Phosphate Tethers in Natural Product Synthesis

Abstract

Recent advances in phosphate tether-mediated natural product synthesis are reviewed. Synthetic approaches toward dolabelide C, (-)-salicylihalimide A, (-)-tetrahydrolipstatin, and (+)-strictifolione are included. In addition, current efforts in method development are briefly reviewed, including a detailed study on the effect of stereochemical complexity on the phosphate-mediated, diastereoselective ring-closing metathesis reaction and recent advances in multi-reaction, one-pot sequential processes mediated by the phosphate tether. Overall, this review seeks to highlight the utility of phosphate triesters to serve as multifunctional tethers with protecting group and latent leaving group characteristics and the ability to orchestrate multiple, orthogonal reaction pathways to allow for the facile synthesis of complex, bioactive small molecules and their analogs.

P-Stereogenic Bicyclo[4.3.1]phosphite Boranes: Synthesis and Utility of Tunable P-Tether Systems for the Desymmetrization of C2-Symmetric 1,3-anti-Diols

“…1 While silicon-based tethers are the most widely used and studied systems, 2 their phosphorus counterparts have emerged as viable alternatives. 3 In particular, we have been interested in the development of P -stereogenic, bicyclic phosphates as tripodal, temporary tether systems for the synthesis of polyketide natural products (Figure 1). 3 Despite the notable features of temporary phosphate-tether methods, current efforts in our group have aimed at exploring alternative tripodal tether systems in order to identify unique reactivity profiles that may be exploited in the synthesis of chemical scaffolds which would be difficult or laborious to access via previously reported methods.…”

“…3 In particular, we have been interested in the development of P -stereogenic, bicyclic phosphates as tripodal, temporary tether systems for the synthesis of polyketide natural products (Figure 1). 3 Despite the notable features of temporary phosphate-tether methods, current efforts in our group have aimed at exploring alternative tripodal tether systems in order to identify unique reactivity profiles that may be exploited in the synthesis of chemical scaffolds which would be difficult or laborious to access via previously reported methods. To this end, we herein report the development of P -stereogenic, bicyclic, P(III)-phosphiteborane systems as electronically tunable, temporary tether strategies for the desymmetrization of 1,3- anti -diol-containing dienes.…”

Modular Synthesis of Novel Macrocycles Bearing α,β‐Unsaturated Chemotypes through a Series of One‐Pot, Sequential Protocols

“…By exploiting the orthogonal leaving and protecting group ability of bicyclic phosphate 6 , we next applied a one-pot Pd-catalyzed, reductive allylic transposition and phosphate tether removal protocol [29g] (Scheme 2). This pot-economical operation provided 1,3- anti -diol 7 in 56% overall yield (83% av/rxn) after a sequence of three reactions and no solvent change.…”

“…[14,29] This first one-pot event derivatives. In particular, vinyl sulfonates and their analogs have a rich biological profile that has seen a resurgence in recent years due to their activities against enzymes involved in parasitic diseases [30] and cancer.…”

“…A notable merit of the method is the application of multiple consecutive pot-economic operations that significantly avoid purification procedures between successive reactions. Based on our previous applications of the RCM/CM/[“H 2 ”] protocol, [29] we expect that a CM partner can be tactically chosen to assemble macrocycles with additional diversity, including various ring s izes. Further expansion of this synthetic approach for the synthesis of a variety of novel medium- and large-sized macrocycles will be reported in due course.…”