazabicyclo-
[2.2.2]-octane) could undergo an intramolecular Smiles
rearrangement10 in the presence of a stronger base such
as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). In contrast
to the usual elimination of one molecular SO2 that involves
in JuliaꢀKocienski-type reaction,9,11 the in situ generated
sulfinate anion12 of intermediate II attacks R,β-unsaturated
carbonyl system, furnishing multifunctional five-membered
After discovering this interesting reaction sequence, we
systematically investigated the asymmetric allylic alkylation
of β-keto sulfones 2a with MBH carbonates 1a catalyzed by
modified cinchona alkaloid in order to access chiral sulfone
4a.7,8 Commercially available (DHQD)2PYR (20 mol %)
exhibited acceptable catalytic activity at 50 °C in 1,2-di-
chloroethane (DCE). A trace amount of cyclic sulfone
product 4a was detected under such asymmetric catalytic
conditions, while full conversion of allylic alkylation inter-
mediate 3a to 4a could be realized after treatment with DBU
in toluene at ambient temperature. Good diastereoselectivity
(5.7:1) was observed for the crude cyclic sulfone product,13
while the pure major diastereomer anti-4a could be smoothly
separated in moderate yield and with modest enantioselec-
tivity (Table 1, entry 1). Subsequently, a few solvents were
screened (entries 2ꢀ7) for AAA reaction, and better results
were attained in toluene (entry 6). (DHQD)2PHAL gave the
similar data (entry 8); pleasingly, higher yield and enantios-
electivity were gained by using (DHQD)2AQN as the catalyst
(entry 9). (DHQ)2AQN produced the product with an
opposite configuration to that of (DHQD)2AQN, but only
a fair ee value was obtained (entry 10). The reaction could be
significantly accelerated at higher 70 °C catalyzed by
(DHQD)2AQN, while both isolated yield and ee were
slightly reduced for product 4a (entry 11). On the other hand,
sulfones 2 with other substitutions, such as N-phenyltetra-
zole, were also investigated, but either inferior results were
given or the later Smiles rearrangement could not be pro-
moted by adding DBU.14
(8) For selected examples, see: (a) Cui, H.-L.; Peng, J.; Feng, X.; Du,
W.; Jiang, K.; Chen, Y.-C. Chem.;Eur. J. 2009, 15, 1574. (b) Cui, H.-L.;
Feng, X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y.-C. Angew. Chem., Int. Ed.
2009, 48, 5737. (c) Huang, J.-R.; Cui, H.-L.; Lei, J.; Sun, X.-H.; Chen,
Y.-C. Chem. Commun. 2011, 47, 4784. (d) van Steenis, D. J. V. C.;
Marcelli, T.; Lutz, M.; Spek, A. L.; van Maarseveen, J. H.; Hiemstra, H.
Adv. Synth. Catal. 2007, 349, 281. (e) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M.
J. Am. Chem. Soc. 2008, 130, 7202. (f) Ma, G.-N.; Cao, S.-H.; Shi, M.
Tetrahedron: Asymmetry 2009, 20, 1086. (g) Sun, W.; Hong, L.; Liu, C.;
Wang, R. Org. Lett. 2010, 12, 3914. (h) Yang, W.; Wei, X.; Pan, Y.; Lee,
R.; Zhu, B.; Liu, H.; Yan, L.; Huang, K.-W.; Jiang, Z.; Tan, C.-H.
Chem.;Eur. J. 2011, 17, 8066. (i) Lin, A.; Mao, H.; Zhu, X.; Ge, H.;
Tan, R.; Zhu, C.; Cheng, Y. Chem.;Eur. J. 2011, 17, 13676.
(j) Furukawa, T.; Nishimine, T.; Tokunaga, E.; Hasegawa, K.; Shiro,
M.; Shibata, N. Org. Lett. 2011, 13, 3972. (k) Mao, H.; Lin, A.; Shi, Y.;
Mao, Z.; Zhu, X.; Li, W.; Hu, H.; Cheng, Y.; Zhu, C. Angew. Chem., Int.
Ed. 2013, 52, 6288.
~
(9) (a) Nielsen, M.; Jacobsen, C. B.; Paixao, M. W.; Holub, N.;
~
Jørgensen, K. A. J. Am. Chem. Soc. 2009, 131, 10581. (b) Paixao, M. W.;
Holub, N.; Vila, C.; Nielsen, M.; Jørgensen, K. A. Angew. Chem., Int.
~
Ed. 2009, 48, 7338. (c) Holub, N.; Jiang, H.; Paixao, M. W.; Tiberi, C.;
Jørgensen, K. A. Chem.;Eur. J. 2010, 16, 4337. (d) Jacobsen, C. B.;
Nielsen, M.; Worgull, D.; Zweifel, T.; Fisker, E.; Jørgensen, K. A. J. Am.
Chem. Soc. 2011, 133, 7398. (e) Jacobsen, C. B.; Jensen, K. L.; Udmark,
J.; Jørgensen, K. A. Org. Lett. 2011, 13, 4790.
With the optimal conditions in hand, an array of MBH
carbonates and β-keto sulfones containing a benzothiazol-2-yl
moiety were explored. The AAA reactions were conducted in
toluene catalyzed by 20 mol % of (DHQD)2AQN at 50 °C.
Then intermediates 3 were isolated, and subsequent Smiles
rearrangementꢀsulfinate addition cascade was promoted by
(10) Warren, L. A.; Smiles, S. J. Chem. Soc. 1930, 1327.
(11) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O.
Tetrahedron Lett. 1991, 32, 1175. (c) Blakemore, P. R. J. Chem. Soc.,
Perkin Trans. 1 2002, 2563. (d) Aissa, C. Eur. J. Org. Chem. 2009, 1831.
(e) Zhao, Y.; Huang, W.; Zhu, L.; Hu, J. Org. Lett. 2010, 12, 1444.
(12) (a) Prakash, G. K. S.; Ni, C.-F.; Wang, F.; Hu, J.-B.; Olah, G. A.
Angew. Chem., Int. Ed. 2011, 50, 2559. (b) Kuwano, R.; Kondo, Y.;
Shirahama, T. Org. Lett. 2005, 7, 2973. (c) Pinnick, H. W.; Reynolds,
M. A. J. Org. Chem. 1979, 44, 160. (d) Wu, X.-S.; Chen, Y.; Li, M.-B.;
Zhou, M.-G.; Tian, S.-K. J. Am. Chem. Soc. 2012, 134, 14694.
(13) The similar dr values (about 5:1) were observed in DCM or
THF.
(14) For more details, see the Supporting Information.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Screening of Conditions for AAAꢀSmiles Rearrange-
mentꢀSulfinate Addition with MBH Carbonate 1a and β-Keto
Sulfone 2aa
Table 2. Substrate Scope for AAAꢀSmiles Rearrange-
mentꢀSulfinate Addition with MBH Carbonates 1 and β-Keto
Sulfones 2a
t (h)b yield (%)c ee (%)d
entry
R1
R3
t (h)b drc yield (%)d ee (%)e
entry
cat.
solvent
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
65 5.7:1 4a, 82
72 5.7:1 4b, 74
72 6.0:1 4c, 80
72 6.0:1 4d, 75
65 6.0:1 4e, 80
65 6.0:1 4f, 78
72 5.7:1 4g, 72
96 5.7:1 4h, 83
96 5.7:1 4i, 78
96 6.0:1 4j, 72
72 6.0:1 4k, 78
65 5.0:1 4l, 65
72 6.0:1 4m, 68
90
96
94
92
89
88
91
93
93
92
96
88
91
52
89
86
90
91
90
84
96
1
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
DCE
65
70
72
85
90
70
50
67
65
96
32
67
72
20
67
65
73
80
75
82
70
77
70
70
2
2-ClC6H4
2-BrC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
2
CHCl3
CH3CN
THF
3
3
79
4
4
75
5
5
dioxane
toluene
PhCF3
75
6
6
79
7f
8
3,4-Cl2C6H3 Ph
7
76
3-MeC6H4
4-MeC6H4
Ph
Ph
8
(DHQD)2PHAL toluene
78
9
9
(DHQD)2AQN
(DHQ)2AQN
(DHQD)2AQN
toluene
toluene
toluene
90
10
11
12
13
14
15
16
17
4-MeOC6H4 Ph
2-naphthyl Ph
10
11e
ꢀ46
88
2-furyl
2-thienyl
n-propyl
Ph
Ph
Ph
Ph
a Unless noted otherwise, reactions were performed with 0.2 mmol of
1a, 0.1 mmol of 2a, 20 mol % of cat. in 0.5 mL of solvent at 50 °C. Then
the intermediate was isolated and treated with DBU in toluene at room
temperature for 8 h. b For AAA step. c Isolated yield for two steps. d By
chiral HPLC analysis. e At 70 °C. (DHQD)2PYR: hydroquinidine 2,5-
diphenyl-4,6-pyrimi-dinediyl diether; (DHQD)2PHAL: hydroquinidine
1,4-phthalazinediyl diether; (DHQD)2AQN: hydroquinidine anthrax-
quinone-1,4-diyl diether; (DHQ)2AQN: hydroquinine anthraxquinone-
1,4-diyl diether.
96 19:1
4n, 45
4-ClC6H4
3-BrC6H4
4-MeC6H4
60 6.0:1 4o, 70
96 6.0:1 4p, 76
96 6.0:1 4q, 72
Ph
Ph
18f Ph
19f Ph
2-naphthyl 96 6.0:1 4r, 78
2-thienyl
Me
72 5.0:1 4s, 70
96 6.0:1 4t, 65
72 6.0:1 4u, 75
20
21g Ph
Ph
Ph
DBU in toluene at ambient temperature. Such two reactions
could not be carried out in a one-pot procedure, because DBU
would catalyze the allylic alkylation of a small amount of
remaining MBH carbonates and β-keto sulfones, which would
significantly decrease the ee values of the final cyclic sulfone
products. The results are summarized in Table 2. In general,
MBH carbonates bearing a variety of aryl or heteroaryl
groups could be well tolerated. The similar diastereoselectivity
was observed in the crude sulfone mixtures, and the major
anti-isomers could be separated in moderate to good yields
and with high enantioselectivity (Table 2, entry 1ꢀ13). Never-
theless, a MBH carbonate with an alkyl group exhibited much
lower reactivity. Although excellent diastereoselecvitiy was
observed in the cyclization, the corresponding cyclic sulfone
4n was obtained in low yield and enantioselectivity (entry 14).
On the other hand, it was found that β-keto counterparts with
diverse aryl or heteroaryl groups could be smoothly applied
(entries 15ꢀ19), and good data was still delivered for a simple
methyl-substituted one (entry 20). Finally, a MBH carbonate
derived from methyl vinyl ketone was tested, and product 4u
was isolated in good yield and with excellent enantioselectivity
(entry 21).
a Unless noted otherwise, reactions were performed with 0.2 mmol of
MBH carbonate 1 derived from methyl acrylate, 0.1 mmol of β-keto
sulfone 2, 20 mol % of (DHQD)2AQN in 0.5 mL of toluene at 50 °C.
Then the intermediate was isolated and treated with DBU in toluene at
room temperature for 8 h. b For AAA step. c Determined by 1H NMR
analysis of the crude product. d Isolated yield for two steps. e By chiral
HPLC analysis. f At 30 °C. g R2 = Me.
As outlined in Figure 2, single crystals suitable for X-ray
crystallographic analysis were fortunately obtained from
enantiopure anti-4j; thus, its chemical structure and abso-
lute configuration could be unambiguously determined.
It was pleasing that the benzothiazol-2-yl moiety of
products 4 could be smoothly removed. As illustrated in
Scheme 2, the alkenyl ether group of 4j was efficiently
Figure 2. X-ray structure of enantiopure anti-4j.
Org. Lett., Vol. XX, No. XX, XXXX
C

intramolecular Smiles rearrangement by subsequent treat-
ment with organic base DBU, and an unusual intramolecular
sulfinate addition was followed to give cyclic sulfone pro-
ducts with dense functionalities in high enantioselectivity and
with good diastereoselectivity. The benzothiazol-2-yl moiety
could be efficiently removed in a traceless manner; thus, the
reported sequence provides a formal [3 þ 2] annulation
process to construct useful five-membered cyclic sulfones
from readily available starting materials. More results will be
reported in due course.
Scheme 2. Hydrolysis of Alkenyl Ether Group
Acknowledgment. We are grateful for the financial
support from the NSFC (21125206 and 21021001), and
the National Basic Research Program of China (973
Program, 2010CB833300).
hydrolyzed by p-TsOH in methanol at 70 °C, cleanly
producing cyclic sulfone 5 with exclusive diastereoselec-
tivity and retained enantiopurity. The relative configura-
tion of the newly formed chiral center could be assigned by
NOE analysis.14 The multifunctionalities of 5 might pro-
vide more opportunities for organic synthesis.
In conclusion, we have investigated the asymmetric
allylic alkylation of β-keto benzothiazol-2-yl sulfones with
MoritaꢀBaylisꢀHillman carbonates catalyzed by modified
cinchona alkaloids. The chiral intermediates underwent
Supporting Information Available. Experimental pro-
cedures, structural proofs, NMR spectra and HPLC
chromatograms of the products, CIF file of enantiopure
anti-4j. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX