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...
Tolerant: Alkylmagnesium reagents can be synthesized from alkenes through a sequence of hydroboration and subsequent boron–magnesium exchange using a method that tolerates different functional groups (see scheme). The resulting alkylmagnesium reagents can be used in carbon–carbon bond forming reactions, such as alkylation reactions or transition‐metal‐catalyzed cross‐coupling reactions.
Tolerant: Ausgehend von Alkenen können Alkylmagnesium‐Reagentien durch Hydroborierung und anschließenden Bor‐Magnesium‐Austausch synthetisiert werden (siehe Schema). Die verwendete Methode toleriert unterschiedliche funktionelle Gruppen. Die erhaltenen Alkylmagnesium‐Reagentien können zur C‐C‐Bindungsbildung eingesetzt werden, z. B. in Alkylierungen oder übergangsmetallkatalysierten Kreuzkupplungen.
Preparation of Alkylmagnesium Reagents from Alkenes Through Hydroboration and Boron-Magnesium Exchange. -A general protocol for the generation of various primary and secondary alkylmagnesium halides is presented, involving a sequence of alkene boration and boron-magnesium exchange. The alkylmagnesium reagents are suitable partners in a diversity of C-C bond formation reactions like alkylation, 1,2-addition or transition metal catalyzed cross coupling reactions. -(REICHLE, M. A.; BREIT*, B.; Angew. Chem., Int. Ed. 51 (2012) 23, 5730-5734, http://dx.
Enantioselective syntheses O 0031Enantioselective Synthesis of α-Tertiary Hydroxyaldehydes by Palladium-Catalyzed Asymmetric Allylic Alkylation of Enolates. -Chiral α-tertiary hydroxyaldehydes are synthesized from α-halo or α-hydroxy ketones or enol silyl ethers with good yields and high enantioselectivities. The synthetic utility is demonstrated in the efficient synthesis of (XIII) which can be converted into (S)-oxybutynin. -(TROST*, B. M.; XU, J.; REICHLE, M.; J. Am. Chem. Soc. 129 (2007) 2, 282-283; Dep. Chem., Stanford Univ., Stanford, CA 94305, USA; Eng.) -S. Adam 24-029
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