Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences.

Tandem and organocatalytic oxa-Michael reactions of α,β-unsaturated aldehydes were explored for the stereoselective synthesis of structurally complex tetrahydropyrans. Thestereoselective synthesis of 2,6-trans-tetrahydropyrans, which are thermodynamically unfavorable, was accomplished through a reagent-controlled, organocatalytic oxa-Michael reaction. A temperature-dependent configurational switch allowed the preparation of both 2,3-trans-2,6-trans- and 2,3-cis-2,6-cis-tetrahydropyrans from a common substrate. This switch was then used to synthesize the precursors of the C21–C29 and C30–C37 fragments of ent-(+)-sorangicin A.

Immunosuppressive drugs are used to prevent rejection of transplanted organs and treat autoimmune diseases. Clinically approved immunosuppressive drugs possess undesirable side effects, including acute neurological toxicity, chronic nephrotoxicity, and osteoporosis. As a result, considerable efforts have been devoted to the identification of immunosuppressive natural products that lack cytotoxicity and undesirable side effects on bone structure. Subglutinols A (1 a) and B (1 b) are diterpene pyrones isolated from Fusarium subglutinans. Compounds 1 a and 1 b are equipotent in the mixed lymphocyte reaction assay and thymocyte proliferation assay (IC₅₀=0.1 μM). Owing to the lack of toxicity, 1 a and 1 b are expected to be promising new immunosuppressive drugs. Herein, we detail our efforts that have culminated in a stereoselective synthesis of 1 a and 1 b from the (S)-(+)-5-methyl-Wieland–Miescher ketone and determined their absolute stereochemistries. We also present initial biological data to show the great potential of 1 a as an immunosuppressive drug with dose-dependent osteogenic activity.