Asymmetric hydrogenation of enol phosphinates by iridium catalysts having N,P ligands

Article abstract of DOI:10.1021/ol070325l

Enol phosphinates, which are structural analogues of enol acetates, have for the first time been employed as substrates for Ir-catalyzed asymmetric hydrogenation. A number of enol phosphinates have been synthesized and reduced successfully with up to and above 99% ee.

Full text of DOI:10.1021/ol070325l

ORGANIC
LETTERS
2007
Vol. 9, No. 9
1659-1661
Asymmetric Hydrogenation of Enol
Phosphinates by Iridium Catalysts
Having N,P Ligands
Pradeep Cheruku,† Suresh Gohil,‡ and Pher G. Andersson*,†
Department of Biochemistry and Organic Chemistry, Box 576,
SE-751 23, Uppsala, Sweden
pher.andersson@biorg.kemi.uu.se
Received February 8, 2007
ABSTRACT
Enol phosphinates, which are structural analogues of enol acetates, have for the first time been employed as substrates for Ir-catalyzed
asymmetric hydrogenation. A number of enol phosphinates have been synthesized and reduced successfully with up to and above 99% ee.
Asymmetric hydrogenation has become a powerful tool to
synthesize various chiral precursors of academic and indus-
trial importance. Particularly, there has been intense interest
in asymmetric hydrogenation of prochiral olefins.1 Since the
first reports of Rh-diop2 and Ru-BINAP3 catalysts, many
phosphine ligands have been developed and evaluated for
the hydrogenation of functionalized olefins.4 Enol esters are
of special interest because the products of their asymmetric
hydrogenation are chiral esters, which can be easily trans-
formed into chiral alcohols. This reaction is therefore an
alternative to the direct hydrogenation of ketones.
However, the hydrogenation of enol esters is generally
more difficult than the reduction of their topological ana-
logues, enamides. This may be due to the weaker coordina-
tion ability of the enol ester to the metal center. To date,
DIPAMP, DuPhos, KetalPhos, and TangPhos complexes of
rhodium have been utilized in asymmetric hydrogenations
of enol esters, with very good enantioselectivities.5
Since the first chiral mimic of Crabtree’s complex6 by
Pfaltz and co-workers,7 and its subsequent successful use in
asymmetric hydrogenation of olefins, there have been many
reports of chiral N,P ligands and Ir-catalyzed hydrogena-
tions.8
† Uppsala University.
‡ Current address: Department of Chemistry, Swedish University of
Agricultural Sciences, Box 7015, Uppsala, Sweden.
(5) (a) Koenig, K. E.; Bachman, G. L.; Vineyard, B. D. J. Org. Chem.
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Chem. Soc. 1991, 113, 8518-8519. (c) Li, W.; Zhang, Z.; Xiao, D.; Zhang,
X. Tetrahedron Lett. 1999, 40, 6701-6704. (d) Li, W.; Zhang, Z.; Xiao,
D.; Zhang, X. J. Org. Chem. 2000, 65, 3489-3496. (e) Tang, W.; Liu, D.;
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S.; Akutagawa, S. J. Chem. Soc., Chem. Commun. 1985, 922-924.
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KGaA: Weinheim, Germany, 2005; pp 1-31. (b) Kitamura, M.; Noyori,
Y. In Ruthenium in Organic Synthesis; Murahashi, S.-I., Ed.; Wiley-VCH
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10.1021/ol070325l CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/28/2007

Although Ir-catalyzed asymmetric hydrogenation is well
studied for unfunctionalized olefins and excellent results for
this reaction have been obtained, there have been very few
successful results with olefins bearing weakly coordinating
functional groups. This was noted in a recent review, which
stated that “more effort has been placed on ligand develop-
ment for iridium systems, than on investigations of substrate
scope”.9
Table 1. Ligand and Substrate Optimization Studiesa
Chiral phosphine-oxazole ligands developed in our
group10a,b have been employed in the Ir-catalyzed hydrogena-
tion of allylic alcohols and corresponding acetates, with ee
values up to 99%. Pfaltz et al. have reported the hydrogena-
tion of allylic esters8a using Ir-phosphinite-oxazoline and
Ir-diaminophosphine-oxazoline complexes. Knochel et
al.10c have demonstrated that amino acid derivatives can be
obtained in 96% ee from enamides. However, the substrate
scope of functionalized olefins has yet to be fully explored
and, to our knowledge, there are very few reports where enol
esters or enol ethers have been used as substrates for Ir-
catalyzed hydrogenations.11
a Conversions were determined by 1H NMR spectroscopy; ee values were
determined by chiral HPLC. b Acetophenone was the major product. c Ethyl
benzene was the major product.
Recently, we have reported on several novel classes of
chiral N,P ligands. Their Ir complexes (Figure 1, 1-4) have
Initially, we screened these four complexes (Figure 1, 1-4)
in the hydrogenation of enol esters and enol ethers to
establish reactivity and selectivity. Hydrogenation of enol
ethers 5a and 5b gave complicated mixtures with all catalysts
tried. Complex 4, which has previously given excellent
results with unfunctionalized olefins, was ineffective for all
enol esters in this study. Complex 3 showed some conversion
but the reactions were generally sluggish and resulted in
multiple products. Complex 2 proved to be more efficient
than 1 in terms of selectivity and reactivity.
When attempting the reduction of 5c with 2 we observed
a significant amount of ethyl benzene as byproduct, and the
alkyl acetate obtained was racemic. This observation may
be explained by the formation of Bro¨nsted acids during the
reaction, as recently reported by Matsuda et al.13 These
authors found that allylic alcohols behave as good leaving
groups in the presence of a catalytic amount of iridium
activated by H2; substitution with external nucleophiles can
then occur. They also noted that the replacement of the Ir
complex with CF3SO3H yielded identical results.
Hydrogenation of 5d also proceeded to completion, but
the hydrogenolysis of the phosphinate group occurred for
around 50% of the substrate. Interestingly, enantioselectivity
improved to 65% upon the replacement of the CdO group
with PdO.
Hydrogenation of enol diphenylphosphinate 5e with com-
plex 2 resulted in high ee (95%), full conversion, and no
detectable loss of phosphityl group. Asymmetric hydrogena-
tion of enol phosphonates and phosphinates was previously
observed using Rh-based catalyst, with moderate ee values.14
Hydrogenation of 5e with 0.5 mol % of catalyst 2 under
standard conditions but varying H2 pressures showed 30 bar
Figure 1. Iridium complexes used in hydrogenation studies.
been employed in asymmetric hydrogenation of aryl imines
(up to 92% ee),12 as well as of di- and trisubstituted
unfunctionalized olefins (up to 99% ee).10a,b In view of these
excellent results, we became interested in applying these
complexes to the hydrogenation of enol esters.
(8) (a) Pfaltz, A.; Blankenstein, J.; Hcrmann, E.; McIntyre, S.; Menges,
F.; Schcnleber, M.; Smit, S. P.; Wustenberg, B.; Zimmermann, N. AdV.
Synth. Catal. 2003, 345, 33-43. (b) Ka¨llsto¨rm, K.; Munslow, I.; Andersson,
P. G. Chem. Eur. J. 2006, 12, 3194-3200.
(9) Cui, X.; Burgess, K. Chem. ReV. 2005, 105, 3272-3296.
(10) (a) Ka¨llsto¨rm, K.; Hedberg, C.; Brandt, P.; Bayer, A.; Andersson,
P. G. J. Am. Chem. Soc. 2004, 126, 14308-14309. (b) Hedberg, C.;
Ka¨llsto¨rm, K.; Brandt, P.; Hansen, L. K.; Andersson, P. G. J. Am. Chem.
Soc. 2006, 128, 2995-3001. (c) Bunlaksananusorn, T.; Polborn, K.;
Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 3941-3943.
(11) (a) Goulioukina, N. S.; Dolgina, T. M.; Bondarenko, G. N.;
Beletskaya, I. P.; Ilyin, M. M.; Danakov, V. A.; Pfaltz, A. Tetrahedron:
Asymmetry 2003, 14, 1397-1401. (b) Stefan, S.; Sebastian, P.; Pfaltz, A.
Angew. Chem., Int. Ed. 2006, 45, 5194-5197.
(12) (a) Trifonova, A.; Diesen, J. S.; Chapman, C. J.; Andersson, P. G.
Org. Lett. 2004, 6, 3825-3827. (b) Trifonova, A.; Diesen, J. S.; Chapman,
C. J.; Andersson, P. G. Chem. Eur. J. 2006, 12, 2318-2328.
(13) Matsuda, I.; Wakamatsu, S.; Komori, K.; Makino, T.; Itoh, I.
Tettrahedron Lett. 2002, 43, 1043-1046.
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Org. Lett., Vol. 9, No. 9, 2007

to be optimal. At lower pressures than 30 bar, prolonged
reaction times were required, though no significant effect
on ee was observed. With use of 30 bar of H2, 5e gave the
corresponding alkylphosphinate (6e) in 95% ee, with almost
quantitative conversion in 30 min. The same conditions were
applied to the hydrogenation of a range of enol phosphinates
7a-i and the results are illustrated in Table 2.
Substrates bearing an electron-withdrawing group at the
para position (entries 5-7) were more reactive (full conver-
sion in 0.5-1 h) than the substrates bearing an electron-
donating group (entries 2-4) (full conversion in 3-4 h).
This indicates that the electronics of the substrate influence
the reactivity but not selectivity. A decrease in ee was noticed
with substrate 7f having a naphthalene moiety.
Hydrogenation of 7c led to decomposition and very little
desired product observed (5-10%). This is presumably due
to the presence of a strong electron-donating group at the
para position, which makes the double bond electron rich.
As a result, the phosphinate may become a good leaving
group. Formation of diphenylphosphinic acid was confirmed
by 31P NMR spectroscopy.
Nevertheless, we were able to improve the yield of the
hydrogenation of this substrate to 45-50% via the addition
of a proton scavenger (10 mg of poly(4-vinylpyridine) resin).
Because the additive also deactivates the catalyst, 2 mol %
of catalyst and longer reaction time (overnight) was required.
However, the ee of the product obtained was good.
Interestingly, alkyl enol phosphinates (7h and 7i) were also
hydrogenated with excellent selectivity, although it was
difficult to achive selectivity for alkyl ketones.4b For 7h and
7i full conversion was accomplished in 3 h, with 92% and
99% ee, respectively.
Table 2. Iridium-Catalyzed Hydrogenation of Substratesa
All alkyl phosphinates were easily transformed to corre-
sponding alcohols without any loss of enantioselectivity by
treatment with n-BuLi.
As depicted in Figure 2, it is also possible to make chiral
phosphane compounds by displacing the phosphityl group
with diphenyl phosphine.15
Figure 2. Applications of chiral alkyl phosphinates.
It should be noted that the ee values obtained here are the
best ever reported for these substrates, even when compared
with reduction of corresponding ketones. In conclusion, we
have shown for the first time that Ir complexes of chiral N,P
ligands can catalyze the asymmetric hydrogenation of enol
esters. Complex 2 has proven to be efficient in hydrogenating
a range of enol phosphinate substrates with high selectivity
(85-99% ee). Our current effort is focus on further broaden-
ing the scope of these catalysts.
Acknowledgment. Dedicated to the memory of Prof.
Yoshihiko Ito, who passed away on December 23, 2006. This
work was supported by grants from AstraZeneca, The
Swedish Research Council (VR), and Ligbank. We are
grateful to Mr. Mattias Engman and Mr. Jarle Diesen for
providing iridium complexes and Dr. Ian Munslow and Dr.
Tamara Church for the help in manuscript preparation.
Supporting Information Available: Experimental pro-
cedures for the preparation of the substrates, hydrogenation
procedures, characterization data, and chiral separation data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL070325L
a Conditions: 30 bar of H2, rt, CH2Cl2, 0.5 mol % catalyst. b Determined
by 1H NMR spectroscopy. c Determined by chiral HPLC or chiral GC.
d Hydrolyzed to the corresponding alcohol and compared with literature
data. e Reaction performed in the presence of poly(4-vinylpyridine) resin
(10 mg) with 50 bar of H2 and 2 mol % catalyst.
(14) Tamio, H.; Koichi, K.; Makoto, K. Tetrahedron Lett. 1981, 22,
4417-4420.
(15) Bergens, U. Eur. Pat. Appl. 2005, 17pp. coden: EPXXDW EP
1582527 A1 20051005.
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