Retro 1,4-additions

Note Although not being correct to describe a reaction, the term ortho effect is well established, and another occasionally used term, retro-1,4-addition, is redundant 1,4-elimination would describe the same. Unfortunately, this might be confused with l,4-H20-eliminations from aliphatic alcohols, for example. Therefore, the term ortho elimination is suggested and used here. 

Easy retro-1,4-additions of 8-ury/-2-azabicyclo[3,3,l]nonan-7-ones were reported, see Bonjoch, J., Quirante, J., Sole, D., Castells, J., Galceran, M., Bosch, J., Tetrahedron, 1991, 47, 4417. 

Over the years, there have been a number of reports on the kinetic conjugate addition of metallated arylacetonitriles to enones. Several proposals have been made to explain the mechanism and outcome of this reaction based on the nucleophile structure or aggregation state or on the HSAB properties of the reactants. A reexamination of these studies has now revealed that in each case the 1,4-adducts resulted from equilibration of the kinetically formed 1,2-adducts to the more stable 1,4-adducts. The 1,2-addition, retro-1,2-addition, 1,4-addition, and retro-1,4- addition of PhC=C=NLi to PhCH=CHCOMe were examined, and a free energy level diagram was constructed.159... 

The synthesis of isoxazolines usually takes the most thermodynamically favorable course to yield solely the more stable isomer. However, cinnamic acids (38) give not only isoxazoline-4-carboxylic acids (39) but also, as a by-product, the less stable isoxazoline-5-carboxylic acids (40)" which on heating undergo retro-addition. ... 

The diphosphabenzvalene-phenyl azide adduct (Scheme 22) undergoes a similar retro addition when treated with silica gel to yield l-phenyl-4,5-bis(trifluoromethyl)-1,2,3-triazole the fate of the diphosphabicyclobutane part, however, is not clear.165... 

Discussion Catalyst 52 is prepared from Boc-(L)-ter -leucine in five steps, with a 75% overall yield [41]. Details of imine and phosphite preparation are also provided by Jacobsen and co-workers [81]. The hydrophosphonylation reactions as reported by Jacobsen can be carried out without any special precautions, in unpurified commercial diethyl ether (Et20) and under an ambient atmosphere. A reduction in temperature was shown to have a beneficial effect on product enantiopurities, but with a decrease in reaction rates. Unbranched aliphatic aldehydes were incompatible with the reaction conditions as reported, due to their rapid decomposition prior to phosphonylation. Although phosphite ester groups that are more electron-withdrawing than o-nitrobenzyl significantly increase the overall reaction rates, products are obtained with diminished optical purities, possibly due to a retro-addition pathway. 

The enantioselective Henry reaction with ketones is challenging, owing to the attenuated reactivity of the ketone carbonyl group compared to the aldehyde carbonyl moiety and the high tendency of tertiary nitro-aldol adducts to undergo a retro-addition reaction under basic conditions [15], Stereoselective construction of... 

A paper on the use of polarized n frontier orbital theory for correctly predicting the selectivities of protonation and sulfenylation of pyranoid and furanoid glycals has appeared. The cycloaddition adducts formed by the high pressure addition of tosyl isocyanate to glycal acetates (see Chmielewski et al.y Vol. 19, p. 131) have been shown to revert on heating to 60 -70 . The rate of retro-addition increases with rising temperatures and increasing solvent polarity. 

Information-oriented systems are based on a Hbrary of known retro-reactions which have been collected and evaluated by a group of chemists while coding them in electronic form. In addition, information on the scope and the expected yield under various conditions, as well as a strategic merit, is usually stored. 

Another category Ic indole synthesis involves cyclization of a-anilino aldehydes or ketones under the influence of protonic or Lewis acids. This corresponds to retro.synthetic path d in Scheme 4.1. Considerable work on such reactions was done in the early 1960s by Julia and co-workers. The most successful examples involved alkylation of anilines with y-haloacetoacetic esters or amides. For example, heating IV-substituted anilines with ethyl 4-bromoacetoacetate followed by cyclization w ith ZnClj gave indole-3-acetate esterfi]. Additional examples are given in Table 4.3. 

This cleavage is a retro aldol reaction It is the reverse of the process by which d fruc tose 1 6 diphosphate would be formed by aldol addition of the enolate of dihydroxy acetone phosphate to d glyceraldehyde 3 phosphate The enzyme aldolase catalyzes both the aldol addition of the two components and m glycolysis the retro aldol cleavage of D fructose 1 6 diphosphate... 

Cleavage reactions of carbohydrates also occur on treatment with aqueous base for prolonged periods as a consequence of base catalyzed retro aldol reactions As pointed out m Section 18 9 aldol addition is a reversible process and (3 hydroxy carbonyl com pounds can be cleaved to an enolate and either an aldehyde or a ketone... 

Vinylpyridine (23) came into prominence around 1950 as a component of latex. Butadiene and styrene monomers were used with (23) to make a terpolymer that bonded fabric cords to the mbber matrix of automobile tires (25). More recendy, the abiUty of (23) to act as a Michael acceptor has been exploited in a synthesis of 4-dimethylaminopyridine (DMAP) (24) (26). The sequence consists of a Michael addition of (23) to 4-cyanopyridine (15), replacement of the 4-cyano substituent by dimethylamine (taking advantage of the activation of the cyano group by quatemization of the pyridine ring), and base-cataly2ed dequatemization (retro Michael addition). 4-r)imethyl aminopyri dine is one of the most effective acylation catalysts known (27). 

In E. coli GTP cyclohydrolase catalyzes the conversion of GTP (33) into 7,8-dihydroneoptetin triphosphate (34) via a three-step sequence. Hydrolysis of the triphosphate group of (34) is achieved by a nonspecific pyrophosphatase to afford dihydroneopterin (35) (65). The free alcohol (36) is obtained by the removal of residual phosphate by an unknown phosphomonoesterase. The dihydroneoptetin undergoes a retro-aldol reaction with the elimination of a hydroxy acetaldehyde moiety. Addition of a pyrophosphate group affords hydroxymethyl-7,8-dihydroptetin pyrophosphate (37). Dihydropteroate synthase catalyzes the condensation of hydroxymethyl-7,8-dihydropteroate pyrophosphate with PABA to furnish 7,8-dihydropteroate (38). Finally, L-glutamic acid is condensed with 7,8-dihydropteroate in the presence of dihydrofolate synthetase. 

Addition of dimethylsulfoxonium methylide has also been studied in the retro steroid (9, 10a) series. Results are somewhat different from observations in the normal series. Thus only the 6, 7)3-methylene adduct is obtained from a 4,6-dien-3-one while 6-chloro-9) ,10a-l,4,6-trien-3-ones undergo attack at the 6,7-double bond in preference to the 1,2-double bond resulting in the formation of 6a-chloro-6)5,7i5-methylene-A -3-ones. ... 

The ratio of products 15 and 16 is dependent on the structures, base, and the solvent. The kinetics of the reaction is likewise dependant on the structures and conditions of the reaction. Thus addition or cyclization can be the rate-determining step. In a particularly noteworthy study by Zimmerman and Ahramjian, it was reported that when both diastereomers of 20 were treated individually with potassium r-butoxide only as-epoxy propionate 21 was isolated. It is postulated that the cyclization is the rate-limiting step. Thus, for these substrates, the retro-aldolization/aldolization step reversible. ... 

The Pictet-Spengler condensation has been of vital importance in the synthesis of numerous P-carboline and isoquinoline compounds in addition to its use in the formation of alkaloid natural products of complex structure. A tandem retro-aldol and Pictet-Spengler sequence was utilized in a concise and enantioselective synthesis of 18-pseudoyohimbone. Amine 49 cyclized under acidic conditions to give the condensation product 50 in good yield. Deprotection of the ketone produced the indole alkaloid 51. 

These amines gave, with methyl propiolate, products of Michael mono- and bis-addition. Adducts underwent further reaction leading to triazolo[4,5-/]quinolones 181, after retro Diels-Alder reaction and acetylene elimination to its methoxycar-... 

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