Revision of the Stereochemistry of Elisabethatriene, a Putative Biosynthetic Intermediate of Pseudopterosins

Abstract

In the past, we have questioned the accuracy of the stereochemistry of elisabethatriene, a putative biosynthetic intermediate of pseudopterosins, in light of the configuration of elisabethatrienol isolated from Pseudopterogorgia elisabethae, which was represented as 1S,4R,9S,11S. We have reinvestigated the stereochemistry of elisabethatriene. Elisabethatriene with the reported 1S,4R,9R,11S configuration was synthesized starting from ( )-isopulegol in its enantiomeric form. The 1 H-and 13 C-NMR data of the synthesized compound differed from those reported for elisabethatriene. In addition to the fact that elisabethatriene is converted into pseudopterosins, this finding has allowed us to propose that elisabethatriene should have the 1S,4R,9S,11S stereochemistry, which is identical to that of elisabethatrienol.Key words elisabethatriene; elisabethatrienol; pseudopterosin; Pseudopterogorgia elisabethae Pseudopterosins are glycosylated tricyclic diterpenes isolated from marine octocoral, Pseudopterogorgia elisabethae, and more than thirty compounds in this class have been reported 1) since the first isolation of pseudopterosins A-D.2) Our group reported the isolation and characterization of pseudopterosins P-V as well as related non-glycosylated diterpenes, including elisabethatrienol (1) and seco-pseudopterosin K from P. elisabethae collected in San Andres and Providencia Islands in the Colombian Caribbean.3,4) It has been reported that pseudopterosin A displays potent anti-inflammatory activity 2) by inhibiting both phospholipase A2 and 5-lipoxygenase. 5)The biosynthesis of pseudopterosins was studied by Kerr's group. 6) These researchers reported the formation of a bicyclic compound named elisabethatriene (2a) upon incubation of geranylgeranyl diphosphate (GGPP) with a cell free preparation of P. elisabethae. Elisabethatriene has four stereogenic centers that were represented as 1S,4R,9R,11S (the pseudopterosin numbering system is applied). 7) These researchers also reported that incubation of elisabethatriene with the same preparation yielded erogorgiaene (3), 8) which was further converted to pseudopterosins 8) (Chart 1). Elisabethatrienol (1), a hydroxylated analogue of elisabethatriene, isolated by our group was determined to have the 1S,4R,9S,11S configuration on the basis of detailed nuclear Overhauser effect (NOE) experiments.4) It is of note that compounds elisabethatrienol and elisabethatriene have the opposite configuration at C-9, even though the stereogenic center disappears in the following intermediate 3. This finding raised the possibility that elisabethatriene could have the 1S,4R,9S,11S configuration (namely compound 4) rather than the reported 1S,4R,9R,11S configuration, since it would be reasonable to assume that the identical stereochemical mechanism is operating in the cyclization of GGPP leading to the two compounds. 4)In this article, we report the results from the reinvestigation of the stereochemistry that was reported for elisabethatriene. This study establishes that the stereochemistry o...

Diels‐Alder Reaction of Cyclopenta‐1,3‐diene and Anthracene to bis‐Fumarates Derived from Menthol Analogues

“…The series of known chiral auxiliaries menthol (‐)‐ 1 a , isopulegol (‐)‐ 1 b , 8‐Me‐menthol (‐)‐ 1 c ([α] D 20 =‐38.5, c=1.0, CHCl 3 . For several signals, our 13 C‐NMR attributions based on DEPT experiments, differ from the multiplicities earlier reported: 73.2 ( d ); 53.3 ( d ); 46.8 ( t ); 35.0 ( t ); 32.9 ( s ); 31.8 ( d ); 29.4 (3 q ); 26.5 ( t ); 22.0 ( q )), 8‐Ph‐menthol (‐)‐ 1 d , (For others 8‐substituted‐menthyl derived dienophiles),,, cyclopropyl‐isopulegol (‐)‐ 1 e , (Although they may eventually be used as diastereoisomeric mixtures, the possible but tedious chromatographic separation of both diastereoisomers of the hydrogenated (1 R ,2 S ,5 R )‐5‐methyl‐2‐(( R )‐6‐methylheptan‐2‐yl)cyclohexan‐1‐ol (‐)‐ 1 f precludes their use as potentially efficient candidates due to purification/analytical reasons, prior to auxiliary cleavage), pulegol (‐)‐ 1 g , and cyclopropylpulegol (‐)‐ 1 h ([α] D 20 =‐48.9, c=1.2, CHCl 3 ) were either prepared according to the literature, or directly purchased, when commercially available. Some of their bis ‐fumarates, such as (‐)‐ 2 a ,, (‐)‐ 2 b , and (‐)‐ 2 d , were already reported, while we prepared the analogous new dienophiles (‐)‐ 2 e (56% yield), and (‐)‐ 2 f (55% yield), by acylation with a half equivalent of bis ‐fumaroyl chloride in refluxing toluene in the presence of equimolar AgCN …”

Enantioselective Access to Robinson Annulation Products and Michael Adducts as Precursors

“…Recently, the same strategy was used for the alkylation of the chiral cyclohexanone 96 derived from (+)-neoisopulegol (Scheme 32). [89] Treatment of the 1,5-diketone 97 with Ba(OH) 2 lead to the cyclization to the bicyclic enone 98 in a moderate yield. Final Tebbe olefination yields the enantiomer of elisabethatriene.…”

Enantioselektive Synthese von Robinson‐Anellierungsprodukten und Michael‐Addukten als Vorstufen

“…[89] Die Umsetzung des 1,5-Diketons 97 mit Ba(OH) 2 führte zur Cyclisierung zum bicyclischen Enon 98 in moderater Ausbeute.Durch eine Te bbe-Olefinierung wurde schließlich das Enantiomer von Elisabethatrien erhalten. [89] Die Umsetzung des 1,5-Diketons 97 mit Ba(OH) 2 führte zur Cyclisierung zum bicyclischen Enon 98 in moderater Ausbeute.Durch eine Te bbe-Olefinierung wurde schließlich das Enantiomer von Elisabethatrien erhalten.…”

“…Die gleiche Strategie wurde fürd ie Alkylierung des chiralen Cyclohexanons 96 genutzt, das aus (+ +)-Neoisopulegol hergestellt wurde (Schema 32). [89] [104] Nach der Umwandlung einiger funktioneller Gruppen erfolgte die Robinson-Anellierung durch die Lewis-Säure-katalysierte Enon-Alkohol-Methode. [44,45] Das bicyclischeE non 134,d essen Enantiomerenreinheit durch die Mosher-Ester-Methode bestimmt wurde,k onnte über sechs weitere Stufen in Sporogen AO-1 umgewandelt werden.…”