A reductase-mimicking thiourea organocatalyst incorporating a covalently bound NADH analogue: Efficient 1,2-diketone reduction with in situ prosthetic group generation and recycling

Article abstract of DOI:10.1039/b618792g

A new class of bifunctional organocatalyst promotes the chemoselective reduction of diketone electrophiles at catalytic loadings in the presence of an inorganic co-reductant. The Royal Society of Chemistry.

Full text of DOI:10.1039/b618792g

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A reductase-mimicking thiourea organocatalyst incorporating a
covalently bound NADH analogue: efficient 1,2-diketone reduction with
in situ prosthetic group generation and recycling{
Barbara Procuranti and Stephen J. Connon*
Received (in Cambridge, UK) 2nd January 2007, Accepted 4th January 2007
First published as an Advance Article on the web 30th January 2007
DOI: 10.1039/b618792g
A new class of bifunctional organocatalyst promotes the
chemoselective reduction of diketone electrophiles at catalytic
loadings in the presence of an inorganic co-reductant.
stoichiometric loadings of an achiral Hantzsch dihydropyridine
hydride donor.
We have been engaged in the design of (thio)urea based
bifunctional catalysts capable of activating electrophilic reaction
11
+
Enzymatic manipulation of the NAD(P) /NAD(P)H redox couple
components through hydrogen bond donation and were
in biotransformations is a fundamental competency common to all
1
living cells. In biological systems levels of these cofactors are
intrigued by the possibility of extending this strategy to include
12
organocatalytic reductions. In particular, the development of a
2
maintained through both continual degradation/biosynthesis and
completely new class of bifunctional organocatalyst incorporating
both a substrate-activating (thio)urea moiety and an organic
hydride donor (as opposed to a binary catalyst system, e.g.
the coupling of oxidation/reduction reactions to sustain a redox
1
,2
balance. A considerable difficulty associated with the exploita-
tion of biocatalytic reduction in preparative chemistry has been the
need for the use of stoichiometric quantities of the expensive and
significantly unstable (in solution) NADH cofactor. In response to
this challenge several approaches to cofactor regeneration in
2
+
Hantzsch ester and Mg /organocatalyst) was appealing due to the
increased potential for synergistic cooperation between the
catalyst’s functional components and for an increased measure
of control (in a catalyst design context) over the catalyst–substrate
interaction. To make the proposed process veritably catalytic in all
organic components we also undertook to develop a conceptually
novel artificial reductase system in which a NADH-model hydride
donor could be both generated and recycled in situ by simple,
chemical means.
3
preparative biooxidations/reductions have been developed, the
4
most practical of which involve either a single (A, Fig. 1) or binary
5
B, Fig. 1) enzyme system using either isolated enzymes or whole
(
cells.
The excellent activity/selectivity of enzymatic reductase systems
has inspired the development of de-novo designed small organic
With this in mind we prepared (thio)ureas 3–11 and evaluated
their performance as promoters of the hitherto unknown (in an
molecules for biomimetic reduction which can be categorised as
6
being either chiral nicotinamide-based reagents or chiral NADH-
13
organocatalytic context) reduction of benzil (1) to benzoin (2) in
both the presence and absence (as appropriate) of substoichio-
metric amounts of N-benzylnicotinamide (BNA) in a biphasic
aqueous/organic solvent medium (Table 1). The readily available
and inexpensive sodium dithionate (a standard reductant for the
preparation of 1,4-dihydropyridines from alkyl pyridinium salts)
was assessed as a co-reductant for ‘cofactor’ generation/recycling.
Surprisingly, a slow (inefficient) background reduction of 1 by the
7–9
analogue dependant organocatalysts. Benchmark systems in the
former category of NADH model are reagents, capable of
effecting highly enantioselective reduction of activated ketones at
2
+
stoichiometric loadings in the presence of Mg ions (100 mol%)
and are not regenerated, while the second class of reductase
mimic can promote efficient reductions of a,b-unsaturated
7–9
10
electrophiles and imines with impressive levels of stereoinduc-
tion at catalytic loadings (1–20 mol%) in the presence of
14
dithionite was observed at room temperature (Table 1, entry 1).
While the introduction of BNA (20 mol%) resulted in marginally
higher conversion (entry 2), the use of BNA in combination with
bis-N-aryl(thio)ureas 3–6 and 1,2-trans-diaminocyclohexane-
derived (thio)ureas 7–8 led to substantial improvements in reaction
rate and efficiency (entries 3–6 and 8–9). Gratifyingly, the most
efficacious promoters of the reaction proved to be bifunctional
thiourea-based pyridinium salt precatalysts 10a,b, the most active
of which was capable of bringing about the clean and
1
5
chemoselective reduction of 1 in 48 h. The clear superiority of
10a,b over both their neutral (non-benzylated) precatalyst
analogue 11 and BNA itself (entries 2, 11, 12 and 13) clearly
indicates that 10a,b operate primarily via a bifunctional reduction
mechanism, i.e. intramolecular hydride donation from the in situ-
generated hydropyridine moiety to the (thio)urea-bound diketone
Fig. 1 Biocatalytic strategies for cofactor regeneration.
Centre for Synthesis and Chemical Biology, School of Chemistry,
University of Dublin, Trinity College, Dublin 2, Ireland.
E-mail: connons@tcd.ie; Fax: +353 1 6712826; Tel: +353 1 6081306
{ Electronic supplementary information (ESI) available: Synthesis of 10a,
general reduction procedure and characterisation data for 2 and 18–23.
–
and not (thio)urea-catalysed reduction of 1 by dithionate. This
See DOI: 10.1039/b618792g
hypothesis is supported by the presence of the reduced form of
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Chem. Commun., 2007, 1421–1423 | 1421

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Table 1 Preliminary catalyst evaluation
variable steric and electronic characteristics to the corresponding
benzoins 2 and 18–23 in good to excellent yield at room
temperature (Table 2). As expected, diketones bearing electron
withdrawing substituents underwent faster reduction than less
16
electrophilic analogues. Of particular interest is the use of this
methodology in the synthesis of unsymmetrical hydroxyketones
(entry 6) difficult to access in appreciable yield from the benzoin
condensation of the corresponding aldehydes.
A preliminary investigation into the promotion of asymmetric
reductions using enantiopure catalyst analogues was also under-
taken. It was found that (R,R)-10a was capable of furnishing (R)-2
from 1 with moderate enantioselectivity (Scheme 1), however,
evaluating the potential of the system is complicated by product
17
racemisation under the reaction conditions.
Table 2 Reaction scope
a
t/h Yield (%)
a
Conv. (%)
Entry Substrate
1
Product
Entry
Catalyst
mol% BNA
t/h
48 96
1
2
3
4
5
6
7
8
9
—
—
3
4
5
6
3
7
8
0
20
20
20
20
20
0
20
20
0
48
48
48
48
48
48
48
48
48
48
48
48
48
6
13
35
40
29
36
12
40
21
30
71
97
8
2
3
4
5
6
48 96
1
1
1
1
a
0
1
2
3
9
10a
10b
11
1
0
0
0
48 77
Determined by H NMR spectroscopy.
1
BNA as the only heterocyclic species observable (by H NMR
spectroscopy) in the organic phase of the reduction of 1 by BNA
b
72 60
(Fig. 2 and Table 1, entry 2).
Further experimentation demonstrated that 10b is also effective
in the reduction of a range of substituted benzils (1 and 12–17) of
b
120 65
96 78
7
96 72
a
b
Isolated yield after chromatography. Refers to conversion – no
further conversion detected after extended reaction time.
Fig. 2 Reduction of 1 by BNA in the presence of dithionate (t = 24 h):
1
detection of the hydropyridine form of BNA by H NMR spectroscopy.
1
422 | Chem. Commun., 2007, 1421–1423
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