Smith s synthesis

RCM can be used not only for five- or six-membered rings, but also for medium sized rings and macrocycles. After optimization of reaction conditions and catalyst, the product is often obtained in excellent yield and, as shown in the example below (Smith s synthesis of salicylhalamide A, 16, Scheme 2 [39]), even in high -selectivity. 

Smith s synthesis of (—)-echinosporin stands out for its good stereo-and regiocontrol at every stage. Its large number of highly chemoselective reactions, and its use of an asymmetric [2 + 2]-photocycloaddition reaction for constructing the m-fused 6,5-bicyclic core are also commendable. The latter reaction provides a beautiful illustration of how properly harnessed photochemistry can be decisively deployed for the stereocontrolled synthesis of complex natural products. 

There is sufficient latitude in the rates for selective removal of a 3,4-dimethoxy-benzyl ether in the presence of an adjacent p-methoxybenzyl ether as illustrated in Scheme 4T74, taken from Smith s synthesis of Zampanolide,247 324 For other examples of the beneficial lability of 3,4-dimethoxybenzyl ethers, see Smith s synthesis of Phorboxazole131 and Nicolaou s synthesis of Apoptoli-dine.325... 

These reagents, usually with further functionalisation, have been widely used. Smith s synthesis of phyllanthoside involved the coupling of the lithium derivative of 90 with the aldehyde 92 and the exposure of one protected ketone to give 93 having two exposed ketones and one concealed as an enol ether.20... 

There is an exception to the poor reactivity exhibited by hydrogen peroxide. When 158 was treated with 30% hydrogen peroxide, in the presence of benzonitrile and potassium hydrogen carbonate, epoxide 159 was formed in 86% yield, in what is known as the Payne epoxidatlon. l The reagents shown generate per-oxybenzimidic acid in situ. This transformation was taken from Smith s synthesis of (+)-calyculin A.250 Payne epoxidation is known to give a diastereofacial preference that is opposite to epoxidations with peroxy-acids. In this particular example, the epoxide 159 was a 3 1 (a P) mixture of isomers at the epoxy carbon. 

A typical example of an application of ozonolysis in synthesis is the cleavage of the alkene unit in 351 to give aldehyde 352, with loss of formaldehyde, a part of Smith s synthesis of (+)-thiazinotrienomycin In this case, the reductive workup used triphenylphosphine. Ozonolysis of 353 gave aldehyde 354, an intermediate in Corey s synthesis of the Cecropia Moth Juvenile hormone, via a reductive workup with DMS. Note that the electron rich vinyl ether moiety reacted in preference to the simple alkene moiety. The ozonolysis product of the methyl vinyl ether was a methyl ester. This method is particularly useful for the preparation of protected acids. In general, electron rich alkenes are oxidized faster than electron-poor alkenes. 

This reagent was used to reduce 112 to the hydroxymethyl derivative (113) in 91%, without racemization of the stereogenic center at C5, taken from Smith s synthesis of pyrrolizidine alkaloids.Hojo showed that silica gel is an effective catalyst for several other reactions. 1 ... 

A particularly useful borane is the chiral reagent (-)-B-allyl(diisopinocampheyl)borane.l 3 Although the chemistry of acyl addition to aldehydes and ketones to give alcohols will not be formally discussed until Section 8.4.C, the addition of this chiral allylborane to carbonyl compounds will be presented here. In a simple example taken from Smith s synthesis of (-)-macrolactin A,n 156 was treated with (-)-B-... 

The other major synthetic use of alkyne anions is their reaction with ketones and aldehydes to give an alkynyl alcohol via nucleophilic acyl addition. The lithium salt of 1-propyne, for example, reacted with aldehyde 40 to give alcohol 41 as part of Smith s synthesis of (+)-acutiphycin.50 The reaction is selective for ketones and aldehydes in the presence of acid derivatives, if the acetylide is not present in large excess. l... 

Mukaiyama conditions were used intramolecularly for the successful closure of an 11-membered ring in Smith s synthesis of normethyljatrophone. 64 Conversion of the alkynyl conjugated ketone in 251 to the silyl-enol ether was followed by reaction with TiCU, leading to reaction with the dioxolane moiety and ring closure (sec. 7.3.B.1 for formation of dioxolanes) to give 252 in 47% yield.l " ... 

Palladium-catalyzed cro.ss-coupling reactions were also reported. In Smith s synthesis of the lipoprotein-associated phospholipase A2 inhibitor discussed in Section 6.2.2.1, the cyclization precursor 23 was prepared by a Heck coupling between bromopyrimidine 55 and ethyl acrylate to give 56, which was then converted to 23 following conventional procedures <01BMCL701>. Yields were not reported. 

The readily available E-ethylidene-y-butyrolactone (55) may serve as precursor for the synthesis of 2-methoxycarbonyl-l,3-dienes (56).The procedure (Scheme 26) involves ring opening of the lactone with potassium or sodium selenoate, and thus extends Liotta and Smith s synthesis of a>-olefinic esters described last year. 

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