Cyclic a,P-unsaturated ketones

Asymmetric induction by sulfoxide is a very attractive feature. Enantiomerically pure cyclic a-sulfonimidoyl carbanions have been prepared (98S919) through base-catalyzed cyclization of the corresponding tosyloxyalkylsulfoximine 87 to 88 followed by deprotonation with BuLi. The alkylation with Mel or BuBr affords the diastereomerically pure sulfoximine 89, showing that the attack of the electrophile at the anionic C-atom occurs, preferentially, from the side of the sulfoximine O-atom independently from the substituent at Ca-carbon. The reaction of cuprates 90 with cyclic a,p-unsaturated ketones 91 was studied but very low asymmetric induction was observed in 92. 

Cyclic a,p-unsaturated ketones can be cleaved by treatment with base of their epoxy tosylhydrazone derivatives to give acetylenic ketones. The reaction can be applied to the formation of acetylenic aldehydes (R=H) by using the corresponding, 2,4-dinitrotosylhydrazone derivatives.Hydrazones (e.g., 47) prepared from... 

The use of cyclic a,p-unsaturated ketones as starting materials in the enantioselective addition of dimethyl- and diethylzinc reagents catalysed by the HOCSAC ligand was introduced by Walsh and Jeon, in 2003. As shown in Scheme 4.16, the corresponding cyclic tertiary alcohols were formed in high enantioselectivities of up to 99% ee. 

Scheme 4.16 Additions of ZnR2 to cyclic a,P-unsaturated ketones with HOCSAC ligand.

Hanessian described the facile addition of cyclic and acyclic nitroalkanes to cyclic a,P-unsaturated ketones using L-proline 58 as the catalyst (3-7 mol%) in the presence of 2,5-dimethylpiperazine [100], The reactions proceeded efficiently at room temperature and consistently provided adduct 59 with increased levels of enantioselectivity when compared with the rubidium prolinate method disclosed by Yamaguchi [29] (Scheme 24). The presence of trace amounts of water in the reaction was found to be essential, suggesting a hydrolytic step is involved in the catalytic... 

Chen extended the scope of his iminium ion catalysed [3+2] cycloaddition with azomethine imines (see Sect. 2.1.2) to encompass cyclic a,P-unsaturated ketone substrates using primary amine 147 as the catalyst [194]. Interestingly, the presence... 

List later applied this strategy to the 1,4 reduction of various acyclic and cyclic a,P-unsaturated ketones using the diasteriomeric salt 15 (Scheme 5.37) [66]. Notably, use of the opposite (S) phosphate counterion resulted in a matched/ mismatched ion pair combination, forming the same enantiomer of the product but in significantly diminished ee. 

Isophorone. Isophorone (3,5,5-trimethyl-2-cyclohexen-l-one) is a cyclic a,p-unsaturated ketone derived from the trimerization of acetone. It has a light yellow color and a disagreeable camphoraceous odor. It has the tendency to discolor and form residues on prolonged storage. Isophorone is completely miscible with organic solvents, and other physical properties are listed in Table 1. 

As an extension of this highly enantioselective Michael addition of silyl nitronates with a, p-unsaturated aldehydes, the reactions with cyclic a,p-unsaturated ketones as a Michael acceptor were also tested (Scheme 9.15). Cyclohexenone and cyclohepte-none were employed as a useful Michael acceptor with various silyl nitronates in the presence of catalyst (R,R)-6c, and gave the corresponding enol silyl ethers 28 with excellent stereoselectivities [30]. 

A chiral complex of (1), L1A1H4, and A/-ethylaniline (molar ratio, 1 1 2) reduces aryl alkyl ketones to optically active alcohols in high ee. a, -Unsaturated ketones are reduced enantioselectively to afford optically active (S)-allylic alcohols with 80-98% ee. An intermediate in an anthracyclinone synthesis is prepared in 92% ee by the enantioselective reduction of a cyclic a,p-unsaturated ketone (eq 2). ... 

Cyclic a,p-unsaturated ketones can be cleaved by treatment with base of... 

The naturally occurring ionone pair 37 and 38 demonstrate again that the effect of conjugation on acyclic carbonyl NMR chemical shift is smaller than that for cyclic a,P-unsaturated ketones. 

The total synthesis of galbulimima alkaloid GB 13 was accomplished by L.N. Mander and co-workers. The Birch reduction of a complex intermediate was necessary in order to prepare a cyclic a,p-unsaturated ketone. The treatment of the substrate with lithium metal in liquid ammonia first resulted in a quantitative reductive decyanation of the C6a cyano group. The addition of excess ethanol to the reaction mixture reduced the aromatic ring to the corresponding enol ether that was hydrolyzed in a subsequent step to afford the unsaturated ketone. 

Carbonylation of the cuprate reagent, R (CN)CuLi2, prepared from copper(I) cyanide and an alkyl-lithium, gives a product which can be used for the direct nucleophilic 1,4-acylation of a,3-unsaturated aldehydes and ketones (equation 16). The reaction works particularly well with cyclic a,p-unsaturated ketones to give high yields of the expected 1,4-diketone. 

The Corey-Bakshi-Shibata reduction (CBS reduction) is a highly enantioselective method for arylketones, diaryl ketones, and dialkylketones. In addition, cyclic a,p-unsaturated ketones, acyclic a,p-unsaturated ketones, and a,p-ynones are reduced enantioselectively in a 1,2-fashion. The high enantioselective nature of this reduction relies on the chiral oxazaborolidine catalyst, shown in the reaction scheme, in the presence of borane or a dialkylborane. Reviews (a) Singh, V. K. Synthesis 1992, 605-617. (b) Deloux, L. Srebnik M. Chem. Rev. 1993,93,163-1. (c) Corey, E. J. Helal, C. J. Angew. Chem. Int. Ed. 1998, 37. 1986-2012. 

The addition of diethyl 1-bromo-l,1-difluoromethylphosphonate to various electron-deficient alkenes initiated by a cobaloxime(III)/Zn bimetallic system gives the corresponding diethyl difluoro-alkylphosphonates (1 1 Michael-type adducts) in moderate to good yields (34-72%). Cyclic a,p-unsaturated ketones and electron-rich alkenes produce somewhat lower yields of addition products (18-58%), along with small quantities of diethyl difluoromethylphosphonate. A radical mechanism has been proposed for this process. ... 

It has been shown recently that 3-oxocycloaIkylphosphonates can be prepared by photochemical phosphonosilylation of cyclic a,P-unsaturated ketones. Thus, irradiation of a mixture of dialkyl trimetylsilyl phosphite and cyclic a,P-unsaturated ketones in MeCN provides essentially conjugate... 

There have been frequent reports of the condensation of cyclic a,p-unsaturated ketones at the 7-position an example is seen in equation (88).102 Other 3-methyIcyclohexenones have been reported to undergo similar reactions.103 Unfortunately, the original literature does not report yields for these transformations. These reactions would bear reinvestigation with modem methods of analysis. Other cy-clohexenones have also been found to undergo aldol condensation at the 7-position. For example, car-vone condenses with two equivalents of benzaldehyde (equation 89).104... 

Reduction of cyclic a,p-unsaturated ketones in which there are substituents on the (3- and y -carbon atoms could give rise to two stereoisomeric products. In many cases one isomer is formed predominantly, generally the more stable of the two. The guiding principle appears to be that protonation of the intermediate anion takes place orthogonal to the enol double bond (axially in six-membered rings). Thus,... 

By treatment of acetals, obtained from chiral 1,3-diols and cyclic a,p-unsaturated ketones with /BU3AI, enolethers are obtained bearing an alcohol functionality, which proved to be necessary to obtain high diastereoselectivity. ... 

In 2004, the tra s-4-amino-L-proline derived di-, tri- and tetrapeptides 13a-c were studied in the group of Tsogoeva for asymmetric 1,4-conjugate addition reactions. The addition of different nitroalkanes to cyclic a,p-unsaturated ketones in the presence of achiral tra s-2,5-dimethylpiperazine (14) of Hanessian as a stoichiometric additive and peptides 13a-c at only 2 mol% loading were investigated. Two 4-trans-amino-proline residues (catalyst 13a) were shown to be sufficient to eatalyse the conjugate addition reactions with up to 88% enantiomeric excess and up to 100% yield (Scheme 13.11). 

Chiral glyoxylic acid derivatives, i.e. (— )-8-phenylmenthyl glyoxylate, imdergoes an MBH reaction with cyclic a,p-unsaturated ketones under the... 

The asymmetric counteranion directed organocatalysis has been also applied to the enantioselective transfer hydrogenation of a,f)-unsaturated ketones employing catalyst 11, which involves a chiral cation such as a valine ester anunonium salt and a chiral binaphthol derived phosphate [23]. This combination, in the presence of the Hantzsch ester 4, is a very active and enantioselective system for the transfer hydrogenation of a variety of cyclic a,P-unsaturated ketones (Scheme 2.5). Acyclic ketones are also reduced but with slightly lower enantioselectivities. 

Scheme 2.36 Cinchoninium-catalyzed dimerization of cyclic a,p-unsaturated ketones...

Maruoka et al. have developed and used A-spiro C2-symmetric chiral quaternary ammonium bifluorides [151] 102, 103, and more recently 104, to promote the regio- and anti-selective Mukaiyama-Michael addition of silyl nitronates to a, 3-unsaturated aldehydes [152], cyclic a,P-unsaturated ketones [153], and nitroalk-enes [154] with good yields and enantioselectivities (Scheme 2.52). Final chiral silyl enol ethers are easily hydrolyzed to the corresponding carbonyl compounds or functionalized at the a-position by reaction with electrophiles. 

Melchiore et al. reported highly stereoselective aziridinations of linear and cyclic a,p-unsaturated ketones with excellent diastereo- and enantio-selectivity (up to 99% ee). Aziridination was performed using N-protected hydrojylamines and a primary amine salt catalyst, made by combining 9-amino-9-deo)y-ep/-dihydroquinine (9-epz-DHQA) with o-N-Boc-phenylglycine (Scheme 15.8). The first step of the reaction is the nucleophilic addition of Af-protected hydro>ylamine to the iminium intermediate (formed from the enone and amine catalyst salt) followed by an intramolecular cyclisation of the resulting enamine to the aziridine product. 

The authors expanded their work to include a,P-unsaturated ketones. Again a series of reactions were performed with 2-phenylpyridine and a,P-unsaturated ketones 254-257 this time using THF as a solvent with a longer reaction periods. The desired Michael addition prodncts 258-261 were produced in high yield regardless of the substituent. Cyclic a,p-unsaturated ketones such as cyclopent-2-enone also gave high yields of the desired products 264-266. 

The primary and fastest photochemical reaction of acyclic and some cyclic a, P-unsaturated ketones is cis-trans isomerisation. This isomerisation is not expected for cyclopent-2-enone or cyclohept-2-enone because of high strain energy, but it has been reported for cis-cyclooct-2-enone and cis-cyclohept-2-enone. It is thought to occur from triplet excited state. 

The strategy was extended to a tandem o-nitroso aldol-Michael reaction with cyclic a,P-unsaturated ketones to produce enantiopure nitroso Diels-Alder adducts 74 in moderate yields (Scheme 1.22) [24]. 

---