Using Symmetrical Olefins

Symmetrical olefins are the best candidates to ensure complete end-functionalization. As Z-olefins typically react much faster than -olefins, many approaches to introduce functional end groups start from the commercially available Z-2-butene-l,4-diol. In fact, Z-2-butene-l,4-diol itself has been 

Using the olefin metathesis reaction itself to prepare symmetrical olefins is an elegant and straightforward method to synthesize suitable substrates from terminal olefins. Kurzhals and Binder [43] used such a homo metathesis approach to prepare a symmetrical olefin for terminal CM. Barbiturate and thymine polymer end groups were successfully introduced in this way. 

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Pentacyclosqualene, the symmetrical hydropicene corresponding to squalene, has not been made by acid-induced cation-olefin cyclization of squalene, despite considerable experimental study. A simple, convergent synthesis of pentacyclosqualene using cation-olefin cyclization to generate ring C was developed. The Cjo-framework was constructed by radical coupling to a tetracyclic intermediate that was also used for the synthesis of onoceradiene. 

A second observation was the fact that isomerization of the starting asymmetric olefin was much faster than the formation of new symmetric olefins. In fact, 40% of the initial cis olefin (Fig. 1) had isomerized to trans after only 4% conversion to new olefins. This result formally parallels the highly selective regenerative metathesis of a-olefins (60, 61), except that steric factors now prevail, because electronic effects should be minimal. Finally, the composition of the initially formed butene from r/j-4-methyl-2-pentene was essentially identical to that obtained when cA-2-pentene was used (18). When tra .v-4-methyl-2-pentene was metath-esized (Fig. 2), the composition of the initially formed butenes indicated a rather high trans specificity. 

While die above reactions will provide carboxylic acid products, each has problems associated with it. The cleavage of olefins to carboxylic acids [reaction (7.1)] can be carried out using potassium permanganate or by ozonolysis at low temperature followed by oxidative workup with hydrogen peroxide. Neither of diese mediods is very useful since only symmetric olefins provide a single carboxylic acid product. Unsymmetrical olefins give a mixture of two acids which must be separated. Furthermore the most useful synthetic processes are those which build up structures, whereas these reactions are degradative in nature. 

In a formal total synthesis of steroid brassindole, sulfide 102 was used as the substrate of the Ramberg-Backlund reaction.57 Chlorination of 102 followed by oxidation with m-CPBA, and treatment of the resulting chloro-sulfone with potassium t-butoxide, provided symmetrical olefin 103. 

Among the multistep solution libraries prepared, Cheng et al. [17,18] reported a dipeptide mimetic template-based 78-member library prepared via four synthetic steps and purified with an excellent protocol based on acid-base extractions. Thomas et al. [19] presented a > 1000-member benzimidazole library prepared via three steps including a 2-ethoxy-1-ethoxycarbonyl- 1,2-dihydro-quinoline (EEDQ)-assisted cyclization. Boger et al. reported two 600-member C -symmetrical [20,21] and unsymmetrical [21] libraries prepared via four-five synthetic steps, based on iminodiacetic acid as a scaffold and using the olefin metathesis reaction. 

The observations of symmetrical cross ozonides from unsymmetrical olefins suggest that unsymmetrical cross ozonides ought to be produced from pairs of symmetrical olefins. Criegee had examined this point earlier (2) and found that no detectable amounts of 3-heptene ozonide were produced when a mixture of 3-hexene and 4-octene was ozonized. Again, this may have been a result of the particular olefin concentrations used. The recent observations that ozonide cis-trans ratios in both cross ozonides (5, 10, 11) and normal ozonides 4-14) can depend on olefin stereochemistry as well as steric factors in the olefin 11) prompted us to reinvestigate the possibility of obtaining unsymmetrical ozonides from pairs of symmetrical olefins. Such an investigation presents an opportunity to examine ozonide cis-trans ratios and yields where several new reaction variables are possible. 

The simplest example of a productive cross-metathesis reaction between acyclic olefins is that between ethene and but-2-ene reaction (1). In this case only one product is possible, apart from cis/trans isomerization of the but-2-ene the equilibrium mixture thus consists of four compounds. At the other extreme, the reaction of two unsymmetrical olefins, R CH=CHR and R CH=CHR , with R, R, R, R all different, can produce cis/trans isomers of four different unsymmetrical olefins by cross-metathesis as well as four symmetrical olefins by self-metathesis. Counting the cis/trans isomers of the reactants as well, this means that the equilibrium mixture will contain 20 different compounds. Side reactions, such as double-bond shift reactions, will complicate the situation still further. The main value of cross-metathesis reactions, apart from their use in the proof of mechanism, lies in their application to the synthesis of olefins that are otherwise expensive or difficult to prepare. A number of higher olefins, useful as insect sex attractants, have been made in this way. 

Other metal-based epoxidation catalysts have been explored to overcome some of the hmitations of the Sharpless procedure. One drawback with the Sharpless asymmetric epoxidation is the slightly lower ees often obtained when using cis-olefin substrates. The group of Yamamoto have achieved highly enantioselective epoxidations of ds-alkenes using vanadium(V) oxytriisopropoxide in the presence of C2-symmetric bishydroxamic acid ligands such as (4.23). In contrast to the Sharpless procedure this process is not hampered by the presence of air or... 

Importantly, prolinamide catalysts (Figure 6.3) work well in Michael addition reactions using nitro-olefins as acceptors. iV-Tritylprolinamide 33 and aminonaphthyridine-derived ProNap 34 served as organocatalysts in asymmetric Michael additions of aldehydes and cyclohexanone to nitro-alkenes. Proline-functionalised C3-symmetric 1,3,5-triallq lbenzene 35 was screened in the reaction of cyclohexanone to nitrostyrene to afford the Michael adducts in good yields and diastereoselectivity but low enantioselectivity. 

The results of many investigations [2-11] demonstrate that at small substrate conversions Z-isomers prevail when the reactant is Z structure and vice versa. If the catalyst has bulky ligands, the stereo-content can be up to 100 % Z or E, when starting Z- or E-2-pentenes are used correspondingly [12]. When using starting terminal olefins R-CH=CH2 and classical catalysts, initial E-content of resulting symmetrical olefins at 25 is close as a rule to thermodynamic equilibrium (83-86 %) [2,3, 13-18]. When a branch point at double bond arises ( for example with R = Pr(Me)CH ), the initial E-content decreases to 46 % [16]. In many cases metathesis of a-olefins in the presence of well- defined Mo-imido... 

Derivatives of Z-2-butene-l,4-diol have been used in terminal CM reactions, most notably esters thereof that served as ATRP initiator sites [39, 38]. The same symmetrical olefin (Figure 3.6, bottom) was used by Gozgen et al. [40] to prepare polymeric terminal azides for subsequent polymer analogous click reactions ... 

Other complex symmetrical architectures were obtained using bis-dendritic CTAs [130]. A symmetrical olefin was functionalized, with third-generation Fr chet-type polyfbenzyl ether) dendrons serving as the CTA. Polymerization of COE with the Grubbs second-generation ruthenium catalyst in the presence of this CTA and subsequent hydrogenation with /j-toluenesulfonylhydrazide in o-xylene resulted in bis-dendritic PE (Figure 3.14). 

What we have shown here is the fact that large inverse values can be obtained for the Br2 addition to a "normal" olefin which should pass through a symmetrical, or nearly so, transition state. Of course, more work involving other systems would be beneficial in assessing the scope and limitation of the use of the a-deuterium kie s in mechanistic studies of Br2 and Br3 reactions with olefins. 

Section B of the Scheme 9.1 shows several procedures for the synthesis of ketones. Entry 6 is the synthesis of a symmetrical ketone by carbonylation. Entry 7 illustrates the synthesis of an unsymmetrical ketone by the thexylborane method and also demonstrates the use of a functionalized olefin. Entries 8 to 10 illustrate synthesis of ketones by the cyanide-TFAA method. Entry 11 shows the synthesis of a bicyclic ketone involving intramolecular hydroboration of 1,5-cyclooctadiene. Entry 12 is another ring closure, generating a potential steroid precursor. 

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