Synthesis pseudopterosine

The oxidative formation of p-benzoquinones from anilides such as 7-108 was used for the synthesis of the core scaffold of the natural products elisabethin A (7-106) and pseudopterosin A aglycone (7-107) (Scheme 7.30). Exposure of anilide 7-108 to DMP [53] led to the formation of the o-imidoquinone 7-109, which underwent an intramolecular Diels-Alder reaction to give 7-110 in 28% yield after hydration. In a competitive pathway, the p-quinone 7-111 is also formed from 7-108, which on heating in toluene again underwent an intramolecular Diels-Alder reaction to give cycloadduct 7-112 in 25% overall yield. Hydrolysis of 7-112 furnished the carbocyclic skeleton 7-113 of elisabethin A (7-106). 

Corey, E.J. Roberts, B.E. (1997B) Total synthesis of dysidiolide. J. Am. Chem. Soc., 119, 12425-31. Corey, E.J. Lazerwith, S.E. (1998) A direct and efficient streocontrolled synthetic route to the pseudopterosins, potent marine anti-inflammatojy agents. J. Am. Chem. Soc., 120, 12777-82. 

This methodology was applied to the total synthesis of naturally occurring compounds, epoxyquinomycin B (66) and BE-10988 (67) and synthetic studies on pseudopterosin A aglycone (68) and elisabethin A (69). 

Kocienski, P. J. Pontiroli, A. Qun, L. Enan-tiospecific syntheses of pseudopterosin agly-cones. Part 2. Synthesis of pseudopterosin K-L aglycone and pseudopterosin A-F agly-cone via a B-BA-BAC annulation strategy. 

Further studies on the synthesis of pseudopterosin A have been published recently L. Eklund, I. Sarvary and T. Frejd, J. Chem. Soc., Perkin. Trans. 1,1996, 303. 

Epoxy-ene cyclizations have been used as key steps in natural products synthesis. The preparations of pseudopterosin, a potent antiflammatory agent and analgesic <88JOCl584>, and (+)-aphidicolin <85TL6147,88JOC4929), (+ )-9,10-jyn- and (+)-9,10-an/i-copalol <92JOC4598> are representative examples of the synthetic utility of Lewis acid-catalyzed epoxide cyclizations. 

As pseudopterosins have proven to have a wide range of medical applications and while natural reserves are limited, extensive research was carried out towards their synthesis. Harrowven and coworkers [14] established an efficient synthesis of the tricyclic carbon skeleton. Two other research groups led by Corey [15] and Broka [16] developed a total enantiospecific synthesis of pseudopterosins. Broka and coworkers. 

Preliminary in vitro bioassay results demonstrate that pseudopterosin lA possesses additional significant biological activity [13]. For example lA has also been found to inhibit the synthesis of leukotrienes (human neutrophil cell studies), infering that it antagonizes lipogenase or enzymes higher in the arachidonic acid cascade, lliere are also indications that pseudopterosin lA inhibits degranulation in the same cells. 

Scheme 7 Total synthesis of the pseudopterosin aglycone 31 and the seco-pseudopterosin aglycone 42 according to Schmalz...

In a series of publications, Nicolaou and coworkers have demonstrated the utility of DMP for the selective oxidation of 4-substituted anilides 894 to p-quinones 895 and 2-substituted anilides 896 to < -azaquinones 897 (Scheme 3.360) [1289-1291], The first process was applied to the short, efficient total synthesis of epoxyquinomycin B [1290], while the second type of oxidation allowed rapid access to complex analogs of pseudopterosin and elisabethin natural products [1291],... 

Although many notable examples of nickel-catalyzed hydrovinylations have been described, their iterative use in the synthesis of the pseudopterosins provides a clear demonstration of the utility of this strategy (Scheme 3-94). In this impressive illustration, three sequential ligand-controlled hydrovinylation processes enable a highly efficient synthesis of the target molecule. 

Corey et al. reported a successful total synthesis of pseudopterosin E (116) through a crucial coupling reaction of 2-0-benzyl-3,4-di-0-p-methoxybenzoyl-a-L-fucosyl bromide (115) and catechol 114 the fucosylation of 114 with 115 proceeded in the complete position-selective and a-stereoselective manner, providing exclusively a-fucoside 116 (Scheme 20), and the a-stereoselectivity of the reaction was ascribed to the internal 1,4-remote participation of the p-methox-ybenzoyl group (Fig. 9) [72],... 

SCHEME 8.10 Total synthesis of pseudopterosin (G-J) aglycon by Sherburn et al. [30]. 

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