J. Org. Chem.

1991,56, 5991-5999 5991

A General Route to Enantiomerically Pure Sulfoxides from a Chiral

Sulfite+
F. Rebiere, 0. Samuel, L. Ricard, and H. B. Kagan*
Laboratoire de Synthlse Asymgtrique (URA CNRS 255), Znstitut de Chimie Molgculaire d'orsay, Universite
Paris-Sud, 91405-0rsay, France
Received July 2, 1991

Enantiomerically pure cyclic chiral sulfite (S)-7 (trans stereochemistry) has been easily obtained in two steps
from (59-ethyl lactate. This compound was found to react cleanly with many organometallicsto give crystalline
sulfmates with high regioselectivity (>%lo). Addition of a second organometallictransforms the purified sulfinate
in excellent yield into a chiral sulfoxide (100% ee) of predictable absolute configuration. The mechanism and
scope of this approach are discussed. This method completes the various other methods of preparation of chiral
sulfoxides and is especially convenient for the preparation of tert-butyl sulfoxides. Examples for the synthesis
of many chiral tert-butyl sulfoxides are given. The case of chiral sulfites derived from a Cz diol or of a chiral
monoalcohol is also proposed as a route to chiral sulfinates, and some promising preliminary results have been
obtained. The general main routes to obtain chiral sulfoxides from sulfites are also discussed.

Introduction Scheme I. Various Possibilities of Conversion of Sulfites

Chiral sulfoxides are useful auxiliaries in asymmetric into Chiral Sulfoxides
The preparation of chiral sulfoxides with
high enantiomeric excess is still of great interest. They
are potentially of interest in the field of biology and in
material science, for example, in the synthesis of liquid
crystals with ferroelectric properties? The known
methods for their preparation (excluding resolution) can
be divided into two classes.
The first is the widely used Andersen method.1° It is
based on the conversion of chiral sulfiiates into sulfoxides
with various types of organometallics. The reaction occurs
with full inversion of configuration at su1fur.l' The
starting sulfinate is usually obtained from a chiral alcohol
as a mixture of epimers at sulfur which have to be sepa-
rated. A convenient crystalline sulfinate to use is (&-
(lR)-menthylp-tolyl sulfiinate because crystallization can
be combined with epimerization at sulfur (catalyzed by
HCl).? Both enantiomers are now available (Aldrich),thus
making very easy the synthesis of various p-tolyl sulfoxides.
This method has also been applied to the synthesis of A-C : different leaving groups
D : diastereotopicleaving groups
menthyl (4-chlorophenyl)~ulfiiate.~~ Although some other E-F : enantiotopic leaving groups
routes are described for the synthesis of diastereomeridy : stated for a chiral moiety
pure alkylsulfinates,ls yields are too low for large-scale
preparations of chiral sulfoxides. In what follows we propose a new approach for the
The second method is the asymmetric oxidation of synthesis of various classes of enantiomerically pure sul-
sulfides and has been efficiently employed in some specific
cases. Chiral sulfides can be prepared from natural com-
pounds such as camphor. Oxidation of m-PCBA when (1) See refs 2-6 for general reviewe. Some recent applications of
sulfoxides to synthesis of natural producta or biologically active com-
controlled by the chiral backbone affords one diastereo- pounds can be found in refs 6-8.
mer.14J6 The chiral sulfoxide has a limitation in its (2) SolladiB, G.Synthesis 1982, 185.
structure; one group necessarily derives from the natural (3) Barbachyn, M. R.; Johnson, C. R. In Asymmetric Synthesis;
Morrison, J. D., Scott, J. W., Eds.;Academic Press New York, 1983, VoL
product. The sulfoxide structure can be rendered more 4, p 227.
flexible by asymmetric oxidation of prochiral sulfides, and (4) Mikolaczyk, M.; Drabowicz, J. Top. Stereochem. 1982, 13, 333.
enzymatic oxidation is sometimes highly enanticwelective.l6 (6) Posner, G.Acc. Chem. Res. 1987, 20, 72.
(6) Hua, D. H.; Bharathi, S. N.; Takuaagawa, F.; Tsujimoto, A.; Pan-
Also, the action of some oxidants in presence of various agadan, J. A. K.; Hung, M.; Bravo, A.; Erpelding, A. M.J. Org. Chem.
modifiers of the Sharpless is very efficient. We 1989,64, 6669.
have developed a reagent (Ti(OiPr)4/(+)-DET/H,O = (7) Davis, F.: Kern, J. R.: Kurtz. L. J.; Pbtar, J. R. J. Am. Chem. SOC.
1988,110,7873.
1:2:1) that leads to asymmetric oxidation of sulfides such (8) Pyne, E. S.; Bloem, P.; Chapman, S. L.; Dixon, C. E.; Griffith, R.
as aryl-S-CH, with ee up to 95-96%.19~20~22-27 Unfortu- J. Om. Chem. 1990.55.1086.
nately, the method is less spectacular for the synthesis of (SjNishide, K.; Nakyama, A.;Kueumoto, T.; Hiyama, T.; Takehara,
dialkyl sulfoxides (ee < 80%). Oxidation with hydroper- S.; Shoji, T.; Osawa, M.; Kuriyama, T.; Nakamura, K.; Fujisawa, T. Chem.
Lett. 1990, 623.
oxides in the presence of BSA2*(ee's up to 90%) or with (10) (a) Anderaen, K. K. Tetrahedron Lett. 1962,18,93. (b) Andereen,
some chiral oxaziridinesmis efficient (ee's up to 96%)but K. K.; Gaffield, W.; Papanikolaou, N. E.; Foley, J. W.; Perkins, R. I. J.
not sufficiently general and not always easy to perform on Am. Chem. SOC. 1964,88,6637.
(11) Jacobus, J.; Mislow, K. J. Am. Chem. SOC.1967,89, 5228.
a large scale. (12) Burgess, K.; Henderson, I. Tetrahedron Lett. 1989, 30, 4325.
(13) Andersen, K. K.; Bujnicki, B.; Drabowicz, J.; Mikolaczyk, M.;
OBrien, J. B. J. Org. Chem. 1984,49, 4070.
'This paper is dedicated to Professor J. K. Stille, who died in (14) De Lucci, 0.; Lucchini, V.; Marchioro, C.; Ville, G.; Modena, G.
1989. J. Org. Chem. 1986,51, 1457.

0022-3263/91/1956-5991$02.50/00 1991 American Chemical Society

6992 J. Org. Chem., Vol. 56, No.21,1991 Rebiere et al.
foxides, especially sulfoxides bearing two alkyl groups.
This synthesis is based on the use of chiral sulfite 7 as a
starting material.

Conversion of Sulfites into Chiral Sulfoxides

Ph

Me x>.c Me
I

Sulfites are compounds that have been known for a long 1 2

time (their chemistry has been reviewed in 1963 by Van Figure 1. Aminosulfites.
Woerdenmand more recent information is found in ref 31,
for example). It was demonstrated in 1952 for the first
time that sulfur in sulfites can be a stereogenic center due
to its stable tetrahedral geometry allowing separation of
epimeric steroidal cyclic ~Ullites.~ Since then, many cyclic HO HO OH
sulfites with a stereogenic sulfur have been prepared, es- 3 R-M@,R'-Ph
pecially with five- or six-membered rings; for example, see 4 R=Me,R-H
refs 33 and 34.
5 R-Me,R=Me
The usual starting material for sulfite chemistry is
thionyl chloride, a low-cost sulfur compound. It can react 6 R-Ph,R'-Ph
with an alcohol to be converted into a chlorosulfite and Figure 2. Preparation of various chiral diols from ethyl lactate.
then into a sulfite.
Conversion of sulfites to chiral sulfoxides R'-S(0)-R2 M e 9 Ph CHpCIp - 4 O O C
Me
H o 8 . h + H
Me
s a g h
needs two consecutive substitution reactions at sulfur that
introduce R' and R2groups. At some point, it is necessary HO OH soc12 Et3N
also to make use of a source of chirality. In Scheme I are oo2:o ,J"\o
analyzed all the possibilities for the conversion of a sulfite 3
7 8
into a chiral sulfoxide. This general classification will be
briefly commented on. In our analysis, it will be assumed Figure 3. Synthesis of cyclic sulfites trans-7 + cis-8.
as usual that nucleophilic substitution at sulfur occurs with tions allowing the transformation of a sulfite into a chiral
fullinversion of configuration.'J1 Different structural types sulfoxide. Sulfite A is already chiral at sulfur. If the
of sulfites can be envisaged as starting material. The first chemical reactivity of OR and O R groups are sufficiently
substitution by organometallics R'M provides a sulfinate different, one expects a transfer of chirality leading to a
R'-S(O)-OR if one can avoid further transformation into chiral sulfinate. In sulfite C there is also already an
symmetrical sulfoxides R'-S(0)-R1. In order that the asymmetric sulfur but the two different leaving groups are
synthetic method becomes useful, it is also necessary that chiral, and in the intermediate situation B there is one
at this stage an asymmetric sulfur is created with high chiral and one achiral leaving group. In sulfite D the two
stereoselectivity. The subsequent step, e.g., the action of chiral leaving groups are chemically equivalent with the
organometallic R2M on sulfinate R'-S(0)-OR, should same absolute configuration; however, due to the tetra-
provide the final sulfoxide R'-S(0)-R2 as is the case with hedral geometry a t sulfur they are not related by a sym-
the Andersen method.1° Scheme I shows the main reac- metry operation (mirror or axis). They have diastereotopic
relationshipss and should have different reactivities in the
presence of an achiral reagent such as RIM. In E and F
(15) Goodrige, R. J.; Hambley, T. N.; Haynes, R. K.; Ridley, D. D. J. cases, one cannot expect any discrimination between the
Org. Chem. 1988,63, 2881.
(16) For a review of enzvmatic oxidations of ~ & a l sulfides. see ref leaving groups since sulfites are achiral (symmetry plane).
17.' Chloroperoxidase w& also recently used -with excellent resulta.18 These compounds have two enantiotopic leaving groups.
(17) Holland, H. Chem. Rev. 1988,88,473. Stereoselective monosubstitution should occur in principle
(18) Colonna. S.: Ganeero. N.: Manfredi.. A.:. Caeella.. L.:. Gulloti. M. J.
Chem: SOC., Chem,' C o b & . 1988,1451. if one combines an organometallic reagent R'M with a
(19) Pitchen, P.; Kagan, H. B. Tetrahedron Lett. 1984,25,1049. chiral auxiliary Z* (acting as a coreagent or as a catalyst).
(20) Pitchen, P.; Dunach, E.; Deshmukh, M. N.; Kagan, H. B. J. Am. In conclusion, the various approaches (A-F) described
Chem. SOC. 1984,106,8188. in Scheme I need to fulfill four conditions: (i) easy syn-
(21) Di Furia, F.; Modena, G.;Seraglia, R. Synthesis 1984, 325.
(22) Dunach, E.; Kagan, H. B. New J. Chem. 1985,9, 1. thesis of the starting sulfites having the right stereochem-
(23) Kagan, H. B.; Dunach, E.; Pitchen, P.; Samuel, 0.; Kagan, H. B. ical features; (ii) high yield in sulfinates a t the first nu-
Pure Appl. Chem. 1985,57,1911. cleophilic substitution (avoiding competitive formation of
(24) Kagan, H. B. In Stereochemistry of Organic and Biorganic RLS(O)-R'); (iii) high regioselectivity, diastereoselectivity,
Transformations; Bartmann, W,, Sharpless, K. B., Eds.; VCH Wein-
heim, 1987; p 31. or enantioselectivity during the first step leading to a
(25) Zhao, S. H.; Samuel, 0.;Kagan, H. B. Tetrahedron 1987,43,5135. sulfinate; and (iv) high stereospecificity for each substi-
(26) Zhao, S. H.; Samuel, 0.; Kagan, H. B. Org. Synth. 1989,68,49. tution reaction.
(27) Samuel, 0.; Ronan, B.; Kagan, H. B. J. Organomet. Chem. 1989, We decided to explore the various possibilities offered
370, 43.
(28) (a) Sugitomo,T.; Kokubo, T.; Myazaki, J.; Tanimoto, S.;Okamo, by Scheme I, and we present here some of our results.
M. Bioorg. Chem. 1981, 10, 311. (b) Colonna, S.; Gaggero, N. Tetrahe- First, we concentrated our efforts on case B, which rep-
dron Lett. 1989, 30, 6233. resents a chiral sulfite with two different leaving groups
(29) Davis, F. A.; ThimmaReddy, R.; Weiamiller, M. C. J. Am. Chem.
SOC. 1989,111, 5984. (for a preliminary report see ref 36). We also started to
(30)Van Woerden, H. F. Chem. Rev. 1963, 63, 557 and references investigate case D where the chiral leaving group is derived
quoted therein. from the same chiral alcohol. This will be developed in
(31) Anderaen, K. K. In Comprehensive Organic Chemistry; Barton,
D., Ollis, W. D., Eds.; Pergamon Press: Oxford, 1979; Vol. 3, p 367. the following sections, following a brief report of the rel-
(32) Henig, P. T.; Ehrenstein, M. J. Org. Chem. 1912,17,724. evant earlier literature.
(33) de la Thare, P. B. D.; Klyne, W.; Millen, D. J.; Pritchard, J. G.;
Wataon, D. J. Chem. SOC.1916, 1813.
(34)Pritchard, J. G.;Lauterbur, P. C. J. Am. Chem. SOC.1961,83, (35) Mislow, K.; Raban, M. Top. Stereochem. 1967, I , 1.
2105. (36) Rebiere, F.; Kagan, H. B. Tetrahedron Lett. 1989, 30, 3659.
Pure Sulfoxides from a Chiral Sulfite J. Org. Chem., Vol. 56, No. 21, 1991 5993
M: ,Ph - Table I. 'H NMR of Sulfinates 9, 10, 13, and 14
H on Me on
asymmetric asymmetric
entry4 sulfinate center center
1 9 (R' = Me) 4.80 1.15
3 10 (R' = Me) 5.15 1.40
k 2 9 (R' = Et) 4.95 1.05
10 (R' = Et) 5.35 1.35
3 9 (R' = n-wtyl) 4.85 1.05
10 (R' n-wtyl) 5.45 1.35
4b 9 (R' = benzyl) 4.70 1.06
10 (R' = benzyl) 5.30 1.35
Figure 4. Pathways for obtention of sulfoxides from sulfite 5' 9 (R1 = vinyl) 4.95 1.10
trans-7. 10 (R' = vinyl) 5.20 1.45
6 9 (R' = t-Bu) 4.70 1.20
10 (R' = t-Bu) 5.40 1.35
Early Reports on the Use of Sulfites and Related 7 9 (R' = mesityl) 4.85 1.15
Compounds in Asymmetric Synthesis. Mikolaczyk and 10 (R' = mesityl) 5.45 1.40
Drabowicz discovered that tertiary-alqhagnesium halides 8 13 (R' t-Bu) 5.25 1.25
are able to transform symmetrical sulfites into tertiary- 14 (R' = t-Bu) 4.70 1.20
alkyl~ulfinates.~~ In 1988, these authors modified the Spectra run in CDCl,, unless otherwise stated. In CD3COCDp
experimental conditions and obtained chiral sulfimtes (ee's In CD3CN.
up to 70%) by addition of alkaloids.% This asymmetric
synthesis corresponds to case E in Scheme I. Cases B or Table 11. Synthesis of Chiral Sulfinates 9 or 10 from
C are unknown in literature, but a related process has been Sulfite 7 (Scheme 111)
described for aminosulfiites1 and 2 by Wudl and Leea and isolated yield' (a)
by Hiroi et ala,"' respectively. In these examples the S-O entry RIMo 9/10 ratiob of pure sulfinate
bond is cleaved rather than the S-N bond (Figure 1). 1 MeLi 75/25 55 9 (R' = Me)
Preparation of a Chiral Sulfite. We decided to study 2 MeMgI 80/20 70 9 (R' = Me)
class B or C of Scheme I by trying to create an asymmetric 3 EtMgBr 92/9 80 9 (R' = Et)
sulfur under the influence of a chiral auxiliary (alkoxy 4 n-OctMgBr 95/5 60 9 (R' = n-wtyl)
group OR*). We also planned to prepare a cyclic sulfite 5 t-BuMgBr 5/95 60 10 (R' = t-Bu)
6 t-BuMgC1 10/90 70 10 (R' = t-Bu)
expecting an enhancement of stereoselectivity and re- 7 t-BuLi d
gioselectivity at the various stages of the process leading 8 BnMgCl 70/30 50 9 (R' = CHZPh)
ultimately to chiral sulfoxides. We envisaged to synthesize 9 BnMgBr 55/45 e
five-membered cyclic sulfites deriving from the most easily 10 HC=CHMgCl 95/5 50 9 (R' = vinyl)
available chiral1,2-diols such as 3-6, lactic acid being one 11 MesMgBr 12/88 70 10 (R' = mesityl)
12 PhMgBr 50/50 e
of the cheapest chiral compounds. Various chiral diols
have been prepared from ethyl lactate by addition of a Ohaction performed in THF at -78 OC (except entry 5, 25 "C)
Grignard reagent (Figure 2).41 with 1 equiv of R'M. bMeasured by 'H NMR on the crude prod-
We selected the diol 34142(prepared in 1 mol scale in uct. 'Purification by crystallization. dDi-tert-butyl sulfoxide is
obtained. eSeparation of the two isomeric sulfinates by crystalli-
75% yield) for the synthesis of cyclic sulfite (Figure 3). zation failed.
The traditional procedure was used to synthesize the
chiral sulfite (thionyl chloride, triethylamine)?O The re- necessary to overcome several difficulties:
action was not stereoselective and gave a 1:l mixture of (i) The first organometallics R'M should avoid over-
cis and trans sulfites (reaction performed at room tem- eaction on intermediate sulfinate (with formation of R'-
perature with slow addition of thionyl chloride to diol 3 S(0)-R').
and triethylamine dissolved in methylene chloride). It was (ii) Sulfinate must be generated by a regioselective
satisfying to determine the experimental conditions giving cleavage involving only one of the two potential leaving
a large preference (90:lO) for one diastereomer 7 (trans groups (formation of either 9 or 10).
stereochemistry, see below). This was obtained stereo- (iii) The substitution reactions at sulfur should occur
chemically pure in 70% yield after crystallization in hex- with the highest possible stereospecificity (most probably
ane. The improved procedure involves an inverse addition inversion, as found in many sulfur compounds4J1).
of reactants, e.g., slow addition at -40 "C of triethylamine We were encouraged by the report of Mikolaczyk and
into a methylene chloride solution of diol 3 and thionyl Drabowicz3' to start our experiments by using tert-bu-
chloride. Cyclic sulfite 7 is a stable compound that can tylmagnesium halides. We expected a good yield of sul-
be stored for a long time. It contains a stereogenic sulfur finate. Indeed, we were delighted to get tert-butylsulfiinate
in a chiral molecule and represented a promising starting in high yield; moreover, the regioselectivity in the ring
material for our project. cleavage is excellent (WlO),affording mainly sulfiiate 10
Reactivity of Cyclic Sulfite 7 toward Organo- (R' = tert-Bu). This pure sulfinate has been obtained in
metallics. In order to transfer efficiently the chirality 70% yield after crystallization. The structures of isomeric
from sulfur of 7 into a sulfoxide 11 or 12 (Figure 4), it was sulfinates 9 (R' = t-Bu) and 10 (R' = t-Bu) were estab-
lished by 'H NMR,H and Me at asymmetric center being
significantly deshielded in 10 by respect to 9 (Table I).
(37) Mikolaczyk, M.; Drabowicz, J. Synthesis 1974, 124. The large difference in chemical shifts also allows one
(38) Drabowin, J.; Legedz, 5.;Mikolaczyk, M. Tetrahedron 1988,4,
5243. to evaluate by 'H NMR the ratio 109 on the crude product
(39) Wudl, F.; Lee,T. B. K. J. Am. Chem. SOC.1973,95,6355. (prior to crystallization). The tert-butylsulfinate 10 (R'
(40)Hiroi, K.;Sato, S.; Kitayame, R. Chem. Lett. 1980, 1595. = t-Bu) is obtained devoid of its epimer at sulfur. This
(41)Rebiere, F.;Riant, 0.;Kegan, H. B. Tetrahedr0n:Asymmetry
1990,1,199. epimeric compound 13 was prepared by the action of t-
(42) Devaut, R.; Malhsr, U.; Braon, M. Chem. Eer. 1988, 121, 397. BuMgCl on cis sulfiite 8 and was isolated as a pure material
5994 J. Org. Chem., Vol. 56, No.21, 1991 Rebiere et al.
Table 111. Synthesis of Enantiomerically Pure Sulfoxides 11 or
12 from Sulfinate 9 or 10 and Orrtanometallic R'M

temp eee
entry sulfinatea R W ("C) (a) config
8 1 3 (major) 14 1 10 (R'= t-Bu) MeLid 25 100 R
2 10 (R'= t-Bu) PhLid 25 100 S
Figure 5. Obtention of sulfinates from sulfite cis-8. 3 10 (R' = t-Bu) n-BuLid 25 100 R
4 10 (R' = t-Bu) H&=CHMgCld 25 100 R
after crystallizationfrom the crude product (1314= %lo). 5 10 (R' = t-Bu) 1-[(2-CH2)C&,N]Lie -72 100 Rf
'H NMR of epimeric sulfinates 10 (R' = t-Bu) and 13 (R1 6 10 (R' t-Bu) PhCHzMgBF 25 100 R
7 10 (R' = t-Bd Ph(CH2)zMgBP 25 100 R
= t-Bu) are different. However, we never detected 13 by 8 10 (R1 = mesityl) MeLid 0 100 R
'H NMR when preparing 10 (R' = t-Bu); similarly, 10 (R' 9 10 (R' = mesityl) PhMgBF 0 100 R
= t-Bu) was absent in crude 13 (R' = t-Bu). These ob- 10 9 (R'= Me) n-OctMgBP 0 100 R
servations establish that the substitution reaction at sulfur 11 9 (R'= Et) PhLie 0 100 R
12 9 (R'= Et) PhCHzMgBP 25 100 R
in cyclic sulfites 7 or 8 occurs with a very high degree of 13 9 (R' = n-octyl) MeMgI' 25 100 S
stereoselectivity (>98%). This conclusion seems also to 14 9 (R' = PhCH2) EtMgBP 0 100 s
hold for reaction of 7 with all the organometallic reagents
"Stereochemicallypure 9 or 10 prepared from 7. Sulfoxides 11 and
that were later used (Table 11). 12 are derived from sulfinates 9 and 10, respectively (see Figure 4).
In order to keep the possibility of stopping the reaction *Quantitativeyield after isolation of product by flash chromatography.
a t the sulfinate stage, we tried another bulky reagent, Measured by 'H NMR with E u ( h f ~ or ) ~ (R)-(3,5-dinitrobenzoyl)-l-
namely mesitylmagnesium bromide. Indeed, the yield is phenylethylamine" and by comparison with maximum specific rotation
excellent (go%), with preferential formation of sulfinate (see Table IV). dProcedure 1 (addition of R2M on sulfinate), see Ex-
perimental Section. 'Procedure 2 (addition of sulfinate on RTM), see
10 (R' = mesityl) (109= 8812). Pure sulfinate 10 (R' = Experimental Section. f Reference 64.
mesityl) is isolated in 65% overall yield after crystalliza-
tion. The sulfinates 10 (R' = t-Bu or mesityl) are stable gives sulfinate 10,while when R' is small the sulfinate 9
compounds, easy to store, and excellent precursors in is the major product. A gratifying behavior of cyclic sulfte
asymmetric synthesis of many sulfoxides as it will be de- 7 is its ability to react with all kinds of Grignard reagents
tailed in the next paragraph. giving sulfinates and not symmetrical sulfoxides, at the
The next step in the investigation of the conversion of difference of acyclic sulfite^.^ This could be related to an
sultite 7 into sulfinates was to consider the use of nonbulky increased reactivity of five-membered cyclic sulfites with
organometallics, namely RIM where R1 is a linear alkyl. respect to their open analogues.44*
Large amounts of byproduct R'-S(0)-R' should be ex- Transformation of Sulfinates 9 or 10 into Chiral
pected if one refers to the behavior of acyclic sulfites?' We Sulfoxides 11 or 12. In principle, the path from sulfinates
found that linear alkyl or vinyl Grignard reagents (R' = 9 and 10 to chiral sulfoxides should not present major
Et, n-octyl, or vinyl) give in excellent yields the corre- difficulties since it corresponds to a conversion widely used
sponding sulfinates and no formation of symmetrical in the Andersen method.1° As in the Andersen method,
sulfoxides. Surprisingly, these Grignard reagents led with one expects inversion of configuration during the substi-
high selectivity (>9010)to the alternate sulfinates 9 (R' tution step." One special feature of 9 or 10 is the presence
= Et, n-octyl or vinyl). MeMgI is less regioselective (80:20). of an hydroxyl group, which will be transformed into an
Structure 9 has been established by 'H NMR (Table I). alcoholate by reaction with 1 equiv of organometallic
Up to now all the sulfinates 9 or 10 have been isolated as reagent. By using 2 molar equiv of various organometallics
crystalline compounds that are easy to obtain chemically in THF at room temperature of 0 "C the expected sulf-
and stereochemically pure by crystallization in good yields oxides 11 or 12 were produced and isolated in quantitative
(6O-80% 1. Results concerning synthesis of sulfinates are yield by flash chromatography (Table 111). Grignard
listed in Table 11. Sulfinates 9 cannot be stored at room reagents or organolithiums are equally suitable for the
temperature, by contrast with 10, presumably because of reaction. In all the investigated cases it has been found
some instability induced by the vicinity of a sulfite function that the recovered sulfoxides are enantiomerically pure.
and a benzylic carbon atom. Crystalline sulfinates 9 de- The ee's were measured by 'H NMR using Eu(hfc), as
composed a t room temperature (within 10 mins to a few chiral shift reagent or (3,5-dinitrobenozyl)-l-phenyl-
days according to the structure), forming diphenylacetone. ethylamine as chiral solvating reagent" and by specific
R'-S(O)-@ group seems to play the role of a leaving group rotation of a purified sample.48 The absolute configuration
giving a stabilized carbocation precursor of diphenyl- of some of the final sulfoxides was known (e.g., Table IV),
a~etone."~A typical procedure for avoiding the decom- allowing us to assign absolute configuration a t the sulfur
position of sulfinates 9 is to store the recrystallized sul- of sulfinate (as indicated in 9 and 10,Scheme 11). These
fiiates at -20 O C . In those conditions the compounds can
be kept for several weeks.
A mixture of sulfinates 9 and 10 (70:30to 5 0 5 0 ) is (44) It has been established that cyclic sulfites with a five-membered
produced by the reaction of some reagents such as ring hydrolyze in base faster than do acyclic analogues.4
(45) (a) Brestow, P. A.; Tillet, J. G.;Wiggins, D. E. J. Chem. SOC.B
PhCH2MgC1, PhCH2MgBr, or PhMgBr. The usual ex- 1968,1360.(b)Kaiser, E. T.; Panar, M.; Weatheimer, F. H. J. Am. Chem.
perimental conditions for the preparation of sulfinates 9 SOC.1963,85,602.
or 10 is to allow sulfite 7 to react with RlMgX in THF at (46) We are currently checking the possibility to use the cyclic sulfite
derived of achiral glycols for sulfinate preparation.
-78 "C. Organolithium reagents are less regioselective and (47) Deshmukh, M. N.; Dunach, E.; Juge, S.; Kagan, H. B. Tetrahe-
sometimes afford symmetrical sulfoxides R'-S(O)-R*. By dron Lett. 1984,25,3467; Erratum: Ibid. 1985,26,402.
looking at the above data (see also Table 11),one concludes (48) We checked that there is not change in ee durlng the purification
that when R' is bulky the regioselective cleavage mainly of sulfoxides by flash chromatography on silica gel. Chromatography on
achiral phase of some partially resolved compounds can give fractions
with different ee'~.'~m
(49) Charles, R.; Gil-Av, E. J. Chromatogr. 1984,298,516.
(43) The ease of benzylsulfiinatee to generate a carbocation is known: (50) Taai, W. L.; Hermann, K.; Hug, B.; Rohde; B.; Dreiding, A. Helu.
Braverman, S.; Duar, Y. Tetrahedron 1990,46,2975. Chrm. Acta 1985,68,2238.
Pure Sulfoxides from a Chiral Sulfite J. Org. Chem., Vol. 56, No. 21, 1991 5995

Table IV. Absolute Configuration of Sulfoxides Prepared in Table I11

lit
sulfinate sulfoxide R1-S(0)-R2 conP [alD conf [alD ref
10 (R' = t-Bu) t-Bu-S(0)-Me R -10.5, CHClS R -10, CHClS 20
-3.6, acetone R -4.2, acetone 62
10 (R' t-Bu) t-Bu-S(O)-Ph S -175, CHCls R 175, CHCls 38
10 (R' t-Bu) t-Bu-S(O)-n-Bu R 125, acetone Sb 125, acetone 63
10 (R' t-Bu) t-Bu-S(O)-CH-CHZ R 283, acetone
10 (R' = t-Bu) t-Bu-S(O)-[ (2-CHz)CSH,N] R 304, acetone 64
10 (R' = t-Bu) t-Bu-S(0)-Bn R 279, EtOH R 280, EtOH 65
10 (R' = t-Bu) g-Bu-S (O)-CH2CH2Ph R 95, CHCl3 R 26, CHClS 66
10 (R' = Mes) Mes-S (0)-Me R 45, EtOH R 43, isooctane 11
9 (R' = Mea) Mes-S(0)-Ph R 256, acetone 203, acetone 67
9 (R1 = Me) Me-S(0)-n-Oct R -63, acetone R -62, acetone 20
9 (R' = Et) Et-S(0)-Ph R 176, EtOH R 177, EtOH 61
9 (R' = Et) Et-S(0)-Bn R 105, CHCl, R 106, CHCl3 61
9 (R' n-oct) N-Oct-S(0)-Me S 62.5, acetone R -62, acetone 20
9 (R' = Bn) Bn-S(0)-Et S -105, CHCl3 R 106, CHClS 61
Absolute configuration deduced from the synthetic scheme (Figure 4) involving two consecutive inversions of configuration. It is the
only discrepancy between absolute configuration deduced by our method and data of literature.
assignments are based assuming inversion of configuration stereospecific, allowing excellent transfer of chirality from
during the substitution step. As expected from Figure 3, sulfite 7 to sulfoxide 11 or 12. The purification of inter-
sulfinates 9 lead to enantiomerically pure (epIS1sulfoxides mediate sulfinate involves removal of the minor constitu-
11 (e.g., R = ethyl phenyl sulfoxide) while sulfinate 10 gives tional isomer, which also has opposite absolute configu-
enantiomerically pure sulfoxides 12 enantiomers of 11 (e.g., ration at sulfur (Figure 4). This is a key operation to get
(S)-tert-butyl phenyl sulfoxide). In all cases, the un- ep sulfoxides. A one-pot synthesis of ethyl phenyl sulf-
changed chiral auxiliary diol 3 is recovered in quantitative oxide has been performed without isolation of sulfinate.
yield, allowing regeneration of chiral sulfite 7. The sequential addition at -78 O C of EtMgBr followed by
Synthesis of Each Enantiomer of a Given Sulf- PhLi transformed sulfite 7 into (R)-ethyl phenyl sulfoxide
oxide. (S)-Lactic acid (and its derivatives) is the enan- 11 of 85% ee. The addition of EtMgBr produces sulfinatea
tiomer that is commercially available. It was therefore 9 and 10 (R = Et) in the ratio 92:8. Isolation of pure 9 (R
important to devise a process starting from cyclic sulfite = Et) (60% yield) and further reaction with PhLi gives
(S)-7 that will generate each enantiomer of a sulfoxide. A (R)-ethyl phenyl sulfoxide 11 of 100% ee. Comparisons
simple way is to permute R' and R2 in organometallics of the data are in excellent agreement with a full stereo-
involved in the two substitution steps. This has been specificity at each substitution step. If one retains the
realized in the synthesis of methyl n-octyl sulfoxide. The hypothesis of inversion of stereochemistry,'" and taking
route involving the sequence MeMgI and n-octylMgBr into account the known absolute configuration of Sulfoxides
gave enantiomerically pure R sulfoxide 11 (R' = Me, R2 11 or 12 generated from sulfinates 9 and 10, respectively,
= n-octyl), while the alternate sequence n-octylMgBr and one concludes that cyclic sulfite 7 (major epimer) has the
MeMgI afforded ep S sulfoxide 12 (R' = n-octyl, R2 = Me). trans stereochemistry (configurationRS). Sulfinates 9 and
Similarly, (8)- or (R)-benzyl ethyl sulfoxide has been ob- 10 should have Rs and Ss configurations, respectively.
tained from benzylsulfinate 9 (entry 8, Table 11) or Since trans stereochemistry in sulfide 7 has been ob-
ethylsulfinate 9 (entry 3, Table 11)by addition of EtMgBr tained by an indirect way it was necessary to confirm this
(entry 14, Table 111)or PhCH2MgBr (entry 12, Table 111), assignment. 'H NMR of epimeric sulfites 7 and 8 don't
respectively. The method should apply in all cases where show significant differences allowing the assignment of
R' and R2 are both small groups (as in the previous ex- their relative configuration. However, sulfite 7 gave mo-
ample) or bulky groups (e.g., t-Bu or mesityl). Unfortu- nocrystals suitable for a X-ray crystallographic study (for
nately, if one group is bulky and the other small (e.g., t-Bu a preliminary report see ref 54). Sulfite 7 has a trans
and Me), the groups permutation will necessarily lead to stereochemistry. The structural information is available
the same R sulfoxide, since the inversion in the order of in the auxiliary material. The five-membered ring has a
introduction of the groups is "on offset" by the change in distorted twist conformation with the sulfinyl group having
the side cleavage of sulfite 7 during the sulfinate synthesis. a pseudoaxial orientation. The S-0-S angle is 93O.
Fortunately, (R)-isobutyl lactate has been recently The X-ray structure of 7 confirms the assignment of
marketed (Fluka). R Diol is easily derived from that ester, configuration at sulfur in sulfiiates 9 and 10 if one assume8
giving access to the enantiomer of sulfite 7 and then to that the two consecutive substitutions likely occur with
sulfoxides 11 or 12 (R' small and R2 bulky). inversion of stereochemi~try.~~*~ It was interesting to
In conclusion, we set up conditions for the synthesis of establish directly at least in one case the stereochemistry
the desired enantiomer of a given sulfoxide. A wide variety at sulfur in a sulfinate. Single-crystal X-ray structure of
of sulfoxides is now available by this approach, the only tert-butyl sulfinate 10 (R' = t-Bu) could be realized (see
drawback being the low chemical yield observed where auxiliary materials for details). The stereochemistry at
some organometallics (like PhMgBr) react with 7, giving
mixtures of sulfinates 9 and 10 in a ratio close to 1:l. ~ ~~~~

(54) Ricard, L.; Rebiere, F.;-Kagan, H. B. C. R. Acad. Sci. Paris, Ser.

Stereochemistry of Sulfite 7 and Sulfinates 9 and I1 1991, 312, 225.
10. As shown above, all the substitution steps are highly (55) Two consecutive substitutions with retention will also correlate
absolute configuration at sulfur in 7 and absolute configuration of eulf-
oxides 9 and 10. This scenario could not be immediately rejected because
(51) We prefer to use the ex ression enantiomerically pure (ep) as of the presence of a five-membered ring in 7 and a y-alcoholate moiety
previously propoeed by Seebach8instead of homochiral, which can have during the second substitution at sulfur.
several meanings.0 (56) A tandem inversion-retention (or vice-versa) is very unlikely un-
(52) Seebach, D.; Hungerbllhler, E. Mod. Synth. Methods 1980, 93. less an additional step is introduced by transfer of sulfinyl from one
(53) Eliel, E.; Wilen, S. Chem. Eng. News 1990, 10, 2. oxygen to the other one in sulfinate during reaction with R W .
5996 J. Org. Chem., Vol. 56, No.21, 1991 Rebiere et al.
Scheme 11. Trigonal Bipyramidal Transition States or
Intermediates

15 16

Figure 6. Chlorosulfite intermediates involved in sulfite for-

R' R' mation.
R' small 9
Scheme 111. Posrible Mechanisms for the Formation of
trans-7 Sulfite

I
R'
R'
R' bulky 10

3
\ n
's'
R' -*' \
15b
8
sulfur is S in this compound in full agreement with the
hypothesis of inversion of configuration at each substitu- be prepared in high yield from diol 3 (7:8 = 9O:lO). The
tion step. diastereoselective formation of 7 has been achieved in very
Sulfiinate 9 (R= t-Bu) (100% de) has also been treated specific conditions, namely the slow addition of triethyl-
by 1 equiv of t-BuMgC1 at room temperature for 1 h amine into a CH2C12solution of diol 3 and thionyl chloride
(formation of alcoholate). The recovered material after (reaction performed at -40 "C). The reverse addition of
hydrolysis was pure 9 (R = t-Bu) devoid of a trace of its thionyl chloride to a solution of 3 and triethylamine leads
diastereomer 10. This shows that the diastereomer ratio to a mixture of the two diastereomers (7:8 = 1:l). We
95:5 to 9010 observed in the synthesis of 9 (R = t-Bu) checked that the reaction is not under thermodynamic
(Table 11) is not the result of an equilibration by sulfinyl controkpure 7 or 8 does not epimerize in the above con-
transfer from one oxygen to the other. An equilibration ditions (or in presence of some HCl). The sulfite formation
is also unlikely when 9 is transformed into sulfoxides 11, involves a chlorosulfite intermediatem In the present case
although in that case it becomes immaterial if the intra- it is reasonable to assume that formation of chlorosulfite
molecular migration occurs with retention of confiiation. 15 is preferred over chlorosulfite 16 because of higher
Regioselectivity in the Cleavage of Cyclic Sulfite reactivity of the secondary alcohol (Figure 6). The sulfur
7. We propose to interpret the selective synthesis of either in 15 is already an asymmetric center.
sulfinate 9 or 10 by the formation of a trigonal bipyramidal One can envisage two extreme mechanisms to explain
transition state or intermediate (I or 11, Scheme 11). In preferred formation of trans sulfite 7. In the first one, a
I, the bulky group (O-CPhJ placed itself in the equatorial slow and stereoselective esterification of 3 will provide 15
position. In this species, the incoming and leaving groups (as diastereomer 15a), and then a fast cyclization with
are both in apical positions and the ring cleavage in sulfite inversion of stereochemistry will lead to 7 (Scheme 111).
7 will occur giving a secondary alcohol and hence eulfiiate The other possibility is to consider that the stereoselective
9. When the incoming nucleophile is bulky it will severely formation of 7 is controlled at the cyclization step by a slow
interact with the O-CPh2 moiety linked to equatorial ox- closure of 15a combined to a fast epimerization equilibrium
ygen. The alternate structure I1 where the 0-CPh2 is between 15a and 15b. We presently favor this latter hy-
apical becomes favored, and as a consequence the altemate pothesis. The addition of 1 equiv of Cl-NBu4+ to the
sulfinate 10 will be produced. There is a good qualitative reaction medium prior to the slow addition of triethyl-
agreement between experimental data and the above amine improves slightly the trans/cis ratio (7:8 = 9223).
picture; however, it is difficult to define the borderline This is in agreement with an enhancement rate of the
cases giving a mixture of sulfinates. Structures I and I1 epimerization reaction at sulfur in 15 by nucleophilic at-
are not the lone trigonal bipyramids, allowing the dis- tack of chloride ions.67
cussion of the regioselective cleavage of 7. One can evisage Cyclic Sulfites Derived from Various Chiral Alco-
structure I11 where there has been apical entrance of the hols. It is interesting to compare the ring cleavage of 3
R' group anti to oxygen of the S ( 0 ) group. Pseudorotation with the ring cleavage of a set of chiral sulfites deriving
is then required in order to place one of the two oxygens from various diols. (S)-Propane-l,Pdiol4 was converted
of the alkoxy group in apical position (anti to S ( 0 ) ) before
opening of the five-membered ring. We do not favor (57) It is known that Cl- catalyzesthe interconversion between su&itea
structure I11 because the 0-S-0angle in sulfite 7 (93O) and chlorosulfites in presence of thionyl chloride." The competitive
is ideal to initiate the substitution reaction through I or formation of an acyclic sulfite of diol 3 (through the secondary hydroxyls)
11. followed by reaction with thionyl chloride is ale0 a route to return to
chloroeulfites 15.
Origin of the Diastereoselective Formation of (58) Bartlett, P. D.; Herdbrandson, H. F. J. Am. Chem. Soc. 1962, 74,
Trans Sulfite 7. It was very fortunate that sulfite 7 could 5971.
Pure Sulfoxides from a Chiral Sulfite J. Org. Chem., Vol. 56, No.21,1991 5997
H H Scheme IV. Obtention of Menthyl tert-Butyl Sulfinate and
(8)-tert-Butyl Phenyl Sulfoxide from Dimenthyl Sulfite

4 1711
67 I 33
17b

A
o/s'o'Q~' Q
A
MgBr2 -
THF, O°C
t-BuLi

Figure 7. Obtention of cyclic sulfites 17 from (S)-propanel,2-diol

(4). 25

n 70% w

+-+
1s 19 70% de
26
'~o<.fl
menthyl tert-butylsulfiiate (0% de). The diastereomeric
HO OH HO OH excess could be measured by 'H NMR on t-Bu signals. We
20 21
checked then the behavior of a 2 1 mixture of t-BuLi and
MgBrz. This combination gives an excellent yield of
'yy / G \ . , , d (
menthyl tert-butylsulfinate, when it was prepared by the
reaction of Mg and 1,Zdibromoethane in THF followed
HO OS-tBu HO OS-tBU
by addition of 2 equiv of t-BuLi. The clean solution
Ii II transforms dimenthyl sulfite into menthyl t-butylsulfihate
0
22 23 26 in excellent yield and 70% de at 0 "C (Scheme IV).
This sample was treated by phenyllithium and trans-
formed into (8)-tert-butyl phenyl sulfoxide (70% ee) in
quantitative yield. This is a very promising result for an
acyclic chiral sulfite. S stereochemistry at sulfur in sul-
finate 26 was assigned by assuming inversion of stereo-
chemistry in the step leading to sulfoxide. With the same
hypothesis for the conversion of 25 and 26 one concludes
that it is the pro-R oxygen in sulfite 25 that preferentidy
24
departed. We are looking for other types of simple chiral
alcohols in order to improve the diastereoselectivity of the
Figure 8. Preparation of sulfites 18 and 19 and sulfinates 22 and reaction. This approach, however, will generate only
23 from some C2 symmetry diols. tertiary-alkylsulfinates as already discussed for acyclic
into an oily mixture of sulfites of 17a and 17b (67:33), sulfites.37*38Indeed, dimenthyl sulfite and various n-butyl
which unfortunately could not be resolved into pure ep- organometallics always led to di-n-butyl sulfoxide.
imers (Figure 7). Conclusion
Sulfites from diols 6 and 24 could not be prepared. We
obtained the chlorohydrin from 24 and a mixture of We investigated in detail the transformation of sulfites
products from 6. Sulfites 18 and 19 were synthetized from into chiral sulfinates and then into enantiomerically pure
diols 20 and 21, respecti~ely.~~ Cyclic sulfites 18 and 19 sulfoxides. The chiral sulfite 7 was selected as the best
correspond to class D of Scheme I, where sulfur is not a starting material since it combines several advantages:
stereogenic center. The compounds (noncrystalline) are (i) It is produced in good yield in two steps from ethyl
easy to prepare since there is no need of separation of lactate (50% overall yield in pure trans-7).
stereoisomers. Sulfites 18, and 19 were treated by t- (ii) Organometallic reagents react smoothly with 7 and
BuMgCl in THF at room temperature, and then by phe- the reaction stops at the sulfinate stage.
nyllithium at the same temperature. tert-Butyl phenyl (iii) Up to now, all the isolated sulfinates were crystalline
sulfoxide was obtained with 50% ee (S configuration) and compounds, allowing their easy purification.
75 % ee (R configuration), respectively. Clearly, cyclic (iv) Very often the ring cleavage of cyclic sulfite 7 occurs
sulfites 18 and 19, which derive from simple Czdiols, are with a high regioselectivity (9010) leading to the isolation
not the best candidates for asymmetric synthesis of sulf- of a chemically and stereochemically pure eulfinate in good
oxides (Figure 8). yield.
We then investigated acyclic sulfites of class D in (v) Transformation of sulfinates is almost quantitative,
Scheme I, e.g., sulfites of enantiomerically pure mono- affording enantiomerically pure sulfoxides with a pre-
alcohols. Dimenthyl sulfite 25 was prepared from (-)- dictable absolute configuration. Chiral diol 3 can be re-
menthol and isolated as a crystalline and stable compound. covered and reused.
We checked its reactivity toward tert-butyl organo- (vi) Enantiomer of 7 is also easy to prepare from com-
metallics. t-BuLi gives only di-tert-butyl sulfoxide, and merically available (R)-isobutyl lactate.
t-BuMgBr reacts very slowly at 60 OC and furnishes Many ep sulfoxides have been prepared by our method.
We hope to see future applications of this approach in
organic synthesis. For example, a-carbanions derived from
(59) We thank Pr A. Tai for a generous gift of chiral diols 23 and 24. tert-butyl sulfoxides (racemic mixture) were used in highly
5998 J. Org. Chem., Vol. 56, No. 21, 1991 Rebiere et al.
stereoselective 1,Cadditions on conjugated esters.* En- 0, 17.50; S, 11.69. Found C, 65.72; H, 5.05;0, 17.49; S, 11.71.
antiomerically pure t-Bu(SO)CH2Ph and t-Bu(S0)- X-ray structure: see supplementary material.
(CHd2Phwere prepared by us (entries 6 and 7, Table 111); (+)-(tSpR)-Sulfite 7 has been ala0 prepared from (R)-3,with
this should extend the scope of the reactions described in 60% yield in crystallized product (cyclohexane-hexane). ["ID:
ref 60. Various types of chiral sulfoxides that are not 244 (c = 1, CHCld. Same NMR data,mp, and centeaimal analpis
as above.
attainable by asymmetric oxidation of sulfides may now Sulfite 8 (epimer of 7) was obtained by crystallization of the
be synthetized as diary1 sulfoxides (e.g. mesityl phenyl above mother liquor (preparation of (-1-71, mp 80-83 "C. ["ID:
sulfoxide, entry 9, Table 111) or sulfoxides with similar -309 (c = 1.5, CHCI,). 'H NMR: 7.2-7.6 (10 H, m); 5.55 (1H,
chains (e.g., n-heptyl n-octyl sulfoxide). Dialkyl sulfoxides q); 1.35 (3 H, d). 13C NMR: 142 (1 C); 138.5 (1 C);
are not easy to synthesize by the Andersen method or by 128.6-128.5-128.3-128-126.5-126 (10 C); 96.2 (1C); 83.3 (1C);
asymmetric oxidation; in contrast, sulfite 7 is an excellent 20.2 (1C). Anal. Calcd for C1&1403S: C, 65.67; H, 5.14; 0,17.50;
starting material for that purpose. S, 11.69. Found C, 65.75; H, 5.08; 0, 17.45; S, 11.74.
Most of the stereochemical problems associated with the Sulfites 17a-17b were obtained from (SI-diol 4 as an oil in
present work have been solved, namely stereochemistry 70% yield (tramcis = 67:33). Epimers could not be separated.
of the chiral sulfite 7 and of the intermediate sulfinate (9 'H NMR of the mixture is similar to data in ref. 70. 'H NMR
1.4 (CH3trans, d); 1.6 (CH3cis, d); 3.86 (1H trans, dd); 4.27 (1
or 10). As discussed above, the method has some limita- H, cis, dd); 4.5 (1 H, cis, dd); 4.6 (1H, cis, m); 4.7 (1 H, trans,
tions in terms of structure of the sulfoxide; nevertheless, dd); 5.1 (1H, trans, m). Anal. Calcd for C3H803S: C, 29.5; H,
as it stands at the moment it already appears to be a useful 4.9; 0, 39.3; S, 26.2. Found: C, 29.5; H, 4.9; 0, 39.4; S, 26.2.
complement to existing routes to chiral sulfoxides.2-*6l We Sulfite (R,R)-18 was prepared from (R,R)-20in 80% yield
are currently working on the extension of the scope of the as a colorless oil and used as such for the reaction with t-BuMgC1.
reaction (e.g., synthesis of functionnalized sulfoxides, 'H NMR 5.1 (1 H, m); 4.45 (1 H, m); 2.05 (2 H, m); 1.6 (3 H,
one-pot process on sulfite 7, ...) and on the exploration of d); 1.35 (3 H, d).
the various facets of sulfite chemistry as a route to ep Sulfite (R,R)-lS was prepared from (R,R)-21in 80% yield
sulfinates, sulfoxides, and derivatives. and used as such for the reaction with t-BuMgC1. 'H NMR: 4.5
(1 H, q); 3.8 (1 H, q); 1.8-2.1 (4 H, m); 0.95 (12 H, m).
General Procedure for the Preparation of Sulfinates.
Experimental Section Grignard reagent RMgCl(1 equiv) is added to sulfite (-1-7 in THF
Materials and General Methods. 'H and lSC NMR spectra according to the procedure described below for synthesis of
(6 ppm) were recorded in CDC18, unless stated otherwise. THF sulfinate 10 (R1 = t-Bu). Ratio of sulfnatea 9 and 10 in the crude
was distilled with sodium benzophenone under argon. Silica gel product is given in Table 11. 'H NMR data of sulfinates 9 and
60 (23b400 mesh) supplied by Merck was used for flash chro- 10 used for analysis of 9110 ratio and assignment of structure are
matography. (SI-Ethyl lactate and (R)-isobutyl lactate were collected in Table I.
purchased from Fluka Co. Diol (S)-3 (mp = 91-93 "C, ["IDe= All sulfinates are crystalline compounds that could be re-
-101 (c = 1, MeOH)) was prepared as described in ref 41. Diol crystallized. Sulfinates 10 are stable and can be stored, while
(R)-3 was prepared by the same procedure from (R)-isobutyl sulfiiates 9 are prone to decomposition at rt and have to be used
lactate. Diols (RBI-20and (R3)-21were given by Pr. A. Tai and immediately (storage is, however, possible at -20 OC for some
are available at Wako Co. (Osaka). Diol 24 has been synthesized weeks).
according to ref 69. (lR,2S,SR)-(-)-mentholwas purchased from Sulfinate 10 (R' = t-Bu) (2,2-Diphenyl-l,Z-dihydroxy-
Janssen Co.; (S)-(+)-1,2-propanediol (4) and diol 6, t-BuMgC1, propyl 2-0-tert-Butylsulfinate). A solution of t-BuMgCl(50
n-BuLi, and t-BuLi, were obtained from Aldrich Co. mmol) in THF was added dropwise to a solution of (4-7 (14 g,
Preparation of Chiral Cyclic Sulfites. The general pro- 50 "01) in THF at -78 OC. Reaction is checked by TLC (eluent,
cedure using chiral diol, SOCl2,and NEt3 is exemplified for the cyclohexane/AcOEt (51)). When conversion was over, the so-
preparation of sulfite 7.@ lution was quenched by H20,extracted by ether, washed by H20,
Sulfite 7 ((2R,SS)-trens-4,4-Diphenyl-S-methyl-l,3~-di- dried on MgS04, and evaporated. The crude product was crys-
oxathiolane 2-Oxide). To a solution of (81-3 (46 g, 0.2 mol) in tallized in 100 mL of cyclohexane, and pure 10 (R' = t-Bu) was
300 mL of CH2C12was added at one time a solution of SOCl2(0.3 obtained in 70% yield (12.1 g), mp 135-137 "C. ["ID: -120 (c
mol, 21 mL) in 100 mL of CH2C!, at -40 "C. The flask was = 0.9, CHCIS). 'H NMR 7.15-7.65 (10 H, m); 5.4 (1H, q); 3.1
maintained at -40 "C, and then triethylamine (0.5 mol, 67 mL) (1H, 8 ) ; 1.35 (3 H, d); 0.9 (9 H, 8). 13C NMR: 145.5 (1C); 143.3
in 600 mL of CHpC12 was added dropwise. At the end point a (1C); 128.4-127-126.5-126 (10 C); 82.5 (1C); 79.7 (1 C); 58 (1
white precipitate appeared. The reaction was quenched by 250 C); 21.5 (3 C); 16.3 (1 C). Anal. Calcd for CleHu03S: C, 68.64;
mL of water. The product was recovered after extraction with H, 7.28; 0, 14.43; S, 9.64. Found: C, 68.67; H, 7.21; 0,14.14; S,
CHpC12, washed with water, dried on MgSO,, and evaporated. The 9.87.
crude solid product (55g) was crystallized in 200 mL of solvent X-ray structure: see supplementary material. Configuration
(cyclohexane/hexane* l/lh Pure (-1-7 was isolated in 68% yield SPC
(38g) mp 104-111"C. [ a ] -246 ~ (c = 1,CHClJ. 'H NMR: 7-7.5 Sulfinate 9 (R' = Me) (l,l-Diphenyl-2-hydroxypropyl
(10 H, m); 5.7 (1H, 9); 1.3 (3 H, d). '% NMR: 140.3 (1C); 138.3 1-Methylsulfinate). configuration, SP,. 70% yield (after
(1C); 128.7-128.5-128.3-128-127.5-126.7 (10 C); 96 (1C); 80.4 crystallization in cyclohexane). ["ID: 46 (c = 0.5, CHCl,). ["ID
(1C);16.5 (1C). Anal. Calcd for: Ci5H140sS:C, 65.67; H, 5.14; -49 (c = 0.5, acetone). Mp: 92-94 OC. 'H NMR: 7.1-7.6 (10 H,
m); 4.8 (1 H, 9); 3.6 (1 H, 8 ) ; 2.7 (3 H, 8 ) ; 1.15 (3 H, d).
Sulfinate 9 (R'= Et). Configuration,S$,. 80% yield (after
(60)(a) Casey, M.; Manage, A. C.; Nizhat, L. Tetrahedron 1988,29, crystallization in cyclohexane). ["ID: -31 (c = 0.5, acetone). Mp:
5821. (b) C a y , M.;%nage, A. C.; Gaims, R. 5. Tetrahedron Lett. 1989, 76-78 "C. 'H NMR (acetone-de): 7.2-7.55 (10 H, m); 4.95 (1H,
30,6919. 4);4.6 (1 H, 8); 2.85 (2 H, 4);1.2 (3 H, t); 1.05 (3 H, d).
(61) Mikolaczyk, M.; Drabowicz, J. J. Am. Chem. Soc. 1978,100,2510. Sulfinate 9 (R'= n-Octyl). Configuration, S&. 60% yield
(62)Gray, 0.G.;Koser, G. F. J. Am. Chem. SOC.1990,112, 5672. (after crystallization in cyclohexane). ["ID: -46 (c = 0.5, acetone).
(63)Lochard, J. P.;Schroeck, C. W.; Johnson, C. R. Synthesis 1973, Mp: 69-71 OC. 'H NMR (acetone-de): 7.2-7.55 (10 H, m); 4.95
485.
(64)Baldenius, K.; Kagan, H. B. Tetrahe~r0n:Asymmetry1990,I, (1H, q); 4.25 (1H, m); 2.85 (2 H, m); 1.65 (2 H, m); 1.2-1.35 (10
597. H, m); 1.05 (3 H, d); 0.85 (3 H, t).
(65)Mislow, K.;Green,M. M.; Reban, M. J. Am. Chem. Soc. 1965,87, Sulfinate 9 (R' = Vinyl). Configuration, S&. 50% yield
2762. (after crystallization in cyclohexane). ["ID: -52 (c = 1,acetone).
(66)Takata, T.; Yamazaki, M.; Fijimori, K.; Kim, Y. M.; Iyanagi, T.;
Oae, 5. Bull. Chem. Soc. Jpn. 1989,66,2300.
(67)Mislow, K.; Green, M. M.; Law, P.; Mellilo, J. P.; Simmons, T.; (69)Toda, F.;Tanaka, K. Tetrahedron Lett. 1988,29,551.
Ternary, A. L. J . Am. Chem. SOC.1966,87,1958. (70)Usieli, V.;Pileradorf,A.; Shor, S.;Katzhendler, J.; Sarel, S. J. Org.
(68) Cyclic sulfite (SI-7haa been recently marketed by Aldrich Co. Chem. 1974,39,2073.
Pure Sulfoxides from a Chiral Sulfite J. Org. Chem., Vol. 56, No. 21, 1991 5999
Mp: 53-55 "C. 'H NMR (acetone-d8): 7.3-7.6 (10 H, m); 7.1 (1 configuration; sulfoxide 12 (R' = t-Bu, R2 = vinyl) R configu-
H, alkene); 6-6.1 (2 H, alkene); 4.95 (1 H, 9); 3.3 (1 H, 8 ) ; 1.05 ration. Yield: 90%. [a]:283 (c = 1, acetone). 'H NMR 6.6
(3 H, d). (1 H, m); 6.1 (1 H, d); 6 (1 H, d); 1.35 (9 H, 8). See N M R spectnun
Sulfinate 9 (R' = Benzyl). Configuration, Sa,.55% yield in supplementary material. Unstable compound, prone to po-
(after crystallization in cyclohexane). ["ID: -31 (c = 1, acetone). lymerization.
Mp: 88-91 "C. 'H NMR (a~et0ne-d~): 7-7.5 (15 H, m); 4.7 (1 Procedure 2. All the other sulfoxides of Table I11 were pre-
H, 9);4.15 (2 H, 4); 3.8 (1 H, 8 ) ; 1.05 (3 H, d). pared by the following procedure here described for sulfoxide
Sulfinate 10 (R1*= Mesityl). Configuration, S&. 70% yield 11 (R' = Et, R2 = Bn). A solution of 13 mmol of sulfinate 9 (R'
after crystallization in cyclohexane. [a]& -113 (c = 0.8, CHC13). = Et) in ether (prepared by reaction between 3.5 g, (13 mmol)
Mp: 110 OC. 'H NMR: 7.1-7.6 (12 H, m); 5.45 (1 H, 9); 2.25 (9, of sulfite (-)-7 and 18 mL of a 1 M solution of EtMgBr in THF)
H, 9); 1.4 (3 H, d). Anal. Calcd for CuHas03S: C, 73.06; H, 6.65; was added slowly at rt to 30 mL of a 1 M solution of PhCH2MgBr
0, 12.17; S, 8.26. Found: C, 73.21; H, 6.55; 0, 12.02; S, 8.26. (prepared by 0.72 g of Mg and 5.13 g of PhCH2Br in 30 mL of
Sulfinate 10 (R'= Benzyl). Configuration,S$,. 50% yield Et20). The mixture was then stirred for 0.5 h, quenched, and
after recrystallizations from cyclohexane. [a]D: -72 (c = 0.5, extracted. After a purification by flash chromatography (eluent
CHC13). Mp: 112-115 "C. 'H NMR (acetone-d8): 6.95-7.55 (15 AcOEt/cyclohexane (41), enantiomericallypure sulfoxide 11 (R'
H, m); 5.3 (1 H, 4); 3.65 (2 H, 4); 1.6 (1 H, 9); 1.35 (3 H, d). See = Et, R2 = Bn) was obtained in 90% yield. [a]: 105 (c = 0.75,
NMR spectrum in supplementary material. Anal. Calcd for CHC13). In a few cases, sulfinates 9 (R' = n-octyl, Bn, or Me)
CzzH,03S C, 71.16; H, 6.25; 0,13.54; S, 9.05. Found: C, 72.04; were dissolved in toluene, as in preparation of sulfoxides 11: R'
H, 6.21; 0, 13.00; S, 8.63. = octyl, R2 = Me, R' = PhCH2, R2 = Et, R1 = Me, R2 = octyl.
Sulfinate 13. Configuration, SP,. Epimeric at sulfur of 10 Preparation of (S)-tert-Butyl Phenyl Sulfoxide from
(R' = t-Bu). Was obtained from cis-sulfite 8 and t-BuMgC1 in Dimenthyl Sulfite. 1. Dimenthyl Sulfite 25. Reaction was
THF. Ratio 13/14 92/8 in the crude product. 45% yield (after performed at -60 "C (in order to eliminate the formation of a
crystallization in cyclohexane). [a]& +50 (c = 1, CHC13). Mp byproduct) using (-)-menthol and following the procedure for the
162-165 "C. 'H NMR 7.15-7.60 (1 H, m); 5.25 (1 H, q); 2.75 synthesis of cyclic sulfte 7. Yield 95%. [a16 4 0 (c = 1, CHClJ.
(1 H, 8 ) ; 1.25 (3 H, d); 1.1 (9 H, 9). Anal. Calcd for ClSHuO3S: Mp: 49 OC (crystallized from hexane after flash chromatography,
C, 68.64; H, 7.28; 0, 14.43; S, 9.64. Found C, 68.74; H, 7.19; 0, eluent cyclohexane/AcOEt (9:l)). 'H NMR: 0.8 (2d, 2 CH3); 0.9
14.09; S, 9.91. (2dd, 4 CH3); 1-1.5 (10 H); 1.7 (2 CH2); 2.1 (2 CH2); 4.25 (dt, 1
Sulfinate 22. 70% yield after flash chromatography into a H); 4.35 (dt, 1 H). Anal. Calcd for C&3809S C, 67.03; H, 10.61;
mixture of two unseparable diastereoisomers: RJJ?,/RJ?J$ = 0, 13.41; S, 8.94. Found: C, 66.63; H, 10.47; 0, 13.34; S, 8.92.
25/75 (calculated from further transformation into tert-butyl 2. Sulfinate 26. (a) Reagent, (2-t-BuLi, MgBr2). 122 mg
phenyl sulfoxide). Oil. [a]D: -137 (c = 0.4, CHC13). 'H NMR: (5 mmol) of Mg turnings were stirred under argon 0.5 h, then 5
4.55 (1 H, m); 4 (1 H, m); 3.95 (1 H, e); 1.65 (1 H, t); 1.6 (1 H, mL of THF was added and 0.44 mL (5 mmol) of 1,a-dibromo-
t); 1.30 (3 H, d); 1.2 (9 H, 8 ) ; 1.18 (3 H, d). See NMR spectrum ethane. The solution refluxed a few min (precipitation occurred)
in supplementary material. Anal. Calcd for C&H,03S C, 51.89; and was stirred vigorously until no more Mg was observed. Then,
H, 9.68; 0, 23.05. Found: C, 51.65; H, 9.48; 0, 23.35. 6 mL of t-BuLi (1.7 M in pentane; 10.2 mmol) was added, and
Sulfinate 23. 65% yield after flash chromatography into a the resulting green solution was stirred during 1 h then cooled
mixture of two unseparable diastereoisomers: R & R , / R & R , = at 0 "C.
88/12 (calculated from further transformation into tert-butyl (b)Sulfinate. To the 2-t-BuLi, MgBr2 reagent was added 1
phenyl sulfoxide). Oil. [a]& 167 (c = 0.8, CHC13). 'H NMR: g (2.8 mmol) of sulfite 25 in 5 mL of THF at 0 "C. The reaction
4.25 (1 H, m); 3.5 (1 H, m); 3.2 (1 H, 8 ) ; 1.7 (1 H, m); 1.4-1.75 (3 was over (no more sulfite) after 4 h. After ususal workup, an oily
H, m); 1.25 (9 H, 8 ) ; 0.85-1 (12 H, m). See NMR spectrum in product was recovered (100% yield) composed of two diaste-
supplementary material. Anal. Calcd for Cl3HUO3S: C, 59.27; reomers (70% de). The diastereomeric ratio could be measured
H, 10.71; 0, 18.22. Found C, 59.96; H, 10.28; 0, 18.43. by 'H NMR (on Me of t-Bu at 1.2 ppm). 'H NMR: 0.8 (1 CH3,
Preparation of Chiral Sulfoxides. Sulfoxideswere obtained d); 0.9 (2 CH3, 2dd); 1.2 (3 CH3, 8 ) ; 1-1.3 (3 H, m); 1.4 (2 H, m);
in quantitative yield by addition of 2 equiv of RMgCl or RLi 1.6 (2 H, m); 2.1 (2 H, m); 3.95 (1 H, m). Anal. Calcd for
reagents on sulfinate 9 or 10 (procedure 1) or addition of sulfiite CiIHm02S: C, 64.9; H, 10.4;0,12.3; S, 12.3. Found: C, 65.2; H,
on RMgBr (procedure 2) in THF at rt, according to the procedures 11.2, 0, 12.1; S, 11.5. The transformation of 26 (70% de) into
described below. Yields, ee's, organometallics, and reaction (S)-tert-butylphenyl sulfoxide (70% ee) was achieved in quan-
temperatures are collected in Table 111. Specific rotations, ab- titative yield by addition of 2.1 equiv of PhLi in THF at r t to
solute configurations, and comparisons with literature data are the crude above sulfinate.
in Table IV.
Procedure 1. Sulfoxide 12 (R' = t-Bu, R2 = m-Bu). A Acknowledgment. We thank CNRS for ita financial
solution of 2.2 equiv of n-BuLi (4.5 mL of a 1.6 M solution in support. One of us (F.R.) is grateful to the Ministery of
hexane) was added slowly to 1 equiv of sulfinate 10 (R' = t-Bu)
(1 g; 3 mmol) in 20 mL of THF at rt. The mixture was stirred Research a n d Technology (M.R.T.) for a fellowship.
0.5 h, then quenched with H20, extracted by ether, washed with
HzO, dried on MgSO,, and evaporated. 0.49 g (100% yield) of Supplementary Material Available: X-ray structures of
pure product was obtained. [a]$ 125 (c = 1, acetone). ee: 100%. cyclic sulfite t r a m 7 and of sulfinate 10 (R' = t-Bu), 'H NMR
This procedure was used for preparation of sulfoxide 12 (R' = spectra of sulfinates 9 and 10 (R'= benzyl), of sulfinates 22 and
t-Bu, R2 = Me), R configuration; sulfoxide 12 (R' = t-Bu, R2 = 23, of sulfoxide 12, and of sulfinate 10 (R' = t-Bu) (25 pages).
Ph), R configuration; sulfoxide 12 (R' = mesityl, R2 = Me) R Ordering information is given on any current masthead page.