Direct amino acid catalyzed asymmetric α oxidation of ketones with molecular oxygen

Article abstract of DOI:10.1002/anie.200460295

(Chemical equation presented). A possible prebiotic pathway for the asymmetric incorporation of molecular oxygen into organic compounds involves the amino acid catalyzed reaction of molecular singlet oxygen with ketones. Amino acids and their derivatives mediate the reaction between oxygen and ketones with high efficiency to produce α-hydroxyketones (see scheme).

Full text of DOI:10.1002/anie.200460295

Communications
Oxidations
Direct Amino Acid Catalyzed Asymmetric
a Oxidation of Ketones with Molecular Oxygen**
In an initial experiment, cyclohexanone 1a (1 mmol) was
added to a vial containing dimethyl sulfoxide (DMSO)
1 mL), l-proline (20 mol%) and tetraphenylporphine
Henrik SundØn, Magnus Engqvist, Jesffls Casas,
Ismail Ibrahem, and Armando Córdova*
(
(
TPP) (1 mol%). A continuous flow of O or air was bubbled
2
Molecular oxygen is fundamental for the existence of com-
plex multicellular life on earth. The initially very small
amounts of molecular oxygen is believed to have been formed
through the vial and the reaction was exposed to visible light
from a 250-W high-pressure sodium lamp (Scheme 1). To our
around 4 billion years ago by the decomposition of CO and
2
[
1]
water promoted by UVirradiation from the sun. Molecular
oxygen can be transferred between its more reactive singlet
1
3
[2]
state ( O ) and its non-excited triplet state ( O ). Singlet
2
2
1
molecular oxygen ( O ) plays a significant role in several
2
biochemical processes. For example, it is involved in the
development of different diseases and biochemical oxida-
Scheme 1. Amino acid catalyzed asymmetric a oxidation of cyclohexa-
none to give 2a and in situ reduction to diol 3a.
[
3,4]
tions.
chemically generated molecular O as an oxygen source for
Furthermore, chemists have utilized photo- or
1
2
1,5]
[
several synthetic transformations. For example, it is used in
the formation of allylic hydroperoxides (analogous to the
delight, complete conversion had occurred after one hour,
and the reaction was quenched by aqueous workup. The crude
ketone 2a existed as a mixture of dimeric and oligomeric
products. The crude product mixture was purified by silica-gel
“
ene” reaction) and to generate cyclic peroxides (analogous
to a Diels–Alder-type reaction). There is a demand in todayꢀs
society for the development of sustainable chemistry from
column chromatography to yield a-hydroxyketone 2a with
[
6]
[13,14]
renewable resources. The content of molecular oxygen in air
is 21%, which allows its use in oxidation reactions. Thus,
molecular oxygen is one of the ultimate oxidants for oxidation
of organic molecules and the development of sustainable
chemistry.
18% ee.
We also performed the reaction with in situ
reduction of a-hydroxyketone 2a with NaBH to afford the
4
corresponding optically active trans- and cis-diols 3a (trans/
cis = 3:1) in 95% combined yield after silica-gel column
chromatography. The enantiomeric excess of the pure trans-
3a diol was determined by chiral-phase GC analyses to be
18% ee.
Asymmetric reactions that are catalyzed by small organic
[
7]
molecules have received increased attention in recent years.
Among several transformations, amine-catalyzed asymmetric
Next, we screened several natural amino acids and their
derivatives for their potential in catalyzing the introduction of
[
8]
epoxidations with dioxirane have been reported. The
employment of non-toxic, small organic molecules has the
potential for allowing environmentally benign reaction con-
ditions. Based on our previous investigations of organic
reactions that are mediated by metal-free organic mole-
1
O2 at the a position of 1a and to improve the stereo-
selectivity of the reaction (Table 1). We found that several of
the amino acids investigated catalyzed the a oxidations with
1
molecular O with high efficiency and chemoselectivity. The
2
[
9]
cules, we became interested in whether an amino acid would
allow the catalytic incorporation of molecular oxygen into
simple amino acids alanine and valine mediated the reaction
with the highest stereoselectivity. In fact, this is the first case
in which an acyclic amino acid provides higher asymmetric
induction than proline and its derivatives in organic solvents.
In previously reported direct organocatalytic intermolecular
transformations, the catalyst required a cyclic five-membered
[
10–11]
ketones [Eq. (1)].
Moreover, this potential amino acid
catalyzed transformation may warrant investigation as a
prebiotic pathway for the synthesis of a-hydroxyketones,
[
12]
which are the building blocks of sugars. Herein, we report
the unprecedented direct amino acid catalyzed asymmetric
incorporation of singlet molecular oxygen into ketones. This
a oxidation of ketones with molecular oxygen or air furnished
a-hydroxyketones and diols.
[
7]
ring to allow high efficiency and enantioselectivity. How-
ever, a higher enantioselectivity was obtained with l-a-
methylproline than with l-proline (increase from 18 to
48% ee for 2a). Thus, the presence of a methyl group at the
a position of proline significantly increased the stereoselec-
tivity. In contrast, this effect was not observed when compar-
ing valine with a-methylvaline. The asymmetric a oxygena-
tion reactions that were catalyzed by a d-amino acid afforded
the opposite enantiomer of 2a to that obtained in the
reactions catalyzed by the corresponding l-amino acid,
without affecting the asymmetric induction. Furthermore,
amino alcohols, dipeptides, amino acids with amide and amine
functionalities, and synthetic amino acid derivatives catalyzed
the direct asymmetric introduction of molecular oxygen into
[
*] H. SundØn, M. Engqvist, Dr. J. Casas, I. Ibrahem, Prof. Dr. A. Córdova
Department of Organic Chemistry, The Arrhenius Laboratory
Stockholm University, 10691 Stockholm (Sweden)
Fax: +(46)8-154-908
E-mail: acordova1a@netscape.net
E-mail: acordova@organ.su.se
[
**] We thank the Swedish National Research council, the Wenner-Gren
Foundation and the Lars-Hierta Foundation for financial support.
We thank Prof. J.-E. Bäckvall for sharing chemicals and one of the
reviewers for suggesting the direct isolation of the a-hydroxyketone.
6
532
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DOI: 10.1002/anie.200460295
Angew. Chem. Int. Ed. 2004, 43, 6532 –6535

Angewandte
Chemie
1
[a]
1
Table 1: Direct amino acid-catalyzed introduction of O to 1a.
Table 2: Solvent screen of the l-alanine-catalyzed incorporation of O to
ketones.
2
2
[
a]
[
b]
[c]
Entry
Amino acid
Product
Yield [%]
ee [%]
[
b]
[c]
Entry
Solvent
T [8C]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
0
1
2
3
4
l-alanine
d-alanine
l-valine
d-valine
l-proline
d-proline
l-hydroxyproline
l-a-methylproline
l-a-methylvaline
l-a-phenylglycine
l-phenylalanine
d-a-phenylglycine
l-threonine
ent-2a
2a
ent-2a
2a
2a
ent-2a
2a
93
88
78
77
95
93
88
20
15
70
89
71
20
67
56
57
49
48
18
16
11
48
6
20
38
21
10
<2
1
2
3
4
5
6
7
8
MeOH
DMSO
DMSO
DMSO
DMSO
NMP
RT
40
RT
traces
79
93
n.d.
55
56
0!RT
80
82
48
56
[
d]
[d]
[d]
RT
RT
RT
86
82
48
49
2a
DMF
TFERT
ent-2a
ent-2a
ent-2a
2a
ent-2a
ent-2a
traces
n.d.
[
e]
[e]
[e]
1
1
1
1
1
9
10
11
phosphate buffer
RT
RT
RT
80
77
18
[
e]
[e]
[e]
H O
2
19
CHCl3
traces
n.d.
[a] See experimental section. [b] Yields of isolated product after column
l-phenylalinol
chromatography on silica gel of the pure ent-3a furnished after reduction
of ent-2a. [c] Determined by chiral-phase GC analyses. [d] Reaction
performed with air as the O source. [e] Protoporphine (1 mol%) was
1
5
2a
62
11
2
used as the sensitizer and DMSO (40% v/v).
1
1
6
7
glycine
ethanolamine
2a
2a
85
81
–
–
1
8
2a
97
<5
Table 3: Direct catalytic asymmetric incorporation of molecular oxygen
to ketones.
[
a]
[
a] See experimental section. [b] Yields of isolated product after column
chromatography on silica gel of the pure 3a furnished after reduction of
a. [c] Determined by chiral-phase GC analyses. The racemic product
2
derived by glycine catalysis was used as reference material. The absolute
configuration was determined by comparison with commercially avail-
able diols and literature data.
[
b]
[c]
Entry
1
Product
Amino acid
Yield [%]
ee [%]
ketones with a similar efficiency to that of the amino acids.
However, the amino acid catalysts were superior to the amino
l-alanine
93
56
alcohols with regards to stereoselectivity. It should be noted
1
that the direct introduction of O into ketones was also
2
readily catalyzed by glycine and ethanolamine, providing a
novel inexpensive entry to a-oxygenated compounds.
We also performed a solvent screen of the l-alanine-
catalyzed asymmetric incorporation of molecular oxygen into
2
l-valine
50
28
3
4
l-valine
l-alanine
75
67
69
72
1
a in different solvents (Table 2). Direct l-alanine-catalyzed
1
asymmetric a oxidations with O2 proceeded smoothly in
DMSO, N-methylpyrrolidinone (NMP), and N,N-dimethyl-
formamide (DMF). In contrast, l-alanine only furnished
trace amount of product in MeOH, trifluoroethanol (TFE),
and CHCl . Hence, the best selectivity and efficiency is
3
[d]
5
6
l-alanine
l-alanine
61
60
52
obtained in the more polar aprotic solvents. We did not
observe any significant temperature dependence of the
stereoselectivity in DMSO. Furthermore, the reactions were
also efficient in aqueous media with air as the molecular
oxygen source, which could allow the development of
environmentally benign reaction conditions.
[d]
58
Next, we investigated the amino acid catalyzed asymmet-
ric a oxidations with molecular oxygen of various ketones
[
a] See experimental section. [b] Yields of isolated products after column
(
Table 3). The direct amino acid catalyzed asymmetric a-
chromatography on silica gel of the diol 3. [c] Determined by chiral-phase
GC analyses. The racemic products were derived by glycine or d-, l-
proline catalysis and were used as reference materials. [d] Reaction
performed in NMP.
oxygenation reactions progressed with excellent chemoselec-
tivity and furnished the corresponding a-oxygenated adducts
ent-2a and 2b–e with good enantioselectivity. For example,
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Communications
1
l-alanine catalyzed the formation of 2c in 67% yield with
2% ee. Furthermore, the amino acid catalyzed reactions with
is formed through proton abstraction by molecular O from
2
[
14]
7
the carboxy group of the acyclic l-amino acids,
which
linear acyclic ketones progressed with excellent regioselec-
tivity, and molecular oxygen was asymmetrically incorporated
at the most substituted side of the ketone. Moreover, the
reactions were readily scaled up and performed on the gram
scale. The amino acids were also able to catalyze the
asymmetric incorporation of molecular oxygen into unmodi-
provides the sterochemical information, together with addi-
tion to the Re face of the amino acid derived enamine to
furnish (2S)-a-hydroxyketone [Eq. (2)]. In the case of a ox-
ygenation mediated by a cyclic l-amino acid, the addition of
1
O occurs at the Si face of the enamine to provide the (2R)-a-
2
hydroxyketone [Eq. (3)].
[
15]
fied aldehydes. For example, l-a-methylproline furnished
R)-2-hydroxy-3-phenylpropanal with 65% ee. The direct
(
1
amino acid catalyzed a oxygenation with molecular O may
2
be considered as a new, simple, metal-free entry into the
synthesis of a-hydroxyketones and diols.
We also tested the amino acid-catalyzed a-oxidations of
3
unmodified ketones with molecular O as the electrophile in
2
16]
[
the presence of triethylphosphite.
The reactions with
3
molecular O did not provide the a-hydroxyketone adducts
or the diol 3. Thus, molecular O is the more reactive
electrophile and not O . Moreover, no products were formed
2
1
2
2
3
2
in the absence of the amino acid catalysts. We also inves-
tigated the possibility of background oxidation by a-hydro-
peroxide ketone intermediates or another peroxide inter-
mediate that potentially could influence the enantioselectivity
We also established that natural amino acids catalyze the
asymmetric incorporation of molecular oxygen into ketones
in aqueous buffer. For example, l-alanine catalyzed the direct
asymmetric synthesis of ent-2a in phosphate buffer at 378C.
Moreover, the amino acids mediated the direct catalytic
asymmetric a oxidations in air with the sun as the light source.
Hence, terrestrial and extraterrestrial amino acids were able
to catalyze the introduction of molecular oxygen under
prebiotic conditions to form a-hydroxyketones. In fact, the
[
13–14]
of the reaction.
However, the use of excess (5 equiv)
H O , NaClO, m-chloroperbenzoic acid (MCPBA), or oxone
2
2
as the oxidants for cyclohexanone (1 mmol) in the presence of
a catalytic amount of l-proline or l-alanine (20 mol%) in
DMSO only provided trace amounts of the diol 3a after
in situ reduction with NaBH . Furthermore, the l-alanine-
4
1
catalyzed a oxygenation with O in the presence of triethyl-
2
phosphite furnished ent-2a in 87% yield with 56% ee, which
is the same ee value of ent-2a obtained without the addition of
phosphite (Scheme 2).
amino acids were able to catalyze the a oxidation of acetone
1
with O to furnish hydroxyacetone and dihydroxyacetone,
2
which are the building blocks and donors in amino acid
catalyzed asymmetric synthesis of sugars under prebiotic
[
12a,17]
conditions.
Thus, the amino acid catalyzed introduction
of molecular oxygen may plausibly have served as the first
step in their homochirality transfer of their asymmetry to
polyhydroxylated compounds, even in the presence of small
[
12]
amounts of oxygen.
In conclusion, we have disclosed the unprecedented
ability of amino acids to catalyze the direct asymmetric
incorporation of singlet molecular oxygen into ketones. The
smallest amino acids alanine and valine catalyzed the trans-
formation with the highest stereoselectivity. The direct
catalytic a oxygenations are a novel, inexpensive, operation-
ally simple, and environmentally benign entry to the prepa-
ration of a-hydroxyketones and diols. All materials in this
process stem from renewable sources, thus allowing a highly
sustainable catalytic process. Readily available amino acids
allow catalytic asymmetric oxidations with molecular oxygen
or air, which has previously been considered to be in the
domains of enzymes and chiral transition-metal complexes.
1
Scheme 2. Direct l-alanine-catalyzed introduction of molecular O to
2
1
a in the presence of triethylphosphite.
These results indicated that the potential background
oxidation by peroxide intermediates was not significant under
the set reaction conditions. We were also able to rule out a 1,2-
cycloaddition between O and the catalytic chiral enamine to
form a dioxetane intermediate, as no cleavage products from
such an intermediate was detected. The stereochemical
outcome of the reaction was determined by optical rotation
and chiral-phase GC analyses of 2a and trans-3a, which
revealed that acyclic l-amino acids provided (2S)-a-hydroxy-
cyclohexanone ent-2a and (1S, 2S)-trans-cyclohexane-1,2-diol
1
2
(
(
ent-3a). In contrast, l-proline and its derivatives furnished
2R)-a-hydroxycyclohexanone (2a). The reaction plausibly
Experimental Section
Typical experimental procedure (Table 1, entry 1): Cyclohexanone
proceeds through a catalytic enamine mechanism [Eq. (2) and
3)]. Hence, the tentative (2S)-a-hydroperoxide intermediate
(
1 mmol) was added to a vial containing TPP (1 mol%) and a
(
catalytic amount of l-alanine (20 mol%) in DMSO (1 mL). A
6
534
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Angew. Chem. Int. Ed. 2004, 43, 6532 –6535

Angewandte
Chemie
continuous flow of O or air was bubbled through the vial, and the
[10] For proline-catalyzed a-aminooxylation reactions reported by
2
reaction was exposed to visible light by a 250-W high-pressure sodium
lamp. After 1 hour, complete conversion had occurred, and the
reaction was quenched either by the addition of brine followed by
extraction with EtOAc to furnish a-hydroxyketone ent-2a or by
other groups, see: a) G. Zhong, Angew. Chem. 2003, 115, 4379;
Angew. Chem. Int. Ed. 2003, 42, 4247; b) S. P. Brown, M. P.
Brochu, C. J. Sinz, D. W. C. MacMillan, J. Am. Chem. Soc. 2003,
125, 10808; c) M. Y. Hayashi, J. Yamaguchi, T. Sumaiya, M.
Shoji, Angew. Chem. 2004, 116, 1132; Angew. Chem. Int. Ed.
2004, 43, 1112; d) M. Y. Hayashi, J. Yamaguchi, K. Hibino, M.
Shoji, Tetrahedron Lett. 2003, 44, 8293; for the use of proline
derivatives as catalysts, see: N. Momiyama, H. Torii, S. Saito, H.
Yamamoto, Proc. Natl. Acad. Sci. USA 2004, 101, 5374, and
reference [9b].
in situ reduction with NaBH to afford the corresponding optically
4
active crude diol ent-3a (trans/cis 3:1). The crude ent-2a existed as an
oligomeric mixture that, upon standing, formed the dimer, which was
isolated by silica-gel column chromatography (EtOAc/pentane 1:20)
with 56% ee (determined by chiral-phase GC-analysis). GC: (CP-
ꢀ
1
Chirasil-Dex CB); Tinj = 2508C, T = 2758C, flow = 1.8 mLmin
,
det
ꢀ
1
ti = 608C (9 min), rate = 858Cmin , t = 2008C (5 min); retention
[11] For examples of proline-catalyzed a aminations, see: a) A.
Bøgevig, K. Juhl, N. Kumaragurubaran, W. Zhuang, K. A.
Jørgensen, Angew. Chem. 2002, 114, 1868; Angew. Chem. Int.
Ed. 2002, 41, 1790; b) B. List, J. Am. Chem. Soc. 2002, 124, 5656.
[12] a) S. Pizarello, A. L. Weber, Science 2004, 303, 1151; b) L. E.
Orgel, Science 2000, 290, 1306.
[13] In addition to the a oxidation of 1a, the DMSO was also
oxidized to the corresponding dimethyl sulfone at prolonged
reaction times.
f
times of 2a: tmaj = 10.64 min, tmin = 10.66 min. The trans-3a and cis-3a
diols were isolated by silica-gel column chromatography (EtOAc/
pentane 1:1) in a combined yield of 92% with 56% ee of the pure
trans-3a diol (determined by GC analyses). (1S, 2S)-trans-cyclohex-
ane-1,2-diol: [a] = + 21 (c = 0.2, CHCl ); GC: (CP-Chirasil-Dex
D
3
ꢀ
1
CB); Tinj = 2508C, Tdet = 2758C, flow = 1.8 mLmin
2 min), t = 1108C, rate = 0.38Cmin ; retention times of acetylated
,
ti = 908C
ꢀ1
(
f
compound: tmaj = 9.75 min, tmin=9.61 min.
[
14] We were only able to isolate the a-hydroxyketone adducts and
not potential a-hydroperoxide intermediate. Hence, we
Received: April 12, 2004
Revised: August 12, 2004
a
believe that the a-hydroperoxide intermediate is rapidly con-
verted into the a-hydroxyketone product.
[
15] A. Cꢂrdova, H. Sundꢁn, M. Engqvist, I. Ibrahem, J. Casas, J. Am.
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b) E. F. J. de Vries, L. Ploeg, M. Colao, J. Brussee, A. van der -
Gen, Tetrahedron: Asymmetry 1995, 6, 1123.
Keywords: amino acids · asymmetric catalysis · ketones ·
molecular oxygen · oxidation
.
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