Carbon expansion

Prior to the actual metathesis event, coupling of 13 and 28 via an ester linkage was required (Scheme 2.3). Two methods were employed in this connection. The first involved the aforementioned two-carbon expansion of aldehyde 28. Thus, condensation of 28 with Rathke anion (lithiated tert-butyl acetate) generated a mixture of dia-stereomeric alcohols the major product was shown to have the requisite 3S configuration. TBS protection of ester 29 and subsequent ester hydrolysis generated the desired add, 31, which could be further esterified with alcohol 13 in 78 % yield. 

One-carbon expansion of the ring-open-chained P-keto ester (240) also readily happens to form a good yield of 7-keto ester (241), (eq. 3.96), and the rate constant of the one-carbon expansion is approximately 104 s-1 at 25 °C. 

The one-carbon expansion of cyclohexanones with introduction of a carbonyl group, trifluromethyl, cyano, phosphonate or benzenesulfonate has also been reported to proceed in the presence of Lewis acids (Scheme 14). The analogous reactions of larger ring ketones [expressed as ring size (yield)] with ethyl diazoacetate [7 (81%), 8 (85%)] and phenylsulfonyldiazomethane [7 (86%), 8 (27%), 12 (43%), 14 (48%), 15 (54%) and 16 (58%)] have also been reported. In the reaction of ethyl diazoacetate and... 

A slightly different approach has been utilized for the three-carbon expansion in a system which does not contain a carboalkoxy group. The initial intramolecular addition step is carried out separately with butyllithium or samarium diiodide to give a bicyclic alcohol (Scheme 78). The radical-induced fiag-mentation step is carried out photochemically in the presence of mercury(II) oxide and iodine to provide the expanded iodo ketone. 

An alternate radical-induced addition-fragmentation sequence relies on the 1,4-elimination of a leaving group to drive the reaction. In this sequence, because the fragmentation is accompanied by the expulsion of a tiibutylstannyl radical, the requirement for the initial tributyltin hydride is only catalytic (Scheme 79). The stereospecificity of the reaction course has been rationalize in terms of a conformational preference for the elimination step, as depicted in Scheme 79 where the rran.r-substituted cyclohexanone forms only one double bond geometry in the product. As shown in equations (40) and (41), the ci.r-substituted cyclohexanones undergo the four- and three-carbon expansions stereospecifically to give the (Z)-alkenes. 

More recently, a radical-mediated variation of this addition-fragmentation has been explored. The reaction, summarized in Scheme 77 for a one-carbon expansion, involves the generation of a radical at the terminus of a chain by homolytic cleavage of a carbon-heteroatom bond. Addition of the radical to the carbonyl produces a bicyclic intermediate, which on cleavage of the alternate bond regenerates the ketone carbonyl group with formation of a new radical. The sequence is terminated by the reduction of the radical with the tributyltin hydride reagent. The near neutral conditions of the reaction avoid the reclo-... 

The Prins-pinacol sequence has been extended to the preparation of oxa bicyclic systems in which hetcrocycle formation is accompanied by one carbon expansion of an existing carbo-cyclic framework39,40. Treatment of dioxolanes 36 with tin(IV) chloride affords, in each case a single, r/v-fused cyclohepta[b]tetrahydrofuran 37. As in the previously noted examples, stereochemical induction derives solely from the homoallylic stereocenter thus rearrangement of the civ-fused dioxolane 36 (R1 = R2 = R3 = H) affords the same product as that obtained from rearrangement of the traws-fused isomer 3840. 

A new concept in the ring expansion of cyclic lactones has been developed by Corey et al. involving internal translactonization. In the most spectacular example, treatment of the nine-membered lactone (115 x = 6, y = 3) with a trace of acid at ambient temperature for two hours gives the 12-membered lactone (116 jc =6, y = 3) in 97% yield. This instability of a nine-membered ring is further exemplified by a six-carbon expansion of (115 x = 6, y = 6) to the 15-membered macrolide (116 JC = 6, y = 6) in 90% yield. By contrast, eight-membered lactones (e.g. 115 JC = 5, y = 3) are converted more slowly and less cleanly into the expanded products (e.g. 116 jc = 5, y = 3) while seven-membered lactones (115 jc=4) failed to translactonize altogether. 

Sodium hydrogen carbonate Expansion of the penicillin ring skeleton... 

The reaction has also been demonstrated in open-chain systems. The efficient eight-carbon expansion of cycloalkanones is discussed in detail in a paper by Wender and his co-workers (Scheme 17). ... 

A three-carbon expansion of cyclic ketones, which is applicable to the preparation of muscone, has been described by Trost etal. (Scheme 21). The insertion of the three-carbon chain also occurred with an acyclic ketone, as shown. 

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