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.
Asymmetric total synthesis of the dimeric diterpenoid hispidanin A was accomplished by non-catalytic Diels-Alder cycloaddition at room temperature. The synthesis relies on iron-catalyzed coupling to construct a Z-configured trisubstituted alkene, an iron-catalyzed radical cascade to generate a labdane-type diene, and both Yamamoto cationic polyene cyclization and palladium-catalyzed Stille coupling to generate a totarane-type dienophile.
We report on our accomplishment of the asymmetric synthesis of hispidanin A and its natural precursor, a labdane diterpenoid. In the first generation of synthesis, a semi-synthesis strategy was employed to construct a labdane-type diterpenoid, a natural precursor of hispidanin A, in which Barton's photolytic remote functionalization was employed as a key transformation. In addition, the totarane-type dienophile counterpart was derived from commercially available (-)-scalareol. In the second generation of synthesis, key elements included an iron-catalyzed radical cascade to access the labdane-type diene on the basis of hydrogen atom transfer, and an enantioselective cationic polyene cyclization furnished the totarane-type dienophile. Reaction optimization and mechanistic analysis of the radical cascade reaction was conducted. Furthermore, the [4+2] cycloaddition reaction was achieved in excellent yield and selectivity under thermal conditions, which has been rationalized by using DFT transition-state analysis and paved the way for final accomplishment of the total synthesis of hispidanin A.
Though chiral pool synthesis is widely
accepted as a powerful strategy
in complex molecule synthesis, the effectiveness of the approach is
intimately linked to the range of available chiral building blocks
and the functional groups they possess. To date, there is still a
pressing need for new remote functionalization methods that would
allow the installation of useful chemical handles on these building
blocks to enable a broader spectrum of synthetic manipulations. Herein,
we report the engineering of a P450BM3 variant for the
regioselective C–H oxidation of sclareol at C6. The synthetic
utility of the resulting product was demonstrated in a formal synthesis
of ansellone B, the first total synthesis of the 2,3-seco-labdane excolide B, and a model study toward (+)-pallavicinin.
Dynamic kinetic resolution (DKR)
is a powerful method to construct
complex molecules with one or more stereocenters. In light of their
exquisite stereospecificity and stereoselectivity, enzymes are becoming
widely used as catalysts in DKR. This review summarizes chemoenzymatic
and biocatalytic methodologies for DKR that have been developed in
the past decade. Additionally, applications of these methodologies
in the preparation of active pharmaceutical ingredients and emerging
paradigms, including the combined use of biocatalysis and photocatalysis
for DKR, are highlighted.
The first synthesis of a labdane-type diterpenoid isolated from Isodon yuennanensis was achieved in fourteen steps from commercially available starting material, (+)-sclareolide. The synthesis features the Barton nitrite ester reaction to introduce an oxime at the angular methyl group and the Jones oxidation to construct the lactone segment. By comparison of the optical rotation of our synthetic sample and the natural sample, the absolute stereochemistry of the natural diterpenoid has been determined.
The key transformation for the total synthesis of the lindenane sesquiterpenoid dimers is the intermolecular Diels?Alder reaction between two lindenane-type monomers. Herein we report our efforts made on examination of the biogenetic hypothesis and the inverse-electron-demand Diels?Alder (IEDDA) reaction. The combination of Tf2NH/AlMe3 was developed to catalyze the model IEDDA reaction.
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