Thromboxane

Three recent syntheses of thromboxane B2 (66) share the common feature that they all begin with compounds readily prepared from inexpensive methyl a-D-glucopyranoside (8 a) and work towards the lactone (65). The route from (65) to thromboxane B2 (66) follows the standard methodology developed by Corey (12). 

The Eschenmoser or Ireland variations of the Claisen rearrangement used by Corey and co-workers gave very good yields of the substituted hex-2-enopyranoside (73). On the other hand, Hernandez used the Johnson variation of the Claisen and obtained lower yields. This is not surprising in view of the pronounced sensitivity of hex-2-enopyranosides (e. g. 73) to acid conditions such as those required in this variation. 

In both routes, the carboxylic substance (73) was subjected to iodo-lactonisation giving (74) which was then reduced to the lactone (65) described above, and converted into thromboxane (66) as previously described 63). 

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Prostaglandins belong to a group of compounds that because they are related to icosanoic acid [CH3(CH2)i8C02H)] are collectively known as icosanoids The other icosanoids are thromboxanes prostacyclins and leukotrienes... 

ANALGESICS,ANTIPYRETICS,ANDANTIINFLAL TATORYAGENTS] (Vol2) Thromboxane A2 [57576-52-0]... 

They release adenosine diphosphate [58-64-0 (ADP) and thromboxane [57576-52-0] which results in vascular contraction and, indirectiy, in the formation of fibrin clot. Platelet transfusions are indicated for patients with thrombocytopenia, ie, a shortage of healthy platelets or thrombocytopathy, ie, platelet malignancy associated with spontaneous hemorrhages. 

The enzyme system responsible for the biosynthesis of PGs is widely distributed in mammalian tissues and has been extensively studied (2). It is referred to as prostaglandin H synthase (PGHS) and exhibits both cyclooxygenase and peroxidase activity. In addition to the classical PGs two other prostanoid products, thromboxane [57576-52-0] (TxA ) (3) and prostacyclin [35121 -78-9] (PGI2) (4) are also derived from the action of the enzyme system on arachidonic acid (Fig. 1). 

The nomenclature of prostaglandins and prostacyclins is based on the basic prostane skeleton (11), whereas thromboxane (12) is the parent for the thromboxanes. 

Both thromboxane A (TXA2) and prostacyclin (PGI2) are extremely unstable compounds. The iastabiUty of TXA2 (3) is due to the strained bicycHc acetal system. Hydrolysis of the acetal to give TXB2 (15) releases the strain. 

Thromboxanes. Because of its highly unstable nature, TXA2 (3) eluded total synthesis until 1985. However, following the disclosure in 1975 of its proposed stmcture and pharmacological importance, a great deal of effort was expended to develop syntheses of its stable metaboHte, TXB2 (15). A practical, short synthesis (220) from the 9,15-diacetate of PGF2Q, (89) follows. 

C. R. P2Lce-Ascx2lk, Advances in Prostaglandins, Thromboxane andEeukotriene Research, Vol. 18, Raven Press, New York, 1989. 

B. Samuelsson and R. Paoletti, eds. Fidvances in Prostaglandin, Thromboxane andFeukotriene Kesearch, Vol. 9, Raven Press, New York, 1982. 

New Synthetic Routes to Prostaglandins and Thromboxanes, S. M. Roberts and F. Scheinmann Eds. Academic Press London, 1982. 

Thromboxane A2 is a potent platelet aggregating agent and vasodilator which undergoes rapid hydrolysis under physiological conditions (ti/2 32 sec. at pH 7 and 37°C). The synthesis of stable analogs was of interest for biological studies of this potent but evanescent prostanoid. 

The synthesis of thromboxane Bj, the hydrolytic deactivation product of thromboxane A2, provided this material for studies of metabolism and bioactivity, and also for the development of a radioimmunassay. Two different synthetic routes were developed. 

A stereocontrolled route to the native form of thromboxane B2 was carried out starting with a-methyl-D-glucoside (Ref. 3). 

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