Combining Asymmetric Catalysis with Natural Product Functionalization through Enantioselective α-Fluorination

Abstract

An examination into the derivatization of various natural products using newly developed α-fluorination methodology is disclosed. An activated ketene enolate, generated from an acid chloride, is allowed to react with an electrophilic fluorine source (NFSi). Quenching the reaction with a nucleophilic natural product produces biologically relevant α-fluorinated carbonyl derivatives of select chemotherapeutics, antibiotics, and other pharmaceuticals.

Advances in Catalytic Enantioselective Fluorination, Mono-, Di-, and Trifluoromethylation, and Trifluoromethylthiolation Reactions

“…In 2010, the same group reported the quenching of the above reaction with nucleophilic natural products to produce biologically relevant α-fluorinated carbonyl derivatives (Scheme 69 ). 82 They found that the solubility of the nucleophile used to quench the reaction proved critical. Glutathione, morphine, and 6-aminopenicillanic displayed marginal solubility, leading to drastically decreased yields.…”

Tertiary Amine Lewis Base Catalysis in Combination with Transition Metal Catalysis

“…Lectka further showcased the synthetic utility of this α-fluorination process in the functionalization of a series of diverse natural products (Scheme 9) [16]. Using Scheme 10 Ternary catalyst system for asymmetric fluorination of aliphatic acid chlorides either p-methoxyphenylacetyl chloride or 3-phthalimidopropionyl chloride, in conjunction with the palladium/BzQD catalyst system previously described, nine natural product derivatives were prepared in good yields (32-98%) and with good-toexcellent levels of diastereocontrol.…”

Palladium and Organocatalysis: An Excellent Recipe for Asymmetric Synthesis

“…The catalytic asymmetric α-fluorination of acid chlorides has been shown by Lectka and co-workers to be a powerful method to synthesize a wide range of α-fluorocarboxylic acid derivatives in good yields and excellent enantioselectivities through electrophilic fluorination of a ketene enolate intermediate [28,29,30]. Lectka’s bifunctional catalytic system is based on the combination of the chiral nucleophiles benzoylquinine ( 6 ) or benzoylquinidine ( 7 ) and a transition metal Lewis acid cocatalyst, such as (PPh 3 ) 2 PdCl 2 , in the presence of Hünig’s base.…”

“…The α-fluorination of acid chlorides developed by Lectka et al . has been successfully employed for the site-specific functionalization of natural products and biologically active molecules with excellent diastereoselectivity [28,29]. For instance, quenching the fluorination reaction of 3-phthalimidopropionyl chloride with the lactol of the anti-malarian agent artemisinin, affords compound 8 in 75% yield and 81% ee (Figure 5) [29].…”