Synthesis of A-Prostaglandins

In spite of the fact that PGA s show a potentially useful and different range of biological properties to those of the E- and F -series, until recently their direct total synthesis had received little attention. The discovery of PGAg in coral and the associated efforts at converting PGA into PGEj and PGFa have perhaps provided the impetus for the present interest in total PGA synthesis. 

Martel, E. Toromanoff, J. Mathieu, and G. Nomine, Tetrahedron Letters, 1972, 1491. 

Zusman has shown that PGB s can be formed from PGA s or PGE s by simple treatment of the latter with methanol. 

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Scheme 2.1.4.31 Asymmetric synthesis of a prostaglandin building block.

An approach to the synthesis of a prostaglandin intermediate began with 2-furanacetonitrile (71JOC3191). Friedel-Crafts acylation with pimelic half-ester acid chloride and Wolff-Kishner reduction of the product with concomitant hydrolysis of the nitrile group to acid yielded the diester (78) on diazomethane treatment. Ring opening of the furan by a standard procedure yielded a diketo diester (79) which on refluxing in aqueous methanolic potassium carbonate underwent hydrolysis and cyclization to the diacid (80 Scheme 19). 

These stable and easily handled alkenylmercurial compounds are important synthetic intermediates and can be used directly for the preparation of other alkenyl metallics. One such application is illustrated in Scheme 5 for the synthesis of a prostaglandin analogue 197). 

The conjugate addition forms a lithium enolate regiospeclfically, and that was why you met this sequence in Chapter 26. We showed you a dramatic use of the stereoselectivity there as weil, in a synthesis of a prostaglandin (p. 686). 

Further variations in dienophile have been equally successful (eqs 6 and 7), including applications to the Michael reaction (eq 7) and in the synthesis of a prostaglandin intermediate (eq8).i ... 

EUmimtion of iodohydrins. Treatment of the iodolactone (1) in dry pyridine with 1.3 eq. of mesyl chloride at -20° for 2 hr. and at 0° for 1.5 hr. affords the unsaturated lactone (2) in practically quantitative yield. The reaction provided a key step in the synthesis of A prostaglandins, which previously were available from the primary E prostaglandins by dehydration of the )S-kctol unit. 

Here is a synthesis of a prostaglandin analogue. Suggest reagents for the steps marked , give mechanisms for those not so marked, and explain any control of alkene geometry. 

Kinetic resolution on diastereoisomeric mixtures Comparison between enzymatic and classical resolution Asymmetric Synthesis of a Prostaglandin with many Chiral Centres... 

We end with a stereochemically involved synthesis of a prostaglandin 155. The racemic synthesis is summarised below - each compound is a single diastereoisomer and all from 146 to 155 are chiral but all are racemic as the synthesis starts with achiral materials. There are 14 steps in the synthesis and the final product 155 contains four chiral centres.37 If we want a single enantiomer, where should we resolve ... 

Furthermore, this regio- and stereoselective bond formation between unsaturated carbon atoms was applied to the synthesis of functionalized dienes under extremely mild conditions. Thus, even vinylic boronic esters containing an allylic acetal moiety and alkenylboronate having a chiral protected allylic alcohol were successfully accomplished with vinylic iodides under aqueous conditions in 60-90% yield [30]. In addition, an exceptionally simple and efficient synthesis of a prostaglandin (PGEj) precursor was reported by Johnson, applying a DMF/THF/ water solvent mixture with a bis(diphenylphosphino)ferrocene palladium catalyst [31]. It is curious that the presence of water is an absolute necessity in order to succeed in this approach (Scheme 3). 

A similar reaction using allylic amines has been employed in an elegant synthesis of a prostaglandin. The dimethylamino substituent directs alkylation to the 2-position while controlling the resulting stereochemistry. Addition of the carbon nucleophile is always... 

Becking L, Schafer HJ (1988) Synthesis of a prostaglandin precursor by nrixed Kolbe electrolysis... 

Elimination reactions in the synthesis of a prostaglandin, an antimalarial drug, and a female sex hormone (Section 8.4)... 

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