Stemodane Diterpenes and Diterpenoids: Isolation, Structure Elucidation, Biogenesis, Biosynthesis, Biological Activity, Biotransformations, Metabolites and Derivatives Biological Activity, Rearrangements.

The scientific activity carried out over forty-five years on stemodane diterpenes and diterpenoids structure elucidation, biogenesis, biosynthesis, biological activity and biotransformations was reviewed.

Unexpected Racemization in the Course of the Acetalization of (+)-(S)-5-Methyl-Wieland-Miescher Ketone with 1,2-Ethanediol and TsOH under Classical Experimental Conditions.

(+)-(S) and (-)-(R)-5-methyl-Wieland-Miescher ketone (+)-1 and (-)-1, are important synthons in the diastereo and enantioselective syntheses of biological and/or pharmacological interesting compounds. A key step in these syntheses is the chemoselective C(1)O acetalization to (+)-5 and (-)-5, respectively. Various procedures for this transformation have been described in the literature. Among them, the classical procedure based on the use of 1,2-ethanediol and TsOH in refluxing benzene in the presence of a Dean-Stark apparatus. Within our work on bioactive natural products, it occurred to us to observe the partial racemization of (+)-5 in the course of the acetalization of (+)-1 by means of the latter methodology. Aiming to investigate this drawback, which, to our best knowledge, has no precedents in the literature, we acetalized with 1,2-ethanediol and TsOH in refluxing benzene and in the presence of a Dean-Stark apparatus under various experimental conditions, enantiomerically pure (+)-1. It was found that the extent of racemization depends on the TsOH/(+)-1 and 1,2-ethanediol/(+)-1 ratios. Mechanism hypotheses for this partial and unexpected racemization are provided.

Stemarane Diterpenes and Diterpenoids.

: In this article the scientific activity carried out on stemarane diterpenes and diterpenoids, isolated over the world from various natural sources, was reviewed. The structure elucidation of stemarane diterpenes and diterpenoids was reported, in addition to their biogenesis and biosynthesis. Stemarane diterpenes and diterpenoids biotransformations and biological activity was also taken into account. Finally the work leading to the synthesis and enantiosynthesis of stemarane diterpenes and diterpenoids was described.

(+)-Podocarpic Acid as Chiral Template in the Synthesis of Aphidicolane, Stemodane and Stemarane Diterpenoids †.

In this review the synthetic work in the field of aphidicolane, stemodane and stemarane diterpenoids, in which readily available (+)-podocarpic acid (4) was used as chiral template for the construction of their polycyclic structures, is described as it developed along the years. In the frame of this work (+)-podocarpic acid (4) was a very useful tool in a model study leading to the syntheses of tetracyclic ketones 7 and 8, models of key intermediates 5a and 6 in the syntheses of (+)-aphidicolin (1) and (+)-stemodin (2a), respectively. (+)-Podocarpic acid (4) was also converted into (+)-2-deoxystemodinone (2d), allowing confirmation of the stemodane diterpenoids absolute configuration, into (+)-aphidicol-15-ene (36) and into Stemodia chilensis tetracyclic diterpenoid (+)-19-acetoxystemodan-12-ol (2f), allowing confirmation of its structure. (+)-Podocarpic acid (4) was then extensively used in the work which led to the synthesis of (+)-stemar-13-ene (57) and (+)-18-deoxystemarin (3b). Finally, (+)-4 was converted into (+)-2-deoxyoryzalexin S (66), which made it possible to demonstrate that the structure of (+)-66 could not be attributed to a Chilean Calceolaria isolated diterpenoid to which this structure had been assigned.

Proof of the Structure of the Stemodia chilensis Tetracyclic Diterpenoid (+)-19-Acetoxystemodan-12-ol by Synthesis from (+)-Podocarpic Acid: X-ray Structure Determination of a Key Intermediate.

The first synthesis of (+)-19-acetoxystemodan-12-ol (1), a stemodane diterpenoid isolated from Stemodia chilensis, is described. The structure was supported by an X-ray crystallographic analysis of intermediate (+)-9a, which confirmed the proposed structure and excluded the structure of (-)-19-hydroxystemod-12-ene as a possible candidate for the Chilean Calceolaria diterpenoid to which the (-)-19-hydroxystemar-13-ene structure (9b) had been erroneously assigned.

Diastereoselective total synthesis of (+)-13-stemarene by fourth generation methods: a formal total synthesis of (+)-18-deoxystemarin.

The problem of constructing diastereoselectively the C/D ring system of stemarane diterpenes from a bicyclo[2.2.2]octane intermediate was solved resulting in very simple synthesis of (+)-13-stemarene 1. The obtaining of the latter represents also a formal synthesis of (+)-18-deoxystemarin 2. In the key step, the epimeric mixture 10, dissolved in toluene, was converted by the action of TsOH into (+)-stemar-13-en-15-one 28.

Spectroscopic characterization of 6-hydroxy and 1-methyl-6-hydroxybicyclo[2.2.2]octan-2-one ethylene acetals and ethylene dithioacetals.

6-endo- and 6-exo-Hydroxybicyclo[2.2.2]octan-2-one and 1-methyl-6-endo- and 6-exo-hydroxybicyclo[2.2.2]octan-2-one ethylene acetals and ethylene dithioacetals 1-4 have been characterized by 1D and 2D NMR methods.

Elusive 6-exo-Hydroxybicyclo[2.2.2]octan-2-ones from the corresponding acetates by methanolysis in the presence of CH(3)ONa/La(OTf)(3).

[reaction: see text] A series of 6-exo-acetoxybicyclo[2.2.2]octan-2-ones were converted into the corresponding 6-exo-hydroxybicyclo[2.2.2]octan-2-ones by methanolysis in the presence of CH(3)ONa/La(OTf)(3). Under the given conditions, epimerization at C(6) of the latter led in the least favorable cases only to traces of the more stable 6-endo-hydroxybicyclo[2.2.2]octan-2-ones. This procedure, when combined with the described conversion of easily available 6-endo-hydroxybicyclo[2.2.2]octan-2-ones into the corresponding 6-exo-acetoxy derivatives, provides a convenient route to elusive 6-exo-hydroxybicyclo[2.2.2]octan-2-ones. Applications to total synthesis are shown and envisaged.