Efficient enantioselective synthesis of optically active diols by asymmetric hydrogenation with modular chiral metal catalysts

Full text of DOI:10.1002/anie.200902835

Communications
DOI: 10.1002/anie.200902835
Asymmetric Synthesis
Efficient Enantioselective Synthesis of Optically Active Diols by
Asymmetric Hydrogenation with Modular Chiral Metal Catalysts**
Renat Kadyrov,* Renꢀ M. Koenigs, Claus Brinkmann, David Voigtlaender, and
Magnus Rueping*
The enantioselective hydrogenation of prochiral ketones is
one of the most elegant and effective methods for the
preparation of optically active secondary alcohols. With
regard to the environment, asymmetric hydrogenations
represent a highly efficient and atom-economical process.
Multiple applications have been developed using chiral
Figure 1. Comparison of the steric demand of alkyl- and aryl-substi-
tuted a-hydroxy ketones.
ruthenium complexes with atropisomeric ligands for the
synthesis of optically active primary and secondary alcohols.
The latter are important building blocks for the synthesis of
natural products, pharmaceuticals and, agrochemicals.[1–3]
The development of a general and efficient enantioselec-
tive route to terminal, vicinal 1,2-diols still presents a great
challenge. These compounds are important chiral building
blocks for the synthesis of natural products such as macro-
diolides,[4a,b] insect pheromones,[4c] b-lactone esterase inhib-
itors,[4d] d-lactones,[4e] and many other biologically active
substances.[4f,5] In the synthesis of the anti-HIV pharmaceut-
ical Tenofovir and related pharmaceuticals the application of
enantiomerically pure (R)-propane-1,2-diol is of critical
importance.[6] A further application of terminal optically
active 1,2-diols is the resolution of atropisomeric com-
pounds.[7] The asymmetric dihydroxylation of terminal
alkenes is the most common method for the preparation for
this class of compounds. However, small sterically less
demanding alkyl derivatives, such as propene, cannot be
enantioselectively oxidized to the diol by asymmetric dihy-
droxylation, nor to the epoxide by asymmetric epoxidation.[8]
The difficulty in the highly enantioselective transforma-
tion of small alkyl derivatives arises from the similar steric
demands of the two groups adjacent to the carbonyl
functionality. The result is poor Re and Si face differentiation
for the sterically less demanding alkyl derivatives; in contrast,
the sterically more demanding aryl ketones can be readily
differentiated (Figure 1).
The hydrogenation of a-hydroxy ketones is one alterna-
tive for the generation of valuable optically active, terminal
1,2-diols. Good progress has been made in the hydrogenation
of the sterically demanding a-hydroxy acetophenones using
various ruthenium[9a-f] and iridium catalysts.[9g] Rhodium[10a]
and ruthenium complexes[10b] were also successfully applied in
asymmetric transfer hydrogenations. Further work concen-
trated on asymmetric enzymatic reductions.[11]
A general, reductive, and highly enantioselective syn-
thesis of aliphatic 1,2-diols has not been reported previously.
Therefore, we began our examination of the enantioselective
synthesis of optically active diols with the application of a new
class of modular diphosphane ligands 1. Particular attention
was given to nonsymmetric ligands as these were considered
more suitable for the enantioface differentiation of the alkyl
hydroxy ketones, which are more challenging substrates.
Ligands 1 can be prepared simply in two steps on a large scale
and are based on a 2,5-disubstituted thiophene core structure,
a chiral phospholane unit,[12,13] and a readily variable diaryl-
phosphino group (Scheme 1).
Scheme 1. Synthesis of the modular diphosphane ligands.
[*] Dr. R. Kadyrov, Dr. D. Voigtlaender
Evonik Degussa GmbH
Thus, we synthesized a series of ligands and tested them in
the asymmetric ruthenium-catalyzed asymmetric hydrogena-
tion of hydroxyacetone (2a), whereby 1,2-propanediol (3a)
could be isolated in high enantiomeric excess (up to 96% ee)
(Table 1). Other privileged ligands including various deriva-
tives of binaphthyl, duphos, deguphos, and members of the
catasium group generally resulted in lower reactivities and
enantioselectivities. The best result with regard to the
selectivity was obtained with the o-tolyl-substituted ligand
1d, which provided the desired propane-1,2-diol in 96% ee.
To further optimize the reaction parameters we varied the
hydrogen pressure, reaction temperature, and solvents.[14]
Rodenbacher Chaussee 4, 63457 Hanau-Wolfgang (Germany)
E-mail: renat.kadyrov@evonik.com
Dipl.-Chem. R. M. Koenigs, Dipl.-Chem. C. Brinkmann,
Prof. Dr. M. Rueping
RWTH Aachen University, Institute of Organic Chemistry
Landoltweg 1, 52074 Aachen (Germany)
E-mail: magnus.rueping@rwth-aachen.de
[**] We thank Evonik Degussa for financial support, the Fonds der
chemischen Industrie for a stipend to R.M.K., and Dr. Juan Almena
and Gerd Geiss for technical assistance.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902835.
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Table 1: Selected ligands employed in the asymmetric ruthenium-
Table 2: Substituted aliphatic a-hydroxy ketones prepared.[a,b]
catalyzed hydrogenation of hydroxyacetone.
Entry[a]
1
R
Ar
L
ee [%][b]
96% ee, 78%[c,d]
96% ee, 81%
94% ee, 74%[c,d]
Me
1a
70
97% ee, 82%
91% ee, 81%
2
3
Me
Me
1b
1c
80
79
96% ee, 77%[d]
93% ee/86% ee,[e] 93%
4
5
Me
Ph
1d
1e
96
81
95% ee, 84%
[a] Reaction conditions: 2a–h (0.3 mmol), [Ru(methylallyl)2(cod)]
(1 mol%, 1d (1.1 mol%), HBr (5 mol%) in 1 mL MeOH. [b] Yield
after chromatography, enantioselectivities determined by GC analysis on
a chiral stationary phase. [c] H2 pressure of 80 bar. [d] Yield of doubly
acylated product.[15] [e] Reaction time of 36 h.
[a] Reaction conditions: Hydroxyacetone (2a), [Ru(methylallyl)2(cod)]
(1 mol%) (cod=cyclooctadiene), 1 (1.1 mol%), HBr (5 mol%) in 1 mL
MeOH. [b] Determined by GC on a chiral stationary phase.
Table 3: Aromatic a-hydroxy ketones prepared.
However, we observed that hydrogen pressure and reaction
temperatures between 50 and 808C had negligible effect on
the hydrogenation. The choice of solvent had a significant
effect on the reaction. In methanol very good selectivities and
yields were obtained while in other solvents, such as
acetonitrile, 1,4-dioxane, dibutyl ether, and water, no reduc-
tion occurred. The reduction can also be conducted in
aromatic solvents such as toluene; however, the yield is
reduced.
Using the optimized reaction conditions we examined the
substrate spectrum of the asymmetric reduction by employing
various aliphatic hydroxy ketones. For the first time a series of
sterically less demanding 1,2-diols could be obtained in good
yields and with excellent enantioselectivities (Table 2). In this
manner it was not only possible to reduce linear substrates
(3a–3d) but also branched substrates (3e–3h) in good yields
and with excellent selectivities (up to 97% ee). It was even
possible to obtain the sterically more demanding tert-butyl-
substituted, terminal diol (3h) in very good enantioselectiv-
ities.
In addition to the reduction of aliphatic a-hydroxy
ketones, we also examined the hydrogenation of the corre-
sponding aromatic substrates. Utilizing the optimized reac-
tion conditions we were able to obtain a series of terminal,
aromatic diols with various substitution patterns as well as
electron-donating and -withdrawing substituents on the arene
in very good yields and with excellent enantioselectivities
(Table 3). In comparison to all the previously reported chiral
catalysts our newly developed, nonsymmetric ruthenium
catalysts exhibits surprisingly high substrate scope, ranging
from linear and branched aliphatic ketones to aromatic
ketones.
Entry[a]
R
3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
phenyl
3i
3j
3k
3l
3m
3n
3o
3p
3q
90
86
99
80
83
88
66
76[e]
55
98
4-Me-C6H4
4-Et-C6H4
4-Cl-C6H4
4-Br-C6H4
2-naphthyl
1-naphthyl
2-Me-C6H4
3-OMe-C6H4
98[d]
98
99
>99
98
91
94
98
[a] Reaction conditions: 2i–q (0.3 mmol), [Ru(methylallyl)2(cod)]
(1 mol%), 1d (1.1 mol%), HBr (5 mol%) in 1 mL MeOH. [b] Yield
after chromatography. [c] Enantioselectivities determined by GC analysis
on a chiral stationary phase. [d] H2 pressure of 80 bar. [e] Reaction time
of 36 h.
In further experiments we concentrated on the application
of the highly efficient enantioselective hydrogenation of a-
hydroxy ketones. Thus we examined the reduction of
hydroxyacetone with low catalyst loadings (Table 4). It was
shown that with a substrate/catalyst ratio of 10000 the
reduction to (R)-propane-1,2-diol could be conducted with-
out loss of selectivity on a multigram scale.
In summary we have developed a highly efficient,
enantioselective hydrogenation[16] for the synthesis of termi-
nal 1,2-diols. Applying new, nonsymmetric diphosphine
ligands, which are based on a chiral phospholane unit and a
variable second donor function and which can be readily
produced on a large scale, we were able to develop an
asymmetric hydrogenation in which not only diverse aromatic
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Communications
[3] Selected book chapters on enantioselective hydrogenation: a) T.
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Table 4: Examination of the catalyst loading.
Entry[a]
S/C
t [h]
Yield [%][b]
ee [%][c]
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Brankovan, R. Datema, M. J. M. Hitchcock, J. C. Martin, J. Med.
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1
2
1000
10000
17
48
80
85
95
94
[a] Reaction condition: [Ru(methylallyl)2(cod)] (5 mg, 1 equiv), 1d
(7.5 mg, 1.1 equiv), 5 equiv HBr, hydroxyacetone (2a) in MeOH.
[b] Yield after chromatography. [c] Determined by GC analysis on a
chiral stationary phase.
but also aliphatic a-hydroxy ketones can be transformed into
valuable 1,2-diols with excellent enantioselectivity.[17] Fur-
thermore, the catalyst loading could be reduced to 0.01 mol%
without loss of enantioselectivity. This underscores the
preparative application of this methodology.
Received: May 27, 2009
Revised: July 7, 2009
Published online: September 8, 2009
Keywords: asymmetric synthesis · diols · hydrogenation ·
.
phosphanes · ruthenium complexes
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[15] For the determination of the yield of the volatile derivatives the
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[17] The modular catalysts can also be applied efficiently in the
synthesis of 1,2-amino alcohols, a- and b-hydroxy esters, and
amines. A manuscript regarding this work is in preparation.
[14] Further information is available in the Supporting Information.
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