Enhancer alkene synthesis

The most common applications of the HWE reaction are in the synthesis of disubsdtuted ( )-alkenes. The stereoselectivity of the reaction can be maximized by increasing the size of the substituents on the phosphoryl portion. In cases where the stabilizing functionality is a carboxy group, the size of the ester may be tuned to enhance ( )-alkene formation. 

In contrast to many other methods commonly employed for stereoselective alkene synthesis such as elimination, alkenylation, alkene metathesis, alkyne addition, the JuUa olefination, and the Peterson olefination [1-3], the olefination reactions of phosphorus-stabilized carbon nucleophiles remain very powerful for modem stereoselective alkene synthesis owing to their convenience, complete positional selectivity, and generally high levels of geometrical control. However, further modifications of these olefination reactions are definitely needed to broaden substrate scope, enhance stereoselectivity, and improve environmental impacts. 

We will focus on the development of ruthenium-based metathesis precatalysts with enhanced activity and applications to the metathesis of alkenes with nonstandard electronic properties. In the class of molybdenum complexes [7a,g,h] recent research was mainly directed to the development of homochi-ral precatalysts for enantioselective olefin metathesis. This aspect has recently been covered by Schrock and Hoveyda in a short review and will not be discussed here [8h]. In addition, several important special topics have recently been addressed by excellent reviews, e.g., the synthesis of medium-sized rings by RCM [8a], applications of olefin metathesis to carbohydrate chemistry [8b], cross metathesis [8c,d],enyne metathesis [8e,f], ring-rearrangement metathesis [8g], enantioselective metathesis [8h], and applications of metathesis in polymer chemistry (ADMET,ROMP) [8i,j]. Application of olefin metathesis to the total synthesis of complex natural products is covered in the contribution by Mulzer et al. in this volume. 

Metal-catalyzed C-H bond formation through isomerization, especially asymmetric variant of that, is highly useful in organic synthesis. The most successful example is no doubt the enantioselective isomerization of allylamines catalyzed by Rh(i)/TolBINAP complex, which was applied to the industrial synthesis of (—)-menthol. A highly enantioselective isomerization of allylic alcohols was also developed using Rh(l)/phosphaferrocene complex. Despite these successful examples, an enantioselective isomerization of unfunctionalized alkenes and metal-catalyzed isomerization of acetylenic triple bonds has not been extensively studied. Future developments of new catalysts and ligands for these reactions will enhance the synthetic utility of the metal-catalyzed isomerization reaction. 

The synthetic utility of the carbonylation of zirconacycles was further enhanced by the development of a pair of selective procedures producing either ketones or alcohols [30] and has been extensively applied to the synthesis of cyclic ketones and alcohols, most extensively by Negishi [22—27,29—33,65,87,131—134], as detailed below in Section I.4.3.3.4. The preparation of unsaturated aldehydes by carbonylation with CO is not very satisfactory. The use of isonitriles in place of CO, however, has provided a useful alternative [135], and this has been applied to the synthesis of curacin A [125]. Another interesting variation is the cyanation of alkenes [136]. Further developments and a critical comparison with carbonylation using CO will be necessary before the isonitrile reaction can become widely useful. The relevant results are shown in Scheme 1.35. 

The most widely used, and often most convenient reagents for such one-pot reactions are sodium hypochlorite (45) or hypobromite (16). These reactions are performed in the presence of an organic base (generally triethylamine) that normally enhances the yield of cycloaddition products (45). This method was employed for many intermolecular reactions (71) and also seems especially suited for intramolecular ones (72-77) as well as for the solid-phase synthesis (78) of 2-isoxazolines. Hypohalite can also be replaced by sodium bromite in combination with a catalytic amount of tri-n-butyltin chloride (79). In a related method, O-tributylstannyl oximes were treated with fert-butyl hypochlorite to produce nitrile oxides that were trapped with alkenes or alkynes to afford the corresponding isoxazolines or isoxazoles in moderate to good yield (80). 

Homer-Wadsworth-Emmons reactions of ketones and aldehydes with phosphono-acetate esters, (R20)2P(=0)CH2C02R1, produce E/Z mixtures of a, /Tunsaturated esters. Use of the conventional reagent, sodium hydride, gives some selectivity. The combination of tin(II) triflate and A -cthylpipcndine enhances—and sometimes also reverses—the selectivity in most cases studied.71 Six-membered oxo-coordinated tin intermediates are proposed to control the selectivities observed. A similarly selective synthesis of trisubstituted exocyclic alkenes from cyclic ketones has been reported.72... 

The enhanced reaction rates and regioselectivities (head-to-head) in the alkene dimerisation (cyclobutane formation e.g. 18-19) via radical cation catalysed reactions have led numerous studies in this direction [5,10, 36-39]. The head-to-head stereochemistry of these dimerisations have been explained in terms of the addition of the radical cation to a neutral molecule giving the stabilised 1,4-radical cation. An interesting application of the cation-radical initiated (2 + 2)-cyclodimerisation strategy was reported by Mizuno et al. [40] for the synthesis of macrocyclic 2-m-dioxabicyclo (m-1,2,0) ring systems (21) from the PET reactions of 20 (Scheme 6). 

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