Angewandte
Chemie
Asymmetric Catalysis
Development of Chiral Spiro P-N-S Ligands for Iridium-Catalyzed
Asymmetric Hydrogenation of b-Alkyl-b-Ketoesters**
Deng-Hui Bao, Hui-Ling Wu, Chao-Lun Liu, Jian-Hua Xie,* and Qi-Lin Zhou*
Abstract: The chiral tridentate spiro P-N-S ligands (Spiro-
SAP) were developed, and their iridium complexes were
prepared. Introduction of a 1,3-dithiane moiety into the ligand
resulted in a highly efficient chiral iridium catalyst for
asymmetric hydrogenation of b-alkyl-b-ketoesters, producing
chiral b-alkyl-b-hydroxyesters with excellent enantioselectivi-
ties (95–99.9% ee) and turnover numbers of up to 355000.
SpiroPAP (3) and the fact that the pyridine moiety in 3 is
vital for obtaining high activity and high enantioselectivity in
the hydrogenation of aromatic ketones and b-aryl-b-keto-
esters, we speculated that the enantioselectivity of the hydro-
genation of b-alkyl-b-ketoesters could be increased by
replacing the planar pyridine moiety in 3 with a thioether
group, the steric bulk of which could be adjusted. Herein we
report the syntheses of new tridentate spiro P-N-S ligands,
SpiroSAP (4), and their applications for iridium-catalyzed
T
ransition-metal-catalyzed asymmetric hydrogenation of
unsaturated compounds is a powerful tool for the synthesis
of chiral molecules in optically active form. Many chiral
ligands have been developed for asymmetric hydrogenation
of diverse substrates such as olefins, ketones, and imines.[1]
Most of the efficient chiral ligands reported to date have been
chiral phosphorus (P) ligands,[2] nitrogen (N) ligands,[3] or
mixed P-N ligands.[4] In contrast, only a few efficient chiral
sulfur containing ligands, mainly P-S ligands, have been
developed for highly enantioselective hydrogenation reac-
tions.[5] Introduction of a thioether moiety into the chiral
ligand is believed to beneficially alter the chiral environment
around the metal of the catalyst; specifically, coordination of
the S atom to the metal not only exerts steric and electronic
effects but also converts the S atom to a new stereogenic
center.[6]
asymmetric
(Scheme 1).
hydrogenation
of
b-alkyl-b-ketoesters
Recently, we developed some chiral spiro pyridine-amino-
phosphine ligands, referred to as SpiroPAP ligands, that
exhibit extraordinary activity and enantioselectivity in iri-
dium-catalyzed hydrogenation of aromatic ketones and b-
aryl-b-ketoesters.[7] However, when we used the SpiroPAP
ligands for iridium-catalyzed asymmetric hydrogenation of b-
alkyl-b-ketoesters to afford b-hydroxyesters, only moderate
enantioselectivity was obtained.[8] Owing to the importance of
chiral b-hydroxyesters in the synthesis of chiral drugs and
natural products,[9] we explored new ligands and catalysts in
the hope of achieving the asymmetric hydrogenation of b-
alkyl-b-ketoesters. On the basis of the structure of Ir-
Scheme 1. The design of chiral spiro iridium catalysts with SpiroSAP
ligands.
SpiroSAP ligands (R)-4a–i were synthesized from chiral
spiro aminophosphines (R)-1[10] by acylation with 2-alkylthio-
or arylthio-substituted acetyl chlorides and subsequent reduc-
tion with LiAlH4 in the presence of AlCl3. SpiroSAP ligands
(R)-4j and (R)-4k were synthesized by reductive alkylation of
(R)-1 with 2,2-dimethoxyacetaldehyde with NaBH(OAc)3 or
H2/Pd-C, followed by transdithioacetalization of the acetal
group with 1,3-propanedithiol in the presence of indium(III)
trichloride (Scheme 2).
Ir-SpiroSAP catalysts 5 were prepared by complexation of
ligands (R)-4 with an iridium precursor under H2 pressure
(Scheme 3). For example, the reaction of (R)-4a and [Ir-
(cod)Cl]2 (cod = cyclooctadiene) in ethanol under 10 atm of
H2 at room temperature gave catalyst (R)-5a (96% yield) as
a light yellow solid. The 1H NMR spectrum of (R)-5a exhibits
two groups of double-doublets; and the 31P NMR spectrum
exhibits a triplet. These NMR results indicate the formation
of an iridium dihydride [Ir(H)2((R)-4a)Cl]. However, the
reaction of (R)-4k with [Ir(cod)Cl]2 under 30 atm of H2
afforded iridium dihydride [Ir(H)2((R)-4k)Cl] as a mixture
[*] D.-H. Bao, H.-L. Wu, C.-L. Liu, Prof. J.-H. Xie, Prof. Q.-L. Zhou
State Key Laboratory and Institute of Elemento-organic Chemistry
Collaborative Innovation Center of Chemical Science
and Engineering (Tianjin)
Nankai University, Tianjin 300071 (China)
E-mail: jhxie@nankai.edu.cn
[**] We thank the National Natural Science Foundation of China, the
National Basic Research Program of China (2012CB821600), and
the “111” project (B06005) of the Ministry of Education of China for
financial support.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2015, 54, 8791 –8794
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8791