Enantioselective addition of aldehydes to amines via combined catalytic biomimetic oxidation and organocatalytic C-C bond formation

Article abstract of DOI:10.1016/j.tetlet.2005.04.047

The biomimetic catalytic enantioselective addition of aldehydes to amines is reported. This was accomplished by combining biomimetic coupled catalytic aerobic oxidation of amines involving ruthenium-induced dehydrogenation and organocatalytic asymmetric M

Full text of DOI:10.1016/j.tetlet.2005.04.047

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3965–3968
Enantioselective addition of aldehydes to amines via
combined catalytic biomimetic oxidation and
organocatalytic C–C bond formation
*
Ismail Ibrahem, Joseph S. M. Samec, Jan E. Backvall and Armando Cordova
¨
*
´
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Received 27February 2005; revised 3 April 2005; accepted 12 April 2005
Abstract—The biomimetic catalytic enantioselective addition of aldehydes to amines is reported. This was accomplished by combin-
ing biomimetic coupled catalytic aerobic oxidation of amines involving ruthenium-induced dehydrogenation and organocatalytic
asymmetric Mannich reactions. The novel one-pot reactions furnished b-amino aldehyde and a-amino acid derivatives in high yields
with excellent chemoselectivity and up to >99% ee.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Oxidation is a fundamental reaction in Nature as well as
in organic chemistry.1 The terminal oxidants used in
nature are molecular oxygen and hydrogen peroxide.
These oxidants are, from both economical and environ-
mental standpoints, also the superior terminal oxidants,
used in chemical applications. This has led to an intense
search to find substrate-selective catalysts to achieve effi-
cient oxidations using molecular oxygen.2 The challenge
when using transition metals is to overcome the high-
energy pathway for reoxidation of the metal. This has
led to the development of biomimetic oxidations, where
the large jump in oxidation potential is divided into
smaller changes by the use of several electron transfer
mediators (ETMs).1,2
Intrigued by NatureÕs way of constructing complex
molecules from simple achiral organic molecules via
enzyme-catalyzed pathways, we became interested in
whether it would be possible to combine biomimetic
catalytic aerobic oxidations with tandem organocatalytic
C–C bond-forming reactions.3,4 This novel reaction
sequence would mimic the connection of two separate
fundamental biochemical pathways of cells. The coupled
catalytic aerobic oxidation of amines involving ruthe-
nium-induced dehydrogenation, which generates
imines,5 linked with tandem direct amino acid-catalyzed
cross-Mannich reactions would serve as a potential
model system (Scheme 1).6
In addition, the combination of these two catalytic
processes would be a new entry to chiral b-amino
aldehydes, which are susceptible to further chemical
manipulation and yield pharmaceutically important
c-amino alcohols and b-amino acids.7 Herein, we report
the first combination of transition metal-catalyzed
The employment of small organic molecules as catalysts
in asymmetric synthesis has experienced a renaissance
in organic chemistry. In particular, amino acid-derived
catalysts have been proved successful in the asymmetric
construction of chiral molecules.3
CO
Ru
O
CO
Ph
O
MeO
OMe
Ph
Ph
Ph
OC
OC
N
Co
Ph
Ph
N
O
N
O
Ph
O
Ru
Ph
O
1
2
3
Keywords: Biomimetic oxidation; Catalysis; Asymmetric synthesis; Ruthenium; Proline.
*
Corresponding authors. Tel.: +46 8 162479; fax: +46 8 154908; e-mail addresses: jeb@organ.su.se; acordova1a@netscape.net; acordova@organ.su.se
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.047

3966
I. Ibrahem et al. / Tetrahedron Letters 46 (2005) 3965–3968
Ar
H
HN
R1
(MLm)ox
Hydro-
[Ru]
H2O
quinone
Ar
H
N
MLm
Quinone
1/2 O2
[Ru] H
R1
+
H+
O
amino acid
Ar
NH OH
H
R1
Ar
H
R
R
Ar
NH
O
NH OH
Nu
R1
H
R1
Nu
R
R
Scheme 1. Combination of catalytic aerobic oxidation of amines with tandem direct amino acid-catalyzed asymmetric Mannich-type reactions.
aerobic oxidations with direct organocatalytic enantio-
selective Mannich reactions furnishing b-amino
aldehydes, c-amino alcohols and a-amino acid derivatives
in up to >95% yield with excellent chemoselectivity and
>99% ee.
aldehyde 4 was reduced in situ to the corresponding c-
amino alcohol by addition of excess NaBH4. The crude
product was isolated by silica gel column chromatogra-
phy (EtOAc/pentane mixtures) to yield the correspond-
ing c-amino alcohol quantitatively with >99% ee.
In an initial experiment (Table 1, entry 1), reaction of
benzyl-p-methoxyphenyl (PMP)-amine in toluene at
110 ꢁC with O2 in the presence of ruthenium complex
1, quinone 2 and cobalt complex 3 afforded the
corresponding imine. After 24 h, the mixture was cooled
to room temperature and the solvent was removed
under reduced pressure. Next, N-methyl-pyrrolidinone
(NMP) and L-proline (30 mol %) were added to the reac-
tion mixture and then propionaldehyde was added at
À20 ꢁC. After 16 h the reaction temperature was
increased to 0 ꢁC and the catalytically generated b-amino
Encouraged by this result, we investigated the one-pot
combination of catalytically linked aerobic oxidations
and direct catalytic enantioselective Mannich additions
to a set of secondary PMP N-protected amines (Table
1).8 The PMP group was chosen since it can be readily
removed to give the free amine.6a–c
The one-pot tandem catalytic reactions proceeded
smoothly furnishing b-amino aldehydes 4–12 with excel-
lent diastereo- and enantioselectivities. For example, the
b-formyl amino acid ester 11 was reduced in situ to the
Table 1. Direct catalytic enantioselective addition of aldehydes to amines
O
H
PMP
PMP
PMP
L-proline
(30 mol%)
HN
N
NH
O
1, 2, 3
R
R
R
H
1/2 O2
NMP, -20˚C
Entry
R
Product
Yield (%)a
Drb
ee (%)c
1
Ph
4
5
>95
>95
76
>19:1
15:1
>99
76
2
2-Naphthyl
4-BrC6H4
4-MeC6H4
3
6
>19:1
8:1
10:1
>99
98
4
7
75
63
5
4-MeOC6H4
2-Furyld
8
98
6
73-Pyridyl
9
99
6:1
>99
>99
>99
99
d
10
11
12
>95
>95e
>95
>19:1
>19:1
15:1
8
9
CO2Etd
4-FC6H4
a Isolated overall yield after silica-gel column chromatography of the c-amino alcohol obtained by in situ reduction of the b-amino aldehydes.
b Determined by NMR.
c Determined by Chiral-phase HPLC analyses. All isolated products were in accordance with previously reported compounds.6
d 8 mol % of 1.
e The oxidation was run for 72 h.

I. Ibrahem et al. / Tetrahedron Letters 46 (2005) 3965–3968
3967
Ar
1. 1, 2, 3
toluene, 120 ˚C
NH
H
Ph
N
1/2 O2
+
H2O
+
Ar
OH
2. L-proline
propionaldehyde
DMF, - 20 ˚C
3. NaBH4
4a Ar = Ph >95% yield, dr >19:1, >97% ee
Scheme 2. One-pot catalytic asymmetric synthesis of 1,3-amino alcohols.
corresponding L-homoserine derivative, which was
quantitatively isolated as a single diastereomer with
>99% ee. The reactions proceeded with excellent chemo-
selectivity and the ruthenium complex 1 did not oxidize
or affect the eeÕs of the b-amino aldehyde products. The
combination of one-pot coupled catalytic aerobic oxida-
tions of amines with tandem catalytic asymmetric
crossed-Mannich reactions circumvented the isolation
of the imines prior to the nucleophilic additions. In addi-
tion, the procedure decreases the generation of waste
products and could be used directly in other small mole-
cule-catalyzed enantioselective Mannich-type reac-
tions.9 The employment of 30 mol % L-proline together
with the use of NMP as the reaction media significantly
improved the efficiency of the reaction and the products
were isolated in excellent yields.
selectivity. The reactions can be readily scaled-up and
provide a low cost entry for either enantiomer of a-amino
acid and c-amino alcohol derivatives. Further studies on
the combination of catalytic coupled aerobic oxidation
and organocatalysis are ongoing.
Acknowledgements
A.C. thanks the Swedish Natural Science Research
Council and Wenner-Gren foundation for financial
support. J.E.B. thanks the Swedish Natural Science
Research Council and the Swedish Foundation for
Strategic Research.
References and notes
The coupled catalytic aerobic oxidation of amines was
also efficient in the generation of ketimines. However,
proline only furnished trace amounts of Mannich prod-
ucts in reactions with aromatic ketimines. The coupled
one-pot aerobic oxidation of amines was also success-
fully linked with direct proline-catalyzed Mannich reac-
tions using aliphatic aldehydes and ketones as donors.
For example, employing the one-pot tandem catalytic
combination of aerobic oxidation and Mannich-type
addition to benzyl-p-methoxyphenyl-amine using ace-
tone as the donor furnished the corresponding Mannich
adduct in 65% overall yield with 98% ee. Furthermore,
the p-methoxyphenyl moiety of the amine can be readily
changed to other aryl groups (Scheme 2). For example,
1,3-amino alcohol 4a was synthesized in a one-pot
sequence from the corresponding amine in >95% yield
with >97% ee.
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amines and this constitutes a formal C–H activation.10
The first one-pot combination of catalytically sequenced
aerobic oxidation of amines involving ruthenium-in-
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catalyzed enantioselective Mannich reactions enabled
this transformation. The catalytic cascade of reactions
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I. Ibrahem et al. / Tetrahedron Letters 46 (2005) 3965–3968
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decreased to À20 ꢁC followed by addition of propional-
dehyde (0.75 mmol) in one portion. After 16 h the reaction
temperature was increased to 0 ꢁC and MeOH (2 mL) was
added followed by portionwise addition of NaBH4. The
reaction was quenched by addition of 1 N HCl solution
and extraction with EtOAc (3 · 15 mL). The combined
dried organic extracts were concentrated and the crude
product purified by silica-gel column chromatography
(pentane/EtOAc mixtures) affording the corresponding
1,3-amino alcohols. The ees of the amino alcohols were
determined by Chiral-phase HPLC analyses using a
Chiralpak AD column.
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8. In a typical experiment, ruthenium complex 1 (10.8 mg,
10 lmol, 4 mol %), quinone 2 (8.4 mg, 50 lmol, 20 mol %)
and cobalt complex 3 (4 mg, 5 lmol, 4 mol %) were
charged into a 5 mL round-bottomed flask under an
argon atmosphere. The amine (1 mL, 0.125 M in toluene,
0.125 mmol) was added to this mixture followed by
flushing with air for ca. 1 min. A stream of air was
allowed to pass through the system and the mixture was
heated to 110 ꢁC in an oil bath. After 24 h, the mixture
was cooled to room temperature and the solvent was
removed under reduced pressure. Next, N-methylpyrrol-
idinone (NMP, 1 mL) and L-proline (30 mol %) were
added to the reaction flask and the temperature was
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