Highly enantioselective sulfenylation of β-ketoesters: H-bond acceptor catalysis

Article abstract of DOI:10.1002/chem.200901099

The asymmetric sulfenylation of β-ketoesters catalyzed by α, α-diaryl prolinols was reported. 2a was selected as a model substrate for the optimization of the catalyst and reaction conditions. The sulfenylation product 4aa was isolated in 83% yield with 9

Full text of DOI:10.1002/chem.200901099

COMMUNICATION
DOI: 10.1002/chem.200901099
Highly Enantioselective Sulfenylation of b-Ketoesters: H-Bond Acceptor
Catalysis
Ling Fang,[a] Aijun Lin,[a] Hongwen Hu,[a] and Chengjian Zhu*[a, b]
Asymmetric organocatalysis[1] has been experiencing a re-
vival since MacMillan[2] and List,[3] independently, disclosed
its potential in 2000, although the l-proline-catalyzed intra-
molecular aldol reaction[4] dated back to the 1970s. For the
past decade, chiral secondary amino compounds have
intermediates in organic chemistry.[20] Moreover, many
chiral sulfur-containing molecules exhibit pharmaceutical ac-
tivities, such as b-lactam antibiotics. However, reports relat-
ed to the direct asymmetric introduction of sulfur were lim-
ited to nucleophilic processes.[21] Recently, electrophilic sul-
fenylation as a complementary procedure was developed by
several groups.[9,22] Jørgensen and co-workers[17f] described
the first enantioselective cinchona-alkaloid derivative cata-
lyzed a-sulfenylation of b-ketoesters, which gave the prod-
ucts in up to 91% ee. Further success in this area was ach-
ieved by Togni and co-workers,[15d,e] who developed chiral Ti
(TADDOLato) complexes for this transformation. The steri-
cally demanding ester moiety plays a crucial role in the re-
action stereoselectivity in their catalytic system. In addition,
an inert atmosphere is a prerequisite due to the use of mois-
ture-sensitive sulfur reagents. Accordingly, we were interest-
ed in finding a facile and practical protocol for this sulfeny-
lation reaction.
emerged as one of the most significant and versatile cata-
[5]
À
lysts in the enantioselective construction of C C and vari-
[6–11]
À
ous C hetero
bonds through covalent activation modes
involving enamines,[12] iminium ion,[13] and even SOMO[14]
mechanisms. Despite this impressive progress, the reaction
substrates activated by secondary amines are mainly restrict-
ed to aldehydes and ketones; therefore, it is desirable to
extend the scope of the involved substrates for the further
application of these catalysts. A quaternary stereocenter is
an essential structural motif in many biologically active mol-
ecules and pharmaceuticals, and the construction of this
framework in an asymmetric catalytic manner is a challenge
in organic synthesis. Although functionalization of a-substi-
tuted b-ketoesters is a simple method for the generation of
chiral quaternary carbon centers due to the a-acidic hydro-
gen, to the best of our knowledge, this transformation is tra-
ditionally catalyzed by a Lewis acid[15,16] or a tertiary
amine.[17,18] Given the inherent basicity of secondary amines,
we questioned whether they might be exploited as an alter-
native H-bond acceptor[19] to activate b-ketoesters.
Herein, we report the asymmetric sulfenylation of b-ke-
toesters catalyzed by a,a-diaryl prolinols (Scheme 1). Initial-
ly, the air-stable and commercially available N-(phenyl-
thio)phthalimide (3a) was chosen as the sulfur source for
Optically active sulfur-containing compounds constitute
an important class of chiral ligands, auxiliaries, and synthetic
Scheme 1. Prolinol derivative catalysts.
the investigations,[9b,22a] and this protocol was examined in
CH2Cl2 with different b-ketoesters using diphenylprolinol
(1a; 20 mol%) as the catalyst. However, preliminary studies
revealed that the reaction activity and enantioselectivity
were strongly dependent on the nature and structure of the
substrates. The acyclic b-ketoester, ethyl 2-methyl-3-oxobu-
tanoate only afforded the sulfenylation products in 35% ee
and poor yield compared with cyclic ones, such as ethyl
ester 2a derived from 1-tetralone (Table 1, entry 1).
[a] L. Fang, A. Lin, Prof. Dr. H. Hu, Prof. Dr. C. Zhu
State Key Laboratory of Coordination Chemistry
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing, 210093 (China)
Fax : (+86)25-83594886
E-mail: cjzhu@nju.edu.cn
[b] Prof. Dr. C. Zhu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
Shanghai, 200032 (China)
On the basis of these studies, 2a was selected as a model
substrate for the optimization of the catalyst and reaction
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901099.
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Table 1. Optimization of the catalyst and reaction conditions for the
enantioselective sulfenylation of b-ketoester 2a.[a]
found to be tolerated in this transformation (Table 2, en-
tries 1–3), of which 3c displayed the higher reactivity. In
general, the electronic properties of the aryl group and the
steric factors associated with the ester moiety appeared to
slightly influence the level of stereoselectivity achieved with
the 1-tetralone derivatives 2a–2e; all of them afforded the
desired products in excellent enantioselectivities and satis-
factory yields (92–97% ee with 70–82% yield, Table 2, en-
.
Entry
Solvent
Catalyst
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
hexane
hexane
Et2O
1a
1b
1c
1d
1e
1b
1b
1b
1b
1b
1b
1b
1b
1b
78
83
90
61
48
80
76
56
92
60
89
83
70
63
77
90
81
15
9
89
97
97
95
91
92
96
97
96
Table 2. Organocatalytic asymmetric sulfenylation of b-ketoesters.[a]
8[d]
9
10[d]
11
12
13[f]
14[g]
Et2O
MTBE[e]
cyclohexane
hexane
hexane
Entry
1
3
t
Product 4
Yield ee
[h]
[%][b] [%][c]
[a] Reaction conditions: compound 3a (0.22 mmol) was added to the so-
lution of b-ketoester 2a (0.2 mmol) and catalyst (0.04 mmol, 20 mol%)
in solvent (2 mL) at room temperature, and stirred for 24 h (Lg=phthali-
mide). [b] Yield of isolated product. [c] Determined by chiral HPLC
analysis. [d] Reaction ran at 08C. [e] MTBE=methyl tert-butyl ether.
[f] 10 mol% of catalyst 1b was used. [g] 5 mol% of catalyst 1b was used.
3a 36
3b 48
4aa 78
97 (R)
95 (R)
2
4ab 68
conditions. The results are summarized in Table 1. Investiga-
tions into the diaryl prolinols 1a–1d revealed that the elec-
tronic properties of the aromatic ring of the catalyst had an
impact on its performance (Table 1, entries 1–4). The sulfe-
nylation product 4aa was isolated in 83% yield with 90% ee
in the presence of catalyst 1b (Table 1entry 2). A minor de-
crease in enantioselectivity (81% ee) was observed albeit
with a higher yield (90%) when 1c, bearing an electron-do-
nating group on the aromatic ring, was tested (Table 1,
entry 3). Interestingly, the trimethylsilyl ether 1e resulted in
a sharp drop in both the reactivity and enantioselectivity
(Table 1, entry 5), whereas it is thought to be one of the
most highly effective and versatile catalysts in organocata-
lytic transformations. It is suggested that the free OH
moiety of the catalyst is necessary in this process. Solvent
screening demonstrated that hexane is the best choice (up
to 97% ee, Table 1, entries 2 and 6–12). Some polar solvents,
such as acetonitrile, had a deleterious effect on the enantio-
selectivity. Use of lower temperature (08C) led to some loss
of catalytic efficiency (from 76% to 56% yield) but without
any increase in the ee value (Table 1, entries 7 and 8). The
same was true when diethyl ether was used as the solvent
(Table 1, entries 9 and 10). Furthermore, a decrease in the
catalyst loading (from 20 mol% to 5 mol%) has a negative
effect on the reaction conversion (Table 1, entries 13 and
14).
3[d]
3c 36
4ac 88
96 (R)
4
3a 36
3a 36
4ba 72
4ca 70
96 (R)
94 (R)
5[d]
6[d]
3a 36
3a 36
4da 73
4ea 82
95 (R)
7
95 (R) (>99)[e]
8
3a
3a
3a
4
4
1
4 fa 88
4ga 89
4ha 98
86
79
30
9
10
Having established the optimal protocol for the reaction,
namely 20 mol% of catalyst 1b in hexane at room tempera-
ture, we then explored the electronic properties of the sulfur
source and the variation in b-ketoesters. As shown in
Table 2, the sulfur reagents 3a–3c with an electron-donating
or an electron-withdrawing group on the aromatic ring were
[a] Reaction conditions: compound 3 (0.22 mmol) was added to the solu-
tion of b-ketoester (0.2 mmol) and catalyst 1b in hexane (2 mL) at room
temperature, and stirred for the given time. [b] Yield of isolated product.
[c] Determined by chiral HPLC analysis, and the absolute configuration
of products 4aa–4da were determined by the comparison of the charac-
teristic CD spectra with that of 4ea. [d] Hexane/CH2Cl2 (4:1) was used as
the solvent. [e] After recrystallization.
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Highly Enantioselective Sulfenylation of b-Ketoesters
COMMUNICATION
tries 1 and 4–7). Optically pure 4ea (>99% ee) was ob-
tained upon recrystallization (Table 2, entry 7), and its abso-
lute configuration was determined to be R by means of an
X-ray crystallographic analysis (Figure 1).[23] Furthermore,
group and the acceptor NH group.[26] This proposed activa-
tion model was partly supported by NMR spectroscopic ex-
periments:[27] i) With the addition of catalyst 1b to the solu-
tion of substrate 2e in CDCl3,[28] the previously stable intra-
molecular H-bond signal of 2e at d=12.34 ppm (99% enol
form, Figure 3a) became rather wide (5 mol% 1b in Fig-
ure 3b, and 10 mol% 1b in Figure 3c).[29] This phenomenon
Figure 1. X-ray crystal structure of 4ea. Thermal ellipsoids set at 30%
probability level.
aliphatic five-membered ring b-ketoesters 2 f and 2g can
complete the reaction in 4 h, with up to 86% ee (Table 2,
entries 8 and 9). These results revealed that the sterically de-
manding substrate was not the significant factor for the high
ee values with diaryl prolinol as the catalyst. However, ste-
reocontrol with methyl ester 2h, derived from 1-indanone,
failed, albeit that the reactivity was higher (Table 2,
entry 10), and no acceptable improvement was achieved
even at À258C.[24]
In effort to gain an insight into the reaction mechanism,
1a with a 100 mol% catalyst loading was added to a solu-
tion of b-ketoester 2 f in CDCl3 (0.5m). After the mixture
had been left to stir overnight, no enamine intermediate was
detected in the NMR spectra, and no distinct changes were
noted in these two components, which suggests that an en-
amine mechanism may be less acceptable.[25]
Instead, we suggest that hydrogen bonding plays a role in
this mechanism. As depicted in Figure 2, the catalyst could
effectively recognize the prochiral faces of the b-ketoester
(probably enol form) by way of the H-bond donor OH
Figure 3. 1H NMR spectra of b-ketoester 2e (enol form) and mixture of
2e with different amount of catalyst 1b: a) 2e without catalyst; b) 2e
with 5 mol% catalyst; c) 2e with 10 mol% catalyst.
indicates the probable existence of an intermolecular hydro-
gen bond. This is in accord with the solvent effects on the
reaction enantioselectivity: an apolar solvent is superior to a
polar one (vide supra). ii) When an equivalent of catalyst 1b
was added, a weak intermolecular NOE could be observed
between the methyl-H group of substrate 2e and the aro-
matic methyl-H group of the catalyst, as well as the intramo-
lecular NOE of the catalyst (Figure 2). Thus, by virtue of
the effective shielding of the aryl group on the catalyst, the
electrophilic attack at the Re-face of the substrate–catalyst
complex leads to the (R)-configured product 4ea.
In summary, we have succeeded in developing the a,a-
diaryl prolinol catalyzed sulfenylation of b-ketoesters for
the construction of quaternary carbon centers with excellent
enantioselectivity and good yields. Studies suggested that
the activation mode involved a molecular interaction rather
than a covalent bond. The proposed H-bond mode opens up
the attractive prospect that chiral secondary amines might
Figure 2. Proposed pre-TS assembly for re-side attack of electrophile on
the b-ketoester 2e promoted by catalyst 1b (other hydrogen atoms are
omitted for clarity).
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7041

C. Zhu et al.
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Acknowledgements
This work was supported by the National Natural Science Foundation of
China (20672053, 20832001), the National Basic Research Program of
China (2007CB925103), and the Program for New Century Excellent Tal-
ents in the Universities of China (NCET-06-0425).
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Keywords: asymmetric
catalysis
·
diarylprolinol
·
organocatalysis · quaternary stereocenter · sulfenylation
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Highly Enantioselective Sulfenylation of b-Ketoesters
COMMUNICATION
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[23] CCDC-714950 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.arc.uk/
data_request/cif.
[24] In fact, we discovered that there is a significant background reaction
without any catalyst when 2h was tested as the substrate. This could
partly account for its poor enantioselectivity displayed under identi-
cal reaction conditions.
[25] For simple pyrrolidine, the corresponding enamine was formed, see:
a) A. Hodgson, J. Marshall, P. Hallett, T. Gallagher, J. Chem. Soc.
Perkin Trans. 1 1992, 2169–2174; b) R. K. Vohra, J.-L. Renaud, C.
Bruneau, Synthesis 2007, 731–738. However, this synthetic method
may be not applied to diaryl prolinols due to the steric effects.
[26] Similar models have been reported for tertiary amine catalysts, for
examples, see: a) A. Ting, S. Lou, S. E. Schaus, Org. Lett. 2006, 8,
2003–2006; b) J. Luo, L.-W. Xu, R. A. S. Hay, Y. Lu, Org. Lett.
2009, 11, 437–440; and reference [17a].
[27] See the Supporting Information for details.
[28] To exclude the trace of acid, CDCl3 was flushed through a short
plug of anhydrous K2CO3 before use.
[29] An amount of the keto form of 2e was also observed in the NMR
spectra. However, the stable intramolecular H-bond signal com-
pletely disappeared on increasing the catalyst loading to 20 mol%.
In fact, the sharp 1H NMR resonance is visible even in unpurified
CDCl3, in which the equilibrium between the enol and the keto
forms exists.
Received: April 26, 2009
Published online: June 16, 2009
Chem. Eur. J. 2009, 15, 7039 – 7043
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7043