Synthesis prostaglandins

Our hope is that LHASA will help us to insure that we have considered all reasonable routes to our major products. 

The LHASA project has been in existence since 1968. During the years a number of extraordinately able graduate students and post doctoral fellows came to work with Professor Corey, almost all laboratory synthetic chemists. Whether it is the infectious enthusiasm for the project or just an enjoyment of using the computer as a research tool, not one alumnus of the LHASA project has abandoned his involvement with computers and returned to bench chemistry. They are (with current locations) 

Barth - Harvard Business School W. L. Jorgensen - Purdue R. D. Cramer - Smith Kline and French W. Todd Wipfce - Santa Cruz 

ACS Symposium Series American Chemical Society Washington, DC, 1977. 

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Review Problem 14 Cyclopentenones (e.g. TM 190) occur in nature and are important in prostaglandin synthesis. How would you make this one ... 

In the prostaglandin synthesis shown, silyl enol ether 216, after transmetaJ-lation with Pd(II), undergoes tandem intramolecular and intermolecular alkene insertions to yield 217[205], It should be noted that a different mechanism (palladation of the alkene, rather than palladium enolate formation) has been proposed for this reaction, because the corresponding alkyl enol ethers, instead of the silyl ethers, undergo a similar cyclization[20I],... 

The class III cytokine receptor family includes two TNE receptors, the low affinity NGE receptor and 7-ceU surface recognition sites that appear to play a role in proliferation, apoptosis, and immunodeficiency. TNE-a (- 17, 000 protein) is produced by astrocytes and microglia and can induce fever, induce slow-wave sleep, reduce feeding, stimulate prostaglandin synthesis, stimulate corticotrophin-releasing factor and prolactin secretion, and reduce thyroid hormone secretion. TNE-a stimulates IL-1 release, is cytotoxic to oligodendrocytes, and reduces myelination this has been impHcated in multiple sclerosis and encephalomyelitis. Astrocyte TNE-a receptors mediate effects on IL-6 expression and augment astrocytic expression of MHC in response to other stimulants such as lEN-y. 

To control the stereochemistry of epoxidation at the 10,11-double bond in intermediates in prostaglandin synthesis, a bulky protective group was used for the C15-OH group. Epoxidation of the tribenzylsilyl ether yielded 88% a-oxide epoxidation of the tri-/ -xylylsilyl ether was less selective. ... 

In a prostaglandin synthesis a carbonyl group was protected as an oxime in which the hydroxyl group was protected against Collins oxidation by the phenylthiome-thyl-group. The phenylthiomethyl group is readily removed to give an oxime that is then cleaved to the carbonyl compound. ... 

J. S. Bindra and R. Bindra, Prostaglandin Synthesis, Academic Press London, 1977. 

Fluormated agents such as flurbiprofen (II), flunisal(i2), diflunisal (13), and sulindac (14), acting as prostaglandin synthesis mhibitors, have been available for some time [5] The recent introduction of flunoxaprafen (15), a lipoxygenase inhibitor, is notable It reportedly produces considerably less severe gastric disturbance [75]... 

Take Two Aspirin and. . Inhibit Your Prostaglandin Synthesis... 

A key transformation in Corey s prostaglandin synthesis is a Diels-Alder reaction between a 5-(alkoxymethyl)-l,3-cyclopenta-diene and a ketene equivalent such as 2-chloroacrylonitrile (16). As we have already witnessed in Scheme 3, it is possible to bring about a smooth [4+2] cycloaddition reaction between 5-substituted cyclopentadiene 15 and 2-chloroacrylonitrile (16) to give racemic 14 as a mixture of epimeric chloronitriles. Under these conditions, the diastereomeric chloronitriles are both produced in racemic form because one enantiotopic face of dienophile 16 will participate in a Diels-Alder reaction with the same facility as the other enantiotopic face. In subsequent work, Corey s group demonstrated that racemic hydroxy acid 11, derived in three steps from racemic 14 (see Scheme 3), could be resolved in a classical fashion with (+)-ephe-... 

For an informative discussion and a compilation of leading references, see Bindra, J. S. Bindra, R. Prostaglandin Synthesis, Academic Press New York, 1977, p. 7. 

Scheme 5. Larock s palladium-promoted, three-component coupling strategy for prostaglandin synthesis.

Bradykinin stimulates natriuresis and, through stimulation of prostaglandin synthesis, inhibits the actions of antidiuretic hormone (ADH), thereby inhibiting water retention. Bradykinin further improves insulin sensitivity and cellular glucose utilization of skeletal muscle cells in experimental models. This, however, appears not to be relevant in the clinical context. 

Dronabinol (tetrahydrocannabinol), the active principle from cannabis and synthetic cannabinoids, nabilone and levonantradol are effective in treating nausea and vomiting in cancer chemotherapy. The mode of action is unclear but appears to involve cannabinoid CBi receptors. Cannabinoids have been shown to reduce acetylcholine release in the cortex and hippocampus, and have been suggested to inhibit medullary activity by a cortical action. Inhibition of prostaglandin synthesis and release of endorphins may also be involved in the antiemetic effect. A review of trials of dronabinol, nabilone or levonantradol concluded that while the cannabinoids were superior to placebo or dopamine receptor antagonists in controlling emesis... 

Vane JR (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 231 232-235... 

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