Diastereoselective Total Synthesis of (+)-13-Stemarene by Fourth Generation Methods: A Formal Total Synthesis of (+)-18-Deoxystemarin

Abstract

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.

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

“…(+)-Podocarpic acid (4) was also converted into (+)-aphidicol-15-ene (36) [51] and into the Stemodia chilensis tetracyclic diterpenoid (+)-19-acetoxystemodan-12-ol (2f) allowing confirmation of the structure attributed to the latter only on the basis of NMR experiments [54]. (+)-Podocarpic acid (4) was then extensively used in the work which led to the synthesis of (+)-stemar-13-ene (57) and (+)-18-deoxystemarin (3b) [55,56,59,60,62]. (+)-Podocarpic acid (4) was also converted into (+)-2-deoxyoryzalexin S (66) [69].…”

“…After 24 h the rearrangement of 33 to (+)-63 was completed (see Section 8.6). Thioacetalization of (+)-63 by standard procedures afforded then (+)-64 which was desulphurized to (+)-57 [55,62]. The remarkable feature of this approach is that, owing to the stereospecificity of the rearrangement and to the 1-methyl-6-hydroxybicyclo[2.2.2]octan-2-ones endo/exo equilibrium, the whole endo/exo mixture 33 is converted into the rearrangement product in which the C(13)-C(14) double bond is also present, a characteristic feature of some stemarane diterpenoids such as (+)-oryzalexin S (65) (Figure 4) [63,64] (induced in rice leaves in response to the invasion of the fungus Pyricularia oryzae or when exposed to UV radiation or heavy metals [65]) and a necessary tool for the introduction of the α-configured HO-C(13) if necessary.…”

“…After 24 h the rearrangement of 33 to (+)-63 was completed (see Section 8.6). Thioacetalization of (+)-63 by standard procedures afforded then (+)-64 which was desulphurized to (+)-57 [55,62]. …”

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

“…In the course of our work on bioactive natural products and bioactive materials [117][118][119][120][121][122][123][124], it occurred to us to observe the partial racemization of (+)-5 during the acetalization of (+)-1 with 1,2-ethanediol and TsOH in the presence of a Dean-Stark apparatus. According to our best knowledge, obtaining partially racemized (+)-5 or (−)-5 when the acetalization reaction is carried out by this procedure on (+)-1 or (-)-1 [33,35,39,40,44,48,49,72,77,81,84,87-91,116], respectively, has not been previously reported in the literature, which was the reason behind investigating this reaction.…”

“…According to our best knowledge, obtaining partially racemized (+)-5 or (−)-5 when the acetalization reaction is carried out by this procedure on (+)-1 or (-)-1 [33,35,39,40,44,48,49,72,77,81,84,87-91,116], respectively, has not been previously reported in the literature, which was the reason behind investigating this reaction. In the course of our work on bioactive natural products and bioactive materials [117][118][119][120][121][122][123][124], it occurred to us to observe the partial racemization of (+)-5 during the acetalization of (+)-1 with 1,2-ethanediol and TsOH in the presence of a Dean-Stark apparatus. According to our best knowledge, obtaining partially racemized (+)-5 or (−)-5 when the acetalization reaction is carried out by this procedure on (+)-1 or (-)-1 [33,35,39,40,44,48,49,72,77,81,84,[87][88][89][90][91]116], respectively, has not been previously reported in the literature, which was the reason behind investigating this reaction.…”