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Asymmetric Counteranion-Directed Catalysis.

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DOI: 10.1002/anie.200600512
Asymmetric Counteranion-Directed Catalysis**
Sonja Mayer and Benjamin List*
Most chemical reactions proceed via charged intermediates
or transition states. Such “polar reactions” can be influenced
by the counterion, especially if conducted in organic solvents,
where ion pairs are ineffectively separated by the solvent.
Although efficient asymmetric catalytic transformations involving anionic intermediates with chiral, cationic catalysts
have been realized (for example, in phase-transfer catalysis),[1] analogous versions of inverse polarity with reasonable
enantioselectivity have been illusive, despite several attempts.[2] We report here a catalytic organic salt that consists
of an achiral ammonium cation and a chiral phosphate anion,
which catalyzes transfer hydrogenations with remarkably
high enantioselectivities.
Recently, a metal-free biomimetic transfer hydrogenation
of a,b-unsaturated aldehydes was discovered in our research
group and independently by MacMillan and co-workers.[3]
The reaction is catalyzed by salts of chiral amines and
proceeds via iminium ion intermediates. The process utilizes a
Hantzsch dihydropyridine as the reductant and synthetic
NADH analogue. Intrigued by the observation of a strong
counteranion effect on the yield and enantioselectivity of the
reaction, and inspired by the recent introduction of chiral
phosphates as asymmetric Brønsted acid catalysts,[4] we
hypothesized that catalytic salts of achiral amines and chiral
phosphoric acids could induce asymmetry in the process. We
expected the asymmetry of the chiral phosphate anion to
influence the enantioselectivity of the reaction through a
stereochemical communication within the iminium phosphate
ion pair.
We have now screened such salts, which are easily
prepared by mixing various commercially available primary
and secondary amines with known chiral binaphthol-derived
phosphoric acids. Several ammonium phosphate salts gave
products in significant enantioselectivities. Remarkably, we
consistently observed the highest enantiomeric ratios (e.r.)
with ammonium salts of the sterically hindered chiral phosphoric acid derivative 3,3’-bis(2,4,6-triisopropylphenyl)-1,1’binaphthyl-2,2’-diyl hydrogen phosphate (TRIP), which we
recently introduced as powerful catalysts for imine reductions
and Pictet–Spengler cyclizations.[4i,j] Its morpholine salt 1 was
identified as widely applicable and a highly enantioselective
catalyst for our organocatalytic transfer hydrogenation. Thus,
treating a,b-unsaturated aldehydes 2 with a slight excess of
dihydropyridine 4 and a catalytic amount of salt 1 at 50 8C in
dioxane for 24 h gave the corresponding saturated aldehydes
3 in high yields and in enantioselectivities between 98:2 and
> 99:1 e.r. (Table 1).[5]
Table 1: Asymmetric counterion-mediated organocatalytic transfer hydrogenation of a,b-unsaturated aldehydes.
Yield [%] e.r.[a]
> 99: < 1
[a] Determined by GC. n.d. = not determined.
[*] S. Mayer, Prof. Dr. B. List
Max-Planck-Institut f5r Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 M5lheim an der Ruhr (Germany)
Fax: (+ 49) 208-306-2999
[**] Technical assistance by Simone Marcus, Jutta Rosentreter, Michael
Stadler, and Dr. Jung Woon Yang is gratefully acknowledged. We
thank the Max-Planck Institut, Degussa, Lanxess, and Wacker for
support of our work, the Deutsche Forschungsgemeneinschaft for
the priority program “Organocatalysis” (SPP 1179), and Novartis for
a Young Investigator Award.
Angew. Chem. Int. Ed. 2006, 45, 4193 –4195
Although our new catalyst was ineffective in converting
the sterically hindered substrate 2 g, the enantioselectivities
with aromatic substrates 2 a–2 f are the highest reported for
this reaction. Significantly, the previously developed chiral
amine based catalysts that we and McMillan and co-workers
have studied have not been of use for sterically nonhindered
aliphatic substrates. For example, citral (5), of which the
hydrogenation product citronellal (6) is an intermediate in the
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
industrial synthesis of menthol and used as a perfume
ingredient, could not readily be used. We could not achieve
high enantioselectivity for this particular substrate with either
our previous system[3b] or with that of MacMillan and coworkers[3c] (Table 2). However, with our novel chiral countTable 2: Organocatalytic asymmetric transfer hydrogenation of (E)-citral.
Yield [%]
[a] Determined by GC. [b] Commercially available Hantzsch ethyl ester
was used and gave a higher e.r. value than ester 4. [c] Using the
conditions reported in Ref. [3b]. [d] Using the conditions reported in
Ref. [3c]. [e] Hantzsch ester 4 was used.
eranion catalyst 1, citral is converted into (R)-citronellal (6)
with an e.r. value of 95:5 (Table 2, entry 3). This is the highest
enantioselectivity so far reported for a catalytic asymmetric
(transfer) hydrogenation of citral.[6]
Similarly, farnesal (7) gave (R)-dihydrofarnesal (8) in
77 % yield and 96:4 e.r. [Eq. (1)]. Enantiomerically enriched
the same enantiomeric product, a phenomenon which has
previously been observed in the versions catalyzed by chiral
amines. We believe the reaction proceeds via an iminium ion
intermediate since salts of tertiary amines (e.g. triethylamine)
are ineffective. Asymmetric induction presumably occurs in
the cationic transition state of the reaction by virtue of a
stereochemical communication with the chiral phosphate
counteranion, possibly through CH···O hydrogen-bonding
interactions. The details of these interactions will be elucidated in future investigations.
In summary, we have developed a new catalyst salt (1) that
consists of an achiral ammonium ion and a chiral phosphate
anion which catalyzes highly enantioselective transfer hydrogenations of a,b-unsaturated aldehydes to the corresponding
saturated derivatives. Our new catalyst considerably widens
the substrate scope of the iminium catalytic transfer hydrogenation by allowing the use of sterically nonhindered a,bunsaturated aldehydes. The underlying principle, namely
asymmetric counteranion-directed catalysis (ACDC), is a
new strategy for highly enantioselective synthesis and may
turn out to be of general utility for other reactions that
proceed via cationic intermediates.
Experimental Section
General procedure: Catalyst 1 (84.0 mg, 0.1 mmol, 20 mol %) was
added to a stirred solution of the a,b-unsaturated aldehyde 2
(0.5 mmol) in dioxane (THF with aldehydes 5 and 7; 5 mL) at 50 8C
(RT with aldehydes 5 and 7). After five minutes, dihydropyridine 4
(139 mg, 0.55 mmol; 189 mg, 0.75 mmol for aldehyde 7) was added.
After 24 h (96 h for 7), the mixture was poured into distilled water
(20 mL) and extracted with dichloromethane (Et2O with aldehydes 5
and 7; 2 F 15 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated. Flash chromatography (SiO2, ethyl acetate/hexane or diethyl ether/pentane) provided the pure products 3, 6,
and 8. Aldehydes 2 a–g were synthesized according to previously
reported methods and their analytical data as well of those of
aldehydes 3 correspond to literature values.[8] The absolute configuration of 3 f was determined by measurement of its known optical
rotation.[9] Enantiomeric ratios were determined by GC analysis on a
chiral stationary phase. The absolute configuration of (R)-citronellal
(6) was determined by comparison with a commercial sample.
Received: February 7, 2006
Revised: March 22, 2006
Published online: May 24, 2006
Keywords: asymmetric organocatalysis · binaphthol derivatives ·
iminium ions · ion pair catalysis · transfer hydrogenation
2,3-dihydrofarnesal (8) has been identified as a marking
pheromone of several bumblebee species, a constituent of the
scent of orchids and the blossom fragrance of Citrus limon,
and in fresh juniper needles.[7] To our knowledge, the reaction
described herein constitutes the first asymmetric synthesis of
Although all the experiments reported here have been
conducted with diastereomerically pure E isomers, initial
experiments indicate that our new catalyst system is stereoconvergent and a rapid E–Z equilibration precedes the
hydrogenation, as can be seen by NMR spectroscopic studies.
Thus both E and Z isomers as well as their mixtures provide
[1] For reviews, see the special edition on “Asymmetric Organocatalysis”: Acc. Chem. Res. 2004, 37, 487 – 631.
[2] For a review, see: a) J. Lacour, V. Hebbe-Viton, Chem. Soc. Rev.
2003, 32, 373 – 382; see also: b) D. B. Llewellyn, B. A. Arndtsen,
Tetrahedron: Asymmetry 2005, 16, 1789 – 1799; c) R. Dorta, L.
Shimon, D. Milstein, J. Organomet. Chem. 2004, 689, 751 – 758;
d) C. Carter, S. Fletcher, A. Nelson, Tetrahedron: Asymmetry
2003, 14, 1995 – 2004.
[3] a) J. W. Yang, M. T. Hechavarria Fonseca, B. List, Angew. Chem.
2004, 116, 6829 – 6832; Angew. Chem. Int. Ed. 2004, 43, 6660 –
6662; b) J. W. Yang, M. T. Hechavarria Fonseca, N. Vignola, B.
List, Angew. Chem. 2005, 117, 110 – 112; Angew. Chem. Int. Ed.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 4193 –4195
2005, 44, 108 – 110; c) S. G. Ouellet, J. B. Tuttle, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127, 32 – 33.
a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem.
2004, 116, 1592 – 1594; Angew. Chem. Int. Ed. 2004, 43, 1566 –
1568; b) T. Akiyama, H. Morita, J. Itoh, K. Fuchibe, Org. Lett.
2005, 7, 2583 – 2585; c) T. Akiyama, Y. Saitoh, H. Morita, K.
Fuchibe, Adv. Synth. Catal. 2005, 347, 1523 – 1526; d) T. Akiyama,
Y. Tamura, J. Itoh, H. Morita, K Fuchibe, Synlett 2006, 141 – 143;
e) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356 –
5367; f) D. Uraguchi, K. Sorimachi, M. Terada, J. Am. Chem. Soc.
2004, 126, 11 804 – 11 805; g) D. Uraguchi, K. Sorimachi, M.
Terada, J. Am. Chem. Soc. 2005, 127, 9360 – 9361; h) M. Rueping,
E. Sugiono, C. Azap, T. Theissmann, M. Bolte, Org. Lett. 2005, 7,
3781 – 3783; i) S. Hoffmann, A. Seayad, B. List, Angew. Chem.
2005, 117, 7590 – 7593; Angew. Chem. Int. Ed. 2005, 44, 7424 –
7427; j) J. Seayad, A. M. Seayad, B. List, J. Am. Chem. Soc. 2006,
128, 1086 – 1087; k) G. B. Rowland, H. Zhang, E. B. Rowland, S.
Chennamadhavuni, Y. Wang, J. C. Antilla, J. Am. Chem. Soc.
2005, 127, 15 696 – 15 697; l) R. I. Storer, D. E. Carrera, Y. Ni,
D. W. C. MacMillan, J. Am. Chem. Soc. 2006, 128, 84 – 86.
Alternative dialkyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Hantzsch esters have been screened for the reduction of
substrate 2 c: bis-tert-butyl (82:18 e.r.), bisneopentyl (83:17 e.r.),
mixed methyl-tert-butyl (85:15 e.r.). The use of alternative substituents in the 2,6 positions of the Hantzsch ester leads to
diminished enantioselectivities. Alternative amines that were
screened with the TRIP counteranion using 2 c as substrate are:
pyrrolidine (98:2 e.r.), dibenzylamine (97:3 e.r.), O,N-dimethylhydroxylamine (94:6 e.r.), and methylamine (90:10 e.r.).
Other chiral phosphate and carboxylate counteranions have been
studied but typically gave lower e.r. values. The full details of the
catalyst screen will be reported in due course.
a) “Optical active citronellal” (Rhone-Poulenc Industries S.A.,
Fr.), JP 78-80630, 1979; b) T.-P. Dang, P. Aviron-Violet, Y.
Colleuille, J. Varagnat, J. Mol. Catal. 1982, 16, 51 – 59; c) G.
Kortvelyessy, Acta Chim. Hung. 1985, 119, 347 – 354.
A. Luxova, K. Urbanova, I. Valterova, M. Terzo, A.-K. BorgKarlson, Chirality 2004, 16, 228 – 233, and references therein.
a) R. Martin, I. Islas, A. Moyano, M. A. Pericas, A. Riera,
Tetrahedron 2001, 57, 6367 – 6374; b) M. I. Al-Hassan, Gazz.
Chim. Ital. 1985, 115, 441; c) M. Akhtar, L. Jallo, A. Johnson, J.
Chem. Soc. Chem. Commun. 1982, 1, 44 – 46; d) A. I. Meyers, A.
Nabeya, H. W. Adickes, I. R. Politzer, J. Am. Chem. Soc. 1969, 91,
764 – 765.
T. Lee, J. B. Jones, J. Am. Chem. Soc. 1997, 119, 10 260 – 10 268.
Angew. Chem. Int. Ed. 2006, 45, 4193 –4195
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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