Prostaglandins are a family of biologically active lipid acids that possess as a common feature the prostan-1-oic acid structure ##STR2## Prostaglandins are grouped into the types E, F, A, B, C and D, based on the presence or absence of certain functionalities in the cyclopentane ring. The numerical subscripts, as in, for example, prostaglandin "E.sub.1 " and prostaglandin "E.sub.2, " refer to the number of unsaturated bonds in the side chains; the subscripts ".alpha." or ".beta." as in prostaglandin "F.sub.1.alpha. " or prostaglandin "F.sub.1.beta.," refer to the configuration of substituents in the ring.
Biological activities of the prostaglandins include stimulation of smooth muscle, dilation of small arteries, bronchial dilation, lowering of blood pressure, inhibition of gastric secretion, lipolysis, and platelet aggregation, induction of labor, abortion, and menstruation, and increase in ocular pressure. PGE.sub.1, specifically, is known as a bronchodilator and a vasodilator, and is also known to stimulate release of erythropoietin from the renal cortex and to inhibit allergic responses and blood-platelet aggregation. PGE.sub.2, the most common and most biologically potent of the mammalian prostaglandins, acts to contract the uterine muscle, to inhibit gastric acid secretion and protect the gastric mucosal lining and, like PGE.sub.1, has been established to be a bronchodilator and a stimulant of the release of erythropoietin from the renal cortex. Properties of the various prostaglandins have been reviewed extensively; see, e.g., Ramwell et al., Nature 221:1251 (1969).
Biosynthesis of the prostaglandins occurs by enzymatic conversion of unsaturated twenty-carbon fatty acids. For example, the endoperoxides PGG.sub.2 and PGH.sub.2 are prepared by the action of the enzyme complex prostaglandin cyclooxygenase on the lipid precursor arachidonic acid, while PGE.sub.1 is biosynthesized by enzymatic conversion of 8,11,14-eicosatrienoic acid. Biosynthetic studies of the prostaglandins are reviewed in Samuelsson, Prog. Biochem. Pharmacol. 5:109 (1969).
A number of synthetic routes to the various prostaglandins have been explored. A twenty-step synthesis to PGE.sub.2 and PGF.sub.2.alpha., starting with thallous cyclopentadiene, was developed by Corey et al. The process has also proved to be useful in the synthesis of the one-series prostaglandins. Catalytic reduction of bis-protected PGF2.alpha. results in selective saturation of the 5,6-double bond to afford ##STR3## followed by transformations leading to PGE.sub.1 and PGF.sub.1.alpha.. See, e.g., Corey et al., J. Am. Chem. Soc. 91:5675 (1969), Corey et al., J. Am. Chem. Soc. 92:2586 (1970) , and Corey et al., Tetrahedron Letters 307 (1970).
Another synthetic route uses norbornadiene as a starting material, while still another approach involves the use of racemic bicyclo[3.2.0]hept-2-en-6-one as a starting material. This latter synthesis involves an enantioconvergent approach, such that the following two enantiomers are used, obviating the need for optical resolution: ##STR4##
However, there remains a need in the art for a simpler and more direct route to the various prostaglandins, particularly prostaglandin E.sub.1, prostaglandin E.sub.2, and derivatives thereof. It is also desirable that such a synthesis provide the desired product in relatively high yield, be simple and straightforward to scale up, and involve inexpensive, commercially available reagents. The present invention is directed to such a method, and involves the use of a lithium copper reagent in a "one-pot" synthesis of PGE.sub.1, PGE.sub.2 and analogs thereof.