Cycloalkenes natural products

An obvious drawback in RCM-based synthesis of unsaturated macrocyclic natural compounds is the lack of control over the newly formed double bond. The products formed are usually obtained as mixture of ( /Z)-isomers with the (E)-isomer dominating in most cases. The best solution for this problem might be a sequence of RCAM followed by (E)- or (Z)-selective partial reduction. Until now, alkyne metathesis has remained in the shadow of alkene-based metathesis reactions. One of the reasons maybe the lack of commercially available catalysts for this type of reaction. When alkyne metathesis as a new synthetic tool was reviewed in early 1999 [184], there existed only a single report disclosed by Fiirstner s laboratory [185] on the RCAM-based conversion of functionalized diynes to triple-bonded 12- to 28-membered macrocycles with the concomitant expulsion of 2-butyne (cf Fig. 3a). These reactions were catalyzed by Schrock s tungsten-carbyne complex G. Since then, Furstner and coworkers have achieved a series of natural product syntheses, which seem to establish RCAM followed by partial reduction to (Z)- or (E)-cycloalkenes as a useful macrocyclization alternative to RCM. As work up to early 2000, including the development of alternative alkyne metathesis catalysts, is competently covered in Fiirstner s excellent review [2a], we will concentrate here only on the most recent natural product syntheses, which were all achieved by Fiirstner s team. 

Two illustrations that show the power of this reaction for the preparation of strained cycloalkenes are the contractions of 102 to the propellane 103 , an application that has been reviewed , and of 104 to the bicyclo[2.1.1]hexene 105 . The utility of the Ramberg-Backlund rearrangement in the preparation of various natural products such as steroids , terpenoids and pheromones has been demonstrated. In addition to the synthetic applications mentioned in the previous subsection, several selected examples taken from the recent literature are given in equations 66-69. These examples further demonstrate the potential of this method for alkene synthesis in general. 

RCM of dienes to cycloalkenes provides a useful method for the syntheses of carbo- and heterocycles and thus has been proved to be extremely effective in total synthesis of various natural products. Usually, however, mixtures of (E)- and (Z)-olefms result. In contrast, ring-closing alkyne metathesis provides a reliable route for synthesis of both (E)- and (Z)-macrocycloalkenes in a stereoslective manner taking advantage of stereoselective partial reduction of resulting cycloalkynes. A Lindlar reduction gives (Z)-cycloalkenes, whereas a hydroboration/ protonation sequence afford ( )-cycloalkenes (Equation (23)). Recently, Trost reported an alternative procedure for the synthesis of (E)-olefins from alkynes through hydrosilylation by a ruthenium catalyst. This procedure converts cycloalkyne 130, for example, to vinylsilane 131 and then to (E)-cycloalkene 132 in a stereoselective manner (Scheme 46)7 ... 

Although the ( )-cycloalkene structures have been found in a large variety of natural products especially in macrolides 36a-c), only a brief comment on the conformational aspects of some sesquiterpenes 37 will conclude this section. 

The Claisen ester enolate reaction has proved to be extremely useful in the synthesis of a large number of natural products.3 In addition, the rearrangement has been extended to allow the preparation of useful intermediates such as a-alkoxy esters,88 329 33 336 343 a-phenylthio esters,339344-345 a- and [3-amino acids,340 346-350 a-fluoro esters,351 cycloalkenes,352353 tetronic acids,354 and dihydro-pyrans.355-357... 

Scheme 13). These [3 + 2] cycloaddition reactions have been applied to the synthesis of natural products, ( )-hirsutene,f " ( )-albene, ( )-brefeldin,f loganin aglucon, and pentalenene3 In earUer applications, reactions with cycloalkenes were employed to construct bicychc compounds (Scheme 14)3 Then, tran -alkenes having a stereogenic center derived from mannitol were employed to control the stereochemistry of the cycloaddition (Scheme 15). ... 

Many cyclic and polycyclic (more than one ring) compounds containing double bonds are known, including a great many natural products. Figure 3.43 shows some common structures incorporating cycloalkenes. 

FIGURE 3.43 Some natural products incorporating cycloalkenes. 

ROM-CM Sequence The ROM reaction of a cycloalkene engaged in the subsequent CM reaction with an olefinic partner provides the straightforward procedure for the synthesis of diene products having the isolated double bonds. This sequence is applicable not only to relatively strained cycloalkenes but also to unstrained compounds such as cyclohexene. The ROM-CM sequence of norbor-nene compounds or cyclopropene ketals with various olefins is reported for the preparations of natural products. 

The stereochemistry of ketene to alkcne cycloadditions is such that retention of the alkene configuration is observed. Furthermore, in cycloadditions with unsymmetrically substituted ketenes the larger of the two ketene substituents ends up as with respect to the adjacent alkene substituent (or eiulo in cycloalkene cycloadditions). This stereochemical outcome was originally attributed to the concerted [ff2a + n2a] nature of kctcnc to alkene cycloadditions,21 although more recent experimental and theoretical evidence indicate that these reactions are asynchronous and in some cases in which polarized double bonds are involved actual zwittcrions may be intermediates.9 1195 Also in certain cases the endo product in ketene to alkene cycloadditions may be the thermodynamic product from equilibration studies.22,23 Nevertheless, stereochemical control can be achieved in most such reactions as shown by the examples of 12,24 13,29 14,25 15,26 16,27 and 17.28... 

Further studies with other alkenes and cycloalkenes proved the general nature of the reaction. 474 475 B2F4 is less reactive but forms more stable products.474... 

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