Biaryl hydroxy aldehydes

The lactone concept is not restricted to the simple model biaryl synthesis presented here. It has been successfully expanded to a broad series of structurally diverse biaryl substrates (e.g., lactones with additional stereocenters and functional groups, configurationally stable lactones, seven-membered lactones, and again configurationally unstable biaryl hydroxy aldehydes ), to different activation modes in the ring-opening step (e.g., use of metallated nucleophiles, carbonyl activation by Lewis acids, (Ti -complexation, etc.), and for various strategies of stereoselection (e.g., external vs. internal asymmetric induction). ... 

The strategy based on the lactone concept is not restricted to biaryl lactones as substrates, but can be applied to other configurationally unstable biaryls such as biaryl hydroxy aldehydes. As an example, the reduction of biaryl hydroxy aldehydes in the presence of a CBS catalyst and catecholborane yielded the corresponding alcohols, as shown in Scheme 5.21. ... 

The first catalytic atropoenantioselective addition of a C-nucleophile such as diethylzinc in the presence of 10 mol % of (-)-DBNE to biaryl hydroxy aldehydes was reported by Bringmann et al, providing the corresponding secondary alcohols, albeit in low diastereoselectivity and moderate enantio-... 

Scheme 5.22 Addition of Et2Zn to biaryl hydroxy aldehydes.

Since ketone R)-16 was prepared in a non-selective way when an achiral imino enolate was alkylated, it was considered whether alkylation of chiral enolates, such as that of oxazoline 18, with benzyl bromide 14, would provide stereoselective access to the corresponding alkylation product 19 with R-configuration at C(8) (Scheme 4). Indeed, alkylation of 18 with 14 gave the biaryl 19 and its diastereoisomer almost quantitatively, in a 14 1 ratio. However, reductive hydrolysis using the sequence 1. MeOTf, 2. NaBH4, and 3. H30", afforded hydroxy aldehyde 20 in 25% yield at best. Furthermore, partial epimerization at C(8) occurred (dr 7.7 1). An alternative route, using chiral hydrazones, was even less successful. 

Apart from triarylindiums, diarylindium halides and arylindium dihalides, stable in an aqueous media, smoothly react with aryl iodides and bromides at a very low palladium-catalyst loading in a THF / water mixture (8 1 to 6 1, v/v) to give the biaryls in very high yields tolerating free-amino, hydroxy, carboxy groups, as well as aldehyde, nitro group, etc. The presence of a polar cosolvent (water) has been essential... 

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