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.
Highlights
Pure alcohols are abundant in nature and attractive as feedstock for organic synthesis but challenging for further transformation using atom efficient and sustainable methodologies, when there is a desire to conserve the chirality
The catalytic reactivity and chirality transfer of different Lewis acids were screened with model compound 1a, from those oxophilic iron-based catalysts gave higher yields and chirality transfers than other Lewis acids in this series (Supplementary Table 2). (Chirality transfer is determined as percentage of conserved ee.) In further studies, the most Lewis acidic complex, Fe(OTf)[3], was found to be the most efficient catalyst for the transformation, and it gave desired pyrrolidine 2a in 62% yield (Table 1, entry 12)
This direct substitution method works for enantioenriched tertiary alcohols, where the chirality is preserved to the product and water is generated as the only by-product
Summary
Pure alcohols are abundant in nature and attractive as feedstock for organic synthesis but challenging for further transformation using atom efficient and sustainable methodologies, when there is a desire to conserve the chirality. Recently have SN2′-type reactions been reported for gold-catalyzed and palladium-catalyzed intramolecular amination and etherification reactions of stereogenic allylic alcohols (Fig. 1a)[14,15,16,17,18,19,20,21] These reactions are substrate dependent and if the double bond and OH group was juxtapositioned, the reactivity collapsed (Fig. 1b)[22,23]. Chirality transfer will be used.) Interestingly, it was found that the protocol was chemoselective for tertiary alcohols over secondary and primary alcohols[27] Despite these recent advances emphasized above, there are no reported methods on either the synthesis of non-allylic sixmembered heterocyclic compounds through intramolecular substitution of the OH group or the direct intramolecular substitution of tertiary alcohols with chirality transfers, or the use of substrates containing weak nucleophiles (such as phenolic OH)[28]. In order to offer a synthetic route to overcome these limitations, we continued our efforts on acid-catalyzed transformations and report a Previous work a
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