Stereoselective synthesis of 2,3-epoxy alcohols mediated by a remote sulfinyl group

Article abstract of DOI:10.1016/j.tet.2009.12.006

The influence of the sulfinyl group as a chiral auxiliary in the stereoselective addition of oxiranyllithiums to (S)-2-p-tolylsulfinylbenzaldehyde has been studied. All reactions evolve with retention of configuration at the starting lithiated carbon. Completely stereoselective additions have been observed when configurations at sulfur and the lithiated carbon are different (matched pair), whereas variable dr's values (ranging between 52:48 and >99:<1%) when they are identical (mismatched pair).

Full text of DOI:10.1016/j.tet.2009.12.006

Tetrahedron 66 (2010) 1581–1585
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of 2,3-epoxy alcohols mediated by
a remote sulfinyl group
a
,
a
,
a
a
*
*
´
´
´
Jose Luis Garcıa Ruano , Ana M. Martın-Castro , Francisco Tato , Esther Torrente ,
M. Giovanna Tocco a b, Saverio Florio b , Vito Capriati
,
,
b
*
a
´
´
´
Departamento de Quımica Organica, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
Dipartimento Farmaco-Chimico, Universita degli Studi di Bari, 70126 Bari, Italy
b
`
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 October 2009
Received in revised form 1 December 2009
Accepted 2 December 2009
Available online 21 December 2009
The influence of the sulfinyl group as a chiral auxiliary in the stereoselective addition of oxiranyllithiums
to (S)-2-p-tolylsulfinylbenzaldehyde has been studied. All reactions evolve with retention of configura-
tion at the starting lithiated carbon. Completely stereoselective additions have been observed when
configurations at sulfur and the lithiated carbon are different (matched pair), whereas variable dr’s
values (ranging between 52:48 and >99:<1%) when they are identical (mismatched pair).
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
coordination of the sulfinyl oxygen with the lithium at the oxirane,
which would determine an intramolecular and consequently more
Chiral
a,b-epoxy alcohols are versatile and useful building blocks
stereoselective nucleophilic attack.
for asymmetric organic synthesis since they exhibit three adjacent
potentially stereogenic functionalized carbons liable to be further
elaborated.1 The oxiranyl anion-based methodology has been repor-
In the present paper we report the results obtained in the re-
actions of (S)-2-p-tolylsulfinylbenzaldehyde (1) with the differently
substituted oxiranyllithiums derived from oxiranes bearing an
oxazoline subunit 2–4 shown in Figure 1 and the influence of the
different relative configurations of substrate and reagents on the
stereoselectivity of the process. In addition to the methodologic
interest of the study, the resulting 2,3-epoxy alcohols can be con-
ted as a valuable method for preparing functionalized epoxides.2
a-
Lithiated styrene oxides have been reported to be chemically and
configurationally stable, and their reaction with a series of electro-
philes evolve stereospecifically into differently substituted epoxides.3
Similarly, lithium oxazolinyloxiranes have also been trapped with
electrophiles to provide functionalized oxiranes.4 However, despite
thewidescopeofthismethodology, thereactionsoftheabovelithium
oxiranes with aldehydes evolved with poor diastereoselectivities,3c,4c
and mixtures of epimers at the newly generated carbinolic carbon
were obtained. Recent reports have demonstrated that the sulfinyl
group in ortho position of benzaldehydes is able to control the ster-
eoselective addition of some nucleophiles to the carbonyl group5
mainlywhenreactionstakeplaceinthepresenceofsomeLewis acids,
such as Yb(OTf)3 or Y(OTf)3. Bearing in mind these facts we reasoned
that the reactions of lithium oxiranes with optically pure 2-p-tol-
ylsulfinylbenzaldehydes could evolve in a highly stereoselective
manner as a result of a double asymmetric induction process. More-
over the discrimination exerted by the sulfinyl group on the diaster-
eotopic faces of the carbonyl could be, in principle, increased by
sidered as potential starting materials for the synthesis of chiral a-
substituted a,b-dihydroxy b-phenylpropionic acids by nucleophilic
opening of the three-membered ring.6
Figure 1.
* Corresponding authors. Tel.: þ34 91 497 4701; fax: þ34 91 497 3966 (J.L.G.R.);
tel.: þ34 91 497 4717; fax: þ34 91 497 3966 (A.M.M.C.); tel.: þ39 080 544 2749; fax:
þ39 080 544 2534 (S.F.).
2. Result and discussion
Enantiomerically pure (S)-2-p-tolylsulfinylbenzaldehyde (1)
E-mail addresses: joseluis.garcia.ruano@uam.es (J.L. Garcı´a Ruano), martin.castro@
uam.es (A.M. Martın-Castro), florio@farmchim.uniba.it (S. Florio).
was synthesized in high overall yield (91%)7 by sulfinylation of the
´
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.12.006

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J.L. Garc´ıa Ruano et al. / Tetrahedron 66 (2010) 1581–1585
commercially available 2-bromobenzaldehyde diethyl acetal and
subsequent hydrolysis of the acetal function.
Oxazolinyl diphenyl and p-tolyloxiranes 2 and 3 (Fig. 1) were
prepared by reaction of lithiated 2-chloromethyl-4,4-dimethylox-
azoline with the suitable substituted carbonyl compound, as repor-
ted.4a–c Chiral (S)-4-isopropyloxazolinyloxirane 4 was prepared as
a 45:55 diastereoisomeric mixture at C-1 (4a and 4b) (Fig. 1) in 60%
overall yield, by lithiation of (S)-2-chloromethyl-4-isopropyloxazo-
line with LDA, followed by lithium–titanium transmetalation with
Ti(i-PrO)4 and subsequent addition of diphenylketone, as reported.8
As the lithium derivative of 4 is most likely configurationally un-
stable,9 the diastereoisomeric mixture 4aþ4b was used for further
reactions without a preliminary separation.
Initially, we studied the reaction of racemic 2-oxazolinyl-3,3-
diphenyloxirane (2) with (S)-2-p-tolylsulfinylbenzaldehyde (1).
Compound 2 was rapidly lithiated when treated with s-BuLi/
TMEDA in THF at ꢀ98 ꢁC, affording presumably interchangeable
enantiomeric anions 2-Li and ent-2-Li,10 which reacted with 1 to
give a 50:44:6 mixture of diastereoisomeric sulfinyl hydroxybenzyl
oxazolinylepoxides 5a–c (Scheme 1), in 65% combined yield. These
isomers could be separated by column chromatography and
crystallization.
Scheme 2.
Scheme 3.
From these studies a significant role of the sulfinyl group can be
inferred in the control of the configuration at the carbinolic carbon,
determining a completely stereoselective evolution of 2-Li, yielding
5a only, and a highly stereoselective transformation of ent-2-Li to
give a 88:12 mixture of 5b and 5c.
Scheme 1.
Then, we studied the influence of an additional stereogenic
centre at the skeleton of nucleophile on the stereoselectivity of the
process. To this purpose, oxazolines 4a and 4b were synthesized
(see above) and used as an epimeric mixture at C-1 because of the
presumed configurational instability of the corresponding lithiated
derivatives 4a-Li and 4b-Li (Scheme 5).9 Reaction of a 55:45 mix-
ture of 4aþ4b with (S)-2-p-tolylsulfinylbenzaldehyde (1) also
afforded a 52:25:23 mixture of three epoxy alcohols 8a–c, in 45%
combined yield (Scheme 4).
When the reaction was performed under Yb(OTf)3 catalysis,
the obtained yield decreased (presumably due to the attack of
the acid on the epoxide) but the stereoselectivity remained al-
most unaltered. Similar stereochemical results were observed
when the reaction was conducted in the presence of 12-crown-4
ether, able to trap the Liþ cation. These results could suggest
that the role played by both the Lewis acid and the Liþ cation in
the observed stereoselectivity must be scarcely significant.11
Absolute configuration of (1S,2S,SS)-5b was unequivocally de-
termined by X-ray diffraction studies of its crystals.12 Chemical
correlation of 5c with 5b (MnO2 oxidation of their mixture
provides ketone 6 only, Scheme 3) allowed us to assign 1R,2S,SS
configuration to 5c. This unequivocal assignment indicates that
5b and 5c derive from ent-2-Li, whose reaction with 1 is highly
but not completely stereoselective (88:12 dr), since the config-
uration at oxiranic carbon of the resulting epoxy alcohols must
be coincident with the configuration at the precursor lithium
anion.
In turn, the results depicted in Scheme 2 suggest that 5a should
derive from 2-Li. The oxidation of 5a and 5b with m-CPBA afforded
two diastereoisomeric sulfones 7a and 7b. As their configuration at
the oxiranyl carbon must be the opposite (5a and 5b derive from 2-
Li and ent-2-Li, respectively), we can conclude that the configura-
tion at the carbinolic carbon is the same (S) for both 7a and 7b, and,
therefore, for 5a and 5b (Scheme 3).
Scheme 4.

J.L. Garc´ıa Ruano et al. / Tetrahedron 66 (2010) 1581–1585
1583
If the reactivity of 4a-Li and 4b-Li is assumed to be similar, these
results suggest a completely stereoselective evolution of 4a-Li [as it
was also the case for 2-Li (Scheme 2)], which is scarcely affected by
the additional chiral centre at the oxazoline. However, the dia-
stereoselectivity of 4b-Li was quite low, in contrast with that of ent-
2-Li (Scheme 2), which indicates the negative influence of the
additional chiral centre in this transformation. These results could
be interpreted in terms of matched pair (1/2a) and mismatched
pair (1/4b).
Next, we investigated the nucleophilic addition of the anion
derived from trans-1-(4,4-dimethyl-2-oxazolinyl)2-p-tolylepoxy-
ethane (3) to aldehyde 1. Despite having used racemic (ꢂ)-3 as the
substrate (in order to obtain the stereochemical information about
both enantiomers simultaneously), this reaction can be performed
independently from any of them, because their synthesis had been
previously reported.4a Oxiranyllithiums formed by deprotonation
of 3 with s-BuLi/TMEDA (Scheme 5) have been reported to be
configurationally stable for at least 1 h at ꢀ100 ꢁC,4b,c in contrast to
those generated from the cis ones. As we started from (ꢂ)-3, a 1:1
mixture of enantiomeric anions 3-Li and ent-3-Li was formed, both
acting as nucleophiles towards (S)-2-p-tolylsulfinylbenzaldehyde
(1). The formation of a 1:1 mixture of diastereomeric epoxy alco-
hols 9a (24% isolated yield) and 9b (26% isolated yield) suggests
that the reactions of 3-Li and ent-3-Li with aldehyde 1 are both
completely stereoselective (Scheme 5).13
Figure 2.
As a summary of the stereochemical results obtained in this
paper, we can conclude that the reactions of the studied oxir-
anyllithiums with 2-p-tolylsulfinylbenzaldehyde (1) evolve with
complete retention of the configuration at the lithiated carbon, as it
happened with all the reactions with carbonyl compounds, which
had been previously reported,4 evidencing a scarce or no influence
of the sulfinyl group at that reaction site. By contrast, the chiral
auxiliary exerts a significant role on the stereochemical control at
the hydroxylic centre. Compounds 9a and 9b, both with the S
configuration at carbinolic carbon (Scheme 5), are exclusively
formed in the reactions with oxiranyllithiums 3-Li (with R config-
uration at the nucleophilic carbon) and ent-3-Li (with S configu-
ration at the nucleophilic carbon). The high stereoselectivity can be
explained taking into account what it should be the preferred
conformation of compound 1 (depicted in Fig. 3) in terms of elec-
trostatic interactions (indeed, the negatively charged carbonyl ox-
ygen atom interacts with the positively charged sulfinyl sulfur
atom). The tolyl group hinders the approach of the oxiranyllithium
from the upper face of the carbonyl group, thus privileging adducts
with S configuration at the carbinolic carbon.
Scheme 5.
Assuming that enantiomeric oxiranyllithiums 3-Li and ent-3-Li
are configurationally stable, the favoured attacked diastereotopic
carbonyl face of 1 being the same as that observed in the reactions
of 2-Li and ent-2-Li (Scheme 1), the absolute configurations of 9a
and 9b should be those depicted in Scheme 5 (i.e., identical con-
figuration at both carbinolic carbon and sulfur but different at the
oxiranyl centres). These assignments were confirmed by the NMR
parameters of their hydroxylic protons. Compounds 9a and 9b
exhibit similar chemical shifts (4.06 ppm for 9a and 4.18 ppm for
9b), but very different vicinal coupling constants, 11.0 Hz for 9a
and smaller than 1.0 Hz for 9b (the latter indeed appearing as
Figure 3. Favoured approach of nucleophile to the most stable conformation
aldehyde 1.
This complete control of the stereoselectivity was observed in all
the reactions with oxiranyllithiums exhibiting R configuration at
the nucleophilic carbon (4a-Li and 2-Li), according to the matched
pair protocol (R-configured nucleophilic carbon and S-sulfur at
electrophile). By contrast, the stereoselectivity control was partially
lost in the reactions involving the enantiomeric oxiranyllithiums
4b-Li and ent-2-Li, both S-configured at the nucleophilic carbon,
which conform the mismatched pair (S anionic carbon and S sulfur
atom). Nevertheless, alcohols with the S configuration at the car-
binolic carbon were always the major products. In the case of 4b-Li
and ent-2-Li the presence of a phenyl group at C-3 position of the
oxirane ring in cis arrangement with respect to the oxazoline ring,
might cause changes in the spatial arrangement of both groups
provoking steric interactions disfavouring the approach of the
lithiated species to the most stable conformation of aldehyde 1. This
effect, which should be much more severe for 4b-Li with a bulky
i-Pr group at the oxazoline ring, would shift the conformational
equilibrium of 1 towards other conformations, which would evolve
a broad singlet). Their
d values suggest that the hydroxylic hy-
drogen in both compounds is involved in intramolecular hydrogen
bonding. Its association to the oxiranyl oxygen, as reported for
similar syn-epoxy alcohols,4b determines that benzylic and hy-
droxylic protons adopt a rigid anti conformation (Fig. 2), thus
justifying a large value of the vicinal coupling constant. This syn
stereochemistry has been assigned to isomer 9a showing
a JH–OH¼11.0 Hz. In turn, for the anti isomer 9b (where a similar
intramolecular association is not possible for steric reasons) an-
other hydrogen bonding can be now postulated but with the
sulfinyl oxygen, so leaving both hydroxylic and benzylic protons in
a quasi gauche arrangement; this accounts for the observed small
vicinal coupling constant value (Fig. 2).

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J.L. Garc´ıa Ruano et al. / Tetrahedron 66 (2010) 1581–1585
into (R)-alcohols, with the consequent detriment of the stereo-
selectivity. However, the accurate structure of the operative tran-
sition state cannot be easily conceived.
9.6 Hz, 1H), 3.66 (d, J 8.2 Hz, 1H), 3.18 (d, J 8.2 Hz, 1H), 2.32 (s, 3H),
1.11 (s, 3H), 1.05 (s, 3H) ppm; 13C NMR:
162.1, 144.7, 142.9, 141.1,
138.2, 136.6, 130.4, 129.7, 129.2, 128.8, 128.5, 128.0, 127.6, 126.7,
126.3, 125.9, 124.5, 78.6, 72.5, 69.4, 68.0, 65.9, 27.8, 27.7, 21.3 ppm.
Diastereoisomer [1R,2S,SS]-5c was obtained by crystallization of the
d
3. Conclusions
diasteroisomeric mixture 5bþ5c (CH2Cl2–hexane): yield: 28%,
20
In conclusion, the previously observed low stereoselectivity
observed in reactions of oxiranyllithiums with carbonyl com-
pounds3c,4c has been efficiently circumvented by incorporation
onto the reactive nucleophile of a chiral sulfinyl group having the
suitable configuration at sulfur (the opposite one to that of the
oxiranyllithium).
white solid; [
a]
ꢀ76.5 (c 1.0, CHCl3); mp: 116–118 ꢁC; IR (film):
D
3320, 3057, 2981, 2928, 1678, 1494, 1100, 1032, 729 cmꢀ1; 1H NMR:
d
7.76 (dd, J 7.9 and 1.1 Hz, 1H), 7.59 (d, J 8.3 Hz, 2H), 7.54–7.51 (m,
4H), 7.36–7.12 (m, 11H), 7.0 (d J 8.1 Hz, 1H), 5.41 (s, 1H), 3.60 (br s,
1H), 3.52 (d, J 8.1 Hz, 1H), 3.49 (d, J 8.1 Hz, 1H), 2.35 (s, 3H), 0.96 (s,
3H), 0.63 (s, 3H) ppm; 13C NMR:
d 160.4, 145.5, 142.6, 140.5, 137.9,
136.6, 130.3, 129.6, 129.2, 128.6, 128.4, 128.3, 127.9 (2C), 127.1, 127.0,
125.9, 125.7, 79.3, 71.5, 71.3, 68.1, 67.1, 27.5 (2C), 21.4 ppm; MS
(ESIþ) m/z 538 [MþH]þ; HRMS (ESIþ): calcd for C33H32NO4S:
538.2052; found: 538.2057.
4. Experimental
4.1. General information
NMR spectra were obtained in a Bruker spectrometer (300 and
75 MHz for 1H and 13C NMR, respectively) in CDCl3 solutions.
Melting points were measured using a Gallemkamp apparatus in
open capillary tubes. Mass spectra (MS) were determined by ESI,
using an HP1100MSD apparatus. Specific optical rotations were
measured in a Perkin–Elmer 241 MC polarimeter. All reactions were
carried out in anhydrous solvents under argon atmosphere. Com-
mercially available anhydrous tetrahydrofuran (THF) was dried
over 4 Å molecular sieves. Flash column chromatography was
performed using silica gel Merck-60 (230–400 mesh).
4.2.1.2. [1S,2R,Ss], [1S,2S,Ss] and [1R,2S,Ss]-[2-(4S)-Isopropyl-4,5-
dihydrooxazol-2-yl-3,3-diphenyloxiran-2-yl]-[2-(p-tolylsulfinyl)phe-
nyl]methanol (8aþ8bþ8c). The diastereoisomeric mixture 8a:8b:8c
(52:25:23) was obtained when using a 55:45 mixture of 4aþ4b as
the nucleophile. The diastereoisomers mixture were separated and
purified by flash column chromatography (eluent Et2O–AcOEt 7:3).
Combined yield (for diastereoisomer mixture): 45%. Diastereoisomer
20
[1S,2R,Ss]-8a: yield: 27%, white solid; [
a
]
ꢀ72.0 (c 1.0, CHCl3); mp:
D
185–187 ꢁC; IR (film): 3235, 3059, 2962, 2923, 1667, 1456, 1023,
750 cmꢀ1; 1H NMR:
d
7.70 (dd, J 7.9 and 1.0 Hz, 1H), 7.50 (d, J 8.3 Hz,
2H), 7.44–7.35 (m, 4H), 7.28–7.10 (m, 10H), 6.90 (d J 7.4 Hz, 1H), 5.17
(br s,1H), 3.93 (br s, 1H), 3.84 (dd, J 8.1 and 9.6 Hz,1H), 3.74–3.66 (m,
1H), 3.52 (dd, J 7.9 and 7.7 Hz,1H), 2.27 (s, 3H),1.23–1.10 (m,1H), 0.55
4.2. Experimental procedures
Oxyranes rac-2, rac-3 and 4a,4b and (S)-2-p-Tolylsulfi-
nylbenzaldehyde (1) were synthesized following the experimental
protocol described in the bibliography.
(d, J 6.8 Hz, 3H), 0.44 (d, J 6.8 Hz, 3H) ppm; 13C NMR:
d 162.3, 145.6,
142.4, 140.5, 138.0, 136.8, 136.6, 130.1, 129.5, 129.0, 128.3, 128.1, 128.0,
127.9, 127.7, 127.0, 126.0, 125.8, 125.7, 72.8, 71.9, 71.8, 70.7, 68.4, 32.0,
21.3, 18.5, 17.9 ppm; MS (ESIþ) m/z 552 [MþH]þ; HRMS (ESIþ): calcd
for C34H34NO4S: 552.2130; found: 552.2132. Diastereoisomer
[1S,2S,Ss]-8b and [1R,2S,Ss]-8c: yellow solid; IR (film): 3301, 3061,
4.2.1. General procedure for the synthesis of 2,3-epoxy alcohols. To
a precooled solution (ꢀ98 ꢁC, methanol/liq N2) of the correspond-
ing oxyrane (2, 3, 4a or 4b) (1.0 mmol) and TMEDA (3.0 mmol) in
THF (7.0 mL) under argon, was added a solution of s-BuLi (1.4 mmol,
0.86 mL, 1.4 M in hexane). After 15 min, a solution of (S)-2-p-tol-
ylsulfinylbenzaldehyde 1 (1.0 mmol, 268 mg) in THF (1.0 mL) was
slowly added. The resulting mixture was stirred at ꢀ98 ꢁC for
30 min, then is quenched with a saturate solution of NH4Cl (2.0 mL)
and extracted with AcOEt (3ꢃ20.0 mL). Collected organic layers
were dried over anhydrous Na2SO4 and evaporated in vacuo. The
residue was purified by flash column chromatography employing
Et2O–AcOEt 7:3 as the eluent.
2973, 2965, 1701, 1652, 1455, 1030, 912, 734 cmꢀ1
;
1H NMR (56:44
8.10–8.04 (m, 2H), 7.93–7.87 (m, 2H), 7.68–7.23
mixture of 8bþ8b):
d
(m, 3H), 7.61–7.17 (m, 25H), 7.08 (d, J 8.3 Hz, 2H), 7.01 (d, J 8.1 Hz, 2H),
6.34 (d, J 10.3 Hz, 2H), 6.21 (d, J 11.1 Hz, 1H), 4.70 (d, J 10.3 Hz, 1H),
4.22 (d, J 11.1 Hz, 1H), 3.98 (dd, J 9.7 and 8.5 Hz, 1H), 3.76–3.62 (m,
3H), 3.53–3.41 (m, 1H), 3.16 (dd, J 9.6 and 8.7 Hz, 1H), 2.32 (s, 3H),
2.29 (s, 3H), 1.45 (m, 1H), 1.26 (m, 1H), 0.86 (d, J 6.8 Hz, 3H), 0.68 (d, J
6.5 Hz, 3H), 0.65 (d, J 6.8 Hz, 3H), 0.61 (d, J 6.8 Hz, 3H) ppm; 13C NMR
(56:44 mixture of 8bþ8c):
d 164.2, 163.5, 145.7, 145.4, 141.9, 141.6,
140.8, 140.5, 138.8, 138.7, 137.8, 137.5, 134.9, 134.2, 130.7, 130.3, 130.2,
129.7, 129.6, 129.5, 129.1, 128.8, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0,
127.9, 127.3, 127.1, 126.7, 126.6, 126.5, 126.0, 125.9, 125.4, 125.1, 72.4,
72.3, 72.1, 71.8, 71.7, 71.7, 70.3, 70.1, 69.9, 66.5, 65.7, 32.4, 32.3, 21.3,
21.2, 18.9, 18.6, 18.5, 18.4 ppm; MS (ESIþ) m/z 552 [MþH]þ; HRMS
(ESIþ): calcd for C34H34NO4S: 552.2130; found: 552.2136.
4.2.1.1. [1S,2R,SS], [1S,2S,SS] and [1R,2S,SS]-[2-(4,4-Dimethyl-4,5-
dihydrooxazol-2-yl)-3,3-diphenyloxiran-2-yl]-[2-(p-tolylsulfinyl)phe-
nyl]methanol (5aþ5bþ5c). The diastereoisomer mixture 5a:5b:5c
(50:44:6) was obtained using oxyrane rac-2 as the nucleophile. The
diastereoisomeric were separated and purified by flash column
chromatography (eluent Et2O–AcOEt 7:3). Combined yield (for di-
4.2.1.3. [1S,2R,3S,Ss] and [1S,2R,3R,Ss]-[2-(4,4-Dimethyl-4,5-dihy-
drooxazol-2-yl)-3-p-tolyl-oxiranyl]-[2-(p-tolylsulfinyl)phenyl]metha-
nol (9aþ9b). The diastereoisomeric mixture 9a:9b (50:50) was
obtained using oxirane rac-3 as the nucleophile. The di-
astereoisomers were separated and purified by flash column
astereoisomeric mixture): 65%. Diastereoisomer [1S,2R,SS]-5a:
20
yield: 33%, white solid; [
a]
ꢀ148.1 (c 1.0, CHCl3); mp: 196–197 ꢁC;
D
IR (film): 3391, 2968, 2932, 1659, 1443, 1078, 1024, 754, 702 cmꢀ1
;
1H NMR:
d 8.05 (dd, J 7.8 and 1.3 Hz, 1H), 7.59–7.24 (m, 15H), 7.00 (d,
J 8.1 Hz, 2H), 5.86 (d J 11.0 Hz, 1H), 4.22 (d, J 10.9 Hz, 1H), 3.61 (d, J
8.1 Hz,1H), 3.17 (d, J 8.1 Hz,1H), 2.30 (s, 3H),1.05 (s, 3H), 0.89 (s, 3H)
chromatography (eluent Et2O–AcOEt 7:3). Diastereoisomer
20
[1S,2R,3S,Ss]-9a: yield: 24%, white solid; [
a
]
ꢀ128.6 (c 0.5, CHCl3);
D
ppm; 13C NMR:
d
161.9, 145.8, 141.9, 140.5, 138.8, 137.7, 136.5, 130.0,
pf: 160–158 ꢁC; IR(film): 3328, 3055, 2970, 2926, 1655, 1457, 1187,
129.5, 128.8, 128.4, 128.2, 128.0, 127.0, 126.8, 126.1, 125.8, 125.2,
78.8, 71.5, 71.4, 67.9, 66.2, 27.6, 27.5, 21.4 ppm; MS (ESIþ) m/z 538
[MþH]þ; HRMS (ESIþ): calcd for C33H32NO4S: 538.2052; found:
538.2065. Diastereoisomer [1S,2S,SS]-5b: 1H NMR (83:17 mixture of
1033, 812 cmꢀ1; 1H NMR:
d
8.07 (dd, J 7.9 and 1.3 Hz, 1H), 7.53–7.35
(m, 5H), 7.21 (d, J 8.1 Hz, 2H), 7.13 (d, J 8.1 Hz, 2H), 6.99 (d, J 8.1 Hz,
2H), 5.47 (br s, 1H), 4.44 (s, 1H), 4.18 (br s, 1H), 4.01 (d, J 8.1 Hz, 1H),
3.94 (d, J 8.1 Hz, 1H), 2.41 (s, 3H), 2.31 (s, 3H), 1.32 (s, 3H), 1.09 (s,
5bþ5b):
d
8.15 (dd, J 7.9 and 1.2 Hz, 1H), 7.84–7.82 (m, 2H), 7.65–
3H) ppm; 13C NMR:
d
162.2, 145.8, 141.7, 140.5, 138.7, 138.2, 129.8,
7.28 (m, 13H), 7.08 (d, J 8.1 Hz, 2H), 6.15 (d J 10.0 Hz, 1H), 4.72 (d, J
129.4, 129.1, 128.6, 126.5, 126.3, 126.1, 125.2, 79.1, 69.5, 68.3, 62.4,

J.L. Garc´ıa Ruano et al. / Tetrahedron 66 (2010) 1581–1585
1585
60.4, 28.0, 27.9, 21.3 (2C) ppm; MS (ESIþ) m/z 476 [MþH]þ; HRMS
(c) For an account on
R. Synlett 2005, 1359–1369; (d) For a recent computational and multinuclear
magnetic resonance investigation on -lithiated styrene oxide, see: Capriati,
V.; Florio, S.; Perna, F. M.; Salomone, A.; Abbotto, A.; Amedjkouh, A.; Nilsson
Lill, S. O. Chem.d Eur. J. 2009, 15, 7958–7979; (e) The influence of an ortho-
a
-lithiated aryloxiranes, see: Capriati, V.; Florio, S.; Luisi,
(ESIþ): calcd for C28H30NO4S: 476.1895; found: 476.1894. Di-
a
20
astereoisomer [1S,2R,3R,Ss]-9b: yield: 26%, white solid;
[a]
D
ꢀ135.5 (c 1.0, CHCl3); mp: 157–155 ꢁC; IR (film): 3324, 3053, 2971,
2928, 1656, 1457, 1187, 1031, 812, 732 cmꢀ1 1H NMR:
; d 8.08 (dd,
sulfinyl group on the configurational stability of a-lithiated aryloxiranes has been
´
also described Capriati, V.; Florio, S.; Luisi, R.; Salomone, A.; Tocco, M. G.; Martın
Castro, A. M.; Garcı´a Ruano, J. L.; Torrente, E. Tetrahedron 2009, 65, 383–388.
4. (a) Florio, S.; Capriati, V.; Luisi, R. Tetrahedron Lett. 1996, 37, 4781–4784; (b)
Florio, S.; Capriati, V.; Di Martino, S.; Abboto, A. Eur. J. Org. Chem. 1999, 409–417;
(c) Abbotto, A.; Capriati, V.; Degennaro, L.; Florio, S.; Luisi, R.; Pierrot, M.; Sal-
omone, A. J. Org. Chem. 2001, 66, 3049–3058.
J 7.9 and 1.1 Hz, 1H), 7.42–7.37 (m, 1H), 7.29–7.19 (m, 3H), 7.06 (d,
J 8.1 Hz, 2H), 6.70–6.89 (m, 5H), 5.33 (d, J 11.0 Hz, 1H), 4.76 (s, 1H),
4.06 (d, J 11.0 Hz, 1H), 4.01 (d, J 8.1 Hz, 1H), 3.91 (d, J 8.1 Hz, 1H), 2.38
(s, 3H), 2.26 (s, 3H), 1.26 (s, 3H), 1.03 (s, 3H) ppm; 13C NMR:
d 161.3,
145.3, 141.4, 140.8, 137.8, 137.7, 129.5, 129.2, 129.1, 128.8, 128.3,
126.6, 126.1 125.8 125.2, 78.9, 70.9, 68.0, 61.8, 60.7, 27.8, 27.6, 21.5,
21.1 ppm; MS (ESIþ) m/z 476 [MþH]þ; HRMS (ESIþ): calcd for
C28H30NO4S: 476.1895; found: 476.1894.
5. Recent references: (a) Garcı´a Ruano, J. L.; Alema´n, J.; Alonso, I.; Parra, A.;
´
Marcos, V.; Aguirre, J. Chem.d Eur. J. 2007, 21, 6179–6195; (b) Garcıa Ruano, J. L.;
Alema´n, J.; Catala´n, S.; Marcos, V.; Monteagudo, S.; Parra, A.; del Pozo, C.;
´
Fustero, S. Angew. Chem., Int. Ed. 2008, 47, 7941–7944; (c) Garcıa Ruano, J. L.;
Marcos, V.; Alema´n, J. Angew. Chem., Int. Ed. 2008, 47, 6836–6839; (d) Garcı´a
Ruano, J. L.; Parra, A.; Marcos, V.; del Pozo, C.; Catala´n, S.; Monteagudo, S.;
Fustero, S. J. Am. Chem. Soc. 2009, 74, 9432–9441.
6. (a) Juday, R. E. J. Org. Chem. 1958, 23, 1010–1012; (b) Clerici, A.; Porta, O. J. Org.
Chem. 1982, 47, 2852–2856; (c) Pappas, S.; Pappas, P.; Betty, C.; Okamoto, Y.;
Sakamoto, H. J. Org. Chem. 1988, 53, 4404.
Acknowledgements
We thank DGITYC (Grant CTQ2006-06741/BQU) for financial
support and Italian MIUR for financial support of the National
Project on ‘Stereoselezione in Sintesi Organica. Metodologie e
7. Garcı´a Ruano, J. L.; Martin-Castro, A. M.; Tato, F.; Cardenas, D. J. Tetrahedron:
Asymmetry 2005, 16, 1963–1968.
8. (a) Florio, S.; Capriati, V.; Luisi, R. Tetrahedron Lett. 2000, 41, 5295–5298; (b)
Capriati, V.; Florio, S.; Luisi, R. Eur. J. Org. Chem. 2001, 2035–2039.
9. (a) Luisi, R.; Capriati, V.; Carlucci, C.; Degennaro, L.; Florio, S. Tetrahedron 2003,
59, 9707–9712; (b) Luisi, R.; Capriati, V.; Degennaro, L.; Florio, S. Org. Lett. 2003,
5, 2723–2726; (c) For a recent spectroscopic investigation on the configura-
´
Applicazioni’. One of us (E.T) thanks Ministerio de Educacion y
Ciencia (Spain) for a predoctoral fellowship.
References and notes
tional stability of
Luisa, R.; Perna, F. M.; Spina, A. J. Org. Chem. 2008, 73, 9552–9564.
a-lithiated oxazolinyloxiranes, see: Capriati, V.; Florio, S.;
10. The occurrence of an equilibrium between the two enantiomeric lithiated
1. (a) Lauret, C. Tetrahedron: Asymmetry 2001, 12, 2359–2383; (b) Lurain, A. E.;
Maestri, A.; Kelly, A. R.; Carrol, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126,13608–
13609; (c) Lurain, A. E.; Carrol, P. J.; Walsh, P. J. J. Org. Chem. 2005, 70, 1262–1268.
2. (a) Satoh, T. Chem. Rev. 1996, 96, 3303–3325; (b) Mori, Y. Rev. Heteroat. Chem.
1997, 17, 183–211; (c) Hodgson, D. M.; Gras, E. Synthesis 2002, 12, 1625–1642;
(d) For a special issue on oxiranyl and aziridinyl anions, see: Tetrahedron; Florio,
S., Ed.; 2003; Vol. 59, pp 9683–9864; (e) Hodgson, D. M.; Gras, E. In Topics in
Organometallic Chemistry; Hodgson, D. M., Ed.; Springer: Berlin, 2003;
pp 217–250; (f) Chemla, F.; Vranken, E., Chapter 18. In The Chemistry of Orga-
nolithium Compounds; Rappoport, Z., Marek, I., Eds.; John Wiley: New York, NY,
2004; Vol. 2, pp 1165–1242; (g) Hodgson, D. M.; Bray, C. D., Chapter 5. In
Aziridine and Epoxides in Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH GmbH
& KgaA: Weinheim, 2006; pp 145–184; (h) Padwa, A.; Murphree, S. ARKIVOC
species seems reasonable also considering that, to date,
a-lithiated b,b-di-
substituted oxazolinyloxiranes always proved to be configurationally unstable
on both microscopic and macroscopic time scales. See Ref. 9b,c.
11. However, the role of lithium in the course of the reaction cannot be definitively
ruled out bearing in mind that previous spectroscopic studies demonstrated
that lithium in 2-lithio-3,3-dimethyl-2-oxazolinyloxirane is either strongly in-
tramolecularly coordinated within the same aggregate or involved in tying two
monomeric units to give oxazoline-bridged dimers (see Ref. 9c).
12. Crytallographic data for the structural analysis have been deposited at the
Cambrigde Crystallographic data Centre, CCDC No. 749559 for the compound
5b. Copies of this information may be obtained free of charge from the Director,
CCDC, 12 Union Road, Cambrigde, CB2 1FZ. UK.
13. A possible alternative kinetic resolution, with only one of the anions (3-Li or
ent-3-Li) reacting with 1 in a very low stereoselective way, was readily ruled
out since the recovered unreacted oxirane 4 resulted to be racemic as de-
termined by chiral stationary phase HPLC.
2006, iii, 6–33; (i) For a recent review on a-substituted-a-lithiated oxiranes,
see: Capriati, V.; Florio, S.; Luisi, R. Chem. Rev. 2008, 108, 1918–1942.
3. (a) Capriati, V.; Florio, S.; Luisi, R.; Salomone, A. Org. Lett. 2002, 4, 2445–2448;
(b) Capriati, V.; Florio, S.; Luisi, R.; Nuzzo, I. J. Org. Chem. 2004, 69, 3330–3335;