Diastereoselection prostaglandin synthesis

Finally, Corey reduction was used to solve the particular problem of the diastereoselective reduction of the ketone in C-15 in a prostaglandin synthesis. Corey reported a selectivity of 90 10.39 We have investigated the reduction of a modified prostaglandin and, despite considerable efforts,... 

This CAB has also been applied to the enantioselective Diels-Alder reaction of a-bromo-a,/3-enals with dienes [10]. a-Bromo-a,/3-enals are useful dienophiles in the Diels-Alder process because of the exceptional synthetic versatility of the resulting adducts e.g., an important intermediate for prostaglandin synthesis [17a]. In the presence of 10 mol % 2, R = H, a-bromoacrolein and cyclopentadiene in dichloro-methane undergo a smooth Diels-Alder reaction to give the (5)-bromo aldehyde in quantitative yield, 95 % ee and 94 6 exolendo CHO) diastereoselectivity (Eq. 11). Similar results are obtained for the catalyst 2, R = o-PhOCgHj, in propionitrile quantitative yield, 98 % ee ((5) enantiomer major), 94 6 exolendo CHO) diastereoselectivity (Eq. 11). Other examples are listed below. 

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]. 

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-... 

An important example of heterogeneous diastereoselective synthesis by catalytic way is the synthesis of prostaglandines (a family of compounds having the 20-carbon skeleton of the prostanoic acid) (Scheme 14.14). Naturally, these molecules are biosynthesized via a cyclooxygenase enzyme system that is widely distributed in mammalian tissues. Many of the synthetic routes [272] involve the diastereoselective hydrogenation of a carbonylic bond having a C=C double bond... 

A beautiful illustration of the power of diastereoselective cuprate addition to cy-dopentenone systems is given in the course of the synthesis of the prostaglandin E2 (PGE2) (Scheme 6.2) [7j. Thus, addition of the functionalized organocuprate... 

Scheme 6.2. Diastereoselective addition of a functionalized cuprate to cyclopentenone 14 in the synthesis of prostaglandin E2 (PGE2) (TBS = t-butyidimethylsilyl,...

This enantioselective preparation of allylic alcohols has been applied to the synthesis of the side chain of prostaglandins . The addition to functionalized aldehydes, such as 483, allows the synthesis of C2-symmetrical 1,4-diols, such as 484, with excellent diastereoselectivity and enantioselectivity . An extension of this method allows the synthesis of C3-symmetrical dioF . Aldol-type products result from the catalytic enantioselective addition of functionalized dialkylzincs to 3-TIPSO-substituted aldehydes, such as 485, followed by a protection-deprotection and oxidation sequence affording 486 in 70% yield and 91% ee (Scheme 118) . The addition to a-alkoxyaldehydes provides a... 

Auxiliary-controlled diastereoselective and enantioselective Diels-Alder reactions (Corey) and diastereoselective three-component reactions (Noyori), examples of which were tested for the first time in the total synthesis of prostaglandins, enriched the arsenal of methods in modem preparative organic chemistry. 

Highly stereoselective arylation reactions were reported, as shown in Equation 5.46. With an optically active diamine ligand, a modest asymmetric induction was observed (Equation 5.47). An asymmetric synthesis of a synthetic prostaglandin AH 13 205 was accomplished using the diastereoselective cobalt-catalyzed cycliza-tion/arylation sequence as key step [55]. 

Cyclopentene motifs are present in a number of biologically active molecules and natural products including terpenes and prostaglandins. As such, this rearrangement can provide rapid access to these cores in a step-economical process. Additionally, the use of substituted VCPs allows for the regio- and diastereoselective synthesis of cyclopentene building blocks that can be subjected to postreaction modification to access variety of complex molecular architectures. Finally, the introduction of heteroatoms in VCP moiety provides the opportunity to synthesize heterocyclic rings that are present in a variety of alkaloids, terpenoids, and other natural products. 

This brings to a close to our examination of routes to prostaglandins. I have chosen the geminally activated cyclopropane route as the last route to provide an entree to our next topic, synthesis of pyrrolizidine alkaloids discussed in Chapter 4. This is not the only connection between these two topics. Prostaglandins and pyrrolizidines both contain 5-membered rings as important substructures, and the acyclic diastereoselection problem rears its head in both families of natural products. Thus, there will be some overlap in chemistry as well as some new strategies to study as we move forward. 

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