Enantioselective organocatalytic approach to the synthesis of α,α-disubstituted cyanosulfones

Article abstract of DOI:10.1021/jo801968p

(Chemical Equation Presented) Optically pure cyano tert-alkyl sulfones have been obtained by organocatalytic enantioselective Michael addition of α-substituted cyanosulfones to vinyl ketones using cinchona alkaloids as catalysts. The best results were obt

Full text of DOI:10.1021/jo801968p

lective methods to prepare this kind of compounds have not
been described.
Enantioselective Organocatalytic Approach to the
Synthesis of r,r-Disubstituted Cyanosulfones
During the past few years, asymmetric organocatalysis has
emerged as a powerful strategy in organic synthesis.6 In this
field, Michael addition has been extensively studied as one of
the most versatile strategies in C-C bond formation.7 In
particular, when cinchona alkaloids are used as chiral bases,
R-substituted dicarbonylic compounds8 and cyanoesters9 are
mainly employed as the nucleophiles due to the strong acidity
of their methylene protons. This strategy has allowed the
formation of all-carbon quaternary stereocenters.10
M. Bele´n Cid,* Jesu´s Lo´pez-Cantarero, Sara Duce, and
Jose´ Luis Garc´ıa Ruano*
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma
de Madrid, Cantoblanco, 28049-Madrid, Spain
belen.cid@uam.es; joseluis.garcia.ruano@uam.es
ReceiVed September 11, 2008
At this point, we envisioned that R-cyanosulfones would be
suitable starting materials to prepare enantioenriched tert-alkyl
sulfones by using a similar strategy. In this paper, we describe
the results obtained in the Michael addition of R-substituted
R-cyanosulfones to R,ꢀ-unsaturated ketones catalyzed by cin-
chona alkaloids.11 It is noteworthy that, in contrast with the wide
use of vinyl sulfones as electrophiles in asymmetric organoca-
talysis,12 there are few examples where R-sulfonyl carbanions
have been used as nucleophiles,13 in spite of the high acidity
of the sulfonylated compounds and the large chemical versatility
of the sulfones.
Optically pure cyano tert-alkyl sulfones have been obtained
by organocatalytic enantioselective Michael addition of
R-substituted cyanosulfones to vinyl ketones using cinchona
alkaloids as catalysts. The best results were obtained for
p-trifluorophenylsulfones by using VIII as catalyst in toluene
at -40 °C. Reactions proved to be applicable for a variety
of R,ꢀ-unsaturated ketones, affording R,R-disubstituted cy-
anosulfones in excellent yields with er’s up to 90:10.
We first tried the efficiency of a variety of cinchona alkaloids
(Figure 1) as catalysts to promote the enantioselective Michael
addition of R-phenyl-R-cyano-p-tolylsulfone 1a14 to the com-
mercially available methyl vinyl ketone (MVK) 2a (Table 1).
(6) (a) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (b)
Pellissier, H. Tetrahedron 2007, 63, 9267. (c) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138. (d) Berkessel, A.; Gro¨ger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, Germany, 2005. (e) Seayad, J.; List,
B. Org. Biomol. Chem. 2005, 3, 719. (f) List, B. Chem. Commun. 2006, 819.
(g) Marion, N.; D´ıez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007,
46, 2988. (h) Xu, L.-W.; Lu, Y. Org. Biomol. Chem. 2008, 6, 2047. (i) Bartoli,
G.; Melchiorre, P. Synlett 2008, 1759. (j) Connon, S. J. Chem. Commun. 2008,
2499.
(7) For reviews on organocatalytic enanatioselective Michael reactions, see:
(a) Almasi, D.; Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007, 18,
299. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (c) Vicario, J. L.;
Bad´ıa, D.; Carrillo, L. Synthesis 2007, 14, 2065.
(8) (a) Wynberg, H.; Helder, R. Tetrahedron Lett. 1975, 46, 4057. (b) Ooi,
T.; Miki, T.; Taniguchi, M.; Shiraishi, M.; Takeuchi, M.; Maruoka, K. Angew.
Chem., Int. Ed. 2003, 42, 3796. (c) Bella, M.; Jørgensen, K. A. J. Am. Chem.
Soc. 2004, 126, 5672. (d) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.;
Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105. (e) Wu, F.; Li,
H.; Hong, R.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 947. (f) Elsner, P.;
Bernardi, L.; Dela Salla, G.; Overgaard, J.; Jørgensen, K. A. J. Am. Chem. Soc.
2008, 130, 4897.
Sulfones are gaining an increasing importance in medicinal
chemistry since they are considered as mimics of the carbonyl
moieties in the transition state.1 According to the World Drug
Index, there are more than 40 sulfonyl-containing structures
internationally recognized as drugs for a great variety of illness.2
Chiral sulfonyl compounds have shown interesting activities in
diseases such as glaucoma3 or Alzheimer’s.4 A significant
number of functionalized tert-alkyl sulfones4,5 have been
recently recognized as new chemical entities with a wide range
of biological activities. However, to our knowledge, enantiose-
(9) See, for example: (a) Liu, T.-Y.; Li, R.; Chai, Q.; Long, J.; Li, B.-J.;
Wu, Y.; Ding, L.-S.; Chen, Y.-C. Chem.sEur. J. 2007, 13, 319. (b) Wu, F.; Li,
H.; Hong, R.; Deng, L. Angew. Chem., Int. Ed 2006, 45, 947. For other uses of
cyanoacetates, see: (c) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 2896. (d) Lo´pez-Cantarero,
J.; Cid, M. B.; Poulsen, T. B.; Bella, M.; Garc´ıa Ruano, J. L.; Jørgensen, K. A.
J. Org. Chem. 2007, 72, 7062.
(10) For construction of all-carbon quaternary stereocenters, see: (a) Douglas,
C. J.; Overman, L. E. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5363. (b)
Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688. (c) Corey,
E. J.; Guzman-Pe´rez, A. Angew. Chem., Int. Ed. 1998, 37, 389.
(11) For an example of cyanosulfones with biological activity see: Miyazaki,
H. PCT Int. Appl. WO 2007060839, 2007.
(12) Carretero, J. C.; Arraya´s R. G.; Adrio, J. In Sulfones in Asymmetric
Catalysis (chapter 9) in Organosulfur Chemistry in Asymmetric Synthesis, 1st
ed.; Toru, T., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2008.
(1) See, for example: (a) Lovejoy, B.; Welch, A. R.; Carr, S.; Luong, C.;
Broka, C.; Hendricks, R. T.; Campbell, J. A.; Walker, K. A. M.; Martin, R.;
Van Wart, H.; Browner, M. F. Nat. Struct. Biol. 1999, 6, 217.
(2) Sulfonamides are not included in this number.
(3) Surgrue, M. F.; Harris, A.; Adamsoms, I. Drugs Today 1997, 33, 283.
(4) Scott, J. P.; Lieberman, D. R.; Beureux, O. M.; Brands, K. M. J.; Davies,
A. J.; Gibson, A. W.; Hammond, D. C.; Chris, J.; McWilliams, C. J.; Stewart,
G. W.; Wilson, R. D.; Dolling, U.-H. J. Org. Chem. 2007, 72, 4149, and
references cited therein.
(5) For some recent examples, see: (a) Churcher, I.; Harrison, T.; Kerrad,
S.; Oakley, P. J.; Shaw, D. E.; Teall, M. R.; Williams, S. PCT Int. Appl. WO
2004031137, 2004. (b) Aranapakam, V.; Grosu, G. T.; Davis, J. M.; Hu, B.;
Ellingboe, J.; Baker, J. L.; Skotnicki, J. S.; Zask, A.; DiJoseph, J. F.; Sung, A.;
Sharr, M. A.; Killar, L. M.; Walter, T.; Jin, G.; Cowling, R. J. Med. Chem.
2003, 46, 2361. (c) Berry, A.; Cirillo, P. F.; Hickey, E. R.; Riether, D.; Thomson,
D. S.; Ermann, M.; Jenkins, J. E.; Mushi, I.; Taylor, M.; Chowdhury, C.; Palmer,
C. F.; Blumire, N. PCT Int. Appl. WO 2008014199, 2008. (d) Fernández, M.;
Caballero, J. Bioorg. Med. Chem. 2007, 15, 6298. (e) Miyazaki, H. PCT Int.
Appl. WO 2007060839, 2007.
(13) (a) Mizuta, S.; Shibata, N.; Goto, Y.; Furukawa, T.; Nakamura, S.; Toru,
T. J. Am. Chem. Soc. 2007, 129, 6394. (b) Arai, S.; Ishida, T.; Shiroi, T.
Tetrahedron Lett. 1998, 39, 8299. (c) Pulkkinen, J.; Aburel, P. S.; Halland, N.;
Jørgensen, K. A. AdV. Synth. Catal. 2004, 346, 1077.
10.1021/jo801968p CCC: $40.75
Published on Web 11/20/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 431–434 431

TABLE 2. Reaction Scope of r-Substituted Cyanosulfones 1 and
Unsubstituted Vinyl Ketones 2a
entry
Ar
2
t (h)
3
yield (%)
erb
1
2
3
4
5
6
7
Ph (1e)
2a
2a
2a
2a
2a
2b
2c
3
3
48
24
1.5
5
3e
3i
3j
3k
3l
3m
3n
97
93
97
85
90
98
98
85:15
85:15
87:13
89:11
66:34
86:14c
86:14c
p-Cl-C6H4 (1i)
o-Cl-C6H4 (1j)
p-MeO-C6H4 (1k)
p-F-C6H4 (1l)
Ph (1e)
Ph (1e)
5
FIGURE 1. Structure of cinchona alkaloids used in this paper.
a Unless otherwise specified, the reaction was performed at a 0.1
mmol scale (1) with 2 equiv of 2 and 1 mol % of catalyst (0.14 M in
the indicated solvent referred to 1). b er determined by HPLC. c 5 mol %
of catalyst was employed.
TABLE 1. Asymmetric Michael Addition of Cyanosulfones 1 to
MVK 2a with Cinchone-Alkaloid Catalysta
Next, we studied the influence of the group joined to the
sulfonyl moiety. Yields and enantioselectivities have been
evaluated for aliphatic substituents [1b (R ) Me) and 1g
(CH2Tol)], aromatic substituents with different sizes and
electronic properties [1c (R ) mesityl), 1d (R ) p-MeO-C6H4),
1e (R ) p-CF3-C6H4), and 1f (R ) o-CF3-C6H4)], and
heteroaromatic substituents bearing coordinative heteroatoms
[1h (R ) 2-Py)] by using the commercially available catalyst
III (entries 9-15). Although the p-methoxyphenyl substituent
(entry 11) afforded the highest enantiomeric ratio, the best
enantioselectivity/reactivity balance was found for p-trifluoro-
methyl sulfone 1e (entry 12). Taking into account that about
20-25% of drugs in the pharmaceutical pipelines contain at
least one fluorine atom,18 we chose the p-trifluoromethyl sul-
fones for our studies.19
The influence of the temperature and the solvent was also
explored (entries 16 and 17).20 The higher conversion and
enantiomeric ratio (85:15) was obtained from 1e in toluene at
-40 °C by using catalyst VIII (entry 18). The corresponding
pseudoenantiomer derivative VII (entry 19) affords opposite
selectivity but significantly lower enantiomeric ratio (entry 18).
It is remarkable that under the conditions optimized for
compounds 1e and 2a (Table 1, entry 18) the catalyst loading
can be reduced to 1 mol% (Table 2, entry 1) without erosion
on the enantioselectivity. The scope of the reaction was studied
(Table 2) and a wide range of substituents are allowed in both
T
(°C)
conv
(%)
entry
1
cat.
solvent
3
erb
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
1g
1h
1e
1e
1e
1e
I
I
II
III
IV
V
VI
VIII
III
III
III
III
III
III
III
III
III
VIII
VII
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
25
-20
-20
-20
-20
-20
-20
-20
-20
25
-20
-20
-20
-20
-20
-20
-40
-40
-40
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
3g
3h
3e
3e
3e
3e
100
100
100
<70
50
<5
<50
91
47:53
34:66
32:68
30:70
70:30
50:50
49:51
73:27
30:70
36:64
27:73
31:69
29:71
44:66
30:70
27:73
27:73
85:15
32:68
9
70
<20
57
10
11
12
13
14
15
16
17
18
19
100
60
100
66
100
>80
100
100
a The reaction was performed on a 0.1 mmol scale of 1 with 2 equiv
of 2a and 10 mol % of catalyst (0.14 M in the indicated solvent referred
to 1). b Enantiomeric ratio determined by HPLC.
The conjugate addition proceeded smoothly to give the
desired product 3a using CH2Cl2 in a quite clean fashion using
catalysts I-IV (Table 1, entries 1-5). However, very low
conversion degrees and enantioselectivities were observed with
V and VI15 (entries 6 and 7) as well as with dimeric catalysts
such as (DHQ)2Pyr, (DHQ)2PHAL, or (DHQ)2AQN not in-
cluded in Table 1. These observations suggest a significant role
of the free hydroxyl group at C9.16 Silylated catalyst VIII
afforded higher conversion and enantioselectivities than its
precursor IV (entry 8).17
(16) This effect has also been observed in other examples described in the
literature: (a) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417.
See also ref 9d and references cited therein.
(17) Catalyst VIII has been previously used in (a) Bell, M.; Frisch, K.;
Jørgensen, K. A. J. Org. Chem. 2006, 71, 5407. It was prepared from cinchonine
following the experimental procedure described for the preparation of the
corresponding cinchonidine derivative VII in: (b) Lindholm, A.; Ma¨ki-Arvela,
P.; Toukoniitty, E.; Pakkanen, T. A.; Hirvi, J. T.; Salmi, T.; Murzin, D. Y.;
Sjo¨holm., R.; Leino, R. J. Chem. Soc., Perkin Trans. 1 2002, 2605–2612. (c)
Busygin, I.; Toukoniitty, E.; Sillanpa¨a¨, R.; Murzin, D. Y.; Leino, R. Eur. J.
Org. Chem. 2005, 2811.
(18) Chukwuemeka, I.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303.
(19) For some biologicaly active tert-alkyl sulfones bearing fluoride, see:
(a) Berry, A.; Cirillo, P. F.; Hickey, E. R.; Riether, D.; Thomson, D. S.; Ermann,
M.; Jenkins, J. E.; Mushi, I.; Taylor, M.; Chowdhury, C.; Palmer, C. F.; Blumire,
N. PCT Int. Appl. WO 2008014199, 2008. (b) Hendrix, M.; Baumann, K.;
Grosser, R.; Koenig, G.; Duesterhus, V.; Krueger, J. PCT Int. Appl. WO
2003059335, 2003. (c) Finlay, M. R. V.; Morris, J.; Pike, K. G. PCT Int. Appl.
WO 2008023159, 2008.
(14) All cyanosulfones 1 have been prepared following the general procedure
previously described in: (a) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem.
2000, 65, 8210. (b) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Vakulenko, A. V.;
Tau, H. J. Org. Chem. 2005, 65, 9191. For details of each compound, see the
Supporting Information.
(15) This catalyst afforded high levels of enantioselectivity in the same
reaction but using ꢀ-ketoesters as nucleophiles: (a) Wu, F.; Li, H.; Hong, R.;
Deng, L. Angew. Chem., Int. Ed. 2006, 45, 947–950.
(20) Several solvents were used: CHCl3, THF, acetone, acetonitrile, CH2Cl2,
PhI, xylene, toluene, Tol/CH2Cl2, C2H4Cl2, and Tol/CHCl3 ) 3:1.
432 J. Org. Chem. Vol. 74, No. 1, 2009

TABLE 3. Reaction of Cyanosulfones 1 with Cyclic Enones 4
under Catalysis with VIIIa
We have initiated the study of the transformations of the
resulting cyanosulfones. Interestingly, the Baeyer-Villiger
reaction of the cyclic ketone 5a produce the regioselective
oxidative cleavage of the methylene group far away from the
chiral tertiary carbon yielding lactone 6 with reasonable yield
with no erosion of the enatiomeric ratio.
In conclusion, we have developed a straightforward organo-
catalytic enantioselective aproach to the synthesis of fluorinated
tert-alkyl sulfones by Michael addition of R-substituted cyano-
sulfones to vinyl ketones using cinchona alkaloids as catalysts.
A useful transformation underlines the utility of the methodology.
entry
Ar
4
5
drb
yieldc (%)
erd
1
2
3
4
5
Ph (1e)
Ph (1e)
Ph (1e)
4a
4b
4c
4a
5a
5b
5c
5d
5e
80:20
80:20
65:35
72:28
90:10
75
79
58
62
81
90:10
89:11
80:20
85:15
88:12
p-Cl-C6H4 (1i)
p-MeO-C6H4 (1k) 4a
Experimental Section
a Unless otherwise specified, the reaction was performed at a 0.1
mmol scale (1) with 2 equiv of 4 and 1-10 mol % of catalyst (0.14 M
in the indicated solvent referred to 1). b dr determined by 1H NMR or
HPLC (see the Supporting Information). c Major diastereomer. d er
determined by HPLC. For complete reaction details, such as times and
catalyst loading, see the Supporting Information.
General Procedure for the Catalytic Michael Addition of
r-Aryl-r-cyanosulfones 1 to Vinyl Ketones 2 and 4. A vial
equipped with a magnetic stirring bar was charged with the R-aryl-
R-cyanosulfone 1 (0.2 mmol) and dissolved in toluene (1.5 mL, M
) 0.14 mmol/mL). The vial was placed at -40 °C, and the
corresponding vinyl ketone 2 or 4 (0.4 mmol) and catalyst VIII
(1-10 mol %, see Tables 1 and 2) were sequentially added. No
precautions were taken to exclude moisture or air. The reactions
were followed by TLC (see Tables 1 and 2 for times) and charged
onto a silica gel column when finished. After the column was
washed with hexane, the products 3 or 5 were obtained by flash
chromatography using hexane/AcOEt mixtures (from 4:1 to 2:1).
(S)-5-Oxo-2-phenyl-2-(4-(trifluoromethyl)phenylsulfonyl)hex-
anenitrile (3e). The title compound was obtained as a white solid
according to the general procedure (97% yield): mp 124-126 °C;
1H NMR (300 MHz) δ 7.66 (s, 4H), 7.47-7.32 (m, 5H), 3.03-2.72
(m, 3H), 2.46-2.32 (m, 1H), 2.11 (s, 3H); 13C NMR (75 MHz) δ
204.8 (CO), 137.2 (C), 136.3 (q, J ) 33.6 Hz, C), 131.2 (2CH),
130.6 (CH), 129.2 (2CH), 128.3 (2CH), 127.9 (C), 125.8 (q, J )
3.8 Hz, 2CH), 122.8 (q, J ) 273 Hz, CF3), 115.8 (CN), 71.5 (C),
38.7, 29.8, 25.8; MS (FAB) m/z 396 (M + 1, 34), 186 (100); HRMS
(FAB) calcd for C19H17F3NO3S [M + 1] 396.0881, found 396.0870;
[R]20D -71 (c 1.0, CHCl3); IR (KBr) 2200, 1716, 1336, 1157, 1129
cm-1. Anal. Calcd for C19H16F3NO3S: C, 57.72; H, 4.08; N, 3.54;
S, 8.11. Found: C, 57.93; H, 3.99; N, 3.65; S, 8.07. The
enantiomeric ratio was determined by HPLC using a Chiralpak AD
SCHEME 1. Reaction of Cyclopentanone 5a with m-CPBA
reacting partners, sulfone (1) and ketone (2). Yields of the
corresponding cyano tert-alkyl sulfones 3 are usually very high
in all the cases. The nature and position of the substituents
introduced at the aromatic ring of the sulfone determine a
different reactivity (see reaction times in entries 2-5). The
enantioselectivity ranges between 89:11 and 85:15 er’s except
for the case of the fluorinated compound 1l where was found a
significant variation (entry 5). On the other hand, the increase
in the size of the substituent at the ketone had scarce influence
in the enantioselectivity although it produced a decrease on the
reactivity and 5 mol% of catalyst had to be employed (entries
6 and 7).
column [hexane/i-PrOH ) 80:20]; flow rate 1.0 mL/min; τmajor
)
8.1 min, τminor ) 9.8 min (85:15 er).
(S)-2-((S)-3-Oxocyclopentyl)-2-phenyl-2-(4-(trifluorometh-
yl)phenylsulfonyl) acetonitrile (5a). This compound was obtained
as the major diastereoisomer (80:20 dr) following the general
procedure (75% yield). Diastereomeric and enantiomeric ratios were
determined by HPLC with a Chiralpak AD column [Hex/i-PrOH
(90:10)]; flow rate 1.0 mL/min, T ) 25 °C; minor diastereoisomer,
τmajor ) 11.4 min, τminor ) 12.3 min (50:50 er); major diastereoi-
somer, τmajor ) 15.1 min, τminor ) 17.7 min (89:11 er). White solid:
mp 144-146 °C; [R]20D -118 (c 1.0, CHCl3); 1H NMR (300 MHz)
δ 7.56 (m, 4H, pCF3-Ar), 7.43-7.32 (m, 5H, Ph), 3.76-3.68 (m,
1H, H3), 3.11 (dd, J ) 18.7, 7.4 Hz, 1H), 2.78 (ddd, J ) 18.7,
11.6, 1.2 Hz, 1H), 2.37 (dd, J ) 18.6, 8.7 Hz, 1H), 2.22 (ddd, J )
18.6, 12.1, 8.7 Hz, 1H), 1.92-1.80 (m, 1H), 1.65 (m, 1H); 13C
NMR (75 MHz) δ 214.4 (CO), 137.8 (C), 136.2 (q, J ) 32.9 Hz,
C), 130.7 (4CH), 130.6 (2CH), 129.2 (CH), 128.7 (C), 125.7 (q, J
) 3.3 Hz, 2CH), 122.7 (q, J ) 277 Hz, CF3), 114.4 (CN), 76.5
(C), 42.5, 39.2, 36.8, 26.7; MS (FAB) m/z 408 (M+1, 9), 198 (100);
HRMS (FAB) calcd for C20H17F3NO3S [M + 1] 408.0881, found
408.0893; IR (film) 2242, 1739, 1322, 1154 cm-1. Anal. Calcd for
C20H16F3NO3S: C, 58.96; H, 3.96; N, 3.44; S, 7.87. Found: C, 58.76;
H, 3.93; N, 3.51; S, 7.74.
The reaction also proved to be applicable to cyclic unsaturated
ketones (Table 3), where two stereocenters are simultaneously
created. The stereoselectivity control at the carbon ring ranged
between moderate to good for cyclopentenones (entries 1, 4,
and 5) and cyclohexenone (entry 2), but it slightly decreased
for cycloheptenone (entry 3), which in its turn showed a lower
reactivity. After separation, the major diastereoisomers were
obtained in high yields and er’s similar to those observed for
acyclic ketones (up to 90:10 er). The presence of substituents
at the aromatic ring of the sulfone determined significant changes
in the diastereoselectivity (larger for electron donating groups)
but had scarce influence on the er’s of the major diastereoiso-
mers (entries 4 and 5).
Interestingly, compounds 3 and 5 are crystalline and can be
converted into enantiomerically pure compounds by symple
crystallization. Hence, 3i and 5b were easily obtained in
enantiomerically pure form, and the absolute configuration of
their stereocenters was determined by X-ray analysis. It allowed
us to unequivocally assign the (S) and (S,S) configurations of
the major enantiomers of 3i and 5b, respectively. All compounds
3 and 5 should have the same configuration since a similar
stereochemical evolution should be expected for all the cyano-
sulfonyl compounds.
(S)-2-((S)-2-Oxotetrahydro-2H-pyran-4-yl)-2-phenyl-2-(4-(tri-
fluoromethyl)phenylsulfonyl)acetonitrile (6). m-CPBA (60-75%
in water, 169 mg, 0.98 mmol, 10 equiv) was dissolved in 7 mL of
CH2Cl2, dried over magnesium sulfate, and filtered and the resulting
solution added at room temperature to a flask charged with
J. Org. Chem. Vol. 74, No. 1, 2009 433

cyanosulfone 5a (40 mg, 0.098 mol). Eight drops of TFA were
then added to this mixture, and the reaction was stirred at 40 °C
for 6 days whereupon it was cooled to room temperature and
quenched by addition of a saturated Na2SO3 solution (6 mL). The
organic layer was washed with a NaHCO3 solution (6 mL × 2)
and with brine (6 mL), dried over magnesium sulfate, and filtered
and the solvent removed under vacuo. The crude product was
purified by flash column chromatography [SiO2, hexane/EtOAc)
4:1 to 1.5:1] to afford the title compound 6a as a white solid (29
mg, 70% yield). White solid: mp 181-183 °C; 1H NMR (300 MHz)
δ 7.55 (s, 4H), 7.42-7.30 (m, 5H), 4.45-4.23 (m, 2H), 3.69-3.57
(m, 2H), 3.24-3.13 (m, 1H), 1.77-1.65 (m, 2H); 13C NMR (75
MHz) δ 168.1 (CO), 138.2 (C), 136.2 (q, J ) 33.3 Hz, C), 130.8
(2CH), 130.5 (2CH), 129.6 (2CH), 128.7 (CH), 128.0 (C), 125.8
(q, J ) 3.8 Hz, 2CH), 122.7 (q, J ) 272 Hz, CF3), 114.2 (CN),
75.8, 66.8, 36.1, 33.8, 25.8; MS (FAB) m/z 436 (M + 1, 25), 226
1451, 1405, 1323, 1157 cm-1. HRMS (ESI) calcd for C20H17F3NO4S
[M + H+] 424.0824, found 424.0827. The enantiomeric ratio was
determined by HPLC using a Chiralpak AD column [hexane/i-PrOH
) 80:20]; flow rate 0.8 mL/min; Ta ) 25 °C. τmajor ) 29.3 min,
τminor ) 31.0 min (90:10 er).
Acknowledgment. We thank the Spanish Government and
Universidad Auto´noma de Madrid for financial support
(CTQ2006-06741/BQU and CCG07-UAM/PPQ-1709).
Supporting Information Available: Experimental proce-
dures and characterization data for catalyst VIII and compounds
1a-l, 3e-n, 5a-e, and 6 as well as X-ray ORTEP of 3i and
5b. This material is available free of charge via the Internet at
http://pubs.acs.org.
(95), 57 (100); [R]20 -83 (c 0.5, CHCl3); IR (film) 2240, 1743,
JO801968P
D
434 J. Org. Chem. Vol. 74, No. 1, 2009