Organocatalytic asymmetric reaction cascade to substituted cyclohexylamines

Article abstract of DOI:10.1021/ja072134j

We report a new strategy for organocatalytic cascade reactions. Accordingly, enamine catalysis, iminium catalysis, and Bronsted acid catalysis can work in concert in a highly enantioselective organocatalytic cascade sequence toward chiral cis-3-substituted cyclohexylamines. We found that an achiral amine in combination with a catalytic amount of a chiral Bronsted acid can accomplish an aldol addition-dehydration-conjugate reduction-reductive amination to provide potential intermediates of pharmaceutically active compounds in good yields and excellent enantioselectivities. Copyright

Full text of DOI:10.1021/ja072134j

Published on Web 05/27/2007
Organocatalytic Asymmetric Reaction Cascade to Substituted
Cyclohexylamines
Jian Zhou and Benjamin List*
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim an der Ruhr, Germany
Received March 27, 2007; E-mail: list@mpi-muelheim.mpg.de
Combining different organocatalytic reactions into cascades has
intermediate B. The terminating reductive amination of intermediate
C would be Brønsted acid catalyzed.10
recently become a fruitful concept for complex molecule synthesis.1
The approach fundamentally relies on the reaction compatibility,
often realized in organocatalysis. Especially, amines and their salts
trigger such cascade reactions via enamine or iminium ion forma-
tion.2 Several new carbon-carbon bonds and stereogenic centers
can be created in a highly controlled fashion from readily available
precursors in one-pot operations.3 These aminocatalytic cascades
require chiral secondary amines to facilitate the reaction and to
induce asymmetry. Meanwhile, asymmetric Brønsted acid catalysis
has been introduced and shown to be compatible with amine
substrates and products.4,5 The combination of asymmetric Brønsted
acid catalysis with amine catalysis, however, is largely undeveloped.
We now demonstrate the remarkable efficiency of this concept by
combining both enamine and iminium catalysis with asymmetric
Brønsted acid catalysis. We have developed a highly enantiose-
lective synthesis of pharmaceutically relevant 3-substituted cyclo-
hexylamines from 2,6-diketones via an aldolization-dehydration-
conjugate reduction-reductive amination cascade that is catalyzed
by a chiral Brønsted acid and accelerated by the achiral amine
substrate, which is ultimately incorporated into the product.
We have previously demonstrated that salts consisting of either
an achiral or chiral ammonium cation and a chiral phosphate anion
are powerful catalysts of transfer hydrogenations of R,â-unsaturated
aldehydes and ketones with Hantzsch esters.6,7 On the basis of this
strategy, our experience in Brønsted acid catalyzed asymmetric
imine reductions and reductive aminations,8 and the well-known
capacity of amine salts to catalyze aldolizations,9 we designed a
new triple organocatalytic cascade reaction for the synthesis of
3-substituted cyclohexylamines (eq 1).
Indeed, a non-enantioselective variant could quickly be realized
by treating 2,6-heptandione (1e) with p-anisidine (2a), Hantzsch
ester 3, and a catalytic amount of p-TsOH at 35 °C in toluene. The
major product was the expected racemic 3-methylcyclohexylamine
derivative 4e as a mixture of diastereomers (eq 2). The PMP group
can readily be removed in high yield using H5IO6.11 Acetylation
of the intermediate primary amine provided known amide 5e.
Although 3-substituted cyclohexylamines are constituents of
several pharmaceutically active compounds,12 catalytic and highly
stereoselective methods for their preparation are rare.13 We therefore
systematically screened various reaction conditions involving chial
Brønsted acid catalysts (see Supporting Information) and found that
treating different substituted 2,6-diketones 114,15 with Hantzsch ester
3 (2.2 equiv), p-alkoxyanilines 2a or 2b (1.5 equiv), and (R)-3,3′-
bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phos-
phate [(R)-TRIP]8a (10 mol %) at 50 °C in cyclohexane and in the
presence of molecular sieves afforded the corresponding cis-3-
substituted (hetero)cyclohexylamine derivatives 4 in good yields,
reasonable to very high diastereoselectivities, and in excellent
enantioselectivities (Table 1). The er exceeds 95:5 (ee > 90%) in
most of the studied reactions and is particularly high with aliphatic
substituents. Heterocyclic products can also be obtained in high
enantioselectivity (entries 11 and 12).
The initial aldolization is rapid, and diketones 1 were fully
converted into the corresponding aldol condensation product within
5 min as monitored by GC-MS. This step seems to be kinetically
controlled as regioisomeric products resulting from thermodynamic
control were not formed (<3%). The aldolization is mediated by
the amine substrate and the phosphoric acid; either reagent alone
is inefficient in accelerating the aldolization. The formation of 2,6-
disubstituted piperidines, which may have been expected from a
double reductive amination, was not observed. Similarly, the
conjugate reduction step is accelerated by the acid and by the amine.
In the absence of either reagent, no further conversion of the enone
intermediate is observed.
Accordingly, treating a 2,6-diketone (1) with 1 equiv of an achiral
amine (2), 2 equiv of a Hantzsch ester (3), and a catalytic amount
of a chiral Brønsted acid should lead to the corresponding
cyclohexylamines (4). The initial aldolization step involving
intermediate A was expected to be catalyzed by the amine salt via
enamine catalysis. The conjugate reduction step should proceed via
a combination of iminium and Brønsted acid catalysis involving
The regioselectivity in the conjugate reduction (1,4- vs 1,2-
reduction) is excellent. Only in the case of 2-naphthyl-substituted
diketone 1j, we detected a small amount (<4%) of the 1,2-reduction
product.
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J. AM. CHEM. SOC. 2007, 129, 7498-7499
10.1021/ja072134j CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Scope of the Asymmetric Cascade Reaction
Supporting Information Available: Experimental procedures,
compound characterization, NMR spectra, and HPLC traces (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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(14) Most diketones 1 can be obtained from commercially available lactone 6
or from pyridines 7 (see Supporting Information):
a PEP ) p-ethoxyphenyl; PMP ) p-methoxyphenyl. b Determined by
GC-MS or 1H NMR analysis of the crude product. c Determined by chiral
stationary phase HPLC analysis. d The relative configuration of products 4
was determined by NMR analysis. The absolute configuration of product
4e was assigned via conversion to known amide (1R,3S)-5e (see eq 2).
In the final reductive amination step, TRIP is crucial for the
observed cis-selectivity. Alternative phosphoric acids typically gave
the corresponding trans-isomer. Similarly, the reductive amination
of the intermediate 3-alkyl cyclohexanones generally provides the
corresponding trans-isomer under a variety of reductive amination
conditions (see Supporting Information).
We conclude that combining enamine catalysis and iminium
catalysis with Brønsted acid catalysis constitutes a powerful strategy
for organocatalytic cascade reactions. The combination of a “self-
sacrificing” achiral amine in combination with a chiral Brønsted
acid has been used in a highly enantioselective triple organocatalytic
cascade reaction for the synthesis of cis-3-substituted (hetero)-
cyclohexylamines from 2,6-diones. Further explorations merging
aminocatalysis with asymmetric Brønsted acid catalysis and a
detailed mechanistic investigation are under investigation in our
laboratory.
Acknowledgment. We thank Dr. R. Mynott for careful NMR
studies. Generous support by the Max-Planck-Society, the Deutsche
Forschungsgemeinschaft (SPP 1179, Organocatalysis), and by
Novartis (Young Investigator Award to B.L.) is gratefully acknowl-
edged. We also thank BASF, Degussa, Merck, Saltigo, and Wacker
for general support and donating chemicals.
(15) As expected, 2,5-diketones gave the corresponding pyrroles.
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