Organocatalytic domino reaction of cyanosulfones: Access to complex cyclohexane systems with quaternary carbon centers

Article abstract of DOI:10.1021/ol400356k

When ε-nitro-α,β-unsaturated esters are added to conjugated cyanosulfones in the presence of a bifunctional thiourea catalyst, a highly stereoselective domino reaction occurs to generate complex cyclohexanes with up to four stereogenic centers, one of whi

Full text of DOI:10.1021/ol400356k

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1386–1389
Organocatalytic Domino Reaction of
Cyanosulfones: Access to Complex
Cyclohexane Systems with Quaternary
Carbon Centers
Sundaram Rajkumar,† Kenneth Shankland,† Jonathan M. Goodman,‡ and
Alexander J. A. Cobb*,†
School of Chemistry, Food and Pharmacy (SCFP), University of Reading,
Whiteknights, Reading, Berks RG6 6AD, U.K., and Unilever Centre for Molecular
Science Informatics, Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge CB2 1EW, U.K.
a.j.a.cobb@reading.ac.uk
Received February 6, 2013
ABSTRACT
When ε-nitro-r,β-unsaturated esters are added to conjugated cyanosulfones in the presence of a bifunctional thiourea catalyst, a highly
stereoselective domino reaction occurs to generate complex cyclohexanes with up to four stereogenic centers, one of which is quaternary in
nature. Therefore, it is demonstrated that, like nitro compounds, sulfones can undergo an asymmetric intramolecular conjugate addition to r,β-
unsaturated esters in the presence of a bifunctional organocatalyst.
Cascade reactions, which can construct multiple bonds
and lead to complex molecules in a single step, are of great
interest to the synthetic community.1 Such reactions can
have many advantages, as they are atom-economical2 and
have reduced synthetic steps, minimizing the amount of
purification required and removing the need for protecting
group strategies. Highly functionalized cyclohexane rings
are a class of molecules whose synthesis has benefited from
this cascade approach.3 These systems are ubiquitous in
nature and, as such, are important medicinal and agro-
chemical targets. Of particular note in recent times is the
use of asymmetric organocatalysis in cascade chemistry,
which has contributed toward the synthesis of an impress-
ive diversity of complex structures.4
Recent work in our laboratories has focused on the use
of bifunctional organocatalysts in the stereoselective addition
of nitronates to conjugated esters to generate enantiopure
cyclohexane systems. We have achieved this in both a
direct manner5a and within a cascade process involving
sequential Michael additions, where we demonstrated the
use of this methodology toward the synthesis of lycorane-like
† University of Reading.
‡ University of Cambridge.
(1) See: (a) Pellissier, H. Adv. Syn. Catal. 2012, 354, 237. (b) Tietze,
L. F.; Brasche, G.; Gericke, K. M. In Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2006.
(2) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. 1995, 107, 258.
(3) For recent examples of the use of domino reactions towards the
synthesis (both organocatalytic and nonorganocatalytic) of complex
cyclohexanes, see: (a) Mao, Z. F.; Jia, Y. M.; Xu, Z. Q.; Wang, R. Adv.
Synth. Catal. 2012, 354, 1401. (b) Shi, D. J.; Xie, Y. J.; Zhou, H.; Xia,
C. G.; Huang, H. M. Angew. Chem., Int. Ed. 2012, 51, 1248. (c) Shen, H.;
Yang, K. F.; Shi, Z. H.; Jiang, J. X.; Lai, G. Q.; Xu, L. W. Eur. J. Org.
Chem. 2011, 5031. (d) Zhang, B.; Cai, L. C.; Song, H. B.; Wang, Z. H.;
He, Z. J. Adv. Synth. Catal. 2010, 352, 97. (e) Tan, B.; Chua, P. J.; Li,
Y. X.; Zhong, G. F. Org. Lett. 2008, 10, 2437. (f) Corbu, A.; Gauron, G.;
Castro, J. M.; Dakir, M.; Arseniyadis, S. Org. Lett. 2007, 9, 4745. (g)
Hong, B.-C.; Liao, W.-K.; Dange, N. S.; Liao, J.-H. Org. Lett. 2013, 15,
€
468. See also: (h) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe, G.
Nature 2006, 441, 861 (refs 5 and 6).
r
10.1021/ol400356k
Published on Web 03/05/2013
2013 American Chemical Society

structures.6 Pleasingly, others have since utilized our ap-
proach in the synthesis of a range of related lycoranes.7 As
a further extension of our work, we decided to explore the
use of conjugated cyanosulfones 2 as an initial Michael
acceptor. We hypothesized that addition of nitro com-
pound 1 to such a substrate would reveal a catalyst-bound
C-nucleophile for a subsequent and final asymmetric
ring-closing Michael addition. We further hypothesized
that catalyst activation would occur in the same way as we
have previously proposed,5a,6 whereby one of the thiourea
nitrogens would activate the electrophile and the other, in
tandem with the nitrogen of the protonated amine, would
activate the nucleophile (Figure 1).8 The resulting sul-
fones are synthetically useful compounds and can be
further modified in a number of ways.9 Our initial system
for screening started with the simple nitro compound 1
and the conjugated cyanosulfone 2a. Using a range of
bifunctional thiourea catalysts,10 we were gratified to see
that the expected transformation occurred (Table 1, en-
tries 1À6), and it was determined that catalyst 8 gave the
most promising overall results in terms of balance be-
tween yield, diastereoselectivity, and enantioselectivity
(entry 5). Using this catalyst, we found that changing
the solvent had a profound effect on enantioselectivity
(entries 7À12), and among those tested, diethyl ether was
found to give optimal results. Decreasing the temperature
(entries 13À15), however, had a detrimental effect on the
enantioselectivity, and surprisingly, catalyst loading ap-
peared to have little influence on the overall outcome of
the process (entries 16À19).
Table 1. Optimization of the Domino Reaction
Figure 1. Domino reaction with conjugated cyanosulfones: con-
cept and proposed transition state.
(4) For selected reviews, see: (a) Walji, A. M.; MacMillan, D. W. C.
€
Synlett 2007, 1477. (b) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew.
Chem., Int. Ed. 2007, 46, 1570. (c) Dondoni, A.; Massi, A. Angew. Chem.,
Int. Ed. 2008, 47, 4638. (d) MacMillan, D. W. C. Nature 2008, 455, 304.
(e) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.;
Jørgensen, K. A. Chem. Commun. 2011, 47, 632. (f) Cobb, A. J. A. In
Enantioselective Organocatalyzed Reactions II; Mahrwald, R., Ed.;
Springer-Verlag: Weinheim, 2011; Chapter 1. (g) Grondal, C.; Jeanty, M.;
Enders, D. Nat. Chem. 2010, 2, 167. For recent examples, see: (h)
Albertshofer, K.; Anderson, K. E.; Barbas, C. F., III. Org. Lett. 2012,
5968. (i) Wan, J.-P.; Loh, C. C. J.; Pan, F.; Enders, D. Chem. Commun.
2012, 48, 10049. (j) Rubush, D. M.; Morges, M. A.; Rose, B. J.; Thamm,
D. H.; Rovis, T. J. Am. Chem. Soc. 2012, 134, 13554. (k) Dong, X.-Q.;
Fang, X.; Tao, H.-Y.; Zhou, X.; Wang, C.-J. Chem. Commun. 2012,
7238. (l) Barber, D. M.; Sanganee, H. J.; Dixon, D. J. Org. Lett. 2012, 14,
5290. (m) Xie, X.; Peng, C.; He, G.; Leng, H. J.; Wang, B. A.; Huang, W.;
Han, B. Chem. Commun. 2012, 48, 10487. (n) Coulthard, G.; Erb, W.;
Aggarwal, V. K. Nature 2012, 489, 278. (o) Roy, S.; Chen, K. Org. Lett.
2012, 14, 2496. (p) Albertshofer, K.; Tan, B.; Barbas, C. F., III. Org.
Lett. 2012, 14, 1834.
(5) (a) Nodes, W. J.; Nutt, D. R.; Chippindale, A. M.; Cobb, A. J. A.
J. Am. Chem. Soc. 2009, 131, 16016. (b) Nodes, W. J.; Rajkumar, S.;
Shankland, K.; Cobb, A. J. A. Synlett 2010, 3011. For alternative
methods to synthesise the substrates described in ref 5a, see: (c) Guo,
L.; Chi, Y. G.; Almeida, A. M.; Guzei, A.; Parker, B. K.; Gellman, S. H.
J. Am. Chem. Soc. 2009, 131, 16018. (d) Xu, Y. J.; Lin, L. Q.; Kanai, M.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2011, 133, 5791.
(6) Rajkumar, S.; Shankland, K.; Brown, G. D.; Cobb, A. J. A.
Chem. Sci. 2012, 3, 584.
entry catalyst (mol %) solvent temp, °C % yielda drb eec,d (%)
1e
2e
3e
4
4 (10)
5 (10)
6 (10)
7 (10)
8 (10)
9 (10)
8 (10)
8 (10)
8 (10)
8 (10)
8 (10)
8 (10)
8 (10)
8 (10)
8 (10)
8 (1)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
20
20
97
99
94
97
99
97
99
94
98
92
94
87
64
66
61
42
92
92
97
10:3
4:1
46
57
46
65
68
69
72
78
78
70
55
38
68
68
70
77
78
78
77
20
2.7:1
25:4
25:4
11:2
25:4
25:4
25:6
25:4
5:1
20
5
20
6
20
7
20
8
Et2O
20
9
PhMe
THF
20
10
11
12
13f
14f
15f
16
17
18
19
20
MeCN
MeOH
CH2Cl2
Et2O
20
20
25:4
25:9
25:9
25:6
25:7
5:1
À40
À40
À40
20
PhMe
Et2O
8 (5)
Et2O
20
(7) Wang, Y.; Luo, Y.-C.; Zhang, H.-B.; Xu, P.-F. Org. Biomol.
Chem. 2012, 10, 8211.
(8) A computational study by Wang and co-workers has added
credence to this argument. See: Zhu, J.-L.; Zhang, Y.; Liu, C.; Zheng,
A.-M.; Wang, W. J. Org. Chem. 2012, 77, 9813.
8 (20)
8 (30)
Et2O
20
25:4
25:3
Et2O
20
a Based on isolated product. b Determined by 1H NMR spectros-
copy. The minor diastereosiomer was found to be the (1R)-epimer.
c Determined by HPLC using a chiral stationary phase. d Absolute
configuration determined by Cu-source X-ray crystallography of 3j
and ascribed by analogy. e ent-3a was produced. f Reaction stopped after
7.5 days.
(9) (a) Simpkins, N. S. In Sulphones in Organic Synthesis
(Tetrahedron Organic Chemistry Series; Pergamon Press: Oxford, 1993;
Vol. 10. For reviews on the use of sulfones in organocatalysis, see: (b)
~
Nielsen, M.; Jacobsen, C. B.; Holub, N.; Paixao, M. W.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2010, 49, 2668. (c) Alba, A.-N. R.;
ꢀ
Companyo, X.; Rios, R. Chem. Soc. Rev. 2010, 39, 2018.
Org. Lett., Vol. 15, No. 6, 2013
1387

reaction with nitroester 1 and were pleased to find that
they all exhibited good reactivity (Scheme 1). Most
satisfyingly, however, was our observation that the en-
antiomeric excess could be enhanced significantly by a
single recrystallization. Our recrystallization of the cyclo-
hexane adduct 3j gave an enantiopure crystal that was
subjected to single-crystal X-ray analysis, which allowed
the absolute configuration to be assigned (Figure 2).11
The absolute stereochemical configurations of the other
products were assigned by analogy with this analysis.
Scheme 1. Enantioselective Cascade: Cyanosulfone Scope
Figure 2. Molecular structure of 3j, with absolute stereochem-
istry as determined by X-ray crystallography.11
The diastereomeric ratio for all substrates was fairly
similar, being around 5:1, wherein it was found that the
minor diastereoisomer was the (1R)-epimer, which pre-
sumably results from the conjugated ester presenting its
opposite face to the nitronate prior to cyclization.
Interestingly, the X-ray crystal structure of compound
3g shows a conformational preference for the (P)-atropi-
someric position, where the intramolecular distances from
the centroid of the benzene ring to the centroids of the
˚
naphthalene rings are 3.953 and 4.871 A (Figure 3).
Calculations (B3LYP/6-31G* energies after an OPLSA
conformation search12) demonstrate that the observed geom-
etry of 3g is the thermodynamically preferred one by a ratio
of 500:1 and do not provide evidence of a high energy barrier
between the atropisomers. However, the possibility of a
catalytic influence upon axial chirality has not been totally
ruled out and is the subject of ongoing investigation.
Finally, we have used Raney-Ni under 1 atm of hydro-
gen to convert 3a to the useful functionalized cyclohexane
a Based on isolated product. b Determined by 1H NMR spectroscopy.
The minor diastereosiomer was found to be the (1R)-epimer. c Deter-
mined by HPLC using a chiral stationary phase. d Absolute configura-
tion determined by Cu-source X-ray crystallography of 3j and ascribed
by analogy.
(11) Compound 3g was also assigned in this fashion, and as expected,
the stereochemistry was identical to 3j. Both the Flack parameters and
the Hooft probabilities indicate strongly that the absolute configura-
tions of the refined crystal structures are correct. 3j: Flack parameter
À0.019(11); Hooft probabilities P2(true) = 1, P3(true) = 1, P3(rac-
twin) = 0, P3(false) = 0, Hooft y = À0.012(2). 3g: Flack parameter
0.022(17); Hooft probabilities P2(true) = 1, P3(true) = 1, P3(rac-twin) =
0, P3(false) = 0, Hooft y = 0.007(12). (a) Flack, H. D. Acta Crystallogr.,
Sect. A: Found. Crystallogr. 1983, 39, 876. (b) Hooft, R. W. W.; Straver,
L. H.; Spek, A. L. J. Appl. Crystallogr. 2008, 41, 96.
Using the optimized conditions (entry 8, bold) we selected
a range of conjugated arylcyanosulfones 2 for the
(10) See: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2003, 125, 12672. (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.;
Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119. (c) Okino, T.; Nakamura,
S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625. (d) Vakulya, B.;
Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967. (e) Li, B.-J.; Jiang,
L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y. Synlett 2005, 603. (f)
McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367.
(g) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481.
(12) Calculations carried out using BatchMin (version 9.7) and
Jaguar (version 7.6) from Schrodinger, LLC, New York, NY, 2009.
See also: (a) Jorgensen, W. L.; Maxwell, D. S.; Tirado-Rives, J. J. Am.
Chem. Soc. 1996, 118, 11225. (b) Becke, A. D. Phys. Rev. A 1988, 38,
3098. (c) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. (d)
Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem. Phys. 1980,
72, 650. (e) Gill, P. M. W.; Johnson, B. G.; Pople, J. A.; Frisch, M.
J. Chem. Phys. Lett. 1992, 197, 499.
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Org. Lett., Vol. 15, No. 6, 2013

Scheme 2. Desulfonylation Using Raney Ni
In conclusion, we have demonstrated that bifunctional
thiourea catalysts have the ability to control the asym-
metric reactivity of nitro- and sulfone substituted com-
pounds to generate highly enantioenriched products with
up to four contiguous stereocenters, one of which is
quaternary in nature. Future work will involve both the
theoretical study of the mechanism of reaction, as well as
the use of this new amino acid precursor within peptide
chemistry.
Figure 3. Calculations (B3LYP/6-31G* energies after an OPL-
SA conformation search) indicate a strong thermodynamic
preference (500:1 at room temperature) for the (P)-atropisomer
of 3g.12,13
Acknowledgment. We thank the Felix Foundation for
financial support (to R.S.) and the University of Reading
Chemical Analysis Facility (CAF) for spectroscopic
support.
product 10 (Scheme 2). Under these conditions, there is no
scrambling of the C-2 stereogenic center, where the axial
position of the nitrile, itself unaffected by the reducing
conditions, is retained. Cyclohexane system 10 is envisaged
to be a useful “three-way junction” within peptide chem-
istry, as there is the potential to have two orthogonally
reactiveN-termini(one generating anδ-aminoacidandthe
other an ε-amino acid) as well as a single C-terminus.
Supporting Information Available. Experimental pro-
cedures, NMR characterization, HPLC traces, and X-ray
data (CIF) for compounds 3g and 3j. This material is
available free of charge via the Internet at http://pubs.
acs.org.
(13) For an explanation of our atropisomer assignment, see the
Supporting Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
1389