Catalyst‐Controlled Diastereoselection in the Hydrogenation of Heterocycloalkyl Ketones

Abstract

a-Substituted chiral ketones that have small steric and electronic differences around the reaction sites are difficult substrates to reduce with high diastereoselectivity. Metal hydride reduction of 2-(4-benzoylmorpholinyl) phenyl ketone and 3-(1-tert-butoxycarbonylpiperidinyl) phenyl ketone using sodium borohydride, zinc borohydride, and potassium tri-sec-butylborohydride as reducing agents affords the syn-and anti-alcohols in a lower than 80:20 ratio. Hydrogenation of these ketones with a catalyst system of RuCl 2 A C H T U N G T R E N N U N G (BIPHEP)A C H T U N G T R E N N U N G (DMEN) and potassium tert-butoxide in 2-propanol results in the syn-alcohols with ! 99:1 selectivity [BIPHEP = 2,2'-bis(diphenylphosphino)biphenyl, DMEN = N,N-dimethylethylenediamine]. The marked difference in the diastereoselectivity suggests that the stereoselection in this hydrogenation is primarily regulated by the structure of the catalysts reaction field ("catalyst-controlled diastereoselection") but not the internal stereocontrol of the substrates. This chemistry is applied to the asymmetric hydrogenation through dynamic kinetic resolution with aA series of aryl heterocycloalkyl ketones has been converted to the alcohols in excellent diastereo-and enantioselectivities. The modes of catalyst-controlled diastereoselection and enantioselection are interpreted by using transitionstate molecular models. (S,S)-Reboxetine, a selective norepinephrine uptake inhibitor, was synthesized from one of product alcohols.Keywords: diastereoselectivity; enantioselectivity; hydrogenation; ketones; reboxetine; ruthenium Diastereoselective reduction of a-substituted chiral ketones to the 1,2-syn-or 1,2-anti-alcohols is a fundamental and indispensable reaction in modern organic synthesis.[1] Metal hydride reducing agents have made notable contributions to advance this important class of chemistry. The stereoselective outcome has been explained by using transition-state molecular models, such as the Felkin-Anh model and the chelation-controlled model (Figure 1). [1][2][3] In both cases the metal hydride reagent is recognized as just a hydride, and it reacts within the region of the substrate molecules. Therefore, the intramolecular stereoinduction principally depends on the substrate structure (substrate control), but not the shape of the metal hydrides (reagent control).[4] High diastereoselectivity in this reaction is achieved only when the substrates have a-substituents (L, M, S, and X) with marked differences in size and/or electronic properties. Thus, we thought that a new conceptual approach is required to develop a general method for the diastereoselective reduction of a-substituted ketones.We selected heterocycloalkyl ketones 1a and 1c as substrates to examine the diastereoselective ability of reducing agents [Eq. (1)]. The small electronic and Figure 1. Typical transition-state models in the diastereoselective hydride reduction of a-substituted chiral ketones. L, M, and S = large-, medium-, and small-sized substituents, respectivel...

The NH Functional Group in Organometallic Catalysis

“…Complex 30 showed 92–99 % enantioselectivity in the asymmetric hydrogenation of difficult substrate 1‐tetralones 24a. Complex 31 is an efficient catalyst for the hydrogenation of aromatic ketones,24b,c α‐heteroatom‐substituted ketones,24b,c aryl vinyl ketones,24d and heterocycloalkyl ketones,24g giving the corresponding chiral alcohols with high ee values. Complexes 30 and 32 showed high catalytic activities (S/C up to 50 000 for 30 and 100 000 for 32 ) and excellent enantioselectivities (97–>99 % ee for 30 and 88 % ee for 32 ) in the asymmetric hydrogenation of bicyclic ketones 24e,f.…”

Recent Developments in Asymmetric Hydrogenation and Transfer Hydrogenation of Ketones and Imines through Dynamic Kinetic Resolution

“…as the catalyst (Scheme 3). 15 Under optimized reaction conditions, the corresponding alcohols were efficiently produced in 95-100% yields with good to excellent diastereoselectivities (>99:1) and ee values ranging from 94-99%. The authors noted that the diastereoselectivity of the reaction was essentially controlled by the nature of the X group present on the heterocyclic rings.…”

Current applications of kinetic resolution in the asymmetric synthesis of substituted pyrrolidines

“…40 In 2011, Ohkuma et al employed a similar method, synthesising 2-and 3-monosubstituted pyrrolidines from racemic pyrrolidines containing a ketone (Scheme 11). 41 A ruthenium catalyst 48 was employed in the hydrogenation, obtaining syn-3-substituted pyrrolidine 45 in moderate diastereoselectivity and excellent enantioselectivity and anti-2substituted pyrrolidine 47 in excellent diastereoselectivity and good enantioselectivity.…”