Stereospecific synthesis prostaglandin

The need for adequate amounts of prostaglandins has led to several total syntheses of these substances. A stereospecific synthesis reported by E. J. Corey and co-workers in 1968 is outlined below. Complete the sequence as in Exercise 30-9 by showing the reagents and conditions needed for each step. Note that j implies a mixture of epimers. 

Two recent papers describe several important improvements [459, 460] to the Harvard syntheses (pp. 329-330) which provide advantages over the earlier procedures for large scale operation. Another paper [461] describes the first stereospecific synthesis of natural PGE3 and PGF30,. A series of papers on the chemistry, biosynthesis, metabolism and mechanism of action of prostaglandins and their role in female reproductive physiology was published recently [462]. 

Besides their application at the industrial level (e.g. in the Alfol process or in Ziegler—Natta polymerization catalysts), organoaluminums are the basis of various useful organic reactions. In fact, hydroalumination of acetylenes (a Cp2ZrCl2 catalyzed process when Me3Al is the metallation reagent) is particularly useful for the stereospecific synthesis of prostaglandin precursors. 

Since its discovery two decades ago, the reversible interconversion of allylic sulfenates to sulfoxides has become one of the best known [2,3]-sigmatropic rearrangements. Certainly this is not only because of the considerable mechanistic and stereochemical interest involved, but also because of its remarkable synthetic utility as a key reaction in the stereospecific total synthesis of a variety of natural products such as steroids, prostaglandins, leukotrienes, etc. 

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. 

In the Woodward synthesis of prostaglandin (621, intermediate 172 formed in situ from the corresponding amine was smoothly transformed into bicyclic aldehyde 173. Seebach and co-workers (63) have also observed several stereospecific rearrangements using the same reaction. For example, diazotization of amine 174 gave specifically the cis-cyclopentane 175 which was then epimerized into the more stable trans-cyclopentane 176. 

A stereospecific total synthesis of prostaglandins E3 and F3, containing an additional double bond in this side chain, starts from the optically active phosphonium salt 161. In this synthesis the ( )-13-double bond and the 15-hydroxy function are generated simultaneously by condensation of the chiral bicyclic aldehyde 163 with the P-oxido ylide 162 obtained by treatment of 161 with methyllithium. The corresponding phosphonium salt S) +)-161, already possessing the (Z)-configurated A17-double bond of prostaglandins, was prepared from (S)(—)-tartaric acid 1351 (Scheme 29). 

A key intermediate, 28, of prostaglandin synthesis can be prepared by a stereospecific hydroxylation. Aspergillus niger ATCC 9142 introduces the oxygen function into the prostaglandin precursor 27 at the required position, producing the (/ )-alcohol in 67% yield and 36% ee371. 

Sodium benzenethiolate reacted with 6,6-dimethyl-2-vinyl-5,7-dioxaspiro[2.5]octane-4,8-dione (16) to give the 1,5-addition product only. When ethyl trani-6-(l-heptenyl)-2-oxo-bicyclo[3.1.0]heptane-l-carboxylate (18, R = Et) was treated with potassium benzenethiolate it was converted stereospecifically to the corresponding trawj -cyclopentanone derivative 19 (R = Et) with a defined configuration at the a-carbon atom of the side chain. This reaction proved to be useful for the stereoselective synthesis of prostaglandins. ... 

The versatility of the addition reaction of organocuprates to activated cyclopropanes and the stereospecificity have made this reaction an important step in the synthesis of a variety of natural products such as prostaglandins and sesquiterpenes.One of the advantages of this reaction lies in the possibility of introducing complete side chains into certain structures. An example is the reaction of 3-e Jo-substituted tricyclo[3.2.0.0 ]heptan-6-ones 17 with the lithium cuprate that contains a side chain with a protected functional group. The substituted bicyclo[2.2.1]heptan-2-ones 18 were obtained in high yields. 

Here is a simple example in the field of prostaglandin synthesis where 9-BBN was used on a protected optically active propargyl alcohol.12 The starting material is identical to the alkyne 78 that we reacted with Bu3SnH above and the result is the same - cis hydrometallation with the metal atom at the terminus. However that was a thermodynamically controlled stereoselective radical chain reaction while this is a kinetically controlled stereospecific electrophilic addition to give the vinyl borane -87. 

Prostaglandins.—At a time when one was beginning to feel that interest in the total synthesis of the primary prostaglandins (i.e. E and F series) had evaporated, Newton and Roberts and their respective collaborators report a particularly novel route to PGp2a which starts from cyclopentadiene and involves the stereospecific formation... 

Conjugate addition of lithium divinylcuprate to enones gives a,)9-unsatura-ted ketones (Hooz and Layton, 1970). Addition of di-cw- or di-tran -propenyl-cuprate to 2-cyclohexenone proceeds in a completely stereospecific manner with retention of double-bond geometry (Casey and Boggs, 1971). Particularly important is the application to the synthesis of a variety of prostaglandin... 

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