Total synthesis of natural product-Like 3D molecular scaffolds for drug discovery.

Abstract

The design and total synthesis of a 3D collection compounds containing the spirocyclic piperidine privileged building block, taking into consideration drug-like descriptors (parameters) such as physicochemical and pharmacokinetic properties and based on the natural product molecular core framework of furofuranones, have been achieved via two distinct stereoselective cyclopropanation reactions, for drug discovery. Key reactions included an enantioselective cyclopropanation through a Mn(III)/Cu(II) promoted oxidative cyclisation and a diastereoselective cyclopropanation via the chiral dirhodium(II) catalyst dirhodium tetrakis (S)-N-1,8-naphthanoyl tert-leucinate, Rh2[(S)-NTTL]4. The enantiomerically enriched key intermediate, which have been synthesised implementing an efficient parallel enzymatic kinetic resolution accomplishing excellent enantioselectivity (>99%), was further derivatised with fragments or building blocks of pharmaceutical interest to achieve the synthesis of 7 final drug-like compounds, 3 precursors for further derivatisation, for screening purposes. Additionally, towards the total synthesis of a respective furolactam key intermediate an unusual Mitsunobu reaction has been achieved between a sec-allylic alcohol and the weakly acidic coupling partner para-bromo aniline.

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Identifiers

ORCID for Richard Brown: orcid.org/0000-0003-0156-7087

ORCID for David Harrowven: orcid.org/0000-0001-6730-3573

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