Total Syntheses of Sarcandrolide J and Shizukaol D: Lindenane Sesquiterpenoid [4+2] Dimers

The syntheses of members of a family of lindenane sesquiterpenoid [4+2] dimers led to the total syntheses of sarcandrolide J and shizukaol D. Inspired by a modified biosynthetic pathway, a cascade featuring furan formation/alkene isomerization/Diels–Alder cycloaddition was devised to construct the congested polycyclic architecture of the target molecules with the correct stereochemistry. This study presents a pioneering synthetic entry to this family of natural products and paves the way for fully exploring their biological functions.     

Unified Asymmetric Total Syntheses of (−)‐Alotaketals A–D and (−)‐Phorbaketal A

The novel tricyclic spiroketal alotane‐type sesterterpenoids showed strikingly different biological activities and potency with subtle structural alterations. Asymmetric total syntheses of the tricyclic sesterterpenoids (−)‐alotaketals A–D and (−)‐phorbaketal A were accomplished [29–31 steps from (−)‐malic acid] in a collective way for the first time. The key features of the strategy included 1) a new cascade cyclization of vinyl epoxy δ‐keto‐alcohols to forge the common tricyclic spiroketal intermediate, 2) a late‐stage allylic C−H oxidation, and 3) olefin cross‐metathesis to install the different side chains.     

Biomimetic and Biocatalytic Synthesis of Bruceol

The first total synthesis of bruceol has been achieved using a biomimetic cascade cyclization initiated by a stereoselective Jacobsen–Katsuki epoxidation (and kinetic resolution) of racemic protobruceol‐I. A bacterial cytochrome P450 monooxygenase was also found to catalyze the conversion of protobruceol‐I into bruceol. The first full analysis of the NMR data of natural bruceol suggested that “isobruceol” was a previously unrecognized natural product also isolated from Philotheca brucei. This was confirmed by the re‐isolation, synthesis, and X‐ray analysis of isobruceol. In total, eight stereoisomers and structural isomers of bruceol have been synthesized in a highly divergent approach.     

Biomimetic Total Synthesis of (±)‐Homodimericin A

A biomimetic total synthesis of racemic homodimericin A was achieved in seven steps, including two cascade reactions. Aqueous buffer solutions are found to help both the oxidative dimerization cascade and the intramolecular Diels–Alder cascade. This synthetic sequence validates key steps in the biogenetic proposal of homodimericin A.     

A Ten‐Step Total Synthesis of Speradine C

The first total synthesis of speradine C has been achieved in only ten steps from a commercially available 4‐bromoindole. Salient features of the work are the formation of four rings through three cyclizations, namely a bioinspired [3+2] annulation to form the C/D rings, an NCS‐mediated oxidation to construct the E ring, and a Ru‐catalyzed ketohydroxylation to assemble the F ring. This work highlights how strategic ring constructions can streamline the synthesis of polycyclic compounds.     

Structural Revision and Biomimetic Synthesis of Goupiolone B

Goupiolones A and B are unique phenolic compounds with significant DNA‐damaging activity. In this study, the structure of goupiolone B was revised on the basis of DFT calculations of the ¹³C NMR chemical shifts and biosynthetic considerations. The dibenzobicyclo[3.2.2]nonane skeleton of the revised structure suggested that goupiolone B was produced by oxidative coupling between catechol and goupiolone A, which was strongly supported by biomimetic synthesis. Furthermore, racemization of goupiolone B was observed during the attempted resolution of its racemic mixture. A plausible racemization mechanism involving α‐ketol rearrangement is proposed.     

Divergent Biomimetic Total Syntheses of Ganocins A–C,Ganocochlearins C and D,and Cochlearol T

A divergent synthetic approach to six Ganoderma meroterpenoids, namely ganocins A–C, ganocochlearins C and D, and cochlearol T, has been developed for the first time. This synthetic route features a two-phase strategy which includes early-stage rapid construction of a common planar tricyclic intermediate followed by highly selective late-stage transformations into various Ganoderma meroterpenoids. Key to the strategy are a bioinspired intramolecular hetero-Diels–Alder reaction and Stahl-type oxidative aromatization, allowing efficient formation of the common tricyclic phenol intermediate. A nucleophilic dearomatization of the phenol unit, combined with a regioselective 1,4-reduction of the resulting dienone, enabled rapid access to ganocins B and C. Additionally, site-selective Mukaiyama hydration, followed by an intramolecular oxa-Michael addition/triflation cascade, served as a key strategic element in the chemical synthesis of ganocin A.     

Total Syntheses of Sesterterpenoid Ansellones A and B,and Phorbadione

Ansellane‐type sesterterpenoids including, ansellones A‐G and (+)‐phorbadione are structurally novel marine secondary metabolites which exhibit anticancer and anti‐HIV activity. The first, asymmetric total syntheses of three structurally representative members, (−)‐ansellones A and B and (+)‐phorbadione, were accomplished in 16–23 steps from (+)‐sclareolide. The route features the first regioselective cyclization of vinyl epoxides with internal alcohol nucleophiles in a 1,4‐addition manner (S_N2′). Additionally, the allylic C−H oxidation was exploited at a late stage of the synthesis of (−)‐ansellone A and (+)‐phorbadione. This strategy is expected to be applicable to the synthesis of other ansellane sesterterpenoids.