Cuprates, nucleophile addition

The conversion of a thiolactone to a cyclic ether can also be used as a key step in the synthesis of functionalized, stereochemically complex oxacycles (see 64—>66, Scheme 13). Nucleophilic addition of the indicated higher order cuprate reagent to the C-S double bond in thiolactone 64 furnishes a tetrahedral thiolate ion which undergoes smooth conversion to didehydrooxepane 65 upon treatment with 1,4-diiodobutane and the non-nucleophilic base 1,2,2,6,6-pentamethylpiperidine (pempidine).27 Regio- and diastereoselective hydroboration of 65 then gives alcohol 66 in 89 % yield after oxidative workup. Versatile vinylstannanes can also be accessed from thiolactones.28 For example, treatment of bis(thiolactone) 67 with... 

Bromo-2-(t-butylsulfonyl)propene (79) reacts with nucleophiles such as lithium benzenethiolate, lithium enolates and Grignard reagents to give a, /(-unsaturated sulfones, which undergo nucleophilic addition of lithium cuprates (equation 68)58. 

In Entry 5, the carbanion-stabilizing ability of the sulfonyl group enables lithiation and is then reductively removed after alkylation. The reagent in Entry 6 is prepared by dilithiation of allyl hydrosulfide using n-bulyl lithium. After nucleophilic addition and S-alkylation, a masked aldehyde is present in the form of a vinyl thioether. Entry 7 uses the epoxidation of a vinyl silane to form a 7-hydroxy aldehyde masked as a cyclic acetal. Entries 8 and 9 use nucleophilic cuprate reagents to introduce alkyl groups containing aldehydes masked as acetals. 

The assumed structures of the ketone—zirconocene and oxazirconacyclopentene complexes have not been established spectroscopically due to the excess of cuprate reagent present. However, as discussed in Section 5.3.2.2, (i) direct nucleophilic addition to the... 

The Schollkopf bislactim ether cuprate was also used in the first total synthesis of the antimycotic dipeptide chlorotetaine (equation 19)58. In this case, however, the nucleophilic addition to 4-methylene-2-cyclohexenone did not proceed regioselectively since a 63 37 mixture of the 1,6- and 1,4-adduct was obtained. The 1,6-addition product was converted via several steps into diastereo- and enantioselectively pure chlorotetaine. 

The chemical behavior of heteroatom-substituted vinylcarbene complexes is similar to that of a,(3-unsaturated carbonyl compounds (Figure 2.17) [206]. It is possible to perform Michael additions [217,230], 1,4-addition of cuprates [151], additions of nucleophilic radicals [231], 1,3-dipolar cycloadditions [232,233], inter-[234-241] or intramolecular [220,242] Diels-Alder reactions, as well as Simmons-Smith- [243], sulfur ylide- [244] or diazomethane-mediated [151] cyclopropanati-ons of the vinylcarbene C-C double bond. The treatment of arylcarbene complexes with organolithium reagents ean lead via conjugate addition to substituted 1,4-cyclohexadien-6-ylidene complexes [245]. 

In contrast to nucleophilic addition reactions to activated dienes (Sect. 4.2.1), the mechanism of 1,6-cuprate additions to acceptor-substituted enynes is quite well understood, largely thanks to kinetic and NMR spectroscopic investigations [3oj. 

The results for conjugate additions to pseudodipeptides 83 and 86 may be interpreted along similar lines. Thus, addition of the fairly slim lithium dimethyl-cuprate nucleophile proceeded non-selectively (84, Scheme 6.17) [34, 35]. Con-... 

Vinyl triphenylphosphonium ion has been found to react with cuprate reagents by nucleophilic addition, generating an ylide structure. This intermediate can then be... 

Normally, additions depicted by model C lead to the highest asymmetric induction. The antiperiplanar effect of OR substituents can be very efficient in the Houk model B ( , , , , ) however it plays no role in model C. Furthermore, the Houk model B must be considered in all cycloaddition-like reactions. The Felkin-Anh model A is operative for nucleophilic additions other than cuprate additions ( ). The epoxidation reactions are unique as they demonstrate the activation of one diastereoface by a hydroxy group which forms a hydrogen bridge to the reagent ( Henbest phenomenon ). The stereochemical outcome may thus be interpreted in terms of the reactive conformations 1 and 2 where the hydroxy function is perpendicular to the olefinic plane and has an optimal activating effect. 

These early results paved the way for a myriad of applications of this process in organic synthesis, as described in detail in this chapter. It should be pointed out that only additions of stabilized nucleophiles are included here, with the addition of reactive nucleophiles (organolithiums, Grignards, cuprates, etc.), Lewis acid promoted additions and asymmetric nucleophilic additions, among others, being covered in Chapters 1.3 and 1.5, respectively, in this volume. 

A nontransferable ligand is used to advantage in the above spiroannulation, and is generally important when a highly valued ligand must be transferred. In the synthesis of a steroid nucleus, the nucleophilic addition of a cuprate to enone (51) was one of two key steps (equation 56).117 A good yield of the 3-alky lated product was obtained, and a high stereochemical preference was reported as well. 

Interest in arylsulfonyl acetylenes arose initially because of their powerful Michael acceptor properties. Examples of facile nucleophilic addition involving thiolates (eq. 1), " amines, cuprates (eq. 2), malonate... 

In contrast to nucleophilic addition reactions to activated dienes, the mechanism of 1,6-cuprate additions to acceptor-substituted enynes is quite well understood, the main tools being kinetic and NMR spectroscopic investigations. C-NMR spectroscopic studies have revealed that these transformations proceed via jr-complexes with an interaction between the jr-system of the C=C double bond and the nucleophiUc copper atom (a soft-soft interaction in terms of the HSAB principle), as well as a second interaction between the hard lithium ion of the cuprate and the hard carbonyl oxygen atom (Scheme 4) q of C-labeled substrates has confirmed that the cuprate does... 

The product from reductive ring opening was isolated along with the product from the nucleophilic addition in the reaction of f-Bu2CuCNLi2 with oxabicyclic substrate 253 b, Eq. 158, vide infra [202]. Reduction by of one of the -hydrogens of the ferf-butyl group of the cuprate must be responsible for this product. 

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