Ketones five-membered ring synthesis

Bicyclic ketone 13 is a pivotal intermediate in Corey s approach to the prostaglandins. Buried within 13 is the five-membered ring of PGF2a, albeit in an undeveloped form. It would appear that a particularly direct approach to the synthesis of 13 would involve a [4+2] cycloaddition reaction between substituted cyclopentadiene 15 and ketene. Unfortunately, however, ketene itself is not a suit-... 

Raddeanamine (360) is an unusual spirobenzylisoquinoline alkaloid having a tertiary methyl group in five-membered ring. Methylation of the corresponding ketone gave the methyl carbinol with the reverse stereochemistry, namely, the methyl carbinol 361 was obtained from the reaction of the ketone 294 with methyllithium (Scheme 64). Stereoselective synthesis of ( )-raddeanamine was accomplished by an intramolecular oxyfunctionalization via the 8-methyl-8,14-cycloberbine 364 (175). 

More recently, the same group achieved a simple, highly stereocontrolled total synthesis of (+)-hirsutic acid (Scheme LXXIX) ". This chirally directed effort developed subsequent to reaction of dl-728 with (+)-di-3-pinanylborane, alkaline hydrogen peroxide oxidation, chromatography, PCC oxidation, and hydrogenolysis. The dextrorotatory hydroxy ketone 729 was nicely crafted into keto aldehyde 730 from which 720 was readily obtained. Once again, the Wacker oxidation played an instrumental role in annulation of the third five-membered ring. The remainder of the asymmetric synthesis was completed as before. 

The ion 131 also reacts with epoxides, to form y-hydroxy aldehydes after reduction and hydrolysis,1539 and with aldehydes and ketones (6-41). Similar aldehyde synthesis has also been carried out with thiazoles1540 and thiazolines1541 (five-membered rings containing N and S in the 1 and 3 positions). 

These five-membered rings have lone pair(s) delocalised from the heteroatom round the ring and are electron-rich . They react all too easily with electrophiles and are unstable in acid whether protic or Lewis. We have to find reactions that can be used in neutral or only weakly acidic solution. The synthesis of tolmetin 99 illustrates the two most important reactions.14 The disconnection of the ketone would lead naturally to an AICI3-catalysed Friedel-Crafts reaction between the acid chloride 100 and the pyrrole 101. 

Organotin-zinc derivatives can be used as reagents in organic synthesis. Thus, the stannyl zincate complex Me3Sn(Et)2ZnLi reacts with alkoxy-unsaturated ketones to form five-membered ring heterocycles434. 

Chiral enamine derivatives have also been used as electron-rich alkenes. The oxazoline derivative 17 reacted with benzaldehyde to yield the two stereoiso-meric oxetanes 18a and 18b with a diastereomeric excess of 67% (Scheme 5) [12]. A significantly higher diastereoselectivity was observed in the case of the reaction of the pyrrolidine derivatives 19 where the enamine function is localized inside the five membered ring [13]. Then the oxetane 20a (R — n-Cgil g) was used in an asymmetric synthesis of the antifungal alkaloid (+ )-preussin. The approach of the 3n,7T excited ketone preferentially occurred syn with respect to... 

Intramolecular phosphonate-based olefination has been used to construct five-membered rings in a number of syntheses for example in a novel approach to [3.3.0] fused pyrazolidinones (244) (Scheme 35), a totally synthetic class of antibacterial agents. 44 new, convergent synthesis of the fungal metabolite and useful synthetic intermediate (+)-terrein (248) has been reported. 45 The method is based on two phosphonate olefination steps. The diphosphonate (245), obtained from L-tartaric acid, gives, on treatment with base, a mixture of the required phosphonate (24 6) and the diphosphonate (247). However, under appropriate conditions (246) is the major product and can be converted into (+)-terrein by reaction with acetaldehyde (Scheme 36). Olefination of the ketone (249) with dimethyl diazomethylphosphonate (250) provides, via carbene insertion, the cyclopentene (251) and hence a new route to (-)-frontalin (252) (Scheme 37).146... 

This is a LiAlH4 reduction of the a,(3-unsaturated ketone of the seven-membered ring. The low temperature and the use of only 0.25 eq. of LiAlH4 ensures that only the fastest reaction takes place and no reduction of the ketone in the five-membered ring or of the double bonds is observed. This reduction proceeds with substrate control of the diastereoselectivity, because the hydride attacks the molecule mainly from its convex and not from its concave face. This becomes clear when looking at 44 which is a three-dimensional representation of 31. Whether the diastereomeric ratio of 10 1 is important, will become clear in the further synthesis. 

Tin hydride-mediated radical cyclizations onto a C-0 double bond, coupled with subsequent oxidation, can be applied to ketone synthesis. Fraiser-Reid and co-workers demonstrated that the radical cyclization onto an aldehyde carbonyl group is particularly useful for the construction of cyclohexanol derivatives [35]. Examples shown in Scheme 4-17 well feature the cyclization. As Beckwith s kinetic work predicts (Scheme 4-18) [36], when this method is applied to a five-membered ring system, the rapid ring opening hinders the formation of cyclopen-tanols. Accordingly, only cyclohexanols can be reliably prepared using this approach. 

Corey and Nozoe cyclized a keto aldehyde as one step in a total synthesis of helminthosphoral (equation 106). In this case, note that the aldehyde enolate adds to the more hindered ketone carbonyl to form a five-membered ring. The alternative addition of the ketone enolate to the aldehyde would give a seven-membered ring. 

The power of radical ring closure reactions is demonstrated most elegantly in a synthesis of isoamijiol, in which a whole range of carbon-carbon bond forming reactions are used including the cyclization of the ketone (63).11,6 Additionally, the use of a new substrate in radical cyclizations (64) allows access to both six and five-membered rings in a process which for success requires the halide to be on an sp carbon.1 Furthermore a useful, and... 

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