Ketone reagent control

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

Early work on the asymmetric Darzens reaction involved the condensation of aromatic aldehydes with phenacyl halides in the presence of a catalytic amount of bovine serum albumin. The reaction gave the corresponding epoxyketone with up to 62% ee.67 Ohkata et al.68 reported the asymmetric Darzens reaction of symmetric and dissymmetric ketones with (-)-8-phenylmenthyl a-chloroacetate as examples of a reagent-controlled asymmetric reaction (Scheme 8-29). When this (-)-8-phenyl menthol derivative was employed as a chiral auxiliary, Darzens reactions of acetone, pentan-3-one, cyclopentanone, cyclohexanone, or benzophenone with 86 in the presence of t-BuOK provided dia-stereomers of (2J ,3J )-glycidic ester 87 with diastereoselectivity ranging from 77% to 96%. 

Whereas the thermodynamic route described above relied on reagent control to establish the spongistatin C19 and C21 stereocentres, the discovery of highly stereoselective 1,5-anti aldol reactions of methyl ketones enabled us to examine an alternative,16 substrate-based stereocontrol route to 5. Regioselective enolisation of enantiomerically pure ketone 37, derived from a readily available biopolymer, gave end... 

In reagent-controlled epoxidation the asymmetric induction has its origin in a chiral ylide. The reaction of an achiral aldehyde or ketone with a chiral ylide gives optically active compounds. 

Our synthesis of the C1-C7 fragment 227 of oleandolide started with a substrate-controlled tin-mediated aldol reaction of a-chiral ketone (5)-18 which afforded syn adduct 52 with 93% ds. This same transformation could also be achieved using reagent control with (Ipc)2BOTf, albeit with lower selectivity (90% ds). In a key step, treatment of the aldol adduct 52 with (-i-)-(Ipc)2BH led to controlled reduction of the C3 carbonyl together with stereoselective hydrobora-tion of the C -Cv olefin, affording the desired triol 228 with 90% ds. 

We have already collected some powerful tools for use in stereocontrolled aldol reactions, but we have not finished. We shall see now in Paterson s synthesis of (+)-discodermolide, how reagent control is used not to enhance the intrinsic substrate selectivity, but to overturn it. The aldol reaction is undoubtedly one of the most powerful ways of making carbon-carbon bonds and nature thinks so too. There are numerous natural products that are replete with 1,3 related oxygen functionality. Many of these are acetate or propionate-derived in nature. The methods detailed above developed from studies into the syntheses of these natural products. The manipulations of chiral ethyl ketones of this kind are of particular interest when it comes to natural products that are polypropionate-derived. 

Scheme 5.27. (a) Anti-selective addition of ketone (0)-enolate to aldehydes [137,138] (b, c) Reagent controlled addition of Z(0)-enolate to aldehydes [126] (d) Double asymmetric induction where the mismatched diastereoselectivity is decreased, not reversed [139]. 

A final comment has to be made on the reduction of ketone 150 with Corey s catalyst 157 (19). The mechanism (20) involves the formation of transition state complexes such as 158 in which, by interaction with the rest of the molecule the small substituent (Rs) of the ketone points upward and the large substuent (RL) downward. Remarkable, for ,/j-unsaturated ketones the vinyl group is the large one and this is indeed confirmed by our case. The reduction is reagent controlled, but the substrate in-... 

The synthesis of 112 was then modified to provide a single enantiomer. This called for an asymmetric synthesis of cyclization substrate 111. This was accomplished by Midland reduction of ketone 113 to provide 114 with excellent enantioselectivity (Steroids-21). Alkylation of 114 with the appropriate bromide (prepared from 2-methylfuran according to the procedures described on Steroids-18), followed by a few well-precedented reactions, gave 115, and thence 111 and 112. Application of the Midland reduction is notable. This is a relatively early application of a reagent-controlled asymmetric synthesis. It is also notable that the Midland method works extremely well on alkyl alkynyl ketones (because they look like aldehydes to the reagent) and thus, is well-suited to this application. ... 

Scheme 5.129 Enantioselective silver-catalyzed reaction of silicon enolates 521 with nitrosobenzene 515 to a-aminooxy ketones 519, mediated by ligand 522. Reagent control in the reaction of enantiomeric silicon enolates 523.

A mixture of methanesulfonic acid and P Oj used either neat or diluted with sulfolane or CH2CI2 is a strongly acidic system. It has been used to control the rcgiosclcctivity in cydization of unsymmetrical ketones. Use of the neal reagent favours reaction into the less substituted branch whereas diluted solutions favour the more substituted branch[3]. 

In most cases, the product ratio can be controlled by choice of reaction conditions. Ketones are isolated under conditions where the tetrahedral intermediate is stable until hydrolyzed, whereas tertiary alcohols are formed when the/Tetrahedral intermediate decomposes while unreacted organometallic reagent remains. Bxamples of synthetic application of these reactions will be discussed in Chapter 7 of Bart B. 

The success of the halo ketone route depends on the stereo- and regio-selectivity in the halo ketone synthesis, as well as on the stereochemistry of reduction of the bromo ketone. Lithium aluminum hydride or sodium borohydride are commonly used to reduce halo ketones to the /mm-halohydrins. However, carefully controlled reaction conditions or alternate reducing reagents, e.g., lithium borohydride, are often required to avoid reductive elimination of the halogen. 

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