cis-Dihydroxylated α-Trifluoromethylated N,O-Acetal from l-Tartaric Acid: Synthesis of Tetrasubstituted Stereocenter via Diastereoselective Pictet-Spengler Cyclization of N-Acyliminium Ions

Abstract

The synthesis of cyclic, chiral α-trifluoromethylated N,O-acetals having a protected cis-diol moiety has been readily achieved in two steps from a known bis-Weinreb amide derived from l-tartaric acid. The reaction of O-acetyl analogues of these N,O-acetals with triflic acid in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at 0 °C generated in situ the corresponding electrophilic α-trifluoromethyl N-acyliminium ions that undergo Pictet-Spengler-type cyclizations. After only 10 min of reaction, the original enantiopure aza-tricyclic scaffolds bearing a trifluoromethyl substituent at the bridgehead position were obtained with diastereoselectivities ranging from 75:25 to 97:3.

HFIP in Organic Synthesis

“…N -Acylium ions generated from chiral α-trifluoromethylated N , O -acetals bearing a quaternary center were used in a diastereoselective Pictet–Spengler cyclization (Scheme ). The precursors were synthesized from the bis-Weinreb amide derived from l -tartaric acid. Initial attempts to generate the acyliminium ion in DCE were problematic due to sluggish reaction times, poor diastereoselectivity, and significant byproducts arising from acetonide deprotection and migration.…”

Ruppert‐Prakash Reagent (TMSCF3)‐Catalyzed Chemoselective Esterification of Weinreb Amides

“…With the aim to access esters amenable for subsequent nucleophilic displacements, a series of homologous aliphatic alcohols presenting ωchloro substituents were used for preparing under remarkable chemocontrol the corresponding alkoxides and, then coupled with the Weinreb amides. Although potentially susceptible of chlorine-metal exchange phenomena, the expected esters (34)(35)(36)(37)(38) were formed in high yield. Analogously, glycol-type containing nucleophilic elements underwent the acylation without difficulties (39-40), as well as, a β-N,N-dimethylaminoethyl alcohol (41).…”

“…We would exclude the genesis of the trifluoromethyl anion (CF 3 À ) under our reaction conditions. In this sense, Leadbeater [36] and Grellepois-Portella [37] reported the preparation of CF 3 -ketones from Weinreb amides and initiators such as CsF, TBAF or TBAT, thus highlighting the critical role of the Lewis base in determining the reaction outcome. [38] By reacting bis-Weinreb amide 57 with NaOMe (0.95 equiv.…”