Stereocontrolled protonation

Scott was able to leverage the same type of methodology in an impressive display in which /V-methyltryptamine was dimerized directly to afford chimonanthine (7) (Scheme 9.2b) [9c]. Deprotonation of the indole 1H proton with methyl Grignard followed by treatment with FeCl3 accomplished the singleelectron oxidation and dimerization of the indole moiety. The racemic and meso stereoisomeric products were obtained as a mixture in 19 % and 7 % yields, respectively. Takayama later found hypervalent iodine to be a superior oxidant, affording yields of 17 % and 30 %, respectively [9j]. In both cases, however, as in the case of Hendrickson s example, stereocontrol could not be achieved. 

The only other alkenyl carbenoid with a proton trans to the halide that can readily be generated by deprotonation is the parent 1-lithio-l-chloroethene 57 [43] (Scheme 3.13). Insertion into organozirconocenes arising from hydrozirconation of alkenes and alkynes, followed by protonation, affords terminal alkenes and ( )-dienes 59, respectively [38]. The latter provides a useful complement to the synthesis of 54 in Scheme 3.12 since the stereocontrol is >99%. 

Silyltitanation of 1,3-dienes with Cp2Ti(SiMe2Ph) selectively affords 4-silylated r 3-allyl-titanocenes, which can further react with carbonyl compounds, C02, or a proton source [26]. Hydrotitanation of acyclic and cyclic 1,3-dienes functionalized at C-2 with a silyloxy group has been achieved [27]. The complexes formed undergo highly stereoselective addition with aldehydes to produce, after basic work-up, anti diastereomeric (3-hydroxy enol silanes. These compounds have proved to be versatile building blocks for stereocontrolled polypropionate synthesis. Thus, the combination of allyltitanation and Mukayiama aldol or tandem aldol-Tishchenko reactions provides a short access to five- or six-carbon polypropionate stereosequences (Scheme 13.15) [28],... 

The opening of cyclopropylcarbinols to homoallylic bromides constituted the first use of cyclopropyl compounds for the stereocontrolled synthesis of natural products. The cyclopropyl conjunctive reagents enhance the richness of this notion. The stereocontrolled opening of vinylcyclopropanes by a homopentadienyl proton shift provides an approach to trisubstituted olefins and thereby a new strategy. The fungal prohormone methyl trisporate B (224) as summarized in Scheme 15 illustrates this conceptual development97). 

Cross aldol reactions of silyl enol ethers with acetals (25 - 26, and 27 - 28) are also mediated by EGA. The reaction runs smoothly at —78 °C in a CH2CI2— —LiClO —Et NClO —(Pt) system. At an elevated temperature protonation of both enol ether and acetal occurs competitively to give 28 in a poor yield. Table 5 summarizes yields and diastereoselectivities of 28 obtained by EGA, TiCl TMSOTf and TrtClO 5 . The EGA method is superior to TiCl with regard to the stereocontrol, and comparable with TMSOTf and TrtClO in both stereocontrol and yield. 

With a,p-disubstituted enuiies an unexpected mode of stereocontrol was evidenced [365, 366]. Syn products (7) were obtained by addition of the lithium enethiolate of methyl dithioacetate to an a,3-disubstituted enone via diastereoselective auto-protonation of the intermediate enolate generated in the 1,4 addition. 

The second section, immediately following this introduction, tries to provide an account on the theory and the methods known to give (stereocontrolled) access to the enolates. The third section gathers the most important descriptions available about lithium enolates in the gas or solid phase, as well as in solution. These data are classified according to the physicochemical techniques employed. The fourth section of this chapter, dedicated to the reactivity of lithium enolates, has been restricted to three of their main applications, namely the protonation, alkylation/acylation and aldolisation reactions. 

For weak acids, the proton is directly transferred from the acid to the substrate in a reagent-controlled manner and, in order to increase the selectivity, extremely shielded 2 -substituted m-terphenyls have been developed as concave protonating reagents inspired by the geometry of enzymes. Thus, the diastereoselective protonation by a series of substituted phenols of endocyclic keto enolates, obtained by the stereocontrolled 1,4-addition of lithiocuprates onto substituted cyclohexenones, was reported by Krause and coworkers354 355 and applied to the synthesis of racemic methyl dihydroepijasmonate356. 

The use of the optically active (camphorylsulphonyl)oxaziridine did not afford enantioselectivity. A possible explanation for this lack of stereocontrol lies in the mechanism proposed (Scheme 56). It involves formation of an a-amino epoxide, its nucleophilic ring opening and either loss of a proton (route a) or hydrolysis (route b) (Scheme 56). 

CC>2Me preferably coordinates to the silver metal. Oppolzer s readily removable camphor sultam not only enforces absolute stereocontrol but also enables the underlying reaction cascade (presumably by lowering the pKa of the glycyl a-proton). Pyrrolidine 199 is converted to diol 200 by a 12-step reaction sequence. Since compound 200 corresponds to an advanced intermediate that has been converted to cyanocyline A <87JA1587>, attainment of 200 constitutes an efficient formal synthesis of this natural product. 

Hydrogenation of 2-isoxazolines over Raney nickel as catalyst and in the presence of acids often leads first to 1,3-hydroxyimines, and then, through hydrolysis, to 1,3-hydroxycarbonyl compounds. In some cases the stereochemical integrity of the starting material is maintained, but in others hydrolysis of the intermediate imines may cause scrambling of stereochemistry at the a-carbon atom. Rapid protonation of the imine function minimizes this possibility and the use of Lewis acids, such as boron trichloride or aluminum trichloride which release hydrochloric acid on contact with moist methanol, is frequently recommended. Boric acid serves a similar purpose and is effective in, for example, the stereocontrolled reductive ring opening of the 2-isoxazoline (135) en route to crispatic acid (136 Scheme 6). ... 

It is noticeable that the cis—trans ratio of the reaction products is influenced strongly by proton donor and cathode material [60]. The ratio and the yield increase when a stronger proton donor is used. This may suggest that the protonation of the anionic intermediate is a key step in either cyclization or stereocontrol. The fast protonation of the configurationally unstable anionic species results in the predominant formation of the less stable cis products. 

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