No abstract

Total synthesis of (±)-methyl atis-16-en-19-oate (5c), a tetracyclic diterpenoid possessing a bicyclo[2.2.2]octane ring system, was accomplished. Intramolecular Diels−Alder reaction of tetraene 14 was employed in a construction of kaurene skeleton 13. The pivotal step involved a homoallyl−homoallyl radical rearrangement process of (±)-methyl 12-hydroxykaur-16-en-19-oate monothioimidazolide 12, which led to 5c in good yield. Interestingly, treatment of methyl 12-oxo-kaur-16-en-19-oate 30 with hydrazine monohydrate in the presence of KOH in bis(ethylene glycol) at 200 °C resulted in cyclopropanation to furnish, directly, trachyloban-19-oic acid (4b), together with kaur-16-en-19-oic acid (6b).

To solve the drawback (considerable decrease in yield on a large scale) of cycloalkenylation employing stoichiometric amounts of Pd(OAc) 2 , a novel palladium-catalyzed cycloalkenylation has been developed. Stereoselective total syntheses of several bioactive terpenoids have been achieved by means of the above catalytic reaction.

Total syntheses of serofendic acids A (1a) and B (1b) are described. The key strategic element of the approach involves the novel tin-free homoallyl-homoallyl radical rearrangement of 5 for the construction of bicyclo[2.2.2]octane ring system 4. In addition, the conversion of methyl atisirenoate 2 to serofendic acids A (1a) and B (1b) was achieved on the basis of the Michael reaction of sodium thiomethoxide.[reaction: see text]

Asymmetric total syntheses of (-)-methyl atis-16-en-19-oate (1c), (-)-methyl kaur-16-en-19-oate (2c), and (-)-methyl trachyloban-19-oate (3c) have been achieved by employing a hybrid strategy of palladium-catalyzed cycloalkenylation and homoallyl-homoallyl radical rearrangement. The common synthetic intermediate 5 was prepared from 2-allylcyclohexanone (4) with 98% ee using d'Angelo's asymmetric Michael addition. A series of functional group modifications in 5 via palladium-catalyzed cycloalkenylation led to (+)-14, which had already been prepared by us as racemate. (-)-Methyl atis-16-ene-19-oate (1c) was generated via homoallyl-homoallyl radical rearrangement. On the other hand, Wolff-Kishner reduction of 18 followed by esterification yielded (-)-methyl kaur-16-en-19-oate (2c) together with (-)-methyl trachyloban-19-oate (3c).

Full details of three approaches to an entirely regio- and stereoselective synthesis of the well-known target reserpine are described, culminating in a total synthesis which efficiently meets these requirements.

A six-step formal total synthesis of a natural alkaloid, mappicine (3), has been achieved. The highlight of our synthetic strategy is an intramolecular hetero Diels-Alder reaction that was used for the construction of the CD ring system of mappicine (3). In addition, it was demonstrated that the Sonogashira coupling reaction of 2-chloro-3-hydroxymethylquinoline (8c) with trimethylsilylacetylene proceeded at room temperature in excellent yield.

[reaction: see text] Bicyclo[4.3.0]nonanes (hydrindanes) and bicyclo[3.3.0]octanes (octahydropentalenes) are easily synthesized by palladium-catalyzed cycloalkenylations. Additionally, benzo-fused bicyclo[3.3.0]octanes are prepared for the first time through intramolecular coupling between silyl enol ethers and aromatic rings in the presence of catalytic palladium acetate.