Remote stereocontrol by sulfinyl groups: Reduction of δ- ketosulfoxides

Article abstract of DOI:10.1021/jo047999j

(Chemical Equation Presented) The reduction of δ-ketosulfoxides constitutes the first evidence of the efficiency of the sulfinyl group to control the stereoselectivity of 1,5-asymmetric induction processes. The use of DIBAL/Yb(OTf)₃ or L-Selectride as the reducing agents provides δ-hydroxysulfoxides with the opposite configuration at the hydroxylic carbon in a highly stereoselective way.

Full text of DOI:10.1021/jo047999j

Remote Stereocontrol by Sulfinyl Groups: Reduction of
δ-Ketosulfoxides
Jose´ L. Garc´ıa Ruano,* M. AÄ ngeles Ferna´ndez-Iba´n˜ez, M. Carmen Maestro,* and
M. Mercedes Rodr´ıguez-Ferna´ndez
Departamento de Quı´mica Orga´nica, Universidad Auto´noma de Madrid, Cantoblanco,
28049-Madrid, Spain
joseluis.garcia.ruano@uam.es; carmen.maestro@uam.es
Received November 11, 2004
The reduction of δ-ketosulfoxides constitutes the first evidence of the efficiency of the sulfinyl group
to control the stereoselectivity of 1,5-asymmetric induction processes. The use of DIBAL/Yb(OTf)3
or L-Selectride as the reducing agents provides δ-hydroxysulfoxides with the opposite configuration
at the hydroxylic carbon in a highly stereoselective way.
1. Introduction
interact with such a Lewis acid. The high affinity of the
sulfinyl oxygen toward different Lewis acids has been
evidenced in many 1,2- and 1,3-asymmetric induction
processes.3 By contrast, reactions with a longer distance
between the prochiral center and the sulfur atom have
been much less studied. This was the reason we initiated
a program to investigate the ability of the sulfinyl group
to control the stereoselectivity of reactions taking place
at remote positions (1 - n asymmetric induction pro-
cesses with n > 3). In this context we have recently
reported several papers concerning reactions of γ-sulfinyl
carbanions with different electrophiles4 (nucleophilic 1,4-
asymmetric induction processes) showing the high ef-
ficiency of the sulfinyl group. Additionally, other authors
had shown that it was also the case for reactions of
nucleophiles with 2-sulfinyl derivatives of aromatic al-
dehydes5 (electrophilic 1,4-asymmetric induction pro-
cesses). However, to our knowledge, there has not been
reported to date any highly stereoselective reaction
controlled by sulfinyl groups located farther from the
reaction center.6
Conformational restrictions are in the origin of the
stereodifferentiation of the prochiral centers required in
any asymmetric process. When these are close to the
chiral auxiliary responsible for the asymmetric induction,
there are several plausible mechanisms controlling the
conformational preferences, many of them involving
direct interactions (steric and/or electronic) between
them. This makes the stereoselectivity control easier. The
longer the distance is between the inductor and the
prochiral center the smaller the capability of the former
one to restrict the conformations around the prochiral
center, thus decreasing their efficiency as inductor. Thus,
the remote stereocontrol is one of the most intriguing
challenges to be solved in asymmetric synthesis.1,2
One of the most frequently used strategies to get
prochiral centers and chiral inducers close to each other
involves the use of Li+ as a Lewis acid to form chelated
species.2 Consequently, these groups used to get the
remote stereocontrol usually have basic centers prone to
(3) (a) Carren˜o M. C. Chem. Rev. 1995, 95, 1717. (b) Ferna´ndez I.;
Khiar, N. Chem. Rev. 2003, 103, 3651.
(1) (a) Sailes, H.; Whiting, A. J. Chem. Soc., Perkin Trans. 1 2000,
1785 and references therein. (b) Mitchell, H. J.; Nelson, A.; Warren,
S. J. Chem. Soc., Perkin Trans. 1 1999, 1899. (c) Mikami, K.; Shimizu,
M.; Zhang, H.-C.; Maryanoff, N. E. Tetrahedron 2001, 57, 2917.
(2) (a) Linnane, P.; Magnus, N.; Magnus, P. Nature 1997, 385, 799.
(b) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496. (c) Myers, A. G.;
Schnider, P.; Kwon, S.; Kung, D. W. J. Org. Chem. 1999, 64, 3322. (d)
Pippel, D. J.; Curtis, M. D.; Du, H.; Beak, P. J. Org. Chem. 1998, 63,
2. (e) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2282.
(4) (a) Garc´ıa Ruano, J. L.; Carren˜o, M. C.; Toledo, M. A.; Aguirre,
J. M.; Aranda, M. T.; Fischer, J. Angew. Chem., Int. Ed. 2000, 39, 2736.
(b) Garc´ıa Ruano, J. L.; Alema´n, J.; Soriano, J. F. Org. Lett. 2003, 5,
677. (c) Garc´ıa Ruano, J. L.; Alema´n, J. Org. Lett. 2003, 5, 4513. (d)
Garc´ıa Ruano, J. L.; Alema´n, J.; Padwa, A. Org. Lett. 2004, 6, 1757.
(e) Garc´ıa Ruano, J. L.; Aranda, M. T.; Aguirre, J. M. Tetrahedron 2004,
60, 5383. (f) Garc´ıa Ruano, J. L.; Alema´n, J.; Aranda, M. T.; Ferna´ndez-
Iba´n˜ez, M. A.; Rodriguez-Ferna´ndez, M. M.; Maestro, M. C. Tetrahe-
dron 2004, 60, 10067.
10.1021/jo047999j CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/05/2005
1796
J. Org. Chem. 2005, 70, 1796-1801

Reduction of δ-Ketosulfoxides
TABLE 1. Reaction of 1a under Different Reduction
Conditions
SCHEME 1
entry
hydride
Lewis acid
4a:5a
yield (%)
1
2
3
4
5
6
7
8
DIBAL
43:57
61:39
39:61
58:42
61:49
97
96
94
95
96
The face-selectivity for the reductions of carbonyl
compounds mediated by chiral sulfoxides has been in-
tensively studied in â-ketosulfoxides7 (1,3-induction).
Particularly, their reduction with diisobutylaluminum
hydride (DIBAL) giving â-hydroxysulfoxides proceeded
with high diastereoselectivity through a six-membered
cyclic transition state.7b The number of reports concern-
ing reduction of γ-ketosulfoxides (1,4-induction) is much
lower;8 the best results have been reported by Solladie´9
and Toru.10 We present herein the first results concerning
the stereoselective reduction of δ-ketosulfoxides (1,5-
induction), which demonstrate the ability of the sulfinyl
group in the remote control of the stereoselectivity.
DIBAL
ZnCl2
DIBAL
CeCl3
DIBAL
Ti(OiPr)4
LiBr
Sn(OTf)3
Yb(OTf)3
DIBAL
DIBAL
DIBAL
L-Selectride
97a:3
5:95b
96
75
a Isolated yield 89%. b Isolated yield 71%.
TABLE 2. Reduction of Compounds 1b-d
2. Results and Discussion
As the starting compounds we have used the 1-alkyl
(or phenyl) 2-(2-p-tolylsulfinyl)phenyl ethanones, 1a-d,
and the epimers at C-2 of the methyl derivatives, 2a and
3a (Scheme 1). The synthesis of all these compounds has
been reported recently.4f
We first investigated the reduction of 1a under differ-
ent conditions (Table 1). The use of DIBAL did not give
good stereochemical results and a 43:57 mixture of
epimers 4a and 5a was obtained in high yield (entry 1).
This low stereoselectivity could not be significantly
increased by using either ZnCl2 (which only slightly
inverts the sense of the stereoselectivity, entry 2) or other
Lewis acids (CeCl3, Ti(OiPr)4, and LiBr, entries 3-5) as
the catalysts, and the reaction did not work at all in the
presence of Sn(OTf)3 (entry 6). Fortunately, the reaction
entry
substrate
hydride/LA
4:5
yield (%)
1
2
3
4
5
6
7
8
9
1b (R ) Ph)
1b (R ) Ph)
1b (R ) Ph)
1c (R ) n-Pr)
1c (R ) n-Pr)
1c (R ) n-Pr)
1d (R ) i-Pr)
1d (R ) i-Pr)
1d (R ) i-Pr)
DIBAL
33:67
89b:11
40:60
84:16
92c:8
2:98d
58:42
92e:8
2:98f
96
95
55
96
95
65
95
97
60
DIBAL/LAa
L-Selectride
DIBAL
DIBAL/LAa
L-Selectride
DIBAL
DIBAL/LAa
L-Selectride
a Yb(OTf)3. b Isolated yield 83%. c Isolated yield 90%. d Isolated
yield 61%. e Isolated yield 91%. f It is obtained with 1d.
conducted in the presence of Yb(OTf)3 afforded a 97:3
diastereomeric ratio of epimers, which allowed the isola-
tion of diastereomerically pure 4a by ready flash chro-
matography in 89% yield (entry 7). Finally, we investi-
gated the behavior of other hydrides. The only relevant
results were obtained with L-Selectride. With this re-
agent, a 5:95 mixture of 4a:5a was obtained (entry 8) in
75% yield (71% of pure 5a), therefore affording a complete
inversion of the stereoselectivity.
(5) (a) Arai, Y.; Suzuki, A.; Masuda, T.; Masaki, Y.; Shiro, M. J.
Chem. Soc., Perkin Trans. 1 1995, 2913 and references therein. (b)
Nakamura, S.; Yasuda, H.; Watanabe, Y.; Toru, T. Tetrahedron Lett.
2000, 41, 4157. (c) Girodier, L. D.; Rouessac, F. P. Tetrahedron:
Asymmetry 1994, 5, 1203. (d) Arai, Y.; Masuda, T.; Masaki, Y. Synlett
1997, 1459. (e) Almor´ın, A.; Carren˜o, M. C.; Somoza, A.; Urbano, A.
Tetrahedron Lett. 2003, 44, 5597.
(6) A 1,6-asymmetric induction evolving in moderate de had been
reported: Iwata, C.; Moritani, Y.; Sugiyama, K.; Fujita, M.; Imanishi,
T. Tetrahedron Lett. 1987, 28, 2255.
(7) Selected references: (a) Solladie´, G.; Fre´chou, C.; Demailly, G.;
Greck, C. J. Org. Chem. 1986, 51, 1912 and references therein. (b)
Carren˜o, M. C.; Garc´ıa Ruano, J. L.; Mart´ın, A. M.; Pedregal, C.;
Rodr´ıguez, J. H.; Rubio, A.; Sa´nchez, J.; Solladie´, G. J. Org. Chem.
1990, 55, 2120. (c) Barros, D.; Carren˜o, M. C.; Garcia-Ruano, J. L.;
Maestro, M. C. Tetrahedron Lett. 1992, 33, 2733. (d) Nakamura, S.;
Nakayama, J.; Toru, T. J. Org. Chem. 2003, 68, 5766. (e) Brinkmann,
Y.; Carren˜o, M. C.; Urbano, A.; Colobert, F.; Solladie´, G. Org. Lett.
2004, 6, 4335.
(8) Arai, Y.; Suzuki, A.; Masuda, T.; Masaki, Y.; Shiro, M. Chem.
Pharm. Bull. 1996, 44, 1765.
(9) (a) Solladie´, G.; Hanquet, G.; Rolland, C. Tetrahedron Lett. 1997,
38, 5847. (b) Solladie´, G.; Hanquet, G.; Izzo, I.; Crumbie, R. Tetrahedron
Lett. 1999, 40, 3071. (c) Solladie´, G.; Colobert, F.; Somny, F. Tetrahe-
dron Lett. 1999, 40, 1227.
(10) (a) Nakamura, S.; Yasuda, H.; Watanabe, Y.; Toru, T. J. Org.
Chem. 2000, 65, 8640. (b) Nakamura, S.; Oda, M.; Yasuda, H.; Toru,
T. Tetrahedron 2001, 57, 8469. (c) Nakamura, S.; Kuroyanagi, M.;
Watanabe, Y.; Toru, T. J. Chem. Soc., Perkin Trans. 1 2000, 3143.
We next tried the reduction of ketosulfoxides 1b-d
under the best conditions indicated in Table 1. The
results are reported in Table 2.
The stereoselectivity observed in DIBAL reductions
was not good in any case, yielding mixtures of the
epimeric alcohols 4 and 5. By contrast, reactions with
DIBAL/Yb(OTf)3 or L-Selectride evolved in an opposite
and highly stereoselective manner, yielding alcohols 4
and 5 which could be easily purified by chromatography
from the mixtures where they were the major products.
The only exception was observed for 1b in the reduction
with L-Selectride (entry 3), which afforded a 40:60
mixture of epimers, hence preventing an easy purification
of 5b. Yields were almost quantitative with DIBAL/Yb-
(OTf)3 but only 55-75% with L-Selectride.
J. Org. Chem, Vol. 70, No. 5, 2005 1797

Garc´ıa Ruano et al.
TABLE 3. Desulfinylation of Compounds 4
entry
substrate
R’Li
yield (%)
1
2
3
4
4a (R ) Me)
4b (R ) Ph)
4c (R ) n-Pr)
4d (R ) i-Pr)
t-Bu
n-Bu
t-Bu
n-Bu
6a (67)
6b (60)
6c (54)
6d (70)
Configurational assignment of the hydroxysulfoxides
4a-d was performed by chemical correlations with the
previously reported alcohols 6a-d.11 The reactions of the
hydroxysulfoxides with alkyllithium reagents, under the
conditions collected in Table 3, yielded the alcohols 6.12
These correlations allowed us to assign the configura-
tion of the carbinols according to those indicated in Table
3 (R for 4b and 4d and S for 4a and 4c). As the
configuration at sulfur for all compounds 4 must be S
(identical with that of the starting ketones 1), these
correlations provided the absolute configurations for 4
and 5 (epimers at the hydroxylic carbon).
FIGURE 1. Favored conformations accounting for the ob-
served stereoselectivity.
hydride to the less hindered face of D13 accounts for the
formation of alcohols 4 as the major products (Figure 1).
With the aim of establishing the influence of an
additional stereogenic center on the stereoselectivity, as
well as the competition between both chiral centers, we
have also studied the behavior of 2a and 3a, the two
R-methyl derivatives of 1a. The synthesis of these
compounds as well as their configurational assignment
had been previously reported.4f The results obtained in
their reduction with different hydrides are collected in
Table 4.
Compound 3a did not evolve stereoselectively under
any of the studied reaction conditions (≈1:1 mixtures of
9a and 10a were obtained in all cases). By contrast, 2a
evolved with a complete control of the stereoselectivity
in its reaction with DIBAL/Yb(OTf)3, which makes easy
the synthesis of 7a. Under different conditions (DIBAL
or L-Selectride), mixtures of 7a and 8a were obtained.
In all cases the diastereisomers could be separated and
purified by flash chromatography. These results are
consistent with the stereochemical model indicated in
Figure 1. The presence of the methyl group at the
benzylic position must play a significant role in the
composition of the conformational equilibria. Its interac-
tions with the sulfinyl oxygen in one diastereoisomer or
with Hortho in the other epimer would destabilize the
conformations A in Figure 1. This fact would determine
that several conformations have a significant population,
whose evolution with DIBAL or L-Selectride would ex-
plain the formation of both epimeric alcohols with the
consequent decrease in stereoselectivity. In the presence
of Yb(OTf)3, the stability of the chelated species D (Figure
2) will depend on the configuration of the methyl deriva-
tive. It will be stable for 2a but not for 3a due to the
steric repulsion of the methyl group with the substituents
joined to Yb (Figure 2). As a consequence, only 2a will
be able to evolve in a completely stereoselective way into
7a, according to the approach of the DIBAL to the less
hindered face of the chelated substrate.
The results collected in Tables 1 and 2 suggest that
the sulfinyl group is efficient to control the stereoselec-
tivity of the reduction of δ-ketosulfoxides (1,5-asymmetric
induction) by using the proper conditions. The high
stereoselectivity observed in those reactions with nucleo-
philic hydrides such as L-Selectride suggests that the
sulfinyl group is able to restrict the conformational
mobility differentiating the two diastereotopic faces of the
carbonyl group. Figure 1 depicts the presumably most
stable conformations, A and B, for compounds 1a-d.
They exhibit the lone electron pair at sulfur oriented
toward the benzylic carbon. Additionally, the COR group
adopts the orthogonal arrangement with respect to the
aromatic ring, thus minimizing the allylic strain. Finally,
the anti relationship between the Ar and R groups
around the CH2-CO bond could also be favored by steric
grounds. The conformational equilibrium must be shifted
toward the A conformers because the electrostatic repul-
sion between the sulfinyl and carbonyl oxygens decreases
the stability of the B ones. By assuming that the attack
of the nucleophilic hydrides will be mainly controlled by
steric grounds, the favored approach of the bulky L-
Selectride will take place from the bottom face, resulting
in the formation of 5 as the major alcohols. The smaller
size of DIBAL and mainly its ability to associate with
the sulfinyl oxygen as a previous step to its intramolecu-
lar attack to the upper face of A conformers could be
invoked to justify the poorer face selectivity observed for
DIBAL reductions. The strong capability of the Yb(OTf)3
to associate with the oxygen determines the formation
of the chelated species C and D, the latter one being the
most stable due to steric reasons. The attack of the
(11) (a) D’Arrigo, P.; Lattanzio, M.; Fantoni, G. P.; Servi, S.
Tetrahedron: Asymmetry 1998, 9, 4021. (b) Ziffer, H.; Kawai, K.; Imuta,
M.; Froussios, C. J. Org. Chem. 1983, 48, 3017. (c) Dhokte, U. P.;
Pathare, P. M.; Mahindroo, V. K.; Brown, H. C. J. Org. Chem. 1998,
63, 8276. (d) Vigneron, J. P.; Dhaenens, M.; Horeau, A. Tetrahedron.
1977, 33, 507.
(12) The compounds resulting from the nucleophilic substitution of
the p-tolyl group by the alkyl group of the lithium reagent were also
obtained as nondesired byproducts.
(13) The approach of the DIBAL to the opposite face, which would
yield compounds 4, is hindered by the substituents at Yb.
1798 J. Org. Chem., Vol. 70, No. 5, 2005

Reduction of δ-Ketosulfoxides
SCHEME 2
FIGURE 2. Chelated species for 2a and 3a.
TABLE 4. Reduction of γ-Methyl-δ-ketosulfoxides 2a
and 3a
provides a stereodivergent route to prepare alcohols with
the two possible configurations. Only one of the epimers
resulting from the methylation at C-R is able to evolve
in a completely stereoselective way. The results of the
reactions with other nucleophiles will be published in due
course.
3. Experimental Section
Method A: Reduction with DIBAL. General Proce-
dure. To a solution of sulfoxide 1 (0.14 mmol) in 3 mL of THF
cooled at -78 °C was added a mixture of 0.2 mL (0.20 mmol)
of a 1 M solution of DIBAL in heptane (in the case of 1d, the
addition of three portions of 0.29 mmol of the hydride was
necessary). The resulting solution was stirred for 1 h and the
mixture was quenched with 1.5 mL of methanol. The solvent
was evaporated in vacuo, and the residue was diluted with
10% HCl, extracted with CH2Cl2 (3 × 3 mL), and dried (MgSO4)
and the solvent was evaporated. The residue was purified by
flash-column chromatography.
Method B: Reduction with DIBAL/Lewis Acid. Gen-
eral Procedure. A solution of sulfoxide 1 (0.14 mmol) and
Lewis acid (0.15 mmol) in 3 mL of THF was stirred at room
temperature for 30 min. Then, 0.2 mL (0.2 mmol) of a 1 M
solution of DIBAL in heptane was added to the cooled (-78
°C) solution (in the case of 2a and 3a, the addition of three
portions of 0.29 mmol of the hydride was necessary). The
resulting mixture was stirred for 1 h and quenched, extracted,
and purified as in method A.
The configurational assignment of compounds 7a-10a
was based on the assumption that their configurations
at sulfur and benzylic carbon must be identical with those
of their respective precursors 2a [3R,(S)S] and 3a
[3S,(S)S], which had been previously assigned.4f Thus,
it was only necessary to determine their configurations
at the hydroxylic carbon. It was unequivocally established
as S for compound 7a, from its chemical correlation with
compound 11 (Scheme 2), previously reported in the
literature.14 Additionally, the individual oxidation of 7a
and 10a with MCPBA yielded the enantiomers 12 and
ent-12, respectively, thus allowing us to assign the
configuration of 10a as R at its hydroxylic carbon
(Scheme 2). The absolute configurations of the other two
compounds, 8a and 9a, were assigned as indicated in
Table 4, considering that they are epimers of 7a and 10a,
respectively, at the hydroxylic carbon.
Method C: Reduction with L-Selectride. General Pro-
cedure. To a solution of sulfoxide 1 (0.14 mmol) in 3 mL of
THF cooled at -78 °C was added 0.2 mL (0.28 mmol) of a 1 M
solution of l-Selectride in THF. The resulting solution was
stirred for 1 h and the mixture was quenched with 1.5 mL of
1 M HCl, extracted with CH2Cl2 (3 × 3 mL), and dried (MgSO4)
and the solvent was evaporated. The residue was filtered over
Celite and purified by flash-column chromatography.
[2S,(S)S]-1-[2-(p-Tolylsulfinyl)phenyl]propan-2-ol (4a).
4a was isolated diastereomerically pure by flash-column
chromatography (AcOEt-hexane 1:1) of the crude mixture 4a
+ 5a. Yield 89% (method B), gummy; [R]20 -55.0 (c 0.5,
D
CHCl3); IR (film) 3395, 1083, 810 cm-1; 1H NMR δ 7.75-7.72
(m, 1H), 7.44-7.34 (m, 4H), 7.26-7.18 (m, 3H), 3.93 (br s, 1H),
2.90 (d, J ) 6.1 Hz, 2H), 2.32 (s, 3H), 1.15 (d, J ) 6.0 Hz, 3H);
13C NMR δ 143.5, 141.5, 141.0, 137.5, 131.3, 131.1, 129.9,
127.5, 125.8, 125.7, 67.6, 41.0, 22.9, 21.2; MS (EI) m/z 257 [M+
- H2O]; HRMS [M+ - H] calcd for C16H17O2S 273.0949, found
273.0952.
As a conclusion, we have provided the first evidence
of the efficiency of the sulfinyl group as a chiral inductor
in the reduction of carbonyl groups separated by 4 bonds
from the chiral sulfur (1,5-asymmetric induction). The
use of large hydrides or Lewis acids such as Yb(OTf)3
[2R,(S)S]-1-[2-(p-Tolylsulfinyl)phenyl]propan-2-ol (5a).
5a was isolated diastereomerically pure by flash-column
chromatography (AcOEt-hexane 1:1) of the crude mixture 4a
+ 5a. Yield 71% (method C), gummy; [R]20 -105.6 (c 1.1,
D
CHCl3); 1H NMR δ 7.74-7.71 (m, 1H), 7.40-7.15 (m, 7H), 3.93
(m, 1H), 2.84 (dd, J ) 13.7 and 8.1 Hz, 1H), 2.76 (dd, J ) 13.7
(14) Brown, H. C.; Jadhav, P. K.; Mandal, A. K. J. Org. Chem. 1982,
47, 5074.
J. Org. Chem, Vol. 70, No. 5, 2005 1799

Garc´ıa Ruano et al.
and 4.9 Hz, 1H), 2.50 (br s, 1H), 2.29 (s, 3H), 1.21 (d, J ) 6.0
Hz, 3H); 13C NMR δ 143.3, 141.3, 141.2, 138.6, 131.6, 131.5,
129.9, 127.5, 127.0, 125.4, 68.7, 41.2, 23.9, 21.3.
(S)-1-Phenylpropan-2-ol (6a).11a 6a was prepared by
reaction of 4a with tert-butyllithium. Purification was per-
formed by flash-column chromatography (AcOEt-hexane 1:2).
Yield 67%; colorless oil; [R]20D +36.0 (c 0.8, benzene) [lit.11a [R]D
+40.9 (c 0.5, benzene)]. Ee 99% (determined by integration of
well-separated signals in the 1H NMR spectra of the corre-
sponding Mosher derivative). 1H NMR values are in agreement
with the reported values.
[1R,(S)S]-1-Phenyl-2-[2-(p-tolylsulfinyl)phenyl]etha-
nol (4b). 4b was isolated diastereomerically pure by flash-
column chromatography (AcOEt-hexane 1:1) of the crude
mixture 4b + 5b. Yield 83% (method B); white solid; mp 80-
82 °C; [R]20 -62.7 (c 1.0, CHCl3); IR (film) 3357, 1594, 1082
D
cm-1; 1H NMR δ 7.67-7.64 (m, 1H), 7.41-7.02 (m, 11H), 7.05-
7.02 (m, 1H), 4.80 (dt, J ) 6.1 and 3.6 Hz, 1H), 3.42 (br d, J )
3.6 Hz, OH), 3.13 (d, J ) 6.1 Hz, 2H), 2.36 (s, 3H); 13C NMR
δ 143.7, 143.5, 141.4, 140.7, 137.2, 131.7, 131.0, 129.9, 128.2,
127.5, 127.4, 126.2, 125.8, 125.7, 73.9, 41.4, 21.3; MS (EI) m/z
319 [M - 17]+; HRMS [M + 1]+ calcd for C21H21O2S 337.1262,
found 337.1261.
(R)-1,2-Diphenylethanol (6b).11b 6b was prepared by
reaction of 4b with n-butyllithium. Purification was performed
by flash-column chromatography (AcOEt-hexane 1:2). Yield
60%; colorless oil; [R]20D -43.5 (c 1.4, i-PrOH) [lit.11b [R]D -42.0
(c 1.86, EtOH)]. Ee 99% (determined by integration of well-
separated signals in the 1H NMR spectra of the corresponding
Mosher derivative). 1H NMR values are in agreement with the
reported values.
[1S,(S)S]-1-Phenyl-2-[2-(p-tolylsulfinyl)phenyl]etha-
nol (5b). 5b could not be isolated diastereomerically pure. It
was characterized from a mixture of 4b + 5b obtained by flash-
(S)-1-Phenylpentan-2-ol (6c).11c 6c was prepared by reac-
tion of 4c with tert-butyllithium. Purification was performed
by flash-column chromatography (AcOEt-hexane 1:2). Yield
54%; colorless oil; [R]20D +4.2 (c 1.8, EtOH) [lit.11c [R]D +4.2 (c
0.57, EtOH)]. Ee 99% (determined by integration of well-
separated signals in the 1H NMR spectra of the corresponding
Mosher derivative). 1H NMR values are in agreement with the
reported values.
1
column chromatography (AcOEt-hexane 1:1); H NMR (rep-
resentative parameters) δ 7.80-7.77 (m, 1H), 4.74 (m, 1H),
3.14 (dd, J ) 14.1 and 9.7 Hz), 2.87 (dd, J ) 14.1 and 4.0 Hz),
2.26 (s, 3H); 13C NMR (representative parameters) δ 144.6,
143.6, 141.1, 141.0, 138.5, 132.0, 131.8, 129.8, 128.6, 128.4,
127.5, 127.3, 125.6, 125.1, 74.9, 41.6, 21.2.
[2S,(S)S]-1-[2-(p-Tolylsulfinyl)phenyl]pentan-2-ol (4c).
4c was isolated diastereomerically pure by flash-column
chromatography (AcOEt-hexane 1:1) of the crude mixture 4c
(R)-3-Methyl-1-phenylbutan-2-ol (6d).11d 6d was pre-
pared by reaction of 4d with n-butyllithium. Purification was
performed by flash-column chromatography (AcOEt-hexane
+ 5c. Yield 90% (method B), gummy; [R]20 -54.8 (c 0.7,
1:2). Yield 70%; colorless oil; [R]20 +43.7 (c 1.5, MeOH). Ee
D
D
1
CHCl3); IR (film) 3019, 1083 cm-1; H NMR δ 7.77-7.74 (m,
99% (determined by integration of well-separated signals in
the 1H NMR spectra of the corresponding Mosher derivative)
[lit.11d [R]D +4.6 (c 1.42, MeOH, 11% ee)]. 1H NMR values are
in agreement with the reported values.
1H), 7.45-7.20 (m, 7H), 3.66 (m, 1H), 2.92 (dd, J ) 14.2 and
4.9 Hz, 1H), 2.86 (dd, J ) 14.2 and 7.9 Hz, 1H), 2.59 (br s,
OH), 2.34 (s, 3H), 1.51-1.24 (m, 4H), 0.86 (t, J ) 6.8 Hz, 3H);
13C NMR δ 143.4, 141.5, 141.0, 137.7, 131.1, 131.0, 129.9,
127.5, 125.9, 125.7, 71.2, 39.5, 39.1, 21.3, 18.8, 13.9; MS (EI)
m/z 303 [M + 1]+; HRMS [M + 1]+ calcd for C18H23O2S
303.1419, found 303.1413.
[2S,3R,(S)S]-3-[2-(p-Tolylsulfinyl)phenyl)]butan-2-ol
(7a). 7a was isolated diastereomerically pure by flash-column
chromatography (AcOEt-hexane 1:2) of the crude mixture.
Yield 70% (method B), 29% (method A), colorless oil; [R]20
D
[2R,(S)S]-1-[2-(p-Tolylsulfinyl)phenyl]pentan-2-ol (5c).
5c was isolated diastereomerically pure by flash-column
chromatography (AcOEt-hexane 1:1) of the crude mixture 4c
-69.6 (c 5.1, CHCl3); 1H NMR δ 7.88-7.85 (m, 1H), 7.46-7.36
(AA′BB′ system, 4H), 7.25-7.21 (m, 3H), 3.90 (m, 1H), 3.21
(m, 1H), 2.35 (s, 3H), 1.95 (br s, 1H, OH), 1.23 (d, J ) 5.9 Hz,
3H), 0.95 (d, 3H); 13C NMR δ 142.9, 142.8, 141.9, 141.8, 131.2,
129.9, 127.5, 127.1, 126.0, 124.6, 72.2, 41.9, 21.6, 21.4, 16.4;
MS (MALDI) m/z 271 [M + 1 - H2O]; HRMS [M + 1]+ calcd
for C17H21O2S 289.1262, found 289.1265.
+ 5c. Yield 61% (method C), gummy; [R]20 -96.4 (c 2.2,
D
CHCl3); 1H NMR δ 7.80-7.76 (m, 1H), 7.46-7.22 (m, 7H), 3.79
(m, 1H), 2.84 (m, 2H), 2.63 (br s, OH), 2.36 (s, 3H), 1.58-1.25
(m, 4H), 0.93 (t, J ) 4.8 Hz, 3H); 13C NMR δ 143.2, 141.3,
141.1, 138.9, 131.5, 129.8, 127.3, 126.9, 125.3, 72.1, 40.0, 39.5,
21.2, 18.7, 13.9.
[2R,3R,(S)S]-3-[2-(p-Tolylsulfinyl)phenyl)]butan-2-ol
(8a). 8a was isolated diastereomerically pure by flash-column
chromatography (AcOEt-hexane 1:2) of the crude mixture 7a
+ 8a. Yield 44% (method A), colorless oil; [R]20D -99.9 (c 1.76,
[2R,(S)S]-3-Methyl-1-[2-(p-tolylsulfinyl)phenyl]butan-
2-ol (4d). 4d was isolated diastereomerically pure by flash-
column chromatography (AcOEt-hexane 1:1) of the crude
mixture 4d + 5d. Yield 91% (method B), gummy; [R]20D -33.6
(c 0.6, CHCl3); IR (film) 3390, 1086, 839 cm-1; 1H NMR δ 7.72-
7.66 (m, 1H), 7.46-7.22 (m, 7H), 3.40 (m, 1H), 2.89 (m, 2H),
2.35 (s, 3H), 1.71 (dsp, J ) 6.8 and 2.0 Hz, 1H), 0.93 (dd, J )
6.8 and 1.6 Hz, 6H); 13C NMR δ 143.6, 141.6, 140.8, 138.5,
131.1, 130.9, 129.9, 127.4, 126.0, 125.7, 76.5, 36.4, 33.6, 21.3
(2C), 18.8, 17.1; MS (EI) m/z 303 [M + 1]+; HRMS [M + 1]+
calcd for C18H23O2S 303.1419, found 303.1416.
1
CHCl3); H NMR δ 8.01 (dd, J ) 6.1 and 3.2 Hz, 1H), 7.51-
7.42 (AA′BB′ system, 4H), 7.31-7.25 (m, 3H), 3.93 (dq, J )
6.9 and 6.5 Hz, 1H), 3.18 (dq, J ) 6.9 and 5.7 Hz, 1H), 2.38 (s,
3H), 2.10 (br s, 1H, OH), 1.14 (d, J ) 6.3 Hz, 3H), 1.04 (d, J )
6.5 Hz, 3H); 13C NMR δ 143.8, 142.3, 141.8, 141.7, 131.2, 129.9,
127.6, 127.3, 126.1, 124.5, 72.0, 42.0, 21.3, 21.1, 17.4; MS
(MALDI) m/z 271 [M + 1 - H2O]; HRMS [M + 1] calcd for
C17H21O2S 289.1262, found 289.1261.
[2S,3S,(S)S]-3-[2-(p-Tolylsulfinyl)phenyl]butan-2-ol (9a).
9a was isolated diastereomerically pure by flash-column
chromatography (AcOEt-hexane 1:3) of the crude mixture 9a
+ 10a. Yield 52% (method B), colorless oil; [R]20D -62.5 (c 2.12,
[2S,(S)S]-3-Methyl-1-[2-(p-tolylsulfinyl)phenyl]butan-
2-ol (5d). 5d could not be isolated diastereomerically pure. It
was characterized from a mixture of 4d + 5d obtained by flash-
1
1
column chromatography (AcOEt-hexane 1:1); H NMR (rep-
CHCl3); H NMR δ 7.82 (dd, J ) 7.7 and 1.6 Hz, 1H), 7.49-
resentative parameters) δ 3.58 (ddd, J ) 10.1, 4.9 and 3.2 Hz,
1H), 2.85 (dd, J ) 13.7 and 10.1 Hz, 1H), 2.71 (dd, J ) 13.7
and 3.2 Hz, 1H); 13C NMR (representative parameters) δ 142.9,
141.3, 141.0, 139.9, 131.8, 130.0, 128.4, 127.1, 126.1, 125.1,
77,2, 36.0, 34.3, 18.5, 17.3.
C-S Bond Cleavage. General Procedure. Alkyllithium
(0.85 mmol) was added to a solution of the corresponding
hydroxysulfoxide (0.214 mmol) in THF (1.6 mL) under argon
at -78 °C. The reaction was stirred for 10 min and then it
was hydrolyzed with a saturated aqueous solution of NH4Cl.
The crude mixture was extracted with CH2Cl2 (3 × 5 mL) and
dried (MgSO4) and the solvent was evaporated.
7.37 (AA′BB′ system, 4H), 7.33 (dd, J ) 7.7 and 1.6 Hz, 1H),
7.22 (m, 2H), 3.71 (dq, J ) 6.5 and 5.7 Hz, 1H), 3.34 (dq, J )
6.9 and 5.7 Hz, 1H), 2.59 (br s, 1H, OH), 2.35 (s, 3H), 1.14 (d,
J ) 6.9 Hz, 3H), 0.84 (d, J ) 6.5 Hz, 3H); 13C NMR δ 143.9,
142.5, 141.6, 141.4, 131.5, 129.9, 128.5, 127.5, 127.2, 126.9,
126.0, 70.8, 40.5, 21.3, 19.9, 16.7; MS (MALDI) m/z 271 [M +
1 - H2O]; HRMS [M + 1]+ calcd for C17H21O2S 289.1262, found
289.1263.
(2R,3S,(S)S)-3-[2-(p-Tolylsulfinyl)phenyl)]butan-2-ol
(10a). 10a was isolated diastereomerically pure by flash-
column chromatography (AcOEt-hexane 1:3) of the crude
mixture 9a + 10a. Yield 42% (method B), colorless oil; [R]20
D
1800 J. Org. Chem., Vol. 70, No. 5, 2005

Reduction of δ-Ketosulfoxides
-79.3 (c 2.25, CHCl3); IR (film) 3405, 1083, 1009 cm-1; 1H NMR
δ 7.76 (dd, J ) 7.7 and 1.2 Hz, 1H), 7.52-7.41 (AA′BB′ system,
4H), 7.38-7.22 (m, 3H), 3.72 (dq, J ) 8.5 and 6.1 Hz, 1H),
3.37 (dq, J ) 8.5 and 6.9 Hz, 1H), 2.40 (br s, 1H, OH), 2.36 (s,
3H), 1.22 (d, J ) 6.1 Hz, 3H), 1.04 (d, J ) 6.9 Hz, 3H); 13C
NMR δ 145.4, 143.2, 141.8, 140.9, 132.2, 129.7, 127.7, 127.1,
125.2, 72.5, 42.0, 21.7, 21.3.
(MgSO4) MCPBA solution in the same solvent. The NMR
signals were obtained from the crude mixtures.
(2R,3S)-2-[2-(p-Tolylsulfonyl)phenyl)]-3-butanol (12).
12 was obtained by MCPBA oxidation from hydroxysulfoxide
7a. 1H NMR δ 8.10-7.31 (m, 8H), 3.71 (m, 1H), 3.51 (m, 1H),
2.40 (s, 3H), 1.16 (d, J ) 6.1 Hz, 3H), 6.9 (d, J ) 6.9 Hz, 3H).
(2S,3R)-2-[2-(p-Tolylsulfonyl)phenyl)]-3-butanol (ent-
12). ent-12 was obtained by MCPBA oxidation from hydroxy-
sulfoxide 10a. 1H NMR δ 8.10-7.31 (m, 8H), 3.71 (m, 1H), 3.51
(m, 1H), 2.40 (s, 3H), 1.16 (d, J ) 6.1 Hz, 3H), 6.9 (d, J ) 6.9
Hz, 3H).
(S)-3-Phenyl-2-butanol (11). The sulfoxide 7a (0.079
mmol) was dissolved in a minimal amount of absolute EtOH
and an excess of activated Raney nickel was added. The
reaction was stirred for 1 h at room temperature, then filtered
through a Celite pad, and the residue was purified by chro-
matography (AcOEt-hexane 1:2) to give a colorless oil. Yield
71%; [R]D +19.1 (c 3.0, EtOH) [lit.14 [R]D +16.2 (c 3.6, EtOH),
Acknowledgment. We thank the CICYT (Grant
BQU2003-04012) for financial support. M.A.F.-I. thanks
the Comunidad Auto´noma de Madrid for a predoctoral
fellowship.
1
81% ee]. H NMR values are in agreement with the reported
values.15
Sulfinyl Group Oxidation. General Procedure. A solu-
tion of the corresponding hydroxysulfoxides in CDCl3 was
added to a NMR tube containing an excess of previously dried
Supporting Information Available: 1H and 13C NMR
spectra of compounds 4a-d, 5a-d, 6a-d, 7a-10a, and 11
(1H NMR). This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) Weissfloch, A. N. E.; Kazlauskas, R. J. J. Org. Chem. 1995, 60,
6959.
JO047999J
J. Org. Chem, Vol. 70, No. 5, 2005 1801