Silylation directed lithiation

The enantioselective lithiation of anisolechromium tricarbonyl was used by Schmalz and Schellhaas in a route towards the natural product (+)-ptilocaulin . In situ hthi-ation and silylation of 410 with ent-h M gave ewf-411 in an optimized 91% ee (reaction carried ont at — 100°C over 10 min, see Scheme 169). A second, substrate-directed lithiation with BuLi alone, formation of the copper derivative and a quench with crotyl bromide gave 420. The planar chirality and reactivity of the chromium complex was then exploited in a nucleophilic addition of dithiane, which generated ptilocaulin precnrsor 421 (Scheme 172). The stereochemistry of componnd 421 has also been used to direct dearomatizing additions, yielding other classes of enones. ... 

Silicon protection is also commonly used to direct lithiation chemistry in five-membered heterocycles. For example, oxazoles , thiazoles and Ai-alkylimidazoles ° ° lithiate preferentially at C-2, where the inductive effect of the heteroatoms is greatest. If C-2 is blocked, lithiation occurs at C-5, where there is no adjacent lone pair to destabilize the organolithium. Functionalization of these heterocycles at C-5 can therefore be achieved by first silylating C-2, reacting at C-5 and then removing the silyl group. The synthesis of 666 illustrates this sort of sequence (Scheme 258) °. ... 

Directed lithiation. 2-Arenesul gioselective fashion, furnishing thio 157-96%). 3-Halopyridines, includm lithiation and regioselective reaction that 3-chloro-4-iodopyridine generate t-BuLi. Halogen dance is also obsersx Vinyl esters are silylated at the esters of silyl ketones. The regiosel and the ability of the lithio derivative tion with suitable acceptors are expio cyclopentenones. ... 

Directed lithiations of aromatic and heteroaromatic systems, as well as those involving non-aromatic heterocycles, are processes that have continued to evolve this year. Various 3,5-dialkoxy-4-substituted phenols (18) have been prepared by a selective lithi-ation reaction. The use of a bulky silyl substituent inhibits metallation of (17) at C-2, and the application of this chemistry to a concise synthesis of sophoraflavanone A has been presented... 

Iwao et d. introduced an efficient methodology ftH the synthesis of 3,4-disubstituted indoles 113 (57). Their strategy comprises two sequential steps 1) selective functionalization of l-silyl-3-dimethylaminomethylindole (111) at the 4-position by directed lithiation, followed by quenching with electrophiles, for the preparation of 4-dimethylamino-substituted indole 112 (58) 2) substitution of the dimethylamino group of 112 for various nucleophiles giving 113 upon desilylation through quatemization followed by a fluoride ion-induced elimination-addition reaction (Scheme 17) (59). 

In addition to their role as a source of lithiated diynes or terminal diynes silyl-protected diynes have found direct application in the preparation of Group 8 diynyl complexes. Reactions of Me3SiC=CC=CR (R = Ph, C=CPh, C=CC=CPh) with RuCl(PPh3)2Cp in the presence of KF afford the corresponding poly-ynyl complexes Ru(C=CC=CR)(PPh3)2Cp." ... 

A ferrocenyloxazoline with only one adjacent position available for deprotonation will lithiate at that position irrespective of stereochemistry. This means that the same oxazoline can be used to form ferrocenes with either sense of planar chirality. The synthesis of the diastereoisomeric ligands 311 and 313 illustrates the strategy (Scheme 143), which is now commonly used with other substrates to control planar chirality by lithiation (see below). Ferrocene 311 is available by lithiation of 305 directly, but diastereoselective silylation followed by a second lithiation (best carried out in situ in a single pot) gives the diastereoisomeric phosphine 313 after deprotection by protodesilylation ". ... 

The protected diol side-chain of 456 is introduced by asymmetric dihydroxylation and directs diastereoselectivity in the formation of 457 and 458 by lithiation. The most acidic position of 456, between the two methoxy groups, is first protected by silylation. Suzuki coupling of 459 with the boronic acid 460 gives the kinetic product 461—the more severe hindrance to bond rotation in this compound does not allow equilibration to the more stable atropisomer of the biaryl under the conditions of the reaction. 

For cases where the regioselectivity of lithiation cannot be biased in the required direction, silylation can be used to block acidic sites while further lithiations are carried out. The blocking silyl group is later readily removed with fluoride . This method was used to avoid a competing lateral lithiation in the synthesis of the aldehyde 665 (Scheme 251... 

Direct C-l deprotonation-lithiation occurs on treatment of the O-benzyl-ated or -silylated glycals with strong bases such as tert-butyllithium at low temperatures, and the vinyllithiums (such as 120) can subsequently be stannylated with tributylstannyl chloride.135 Otherwise, compound 121 can be produced from S-phenyl tetra-C-benzyl-l-thio-/f-D-glucopyranoside via sulfone 122 by treatment with tributylstannane and a radical initiator.132... 

Regioselective substitution reactions of a series of 2- and 3-hydroxybiaryls including BINOL have been performed via a new directed orf/io-metallation procedure.75 O-Aryl AMsopropylcarbamates, conveniently prepared from phenols and isopropyl isocyanate, have been temporarily and in situ N-protected by means of silyl inflates to form stable intermediates for low-temperature lithiation reactions using n-BuLi-TMEDA in diethyl ether. The IV,IV-dialkyl aryl O-sulfamate has been reported as a new directed metallation group.76... 

Ketones may direct lateral lithiation even if the ketone itself is enolised enolates appear to have moderate lateral-directing ability. Mesityl ketone 433, for example, yields 434 after silylation - BuLi is successful here because of the extreme steric hindrance around the carbonyl group.396 The lithium enolate can equally well be made from less hindered ketones by starting with a silyl enol ether.396... 

The addition of carbonylated electrophiles to the 2-lithio derivative of 4-oxazolinyloxazole 132 allowed the efficient preparation of 5-phenyloxazoles 134 bearing a variety of hydroxyalkyl groups at C-2 position and a carboxyl (or formyl) function at C-4. This protocol suppresses the troublesome electrocyclic ring-opening reaction and allows access to the target compounds by simple chemical transformation of the oxazoline moiety of 133 <02JOC3601>. A direct chemoselective C-2 silylation of oxazoles was performed by treatment of the lithiated parent compounds with silyl triflates <02TL935>. 

Their stability allows a directed synthesis of asymmetrical bis(silyl)hy-drazines by the reactions of lithiated mono(silyl)hydrazines with halosi-lanes (Section B,2). These reactions often lead to the formation of isomeric products. 

Olefination of aldehydes with a-silyl- and a-stannyl-stabilized phosphonate carbanions derived from cyclo-[L-AP4-D-Val] allow a (Z)-selective access to a,p-substituted vinyl phosphonates (343) that have been transformed into enantiomerically pure 4-alkylidene 4PA derivatives (344) (Figure 54). " Electrophilic fluorination of lithiated bis-lactim ethers derived from cyclo-[L-AP4-D Val] (345) with commercial NFSi allow direct access to a-monofluor-inated phosphonate mimetics of naturally occurring phosphoserine (346) and phosphothreonine (347), in enantiomerically pure form and suitably protected for solid-phase peptide synthesis (Figure 55). ... 

In the case of 2-decyl-l-lithio-l-(methylseleno)cyclopropane and methyl iodide, the alkylation leads to a 1 1 mixture of the stereoisomers35 (Scheme 16), but it is not known which of the alkylation or the lithiation steps is not stereoselective as both stereoisomers of this cyclopropyllithium are formed. Trimethylsilyl chloride reacts efficiently with a-lithiocyclobutyl selenides35 and a-lithiocyclopropyl selenides 77 and produces the corresponding a-silyl selenides (Scheme 23). Trimethyl-silyl-(methylseleno)cyclopropame was found77 to be a powerful precursor of a-silylcyclopropyl lithium which cannot be directly alkylated 78,94), as already mentioned. 

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