New phosphonate-mediated syntheses of cyclopentanoids and prostaglandins*

This account outlines the results obtained in the author’s laboratory on the application of phosphonate reagents in the synthesis of biologically active cyclopentanones and cyclopentenones. The synthesis and reactivity of 3-phosphorylmethyl-cycloalkenones is discussed as a platform for developing the first synthesis of enantiomeric isoterreins as well as the synthesis of racemic and optically active prostaglandins B1a. A different strategy for the total synthesis of racemic and enantiomeric forms of sarkomycin and rosaprostol is described which involves in a key step intramolecular carbenoid cyclization of the corresponding a-diazo-b-ketophosphonates. INTRODUCTION The cyclopentanone and cyclopentenone structural units are present in a wide range of important natural products such as jasmonoids, cyclopentanoid antibiotics and prostaglandins. The broad spectrum of biological activity of this type of compounds has prompted an extensive search for development of new methods of their preparation. Although structures of these natural products are relatively simple, their synthesis is not trivial because of the low chemical stability of many of these compounds and specific functionalization of the five-membered ring. As part of our broad program on the application of phosphorus and sulfur compounds in organic synthesis [1,2] we have also been engaged over the last decade or so in the invention and development of general methods for the synthesis of functionalized cyclopentanones and cyclopentenones. These endeavours have culminated in the elaboration of new and efficient routes to dihydrojasmone 1 [3], cis-jasmone 2 [4] and methylenomycin B 3 [5,6] (Scheme 1). The aim of the present account is to summarize the recent results obtained in the author’s laboratory on the phosphonate-mediated synthesis of both enantiomeric forms of isoterrein 4 and sarkomycin 5, racemic and optically active prostaglandins B1a 6 and racemic rosaprostol 7 (Schemes 2, 3). SYNTHESIS AND REACTIVITY OF BIS-b-KETOPHOSPHONATES AND 3(PHOSPHORYLMETHYL)-CYCLOALKENONES Before presenting our synthesis of isoterrein 4 and prostaglandin B1a 6, it seems desirable to discuss *Lecture presented at the 5th International Conference on Heteroatom Chemistry (ICHAC-5), London, Ontario, Canada, 5–10 July 1998, pp. 369–512. †Corresponding author: E-mail: [email protected] Scheme 1 briefly the synthesis of bis-b-ketophosphonates 8 and 3-(phosphorylmethyl)-cycloalkenones 9 as well as the reactivity of the latter [7]. These basic studies allowed the development of a new methodology for the synthesis of the targets 4 and 6 mentioned above. It was found that bis-b-ketophosphonates 8 could be easily obtained in the reaction between a-phosphonate carbanions and dicarboxylic acid esters. The intramolecular base-catalyzed cyclization of 8 afforded in good yields cycloalkenones 9 (Scheme 4). It is interesting to point out that the kinetically controlled product of this reaction is the Knoevenagel product 10 which is converted into the final Horner–Wittig reaction product 9 under basic reaction conditions. The structure of the cycloalkenone 9 offers many possibilities for further eleboration. Especially interesting is the reactivity of the anion derived from 9 because negative charge in this anion is distributed among several atoms as indicated by the hydrogen-deuterium exchange experiments. It was demonstrated that alkylation of this anion occurs at the a-carbonyl carbon atom, acylation takes place at oxygen, and carbonyl compounds react at the phosphonate carbon atom affording the HornerWittig olefination prducts.Selected examples illustrating the reactivity of the anion 9 are collected in Scheme 5. The ketophosphonate chemistry briefly presented above indicates that the cycloalkenones 9 can be easily functionalized and therefore can serve as synthetic intermediates in the synthesis of natural products. SYNTHESIS OF OPTICALLY ACTIVE ISOTERREIN (þ)-Terrein 11, a metabolite of Aspergillus terreus isolated in 1935 by Raistrick & Smith [8], belongs to the family of cyclopentanoids. Although its synthesis attracted considerable attention, only recently two research groups [9,10] succeeded in synthesizing enantiomeric (þ)-and (1)-terrein 11 (Scheme 6). 474 M. MIKOLAJCZYK et al. q 1999 IUPAC, Pure Appl. Chem. 71, 473–480 Scheme 2