Enantioselective Synthesis of α-Tertiary Hydroxyaldehydes by Palladium-Catalyzed Asymmetric Allylic Alkylation of Enolates

Abstract

Chiral α-tertiary hydroxyaldehydes are very versatile building blocks in synthetic chemistry. Herein, we reported the first examples of a catalytic asymmetric protocol for the synthesis of such compounds from readily available α-halo or α-hydroxy ketones or enol silyl ethers with excellent yields and enantioselectivity. Its synthetic utility is demonstrated in the short, efficient formal synthesis of (S)-oxybutynin. In this process, the chiral ligand controls with the regioselectivity as well as enantioselectivity.α-Hydroxyaldehydes are very versatile building blocks for the synthesis of natural products as well as clinical drugs. 1 Chiral α-hydroxyaldehydes enjoy the added benefit of being a potential source of introducing other stereogenic centers. Up to now, the access of such compounds in enantiomerically enriched form can be classified as a chiral pool approach 1 , a chiral auxiliary approach 2 or a transformation from other enantio-enriched compounds, such as 1,2-diols, 3a-c α-hydroxy acids 3d and cyanohydrins, 3e synthesized by other enantioselective methods.However, to our knowledge catalytic enantioselective synthesis of α-tertiary hydroxyaldehydes directly from prochiral precursors has not been reported. 4 In the course of studying palladiumcatalyzed asymmetric allylic alkylation (AAA) of simple ketone enolates, 5 we postulated that treatment of enol carbonate 2 or 3 bearing a shiftable OR 1 group with a proper chiral palladium catalyst presumably could regio-and enantioselectively generate R 1 protected α-tertiary hydroxyaldehydes 1 (eq. 1). Substrates 2 and 3 can be made from readily available α-halo or α-hydroxy ketones. 6 Herein, we report the first example of a palladium catalyzed highly enantioselective synthesis of α-tertiary hydroxyaldehydes resulting from a novel competition and demonstrated its synthetic utility in a formal synthesis of (S)-oxybutynin. 7We initially subjected 2a-1 and 3a-1 respectively to our previously reported conditions (2.5 mol% Pd 2 (dba) 3 CHCl 3 and 5.5 mol% (R,R)-L in 1,4-dioxane at 23 °C). 5 Although the reaction of 2a-1 was significantly faster, the only product from either was aldehyde (S)-1a with excellent yields and ee's (Table 1, entry 1 and 2). 8 As summarized in Table 1, the scope of the R 1 group was explored. With few exceptions, the reaction favored the formation of aldehyde 1a independent of the O-substituent while, in several cases, reactions with achiral ligand 1,2-bis (diphenylphosphino)ethane (dppe) as ligand the major product was ketone 4a ( entry 13). Support for this contention derives from the observation that the reaction of 3a-1 was severely inhibited by the addition of an equal amount of 3a-9 (6% conversion in contrast to a full conversion in 1 h in the absence of 3a-9.In addition, The E-enolate generated from 5 can not chelate to the catalyst and reacted readily (eq. 2).Although various R 1 groups are suitable, we selected the most commonly used TBDMS as the hydroxy protecting group and investigated the scope of the nucleophilic moiety...

Model Studies To Access the [6,7,5,5]-Core of Ineleganolide Using Tandem Translactonization–Cope or Cyclopropanation–Cope Rearrangements as Key Steps

“…8a At the time, there was limited evidence that α-heteroatoms might be tolerated in the reaction. 10 Coincident with early model system investigations, we developed a general enantioselective alkylation of dioxanone-derived enol ethers, 8a which could be used to prepare alcohol 11 8b by way of chloroallyl dioxanone 15 . Treatment of triethylsilylether 12 with Pd(dmdba) 2 (5 mol%), tris(CF 3 )-( S )- t -BuPHOX ( 14 , 5.5 mol%), 11 and chlorallyl me-sylate ( 13 , 1.05 equiv) with an equivalent of TBAT in PhMe at 25 °C, yielded the desired tetrasubstituted ether 15 with good enantioselectivity (91% ee).…”

Metal catalyzed allylic alkylation: its development in the Trost laboratories

“…73,74 These species are readily available in two steps from the alcohol that becomes the allylating agent and the α- hydroxy- or α-bromoketone. When the silyl ether 57 is subjected to Pd(0) catalysis, the exclusive product is the aldehyde 60 (see eq 73).…”

Ligand Controlled Highly Regio- and Enantioselective Synthesis of α-Acyloxyketones by Palladium-Catalyzed Allylic Alkylation of 1,2-Enediol Carbonates

“…1). 2 The regioselectivity may be interpreted as a faster equilibration between the Pd enolate A and B compared to the rate of alkylation which occurs faster via B (ie. k > k 2 > k 1 ).…”