Synthesis of prostaglandins

After two reaction steps, the prostaglandin 204 was isolated in a yield greater than 50% as a single diastereoisomer. Furthermore, the alkylation reaction on the Merrifield resin gave only poor results. A macroporous resin proved to be more appropriate for this reaction sequence. 

Reagents and conditions i) R -BBN, Pd(0), K2CO3 ii) vinyl cuprate Mi) L-selectrkle iv) TBAF 

Multicomponent assembly strategies with single functional group liberation 

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The prochiral meso form of 2-cyclopenlen-1,4-diol (101) reacts with the (Z)-alkenyl iodide 102 to give the 3-substituted cyclopentanone 103 with nearly complete diastereoselectivity (98 2)[92], The reaction is used for the synthesis of prostaglandin. The alkenyl iodide 102 must be in the Z form in order to obtain the high diastereoselectivity. The selectivity is low when the corresponding (Z)-alkenyl iodide is used[93]. 

Cyclohexane-la,3a,5a-triol (i j -hexahydrophloroglucinol, a-phloroglucite) is a starting material in Woodward s synthesis of prostaglandin 2oc and... 

Fig. 6. Synthesis of prostaglandins via a bicyclo[3.1.0]hexane intermediate where MCPBA = m — chloroperbenzoic acid.

Fig. 7. Synthesis of prostaglandins via cleavage of polycyclic intermediates where R = HC=CHCH(OSi(CH3 )2 C( CH3 )3) C5. ...

Since nonsteroidal antiinflammatory dmgs, such as aspirin, an inhibitor of the synthesis of prostaglandins, will block the diuretic effects of furosemide, their concomitant use should be avoided (13,117). 

A. Mitra, The Synthesis of Prostaglandins, J. Wiley-lnterscience New York, 1977. 

The synthesis of prostaglandin Ei in the naturally occurring leva form was achieved by a modification of the sequence described above in which the racemic amine A was resolved with (-)-oc-bromocamphor-Tt-sulfonic acid. The enantiomer of the natural PGEi ([a]57g+57° (cO.5, THE)) was also synthesized (Ref. 3). 

In the early work on the synthesis of prostaglandins, zinc borohydride was used for the reduction of the 15-ketone function and a 1 1 mixture of epimeric 15(S)- and 15(/ )-alcohols was generally obtained. Subsequent studies led to reaction conditions for highly selective reduction to the desired 15(S)-alcohol. Some of the results are summarized in the following table. The most practical method is E which utilizes borane as the stoichiometric reductant and a chiral, enzyme-like catalyst which is shown. 

Total Synthesis of Prostaglandin A2 and Conversion to Other Prostaglandins... 

Synthesis of Prostaglandins via an Endoperoxide Intermediate Stereochemical Divergence of... 

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. 

The same mixture of H and I was obtained starting with either of the geometrically isomeric radical precursors E or F. A possible explanation is based on the assumption of a common radical conformer G, stabilized in the geometry shown by electron delocalization involving the radicaloid p-orbital, the p-peroxy oxygen and Jt of the diene unit. The structure of the compounds H and I were determined by H NMR spectra and the conversion of H to diol J, a known intermediate for the synthesis of prostaglandins. 

In this bromoaspirin-inactivated structure, Ser , which lies along the wall of the tunnel, is bromoacetylated, and a molecule of salicylate is also bound in the tunnel. Deep in the tunnel, at the far end, lies Tyr, a catalytically important residue. Heme-dependent peroxidase activity is implicated in the formation of a proposed Tyr radical, which is required for cyclooxygenase activity. Aspirin and other NSAIDs block the synthesis of prostaglandins by filling and blocking the tunnel, preventing the migration of arachidonic acid to Tyr in the active site at the back of the tunnel. 

The Michael acldiQon of rutromethane to cyclopentenone clenvaQves is used for synthesis of prostaglandins fScheme 4 20 Here, the aruon of rutromethane is used as a formyl aruon synthon... 

Aspirin and other NSAIDs function by blocking the cyclooxygenase (COX) enzymes that carry out the body s synthesis of prostaglandins (Sections 7.11 and 27.4). There are two forms of the enzyme, COX-1, which carries out the normal physiological production of prostaglandins, and COX-2, which mediates the body s response to arthritis and other inflammatory conditions. Unfortunately, both COX-1 and COX-2 enzymes are blocked by aspirin, ibuprofen, and other NSAIDs, thereby shutting down not only tire response to inflammation but also various protective functions, including the control mechanism for production of acid in the stomach. 

The promising transformation shown in Scheme 7 and some subsequent Studies14 provided the basis for an elegant synthesis of (+)-prostaglandin F2a [(+)-PGF2a] (45 in Scheme 8).15 In the crucial... 

Alkenylcuprates bearing a stereogenic center at the y-position were prepared and used for the synthesis of prostaglandin derivatives. Thus, the conjugate addition of 1 to chiral 2 followed by protonation gave 3 with very high diastereoselectivity623,81. 

In a study concerned with the synthesis of prostaglandins, it was reported that the anion of 3-phenylsulfinyl-l-octene underwent addition to 2-cyclopentenone to give a y-1,4-adduct (57%), which appeared to be a single diastereomer by 13C NMR16... 

An analogous study concerned with the synthesis of prostaglandin analogs was also highly diastereoselective. The initial anionic adducts were quenched with various aldehydes, however, the diastereoselectivity at the carbinol stereocenter was not reported21. 

The diastereoselective addition of [(S)-3-alkoxy-l-octenyl]lithium to an enantiomerically pure cyclic y-(rer/-butyldimethylsilyloxy)-o(,/S-unsaturated sulfone was employed in the synthesis of ( )-prostaglandin E219, with addition occurring exclusively anti to the sterically demand-... 

One of the first uses of the allylic sulfoxide-sulfenate interconversion was made by Jones and coworkers64, who reported exclusive suprafacial rearrangement of the allyl group in the steroidal sulfoxide 17 shown in equation 13. Two other examples are shown in equations 1465 and 1566. Evans and coworkers have demonstrated the utility of the suprafacial allylic sulfoxide-sulfenate rearrangement in a new synthesis of the tetracyclic alcohol 24 (equation 16)67, as well as in a synthesis of prostaglandin intermediates as shown in equation 1768. The stereospecific rearrangement of the unstable sulfenate intermediate obtained from the cis diol 25 indicates the suprafacial nature of this process. 

Calderwood, S.K., Bomstein, B., Famum, E.K.., Stevenson, M.A. (1989). Heat shock stimulates the release of arachidonic acid and the synthesis of prostaglandins and leukotriene B4 in mammalian cells. J. Cell. Physiol. 141, 325-333. 

During recent years, cross metathesis has found a wide range of applications in total synthesis. CM has been the key step in the syntheses of (-)-lasubine 11 [134], (+)-7a-ept-7-deoxycasuarine [135], and melithiazole C [136] to name just a few examples. It has been used for the modification of tetrapyrrolic macrocycles [137] as well as erythromycin derivatives [138], the dimerisation of steroids [139] and the synthesis of prostaglandin analogues [140]. 

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