Enantiopure Quaternary α-Trifluoromethyl-α-alkoxyaldehydes from l-Tartaric Acid Derived Ketoamides

Abstract

The diastereoselective nucleophilic trifluoromethylation of a range of ketoamides derived from L-tartaric acid has been studied. TMSCF3 in the presence of a catalytic amount of K2CO3 in DMF has been identified as the conditions leading to the highest diastereoselectivities. A sequential one-pot reaction trifluoromethylation-etherification of the trifluoromethylcarbinol has been developed. Only one further one-pot reaction, ketal hydrolysis-oxidative cleavage, led to the final alpha-trifluoromethylated alpha-alkoxyaldehydes. This procedure was applied to the preparation of a series of enantiopure aryl, heteroaryl, and alkyl alpha-trifluoromethyl-alpha-alkoxyaldehydes.

Enantiopure 2‐(Trifluoromethyl)‐1,2,3,4‐tetrahydronaphthalene‐1,2‐diols from a Tartaric Acid Derived Scaffold

“…O-Allyl trifluoromethylated intermediate 4 was first synthesized from keto amide 2 prepared from the bis(dimethylamide) of tartaric acid (1), [7] according to the one-pot procedure depicted in Scheme 2. [4] As previously observed, the trifluoromethylation step with aliphatic ketones is less diastereoselective than it was with aromatic ones, which is advantageous to have access to the whole set of stereoisomers. Unfortunately, the separation of the diastereomers of 4 proved to be difficult and a stepwise procedure had to be carried out.…”

“…based on our recently reported methodology, [4] where the key step is a nucleophilic trifluoromethylation of a tartaric acid derived keto amide. O-Allyl trifluoromethylated intermediate 4 was first synthesized from keto amide 2 prepared from the bis(dimethylamide) of tartaric acid (1), [7] according to the one-pot procedure depicted in Scheme 2.…”

“…The R configuration was ascribed to the major diastereomer according to 19 F NMR spectroscopy correlation: the CF 3 signal of the major R isomer appears at upper field. [4] Compounds 4a and 4b were then submitted to hydrolysis of the ketal moiety and subsequent oxidative cleavage according to the reported procedure. [4] Under these acidic conditions, the intramolecular Friedel-Crafts reaction was easily activated so that the intermediate aldehyde was directly converted into the final tetrahydronaphthalene derivative 5 as a mixture of easily separated diastereomers.…”

“…[4] Compounds 4a and 4b were then submitted to hydrolysis of the ketal moiety and subsequent oxidative cleavage according to the reported procedure. [4] Under these acidic conditions, the intramolecular Friedel-Crafts reaction was easily activated so that the intermediate aldehyde was directly converted into the final tetrahydronaphthalene derivative 5 as a mixture of easily separated diastereomers. As a 276 Finally, palladium-catalyzed deallylation [8] of (-)-cis-5 and (-)-trans-5 afforded the corresponding enantiopure 2-Tfm-tetrahydronaphthalene-1,2-diols (-)-cis-6 and (-)-trans-6 (Scheme 5).…”

The Role of the Counterion and of Silicon Chelation in the Selective Mono(trifluoromethylation) of Tartaric Acid Derived 1,4‐Diketones

“…To gain insights into the possible role of the TMS group in stopping the reaction at the monoadduct stage, the Oallyl ketoether analogue 8 was prepared from the corresponding amido ether [6] and treated with TFMTMS under similar conditions (TBAF, THF). We were unable to isolate the bisTFM derivative 9, even after adding an excess of reagents (Scheme 6).…”