TiIV-catalyzed asymmetric sulfenylation of 1,3-dicarbonyl compounds

Article abstract of DOI:10.1002/chem.200700920

The electrophilic enantioselective sulfenylation of 1,3-dicarbonyl compounds with phenylsulfenyl chloride is effectively catalyzed by [Ti-(TADDOLato)] complexes. The corresponding products are obtained in moderate to high yields. The highest ee values (up to 97%) are obtained in toluene at room temperature and with a typical catalyst loading of 5mol%. Bulky ester groups and sterically undemanding substituents at the α-position were found to be crucial structural features of the starting materials in order to assure high enantioselectivity. The absolute configuration of one of the chiral products has been determined. The stereochemical course of the reaction is similar to that of analogous [Ti-(TADDOLato)]-catalyzed atom-transfer reactions. A common side-reaction the sulfenylated products undergo is a deacylation leading to racemic α-sulfenylated esters.

Full text of DOI:10.1002/chem.200700920

DOI: 10.1002/chem.200700920
TiIV-Catalyzed Asymmetric Sulfenylation of 1,3-Dicarbonyl Compounds
Marjan Jereb[b] and Antonio Togni*[a]
Abstract: The electrophilic enantiose-
lective sulfenylation of 1,3-dicarbonyl
compounds with phenylsulfenyl chlo-
ride is effectively catalyzed by [Ti-
Bulky ester groups and sterically unde-
manding substituents at the a-position
were found to be crucial structural fea-
tures of the starting materials in order
to assure high enantioselectivity. The
absolute configuration of one of the
chiral products has been determined.
The stereochemical course of the reac-
tion is similar to that of analogous [Ti-
(TADDOLato)] complexes. The corre-
ACHTRE(UGN TADDOLato)]-catalyzed atom-trans-
sponding products are obtained in
moderate to high yields. The highest ee
values (up to 97%) are obtained in tol-
uene at room temperature and with a
typical catalyst loading of 5 mol%.
fer reactions. A common side-reaction
the sulfenylated products undergo is a
deacylation leading to racemic a-sulfe-
nylated esters.
Keywords: dicarbonyl compounds ·
asymmetric catalysis · sulfenylation ·
titanium
Introduction
b-keto esters, as reported from our laboratory.[2] Catalytic
asymmetric fluorination has been the subject of extensive
research, undoubtedly because of the higher importance of
fluorine, as compared to the other halogens.[3] Indeed, cata-
lytic asymmetric chlorination, bromination and mixed-halo-
genation reactions have attracted less attention.[4] Asymmet-
ric hydroxylation of b-keto esters has been accomplished by
involving metal-catalyzed and organocatalytic approaches,
Catalytic asymmetric processes involving molecules contain-
ing a carbonyl moiety are a rapidly expanding area in the
field of enantioselective catalysis. Impetus for such an inten-
sive research is the development of new reactions, but also
the simplification of existing methods for the synthesis of
optically active molecules bearing a stereogenic center adja-
cent to a carbonyl group, as it is often the case for biologi-
cally active molecules. Functionalized b-keto esters are very
versatile building blocks and synthons in organic chemistry,
therefore constituting an incentive for the development of
new methods for the preparation of their optically active de-
respectively.[5] Direct formation of carbon nitrogen bond in
À
catalytic asymmetric processes has been a subject of exhaus-
tive studies due to the potential biological activity of the
products.[6] Optically active sulfur-containing molecules, as
well, have been of wide interest since decades. Molecules
bearing a thio ether functionality exhibit several different
biological activities, especially as antibiotics.[7]
À
À
rivatives containing a carbon heteroatom bond (C E; E =
that is, halogen, N, O and S). The enantioselective a-hetero-
functionalization of carbonyl compounds has recently wit-
nessed a boost based on organocatalytic approaches.[1] How-
ever, one of the turning points in this field has been the de-
velopment of TiIV-catalyzed enantioselective fluorination of
Numerous chiral sulfur-containing molecules, underesti-
mated in the past, have been put forward as ligands with
rapidly growing relevance in enantioselective catalysis.[8]
À
Carbon sulfur bond forming reactions and simultaneous
generation of a stereogenic center were based on different
strategies, the most popular being the application of chiral
auxiliaries.[9] On the other hand, optically active sulfenylat-
ing reagents[10] and chiral phase-transfer catalysts[11] have
been rarely employed. Indeed, there are also reports on cat-
alytic asymmetric sulfenylation, but the known examples are
mainly limited to conjugative addition of thiols to alkenes
bearing electron-withdrawing substituents.[12] The first report
on electrophilic sulfenylation based on organocatalysis was
published not long ago.[13] Aldehydes and ketones in reac-
tions catalyzed by l-proline derivative with N-(phenyl-
[a] Prof. Dr. A. Togni
Department of Chemistry and Applied Biosciences
Swiss Federal Institute of Technology, ETH Zurich
8093 Zurich (Switzerland)
Fax : (+41)44-632-1310
E-mail: togni@inorg.chem.ethz.ch
[b] Dr. M. Jereb
Department of Organic Chemistry
Faculty of Chemistry and Chemical Technology
University of Ljubljana, Askerceva 5
1000 Ljubljana (Slovenia)
ˇ
ˇ
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Chem. Eur. J. 2007, 13, 9384 – 9392

FULL PAPER
thio)phthalimide furnished a-sulfenylated carbonyl deriva-
tives in yields between 42 and 88%, but ee values were not
reported. More recently, the organocatalytic formation of
optically active products upon electrophilic sulfenylation of
aldehydes was reported by Jørgensen.[14] In this case, the re-
action with aldehydes gave the best results in toluene at
room temperature and was accomplished using a reagent
bearing the sulfur functionality protected by a heteroaro-
matic ring able to form a non-destructive leaving group,
compatible with the reaction system.[15] The same group ex-
tended this study also to lactones, lactams and b-dicarbonyl
molecules.[16] In cinchona-alkaloid-catalyzed reactions with
the best reagent firstly reported,[14] that is, 1-benzylsulfanyl-
Scheme 1. Ti(TADDOLato)-catalyzed sulfenylation of b-keto esters with
PhSCl.
A
keto ester (53% ee),[18] as caused by a single methylene
spacer, reflects the subtle nature of the microenvironment
of the ester group. We can therefore conclude that the vicin-
ity of the bulky group to the reaction center is of prime im-
portance for high enantioselectivity. This is also shown by
the long, linear chain octyl ester 2b, as well as by derivative
2c having a yet bulky 2,2-diphenylethyl ester group (49%
ee), both not contributing to a better enantioselectivity.
The pentafluorophenyl group is a frequently used struc-
tural fragment and valuable marker due to its ability to dra-
matically modify molecular properties.[20] Because of this in-
triguing behavior, it was interesting to compare the two sub-
strates 2d and 2e, the benzyl and pentafluorobenzyl ester,
respectively, with respect to the enantioselectivity of the sul-
fenylation reaction. Indeed, the pentafluorobenzyl group
has a beneficial influence on the enantioselectivity (73% ee)
when compared to the corresponding non-fluorinated deriv-
ative 2e (62% ee). This result can hardly be interpreted
only on the basis of steric effects. We can speculate that the
ability of the pentafluorobenzyl group to undergo additional
weak p interactions[21] may contribute in stabilizing the
high yields and with enantioselectivity up to 91%.
Chiral TiIV complexes have been extensively studied as
they play an important role in a variety of catalytic asym-
metric transformations.[17] In recent years, we studied the
catalytic properties of such complexes in enantioselective
fluorination,[2] bromination,[4e] chlorination,[4d–e] chloro-fluo-
rination[4f] and hydroxylation.[5b] More recently, we reported
the first metal-catalyzed asymmetric sulfenylation using
chiral Ti(TADDOLato) complex and phenylsulfenyl chlo-
ride as the source of electrophilic sulfur.[18] b-Keto esters
were efficiently transformed into their a-phenylsulfenyl de-
rivatives with high enantioselectivity and good yields. Inter-
estingly, the evolved hydrogen chloride did not hamper the
reaction or the stereoselectivity. Very recently, we have de-
veloped another Ti-catalyzed asymmetric sulfenylation of b-
keto esters.[19] The source of electrophilic sulfur was phthali-
mide-N-sulfenyl chloride. When the reaction was carried out
in toluene, the reaction times were short and the products
could be obtained in high yields, but the ee values did not
go beyond about 60%.
Typical catalyst loading in asymmetric electrophilic atom-
transfer reactions using the Ti(TADDOLato) catalyst 1 was
5 mol%, with a limiting value around 1 mol% in the case of
the sulfenylation reaction. Therefore, for convenience, all
experiments were carried out by using 5 mol% of complex 1
with toluene being the optimal solvent with respect to enan-
tioselectivity. The top enantioselectivities (88% ee) were ob-
tained with substrates bearing bulky ester group, that is, tBu
or tAm.[18]
(enolato) intermediate,[2c] thus
major diastereoisomeric TiACHTREUNG
leading to a relatively modest, but significant increase in
enantioselectivity. The phenyl ester of 2-methyl-3-oxopenta-
noic acid (2 f) was converted to 2-phenylsulfenyl derivative
3 f in good isolated yield and with 72% ee. On the other
hand, the more crowded 3’,5’-di-tert-butylphenyl ester ana-
logue 2g was transformed into 3g in good yield, but the ee
dropped to 63%. All these observations taken together cor-
roborate the intuitive notion that steric effects on enantiose-
lectivity are not only a matter of size, but mainly of shape
and position of corresponding substituents.
Results and Discussion
Optically active, fluorine-containing molecules are useful
synthons in organic synthesis and, often due to increased
biological activity, are indispensable as drugs for the treat-
ment of various diseases and infections.[22] Reports on the
preparation of chiral a-fluoro-a-sulfenylated b-keto esters
are extremely rare,[23] and there is a complete lack of meth-
ods based on asymmetric catalysis for the preparation of
this class of compounds. We tested the tert-butyl ester of 2-
fluoro-3-oxobutanoic acid (2h) in the catalytic asymmetric
sulfenylation reaction. We were pleased to find that the de-
sired product was formed in 90% ee, although the isolated
yield was only 60% despite the full conversion of the start-
Varying the substrate—Scope and limitations: Trying to
extend the scope of the new [Ti(TADDOLato)]-catalyzed
asymmetric sulfenylation reaction with phenylsulfenyl chlo-
ride (Scheme 1), we decided to study the role of the struc-
ture of b-keto esters as a selectivity determining factor. The
results of this broader screening are collected in Table 1.
The neopentyl b-keto ester 2a afforded only 52% ee, a
value which is by 36% lower than the enantioselectivity ob-
served with the corresponding tert-butyl ester. A remarkable
drop of enantioselectivity down to the level of the ethyl b-
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A. Togni and M. Jereb
Table 1. Ti-Catalyzed enantioselective sulfenylation of b-keto esters using PhSCl.[a]
ence between the ester group
and the a-substituent in this re-
spect. The latter should be as
sterically undemanding as pos-
sible.
Entry
Reactant 2
Product 3
Yield [%][b]
75
ee [%][c]
1
2a
2b
2c
2d
2e
2 f
3a
3b
3c
3d
3e
3 f
52
We also examined the role of
the structure of the group at-
tached to ketone carbonyl
moiety by comparing the 2-ben-
zoyl and 2-naphthoyl propio-
nates 2i and 2j. The tert-amyl
ester 2i was transformed to the
sulfenylated derivative 3i in
75% isolated yield and the ee
reached 86%, thus showing
that the replacement of the
methyl by a phenyl group does
not represent any significant
advantage in terms of enantio-
selectivity. Additionally, the
ethyl ester 2j, containing the 2-
2
3
4
5
6
73
71
57
60
93
53
49
73
62
72
7
2g
3g
78
63
naphthyl
substituent,
gave
8
2h
2i
3h
3i
60
75
75
89
86
66
product 3j in 75% isolated
yield, but with an enantioselec-
tivity not exceeding 66%. It is
obvious that the structure of
the ester functionality possesses
a considerable higher impact on
enantioselectivity that the keto
group.
Finally, on the basis of the
previous findings concerning
the steric influence of the ester
group, three isomeric b-keto
esters 2k, 2l and 2m were pre-
pared and anticipated to afford
9
10
2j
3j
11
12
13
2k
2l
3k
3l
85
86
82
90
92
97
2m
3m
high
enantioselectivities.
[a] Reaction conditions: 0.2 mmol b-keto ester 2, 0.01 mmol 1, 2 mL toluene and 0.25 mmol PhSCl, stirring at
Indeed, they could be convert-
ed to their corresponding prod-
ucts in high yields and ee values
up to 97% in the case of 1,1,2-
RT up to 14 h. [b] Isolated yield. [c] Determined by chiral stationary phase HPLC.
trimethylpropyl ester 2m.
A
ing material 2h. This is the consequence of the instability of
the product, as indicated by the NMR spectrum of the crude
reaction mixture already showing partial deacylation (10–
15%). It is interesting to note the beneficial influence of the
fluorine atom in substrate 2h on enantioselectivity, as com-
pared to the corresponding compound with a methyl group
giving a slightly lower ee (88%).[18]
Furthermore, we varied the size of the a-substituent in
order to ascertain its role on the course of the reaction. As
a model substrate we chose the ethyl ester of 2-isopropyl-3-
oxobutanoic acid and found that it was much less reactive
than the analogous 2-methyl derivatives, the conversion to
product not going beyond 10–15% (the ee has therefore not
been determined). As discussed above, steric factors are of
crucial importance and there is clearly a fundamental differ-
closer examination of the structure of the three esters 2k, 2l
and 2m reveals that the branching of the ester group is cru-
cial, thus being responsible for the most beneficial effect on
enantioselectivity. Again, the positive steric effect of the
ester group is here a matter of it being a bulky, rigid and
compact aliphatic group.
We also explored benzylsulfenyl chloride as an electro-
philic sulfur source. However, this reagent is less stable and
therefore less convenient than the phenylsulfenyl chloride.
Nevertheless, ethyl 2-methylacetoacetate was converted
under the usual catalytic conditions into its benzylsulfenyl
derivative 2n with 56% ee and 82% isolated yield. We also
tested two structurally different potential phenylsulfenyl
group transfer reagents, that is, phenyl thiocyanate (PhSCN)
and N,N-diethylbenzenesulfenamide (PhSNEt2). Both were
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Asymmetric Sulfenylation
FULL PAPER
found to be unsuited under Ti-catalytic conditions, since the
starting material remained unreacted.
Beside b-keto esters we also studied catalytic asymmetric
sulfenylation reactions of other 1,3-dicarbonyl compounds
(Table 2).
Chromatographic separation in the case of 6a gave,
beside the expected 7a, also the deacylated derivative 7c.
The optical yield of 7a was a modest 21%, whereas 7c was
isolated in racemic form. The crude reaction mixture of 6b
contained, analogously to 6a, both 7b and 7c. However,
upon column chromatographic purification complete deben-
zoylation of 7b took place yielding racemic 7c as the only
isolable product. A possible explanation for such a facile de-
composition of the desired products is shown in Scheme 2.
Table 2. Role of the structure of b-dicarbonyl compounds in the Ti-cata-
lyzed enantioselective sulfenylation using PhSCl.[a]
Entry
R1
R2
Yield [%][b]
ee [%][c]
1
2
3
Et
Et
EtO
NHPh (4a)
NHCHPhMe (S) (4b)
OtBu (4c)
75 (5a)
79 (5b)
87 (5c)
36
0[d]
64
[a] Reaction conditions: 0.2 mmol substrate 4, 2 mL toluene and
0.25 mmol PhSCl, stirring at RT up to 14 h. [b] Isolated yield. [c] Deter-
mined by chiral stationary phase HPLC. [d] 1:1 mixture of diastereoiso-
mers.
b-Keto amides and b-keto lactams usually display a lower
enol content than b-keto esters and are therefore less reac-
tive in asymmetric electrophilic atom transfer reactions. To
our surprise, we found that even unenolized b-keto amides
react with phenylsulfenyl chloride instantaneously without
the need of any catalyst. This was not the case for 3-acetyl-
1-phenyl-2-pyrrolidone which, however, gave the sulfenylat-
ed product with low ee. The open-chain, non-enolized sub-
strate 4a reacts very rapidly in toluene giving the corre-
sponding product with 36% ee and in good yield. The b-
keto amide 4b, derived from (S)-phenethylamine, is very re-
active as well and the reaction in the presence of catalyst 1
yielded a 1:1 diastereoisomeric mixture of sulfenylated prod-
ucts. Malonate ester 4c, similarly to b-keto amide 4a, can
hardly enolize and could be regarded as a tough substrate
for catalytic reactions using complex 1. Unexpectedly, the
reaction of 4c proceeded smoothly to completion with phe-
nylsulfenyl chloride leading to the optically active sulfeny-
lated derivative 5c (64% ee) in high yield. The results ob-
served with the three substrates 4a–c had not been antici-
pated and reflect a somewhat anomalous behavior, at least
in the context of our current understanding of this reaction
system.
Scheme 2. Deacylation of sulfenylated lactones.
À
We think that the scission of the strong carbon carbon bond
is an acid-catalyzed process, relying on the nucleophilic as-
sistance of the sulfur atom adjacent to the acyl group, there-
by increasing the basicity of the carbonyl oxygen. The pro-
tonated form of 7b is stabilized as an episulfonium which is
then attacked by a water molecule leading to a tetrahedral
intermediate, readily decomposing to 7c and benzoic acid.
Mechanistic considerations: We previously put forward a
stereochemical model for the electrophilic sulfenylation re-
action.[18] This model is based on an analogy with the related
electrophilic asymmetric halogenation and hydroxylation
processes using the same catalyst 1.[2b,c,5b] Thus, despite the
lack of final experimental evidence, the current mechanistic
interpretation takes into account the formation of a mixture
of diastereoisomeric Ti(carbonylenolato) complexes under-
going external attack by the electrophile.[2c] Derivatization
of tert-butyl 2-oxocyclopentanecarboxylate (8) with 2,4-dini-
trophenylsulfenyl chloride (9) produces tert-butyl 1-(2,4-dini-
1,3-Diketones are usually highly enolized and therefore
Ti[TADDOLato]-catalyzed transformation result in a prod-
uct with negligible, or at best, low enantioselectivity.[5b] We
tested 2-acetylcyclohexanone and isolated its 2-sulfenylated
derivative, indeed in racemic form.
trophenylsulfanyl)-2-oxocyclopentanecarboxylate (10),
a
crystalline compound whose absolute configuration had pre-
viously been determined.[16] The optical rotation of a sample
of 10, obtained using (R,R)-1 as catalyst, was compared with
the literature value, thus establishing the S absolute configu-
ration. This is consonant to the proposed stereochemical
model governing the previously reported reactions.[2b,5b] The
Re enantioface of the enolate in the prevalent diastereoiso-
meric intermediate is shielded by one of the two face-on
naphthyl groups of the (R,R)-configured TADDOL. The
To complete the range of obvious 1,3-dicarbonyl sub-
strates, we also examined the reactivity of b-keto lactones.
Compounds 6a and 6b reacted completely when 1.5 mol%
of 1 was used, as monitored by NMR spectroscopic analysis
of the crude reaction mixture. However, some additional
1
signals in the H NMR spectrum that could not be assigned
to the expected sulfenylated compound indicated the pres-
ence of another product.
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9387

A. Togni and M. Jereb
bond-forming interaction with the electrophile takes place
at the Si side, thus yielding the S enantiomer of the product
preferentially.
The reaction of tert-butyl 2-oxocyclopentanecarboxylate
(8) with 2,4-dinitrophenylsulfenyl chloride (9) is more rapid
than the one with phenylsulfenyl chloride and was complet-
ed in less than 30 min (Scheme 3). Similarly, phthalimide-N-
Experimental Section
General methods: Reactions with air- or moisture-sensitive materials
were carried out under an argon atmosphere using Schlenk techniques.
1H, 13C and 19F NMR spectra were recorded on Bruker AVANCE spec-
trometers AC 200, DPX 250, and DPX 300. 1H and 13C spectra were re-
corded in CDCl3, chemical shifts are reported in ppm relative to the re-
1
sidual chloroform peak (7.26 ppm) for H NMR and to the central line of
CDCl3 (77.0 ppm) for 13C NMR. IR spectra were recorded on a Perkin
Elmer FT-IR Paragon 1000. Optical rotations were measured by using a
Perkin Elmer 341 polarimeter with a 1-dm cell. Column chromatography
was carried out using Fluka silica gel 60 (230–400 mesh). Elemental anal-
yses were carried out by the Laboratory of Microelemental Analysis
(ETH Zürich). HRMS measurements were performed by the MS-service
of the Laboratorium für Organische Chemie der ETH Zürich. Enantio-
meric excesses were determined by HPLC with Agilent (Palo Alto, CA)
HPLC 1100 or HPLC 1050 Series systems.
Scheme 3. Synthesis of compound 10 whose absolute configuration is
known.
Materials: All solvents were distilled prior to use. Complex [TiCl
2ACHTREUNG((R,R)-
1-Np-TADDOLato)(MeCN)2] (1, bis(acetonitrile)dichloro [(4R,5R)-2,2-
AHCTREUNG
dimethyl-a,a,a’,a’-tetra(naphthalene-1-yl)-1,3-dioxolane-4,5-dimethanola-
to(2-)-kO,kO’]titanium),[24] phenylsulfenyl chloride[25] and benzylsulfenyl
chloride[26] were prepared following published procedures. 2,4-Dinitro-
phenylsulfenyl chloride was obtained from Aldrich. Starting b-dicarbonyl
compounds 2a,[27] 2b,[27] 2c,[28] 2d,[29] 2e,[27] 2f,[30] 2i,[28] 2j,[4e] 4a,[31] 4c[32]
and 8[33] were prepared according to the published procedures. b-Keto
lactones 6a[34] and 6b[34] were prepared from g-butyrolactone by deproto-
nation and subsequent quenching with acetyl or benzoyl chloride, respec-
tively, according to standard procedures.
sulfenyl chloride also displays a higher reactivity. Electron-
withdrawing groups make the sulfur atom more electron de-
ficient, that is, more electrophilic. In principle, this would
make it more prone to undergo ionic transformations, but it
makes it also a better electron acceptor which, in turn,
would possibly implicate a single-electron-transfer (SET)
mechanism. The free-radical trap TEMPO was shown in the
reaction of ethyl 2-methylacetoacetate with phenylsulfenyl
chloride to decrease the ee from 49 to 38%, while the yield
remained unchanged at 94%. We also conducted experi-
ments with ethyl 2-methylacetoacetate in toluene that was
previously purged with molecular oxygen and found that
both enantioselectivity and yield are only moderately dimin-
ished. While both experiments seem to indicate that free
radicals are not involved in the process, they cannot be con-
sidered as evidence against SET, as SET does not necessari-
ly imply the formation of free radicals with a discrete life
General procedure for the enantioselective catalytic sulfenylation of b-di-
carbonyl compounds: b-Keto ester 2a (29 mg, 0.2 mmol) and catalyst 1
(2.4 mg, 0.003 mmol, to 7.6 mg, 0.01 mmol) were placed in a heat-gun
dried Schlenk tube containing freshly distilled toluene (2 mL). After
10 min of stirring, phenylsulfenyl chloride (0.25 mL, 0.25 mmol) solution
in toluene (0.25 mL) was added via syringe. After stirring for 12–14 h at
room temperature, the reaction mixture was diluted with tBuOMe and
filtered over a pad of alumina. The solvent was evaporated and the prod-
uct was purified by column chromatography (SiO2, hexane/tBuOMe mix-
tures).
2,2-Dimethylpropyl 2-methyl-3-oxo-2-(phenylsulfanyl)butanoate (3a):
The ee was determined by HPLC using a ReproSil Chiral-DP column
(hexane/iPrOH 99.5:0.5); flow rate 0.6 mLminÀ1; tmajor = 22 min; tminor
=
24 min); [a]RDT
(250 MHz, CDCl3, 258C): d = 0.95 (s, 9H; CMe3), 1.51 (s, 3H; CH3),
2.39 (s, 3H; CH3), 3.82 (d, J(H,H) = 10.5 Hz, 1H; CHH), 3.92 (d, J-
AHCTREUNG
(H,H) = 10.5 Hz, 1H; CHH), 7.26–7.46 ppm (m, 5H; Ar-H); 13C NMR
=
À29.5 (c
=
0.5 in CH2Cl2, 50% ee); 1H NMR
À
time. Thus, the intimate nature of the carbon sulfur bond-
forming process remains a debatable issue.
AHCTREUNG
(62.9 MHz, CDCl3, 258C): d = 20.7, 26.1, 26.3, 31.5, 65.8, 75.7, 129.0,
129.3, 129.8, 136.9, 169.9, 199.2 ppm; IR (KBr): n˜ = 2961, 1715, 1475,
Conclusion
1440, 1368, 1247, 1124, 976, 751, 693 cmÀ1
; HRMS: m/z: calcd for
C16H22O3S: 294.1285; found 294.1282 [M]+.
We have reported a Ti asymmetric sulfenylation of 1,3-dicar-
bonyl compounds using phenylsulfenyl chloride. Reactions
proceed with good yields and enantioselectivity up to 97%.
The best results were obtained in toluene at room tempera-
ture, the by-product hydrogen chloride not affecting the ste-
reoselectivity. The proposed stereochemical model for this
reaction involves diastereoisomeric intermediates containing
the b-keto ester enolate coordinated to the TiIV center in a
bidentate fashion. This leads to a preferential shielding of
one of the enolate enantiofaces by a face-on naphthyl group
of the ligand, as previously demonstrated for the analogous
halogenation and hydroxylation reactions. This Ti(TADDO-
Lato) catalyst remains the only highly effective transition-
metal system for a sulfenylation reaction and maintains a
unique character in view of the rather broad scope of appli-
cable electrophiles.
Octyl 2-methyl-3-oxo-2-(phenylsulfanyl)butanoate (3b): The ee was de-
termined by HPLC using a Daicel Chiralcel AD-H column (hexane/
iPrOH 99:1); flow rate 0.5 mLminÀ1; tmajor = 16.5 min; tminor = 15 min);
[a]RDT
=
À30.5 (c
CDCl3, 258C): d = 0.88 (m, 3H; CH3), 1.20–1.39 (m, 10H; 5”CH2), 1.50
(s, 3 H; CH3), 1.65 (m, 2H; CH2), 2.37 (s, 3H; CH3), 4.18 (t, J(H,H) =
=
0.51 in CH2Cl2, 56% ee); 1H NMR (250 MHz,
ACHTREUNG
6.3 Hz, 2H; OCH2), 7.27–7.46 ppm (m, 5H; Ar-H); 13C NMR (62.9 MHz,
CDCl3, 258C): d = 14.1, 20.7, 22.6, 25.8, 26.0, 28.3, 29.1, 31.7, 65.7, 66.6,
128.9, 129.4, 129.8, 136.9, 170.0, 199.3 ppm; IR (neat): n˜ = 2929, 2857,
1715, 1440, 1246, 1120, 749, 693 cmÀ1; HRMS: m/z: calcd for C19H28O3S:
336.1754; found 336.1752 [M]+.
2,2-Diphenylethyl 2-methyl-3-oxo-2-(phenylsulfanyl)butanoate (3c): The
ee was determined by HPLC using a Daicel Chiralcel AD-H column
(hexane/iPrOH 99:1); flow rate 0.6 mLminÀ1; tmajor = 44 min; tminor
=
35 min); [a]RDT
(200 MHz, CDCl3, 258C): d = 1.34 (s, 3H; CH3), 1.96 (s, 3H; CH3), 4.39
(t, J(H,H) = 7.6 Hz, 1H; CH), 4.73 (m, 2H; CH2), 7.10–7.40 (m, 15H;
3”Ar-H); 13C NMR (62.9 MHz, CDCl3, 258C): d = 20.5, 25.6, 49.7, 65.7,
=
À21.0 (c
=
0.50 in CH2Cl2, 49% ee); 1H NMR
AHCTREUNG
9388
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9384 – 9392

Asymmetric Sulfenylation
FULL PAPER
68.4, 127.0, 127.1, 128.1, 128.7, 128.9, 129.3, 129.8, 136.9, 140.3, 169.7,
199.1; IR (neat): n˜ = 2930, 1714, 1245, 1122, 750, 701 cmÀ1; HRMS: m/z:
calcd for C25H24O3S: 404.1437; found 404.1439 [M]+.
JACHTRENU(G C,F) = d =
28.8 Hz, CF); 19F NMR (188.3 MHz, CDCl3, 258C):
À133.1 ppm (q, J
ACHTRE(UNG F,H) = 3.2 Hz; F); IR (neat): n˜ = 2981, 2932, 1737,
1371, 1258, 1153, 747, 691 cmÀ1; HRMS: m/z: calcd for C14H17FO3S:
284.0877; found 284.0880 [M]+.
Pentafluorobenzyl 2-methyl-3-oxo-2-(phenylsulfanyl)butanoate (3d): The
ee was determined by HPLC using a Daicel Chiralcel AD-H column
2-Methyl-3-oxo-3-phenyl-2-phenylsulfanyl-propanoic acid-tert-amyl ester
(3i): The ee was determined by HPLC using a Daicel Chiralcel AD-H
column (hexane/iPrOH 99:1); flow rate 0.2 mLminÀ1; tmajor = 40 min;
tminor = 36 min); [a]DRT = +104 (c = 0.5 in CH2Cl2, 83% ee); 1H NMR
(hexane/iPrOH 99:1); flow rate 0.6 mLminÀ1; tmajor = 25 min; tminor
=
22 min); [a]RDT
=
À37.0 (c
=
0.50 in CH2Cl2, 74% ee); 1H NMR
(250 MHz, CDCl3, 258C): d = 1.51 (s, 3H; CH3), 2.34 (s, 3H; CH3), 5.27
(s, 2 H, CH2), 7.24–7.44 ppm (m, 5H, Ar-H); 13C NMR (62.9 MHz,
CDCl3, 258C): d = 20.7, 25.8, 54.8, 65.5, 108.4, 129.0, 130.0, 135.5, 136.8,
139.7, 143.7, 147.7, 169.4, 198.9 ppm; 19F NMR (188.3 MHz, CDCl3,
(250 MHz, CDCl3, 258C): d = 0.63 (t, JCAHTRE(UNG H,H) = 7.5 Hz, 3H; CH3), 1.19
(s, 3 H; CH3), 1.30 (s, 3H; CH3), 1.47 (m, 2H; CH2), 1.65 (s, 3H; CH3),
7.24–7.37 (m, 5H; Ar-H), 7.40–7.49 (m, 2H; Ar-H), 7.51–7.59 (m, 1H;
Ar-H), 8.15 ppm (m, 2H; Ar-H); 13C NMR (75.5 MHz, CDCl3, 258C): d
= 7.8, 23.3, 24.4, 24.8, 33.8, 63.9, 86.0, 128.2, 128.8, 129.4, 129.6, 129.7,
132.7, 135.5, 137.3, 170.1, 191.9 ppm; IR (neat): n˜ = 2977, 2933, 1729,
1682, 1370, 1266, 1156, 1129, 1107, 963, 842, 748, 691 cmÀ1; HRMS: m/z:
calcd for C21H24O3S: 356.1441; found 356.1441 [M]+.
258C): d
=
À160.9 (m, 2F), À151.2 (tt, J
ACHTRE(UNG F,H) = 21, 2.2 Hz, 1F),
À141.6 ppm (m, 2F); IR (neat): n˜ = 2936, 1716, 1524, 1508, 1440, 1310,
1233, 1133, 1056, 940, 751, 693 cmÀ1; HRMS: m/z: calcd for C18H13F5O3S:
404.0501; found 404.0504 [M]+.
Benzyl 2-methyl-3-oxo-2-(phenylsulfanyl)butanoate (3e): The ee was de-
termined by HPLC using a Daicel Chiralcel AD-H column (hexane/
iPrOH 99:1); flow rate 0.6 mLminÀ1; tmajor = 39 min; tminor = 31 min);
Ethyl 2-methyl-3-(2-naphthyl)-3-oxo-2-(phenylsulfanyl)propanoate (3j):
The ee was determined by HPLC using a Daicel Chiralcel AS column
[a]RDT
=
À46.0 (c
=
0.50 in CH2Cl2, 63% ee); 1H NMR (250 MHz,
(hexane/iPrOH 99:1); flow rate 0.6 mLminÀ1; tmajor = 19 min; tminor
=
CDCl3, 258C): d = 1.51 (s, 3H; CH3), 2.28 (s, 3H; CH3), 5.22 (s, 2H;
CH2), 7.24–7.43ppm (m, 5H; Ar-H); 13C NMR (75.5 MHz, CDCl3, 258C):
d = 20.7, 26.0, 65.7, 67.9, 128.5, 128.6, 128.9, 129.2, 129.8, 134.8, 136.9,
17 min); [a]RDT
(250 MHz, CDCl3, 258C): d = 0.99 (t, J
(s, 3 H; CH3), 4.13 (dq, J(H,H) = 7.2, 1.1 Hz, 2H; CHH), 7.20–7.41 (m,
5H; Ar-H), 7.58 (m, 2H), 7.88 (d, J(H,H) = 8.5 Hz, 2H; Ar-H), 7.97 (d,
(H,H) = 8.2 Hz, 1H; Ar-H), 8.08 (dd, J(H,H) = 8.7, 1.7 Hz, 1H; Ar-
=
+176 (c
=
0.56 in CH2Cl2, 68% ee); 1H NMR
AHCTREUNG
AHCTREUNG
169.7, 199.2 ppm; IR (neat): n˜ = 2934, 1713, 1234, 1115, 750, 693 cmÀ1
HRMS: m/z: calcd for C18H18O3S: 314.0972; found 314.0971 [M]+.
;
ACHTREUNG
J
C
ACHTREUNG
Phenyl 2-methyl-3-oxo-2-(phenylsulfanyl)pentanoate (3 f): The ee was de-
termined by HPLC using a Daicel Chiralcel AD-H column (hexane/
iPrOH 99:1); flow rate 0.6 mLminÀ1; tmajor = 22 min; tminor = 26 min);
[a]RDT = À25.5 (c = 1 in CH2Cl2, 71% ee); 1H NMR (250 MHz, CDCl3,
1018, 938, 866, 742, 692 cmÀ1
; HRMS: m/z: calcd for C22H20O3S:
258C): d = 1.19 (t, J
(dq, J(H,H) = 17.8 Hz, J
= 17.8 Hz, J
ACHTREUNG(H,H) = 7.2 Hz, 3H; CH3), 1.67 (s, 3H; CH3), 2.76
364.1128; found 364.1133 [M]+.
A
ACHRTUNEG(H,H) = 7.2 Hz, 1H; CHH), 2.98 (dq, JCAHTRE(UGN H,H)
(H,H) = 7.2 Hz, 1H; CHH), 7.08 (m, 2H; Ar-H), 7.22–
1-Ethyl-1-methylpropyl
(250 MHz, CDCl3, 258C): d = 0.83 (t, J
1.28 (d, J(H,H) = 7.2 Hz, 3H; CH3), 1.37 (s, 3H; CH3), 1.80 (m, 4H; 2”
2-methyl-3-oxobutanoate
(2k):
1H NMR
7.53 ppm (m, 8H; Ar-H); 13C NMR (62.9 MHz, CDCl3, 258C): d = 8.5,
21.1, 31.7, 65.5, 121.0, 126.3, 129.0, 129.2, 129.6, 130.0, 137.1, 150.4, 168.7,
202.5 ppm; IR (neat): n˜ = 2935, 1754, 1716, 1592, 1493, 1191, 1162, 1086,
ACHTREUNG
AHCTREUNG
CH2), 2.22 (s, 3H; CH3), 3.42 ppm (q,
JACHTRE(UNG H,H) = 7 Hz, 1H; CH);
749, 689 cmÀ1
314.0974 [M]+.
3,5-Di-tert-butylphenyl
(250 MHz, CDCl3, 258C): d = 1.31 (s, 18H; 2”CMe3), 1.49 (d, J
7.2 Hz, 3H; CH3), 2.38 (s, 3H; CH3), 3.76 (q, J(H,H) = 7.2 Hz, 1H;
CH), 6.90 (d, J(H,H) 1.5 Hz, 2H; Ar-H), 7.29 ppm (t, J(H,H)
;
HRMS: m/z: calcd for C18H18O3S: 314.0972; found
13C NMR (62.9 MHz, CDCl3, 258C): d = 7.9, 12.8, 22.6, 28.6, 30.3, 30.4,
54.7, 87.1, 169.5, 204.0 ppm; IR (neat): n˜ = 2978, 1715, 1508, 1267, 1134,
849 cmÀ1
.
2-methyl-3-oxobutanoate
(2g):
1H NMR
(H,H) =
A
1,1-Dimethylbutyl 2-methyl-3-oxobutanoate (2l): 1H NMR (250 MHz,
CDCl3, 258C): d = 0.90 (t, J(H,H) = 7.5 Hz, 3H; CH3), 1.24–1.36 (m,
5H; CH2, CH3), 1.43 (s, 6H; 2”Me), 1.65–1.75 (m, 2H; CH2), 2.21 (s,
3H; CH3), 3.39ppm (q, J
(H,H) = 7 Hz, 1H; CH); 13C NMR (75.5 MHz,
CDCl3, 258C): d = 12.7, 14.4, 17.1, 25.7, 25.8, 28.4, 43.2, 54.7, 84.1, 169.6,
R
ACHTREUNG
A
=
A
=
1.5 Hz, 1H; Ar-H); 13C NMR (62.9 MHz, CDCl3, 258C): d = 12.8, 28.7,
31.3, 35.0, 53.7, 115.3, 120.1, 150.2, 152.4, 169.2, 203.4 ppm; IR (KBr): n˜
= 2968, 1763, 1709, 1362, 1195, 1144, 1091, 910, 707 cmÀ1; HRMS: m/z:
calcd for C19H28O3: 304.2033; found 304.2036 [M]+.
ACHTREUNG
204.0 ppm; IR (neat): n˜ = 2964, 1716, 1508, 1267, 1147, 846 cmÀ1
1,1,2-Trimethylpropyl 2-methyl-3-oxobutanoate (2m):
(250 MHz, CDCl3, 258C): d = 0.89 (d, J
1.30 (d, J(H,H) = 7 Hz, 3H; CH3), 1.43 (s, 6H; 2”CH3), 2.15 (m, 1H;
CH), 2.23 (s, 3H; CH3), 3.42 ppm (q, (H,H) 7 Hz, 1H; CH);
13C NMR (75.5 MHz, CDCl3, 258C): d = 12.7, 17.2, 22.5, 22.7, 28.5, 36.5,
54.8, 87.0, 169.6, 203.9 ppm; IR (neat): n˜ = 2981, 1715, 1136 cmÀ1
1-Ethyl-1-methylpropyl 2-methyl-3-oxo-2-(phenylsulfanyl)butanoate
.
1H NMR
3,5-Di-tert-butylphenyl 2-methyl-3-oxo-2-(phenylsulfanyl)butanoate (3g):
The ee was determined by HPLC using a Daicel Chiralcel OD-H column
ACHTRE(UNG H,H) = 6.8 Hz, 6H; CHMe2),
AHCTREUNG
(hexane/iPrOH 99.7:0.3); flow rate 0.1 mLminÀ1; tmajor = 79 min; tminor
=
J
A
=
72 min); [a]RDT
(250 MHz, CDCl3, 258C): d
=
À34.0 (c
=
0.61 in CH2Cl2, 63% ee); 1H NMR
1.31 (s, 18H; 2”CMe3), 1.68 (s, 3H;
(H,H) = 1.3 Hz, 2H; Ar-H), 7.26–7.44
=
.
CH3), 2.52 (s, 3H; CH3), 6.87 (d, JACHTREUNG
(m, 4H; Ar-H), 7.52 ppm (m, 2H; Ar-H); 13C NMR (62.9 MHz, CDCl3,
258C): d = 20.9, 26.3, 31.3, 35.0, 65.9, 114.9, 120.3, 129.1, 129.2, 130.0,
137.0, 150.2, 152.5, 168.6, 199.3 ppm; IR (KBr): n˜ = 2964, 1754, 1719,
(3k): The ee was determined by HPLC using a Daicel Chiralcel OJ
column (hexane/iPrOH 99:1); flow rate 0.6 mLminÀ1; tmajor = 28 min;
1
tminor = 22 min); [a]RDT = À49.5 (c = 0.52 in CH2Cl2, 91% ee); H NMR
1612, 1588, 1226, 1089, 749, 704, 692 cmÀ1
; HRMS: m/z: calcd for
(250 MHz, CDCl3, 258C): d
= 0.88 (t, JACHTRE(GNU H,H) = 7.5 Hz, 6H; 2”
C25H32O3S: 412.2067; found 412.2072 [M]+.
CH2CH3), 1.45 (brs, 6H; 2”CH3), 1.69–1.99 (m, 4H; 2”CH2CH3), 2.41
(s, 3 H; CH3), 7.26–7.45 ppm (m, 5H; Ar-H); 13C NMR (62.9 MHz,
CDCl3, 258C): d = 8.0, 20.8, 22.4, 26.1, 30.3, 30.4, 66.5, 89.1, 128.9, 129.7,
129.7, 136.7, 168.7, 199.3 ppm; IR (neat): n˜ = 2977, 1712, 1254, 1120, 852,
tert-Butyl 2-fluoro-3-oxobutanoate (2h): 1H NMR (250 MHz, CDCl3,
258C): d = 1.51 (s, 9H; CMe3), 2.32 (d, J(H,F) = 3.9 Hz, 3H; CH3),
5.07 ppm (d, J
(H,F) = 49.9 Hz, 1H; CH); 19F NMR (188.3 MHz, CDCl3,
258C): d = À191.6 ppm (qd, J(F,H) = 49.9 Hz, J(F,H) = 3.9 Hz; F).
AHCTREUNG
ACHTREUNG
A
N
748, 693 cmÀ1
308.1439 [M]+.
; HRMS: m/z: calcd for C17H24O3S: 308.1441; found
tert-Butyl 2-fluoro-3-oxo-2-(phenylsulfanyl)butanoate (3h): The ee was
determined by HPLC using a Daicel Chiralcel OJ column (hexane/
iPrOH 99:1); flow rate 0.3 mLminÀ1; tmajor = 66 min; tminor = 59.5 min);
1,1-Dimethylbutyl 2-methyl-3-oxo-2-(phenylsulfanyl)butanoate (3l): The
ee was determined by HPLC using a Daicel Chiralcel AD-H column
[a]RDT
=
À41.0 (c
CDCl3, 258C): d = 1.40 (s, 9H; CMe3), 2.20 (d, J
CH3), 7.30–7.42 (m, 3H; Ar-H), 7.53–7.60 ppm (m, 2H; Ar-H); 13C NMR
(62.9 MHz, CDCl3, 258C): d 26.0, 27.6, 85.3, 105.2 (d, J(C,F)
243.7 Hz, CF), 127.4 (d, J = (C,F) = 1.5 Hz, CF), 129.2, 130.0, 135.7 (d,
(C,F) 1.7 Hz, CF), 162.2 (d, J(C,F) 28 Hz, CF), 196.6 ppm (d,
=
0.545 in CH2Cl2, 90% ee); 1H NMR (250 MHz,
(hexane/iPrOH 99:1); flow rate 0.3 mLminÀ1; tmajor = 22 min; tminor
=
A
24 min); [a]RDT
(250 MHz, CDCl3, 258C): d = 0.92 (t, JAHCTREUNG
=
À62.0 (c
=
0.735 in CH2Cl2, 92.5% ee); 1H NMR
(H,H) = 7.5 Hz, 3H; CH3), 1.25–
=
A
=
1.41 (m, 2H; CH2), 1.45 (s, 3H; CH3), 1.47 (s, 3H; CH3), 1.48 (s, 3H;
CH3), 1.72 (m, 2H; CH2), 2.39 (s, 3H; CH3), 7.27–7.44 ppm (m, 5H; Ar-
H); 13C NMR (62.9 MHz, CDCl3, 258C): d = 14.3, 17.1, 20.6, 25.5, 25.5,
J
A
=
A
=
Chem. Eur. J. 2007, 13, 9384 – 9392
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9389

A. Togni and M. Jereb
26.0, 43.3, 66.5, 85.9, 128.9, 129.6, 129.7, 136.8, 168.8, 199.3 ppm; IR
(neat): n˜ = 2962, 2935, 2874, 1712, 1370, 1260, 1230, 1158, 1123, 749,
693 cmÀ1; HRMS: m/z: calcd for C17H24O3S: 308.1441; found 308.1441
[M]+.
258C): d = 1.26 (t, JAHCTREUN(G H,H) = 7 Hz, 3H; CH3), 1.44 (s, 9H; CMe3), 1.58
(s, 3 H; CH3), 4.20 (m, 2H; CH2), 7.27–7.39 (m, 3H; Ar-H), 7.55 ppm (m,
2H; Ar-H); 13C NMR (62.9 MHz, CDCl3, 258C): d = 14.0, 22.3, 27.7,
60.5, 61.9, 82.8, 128.7, 129.6, 130.2, 137.1, 168.1, 169.5 ppm; IR (neat): n˜
= 2981, 2936, 1729, 1370, 1259, 1164, 1110, 1024, 846, 752, 692 cmÀ1
HRMS: m/z: calcd for C16H22O4S: 310.1234; found 310.1231 [M]+.
;
1,1,2-Trimethylpropyl 2-methyl-3-oxo-2-(phenylsulfanyl)butanoate (3m):
The ee was determined by HPLC using a Daicel Chiralcel AD-H column
(hexane/iPrOH 99:1); flow rate 0.3 mLminÀ1; tmajor = 25 min; tminor
=
a-Acetyl-a-phenylsulfanyl-g-butyrolactone (7a): The ee was determined
by HPLC using a Daicel Chiralcel OD-H column (hexane/iPrOH 99:1);
23 min); [a]RDT
=
À60.8 (c
=
0.56 in CH2Cl2, 97% ee); 1H NMR
flow rate 0.6 mLminÀ1; tmajor
= 50.4 min; tminor = =
56 min); [a]RDT
(250 MHz, CDCl3, 258C): d = 0.91 (m, 6H; CHMe2), 1.44–1.50 (m, 9H;
3”CH3), 2.11 (m, 1H; CH), 2.40 (s, 3H; CH3), 7.27–7.44 ppm (m, 5H;
Ar-H); 13C NMR (62.9 MHz, CDCl3, 258C): d = 17.2, 17.3, 20.6, 22.3,
22.5, 26.0, 37.0, 66.6, 88.8, 128.9, 129.6, 129.7, 136.8, 168.7, 199.3 ppm; IR
(neat): n˜ = 2980, 1712, 1254, 1122, 748, 693 cmÀ1; HRMS: m/z: calcd for
C17H24O3S: 308.1441; found 308.1441 [M]+.
1
À38.6 (c = 0.56 in CH2Cl2, 20% ee); H NMR (250 MHz, CDCl3, 258C):
d = 2.22 (m, 1H; CHH), 2.60 (s, 3H; CH3), 2.89 (m, 1H; CHH), 4.26
(m, 2H; CH2), 7.30–7.50 ppm (m, 5H; Ar-H); 13C NMR (62.9 MHz,
CDCl3, 258C): d = 26.0, 31.2, 63.7, 65.8, 129.0, 129.5, 130.3, 135.6, 171.4,
199.0 ppm; IR (neat): n˜ = 1770, 1704, 1158, 1023, 751, 690 cmÀ1; HRMS:
m/z: calcd for C12H12O3S: 236.0502; found 236.0504 [M]+.
Ethyl 2-(benzylsulfanyl)-2-methyl-3-oxobutanoate (3n): The ee was deter-
mined by HPLC using a Daicel Chiralcel AD-H column (hexane/iPrOH
a-Phenylsulfanyl-g-butyrolactone (7c):[35] The ee was determined by
99:1); flow rate 0.4 mLminÀ1; tmajor = 32 min; tminor = 30 min); [a]RDT
=
HPLC using a Daicel Chiralcel OD-H column (hexane/iPrOH 99:1);
1
flow rate 0.6 mLminÀ1; t1 = 101 min; t2 = 110 min, racemate); H NMR
1
À15.5 (c = 0.46 in CH2Cl2, 56% ee); H NMR (250 MHz, CDCl3, 258C):
(250 MHz, CDCl3, 258C): d = 2.29 (m, 1H; CHH), 2.66 (m, 1H; CHH),
d = 1.31 (t, J
ACHTREUNG
3.86 (dd, JCAHTER(UNG H,H) = 7.2 Hz, 1H; SCH), 4.21 (m, 2H; CH2), 7.35 (m, 3H;
CH3), 3.93 (s, 2H; SCH2), 4.28 (q, JAHCTRENUG
Ar-H), 7.55 ppm (m, 2H; Ar-H); 13C NMR (62.9 MHz, CDCl3, 258C): d
= 29.9, 44.3, 66.4, 128.7, 129.2, 131.7, 133.5, 174.9 ppm; IR (neat): n˜ =
2918, 1765, 1479, 1439, 1371, 1153, 1023, 743, 690 cmÀ1; HRMS: m/z:
calcd for C10H10O2S: 194.0397; found 194.0397 [M]+.
7.40 ppm (m, 5H; Ar-H); 13C NMR (62.9 MHz, CDCl3, 258C): d = 14.0,
20.1, 26.1, 44.0, 62.5, 66.5, 127.7, 128.7, 129.3, 136.2, 169.7, 199.6 ppm; IR
(neat): n˜ = 2982, 1713, 1454, 1249, 1110, 1016, 699 cmÀ1; HRMS: m/z:
calcd for: 265.0893; found 265.0891 [MÀH]+.
2-Methyl-3-oxo-N-(1(S)-phenylethyl)pentanamide (4b): [a]RDT = À33.6 (c
tert-Butyl
1-(2,4-dinitrophenylsulfanyl-2-oxocyclopentanecarboxylate
(10):[16] The ee was determined by HPLC using a Daicel Chiralcel AD
column (hexane/iPrOH 90:10); flow rate 1 mLminÀ1; tmajor = 12.1 min;
tminor = 9.2 min); [a]DRT = À147 (c = 0.5 in CHCl3, 39% ee); 1H NMR
(300 MHz, CDCl3, 258C): d = 1.43 (s, 9H; CMe3), 2.12–2.22 (m, 2H;
CH2), 2.32–2.42 (m, 1H; CHH), 2.50–2.62 (m, 1H; CHH), 2.63–2.76 (m,
= 0.50 in CH2Cl2, 0% de); 1H NMR (250 MHz, CDCl3, 258C): d = 1.04
(t, J
1.48 (d, J
CH2), 3.42 (q, JACHTREUNG
H
ACHTREUNG
T
ACHTREUNG
1H; NH), 7.24–7.37 ppm (m, 5H; Ar-H); 13C NMR (62.9 MHz, CDCl3,
258C), 2 diastereoisomers: d = 7.5, 7.5, 15.3, 15.3, 21.9, 21.9, 34.8, 34.8,
48.9, 49.0, 54.1, 54.1, 125.9, 126.0, 127.3, 127.4, 128.7, 143.0, 143.0, 168.5,
168.6, 210.6, 210.7 ppm; IR (KBr): n˜ = 3296, 2979, 2937, 1727, 1637,
1544, 1447, 1135, 1020, 970, 753, 700 cmÀ1; elemental analysis calcd (%)
for C14H19NO2 (233.3): C 72.07, H 8.21, N 6.00; found C 71.93, H 8.66, N
5.97.
2H; CH2), 8.13 (d, JACTHERNGU(H,H) = 9 Hz, 1H; Ar-H), 8.30 (d, JHCATRE(UGN H,H) = 9 Hz,
1H; Ar-H), 8.97ppm (s, 1H; Ar-H); 13C NMR (62.9 MHz, CDCl3, 258C):
d = 19.4, 27.7, 37.1, 37.3, 63.9, 84.6, 121.0, 126.3, 131.5, 142.3, 145.0,
167.3, 207.7 ppm; LRMS: m/z: calcd for C16H18N2O3S: 405; found 404.9
[M+Na]+.
2-Methyl-3-oxo-N-phenyl-2-(phenylsulfanyl)pentanamide (5a): The ee
was determined by HPLC using a Daicel Chiralcel OJ column (hexane/
iPrOH 99:1); flow rate 0.9 mLminÀ1; tmajor = 89 min; tminor = 59 min);
Acknowledgement
[a]RDT
CDCl3, 258C): d = 1.13 (t, J
CH3), 2.69 (dq, J(H,H) = 18.1, 7.2 Hz, 1H; CHH), 2.89 (dq, J
18.1, 7.2 Hz, 1H; CHH), 7.13 (t, J
=
À20.0 (c
=
0.54 in CH2Cl2, 36% ee); 1H NMR (250 MHz,
AHCTREUNG
Financial support by ETH to M.J. is gratefully acknowledged.
A
ACHTREUNG
À
AHCTREUNG
(m, 9H), 9.05 ppm (brs, 1H); 13C NMR (62.9 MHz, CDCl3, 258C): d =
8.4, 20.6, 31.8, 64.9, 119.9, 124.7, 129.0, 129.2, 130.1, 136.3, 137.3, 167.0,
206.1 ppm; IR (KBr): n˜ = 3251, 2975, 2937, 1710, 1656, 1597, 1541, 1500,
1489, 1444, 1316, 1250, 1157, 1096, 1084, 1028, 966, 925, 901, 756,
692 cmÀ1; HRMS: m/z: calcd for C18H19NO2S: 313.1132; found 313.1133
[M]+.
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2
A
ACHTRE(UGN R,S)-(phenylsulfanyl)penta-
OD-H column (hexane/iPrOH 99:1); flow rate 0.5 mLminÀ1
;
=
46 min; t2 = 49.5 min); [a]DRT = À48.6 (c = 0.505 in CH2Cl2, 0% de);
1H NMR (250 MHz, CDCl3, 258C), 2 diastereoisomers: d = 1.04 (t, J-
A
ACHTRE(UNG H,H) = 7.5 Hz, 3H; CH3), 1.45 (d,
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J
G
=
CH3), 2.44–2.79 (m, 4H, 2”CH2), 5.08 (m, 2H, 2”CH), 7.15–7.43 ppm
(m, 20H; Ar-H); 13C NMR (62.9 MHz, CDCl3, 258C), 2 diastereoisomers:
d = 8.3, 8.5, 20.9, 21.6, 21.8, 31.5, 31.5, 49.6, 49.6, 64.9, 65.2, 125.9, 126.3,
127.4, 127.6, 128.7, 128.8, 129.0, 129.1, 129.2, 129.5, 129.6, 129.7, 135.9,
136.0, 142.5, 142.8, 168.0, 168.2, 205.6, 205.6 ppm; IR (KBr): n˜ = 3360,
2971, 2930, 1708, 1670, 1521, 1454, 1438, 1240, 1168, 1086, 1025, 970, 772,
751, 705, 692, 604 cmÀ1; elemental analysis calcd (%) for C20H23NO2S
(341.5): C 70.35, H 6.79, N 4.10; found C 70.24, H 6.87, N 4.13.
tert-Butyl ethyl methyl(phenylsulfanyl)malonate (5c): The ee was deter-
mined by HPLC using a Daicel Chiralcel AD-H column (hexane/iPrOH
99:1); flow rate 0.6 mLminÀ1; tmajor = 10.9 min; tminor = 9.9 min); [a]RDT
=
+6.7 (c
=
0.55 in CH2Cl2, 64% ee); 1H NMR (250 MHz, CDCl3,
9390
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9384 – 9392

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Published online: September 21, 2007
9392
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9384 – 9392