Cyclic reaction with cuprates

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. 

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

Cyclic amino-carbenes, in molybdenum carbonyls, 5, 457 Cyclic bis(phosphine) dichlorides, with iron carbonyls, 6, 48 Cyclic carbenes, as gold atom ligands, 2, 289 Cyclic carbometallation, zirconium complexes, 10, 276 Cyclic carbozirconation characteristics, 10, 276 intermolecular reactions, 10, 278 intramolecular reactions, 10, 278 Cyclic dinuclear ylides, and gold , 2, 276 Cyclic 1,2-diols, intramolecular coupling to, 11, 51 Cyclic enones, diastereoselective cuprate additions, 9, 515 Cyclic esters, ring-opening polymerization, via lanthanide catalysis, 4, 145 Cyclic ethers... 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

Corey and Wollenberg have found it possible to introduce a THP-blocked trans allylic alcohol unit via reaction of 2-cyclopentenone and other cyclic enones with the highly reactive mixed cuprate 28.58 Through hydrolysis, mesylation, and base-promoted cyclization of adduct 29, the vinylcyclopropane 30 was obtained (Scheme 8). Thermolysis at 600 °C caused ring expansion to 31. 

Etiolates formed by organocopper conjugate addition may be acylated cleanly by acid chlorides to give 3-diketones. Although 0- and C-acylation are both possible, the latter is favored by the use of acid chlorides rather than anhydrides and by the use of diethyl ether as solvent, rather than DME. Good yields of 3-diketones have been obtained by acylation of the anions derived from both acyclic and cyclic unsaturated ketones with cuprates, or in copper-catalyzed Grignard reactions. Some synthetic applications are given in Scheme 54. 

Alkynes can be transformed into alkenylstannanes by reaction with stannyl-cuprates. It is possible to trap the 1,2-dimetallic alkene species with various electrophiles. The analogous vicinal difunctionalization of alkynyl selenides " has also been reported. A route to trisubstituted alkenes from phenylthioacetylene"" starts with cuprate addition, but a 1,2-metal rearrangment is involved. Enamines are obtained from N-ethynyldiphenylamine. The alkenylcopper intermediate is also reactive toward many electrophiles. Silylcupration of functionalized alkynes may lead to cyclic products by virtue of intramolecular alkylation. ... 

Reaction with cyclic enones. In the presence of HMPT, this cuprate undergoes 1,2-addition to cyclic enones in high yield (equation I). The reaction may... 

Ozonolysis of the olefin followed by the reaction with lithium vinyl cuprate reagent produced 1,3-amino alcohol derivative 107 in 1 3 diastereomeric ratio. Protection of the compound 107 as tert-butyldimethylsilyl (TBS) ether, followed by treatment with a Pd catalyst and PhBr in a carboa-mination reaction condition, produced cyclic pyrrolidine derivative 109, which after subsequent reduction of the Boc group with LiAlH4 and deprotection of TBS ether was transformed into (-l-)-preussin 100 in 12% overall yield and 96% enantiomeric excess. 

Now let s draw the forward scheme. Benzoic acid is converted to benzoyl chloride upon treatment with thionyl chloride. Subsequent reaction with lithium diethyl cuprate installs an ethyl group, giving a ketone. An acid-catalyzed reaction with ethylene glycol (with removal of water) produces the desired cyclic acetal. 

The mixed lithium neophyl(phenyl)cuprates react with high SN2-selectivity with chiral cyclic allylic acetates such as 37 providing chiral alkenyl iodides of type 38. In the presence of zinc bromide, a change of regioselectivity is observed and the reaction with the chiral acyclic pentafluorobenzoate 39 provides only SN2 -product 40 with 85% yield and 95% ee (Scheme 9.11) [22]. 

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

The reaction of propargylic chiral acetals with a catalytic copper reagent (RMgX/5% CuX) provides the expected alkoxy allenes in quantitative yield (Table 3)61. The diastereomeric excess is highly dependent on the size of the ring of the acetal and on the type of substituents it contains. The best diastereomeric excess is 85% with the acetal derived from cyclooctanediol. The use of lithium dimethylcuprate results in 1,2-addition lo the triple bond and the resulting lithium alkenyl cuprate bearing a cyclic acetal does not eliminate even at reflux temperature ( + 35°C). 

Associated with the propensity to intramolecular delivery of the organocopper reagent is the benefit of high regioselectivity, since an intramolecular trajectory prohibits the alternative a-attack. This is best exemplified by the reaction behavior of the cyclic system 161 (Scheme 6.33). For this substrate, y-attack is sterically hindered. Hence, treatment of the acetate of 161 with a higher order methyl cuprate... 

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