Lithium-mediated deprotonation

An efficient kinetic resolution was also observed during the (—)-sparteine-mediated deprotonation of the piperidin-2-yhnethyl carbamate rac-112 (equation 25). By treatment of rac-112 with s-BuLi/(—)-sparteine (11), the pro-S proton in (/ )-112 is removed preferentially to form the lithium compound 113, which undergoes intramolecular cyclo-carbolithiation, and the indolizidinyl-benzyllithium intermediate 114 was trapped with several electrophiles. The mismatched combination in the deprotonation of (5 )-112, leading to cp/-113, does not significantly contribute to product formation. Under optimized conditions [0.75 equivalents of s-BuLi, 0.8 equivalents of (—)-sparteine, 22 h at —78°C in diethyl ether] the indolizidine 115 was isolated with 34% yield (based on rac-112), d.r. = 98 2, e.r. = 97 3 optically active (5 )-112 was recovered (46%, 63% ee). 

A-Boc-4-tosyloxypiperidine (161) undergoes, upon (—)-sparteine-mediated deprotonation, cycloalkylation to form via the lithium compound 162 the l-azabicyclo[3.1.0]hexane 163. 163 is subsequently deprotonated at the bridged-head carbon atom and lithium compound 164 is trapped by silylation the yield of 165 and the e.r. are low (equation 37)" " . 

The kinetic reprotonation by a series of carbonyl-based acids, of the lithium enolate obtained from 2,4-dimethyltetralone either by LDA-mediated deprotonation or by cleavage of its silyl enol ether, was studied by Eames (Scheme 71)352. The diastereoselective ratio, close to the thermodynamic value, obtained with methanol (pKa = 29 in DMSO) is probably due to equilibration. The difference observed in the presence of an additive was interpreted as the result of a fine balance between the coordinating ability, the intrinsic acidity, and probably the concentration of the enolic form of the cyclic and linear dicarbonyl acidic compounds. 

For example, the 5-(tert-butyldimethylsilyloxy)pentyl carbamate 159a was converted to the enantiomerically emiched (>95% ee) stannane 159b via sparteine-mediated deprotonation. Then an aUyl chloride unit was elaborated, finally, the (S)-lithium intermediate 179 was generated by lithiodestannylation. The (li ,2S)-2-vinylcyclopentyl carbamate 180 was produced with essentially complete enantio- and diastereoselectivity [Eq. (46)] [98]. AUyl chloride (178,H for Bu3Sn) and epoxides do not survive direct lithiation [117]. 

A similar situation is given in the meso-dicarbamate 192 [see Eq. (61)] [120]. The pro-S proton at the pro-R branch exhibits the highest reactivity in the (-)-sparteine-mediated deprotonation to form the lithium compound 193 with a small amount of the diastereomer 195. By applying prolonged reaction times (4-5 h), it is found that 195 is decomposed more rapidly than 193, leading to a further enrichment. Trapping of the reaction mixture by different electrophiles leads to essentially enantiomerically and diastereomerically pure products 194a-c. Allylation and benzylation result in lower diastereomeric ratios, probably due to SET mechanisms in the substitution step. 

Mesylation of the alcohol 65 followed by deprotonation afforded the sul-fone-stabilized carbanion 66 that underwent a macrocyclization to afford the artificial dolabellane 67 in moderate yield (Scheme 9). Hydrolytic cleavage of the ketal (67) followed by a base-mediated double bond isomerization (into conjugation) afforded an enone containing an exocyclic carbonyl group. Nucleophilic 1,2-addition of methyl lithium introduced the missing... 

Lewis acid-mediated addition of (phenylthio)trimethylsilane to acryloyl silane takes place to give l,3-bis(phenylthio)-l-trimethylsilylprop-l-ene (18). This compound may be deprotonated with t-butyl lithium at the /J-position and alkylated to give a range... 

The mechanism does not proceed through a direct hydroamination of one of the diastereotopic alkenes, but involves a series of very selective processes including a deprotonation of (22), diastereoselective protonation of (26), intramolecular addition of lithium amide (27) to the 1,3-diene moiety, and final regioselective protonation of the allyl anion (28), all mediated by a substoichiometric amount of n-BuLi. 

As shown by the last reaction in Scheme 5.23, the metalation of benzamides is complicated by several potential side reactions (Scheme 5.24). Thus, benzamides can also undergo ortho-metalation [181, 217-222] or metalation at benzylic positions [223-225], Ortho-metalation seems to be promoted by additives such as TMEDA, and benzylic metalation can be performed selectively with lithium amide bases [217,224], which are often not sufficiently basic to mediate ortho- or a-amino metalation. If deprotonation of the CH-N group succeeds, the resulting product might also undergo cydization by intramolecular attack at the arene [214, 216] (see also Ref. [226] and Scheme 5.27) instead of reacting intermolecularly with an electrophile. That this cydization occurs, despite the loss of aromatidty, shows how reactive these intermediates are. 

The chiral auxiliary mediated aza-Claisen rearrangement of /V-allylketcnc. V.O-acetals also allows the diastereoselective construction of quaternary carbon centers642. Butyllithium proved to be an unsuitable base for the neutralization step in this case because the increased steric hindrance at C-l causes C-2 nucleophilic addition to become competitive with C-l deprotonation. However, this problem can be overcome by the use of lithium tov-butoxide or lithium isopropoxide. This is shown for the achiral. V-allylketene A. O-aceta] precursor 8. 

Asami, M., Ishizuka, T. and Inoue, S. (1994) Catal3ftic enantioselective deprotonation of mejo-epoxides by the use of chiral lithium amide. Tetrahedron.Asymmetry, 5, 793-796 Seki, A. and Asami, M. (2002) Catalytic enantioselective rearrangement of mejo-epoxides mediated by chiral lithium amides in the presence of excess cross-linked polymer-bound hthium amides. Tetrahedron, 58, 4655 663. 

Asymmetric transformation mediated by chiral lithium amide bases has been used to advantage in an enantioselective pathway for formation of 8-oxanorcocaines (22) by deprotonation of 8-oxabicyclo[3.2.1]octan-3-one (21) and subsequent carbomethoxy-lation reaction with methyl cyanoformate (Scheme 2) ... 

The preparation of enantiopure or enriched complexes possessing planar chirality has been accomplished either by resolution of racemic mixtures or by asymmetric syntheses. Reported methods for the resolution of planar chirality include both chemical and kinetic resolution procedures, whilst reported asymmetric syntheses of enantiomerically pure or enriched benchrotrenic complexes include enantioselective ort/io-deprotonations with chiral lithium amide bases, and the transfer of side chain chirality onto the arene ring mediated by diastereoselective orf/io-nucleophilic additions and o/tfeo-metalations. 

In the synthesis of a second-generation anticancer taxoid ortataxel, deprotonation of 13-oxobaccatinIIIby KHMDS (THF-HMPA, 83 17) followed by electrophilic oxidation with (IR)-(lO-camphorsulfonyl)oxaziridine afforded the C14-hydroxylated taxoid in 70% yield (eq 62). An analogous oxidation mediated by f-BuOK (THF-DMPU, 83 17) afforded the product in 83% yield (eq 62). The 14)8-OH epimer was formed exclusively, in accord with the approach of the oxidant from the less sterically hindered )8-face. The performance of several bases was compared, indicating the order of reactivity t-BuOK > LDEA (lithium diethylamide) > KHMDS > NaHMDS, in THF/HMPA or DMPU solvent mixtures. 

Deprotonation of (1) with lithium diisopropylamide takes a different course (eq 4). The initially formed allenyl anion isomerizes to the acetylide, which is trapped with ketones or aldehydes to produce propargyl alcohols (S). The isomerization is postulated to take place through proton transfer steps mediated by diisopropylamine. This is consistent with the observation that no such isomerization takes place with alkyUithium reagents. The propargyl alcohols (3) are converted to methoxydihydrofurans (4) with catalytic potassium hydride in DMSO. ... 

Further work on the preparation of chiral a-amino-acids reported in the past year (see also the section on asymmetric hydrogenation) includes an extension of the utility of anions derived from lactim ethers (228) in the synthesis of such compounds by condensations with aldehydes and ketones chiral inductions are somewhat lower than in the alkylations of (228) reported previously (4, 320). Enzyme-mediated hydrolysis of 5(4H)-oxazolones by chymotrypsin or subtilisin gives a-acylamino-acids with good enantiomeric enrichments, especially if the substrate carries bulky substituents. Schiff s bases of a-amino-esters can be enriched enantiomerically to an extent of up to 70% by sequential deprotonation with a chiral lithium amide and protonation with an optically pure tartaric acid. ... 

Oxiranyllithiums are generated from activated oxiranes by deprotonation or by tin/lithium permutation. Frequently oxiranyllithium/2-lithiooxyethylidene equilibria are invoked for the ensuing transformations. However, evaluated in the light of recent investigations, they are are mostly carbenoid- rather than carbene-mediated. 

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