Enone sulfoxide

We reasoned that some cyclic enone sulfoxides should form an even more rigid chelate than that formed from the corresponding acyclic alkenyl sulfoxides when complexed with metal ions model exemplifies the case for a cyclopentenone sulfoxide and suggests a high degree of stereocontrol during the nucleophilic addition reaction. 

To preform a strong enone sulfoxide-metal ion complex and thus possibly to increase the amount of asymmetric induction, several metal dibromides were added to eyelopentenone sulfoxide ( )-(+)-10. As shown in eq. 12, only zinc dibromide was highly effective in raising the extent of asymmetric induction during methyl Grignard conjugate addition. 

The best stereochemical results, however, were obtained with the new and bulky methylmetallic reagent, methyl triisopropoxy-titanium, (12) and with methylmagnesium chloride (eq. 13). Presumably, the more electrophilic chloromagnesium species formed a stronger complex with the bidendate enone sulfoxide than did the bromo or the lodomagnesium species (13) and thus forced the 3-addltlon to proceed entirely through the chelated and therefore locked conformation shown in model 9. 

In the absence of divalent metals, the enone sulfoxide was thought to exist mainly in the conformation shown in Figure 5.3, having the sulfoxide and carbonyl dipoles oriented in opposite directions. Conjugate addition then occurs at the face not shielded by the p-tolyl group, i.e. that containing the sulfur lone pair (si-face). The zinc bromide-mediated addition of vinylmagnesium bromide to (98a) has led... 

The diastereoselectivity observed for the conjugate addition to the nonchelated enone sulfoxide (98a) was improved by the use of diorganomagnesium reagents with DME as solvent. Under the same reaction conditions, nucleophilic additions to the corresponding cyclohexenone (101) proceeded with moderate stereoselectivity, giving cyclohexanones (102) as products with somewhat lower enantiomeric excesses than for cyclopentanones (99b) (Scheme 5.35 and Table 5.4) [99]. It should also be noted that in several cases the addition of a highly complexing additive such as 18-crown-6 served to raise the amount of asymmetric induction by about 20% (Table 5.4). 

In contrast, Michael additions of a,a-disubstituted lithium enolates proceed, apparently via the chelated form of enone sulfoxides (Figure 5.2), with almost complete jt-facial diastereoselectivity [104]. This methodology has been used in the asymmetric synthesis of the pheromone, (-)-methyl jasmonate (121), from cyclopentenone sulfoxide (98b) [105] via the intermediate (120), which was formed in at least 98% enantiomeric purity upon asymmetric Michael addition of bis a-silylated a-lithioacetate to (98b). Addition of the a-bromo enolate (122) to enantiomerically pure (98a) and oxidation gives the product sulfone (123), with almost complete asymmetric -induction with respect to the sulfoxide. Sulfone (123) was then converted into the steroidal sex hormone, (+)-oestradiol (124) (Scheme 5.42) [106]. 

The reaction of the enantiomerically pure sulfoxide anion (0.5 equiv) with a racemic bicyclic enone allows for the kinetic resolution of the enone15b. 

The addition of the anions of racemic cyclic allylic sulfoxides to various substituted 2-cyclopentenones gives y-l,4-adducts as single diastereomeric products22. The modest yields were due to competing proton-transfer reactions between the anion and enone. The stereochemical sense of these reactions is identical to that for the 1,4-addition reaction of (Z)-l-(/erf-butylsulfinyl)-2-methyl-2-butene to 2-cyclopentenone described earlier. 

To a cold (—78 C) solution of 0.8 g (3.9 mmol) of 3-(phenylsulfinyl)-l-cyclohcxcnc in 20 mL of THF is added a cold ( — 78 lC) solution of 4.37 mmol of LDA in 20 mL of THF via a cannula. The resulting yellow solution is stirred at —78 C for 30 min, and then 0.7 mL (4.0 mmol) of HMPA is added, followed after 5 min by the addition of 0.320 g (3.9 mmol) of 2-cyclopentenone, and the solution is stilted at —78 C for 15 min. A solution of 0.26 mL of acetic acid in 2 mL of diethyl ether is added and the solution warmed to 25 C, diluted with aq NH4C1, and extracted with three portions ol diethyl ether. The combined extracts are washed with aq NaCl, dried over MgSC)a, concentrated, and column chromatographed to give the title compound yield 0.562 g (50%). Starting sulfoxides and enones were also recovered. 

Mainly sulfoxide groups are introduced as chiral auxiliaries for the modification of a,/J-unsat-urated enones (see Section D.1.5.3.5.). Chiral imine derivatives have also been used (see Section D.1.5.3.1.). Various chiral alcohols, and in particular 8-phenylmenthol, have been successfully used as auxiliaries, mainly in two-fold Michael additions to a,/ -unsaturatcd esters. 

Halogenation of 106 with triphenylphosphine, iodine, and imidazole provided the iodo derivative 109. On treatment with lithium aluminum hydride, 109 was converted into two endocyclic alkenes, 110 and di-O-isopro-pylidenecyclohexanetetrol, in the ratio of 2 1. Oxidation of 110 with dimethyl sulfoxide - oxalyl chloride afforded the enone 111.1,4-Addition of ethyl 2-lithio-l,3-dithiane-2-carboxylate provided compound 112. Reduction of 112 with lithium aluminum hydride, and shortening of the side-chain, gave compound 113, which was converted into 114 by deprotection. ... 

The reaction of the aldehyde 174, prepared from D-glucose diethyl dithio-acetal by way of compounds 172 and 173, with lithium dimethyl methyl-phosphonate gave the adduct 175. Conversion of 175 into compound 176, followed by oxidation with dimethyl sulfoxide-oxalyl chloride, provided diketone 177. Cyclization of 177 with ethyldiisopropylamine gave the enone 178, which furnished compounds 179 and 180 on sodium borohydride reduction. 0-Desilylation, catalytic hydrogenation, 0-debenzyIation, and acetylation converted 179 into the pentaacetate 93 and 5a-carba-a-L-ido-pyranose pentaacetate (181). 

Scheme 2.34 Rh-catalysed 1,4-additions of arylboronic acids to cyclic enones with bis(sulfoxides) ligand.

Functionality can be built into either the diene or dienophile for purposes of subsequent transformations. For example, in the synthesis of prephenic acid, the diene has the capacity to generate an enone. The dienophile contains a sulfoxide substituent that is subsequently used to introduce a second double bond by elimination. 

Reactions where NLE have been discovered include Sharpless asymmetric epoxi-dation of allylic alcohols, enantioselective oxidation of sulfides to sulfoxides, Diels-Alder and hetero-Diels-Alder reactions, carbonyl-ene reactions, addition of MesSiCN or organometallics on aldehydes, conjugated additions of organometal-lics on enones, enantioselective hydrogenations, copolymerization, and the Henry reaction. Because of the diversity of the reactions, it is more convenient to classify the examples according to the types of catalyst involved. 

As indicated in Section ni.B, deprotonation of a carbamate affords a dipole-stabilized a-amino-organolithium that can be transmetalated with copper salts to form cuprates, thereby expanding the versatility of the organolithium. Suitable electrophiles include enones, alkenyl, alkynyl, allenyl and dienyl carboxylic acid derivatives, nitriles and sulfoxides. Dieter and coworkers have shown that the same process can be accomplished via transmetalation of a stannane (Scheme 36). The procedure is particularly... 

Starting from optically active 1-chlorovinyl p-tolyl sulfoxide derived from 2-cyclohex-enone, the asymmetric synthesis of cyclopropane derivative (85) was realized (equation 23) . Addition reaction of lithium enolate of tert-butyl acetate to 83 gave the adduct (84) in 96% yield with over 99% ee. Treatment of the latter with i-PrMgCl in a similar way as described above afforded optically pure (15,6/ )-bicyclo[4.1.0]hept-2-ene (85) in 90% yield. 

In summary, the direct insertion of zinc dust to organic halides is an excellent method for preparing a broad range of polyfunctional organozinc halides bearing various functional groups like an ester" , an ether, an acetate" , a ketone, cyano", halide" , N,N-bis(trimethylsilyl)amino °, primary and secondary amino, amide, phthalimide , sulfide, sulfoxide and sulfone , boronic ester , enone " or a phosphonate . An alternative method is based on transmetalation reactions. 

The use of a-thiophenyl enones (106 Scheme 12) allows the preparation of phenols such as (107) from cyclic ketones (18).30 The same product can also be obtained by normal Robinson annulation of methyl vinyl ketone (30) and the p-keto sulfoxide (lOS).30 Acceptors other than a, 3-unsaturated carbonyls have been used in both the Michael reaction and the Robinson annulation process. For example, nu-... 

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