Intramolecular substitutions of secondary and tertiary alcohols with chirality transfer by an iron(III) catalyst

Abstract

Optically pure alcohols are abundant in nature and attractive as feedstock for organic synthesis but challenging for further transformation using atom efficient and sustainable methodologies, particularly when there is a desire to conserve the chirality. Usually, substitution of the OH group of stereogenic alcohols with conservation of chirality requires derivatization as part of a complex, stoichiometric procedure. We herein demonstrate that a simple, inexpensive, and environmentally benign iron(III) catalyst promotes the direct intramolecular substitution of enantiomerically enriched secondary and tertiary alcohols with O -, N -, and S -centered nucleophiles to generate valuable 5-membered, 6-membered and aryl-fused 6-membered heterocyclic compounds with chirality transfer and water as the only byproduct. The power of the methodology is demonstrated in the total synthesis of (+)-lentiginosine from D-glucose where iron-catalysis is used in a key step. Adoption of this methodology will contribute towards the transition to sustainable and bio-based processes in the pharmaceutical and agrochemical industries.

Hydrogen-bond donor and acceptor cooperative catalysis strategy for cyclic dehydration of diols to access O-heterocycles

“…Moreover, an inverse deuterium kinetic isotope effect ( k H / k D = 0.89) was observed by comparing the rate of dehydrative etherification of 1c with that of CD 3 OH ( 1c′ ), which supports the idea that the reaction mainly follows an S N 2-like pathway (fig. S14, B and C) ( 7 , 9 , 39 ). In addition, tertiary alcohol (e.g., 5a ) was also tolerant to this IL catalyst but showed a low reactivity with a 36% yield of 5b under the similar reaction conditions.…”

Stereospecific nucleophilic substitution at tertiary and quaternary stereocentres

“…By using a mixture of n-hexane and DCE at either À15 C or room temperature (depending of the nucleophilicity of the heteroatom), various O-, N-and S-substituted heterocycles were prepared with a complete chirality transfer (Scheme 12). 26 It is interesting to note that for the substrate with X ¼ O and R ¼ alkyl, the combination of a tertiary alcohol prone to undergo elimination with a weak nucleophile still generates the product 16c with high chirality transfer. Experimental results suggests that the coordination of iron to the nucleofuge would lead to C-O bond cleavage to generate a tight ion pair intermediate.…”

Chemistry of Tertiary Carbon Center in the Formation of Congested C−O Ether Bonds

“…Shenvi's group found that an S N 1‐like reaction of a chiral tertiary alkyl trifluoroacetate results in an inversion product via ion pairs [10] . Baik and Cook's group and Samec's group reported that an intramolecular S N 2 reaction using an iron Lewis acid‐activated chiral tertiary alkyl alcohol proceeds with stereoinversion [11, 12] …”