Direct organocatalytic asymmetric α-oxidation of ketones with iodosobenzene and N-sulfonyloxaziridines

Article abstract of DOI:10.1016/j.tetlet.2005.01.167

The novel, direct amino acid-catalyzed α-oxidation of ketones with iodosobenzene and N-sulfonyloxaziridines is presented. A screen of several synthetically common oxidants revealed that iodosobenzene and N-sulfonyloxaziridines act as electrophiles in the direct organocatalytic asymmetric α-hydroxylation of ketones. The direct proline-catalyzed asymmetric α-oxidation of ketones with iodosobenzene yielded the corresponding α-hydroxylated ketones with up to 77% ee. Furthermore, several amino acid derivatives catalyze the stereoselective α-oxidation of ketones with N-sulfonyloxaziridines. For example, the direct diamine-catalyzed enantioselective α-hydroxylation of ketones with N-sulfonyloxaziridines furnished the corresponding α-hydroxylated products in moderate yield with up to 63% ee.

Full text of DOI:10.1016/j.tetlet.2005.01.167

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2053–2057
Direct organocatalytic asymmetric a-oxidation of ketones with
iodosobenzene and N-sulfonyloxaziridines
*
´ ´
Magnus Engqvist, Jesu´s Casas, Henrik Sunden, Ismail Ibrahem and Armando Cordova
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Received 25 October 2004; revised 17 January 2005; accepted 26 January 2005
Abstract—The novel, direct amino acid-catalyzed a-oxidation of ketones with iodosobenzene and N-sulfonyloxaziridines is pre-
sented. A screen of several synthetically common oxidants revealed that iodosobenzene and N-sulfonyloxaziridines act as electro-
philes in the direct organocatalytic asymmetric a-hydroxylation of ketones. The direct proline-catalyzed asymmetric a-oxidation
of ketones with iodosobenzene yielded the corresponding a-hydroxylated ketones with up to 77% ee. Furthermore, several amino
acid derivatives catalyze the stereoselective a-oxidation of ketones with N-sulfonyloxaziridines. For example, the direct diamine-cata-
lyzed enantioselective a-hydroxylation of ketones with N-sulfonyloxaziridines furnished the corresponding a-hydroxylated products
in moderate yield with up to 63% ee.
Ó 2005 Elsevier Ltd. All rights reserved.
One of the ultimate goals and challenges in chemistry is
to develop stereoselective transformations for the crea-
tion of optically active functional molecules from simple
readily available starting materials. There are several
methods for the preparation of enantiomerically pure
compounds and among these asymmetric catalysis is a
highly active research field.1
tion with excellent stereoselectivities.7 These initial
reports by Zhong,7c MacMillan and co-workers,7d Hay-
ashi and co-workers7e–g and us7a,b were later followed
up by the excellent studies of Yamamoto,8 Blackmond
and others.9 Furthermore, we recently demonstrated
that amino acids catalyze the biomimetic asymmetric
aerobic a-oxidation of aldehydes and ketones.10 Based
on this research and our interest in amino acid-catalyzed
asymmetric reactions,11 we became interested in whether
other oxidants could be employed in transformations
with catalytically generated chiral enamines. Herein,
we disclose the first examples of direct organocatalytic
a-oxidation of ketones with iodosobenzene and N-sulfon-
yloxaziridines yielding a-hydroxylated ketones and diols
with up to 77% ee.
Optically active a-hydroxy carbonyl moieties are com-
monly found in numerous important natural products.2
This has led to extensive research to find new diastereo-
selective and enantioselective routes for their syntheses.3
One way of preparing these compounds is by asym-
metric a-hydroxylation of enolates employing chiral
auxiliaries or substrates.4 Recently, Momiyama and
Yamomoto reported a more efficient catalytic system
based on AgX/BINAP-complexes that mediate indirect
a-oxidation of activated tin enolates with nitrosobenz-
ene as the electrophile.5
In an initial screen of different oxidants for the a-oxida-
tion of cyclohexanone 1a in the presence of a catalytic
amount of L-proline (20 mol %), we found that iodoso-
benzene (PhIO) and trans-2-(p-methylphenylsulfonyl)-
3-phenyloxaziridine 3 furnished the corresponding a-
hydroxylated ketone 2a in 27% and 44% yields with
67% and 29% eeꢀs, respectively.12 On standing the a-
hydroxy ketone 2a dimerized and oligomerized and
was therefore reduced in situ with excess NaBH4 to
the corresponding diol 4a (Eq. 1).
Organocatalysis has experienced a renaissance in organ-
ic chemistry.6 In this context, we and other researchers
have reported that amino acids and their derivatives cata-
lyze the direct Yamamoto-type a-aminoxylation reac-
*
Encouraged by these preliminary results we carried out
a catalyst and solvent screen on the direct asymmetric
Corresponding author. Tel.: +46 8 162479; fax: +46 8 154908; e-mail
addresses: acordova@organ.su.se; acordova1a@netscape.net
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.167

2054
M. Engqvist et al. / Tetrahedron Letters 46 (2005) 2053–2057
utilizing the proline-derived catalysts 5–9 (Table 2). We
found that diamine catalyst 5 provided the a-hydroxyl-
ated ketone ent-2a with the highest ee (entry 2). The most
efficient catalyst was 5-(pyrrolidin-2-ylmethyl)tetrazole
7, which furnished 2a in 69% yield with 17% ee (entry
4).13 We also investigated the possibility of adding a sub-
stoichiometric amount of acid in the diamine-catalyzed
reactions, which has previously been shown to accelerate
the reaction rate as well as increase the enantioselectivity
in enamine-catalyzed asymmetric reactions.6g,14 We
found that the yield of 2a was augmented by addition
of 0.3 equiv of TFA, however the ee of 2a did not signifi-
cantly increase (entry 7). We also performed the novel
amine-catalyzed asymmetric a-oxidation of 1a with 3 in
different solvents. The solvent screen revealed that the
efficiency and enantioselectivity of the reactions cata-
lyzed by diamines 5 and 6 significantly improved in
THF and CHCl3. For example, diamine 6 furnished the
corresponding ent-2a in 29% yield with 52% ee (entry
10). We also investigated the possibility of adding water
to the diamine-catalyzed reaction in the hope of increas-
ing the hydrophobic interactions of the substrate and the
catalyst, however, no significant enhancement of the rate
or enantioselectivity was observed. Furthermore,
decreasing the reaction temperature did not improve
the enantioselectivity of the reaction (entry 9). The di-
amine-catalyzed reactions with trans-2-(phenylsulfonyl)-
3-phenyloxaziridine furnished the a-hydroxy ketones
with similar eeꢀs to the reactions with 3.
O
O
OH
oxidant,
OH
L-proline (20 mol%)
OH
NaBH4
MeOH
DMSO, rt
1a
2a
ð1Þ
4a
O
S
N
Oxidant: NaOCl, H2O2, t-BuOOH, Oxone, PhIO,
O
O 3
a-hydroxylation of 1a with PhIO and N-sulfonyloxazir-
idine 3 as the oxidants (Tables 1 and 2).
The catalyst screen of the direct organocatalytic a-oxi-
dation of ketone 1a with PhIO revealed that L-proline
provided ketone 2a with the highest enantioselectivity
in comparison to catalysts 5–8 (Table 1). In fact, organic
catalysts 5–8 only furnished trace amounts of 2a (entries
2–5). Conducting the a-oxidation of 1a with PhIO in
DMF improved the enantioselectivity of the transforma-
tion and the corresponding diol 4a was obtained in 29%
yield (trans/cis 5:1) with 77% ee after in situ reduction of
2a (entry 6). Attempts to increase the enantioselectivity
by decreasing the reaction temperature from room tem-
perature to 0 °C were unsuccessful (entry 8). Potential
background oxidation of the enamine intermediates
may occur, however, the initial oxidant screen indi-
cates that it was not significant under the reaction
conditions.12
We next investigated the organocatalytic enantioselec-
tive a-hydroxylation reactions for a set of different
ketones (Table 3).15 The proline-catalyzed asymmetric
a-oxidation of ketones 1a–c with PhIO proceeded
Next, we investigated the direct stereoselective reaction
between N-sulfonyloxaziridine 3 and ketone 1a in DMSO
Table 1. Direct organocatalytic asymmetric a-oxidations of 1a with PhIOa
O
O
O
I
OH
, solvent, rt
catalyst (10-30 mol%)
1a
2a
N
N
COOH
N
N
N
N
H
N
HN
N
H
H
N
H
5
6
7
8
O
Entry
Catalyst
Solvent
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
9
10
L-Proline
5
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
27 (32)d
Traces
Traces
Traces
10
67 (65)d
ND
ND
<5
6
7
8
<5
77
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
29
CH3CN
DMF
Traces
22e
10
5
70e
50
Dioxane
CHCl3
Traces
ND
a To PhIO (1 mmol) in 4 mL of organic solvent in the presence of organic catalyst (10–30 mol %) was added ketone 1a (3 mmol). After stirring for 16–
24 h at room temperature the reaction was quenched either by addition of brine followed be extraction with EtOAc to furnish a-hydroxy ketone 2a
or by in situ reduction with excess NaBH4 (15 mmol) at 0 °C to afford the corresponding optically active crude diol 4a.
b Yield of the isolated pure diol 4a.
c The ee of trans-4a as determined by chiral-phase GC analyses.
d 10 equiv of 1a was used.
e Temperature = 0 °C.

M. Engqvist et al. / Tetrahedron Letters 46 (2005) 2053–2057
Table 2. Direct organocatalytic asymmetric a-oxidations of 1a with 3a
2055
O
O
O
S
N
O
OH
O 3
, solvent, rt
catalyst (10-30 mol%)
1a
2a
N
O
N
N
N
H
N
H
N
N
N
H
HN
NH2
N
H
9
5
6
7
O
Entry
Catalyst
Solvent
Product
Yieldb (%)
Eec (%)
1
L-Proline
5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
THF
2a
44
35
29
39
10
17
0
2
ent-2a
ent-2a
2a
3
6
Traces
69
4
7
5
9
2a
Traces
Traces
50
6
5ÆAcOH (0.3 equiv)
5ÆTFA (0.3 equiv)
5
5
6
6
ent-2a
ent-2a
ent-2a
ent-2a
ent-2a
ent-2a
ND
33
37
15d
52
45
7
8
46
9
THF
THF
CHCl3
11d
29
10
11
44
a To 3 (1 mmol) in 4 mL of organic solvent in the presence of catalyst (10–30 mol %) was added ketone 1a (3 mmol). After stirring for 16–24 h at
room temperature the reaction was quenched either by addition of brine followed by extraction with EtOAc to furnish a-hydroxy ketone 2a or by in
situ reduction with excess NaBH4 (15 mmol) at 0 °C to afford the corresponding optically active crude diol 4a.
b Yield of isolated pure diol 4a.
c The ee of trans-4a as determined by chiral-phase GC analyses.
d Temperature = 0 °C.
Table 3. Direct organocatalytic asymmetric a-oxidations of ketones with PhIO and 3
O
O
OH
R1
R1
, solvent, rt
PhIO or 3
R2
R2
catalyst (30 mol%)
2
1
Entry
1
Catalyst
Ketone
Oxidant
Solvent
DMF
Product
Yielda (%)
29 (48)c
Eeb (%)
77 (76)c
L-Proline
1a
PhIO
2a
O
2
L-Proline
PhIO
DMSO
2b
20
70
1b
1b
3
4
L-Proline
L-Proline
PhIO
PhIO
DMF
2b
2c
22
21
68
65
O
DMSO
1c
O
5
L-Proline
PhIO
DMSO
2d
10
ND
1d
6
7
8
9
6
6
6
7
1a
1b
1c
1b
3
3
3
3
THF
THF
ent-2a
ent-2b
ent-2c
2b
29
28
27
92
52
63
34
21
THF
DMSO
a Yield of isolated pure diol 4 following in situ reduction.
b The ee of trans-4 as determined by chiral-phase GC analyses.
c 45 lL Water was added to the reaction.

2056
M. Engqvist et al. / Tetrahedron Letters 46 (2005) 2053–2057
smoothly furnishing the corresponding ketones 2a–c in
low yield with up to 77% ee. Attempts to increase the
yield by addition of the PhIO in small portions were
not successful. The diamine 6-catalyzed a-oxidation of
ketones 1a–c with oxaziridine 3 proceeded smoothly
and furnished the corresponding ketones ent-2a–ent-2c
in low yields with up to 63% ee (entries 6–8). The low
yields could be due to decomposition of the electro-
philes. However, addition of water (100 mmol) or
employing catalyst 7 increased the yield (entries 1 and
9). In addition, the reactions can be readily scaled-up
and are operationally simple. The reactions with acyclic
ketones 1 were slow and provided only small amounts of
the corresponding a-hydroxylated ketones 2.
Acknowledgements
We thank the Swedish Research Council and Wenner-
Gren Foundation for financial support. We also thank
Professor Jan-E. Ba¨ckvall for sharing chemicals.
References and notes
1. (a) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg,
1999; (b) Noyori, R. Asymmetric Catalysis in Asymmetric
Organic Synthesis; John Wiley and Sons: New York, 1994;
(c) Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.,
Wiley–VCH: New York, 2000.
2. (a) Davis, F. A.; Chen, B. C. In Houben-Weyl: Methods of
Organic Chemistry; Helmchen, G., Hoffmann, R. W.,
Mulzer, J., Schaumann, E., Eds.; George Thieme: Stutt-
gart, 1995; Vol. E21, p 4497; (b) Enders, D.; Reinhold, U.
Liebigs Ann. 1996, 11; (c) Enders, D.; Reinhold, U. Synlett
1994, 792.
3. (a) Davis, F. A.; Chen, B. C. Chem. Rev. 1992, 92, 919,
and references cited therein; (b) Lohray, B. B.; Enders, D.
Helv. Chim. Acta 1989, 72, 980.
4. Paquette, L. A.; Hartung, R. E.; Hofferberth, J. E.;
Vilotijevic, I.; Yang, J. J. Org. Chem. 2004, 69, 2454, and
references cited therein.
5. Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003,
125, 6038.
6. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2001, 40, 3726; (b) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138; (c) List, B. Tetrahedron
2002, 58, 5573; (d) Merino, P.; Tejero, T. Angew.
Chem., Int. Ed. 2004, 43, 2995; For a-aminations see: (e)
Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang,
W.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41,
1790; (f) List, B. J. Am. Chem. Soc. 2002, 124, 5656; (g)
Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bøgevig,
A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124,
6254; For a-chlorinations of ketones, see: (h) Marigo,
M.; Bachmann, S.; Halland, N.; Braunton, A.; Jørgen-
sen, K. A. Angew. Chem., Int. Ed. 2004, 43, 5507; For
amine-catalyzed epoxidations, see: (i) Bohe, L.; Han-
quet, M.; Lusinchi, M.; Lusinchi, X. Tetrahedron Lett.
1993, 34, 7271; (j) Adamo, M. F. A.; Aggarwal, V. K.;
Sage, M. A. J. Am. Chem. Soc. 2000, 122, 8317; (k)
Armstrong, A. Angew. Chem., Int. Ed. 2004, 43, 1460,
and references cited therein.
The stereochemistry of the reaction was determined by
synthesis and by comparison with the previously re-
ported trans-diol 4a. The stereochemical outcome of
the proline-catalyzed reaction is explained by re-facial
attack on the catalytically generated enamine by the
oxygen of PhIO or N-sulfonyloxaziridine 3, which is
protonated by the acid moiety of L-proline to furnish
the a-hydroxylated ketone 2a (I and II). This is in accor-
dance with the previous proline-catalyzed a-oxidations
with nitrosobenzene and molecular oxygen.8–10 The ste-
reochemical outcome of the diamine-catalyzed reaction
is opposite to that of the proline-catalyzed reactions.
In this case, si-facial attack on the catalytically gener-
ated diamine by the oxygen of N-sulfonyloxaziridine 3
occurs and yields a-hydroxy ketone ent-2a (III). This
proposed transition state is favored due to hydrophobic
interactions.16
O
O
Ph
N
N
I
MeC6H4O2S
O
O
N
H
H
O
O
Ph
II
I
R2N
N
Ph
O
N
´
´
7. (a) Bøgevig, A.; Sunden, H.; Cordova, A. Angew. Chem.,
SO2C6H4Me-4
´
´
Int. Ed. 2004, 43, 1109; (b) Cordova, A.; Sunden, H.;
Bøgevig, A.; Johansson, M.; Himo, F. Chem. Eur. J. 2004,
10, 3673; (c) Zhong, G. Angew. Chem., Int. Ed. 2003, 42,
4247; (d) Brown, S. P.; Brochu, M. P.; Sinz, C. J.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808;
(e) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M.
Tetrahedron Lett. 2003, 44, 8293; (f) Hayashi, Y.;
Yamaguchi, J.; Hibino, K.; Shoji, M. Angew. Chem., Int.
Ed. 2004, 43, 1112; (g) Hayashi, Y.; Yamaguchi, J.;
Sumiya, T.; Hibino, K.; Shoji, M. J. Org. Chem. 2004, 69,
5966.
III
In summary, we present the first examples of direct
organocatalytic asymmetric a-oxidation of ketones with
iodosobenzene and N-sulfonyloxaziridines. In compari-
son to singlet molecular oxygen as the oxidant,10 the
amino acid-catalyzed a-oxidations with PhIO and N-sul-
fonyloxaziridine exhibited similar stereoselectivity yield-
ing a-hydroxylated ketones with up to 77% ee. The large
degree of variation in the synthesis of chiral amine- and
amino acid-derived catalysts makes the likelihood
of finding highly enantioselective catalysts a real possi-
bility for the a-oxidation of carbonyl compounds with
readily available oxidants. Efforts in this area are in
progress.
8. (a) Momiyama, N.; Torii, H.; Saito, S.; Yamamoto, H.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5374; (b)
Yamamoto, Y.; Momiyama, N.; Yamamoto, H. J. Am.
Chem. Soc. 2004, 126, 5962.
9. (a) Mathew, S. P.; Iwamura, H.; Blackmond, D. G.
Angew. Chem., Int. Ed. 2004, 43, 3317; (b) Wang, W.;
Wang, J.; Hao, Li.; Liao, L. Tetrahedron Lett. 2004, 45,
7235; For density functional calculations see: Ref. 7b and

M. Engqvist et al. / Tetrahedron Letters 46 (2005) 2053–2057
2057
(c) Cheong, P.H.-Y.; Houk, K. N. J. Am. Chem. Soc.
2004, 43, 13912.
column chromatography (EtOAc–pentane 1:1) and the ee
of the pure trans-4a diol was determined by GC analyses.
(1R,2R)-trans-Cyclohexane-1,2-diol: [a]D ꢀ21 (c 0.2,
´
10. (a) Cordova, A.; Sunden, H.; Engqvist, M.; Ibrahem, I.;
Casas, J. J. Am. Chem. Soc. 2004, 126, 8914; (b) Sunden,
´
´
CHCl3); GC: (CP-Chirasil-Dex CB); Tinj = 250 °C, Tdet
=
´
H.; Engqvist, M.; Casas, J.; Ibrahem, I.; Cordova, A.
Angew. Chem., Int. Ed. 2004, 43, 6532.
11. (a) Casas, J.; Persson, P. V.; Iversen, T.; Cordova, A. Adv.
275 °C, flow = 1.8 mL/min, Ti = 110 °C (2 min), Tf =
200 °C, rate = 80 °C/min; retention times of the acetylated
compound: tmin = 9.75 min, tmaj = 9.61 min. The results
from the a-oxidation screen of 1a with different oxidants
for the diol 3a was: aq NaOCl (traces, 0% ee), H2O2
(traces, 4% ee), t-BuOOH (traces, 0%), oxone (traces, 0%
ee), PhIO (27% yield, 67% ee), m-CPBA (traces, 5% ee),
oxaziridine 3 (44% yield, 29% ee).
´
Synth. Catal. 2004, 346, 1087; (b) Cordova, A. Tetrahe-
´
dron Lett. 2004, 45, 3949; (c) Casas, J.; Sunden, H.;
´
Cordova, A. Tetrahedron Lett. 2004, 45, 6117; (d) Ibra-
´
hem, I.; Casas, J.; Cordova, A. Angew. Chem., Int. Ed.
´
2004, 43, 6528; (e) Cordova Acc. Chem. Res. 2004, 37, 102;
´
(f) Cordova, A.; Notz, W.; Barbas, C. F., III. J. Org.
´
Chem. 2002, 67, 301; (g) Cordova, A. Chem. Eur. J. 2004,
13. For previous use of catalyst 7, see: (a) Refs. 8a,b,10, and
Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558;
(b) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983;
(c) Hartikaa, A.; Arvidsson, P. I. Tetrahedron: Asymmetry
2004, 15, 1831.
´
10, 1987; (h) Cordova, A. Synlett 2003, 1651, and
´
references cited therein.
12. In a typical experiment, the ketone 1a (1 mmol) was
dissolved in DMSO (4 mL) and the oxidant (10 mmol) was
added to the reaction mixture. In the cases of a-oxidation
with PhIO and 3, 1 mmol of the oxidant was used and
3 mmol of ketone 1a. After 16–24 h of vigorous stirring at
room temperature, the reaction was quenched either by
addition of brine followed be extraction with EtOAc to
furnish a-hydroxy ketone 2a or by in situ reduction with
NaBH4 at 0 °C to afford the corresponding optically active
crude diol 4a. The crude a-hydroxy ketone 2a existed as an
oligomeric mixture that upon standing formed the dimer,
which was isolated by silica-gel column chromatography
(EtOAc–pentane 1:20) and the ee was determined by
chiral-phase GC-analysis. GC: (CP-Chirasil-Dex CB);
Tinj = 250 °C, Tdet = 275 °C, flow = 1.8 mL/min, Ti =
60 °C (9 min), rate = 85 °C/min, Tf = 200 °C (5 min);
retention times of 2a: tmaj = 10.64 min, tmin = 10.66 min.
The trans-4a and cis-4a diols were isolated by silica-gel
14. Mase, N.; Tanaka, F.; Barbas, C. F., III. Angew. Chem.,
Int. Ed. 2004, 43, 2420.
15. In a typical experiment, the ketone 1 (3 mmol) was
dissolved in organic solvent (4 mL) and PhIO or 3
(1 mmol) was added to the reaction mixture. After 16–
24 h of vigorous stirring at room temperature, the reaction
was quenched either by addition of brine followed be
extraction with EtOAc to furnish a-hydroxy ketone 2a or
by in situ reduction with excess NaBH4 (15 mmol) at 0 °C
to afford the corresponding optically active crude diol 3.
The enantiomeric excess was determined by chiral-phase
GC analyses.
16. (a) Vinkovic, V.; Sunjic, V. Tetrahedron 1997, 53, 689; (b)
´
Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2002,
43, 7749; (c) Zhuang, W.; Saaby, S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2004, 43, 4476.