used in a number of asymmetric hydrogenation reactions with
enantioselectivities up to 99%.6 In the last three years, this
small but rapidly expanding class of monodentate ligands
has shown enantioselectivities comparable to or better than
those reached with bidentate ligands reported so far.7
Monodentate phosphonites, phosphites, and phosphoramidites
have the advantage of being readily accessible, highly
diverse, and extraordinarily inexpensive compared to various
privileged bidentate ligands. Bearing in mind that asymmetric
hydrogenation is continuously expanding as an important
methodology in the industrial preparation of chiral building
blocks, those characteristics mentioned above are vital
features. However, to date, mono- and bidentate ligands have
not been compared yet in terms of catalytic activity; another
crucial parameter for implementation of asymmetric catalysis
methodology. Herein we report a study demonstrating for
the first time that a monodentate ligand can lead not only to
higher enantioselectivities but also to faster asymmetric
hydrogenations of prochiral olefins compared to several of
the best bidentate ligands used so far.
phosphoramidite appear to be necessary.5d,6g In this way, the
presence in ligand 2 of a hydrogen attached to the nitrogen
instead of a methyl group as in the case of MonoPhos should
influence the rate of the hydrogenation. Nevertheless, the
different enantioselectivies found with both phosphoramid-
ites12 suggest a more complex mechanistic picture. The
differences in reaction rates and ees are probably based on
the influence of the NH group present in 2, as this is the
major chemical difference between both ligands. Similar to
its monophosphite analogue (S,R)-3,5c in this particular
hydrogenation, the ee of the product when using ligand
(S,R)-2 only depends on the chirality of the bisnaphthol unit.10
Encouraged by these findings, we decided to compare the
rate of the reaction of monophosphoramidites 1 and 2 and
monophosphite 35c with some of the most successful and
commercially available bidentate phosphines used in asym-
metric hydrogenation, in particular DuPhos,13 PhanePhos,14
and JosiPhos15 (Figure 1). For the rate comparison, we first
MonoPhos (1)8 is an extremely stable monodentate phos-
phoramidite that affords very good enantioselectivities when
used as a ligand in the rhodium-catalyzed hydrogenation of
R-dehydroamino acid derivatives5d and enamides.6h This
phosphorus ligand can be easily prepared from bis-â-naphthol
and HMPT in excellent yield.6j,9 In the course of a study to
find an efficient ligand for the enantioselective hydrogenation
of â-dehydroamino acid derivatives,10 we carried out a
systematic optimization of the structure of MonoPhos by
variations of the amine functionality via amine exchange
(Scheme 1). In this way, ligand 2 was obtained from (S)-
Scheme 1. Preparation of Phosphoramidite 2.
Figure 1. Ligands used in the comparison with phosphoramidites.
carried out parallel experiments using methyl 2-acetamido
cinnamate (7), a common substrate normally hydrogenated
MonoPhos and commercial (R)-R-methylbenzylamine in
96% yield.
(6) For other recent examples: (a) Reetz, M. T.; Sell, T. Tetrahedron
Lett. 2000, 41, 6333. (b) Chen, W.; Xiao, J. Tetrahedron Lett. 2001, 42,
2897. (c) Zeng, Q.; Liu, H.; Cui, X.; Mi, A.; Jiang, Y.; Li, X.; Choi, M. C.
K.; Chan, A. S. C. Tetrahedron: Asymmetry 2002, 13, 115. (d) Junge, K.;
Oehme, G.; Monsees, A.; Riermeier, T.; Dingerdissen, U.; Beller, M.
Tetrahedron Lett. 2002, 43, 4977. (e) Fu, Y.; Xie, J.-H.; Hu, A.-G.; Zhou,
H.; Wang, L.-X.; Zhou, Q.-L. Chem. Commun. 2002, 480. (f) Jia, X.; Guo,
R.; Li, X.; Yao, X.; Chan, A. S. C. Tetrahedron Lett. 2002, 43, 5541. (g)
Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L. Angew.
Chem., Int. Ed. 2002, 41, 2348. (h) van den Berg, M.; Haak, R. M.;
Minnaard, A. J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. AdV.
Synth. Catal. 2002, 344, 1003. (i) Guillen, F.; Rivard, M.; Toffano, M.;
Legros, J.-Y.; Daran J.-C.; Fiaud, J.-C. Tetrahedron 2002, 58, 5895. (j)
van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman, M.; Schudde, E.
P.; Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.; Maljaars, C. E. P.;
Willans, C. E.; Hyett, D.; Boogers, J. A. F.; Henderickx, H. J. W.; de Vries,
J. G. AdV. Synth. Catal. 2003, 345, 1.
Initially, we tested monophosphoramidite 2 in the asym-
metric hydrogenation of a benchmark substrate, methyl
2-acetamido cinnamate (dehydrophenylalanine methylester,
7) under standard conditions.11 Although the enantiomeric
excess of 8 was somewhat lower compared to the value
obtained with MonoPhos (90 vs 95% ee), the reaction
appeared to be dramatically faster (5 min vs 4 h). To obtain
an efficient ligand in the rhodium-catalyzed asymmetric
hydrogenation, small R-groups on the amine unit of the
(5) (a) Guillen, F.; Fiaud, J.-C. Tetrahedron Lett. 1999, 40, 2939. (b)
Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.; Martorell,
A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961. (c) Reetz, M.
T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889. (d) van den Berg,
M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de Vries, A. H. M.; de
Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539.
(7) For a recent review, see: Komarov, I. V.; Bo¨rner, A. Angew. Chem.,
Int. Ed. 2001, 40, 1197.
(8) Now commercially available through Strem Chemicals. See also: van
den Berg, M.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. (DSM N.
V.). World Patent WO 02/04466, 2002.
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