The direct amino acid-catalyzed asymmetric incorporation of molecular oxygen to organic compounds

Article abstract of DOI:10.1021/ja047930t

We have disclosed the direct catalytic incorporation of ¹O₂ to aldehydes. The unprecedented amino acid-catalyzed asymmetric α-oxidation of aldehydes with molecular oxygen or air proceeded with high chemoselectivity and was a direct entry for the synthesis of both enantiomers of terminal diols. The results demonstrated that simple amino acids accomplished catalytic asymmetric oxidations with molecular oxygen or air, which has previously been considered to be in the domain of enzymes and chiral transition-metal complexes. The efficiency of the catalytic process may warrant the existence of an ancient pathway for the synthesis of hydroxylated organic compounds. Copyright

Full text of DOI:10.1021/ja047930t

Published on Web 07/03/2004
The Direct Amino Acid-Catalyzed Asymmetric Incorporation of Molecular
Oxygen to Organic Compounds
Armando Co´rdova,* Henrik Sunde´n, Magnus Engqvist, Ismail Ibrahem, and Jesu´s Casas
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm UniVersity, SE-10691 Stockholm, Sweden
Received April 9, 2004; E-mail: acordova1a@netscape.net, acordova@organ.su.se
Table 1. Direct Catalytic Asymmetric Incorporation of 1O2 to
Molecular oxygen is an essential part of complex multicellular
life on earth. Along with newer geochemical research, the secondary
Aldehydesa
atmosphere on the earth around 4 billion years ago, was mainly
formed by volcanic outgassing after hydrogen and helium had
escaped the earth’s weak gravitational field.1 As ammonia and
methane were too unstable under the UV irradiation of the sun,
entry
R
temp (°C)
yield (%)b
er (R/S)c
cmpd
this atmosphere should predominantly have consisted of water,
carbon dioxide, nitrogen, and smaller amounts of other gases
including oxygen that could have formed through the decomposition
of carbon dioxide and water.1,2 Molecular oxygen can be transferred
between its triplet state (3O2) and the more reactive singlet state
(1O2).3 Singlet molecular oxygen (1O2) plays a significant role in
several biochemical processes. For instance, it is involved in the
development of different diseases and biocatalytic oxidations.4,5
Furthermore, chemists have utilized photo- or chemically generated
molecular 1O2 as an oxygen source for several synthetic transforma-
tions.3,6 For example, it is used to generate cyclic peroxides
analogous to a Diels-Alder-type reaction and in the formation of
allylic hydroperoxides analogous to the “ene” reaction. Asymmetric
reactions that are catalyzed by small organic molecules have
received increased attention in recent years.7 In particular, the
employment of nontoxic small organic molecules have the potential
for allowing development of a sustainable process from renewable
resources.8 On the basis of our previous investigations of asym-
metric transformations mediated by amino acids,9 we became
interested whether a catalytically generated enamine would be able
to react with molecular oxygen and form an oxygenated organic
compound.10 In addition, this potential amino acid-catalyzed
transformation may warrant investigation for a prebiotic entry for
the creation of R-hydroxy aldehydes, which are the building blocks
of sugars.11 Herein, we report that amino acids are able to catalyze
direct asymmetric incorporation of singlet molecular oxygen to
aldehydes. The unprecedented amino acid-catalyzed R-oxidations
of aldehydes with molecular oxygen or air afforded terminal diols
and R-hydroxy aldehydes.
1
2
3
4
5
6
7
CH2Ph
CH2Ph
Ph
27
-5
45
91
92
95
93d
91
92
61/39
74/26
62/38
71/29
28/69d
58/42
61/39
1
1
2
3
-20
-5
i-Pr
i-Prd
-5d
-5
-5
ent-3
4
5
n-Pent
n-Bu
a In a typical experiment, the amino acid (20 mol %) was stirred in the
solvent (5 mL) for 20 min followed by addition of tetraphenylprophine
(TPP) (5 mol %) and the aldehyde (1 mmol). The reaction was initiated
and performed by bubbling a continuous flow of molecular oxygen or air
for 0.5-3 h in the presence of visible light by a 250-W high-pressure sodium
lamp. b Isolated yield after silica gel column chromatography. c Determined
by chiral-phase HPLC or GC. The racemic diols derived by D,L-proline
catalysis were used as reference materials. The absolute configuration was
determined by comparison with commercially available diols and/or
d
literature data. D-Proline was used as the catalyst.
The proline-catalyzed R-oxygenation reactions proceeded with
excellent chemoselectivity, affording the optically active terminal
diols 1-5 in high yield after in situ reduction with NaBH4. The
ee’s of the diols derived by proline-catalysis were between 16 and
48%. Moreover, the reaction with a D-amino acid afforded the
opposite enantiomer as compared to the same L-amino acid without
affecting asymmetric induction. To improve the enantioselectivity
of the R-oxygenations, a catalyst screen of different amino acid
derivatives was performed.12 The screen revealed that a methyl
group at the R-position of proline significantly increased the
stereoselectivity of the reaction, and L-R-methyl proline was
therefore further investigated (Table 2). The L-R-methyl proline-
catalyzed reactions were highly chemoselective, and all aldehydes
exclusively converted to the corresponding R-oxygenated products
within 1 h and afforded diols 1-5 in good yields with up to 66%
ee (Table 2). The catalytic introduction of molecular oxygen at the
R-position of unmodified aldehydes was also efficient with air as
the oxygen provider. The catalyst loading could be decreased to
10 mol % without significantly affecting the efficiency of the
reaction. In addition, unmodified ketones can be used as substrates.
For example, L-alanine was able to mediate the synthesis of trans-
(1S,2S)-cyclohexan-1,2-diol in 56% ee. The presence of an R-hy-
droperoxide intermediate was confirmed by the high yield of the
diol derived from the R-oxygenation of 2-phenylacetaldehyde, since
no benzaldehyde or benzyl alcohol was detected during the reaction.
In an initial catalyst screen of natural amino acids for the reaction
1
between 3-phenyl propionaldehyde (1 mmol) and O2, we found
that several amino acids were able to mediate the asymmetric
incorporation of molecular oxygen at the R-position of the
aldehyde.12 Among the amino acids tested L-proline was the most
effective catalyst affording the corresponding (2R)-hydroxy-3-
phenylpropanol 1 after in situ reduction of the R-hydroperoxide
intermediate with NaBH4 in 45% yield with 22% ee (eq 1).
1
These results rule out a 1,2-cycloaddition between O2 and the
Next, we tested proline as a catalyst for the direct asymmetric
R-oxidation reaction with molecular oxygen for a variety of
aldehydes (Table 1).
catalytic chiral enamine forming a dioxetane intermediate, which
would have decomposed to benzaldehyde.3a Furthermore, we tested
the proline-catalyzed R-oxidations of unmodified aldehydes with
9
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J. AM. CHEM. SOC. 2004, 126, 8914-8915
10.1021/ja047930t CCC: $27.50 © 2004 American Chemical Society

C O MMU N I C A T I O N S
a
Table 2. Direct L-R-Me-proline Catalyzed Introduction of 1O2
In conclusion, we have revealed that natural amino acids catalyze
the asymmetric incorporation of molecular oxygen to the R-position
of aldehydes. The transformations are unprecedented direct catalytic
asymmetric oxidations with singlet oxygen. Furthermore, the direct
catalytic asymmetric R-oxygenations may be considered a metal-
free entry for the preparation of optically active building blocks
such as terminal diols. The R-oxygenations are inexpensive,
operationally simple, and environmentally benign. All materials in
this process are from renewable resources, thus allowing for a highly
sustainable catalytic process. Our results demonstrate that simple
amino acids can accomplish catalytic asymmetric oxidations with
singlet molecular oxygen, which has previously been considered
to be in the domains of enzymes and chiral transition-metal
complexes.
entry
R
cmpd
yield (%)b
ee (%)c
1
2
3
4
5
CH2Ph
CH2Phd
i-Pr
n-Pent
n-Bu
1
1
3
4
5
77
72d
75
77
73
66
66d
57
54
57
a In a typical experiment, the amino acid (20 mol %) was stirred in the
DMF (1 mL) for 20 min followed by addition of tetraphenylprophine (TPP)
(5 mol %) and the aldehyde (1 mmol). The reaction was initiated and
performed by bubbling a continuous flow of molecular oxygen or air for
0.5-3 h in the presence of visible light by a 250-W high-pressure sodium
lamp. b Isolated yield after silica gel column chromatography. c Determined
by chiral-phase HPLC or GC. d The reaction performed with air as the
oxygen provider.
Acknowledgment. We thank the Swedish National Research
Council and Wenner-Gren foundation for financial support and Jan-
Erling Ba¨ckvall for valuable discussions.
Supporting Information Available: Experimental procedures. This
material is available free of charge via the Internet at http://pubs.acs.org.
molecular 3O2 as the electrophile in the presence of triethyl
3
phosphite.13,14 The reactions with molecular O2 did not provide
the diols. Thus, molecular 1O2 was the fastest reacting electrophile
and not 3O2. Moreover, no diol product was formed without addition
of the amino acid catalysts. The reaction plausibly proceeded via
a catalytic enamine mechanism (eq 2). Hence, the (2R)-R-hydrogen
peroxide aldehyde intermediate was formed via molecular 1O2
proton abstraction of the L-amino acid carboxyl group, which
provided the sterochemical information, together with addition to
the si-face of the amino acid-derived enamine.
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