Substitution olefin synthesis

We will then leave alkaloids and move back in time to a target that became important in the 1960 s, Cecropia juvenile hormone (Introduction-5). Approaches to this deceptively simple structure constitute a study in stereoselective tri-substituted olefin synthesis. Given the importance of olefins (both synthesis and chemistry of) to modern organic synthesis, I think that a visit to this old topic will be instructive, and will help set the stage for a discussion of targets of more contemporary interest. In addition, it will focus on the important role synthesis plays in structure determination, and the stimulus natural products can provide for the development of new synthetic methodology. 

The problem of the synthesis of highly substituted olefins from ketones according to this principle was solved by D.H.R. Barton. The ketones are first connected to azines by hydrazine and secondly treated with hydrogen sulfide to yield 1,3,4-thiadiazolidines. In this heterocycle the substituents of the prospective olefin are too far from each other to produce problems. Mild oxidation of the hydrazine nitrogens produces d -l,3,4-thiadiazolines. The decisive step of carbon-carbon bond formation is achieved in a thermal reaction a nitrogen molecule is cleaved off and the biradical formed recombines immediately since its two reactive centers are hold together by the sulfur atom. The thiirane (episulfide) can be finally desulfurized by phosphines or phosphites, and the desired olefin is formed. With very large substituents the 1,3,4-thiadiazolidines do not form with hydrazine. In such cases, however, direct thiadiazoline formation from thiones and diazo compounds is often possible, or a thermal reaction between alkylideneazinophosphoranes and thiones may be successful (D.H.R. Barton, 1972, 1974, 1975). 

General procedure for the reaction of an o-substituted aryl iodide and a terminal olefin. Synthesis of vinylbiphenyls. 

The procedure illustrates a fairly general method for the preparation of -substituted perfiuoroolefins. The method has been applied to the synthesis of 2-cyclohexyl- (70%), 2-benzyl- (61%), and 2-(/>-fluorophenyl)perfluoropropenes (67%), and it is probably applicable to any a-trifluoromethyl ketone. Olefins containing a perfluoroalkyl group other than trifluoromethyl can be prepared by the same procedure by the substitution of lithium chlorodifluoroacetate for sodium chlorodifluoroacetate.7 Other routes to / -substituted perfiuoroolefins are not general or convenient. Routes to perfiuoroolefins generally yield the a-substi-tuted olefin rather than the /3-substituted olefin. 

Electroreductive coupling of ketones with silyl-substituted olefins promotes interesting reactions that are useful for organic synthesis. For example, coupKng of ketones with trimethylvinylsilanes affords /I-trimethylsilyl alcohols, which are easily transformed to the corresponding olefins (Scheme 40). This reaction is interesting from the synthetic point of view since vinylsilane behaves as the equivalent to a /I-trimethylsilyl group-substituted anion [77, 83]. 

Sn2 substitution using organocopper reagents is an efficient method for the synthesis of 3-substituted olefins. In the synthesis of farnesyl diphosphate analogues (43, 45) as potential inhibitors of the enzyme protein-farnesyl transferase, for example, organocopper methodology was compared with the Stifle reaction [33] and the Suzuki reaction [34], frequently used in the coupling of vinyl triflates with... 

The oxazolidinone-substituted olefin Ic (Scheme 3) constitutes another fortunate substrate for the diastereoselective synthesis of a chiral dioxetane , which is of preparative value for the enantiomeric synthesis of 1,2 diols . For example, the photooxygenation of the enecarbamate Ic produces the asymmetric dioxetane 2c in >95% jt-facial diastereoselectivity. The attack of the O2 occurs from the jt face anti to the isopropyl... 

Over the past several years, Mascarenas and co-workers (150-153) utilized the oxidopyrylium ion with variously hetero-substituted olefin tethers. Mascarenas has used this methodology in tandem with a Diels-Alder reaction to prepare tricyclic cycloheptanoid substrates. Further, Mascarenas and co-workers (154—156) achieved the synthesis of optically active oxabicyclic[3.2.1]octane derivatives through the addition of a homochiral p-tolylsulfinyl group substituted at the olefin tether. The Mascarenas group has also used this methodology to prepare the THF portion of ( )-nemorensic acid via oxidative cleavage of the substituted a-hydroxyketone moiety (157) (Scheme 4.78). 

This method is generally applicable to the stereospecific synthesis of cyclopropane derivatives from a large variety of substituted olefins.4... 

On the other hand, the addition of a quaternary ammonium salt to the reaction medium accelerates the isomerization of the radical intermediate [36]. Thus, the epoxidation of c/j-stilbene in the presence of A -benzylquinine salt gives rranr-stilbene oxide with 90% ee as major product (Table 6B.1, entry 24). This protocol provides an effective method for the synthesis of trans-epoxides. In contrast to the epoxidation of c/s-di- and tri-substituted olefins for which complexes 11-13 are the catalysts of choice, the best catalyst for the epoxidation of tetra-substituted conjugated olefins varies with substrates (Table 6B.1, entries 27 and 28) [37]. The asymmetric epoxidation of 6-bromo-2,2,3,4-tetramethylchromene is well-promoted by complex 14 and that of 2-methyl-3-phenylindene, by complex 12a. 

The trimethylsilylated ylides (1), easily generated from trimethyl chlorosilane and ylides, react with aldehydes 2 to form vi-nylsilanes 3 (2,3). The vinylphosphonium silanolates 4 are also formed. Compounds 3 are versatile reagents for further reactions (4). The ylide J (with R1 =H) reacts with aldehydes 2 to give the dienes j). The oxidation of with the adduct 6, from triphenyl-phosphite and ozone, gives access to a generaT synthesis of acyl-silanes (trimethylsilylketones) (2). The silylated ylides react to form phosphonium salts 7 with halogen compounds. The salts 7.can be desilylated by fluorine ions. The disubstituted ylides JO Tormed can be converted in statu nascendi with aldehydes V[ into the tris-substituted olefin J2 (2,3). In the case of R3-I, vinyl... 

The allylmetallation of an alkynyl metal leads to a vinylic 1,1-organogem-bismetallic derivative,22 and the stereoselective reaction of this latter with different electrophiles gives a new access to the synthesis of stereodefined poly-substituted olefins, as single stereoisomers23 (Equation 7.6 and Protocol 10). 

The regioselectivity of the Paterno-Biichi reaction with acyclic enol ethers is substantially higher than with the corresponding unsymmetrically alkyl-substituted olefins. This effect was used for the synthesis of a variety of 3-alkoxyoxetanes and a series of derivatives [55]. The diastereoisomeric cis-and tnms-l-methoxy-l-butenes were used as substrates for the investigation of the spin state influence on reactivity, regio- and stereoselectivity [56]. The use of trimethylsilyloxyethene 62 as electron rich alkene is advantageous and several 1,3-anhydroapiitol derivatives such as 63 could be synthesized via photocycloaddition with l,3-diacetoxy-2-propanone 61 (Sch. 17) [57]. 

S l substitution of different compounds by nitronate anions followed by elimination of nitrous acid is a good method for the synthesis of various substituted olefins. A clear example is the base-promoted HN02 elimination from the C-alkylation products formed by the S l reaction between 2-chloromethyl-3-nitroimidazo[l,2-a]pyridine (11) and various aliphatic, cyclic and heterocyclic nitronate anions87, affording new potential pharmacological derivatives with a trisubstituted double bond at the 2-position. A representative example is shown in equation 32. 

Formation and Cleavage of Bonds to Silicon Organosilicon Protecting Groups Electrophilic Substitution Reactions Synthesis of Olefins... 

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