Total Synthesis of Stemarene and Betaerene Diterpenoids: Divergent Ring-Formation Strategy and Late-Stage C–H Functionalization

Abstract

A unified protecting-group-free approach to two stemarene and two betaerene diterpenoids through a bioinspired two-phase strategy has been developed, and three of them were obtained for the first time via chemical synthesis. Starting from a common intermediate, two distinct tetracyclic frameworks containing diastereoisomeric bridged bicycles were constructed by divergent ring reorganization strategy. Late-stage C−H functionalization through xanthylation-oxygenation protocol furnished the corresponding oxygenated stereocenters or oxo functionality in high regio-and diastereoselective fashion within a complex hydrocarbon system. The stereochemical puzzles in (-)-2-acetoxybetaer-13(17)-ene and (+)-7-acetoxybetaer-13(17)-ene were first predicted by the comparison of DFT-NMR data with the reported data and later were unambiguously addressed through the total syntheses of natural products and three diastereomers.

Ring contraction in synthesis of functionalized carbocycles

“…91 (G) Conversion of a diol 87 to a cyclopentane 89 achieved through the selective mesylation via a 1,2-carbon migration in the synthesis of (+)-2-oxostemar-13-ene (10). 92 using IBX gave 1,2-diketone 96, this reaction proceeded via the a-hydroxy group attacking the least hindered ketone to give oxetanone 97. This step was followed by a 1,2-carbon migration to give the unstable b-lactone 98.…”

“…The synthesis of (+)-2-oxostemar-13-ene ( 10 ) utilized a semi-pinacol rearrangement to prepare spirocyclopentane 89 92 (Scheme 4(G)). The selective mesylation of the C12 hydroxy group of 87 , followed by treatment with potassium tert -butoxide enabled a semi-pinacol rearrangement giving diketone 89 in 70% yield over two steps with a 1 : 1 epimeric ratio (contractive synthesis: 11 steps, 92 asymmetric; non-contractive synthesis: N/A).…”

Diastereoselectivity Switch During Alkene Reductions: Diastereodivergent Syntheses of Molecular Fossils via MHAT or Homogeneous Catalytic Hydrogenation Reactions

“…Concerning the diastereoselection switch in olefin reduction to form the axial products, we eventually turned to Crabtree hydrogenation, [16] which performed better than most of the other conditions we investigated: Wilkinson, [16e] Adams (under high H 2 pressure), [15,16f] and diimide [16g] . Conversely, the use of magnesium turnings in methanol furnished slightly higher d. r. for axial derivatives 3 Aa and 4 Aa in the case of the α,β‐unsaturated esters 9 a and 10 a (2.3 : 1 and 1.8 : 1, respectively, in quantitative yields) due to due to kinetic protonation of the intermediates [17] .…”

Direct C−H Sulfuration: Synthesis of Disulfides, Dithiocarbamates, Xanthates, Thiocarbamates and Thiocarbonates

“…In 2022, by merging a divergent ring‐formation strategy with the late‐stage photoinduced xanthylation protocol developed by Alexanian's group, Zhang and coworkers developed a bioinspired two‐phase strategy for the total synthesis of stemarene and betaerene diterpenoids ( 139 , 142 – 143 ) starting from a common tricyclic diol intermediate 132 prepared from inexpensive (+)‐sclareolide 131 (Scheme 38). [134] With diol 132 in hand, two distinct tetracyclic ketones 133 – 134 containing diastereoisomeric bridged bicycles were constructed through a divergent ring reorganization strategy. Subsequently, compounds 133 – 134 underwent blue light‐irradiated C−H xanthylation at the sterically most accessible and electron‐rich C2‐ and C7‐methylene sites to afford the corresponding xanthylation products 135 , 140 – 141 , which were further oxygenated and underwent additional transformations to yield diterpenoids 139 , 142 – 143 .…”