Asymmetric synthesis of β-hydroxy sulfides controlled by remote sulfoxides

Article abstract of DOI:10.1021/jo062053q

(Chemical Equation Presented) Reactions of (S)-α-(methylthio)-2-(p- tolylsulfinyl)benzyl carbanion with different carbonyl compounds proceeds with complete control of the configuration at the benzylic position. Aldehydes yield easily separable mixtures of

Full text of DOI:10.1021/jo062053q

methods. Among the first, the asymmetric reduction of â-keto
sulfides using baker’s yeast1a,9 and lipase-mediated kinetic
resolution of racemic â-hydroxy sulfides6,10 have been reported.
Chemical methods provide better results, but to our knowledge,
only two reactions have been reported. The CBS-oxazaboroli-
dine-catalyzed asymmetric borane reduction of â-ketosulfides11
affords very high optical and chemical yields, but it has never
been applied to R-substituted carbonyl derivatives, thus restrict-
ing its scope to the synthesis of hydroxy sulfides only containing
one chiral center. The second reaction consists in desymmetri-
zation of cyclic meso-epoxides by opening with thiolates assisted
by chiral catalysts.12 The most direct retrosynthetic route to these
compounds implies the C(1)-C(2) bond disconnection. So the
search for highly stereoselective methods involving nucleophilic
addition of prochiral R-thio carbanions to carbonyl compounds
would be an efficient and unprecedented path to chiral â-hy-
droxy sulfides, simultaneously creating two contiguous stereo-
genic centers in a single step and avoiding the regioselectivity
problems in the epoxide opening.
Asymmetric Synthesis of â-Hydroxy Sulfides
Controlled by Remote Sulfoxides
Yolanda Arroyo,† J. Fe´lix Rodr´ıguez,† Mercedes Santos,*,†
M. Ascensio´n Sanz Tejedor,† and Jose´ Luis Garc´ıa Ruano*,‡
Departamento de Qu´ımica Orga´nica (ETSII), UniVersidad de
Valladolid, Paseo del Cauce s/n, 47011 Valladolid, and
Departamento de Qu´ımica Orga´nica (C-I), UniVersidad
Auto´noma, Cantoblanco, 28049 Madrid, Spain
msantos@eis.uVa.es; joseluis.garcia.ruano@uam.es
ReceiVed October 4, 2006
We have recently reported the almost completely stereose-
lective transference of chiral benzyl groups to different elec-
trophiles13 mediated by an o-sulfinyl group. In particular, the
reactions of R-(methylthio)-2-(p-tolylsulfinyl)benzyl carbanions
with N-(p-tolylsulfinyl)aldimines evolve in a completely ste-
reoselective manner, providing enantiomerically pure 1,2-amino
sulfide derivatives.14 Bearing in mind these antecedents, we
reasoned that the reactions of carbonyl compounds with the
R-(methylthio)-2-(p-tolylsulfinyl)benzyl carbanion derived from
(S)-2 (Scheme 1) could provide a new and easy access to chiral
1,2-diaryl- and 1-alkyl-2-aryl-2-(methylthio)ethanols in a short
number of steps. The results obtained in this study are reported
in this paper.
The synthesis of (S)-R-(methylthio)-2-(p-tolylsulfinyl)toluene
[(S)-2] was performed starting from enantiopure (S)-2-(p-
tolylsulfinyl)toluene [(S)-1] according to the procedure previ-
ously reported by us14a (Scheme 1). (S)-2 was reacted with LDA
(which provides the R-thiocarbanion Li-(S)-2) followed by
further addition of tert-butyl chloroformate (3). After a detailed
Reactions of (S)-R-(methylthio)-2-(p-tolylsulfinyl)benzyl car-
banion with different carbonyl compounds proceeds with
complete control of the configuration at the benzylic position.
Aldehydes yield easily separable mixtures of â-hydroxy
sulfides, epimers at the hydroxylic carbon, where the
stereoselectivity depends on steric factors (from 20% to
>98% de).
Enantiopure â-hydroxy sulfides are outstanding structural
subunits because of their occurrence in natural products1 and
their importance as valuable intermediates in the synthesis of
naturally occurring spiroketal pheromones,2 chiral oxiranes,3
thiiranes,4 tetrahydrofurans,5 and 4-acetoxyazetidinones.6 More-
over, they are easily oxidized to â-hydroxy sulfoxides7 or
sulfones,8 which serve as extremely useful chiral building
blocks.
The available synthetic approaches for obtaining enantiopure
â-hydroxy sulfides involve both biological and chemical
(9) Fujisawa, T.; Itoh, T.; Yonekawa, Y.; Sato, T. Tetrahedron Lett. 1986,
27, 5405-5408. (b) Fujisawa, T.; Itoh, T.; Sato, T. Tetrahedron Lett. 1984,
25, 5083-5086.
(10) (a) Chimni, S. S.; Singh, S.; Kumar, S.; Mahajan, S. Tetrahedron:
Asymmetry 2002, 13, 511-517. (b) Chimni, S. S.; Singh, S.; Kumar, S.
Tetrahedron: Asymmetry 2001, 12, 2457-2462.
* To whom correspondence should be addressed. (M.S.) Phone: +34983185952.
Fax: +34983423310. (J.L.G.R.) Phone: +34914974701. Fax: +34914973966.
† Universidad de Valladolid.
‡ Universidad Auto´noma.
(11) Cho, B. T.; Shin, S. H. Tetrahedron 2005, 61, 6959-6966; Cho,
B.T.; Choi, O. K.; Kim, D. J. Tetrahedron: Asymmetry 2002, 13, 697-
703.
(1) De Paolis, M.; Blankenstein, J.; Bois-Choussy, M.; Zhu, J. Org. Lett.
2002, 4, 1235-1238.
(2) Liu, H.; Cohen, T. J. Org. Chem. 1995, 60, 2022.
(3) (a) Fujisawa, T.; Itoh, T.; Nakai, M.; Sato, T. Tetrahedron Lett. 1985,
26, 771-774. (b) Goergens, U.; Schneider, M. P. J. Chem. Soc., Chem.
Commun. 1991, 1064. (c) Sa´nchez-Obrego´n, R.; Ortiz, B.; Walls, F.; Yuste,
F.; Garc´ıa-Ruano, J. L. Tetrahedron: Asymmetry 1999, 10, 947.
(4) Dinunno, L.; Franchini, C.; Nacci, A.; Scilimati, A.; Sinicropi,
M. S. Tetrahedron: Asymmetry 1999, 10, 1913.
(5) (a) Gruttadauria, M.; Meo, P.; Noto, R. Tetrahedron 1999, 55, 1409.
(b) Gruttadauria, M.; Meo, P.; Noto, R. Tetrahedron 1999, 55, 4769.
(6) Nakatsuka, T.; Iwata, H.; Tanaka, R.; Imajo, S.; Ishiguro, M. J. Chem.
Soc., Chem. Commun. 1991, 662.
(7) (a) Garc´ıa-Ruano, J. L.; Ferna´ndez, M. A.; Maestro, M. C.; Rodr´ıguez,
M. M. Tetrahedron 2006, 62, 1245-1252. (b) Carren˜o, M. C. Chem. ReV.
1995, 95, 1717-1760. (c) Walker, A. J. Tetrahedron: Asymmetry 1992, 3,
961-998.
(8) Bernabeu, M. C.; Bonete, P.; Caturla, F.; Chinchilla, R.; Na´jera, C.
Tetrahedron: Asymmetry 1996, 7, 2475-2478 and references therein.
(12) (a) Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985, 1643-1646.
(b) Yamashita, H. Bull. Chem. Soc. Jpn. 1988, 61, 1213-1220. (c) Iida,
T.; Yamamoto, N.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1997, 119,
4783-4784. (d) Wu, M. H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 5252-
5254.
(13) (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-
2737. (b) Garc´ıa-Ruano, J. L.; Alema´n, J.; Soriano, J. F. Org. Lett. 2003,
5, 677-680. (c) Garc´ıa-Ruano, J. L.; Alema´n, J. Org. Lett. 2003, 5, 4513-
4516. (d) Garc´ıa-Ruano, J. L.; Aranda, M. T.; Aguirre, J. M. Tetrahedron
2004, 60, 5383-5392. (e) Garc´ıa-Ruano, J. L.; Alema´n, J.; Parra, A.
J. Am. Chem. Soc. 2005, 127, 13048-13054. (f) Garc´ıa-Ruano, J. L.;
Aleman, J.; Cid, B. Synthesis, 2006, 687-691.
(14) (a) Arroyo, Y.; Meana, A.; Rodr´ıguez, J. F.; Santos, M.; Sanz-
Tejedor, M. A.; Garc´ıa-Ruano, J. L. J. Org. Chem. 2005, 70, 3914-3920.
(b) Arroyo, Y.; Meana, A.; Rodr´ıguez, J. F.; Santos, M.; Sanz-Tejedor,
M. A.; Garc´ıa-Ruano, J. L. Tetrahedron 2006, 62, 8525-8532.
10.1021/jo062053q CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/24/2006
J. Org. Chem. 2007, 72, 1035-1038
1035

TABLE 1. Reactions of (S)-2 with Aldehydes 5c-k
SCHEME 1
SCHEME 2
dr
(6:6′)
yielda
(%)
entry
aldehyde
R
1
2
3
4
5
6
7
8
9
5c
5d
5e
5f
5g
5h
5i
C6H5
75:25
71:29
68:32
70:30
84:16
100:0
60:40
60:40
100:0
56
73
92
quant
70
78
74
54
60
p-MeOC6H4
2-naphthyl
p-CNC6H4
2,6-di-MeC6H3
2,4,6-tri-MeOC6H2
Bu
iPr
tBu
study of the conditions we were able to obtain compound 4 in
89% yield as only one diastereoisomer (>98% de, Scheme 1).15
These results are obtained through a careful control of the
reaction time. The reaction must be stopped after 1 min because
longer reaction times determine the formation of mixtures of
epimers at benzylic carbon, presumably due to the low
configurational stability of the R-lithiobenzyl sulfides.16
5j
5k
a Isolated yield
SCHEME 3
We then studied the reactions of (S)-2 with the symmetrical
ketones 5a and 5b (Scheme 2). As in the previous case, the
observed stereoselectivity is strongly dependent on the reaction
conditions. Under the optimal conditions15 the reactions are
completely stereoselective, only yielding one â-hydroxy sulfide
(6a or 6b)17 in higher than 98% de by 1H NMR. We assign the
configuration (2S,SS) to compounds 6a and 6b (as well as to
4) by assuming that the stereochemical course of these reactions
is identical to that of the reactions of (S)-2 with N-sul-
finylimines14 and other o-sulfinylbenzyl carbanions with dif-
ferent electrophiles.13
TABLE 2. NMR Parameters of Compounds 6 and 6′ Used for
Their Configurational Assignment
Then we studied the reactions of (S)-2 with aromatic (5c-h)
and aliphatic (5i-k) aldehydes (Table 1). Benzaldehyde (5c)
afforded a 75:25 mixture of two alcohols, anti-6c and syn-6′c,
with the first one being the major one. Similar results were
obtained with aldehydes 5d-f of similar size but different
electronic density, which indicates the minor influence of this
factor on the stereoselectivity. The anti:syn ratio increased to
84:16 for the aldehyde 5g (Table 1, entry 5), and only one
diastereoisomeric â-hydroxy sulfide, 6h (>98% de), was
obtained from 5h (Table 1, entry 6). This suggests that the
stereoselectivity increases when the size of the aldehyde
becomes larger. The behavior of the alkyl aldehydes is similar.
Valeraldehyde (5i) and isobutyraldehyde (5j) afforded 60:40
mixtures of anti-6 and syn-6′ â-hydroxy sulfides (entries 7 and
8), whereas the reaction of (S)-2 with pivalaldehyde (5k)
afforded anti-6k as the only diastereoisomer (>98% de, entry
9). Compounds 6 and 6′ could be isolated by chromatography
in enantiomerically pure form.
J1,2
(Hz)
J1,OH
(Hz)
J1,2
(Hz)
J1,OH
(Hz)
compd
compd
6c
6d
6e
6i
6j
6h
9.5
9.1
7.9
8.6
10.1
9.6
8.5
9.0
9.3
8.4
9.4
9.8
6′c
6′d
6′e
6′i
6.9
7.0
6.5
6.9
6.5
2.2
1.1
2.7
4.4
6′j
and syn-6′e (obtained under the conditions of entry 3) with PCC.
Only ketone 7 was obtained (Scheme 3), indicating that both
isomers only differed in the configuration at the hydroxylic
carbon.
The anti arrangement of the heteroatomic functions assigned
to compounds 6c-e and 6h-j, obtained as major epimers in
their respective reactions, is based on their 1H NMR parameters.
In all of them (Table 2), the value observed for the vicinal
coupling constants of their (1)HC-CH(2) fragments ranges
between 7.9 and 10.1 Hz, which indicates the predominance of
the rotamer with H(1) and H(2) in an antiperiplanar arrangement.
Moreover, a very large vicinal coupling constant, JH-O-C-H(1)
(J g 8.4 Hz; see Table 2), is observed for compounds 6,
evidencing a similar arrangement between H(1) and OH. These
unusually high values for the coupling constants of the hy-
droxylic protons suggest they are involved in strong hydrogen
bonds.18 The only possible stereochemistry able to explain the
coupling constants measured for compounds 6 is that depicted
On the basis of the complete stereoselectivity control exerted
by the sulfinyl group on its benzylic position, we assume that
6 and 6′ are epimers at the hydroxylic carbon. To check this
assumption, we performed the oxidation of the couple anti-6e
(15) See the Experimental Section.
(16) (a) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. 1997, 36, 2282-
2316. (b) Basu, A.; Thayumanauan, S. Angew. Chem., Int. Ed. 2002, 41,
716-738. (c) Toru, T.; Nakamura, S. Top. Organomet. Chem. 2003, 177-
216.
(17) Higher reaction times lead to mixtures of epimers.
1036 J. Org. Chem., Vol. 72, No. 3, 2007

FIGURE 1. Favored conformation for compounds anti-6.
FIGURE 2. Transition states for reactions of (S)-2 with 5c-k.
SCHEME 4
the carbanion derived from (S)-2, which is that depicted in
Figure 2. On the basis of the steric interactions, TS-1 (affording
the anti compound) must be favored with respect to TS-2
(yielding the syn isomer). This agrees with the increase of the
stereoselectivity with the steric size of the aldehyde.
In summary, we have been able to synthesize enantiomerically
pure â-hydroxy sulfides with the two contiguous stereogenic
centers in two steps, reaction of the lithium benzylcarbanion
derived from (S)-2 with aliphatic and aromatic aldehydes and
in Figure 1, with H(1) adopting the anti arrangement with
respect to both H(2) and OH, and with the sulfinyl oxygen acting
as an acceptor of the hydrogen bond with the hydroxy group.
As the configuration of the sulfinyl sulfur should not be affected
by the reaction, the absolute configuration of compounds 6 must
be (1R,2S,SS).19 The configurational assignment of the hydroxy
thioethers anti-6 not listed in Table 2 is not so clear from their
NMR parameters. However, we have done the assignment
indicated in Table 1, by assuming similar stereochemical
pathways for all these reactions.
By contrast, compounds syn-6′ show 3J1,2 values of 6-7 Hz
(Table 2), suggesting a significant contribution of rotamers with
such protons in gauche and anti relationships, and JH-O-C-H(1)
ranging between 1.1 and 4.4 Hz. The configurational assignment
of these diastereoisomers was unequivocally confirmed in the
case of syn-6′d by X-ray analysis.20
t
subsequent hydrogenolysis of the C-SO bond with BuLi.
Experimental Section
General Method. Synthesis of â-Hydroxy Sulfides. A solution
of n-BuLi (1.6 M) in hexane (0.60 mmol, 1.2 equiv) was added
i
over Pr2NH (0.89 mmol, 1.8 equiv) in THF (3 mL) at -40 °C.
After 15 min of stirring at room temperature, the mixture was cooled
at -78 °C, and then a solution of (S)-R-(methylthio)-2-(p-
tolylsulfinyl)toluene [(S)-2] (0.50 mmol, 1.0 equiv) in THF (2 mL)
was added. After 1 min of stirring, the electrophile 4 or 5 (1.0
mmol, 2.0 equiv) dissolved in THF (4 mL) was added at -78 °C.
When the reaction was complete (1 min), the mixture was quenched
at that temperature with methanol (2 mL). The solvent was removed
under reduced pressure, and the residue was purified by flash
column chromatography.
Compounds 6a-k can be easily transformed into â-hydroxy
sulfides by C-desulfinylation with organolithium compounds
following reported procedures.21 We have illustrated these
transformations by desulfinylation of anti-6g with tBuLi22 (1.8
equiv), which affords the hydroxy sulfide 8g in 80% yield, with
the same optical purity as the precursor (Scheme 4).
Data for [1R,2S,SS]-2-(methylthio)-1-(2,4,6-trimethoxy)phe-
nyl-2-[2-(p-tolylsulfinyl)phenyl]-1-ethanol (6h): eluent for chro-
matography, hexane/Et2O/CH2Cl2, 1:2:1; yield 78%; colorless syrup;
[RD20] ) -109.6 (c 1.2, CHCl3); H NMR 7.88-7.86 (m, 1H),
1
7.63 (dd, 1H, J ) 7.8 and 1.1 Hz), 7.56-7.54 (m, 1H), 7.37 (dt,
1H, J ) 7.6 and 1.1 Hz), 7.48 and 7.25 (AA′BB′ system, 4H),
5.45 (dd, 1H, JHO,1 ) 9.8 Hz, J2,1 ) 9.6 Hz), 5.28 (d, 1H, J ) 9.6
Hz), 3.81 (s, 9H), 2.29 (d, 1H, J ) 9.9 Hz), 2.37 (s, 3H), 1.56 (s,
3H); 13C NMR δ 160.9, 158.3, 145.0, 141.0, 140.8, 140.4, 109.3,
131.1, 130.0, 129.7, 129.4, 128.4, 126.6, 125.3, 90.7, 90.8, 69.9,
The stereochemical outcome of these reactions can be
rationalized according to four-membered cyclic transition states
TS-1 and TS-2, similar to those proposed for the reactions of
other R-sulfinylbenzyl carbanions with different electrophiles
(Figure 2).13a,b,14 They result in the two possible approaches of
the aldehyde to the presumably most stable conformation of
55.5, 55.2, 21.3, 14.3; HRMS m/z calcd for C25H26O4S2 (M+
-
H2O) 454.1273, found 454.1283.
(18) In the absence of hydrogen bonds, the quick interchange of the OH
protons (absence of coupling) or the free rotation around the C-O bonds
determines average values for the vicinal coupling constants (4-6 Hz). For
references using these criteria in configurational assignment see: (a)
Kingsbury, C. A.; Aerbach, R. A. J. Org. Chem. 1971, 36, 1737-1742
and references therein. (b) Brunet, E.; Garc´ıa Ruano, J. L.; Hoyos, M. A.;
Rodr´ıguez, J. H.; Prados, P.; Alcudia, F. Org. Magn. Reson. 1983, 21, 643.
(c) Brunet, E.; Garc´ıa Ruano, J. L.; Rodr´ıguez, J. H.; Alcudia, F. Tetrahedron
1984, 40, 4433. (d) Carretero, J. C.; Garc´ıa Ruano, J. L.; Mart´ınez, M. C.;
Rodr´ıguez, J. H. Tetrahedron 1985, 41, 2419. (e) Carren˜o, M. C.; Carretero,
J. C.; Garc´ıa Ruano, J. L.; Rodr´ıguez, J. H. Tetrahedron 1990, 46, 5649.
(19) As additional data reinforcing the configurational assignment, the
anti isomers exhibit higher δOH but lower δMe values than their correspond-
ing syn epimers, as had been previously observed for similar compounds
(see ref 13d).
General Method. Oxidation of â-Hydroxy Sulfides to Ketones.
A mixture of epimeric alcohols 6e + 6′e (20 mg, 0.048 mmol, 1
equiv) was dissolved in dry CH2Cl2 (2 mL), and PCC (15.7 mg,
0.073 mmol, 1.5 equiv) was added. The mixture was stirred at room
temperature for 2 h. The solvent was partially evaporated, and the
residue was purified by flash column chromatography (hexane/
Et2O/CH2Cl2, 2:1:1) to give pure 2-(methylthio)-1-(2-naphthylphe-
nyl)-2-[2-(p-tolylsulfinyl)phenyl]ethanone (7) in 50% yield: col-
orless syrup; [RD20] ) -74.0 (c 0.2, CHCl3); H NMR δ 8.39 (s,
1
1H), 7.92-7.81 (m, 5H), 7.65-7.48 (m, 5H), 7.28 (AA′BB′ system,
2H, J ) 8.3 Hz), 6.97 (d, 2H, J ) 8.3 Hz), 6.20 (s, 1H), 2.19 (s,
3H), 2.12 (s, 3H).
General Method for C-S Desulfinylation. To a stirred solution
of 6g (43.6 mg, 0.106 mmol, 1 equiv) in THF (2 mL) was added
tBuLi (127 µL, 0.19 mmol, 1.5 M in hexane, 1.8 equiv) at
-78 °C. When the reaction was complete (5 min), the mixture was
hydrolyzed with saturated aqueous NH4Cl solution (2 mL) and
(20) X-ray data are available in the Supporting Information.
(21) Clayden, J.; Mitjans, D.; Youssef, L. H. J. Am. Chem. Soc. 2002,
124, 5266-5267.
(22) The use of Raney nickel for desulfinylation also affects the benzylic
C-S bond.
J. Org. Chem, Vol. 72, No. 3, 2007 1037

extracted with CH2Cl2. The combined organic layers were dried
over MgSO4, and the solvent was removed under reduced pressure.
The residue was purified by flash column chromatography (hexane/
Et2O/CH2Cl2, 2:1.5:1.5) to give pure 8g in 80% yield: colorless
Acknowledgment. We thank DGYCIT (Grants BQU2003-
04012 and CTQ-2006-06741-BQU) and JCYL (Grant VA07905)
for financial support and Dr. Daniel Miguel San Juan for X-ray
elucidation.
1
syrup; [RD20] ) -31.3 (c 0.2, CHCl3); H NMR 7.54-7.40 (m,
Supporting Information Available: Experimental data of
compounds 4, 6a-k (except for 6h), and 6′c-j, NMR spectra of
all compounds, and X-ray data of compound 6′d. This material is
available free of charge via the Internet at http://pubs.acs.org.
4H), 7.31-7.27 (m, 1H), 7.15-7.11 (m, 1H), 7.06-7.04 (m, 2H),
5.46 (d, 1H, J ) 9.8 Hz), 4.41 (d, 1H, J ) 9.8 Hz), 2.60 (s, 6H),
2.43 (s, 1H), 1.67 (s, 3H); 13C NMR δ 141.5, 140.0, 137.2, 136.6,
129.0, 128.8, 128.6, 127.7, 126.2, 74.4, 56.1, 22.6, 15.1.
JO062053Q
1038 J. Org. Chem., Vol. 72, No. 3, 2007