Ketones stereoselective reactions

The condensation of aldehydes or ketones with secondary amines leads to "encunines via N-hemiacetals and immonium hydroxides, when the water is removed. In these conjugated systems electron density and nudeophilicity are largely transferred from the nitrogen to the a-carbon atom, and thus enamines are useful electroneutral d -reagents (G.A. Cook, 1969 S.F. Dyke, 1973). A bulky heterocyclic substituent supports regio- and stereoselective reactions. 

In most cases, however, many substrates give a mixture of stereoisomers with a certain degree of stereoselectivity. When ketone 39 was treated with potassium cyanide and ammonium carbonate in ethanol/water, a mixture of epimeric hydantoins 40 and 41 were isolated.Similarly, the Bucherer-Bergs reaction of ketone 42 gave rise to a... 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

In the course of some stereoselective reactions the inducing chiral unit is destroyed. A classical example is the enantioselective Meerwein Ponndorf reduction of a ketone with a chiral Grig-nard compound33 ... 

Stereoselective reaction with ketones. The reaction of ketone 1 with methyl-lithium, trimethylaluminum, and lithium letramethylaluminate shows no stcrco-specificity. The reaction with mcthylmagncsium bromide gives the two possible adducts in the ratio 2.4 1. The best stereospccificity is observed with dimethylsulf-oxonium methylide, which converts 1 into 2 and 3 in a ratio about 5 1. Reduction of the epoxides with lithium triethylborohydride gives the desired tertiary alcohols. This reaction was used in a synthesis of ( ) stemodin (4).2... 

The product is the racemic [(R)/(S)] alcohol since the free energies of the two diastereoisomeric transition states, resulting from hydride attack on the si-face of the ketone as shown (order of priorities O > R1 > R2, p. 16) or the re-face, are identical. The use of an aluminium alkoxide, derived from an optically pure secondary alcohol, to effect a stereoselective reaction (albeit in low ee%) was one of the first instances of an asymmetric reduction.48 Here (S)-( + )-butan-2-ol, in the form of the aluminium alkoxide, with 6-methylheptan-2-one was shown to give rise to two diastereoisomeric transition states [(5), (R,S) and (6), (S,S)] which lead to an excess of (S)-6-methylheptan-2-ol [derived from transition state (6)], as expected from a consideration of the relative steric interactions. Transition state (5) has a less favourable Me—Me and Et—Hex interaction and hence a higher free energy of activation it therefore represents the less favourable reaction pathway (see p. 15). 

The key to the difference is in the conformations. The cyclic ketone has one conformation and the two approaches to the faces of the ketone are very different. The open-chain compound has an indefinite number of conformations as rotation about all the C-C bonds is possible. In any one conformation, attack on one face of the ketone or the other may happen to be preferred, but on average there will be very little difference. There is all the difference in the world between cyclic and open-chain compounds when it comes to stereoselective reactions. This is why we have made this topic into two chapters this one (33) dealing with rings, the next (34) with what happens without rings. 

The report includes details for asymmetric a-alkylation of a symmetrical ketone (97% ee) via the SAMP hydrazone and references to other stereoselective reactions of SAMP (or RAMP) hydrazones. Under standard conditions (LDA, 0°), deprotonation takes place regioselectively at the less substituted a-position with uniform dia.stereoface differentiation. 

Arenetellurolates, ethenetellurolates, and alkanetellurolates prepared by reduction of diorgano ditellurium compounds with sodium borohydride in ethanol, THF/ethanol, or DMSO add to acetylenes in regioselective and tran.v-stereoselective reactions to produce aryl ethenyl tellurium products either predominantly or exclusively as fZ)-isomers. The yields are almost always higher than 70%. In reactions with acetylenic aldehydes, ketones, carboxylic acids, and esters the arenetellurolate becomes bonded to the carbon atom in a fi-position to the carbonyl group. 

Af-Unsubstituted pyrazoles and indazoles add to compounds containing activated double and triple bonds (67HC 22)1,B-76MI40402>. Amongst C—C double and triple bonds, maleic anhydride, acrylic acid esters and nitriles, acetylene-carboxylic and -dicarboxylic esters (78AHC(23)263), quinones, and some a,/3-unsaturated ketones have been used with success. Phenylacetylene reacts with pyrazole in the presence of Na/HMPT as catalyst to yield the Z isomer of 1-styrylpyrazole in a highly stereoselective reaction (78JHC1543). 

A stereoselective reaction leads to the exclusive or predominant formation of one of several possible stereoisomeric products. Thus, one reaction pathway from a given substrate is favored over the other (as in nucleophilic additions to cyclic ketones or alkylations of enolate ions). 

In each of the stereoselective reactions described above, the double bond is formed by connecting two separate molecules. The steps leading to the alkene involve addition of a carbanion to the carbonyl carbon of an aldehyde or a ketone followed by an elimination process. 

Allyltri- -butyltin usually requires activation to perform effective allylation of carbonyl compounds. Stereoselective reactions occasionally occur in the presence of the strong Lewis acids TiCU, SnCU, and BF3-OEt2. These conventional Lewis acids cannot, however, be used for chemoselective allylation of carbonyl compounds bearing other reactive functional groups, because of further transformation and decomposition of the products. It has been found that the lead diiodide-HMPA complex is a good catalyst for chemo- and diastereoselective allylation of a,73-epoxy ketones under mild neutral conditions (Scheme 13.62) [81]. 

The structure and absolute stereochemistry of hinesol (282) has now been firmly established by an unequivocal synthesis which involved the tricyclic dienone (329) prepared from 6-methoxy-l-tetralone. Treatment of the dienone with lithium dimethylcopper gave a mixture of syn and anti enones (330). By a series of stereoselective reactions this compound was converted to the diol (331) whose mono-mesylate underwent a base-induced cleavage to give the spiro[4,5]-ketone (332). Elaboration of this ketone to hinesol was accomplished along... 

A new approach to isocomene synthesis involving a transannular reaction has been described 2i. Rcgioselective oxirane ring opening after protonation initiates a stereoselective reaction to give the hydroxy ketone 15, w hich can be transformed into the natural product in several steps. 

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