Target-Directed Organocatalysis: A Direct Asymmetric Catalytic Approach to Chiral Propargylic and Allylic Fluorides

Abstract

A simple, direct one-pot organocatalytic approach to the formation of optically active propargylic fluorides is presented. The approach is based on organocatalytic alpha-fluorination of aldehydes and trapping and homologation of the intermediate providing optically active propargylic fluorides in good yields and enantioselectivities up to 99% ee. The procedure takes place by addition of NFSI, in the presence of 2-[bis(3,5-bis-trifluoromethylphenyl)trimethylsilyloxymethyl]pyrrolidine (as low as 0.25 mol %) as the catalyst, to aldehydes in combination with dimethyl 2-oxopropylphosphonate and 4-acetamidobenzenesulfonyl azide. The scope of the reaction is demonstrated by the formation of a number of optically active propargylic fluorides. It is also shown that optically active fluoro-containing triazoles can be obtained in one-pot procedures from aldehydes using click-chemistry. Furthermore, important coupling and multicomponent reactions of the optically active propargylic fluorides can be performed without affecting the enantiomeric excess. The direct one-pot formation of optically active allylic fluorides from aldehydes is also demonstrated. Finally, the mechanisms for both the formation of the propargylic and allylic fluorides are outlined.

Recent Advances in Catalytic Enantioselective Fluorination Reactions

“…Considering the increasing demand for propargylic fluorides, [56] and the limited number of methodologies available to access optically pure materials, [57] Jørgen-sen described in 2009 a simple approach involving a one-pot proline-catalyzed a-fluorination/Seyferth-Gilbert reaction (Ohira-Bestmann modification). [58] In place of simple reduction after a-fluorination of aldehydes, Jørgensen considered that the intermediate a-fluoro aldehyde would be likely to react with an olefination reagent. The main issue was to avoid racemization of the newly formed stereocenter.…”

Simple strategy for synthesis of optically active allylic alcohols and amines by using enantioselective organocatalysis

“…Incorporation of organocatalytic functionalizations in complex one-pot reactions has recently emerged as an efficient strategy for the formation of many important optically active compounds, otherwise difficult to obtain (19)(20)(21)(22)(23)(24)(25). The present work shows the development of an organocatalytic synthetic process, making use of a single amino-catalyst (26)(27)(28)(29)(30)(31) in combination with cheap and readily available starting materials, for the formation of allylic alcohols and amines in moderate to good yields and excellent enantioselectivities (Scheme 2).…”

Recent Advances on the Organocatalyzed Enantioselective α-heterofunctionalization of Carbonyl Compounds

“…The use of the organocatalyzed α-fluorination reaction of aldehydes in combination with other synthetic processes has provided a valuable tool for the asymmetric synthesis of these privileged classes of chiral fluorine compounds. Thus, the one-pot α-fluorination of aldehydes mediated by catalyst 72a (1 mol%) , followed by in situ trapping and homologation of the aldehyde using the Ohira-Bestmann reagent 138 in combination with methanol and potassium carbonate, afforded chiral propargylic fluorides 139 in moderated yields and excellent enantioselectivities (Scheme 35) [132]. Linear saturated and unsaturated aldehydes, arenecarbaldehydes with different substitution patterns and even functionalized aldehydes were suitable substrates for this transformation, showing its versatility.…”