Synthesis of -Thromboxane

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). 

Synthesis of Prostaglandins via an Endoperoxide Intermediate Stereochemical Divergence of 

Prostaglandin biosynthesis from C20 polyunsaturated fatty acids occurs by way of the endoperoxides PGG2 and PGH2. 

A chemical synthesis of prostaglandins by a free radical pathway through an endoperoxide intermediate showed a strong stereochemical preference for the formation of the endoperoxides having cis alpha and omega appendages. 

---

In the first total synthesis of thromboxane A2, lactone 340 is opened by potassium trimethylsilanolate 97 to give the potassium salt 341 [120]. The potassium salt of the methoxymethyl ether of salicylic acid is prepared likewise [121], as are... 

Acetylsalicylic acid and related non-steroidal anti-inflammatory drugs (NSAIDs) selectively inhibit the cyclooxygenase activity of prostaglandin synthase [2] and consequently the synthesis of most eicosanoids. This explains their analgesic, antipyretic, and antirheumatic effects. Frequent side effects of NSAIDs also result from inhibition of eicosanoid synthesis. For example, they impair hemostasis because the synthesis of thromboxanes by thrombocytes is inhibited. In the stomach, NSAIDs increase HCl secretion and at the same time inhibit the formation of protective mucus. Long-term NSAID use can therefore damage the gastric mucosa. 

The potential of regioselective epoxide opening is shown in the ex-chiral-pool synthesis of thromboxane B2 from levoglucosan via epoxide opening as the key step. 

Effect on blood Platelets are the important factors in thrombus formation and aspirin has been shown to inhibit platelet aggregation. They reduce the blood prothrombin level by inhibition of prothrombin synthesis and prothrombin time is prolonged. The aspirin suppresses the synthesis of thromboxane (TXA ) in the platelets. They also prolong the bleeding time due to prevention of platelet aggregation which may be due to inhibition of release of adenosine diphosphate (ADP) from the platelets by salicylates. 

As described in Chapter 18, aspirin inhibits the synthesis of thromboxane A2 by irreversible acetylation of the enzyme... 

Meloxicam is an enolcarboxamide related to piroxicam that preferentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as celecoxib and may be considered "preferentially" selective rather than "highly" selective. The drug is popular in Europe and many other countries for the treatment of most rheumatic diseases and approved for treatment of osteoarthritis in the USA. It is associated with fewer clinical gastrointestinal symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, even at supratherapeutic doses its blockade of thromboxane A2 does not reach levels that result in decreased in vivo platelet function (see common adverse effects above). 

The chiral synthesis,219-221 by the use of monosaccharides, of optically active natural products having mainly branches of the B-type has now become common in organic chemistry. The reduction of alkylidene derivatives was actually used for the synthesis of thromboxane B2,222 cana-densolide,223 and a degradation product from boromycin.224... 

E. J. Corey, M. Shibazaki, and J. Knolle, Simple stereocontrolled synthesis of thromboxane B2, Tetrahedron Lett. p. 1625 (1977). 

Aspirin also prevents the synthesis of thromboxane which helps the platelet aggregation necessary in clot formation. 

Related Compounds, aspirin inhibits the synthesis of thromboxane A2 by irreversible acetylation of the enzyme cyclooxygenase. Other salicylates and nonsteroidal anti-inflammatory drugs also inhibit cyclooxygenase but have a shorter duration of inhibitory action because they cannot acetylate cyclooxygenase, ie, their action is reversible. 

The asymmetric hydrolysis of (exo,exo)-7-oxabicyclo[2.2.1]heptane-2,3-dimethanol, diacetate ester (37) to the corresponding chiral monoacetate ester (38) (Fig. 12B) has been demonstrated with lipases [61]. Lipase PS-30 from P. cepacia was most effective in asymmetric hydrolysis to obtain the desired enantiomer of monoacetate ester. The reaction yield of 75 M% and e.e. of >99% were obtained when the reaction was conducted in a biphasic system with 10% toluene at 5 g/liter of the substrate. Lipase PS-30 was immobilized on Accurel PP and the immobilized enzyme was reused (5 cycles) without loss of enzyme activity, productivity, or e.e. of product (38). The reaction process was scaled up to 80 liters (400 g of substrate) and monoacetate ester (38) was isolated in 80 M% yield with 99.3% e.e. The product was isolated in 99.5% chemical purity. The chiral monoacetate ester (38) was oxidized to its corresponding aldehyde and subsequently hydrolyzed to give chiral lactol (33) (Fig. 12B). The chiral lactol (33) obtained by this enzymatic process was used in chemoenzymatic synthesis of thromboxane A2 antagonist (35). 

Platelets Low doses of aspirin seem to preferentially inhibit synthesis of thromboxane A2, which normally promotes platelet aggregation. 

Coagulopathy is a common complication of liver disease. Synthesis of vitamin K and clotting factors is impaired in patients with cirrhosis and acute liver failure. Cirrhosis can also cause a reduced platelet synthesis of thromboxane-2, and a platelet adhesion defect is sometimes seen [8]. Cholestatic patients may have deranged clotting due to vitamin K malabsorption. 

Cox-1 is constitutively expressed and responsible for most of the housekeeping functions of eicosanoids, including processes such as calcium metabolism in the bone, and stomach mucous membrane maintenance. It is also responsible for synthesis of thromboxanes in thrombocytes and of prostacyclin (PGI) in endothelial cells, which have antagonistic function in thrombocyte aggregation and activation (see later). 

Many fruits contain salicylates, which inhihit the synthesis of thromboxane A2, and have an anticoagulant action, in amounts that provide the same intake as the low dose of aspirin used as prophylaxis against thrombosis. 

A useful application of this reaction to a cyclic alkene 2 constitutes the key step in the total synthesis of thromboxane B216. Starting from methyl a-D-glucopyranoside (1), 3,6-dihydro-2-hydroxymethyT6-methoxy-ATV-dimethyl-2/y-pyran-3-acetamide (2) is obtained pure in six steps. Treatment of the amide with 3 equivalents of iodine in tetrahydrofuran/water at 0 °C for 1 hour gives the iodolactone 3 in 80% yield. Deiodination with tributyltin hydride quantitatively affords the hydroxy lactone 4. 

Currently, the two antiplatelet agents with proven efficacy are aspirin, which inhibits cyclooxygenase -dependent synthesis of thromboxane Aj (TXj ), and ticlopidine, wdrich blocks the ability of ADP to inhibit stimulated adenyl cyclase. Bodi of these drags have proven prophylactic uses in reducing the risk of thrombo -occlusive and thromboembolic complications for all major arterial beds in individuals with a previous history of such episodes. Controlled trials show that both aspirin and ticlopidine are indicated in the secondary prevention of stroke, myocardial induction and peripheral vascular occlusion. However, there are limitations to their efficacy. No net changes in vascular events are seen with primary prevention. Moreover, antiplatelet drugs do not alter thrombocytopenia or impairment... 

---