Phosphate Tether-mediated Strategies for the Synthesis of Complex Polyols, Natural Products, and Analogs

Abstract

Naturally occurring and synthetic macrocycles are considered as useful scaffolds as therapeutics and probes in both medicine and chemical biology. Due to the pre-organized nature and unique architecture, macrocycles have emerged as an important entity for chemical probe discovery in medicinal chemistry and chemical biology. Moreover, naturally derived macrocyclic secondary metabolites have demonstrated profound pharmacological properties. Chapter 1 discusses synthetic strategies to 14-membered macrolides possessing various chemotypes. In this regard, the family of 14-membered macrolides were divided into six categories based on structural characteristics, namely macrolides containing (i) lactone rings, (ii) -unsaturated macrolactones, (iii) THP rings (iv) pyran hemiketal rings, (v) fused ring systems, and (vi) amides and enamide macrolides. The synthesis of aforementioned chemotypes were discussed briefly in a retrosynthetic fashion to provide a global understanding on distinct synthetic strategies. Chapter 2 focuses on a modular synthetic strategy employing a phosphate-tether mediated-one-pot sequential approach for the formal synthesis of (2S)-epimer of sanctolide A, and the total synthesis of sanctolide A. Sanctolide A is a polyketide nonribosomal peptide (PK-NRP) macrolide, which comprises a 14-membered enamide macrolactone core. A phosphate-tether mediated double diastereotopic group differentiation protocol was employed as the key step for the formal synthesis of the (2S)-epimer of sanctolide A. Concurrently, a phosphate-tether mediated one-pot sequential RCM/CM/substrate-controlled “H2” /tether removal approach was utilized with improved atom- and step-economy to accomplish the total synthesis of the natural product sanctolide A. In order to deconvolute complex characterization issues due to C2 epimerization of the C2-methyl bearing stereocenter, as well as amide rotamers and E/Z isomers, comprehensive and detailed 1H and 13C NMR analysis was carried out, which enabled identification of the source of epimerization and allowed for new conditions to circumvent the issue. Collectively, a strategy for simpler and more stable analogs was developed and reported in Chapter 3. Chapter 3 provides the details of the synthesis of a small library of macrocyclic analogs of aforementioned natural product, sanctolide A that was carried out by adopting a build-couple-couple-pair (BCCP) strategy coupled with phosphate tether one-pot sequential protocols. The synthetic strategy was focused on generating simplified, des-methyl sanctolide analogs containing an ,-unsaturated lactone moiety to simplify the synthesis and importantly, to improve the stability of the analogs. In this regard, a total of 5 -unsaturated macrolides, and 2 enamide macrolides with variable substituents and sidechains were generated. In addition, a one-pot CM/RCM/H2/LAH protocol was developed in the “build phase” for the synthesis of the C1–C10 1,3-anti-diol-containing subunit (sanctolide numbering). Chapter 4 outlines a pot-economical approach for the streamlined synthesis of advanced polyol subunits. The key reactions involved are iterative use of a phosphate tether-mediated one-pot sequential RCM/CM/H2 with subsequent utilization of either a regio-/diasteroselective cuprate addition or a Pd-catalyzed allylic transposition. This method highlights the asymmetric synthesis of 12 complex polyol subunits in 4–6 one-pot sequential operations with a total of 12–14 reactions, with minimal workup and purification procedures. Chapter 5 provides experimental details and spectroscopic data of new compounds, as well as full spectrum 1H, 13C, 31P, 19F, DEPT, 1H 1H COSY, 1H 13C HSQC, 1H 13C HMBC, and nOe. In addition, X-ray data, IR and mass spectral data are provided, as well as a general experimental section detailing instruments used throughout this thesis.