Direct organocatalytic asymmetric α-sulfenylation of activated C-H bonds in lactones, lactams, and β-dicarbonyl compounds

Article abstract of DOI:10.1002/chem.200500512

The application of cinchona alkaloid derivatives as catalysts for enantioselective α-sulfenylation of activated C-H bonds in lactones, lactams, and β-dicarbonyl compounds by different electrophilic sulfur reagents is presented. Optically active products a

Full text of DOI:10.1002/chem.200500512

FULL PAPER
DOI: 10.1002/chem.200500512
À
Direct Organocatalytic Asymmetric a-Sulfenylation of Activated C H Bonds
in Lactones, Lactams, and b-Dicarbonyl Compounds
Sara Sobhani, Doris Fielenbach, Mauro Marigo, Tobias C. Wabnitz, and
Karl Anker Jørgensen*[a]
Abstract: The application of cinchona alkaloid derivatives as catalysts for enantio-
À
selective a-sulfenylation of activated C H bonds in lactones, lactams, and b-dicar-
bonyl compounds by different electrophilic sulfur reagents is presented. Optically
active products are obtained in good to excellent yields and up to 91% ee. Further-
Keywords: asymmetric organoca-
talysis
·
cinchona alkaloids
·
·
more, the diastereoselective reduction of a-sulfenylated b-keto esters to give opti-
cally active a-sulfenylated b-hydroxy esters has been studied. A model for the in-
termediate is presented, in which the protonated cinchona alkaloid interacts with
the substrate leading to face-shielding in accordance with the enantioselective a-
sulfenylation step.
electrophilic sulfur reagents
lactams · lactones · sulfenylation
Introduction
a-functionalization of carbonyl compounds such as a-amina-
tion, a-hydroxylation, and a-halogenation have been pre-
sented.[3–5] For example, enantioselective a-amination of al-
dehydes, ketones, and b-keto esters can be achieved with
azodicarboxylates by chiral organocatalysts.[3] a-Oxidation
of aldehydes and ketones have been reported by using
mainly l-proline as the catalyst and nitrosobenzene or sin-
glet oxygen as the oxidant.[4] Cinchona alkaloid derivatives
can act as catalysts for the a-hydroxylation of b-keto esters
using organic peroxide as the oxidant.[4d] Chiral amines have
been used for the enantioselective chlorination and fluorina-
tion of aldehydes,[5a–f] and the chlorination of ketones in the
presence of different chlorinating agents.[5g]
The application of optically active a-heterosubstituted car-
bonyl compounds in chemistry, pharmacology, and biology
has led to an increased focus on simple and efficient proce-
dures for the formation of enantiomerically enriched a-het-
eroatom-substituted carbonyl compounds. The presence of
enolizable carbon–hydrogen bonds in aldehydes, ketones,
and a-acidic hydrogen(s) in b-keto esters allows the possibil-
ity for reactions with different classes of electrophiles lead-
ing to the formation of carbon–heteroatom bonds. There-
fore, the enantioselective conversion of carbon–hydrogen
bonds to carbon–heteroatom bonds for these classes of com-
pounds is a simple method for the synthesis of optically
active compounds having these functionalities and, conse-
quently, is attractive to chemists.[1] In recent years, a great
deal of attention have been paid to the enantioselective a-
functionalization of carbonyl compounds using chiral organ-
ic compounds rather than chiral metal complexes as cata-
lysts.[2] Along this line, several examples of organocatalytic
In spite of the usefulness of optically active a-sulfenylated
carbonyl compounds as versatile synthetic intermediates, the
procedures for their preparation are rare.[6] To the best of
our knowledge, there are no reports on the direct enantiose-
À
lective a-sulfenylation of activated C H bonds in lactones,
lactams, and b-dicarbonyl compounds. Recently, we intro-
duced 1-benzylsulfanyl[1,2,4]triazole as an electrophilic
sulfur source for the catalytic enantioselective a-sulfenyla-
tion of aldehydes.[7] We envisioned that this kind of electro-
philic sulfur reagent could be applied for the enantioselec-
tive synthesis of optically active a-sulfenylated lactones, lac-
tams, and b-dicarbonyl compounds by the reaction of the ac-
[a] S. Sobhani, Dr. D. Fielenbach, Dr. M. Marigo, Dr. T. C. Wabnitz,
Prof. Dr. K. A. Jørgensen
The Danish National Research Foundation: Center for Catalysis
Department of Chemistry, Aarhus University
8000 Aarhus C (Denmark)
À
tivated C H bonds in these compounds catalyzed by cincho-
na alkaloid derivatives [Eq. (1)].
Fax : (+45)8919-6199
E-mail: kaj@chem.au.dk
Chem. Eur. J. 2005, 11, 5689 – 5694
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5689

Several solvents were investi-
gated and toluene was found to
be the best as shown in Table 1,
entries 1–4. It appears also from
entries 4–6 that the reaction
rate and enantioselectivities
were influenced by the amount
of the quinine (4a).
To study if the size of the
ester group can influence the
enantioselectivity, the organo-
catalytic a-sulfenylation of the
b-keto esters 1a–c catalyzed by
quinine (4a) (10 mol%) was in-
vestigated [Eq. (3)].
The results of this study re-
vealed a strong effect of the
size of the ester group in the b-
keto esters on the enantioselec-
tivity of the product. Whereas
the reaction of the tert-butyl
ester (1c) with the sulfenylation
reagent (2a) produced the de-
sired product 3c with 70% ee,
the a-sulfenylation reactions of
Results and Discussion
First, we examined the feasibility of the reaction between
ethyl 2-oxocyclopentanecarboxylate (1a) and the sulfur elec-
trophile reagent 1-benzylsulfanyl[1,2,4]triazole (2a), apply-
ing catalytic amounts of quinine (4a) as a starting point for
further optimization [Eq. (2)]. The results are summarized
in Table 1.
the corresponding ethyl (1a) and isopropyl esters (1b), re-
spectively, under the same reaction conditions were faster,
however, the products 3a and 3b were formed with 44 and
45% ee, respectively.
The key step in the optimization of the conditions of the
a-sulfenylation was to evaluate the catalytic properties of
different cinchona alkaloid derivatives. Based on the screen-
ing results presented above, we chose the tert-butyl ester
(1c) and the sulfenylating reagent (2a) as the standard
system for the catalyst screening using different cinchona al-
kaloid derivatives 4a–i (Table 2).
Among the cinchona alkaloid derivatives tested, 4d,
(DHQ)2PHAL (4h), and (DHQD)2PYR (4i) turned out to
be the most effective organocatalysts leading to 3c in up to
73% yield and 77%ee at room temperature (Table 2, en-
tries 4, 9, 11). It was found that the enantioselectivity was
dependent on the reaction temperature. Performing the re-
action at, for example, À308C gave 3c in good yields and
with 89%, 81% and 89% ee using 4d, 4h, or 4i as catalysts,
respectively (Table 2, entries 5, 10, 13). A further reduction
of the temperature to À408C lowered the yield of 3a to
Table 1. Screening of solvents and catalyst loading (4a) for the direct
enantioselective a-sulfenylation of ethyl 2-oxocyclopentanecarboxylate
(1a) [Eq. (2)].[a]
Entry
Solvent
Quinine
[mol%]
Time
[h]
Yield[b]
[%]
ee[c]
[%]
1
2
3
4
5
6
CH2Cl2
CH2Br2
hexane
toluene
toluene
toluene
10
10
10
10
40
2.5
1
1
1
0.5
4
98
93
65
85
82
77
36
32
8
44
43
33
4
[a] Reaction conditions: 0.1 mmol of 2a was added to a mixture of 1a
(0.1 mmol) and 4a in the solvent (1 mL) at room temperature. [b] Yield
of isolated product. [c] ee was measured by HPLC (see Experimental
Section for details).
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Chem. Eur. J. 2005, 11, 5689 – 5694

À
Organocatalytic Asymmetric a-Sulfenylation of Activated C H Bonds
FULL PAPER
Table 2. a-Sulfenylation of tert-butyl 2-oxocyclopentanecarboxylate (1c)
with 1-benzylsulfanyl[1,2,4]triazole (2a) catalyzed by different cinchona
alkaloid derivatives (10 mol%) (4a–i).[a]
carboxylate (1 f) also undergo the enantioselective a-sulfe-
nylation reaction with 2a to give the corresponding a-sulfe-
nyl-b-keto esters 3d–f in 84–95% yields and with moderate
asymmetric induction (Table 3, entries 6–8). The a-sulfenyla-
tion reaction of N-tosyl-2-pyrolidone-3-carboxylate esters
using ethyl (1g) and tert-butyl (1h) esters with 2a gave the
products 3g and 3h with 59 and 85% ee, respectively
(Table 3, entries 9 and 10). Furthermore, it should be noted
that the sulfenylation reaction of the b-diketone 1i with 2a
catalyzed by (DHQD)2PYR (4h) occurred at room temper-
ature with 70% ee (Table 3, entry 11). We have also reacted
acyclic b-keto esters with the sulfenylating reagents 2a–c
under various reaction conditions with different cinchona al-
kaloid catalysts, however, the results were not as positive as
those presented above.
Entry
Catalyst
Reaction temp
[8C]
Time
Yield[b]
[%]
ee[c]
[%]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4d
4e
4 f
4g
4h
4h
4i
RT
RT
RT
RT
À30
RT
RT
RT
RT
À30
RT
À24
À30
À40
1 day
2 h
3 days
3 h
3 days
2 h
5 days
2 h
5 h
3 days
5 h
3 days
1 day
3 days
70
73
52
73
76
63
10
80
70
78
73
54
55
23
70
60
27
72
89
43
33
48
70
81
77
87
89
91
9
10
11
12
13
14
4i
4i
4i
The absolute configuration of the stereogenic carbon
center in the a-sulfenylated product 6 was determined to be
(R) by X-ray crystal-structure analysis of the optically active
product 6 obtained in Equation (5).[8]
[a]Reaction conditions: 0.1 mmol of 2a was added to a mixture of 1c
(0.1 mmol) and 4 (10 mol%) in toluene (1 mL). [b] Yield of isolated
product. [c] ee was measured by HPLC.
only 23%, however, the enan-
tioselectivity was improved to
91% ee (Table 2, entry 14).
With the optimized reaction
conditions in hand, we decided
to investigate the organocata-
lytic enantioselective a-sulfe-
nylation of a series of lactones,
lactams, and
a b-dicarbonyl
compound, all having an acti-
À
vated C H bond, with different electrophilic sulfur reagents
(2a–c) using (DHQD)2PYR (4i) as the catalyst [Eq. (4)].
This absolute configuration is in agreement with the Re-
face attack of the sulfur-centered electrophile on the inter-
mediate which is formed by deprotonation of 1c with 4a. A
proposal for the intermediate is outlined in Figure 1. The
protonated catalyst interacts with the two oxygen atoms of
the b-keto ester (the keto-form exists probably as the eno-
late). The Si-face is shielded as outlined in Figure 1 leaving
the Re-face available for attack by the sulfur electrophile.
To show the synthetic versatility of optically active a-sul-
fenylated b-keto esters in the preparation of chiral sulfur
The results of these studies are presented in Table 3.
The catalytic enantioselective a-sulfenylation of the stan-
dard substrate 1c proceeds well with the different sulfe-
nylating reagents. 1-Benzylsulfanyl[1,2,4]triazole (2a), 1-
isobutylsulfanyl[1,2,4]triazole
(2b),
and
1-(2,4-
dinitrophenylsulfanyl)[1,2,4]triazole (2c) reacted with 1c to
produce the corresponding optically active a-sulfenylated b-
keto esters with enantioselectivities in the range of 83–
89% ee (Table 3, entries 3–5). These results demonstrate
that both the yield and enantioselectivity of the optically
active a-sulfenylated products are relatively independent of
the sulfur-protecting group in the sulfenylating reagents 2a–
c. Methyl 5-chloro-1-oxo-2-indan carboxylate (1d), benzyl-1-
oxo-2-indan carboxylate (1e), and methyl 2-oxo-1-indane
Figure 1. Postulated intermediate which is formed by deprotonation of 1c
with 4a Re-face attack of the sulfur electrophile.
Chem. Eur. J. 2005, 11, 5689 – 5694
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5691

K. A. Jørgensen et al.
Table 3. Enantioselective a-sulfenylation of cyclic b-keto esters and lactams 1a–h and b-diketone 1i with the
electrophilic sulfur reagents 2a–c (Lg=traizole) catalyzed by (DHQD)2PYR (4i) (10 mol%) in toluene.
manner to give the a-sulfenylat-
ed b-hydroxy esters 7 and 8
with d.r. values of 95:5 and
98:2, respectively. A lower dia-
stereoselectivity in the reduc-
tion of 6 with the same reduc-
ing agent was observed (d.r.=
70:30).
Entry
Substrate
Sulfur reagent
Reaction temp.
[8C]
Time
[days]
Product
Yield[a]
[%]
ee[b]
[%]
63
1
À30
4
3a
91
In conclusion, we have intro-
duced the first enantioselective
catalytic asymmetric a-sulfenyl-
ation of lactones, lactams, and a
b-dicarbonyl compound, all
2
3
À30
À30
5
5
3b
3c
78
88
71
89
À
having an activated C H bond,
which afford optically active a-
sulfenylated
4
5
RT
RT
2
2
5a
6a
80
83
79
83
functionalized
compounds. The reactions pro-
ceed in moderate to high yields
(up to 95%) and enantioselec-
tivities (up to 91% ee) using 1-
benzylsulfanyl[1,2,4]triazole as
the electrophilic sulfur reagent
and commercially available cin-
chona alkaloid derivatives as
organocatalysts. We have ex-
tended the application of 1-
benzylsulfanyl[1,2,4]triazole as
the electrophilic sulfur reagent
for the preparation of optically
active a-sulfenylated products
and have also shown that
1-(2,4-dinitrophenylsulfanyl)-
[1,2,4]triazole and isopropylsul-
fanyl[1,2,4]triazole are efficient
electrophilic sulfur reagents for
this reaction. Furthermore, the
diastereoselective reduction of
the a-sulfenylated b-keto esters
gives optically active a-sulfe-
nylated b-hydroxy esters.
6
7
À30
À40
3
3
3d
3e
95
84
51
60
8
À30
3
3 f
94
53
9
À30
À40
RT
1
1
1
3g
3h
3I
89
87
66
59
85
70
10
11
[a] Yield of isolated product. [b] ee was measured by HPLC.
compounds, reduction of the b-keto functionality in 3c, 5
and 6 was investigated (Scheme 1).
Experimental Section
In the presence of BH3·DMS, reduction of the b-keto
group in 3c and 5 proceeded in a highly diastereoselective
General methods: The 1H and 13C NMR spectra were recorded at
400 MHz and 100 MHz, respectively. The chemical shifts are reported in
1
ppm downfield to CDCl3 (d=7.26 ppm) for H NMR spectra and relative
to the central CDCl3 resonance (d=77 ppm) for 13C NMR spectra. Cou-
pling constants in 1H NMR measurements are in Hz. The enantiomeric
excess (ee) of the products was determined by HPLC using Chiralpack
AD or AS or Chiralcel OD with iPrOH/hexane as eluent.
Materials: b-Keto esters 1a, 1 f, b-dicarbonyl compound 1i, and cinchona
alkaloids 4a–i were purchased from Aldrich and used as received. b-Keto
esters 1b–e and sulfur reagents 2a–c were prepared according to referen-
ces [7,9]. Compounds 1g and 1h were prepared according to the stan-
dard literature procedures (deprotonation of corresponding N-Ts and re-
action with ethyl chloroformate or (Boc)2O, respectively, in THF).
Scheme 1. Reduction of a-sulfenylated b-keto esters.
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À
Organocatalytic Asymmetric a-Sulfenylation of Activated C H Bonds
FULL PAPER
General procedure for the organocatalytic a-sulfenylation of b-keto
esters: The catalyst (0.05 mmol) was dried in a Schlenk tube by evacuat-
ing for 15 min. Toluene (5 mL) was added under an N2 atmosphere. Then
the b-keto ester (0.5 mmol) was added to the solution at appropriate tem-
perature (Table 3), followed by the addition of the electrophilic sulfur re-
agent (0.6 mmol). The reaction mixture was stirred for the appropriate
time (Table 3) and then quenched with 1m aqueous KHSO4 (3 mL).
After standard aqueous workup, the product was purified by flash chro-
matography.
HRMS: m/z calcd for C18H15ClO3S: 369.0328; found: 369.0318 [M+Na]+;
[a]D =+33.8 (c=10 mgmLÀ1, 51% ee).
Benzyl 2-benzylsulfanyl-1-oxoindan-2-carboxylate (3e): The enantiomeric
excess was determined by HPLC using a Daicel Chiralpack AD column
(hexane/iPrOH) (90:10); flow rate 1.0 mLminÀ1; tmajor =14.9; tminor =16.1;
1H NMR: d=3.02 (d, J=18 Hz, 1H; CH2), 3.78 (d, J=18 Hz, 1H; CH2),
3.98 (d, J=12 Hz, 1H; CH2C6H5), 4.07 (d, J=12 Hz, 1H; CH2C6H5), 5,10
(d, J=12.4 Hz, 1H; CH2C6H5), 5.16 (d, J=12.4 Hz, 1H; CH2C6H5), 7.08–
7.40 (m, 12H; ArH), 7.50–7.54 (m, 1H; ArH), 7.77 ppm (d, J=7.6 Hz,
1H; ArH); 13C NMR: d=35.3, 40.2, 59.3, 68.3, 126.0, 126.6, 127.7–129.9,
135.9, 150.7, 169.6, 196.8 ppm; HRMS: m/z calcd for C24H20O3S:
Ethyl 1-benzylsulfanyl-2-oxocyclopentanecarboxylate (3a): The enantio-
meric excess was determined by HPLC using a Daicel Chiralpack AD
411.1031; found: 411.1096 [M+Na]+; [a]D =+15.2 (c=10 mgmLÀ1
60% ee).
,
column (hexane/iPrOH) (90:10); flow rate 1.0 mLminÀ1
; tmajor =6.0;
tminor =6.5; 1H NMR: d=1.22 (t, J=6.8 Hz, 3H; CH2CH3), 1.88–2.12 (m,
3H; CH2), 2.27–2.39 (m, 1H; CH2), 2.48–2.61 (m, 2H; CH2), 3.70 (d, J=
12 Hz, 1H; CH2C6H5), 4.00 (d, J=12 Hz, 1H; CH2C6H5), 4.14 (q, J=
6.8 Hz, 2H; CH2CH3), 7.15–7.23 ppm (m, 5H; ArH); 13C NMR: d=14.5,
19.6, 35.2, 35.7, 36.7, 62.5, 69.3, 127.6, 129.1, 129.7, 131.7, 169.7,
206.8 ppm; HRMS: m/z calcd for C15H18O3S: 301.0874; found: 301.0862
[M+Na]+; [a]D =À76.9 (c=10 mgmLÀ1, 63% ee).
Methyl 1-benzylsulfanyl-2-oxoindan-1-carboxylate (3 f): The enantiomeric
excess was determined by HPLC using a Daicel Chiralpack AS column
(hexane/iPrOH) (99:1); flow rate 1.0 mLminÀ1; tmajor =14.7; tminor =11.3;
1H NMR: d=3.68 (s, 3H; CH3), 3.71 (d, J=8.8 Hz, 2H; CH2), 3.89 (d,
J=12 Hz, 1H; CH2C6H5), 3.99 (d, J=12 Hz, 1H; CH2C6H5), 7.20–7.38
(m, 8H; ArH), 7.44–7.46 ppm (m, 1H; ArH); 13C NMR: d=35.9, 42.0,
53.8, 64.6, 125.6, 127.6–130.0, 136.4, 138.2, 168.3, 205.7 ppm; HRMS: m/z
calcd for C18H16O3S: 335.0718; found: 335.0709 [M+Na]+; [a]D =+18.7
(c=10 mgmLÀ1, 53% ee).
Isopropyl 1-benzylsulfanyl-2-oxocyclopentanecarboxylate (3b): The enan-
tiomeric excess was determined by HPLC using a Daicel Chiralpack AD
column (hexane/iPrOH) (98:2); flow rate 1.0 mLminÀ1
; tmajor =7.3;
1
Ethyl 3-benzylsulfanyl-2-oxo-1-(toluene-4-sulfonyl)pyrolidine-3-carboxyl-
ate (3g): The enantiomeric excess was determined by HPLC using a
Daicel Chiralpack AS column (hexane/iPrOH) (95:5); flow rate
1.0 mLminÀ1; tmajor =33.8; tminor =30.1; 1H NMR: d=1.15 (t, J=7.2 Hz,
3H; CH2CH3),1.89–1.95 (m, 1H; CH2), 2.38 (s, 3H; CH3), 2.62–2.70 (m,
1H; CH2), 3.38 (d, J=11.2 Hz, 1H; CH2C6H5), 3.71–3.77 (m, 1H; CH2),
3.86 (d, J=11.2 Hz, 1H; CH2C6H5), 3.90–3.92 (m, 1H; CH2), 4.10 (q, J=
7.2 Hz, 2H; CH2CH3) 6.91–6.93 (m, 2H; ArH), 7.13–7.18 (m, 3H; ArH),
7.29 (d, J=8.4 Hz, 2H; ArH), 7.88 ppm (d, J=8.4 Hz, 2H; ArH);
13C NMR: d=14.4, 22.1, 30.5, 35.3, 44.6, 57.6, 63.2, 127.8, 129.0, 129.6,
130.1, 134.3, 135.7, 146.0, 166.9, 167.8 ppm; HRMS: m/z calcd for
C21H23NO5S2: 456.0915; found: 456.0920 [M+Na]+; [a]D =À14.4 (c=
10 mgmLÀ1, 59% ee).
tminor =8.3; H NMR: d=1.28 (d, J=5.6 Hz, 6H; CH3), 1.93–2.17 (m, 3H;
CH2), 2.32–2.43 (m, 1H; CH2), 2.53–2.67 (m, 2H; CH2), 3.79 (d, J=
11.6 Hz, 1H; CH2C6H5), 4.07 (d, J=11.6 Hz, 1H; CH2C6H5), 5.08 (hep,
J=6.4 Hz, 1H; CHCH3), 7.19–7.33 ppm (m, 5H; ArH); 13C NMR: d=
19.7, 22.1, 35.2, 35.4, 36.8, 60.9, 70.4, 127.7, 129.0, 129.8, 136.9, 169.4,
207.0 ppm; HRMS: m/z calcd for C16H20O3S: 315.1031; found: 315.1024
[M+Na]+; [a]D =À102.9 (c=10 mgmLÀ1, 71% ee).
tert-Butyl 1-benzylsulfanyl-2-oxocyclopentanecarboxylate (3c): The enan-
tiomeric excess was determined by HPLC using a Daicel Chiralpack AD
column (hexane/iPrOH) (98:2); flow rate 1.0 mLminÀ1
; tmajor =6.3;
tminor =7.5; 1H NMR: d=1.42 (s, 9H; C4H9), 1.84–2.07 (m, 3H; CH2),
2.13–2.34 (m, 1H; CH2), 2.43–2.57 (m, 2H; CH2), 3.73 (d, J=11.6 Hz,
1H; CH2C6H5), 4.00 (d, J=11.6 Hz, 1H; CH2C6H5), 7.13–7.28 ppm (m,
5H; ArH); 13C NMR: d=19.7, 28.3, 35.2, 35.9, 36.9, 61.4, 83.3, 127.7,
129.8, 129.8, 136.9, 168.8, 207.4 ppm; HRMS: m/z calcd for C17H22O3S:
tert-Butyl
boxylate (3h): The enantiomeric excess was determined by HPLC using
Daicel Chiralcel OD column (hexane/iPrOH) (98:2); flow rate
3-benzylsulanyl-2-oxo-1-(toluene-4-sulfonyl)pyrolidine-3-car-
a
329.1187; found: 329.1179 [M+Na]+; [a]D =À106.0 (c=10 mgmLÀ1
89% ee).
,
1.0 mLminÀ1; tmajor =22.5; tminor =20.3; 1H NMR: d=1.37 (s, 9H; C4H9),
1.85–1.91 (m, 1H; CH2), 2.38 (s, 3H; CH3), 2.60–2.68 (m, 1H; CH2), 3.37
(d, J=11.2 Hz, 1H; CH2C6H5), 3.69–3.75 (m, 1H; CH2), 3.87 (d, J=
12 Hz, 1H; CH2C6H5), 3.91–3.94 (m, 1H; CH2), 6.90–6.95 (m, 2H; ArH),
7.10–7.28 (m, 5H; ArH), 7.87–7.89 ppm (m, 2H; ArH); 13C NMR: d=
22.1, 28.2, 30.6, 35.3, 44.7, 58.5, 84.4, 127.8, 128.8, 130.0, 134.5, 135.9,
145.9, 166.6, 167.2 ppm; HRMS: m/z calcd for C21H23NO5S2: 484.1228;
found: 484.1294 [M+Na]+; [a]D =À42.8 (c=5 mgmLÀ1, 85% ee).
tert-Butyl 1-isopropylsulfanyl-2-oxocyclopentanecarboxylate (5): The en-
antiomeric excess was determined by HPLC using a Daicel Chiralpack
AD column (hexane/iPrOH) (98:2); flow rate 1.0 mLminÀ1; tmajor =4.3;
tminor =4.7; 1H NMR: d=1.12 (d, J=6.4 Hz, 3H; CH3), 1.25 (d, J=
6.4 Hz, 3H; CH3), 1.40 (s, 9H; C4H9), 1.83–1.96 (m, 2H; CH2), 1.99–2.11
(m, 1H; CH2), 2.20–2.29 (m, 1H; CH2), 2.39–2.52 (m, 2H; CH2),
3.15 ppm (hep, J=6.8 Hz, 1H; CHCH3); 13C NMR: d=19.3, 25.1, 28.2,
35.5, 36.3, 36.9, 60.9, 82.8, 169.5, 207.7 ppm; HRMS: m/z calcd for
C13H22O3S: 281.1187; found: 281.1194 [M+Na]+; [a]D =À83.2 (c=
10 mgmLÀ1, 79% ee).
2-Benzylsulfanyl-2-(3,3-dimethyl-butyryl)cyclopentanone (3i): The enan-
tiomeric excess was determined by HPLC using a Daicel Chiralpack AD
column (hexane/iPrOH) (90:10); flow rate 1.0 mLminÀ1
; tmajor =4.8;
tminor =5.4; 1H NMR: d=0.92 (s, 9H; C4H9), 1.76–2.04 (m, 3H; CH2),
2.22–2.34 (m, 2H; CH2), 2.40–2.56 (m, 3H; CH2), 3.59 (d, J=12 Hz, 1H;
CH2C6H5), 3.66 (d, J=12, 1H; CH2C6H5), 7.14–7.25 ppm (m, 5H; ArH);
13C NMR: d=19.4, 29.8, 30.3, 34.0, 38.1, 50.1, 67.5, 127.7, 128.9, 129.5,
136.6, 198.7, 209.4 ppm; HRMS: m/z calcd for C18H24O2S: 327.1395;
found: 327.1393 [M+Na]+; [a]D =À33.7 (c=10 mgmLÀ1, 70% ee).
tert-Butyl
(6): The enantiomeric excess was determined by HPLC using a Daicel
Chiralpack AD column (hexane/iPrOH) (90:10); flow rate 1.0 mLminÀ1
1-(2,4-dinitrophenylsulfanyl)-2-oxocyclopentanecarboxylate
;
tmajor =10.0; tminor =12.8; 1H NMR: d=1.36 (s, 9H; C4H9), 2.04–2.12 (m,
2H; CH2), 2.28–2.35 (m, 1H; CH2), 2,41–2,50 (m, 1H; CH2), 2.51–2.67
(m, 2H; CH2), 8.05 (d, J=9.2 Hz, 1H; ArH), 8.24 (d, J=9.2 Hz, 1H;
ArH), 8.90 ppm (s, 1H; ArH); 13C NMR: d=19.9, 28.2, 37.6, 37.7, 64.4,
85.1, 121.5, 126.8, 131.9, 142.8, 145.5, 167.8, 208.0 ppm; HRMS: m/z calcd
for C16H18N2O7S: 405.0732 found: 405.0740 [M+Na]+; [a]D =+363 (c=
5 mgmLÀ1, 83% ee).
General procedure for the diastereoselective reduction of optically active
a-sulfanyl b-keto esters: To
a solution of a-sulfanyl b-keto ester
(0.5 mmol) in THF (5 mL) was added one equivalent of BH3·DMS. After
the reaction mixture had been stirred at room temperature for 1–2 days,
the reaction was quenched with H2O (5 mL) and the mixture was extract-
ed with Et2O (3”5 mL). The organic layer was then dried over anhy-
drous Na2SO4, filtered, and evaporated. The crude reaction mixture was
purified by flash chromatography to give the optically active a-sulfanyl
b-hydroxy esters.
Methyl 2-benzylsulfanyl-5-chloro-1-oxoindan-2-carboxylate (3d): The en-
antiomeric excess was determined by HPLC using a Daicel Chiralpack
AD column (hexane/iPrOH) (90:10); flow rate 1.0 mLminÀ1; tmajor =11.4;
tminor =12.2; 1H NMR: d=2.99 (d, J=18 Hz, 1H; CH2), 3.63 (s, 3H;
CH3), 3.74 (d, J=18 Hz, 1H; CH2), 3.95 (d, J=12 Hz, 1H; CH2C6H5),
4.09 (d, J=12 Hz, 1H; CH2C6H5), 7.11–7.23 (m, 6H; ArH), 7.29 (d, J=
7.6 Hz, 1H; ArH), 7.66 ppm (d, J=8.8 Hz, 1H; ArH); 13C NMR: d=
35.3, 39.9, 53.8, 59.3, 126.5–129.7, 136.5, 142.4, 152.2, 169.7, 195.4 ppm;
tert-Butyl
1-benzylsulfanyl-2-hydroxycyclopentanecarboxylate
(7):
1H NMR: d=1.45 (s, 9H; C4H9), 1.50–1.55 (m, 1H; CH2), 1.70–1.84 (m,
4H; CH2), 2.15–2.22 (m, 1H; CH2), 3.70 (d, J=12.4 Hz, 1H; CH2C6H5),
3.79 (d, J=12.4 Hz, 1H; CH2C6H5), 4.25 (t, J=4 Hz, 1H; CH), 7.16–
Chem. Eur. J. 2005, 11, 5689 – 5694
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5693

K. A. Jørgensen et al.
7.26 ppm (m, 5H; ArH); 13C NMR: d=20.3, 28.4, 31.0, 32.6, 35.1, 64.8,
75.0, 82.3, 127.8, 129.2, 129.4, 138.0, 172.0 ppm; HRMS: m/z calcd for
C17H24O3S: 331.1344; found: 331.1315 [M+Na]+.
Angew. Chem. 2004, 116, 5248; Angew. Chem. Int. Ed. 2004, 43, 5138;
h) J. Christoffers, A. Baro, T. Werner, Adv. Synth. Catal. 2004, 346,
143; i) B. List, J. Am. Chem. Soc. 2002, 124, 5656; j) G. Zhong,
Angew. Chem. 2003, 115, 4379; Angew. Chem. Int. Ed. 2003, 42, 4247;
k) A. Bøgevig, H. Sundeen, A. Cordova, Angew. Chem. 2004, 116,
1129; Angew. Chem. Int. Ed. 2004, 43, 1109.
tert-Butyl 2-hydroxy-1-isopropylsulfanylcyclopentanecarboxylate (8):
1H NMR: d=1.25 (d, J=6.8 Hz, 3H; CH3), 1.34 (d, J=6.8 Hz, 3H;
CH3), 1.48 (s, 9H; C4H9), 1.57–1.63 (m, 1H; CH2), 1.73–1.93 (m, 4H;
CH2), 2.24–2.29 (m, 1H; CH2), 3.06 (hep, J=6.8 Hz, 1H; CH), 4.33–
4.35 ppm (m, 1H); 13C NMR: d=20.4, 24.9, 26.0, 28.4, 31.2, 33.3, 35.4,
65.0, 74.8, 82.2, 172.3 ppm; HRMS: m/z calcd for C13H24O3S: 283.1314;
found: 283.13552 [M+Na]+.
[3] See, for example: a) B. List, J. Am. Chem. Soc. 2002, 124, 5656; b) A.
Bøgevig, K. Juhl, N. Kumaragurubaran, W. Zhuang, K. A. Jørgensen,
Angew. Chem. 2002, 114, 1868; Angew. Chem. Int. Ed. 2002, 41, 1790;
c) N. Kumaragurubaran, K. Juhl, W. Zhuang, A. Bøgevig, K. A. Jør-
gensen, J. Am. Chem. Soc. 2002, 124, 6254; d) H. Vogt, S. Vanderhei-
den, S. Bräse, Chem. Commun. 2003, 2448; e) S. Saaby, M. Bella,
K. A. Jørgensen, J. Am. Chem. Soc. 2004, 126, 8120; f) N. S. Chowa-
dari, C. F. Barbas, Org. Lett. 2005, 7, 867.
[4] See, for example: a) A. Cordova, H. Sunden, M. Engquist, I. Ibra-
hem, J. Casas, J. Am. Chem. Soc. 2004, 126, 8914; b) S. P. Brown,
M. P. Brochu, C. J. Sinz, D. W. C. MacMillan, J. Am. Chem. Soc. 2003,
125, 10808; c) Y. Hayashi, J. Yamaguchi, T. Sumiya, M. Shoji, Angew.
Chem. 2004, 116, 1132; Angew. Chem. Int. Ed. 2004, 43, 1112;
d) M. R. Acocella, O. García MancheÇo, M. Bella, K. A. Jørgensen,
J. Org. Chem. 2004, 69, 8165.
tert-Butyl 1-(2,4-dnitrophenylsulfanyl)-2-hydroxycyclopentanecarboxylate
(9): 1H NMR: d=1.51 (s, 9H; C4H9), 1.89–2.07 (m, 2H; CH2), 2.16–2.34
(m, 2H; CH2), 2.57–2.67 (m, 2H; CH2), 4.80–4.83 (m, 1H; CH), 7.92 (d,
J=8.8 Hz, 1H; ArH), 8.34 (d, J=6.4 Hz, 1H; ArH), 9.03 ppm (s, 1H;
ArH); 13C NMR: d=28.2, 33.1, 33.6, 35.6, 37.7, 66.9, 80.0, 83.9, 121.7,
126.9, 130.3, 131.3, 144.4, 172.0 ppm; HRMS: m/z calcd for C16H20N2O7S:
407.0889; found: 407.0896 [M+Na]+.
Acknowledgements
[5] See, for example: a) M. P. Brochn, S. P. Brown, D. W. C. MacMillan,
J. Am. Chem. Soc. 2004, 126, 4108; b) N. Haland, A. Braunton, S.
Bachmann, M. Marigo, K. A. Jørgensen, J. Am. Chem. Soc. 2004,
126, 4790; c) M. Marigo, S. Bachmann, N. Halland, A. Braunton,
K. A. Jørgensen, Angew. Chem. 2004, 116, 5623; Angew. Chem. Int.
Ed. 2004, 43, 5507; d) D. Enders, M. R. M. Hüttl, Synlett 2005, 991;
e) M. Marigo, D. Fielenbach, A. Braunton, A. Kjærsgaard, K. A. Jør-
gensen, Angew. Chem. 2005, 117, 3769; Angew. Chem. Int. Ed. 2005,
44, 3703; f) D. D. Steiner, N. Mase, C. F. Barbas, Angew. Chem. 2005,
117, 3772; Angew. Chem. Int. Ed. 2005, 44, 3706; g) T. D. Beeson,
D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127, 8826.
[6] a) J.-H. Youn, R. Herrmann, I. Ugi, Synthesis 1987, 158; b) G. Poli, L.
Belvisi, L. Manzoni, C. Scolastico, J. Org. Chem. 1993, 58, 3165; c) K.
Chibale, S. Warren, Tetrahedron Lett. 1994, 35, 3991; d) D. A. Evans,
K. R. Campos, J. S. Tedrow, F. E. Michael, M. R. Gagne, J. Am.
Chem. Soc. 2000, 122, 7905.
[7] M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A. Jørgensen, Angew.
Chem. 2005, 117, 804; Angew. Chem. Int. Ed. 2005, 44, 794.
[8] CCDC-268711 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
[9] a) S. F. McCann, G. D. Annis, R. Shapiro, D. Piotrowski, G. P. W.
Lahm, J. K. Long, K. C. Lee, M. M. Hughes, B. J. Myers, S. M. Gris-
wold, B. M. Reeves, R. W. March, P. L. Sharpe, P. Lowder, W. E. Bar-
nette, K. E. Wing, Pest Manage. Sci. 2001, 57, 153; b) S.-I. Hashimoto,
Y. Miyazaki, T. Shinoda, S. Ikegami, J. Chem. Soc., Chem. Commun.
1990, 1100; c) J. Christoffers, U. Rossler, T. Werner, Eur. J. Org.
Chem. 2000, 5, 701; d) M. E. Bunnage, S. G. Davies, R. M. Parkin,
P. M. Roberts, A. D. Smith, J. M. Withey, Org. Biomol. Chem. 2004,
2, 3337; e) A. Padwa, W. S. Kissell, C. K. Eidell, Can. J. Chem. 2001,
79, 1681.
This work was made possible by a grant from The Danish National Re-
search Foundation and EU-HMPT-CT-2001–00317. S.S. thanks Iran
MRST and NOVO-NORDISK. Thanks are expressed to Jacob Over-
gaard for performing X-ray analysis and to Anne Kjærsgaard for model-
ing intermediates.
[1] See, for example: a) J. P. Genet, C. Greck, D. Lavergne, In Modern
Amination Methods, (Ed.: A. Ricci), Wiley–VCH, Weinheim, 2000,
Chapter 3; b) D. J. Ramon, M. Yus, Curr. Org. Chem. 2004, 8, 149;
c) K. Juhl, K. A. Jørgensen, J. Am. Chem. Soc. 2002, 124, 2420;
d) D. A. Evans, S. G. Nelson, J. Am. Chem. Soc. 1997, 119, 6452; e) L.
Hintermann, A. Togni, Angew. Chem. 2000, 112, 4530; Angew. Chem.
Int. Ed. 2000, 39, 4359; f) S. Piana, I. Devillers, A. Togni, U. Rothis-
berger, Angew. Chem. 2002, 114, 1021; Angew. Chem. Int. Ed. 2002,
41, 979; g) R. Frantz, L. Hintermann, M. Perseghini, D. Brogginio, A.
Togni, Org. Lett. 2003, 5, 1709; h) N. Momiyama, H. Yamamoto, J.
Am. Chem. Soc. 2004, 126, 6038; i) Y. Hamashima, K. Yagi, H.
Takano, L. Tamas, M. Sodeoka, J. Am. Chem. Soc. 2002, 124, 14530;
j) Y. Masashima, H. Takano, D. Hotta, M. Sodeoka, Org. Lett. 2003,
5, 3225; k) D. Y. Kim, E. J. Park, Org. Lett. 2002, 4, 545; l) L. Hinter-
mann, A. Togni, Helv. Chim. Acta 2000, 83, 2425; m) M. Marigo, K.
Juhl, K. A. Jørgensen, Angew. Chem. 2003, 115, 1405; Angew. Chem.
Int. Ed. 2003, 42, 1367; n) H. Ibrahim, A. Togni, Chem. Commun.
2004, 1147.
[2] See, for example: a) P. I. Dalko, L. Moisan, Angew. Chem. 2001, 113,
3840; Angew. Chem. Int. Ed. 2001, 40, 3726; b) B. List, Tetrahedron
2002, 58, 5573; c) R. O. Duthaler, Angew. Chem. 2003, 115, 1005;
Angew. Chem. Int. Ed. 2003, 42, 975; d) P. Merino, T. Tejero, Angew.
Chem. 2004, 116, 3055; Angew. Chem. Int. Ed. 2004, 43, 2995; e) B.
List, Acc. Chem. Res. 2004, 37, 548; f) W. Notz, F. Tanaka, C. F.
Barbas III, Acc. Chem. Res. 2004, 37, 580; g) P. I. Dalko, L. Moisan,
Received: May 6, 2005
Published online: July 20, 2005
5694
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 5689 – 5694