Substitution, geminal dimethyl

All the ring transform packages in LHASA employ binary search techniques. This means that all structural questions are to be answered with a yes or a no. Preparation of the sequence of questions relating to straightforward chemical situations poses no real problems. It is the identification and resolution of the extraordinary cases that are difficult. For example, in a Robinson disconnection for the sequence below, the geminal dimethyl substitution is a formidable problem. 

It is up to the chemist designing the tables to first perceive that this situation might occur. Second, decide whether he wishes to have the tables salvage the difficult situation and if he does, he has to manually determine what kind of chemistry should be attempted. 

The above example is a clear black or white situation. Unless the dimethyl substituent is removed, the transform just cannot proceed. The grey areas cause just as much of a dilemma for the chemist, In Marshall s synthesis of isonootkatone two possible stereoisomers could have resulted. 

ACS Symposium Series American Chemical Society Washington, DC, 1977. 

As we have been adding to the data base at Du Pont (to the one and two group tables), the question has often been raised how much detail should we go into in the qualifiers This is somewhat of a dilemma, many of the industrial reactions we are dealing with have only been considered for a limited number of substrates. It is not clear whether qualifiers should be incorporated that restrict the transforms to only those cases where it is known to work or whether only those which are known to fail should be specifically excluded. Both ways take an immense amount of literature work to do consistently. 

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The 1,3-dipolar cycloaddition of diazomethane to bicyclic 2,/S-unsaturated /-lactams produces pyrazolidines which are transformed photolytically into cyclopropane derivatives80. The overall yields arc moderate to good while the diastereomeric ratio is at least 95 5. Reaction of the thiomethyl-substituted lactam with 2-diazopropane provides the corresponding geminal dimethyl-substituted cyclopropane with a d.r. of 95 5. These cyclopropane derivatives have been used for the synthesis of optically active cyclopropanecarboxylates and ethenylcyclopropanes80. 

The a,/ -unsaturated y-lactam 37 which incorporates i -/m-leucinol as an auxiliary is cyclo-propanated by diphenylsulfonium isopropylidene in very high yield to afford the geminal dimethyl-substituted cyclopropane derivative 38. This enantiomerically pure compound is used for the preparation of the pyrethroid (15,3/ )-cw-deltamethrinic acid80. 

A similar desire for geminal dimethyl-substituted cyclopropanes resulted in the use of isopropylidene triphenylphosphorane as the carbene source. Reaction with acceptor-substituted alkenes carrying inducing auxiliaries gave intermediates for syntheses of chrysanthemic acid derivatives. Thus, the addition to (A )-butencdioatcs provides 3,3-dimethyl-1,2-cyclopropanedi-earboxylates 3986. The highest diastereoselectivity is observed with the (—)-8-phenylmenthyl derivative which gives the cyclopropane with a d.r. of 91 9. 

The use of titanium species in organic synthesis is increasing notably. Ketones react with dimethyltitanium dichloride under mild conditions leading directly to the corresponding geminal dimethyl-substituted compounds (Scheme 12). As the geminal dimethyl substituent occurs in many natural products, this procedure could find many applications. 

Ethylene dithioacetals of benzophenone and its 4-fluoro-, 4-bromo-, 4,4 -difluoro-, 4,4 -dichlo-ro-, and 3,5-dimethyl-substituted analogs react with sulfuryl chloride or sttlfuryl chloride fluoride in hydrogen fluoride/ pyridine at — 78 C to room temperature to give the corresponding geminal difluorides in 85-90% yield. The reaction is, however, not applicable to dialkyl or alkyl aryl ketones as they undergo chlorination under these conditions.73... 

More specifically, it was found that with geminal dimethyl-trisubstituted alkenes, the methyl group in the less substituted side of the double bond became significantly more reactive within zeolite compared to the solution. This result is illustrated in Scheme 27. 

Catalytic hydrogenation of alkyl-substituted cyclopropanes usually breaks the least hindered bond . This constitutes a nice method for converting ketones into geminal dimethyl compounds (equation 13) , a principle realized for the syntheses of natural and unnaturaP products. 

Transformation of the C4 carbonyl to the necessary geminal dimethyl group would eliminate the cross-conjugati(Mi and allow for a selective saturation of the less substituted C6-C7 alkene. It was intended that compound 69... 

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