Lithiation enantioselective

We became interested in a disconnection between the pyrrolidine and the aryl group (Approach D) as the most convergent method for enantioselective construction of 12 [10]. Although (-)-sparteine mediated enantioselective lithiation of N-Boc pyrrolidine 19 is well established by Beak [11], arylation of the resulting chiral... 

The key to the success of the synthesis was the development of a novel method for enantioselective formation of a-arylpyrrolidines. In this method, (-)-sparteine-mediated, enantioselective lithiation of N-Boc-pyrrolidine 19 was followed by an in situ transmetallation to zinc and Pd-catalyzed coupling reaction with aryl bromide 3, which afforded 2-arylpyrrolidine in 63% isolated yield and 92% ee. Notably, the acidic aniline NH2 group was tolerated under the coupling reaction conditions. 

Azepanes and azepanones continue to attract attention synthetically because of their incorporation in compounds of biological significance. A new diastereoselective and enantioselective lithiation - addition methodology has been described to provide access to the azepine precursors 25 (Ar1 = jb-BrPh, Ar = p-MeOPh)) these were then converted into 27 via 26, and subsequently to the further substituted azepan-2-ones 30 via 28 and 29 <06JA2178>. 

Enantioselective lithiation of achiral arena-chromium complexes... 

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. ... 

The chiral base 360 turns out not to be the best choice for enantioselective lithiation of the sulphur analogue 437 (Scheme 177) the bis-lithium amide 438 in the presence of LiCl at — 100°C gives better yields and enantioselectivity The base 438 often turns out to be a good choice as an alternative to 360 for reactions that fail to give good enantioselectivity. ... 

Enantioselective reactions of laterally lithiated amides and anilides have been reported by Beak and coworkers but these are properly asymmetric transformations in which stereoselectivity arises subsequent to the lateral lithiation step they are not enantioselective lithiations. 

While not strictly a directed metallation, an important early example of enantioselective lithiation in a benzyhc position was the lithiation of the achiral biaryl 598 using n-BuLi-(—)-sparteine. The product 599 of unknown configuration was obtained in moderate ee (Scheme 236) . ... 

Thayumanavan, S. Regioselective, diastereose-lective, and enantioselective lithiation—substitution sequences reaction pathways and synthetic applications. Ace. Chem. Res. 1996, 29, 235... 

Hoppe, D. Zschage, O. Asymmetric homoal-dol reaction by enantioselective lithiation of a prochiral 2-butenyl carbamate. Angew. Chem. Int. Ed. 1989, 28, 69-71. 

Quantum chemical DFT calculations at the B3LYP/6-31G(d) level have been used to study the enantioselective lithiation/deprotonation of O -alkyl and O-alk-2-enyl carbamates in the presence of (—)-sparteine and (—)-(f )-isosparteine.7 Complete geometry optimization of the precomplexes consisting of the carbamate, the chiral ligand, and the base (/-PrLi), for the transition states of the proton-transfer reaction, and for the resulting lithio carbamates have been performed in order to quantify activation barriers and reaction energies. 

Deprotonation of O-alkyl carbamates may be achieved in an enantioselective manner with s-BuLi-(-)-sparteine, and the most effective of these reactions employ the oxazolidinones 411. The related compounds 412 perform similarly, but have less neat NMR spectra. Enantioselective lithiation of 413, followed by carboxylation and methylation with diazomethane, generates the protected a-hydroxy acid 414 in >95% ee.176 Many other electrophiles perform well in the quench step, but not allylic or benzylic halides, which lead to partial racemisation.177 30... 

Gibson and coworkers have examined the possibility of using chiral base methodology to enantioselectively lithiate the benzylic position of arene complexes (Scheme 46). (R,R)-3 has been used in combination with LiCl and followed by quenching with... 

It is especially remarkable that optically active homoaldoi adducts can be obtained when enantiomeri-cally pure 2-alkenyl carbamates (47 R = alkyl) are employed. Apparently the deprotonation occurs with retention of configuration and leads to configurationally stable liAium derivatives, which, after metal exchange with Ti(OPr )4, again with retention, add to aldehydes with efficient 1,3-chirality transfer coupled with enantiofacial differentiation at the carbonyl group, indicating a rigid six-membered transition state. Recently even an asymmetric homoaldoi reaction by enantioselective lithiation of prochiral primary alkenyl carbamates in the presence of (-)-sparteine was reported. ... 

A third mode of asymmetric induction is offered via planar chiral complexes. Diastereoselective hthiation and enantioselective lithiation provide efficient... 

Chiral a-Oxybenzyllithium Compounds by Enantioselective Lithiation in the Presence of Chiral Ligands... 

Enantioselective lithiation can be used to introduce and control new elements of planar or of axial chirality. The principal classes of compounds displaying these stereochemical features are ferrocenes, arenechromium tricarhonyl complexes, biaryls, atropisomeric amides and al-lenes. Methods for the enantioselective lithiation of these compound classes, relying on either substrate (chiral auxihary) or reagent (chiral base) control will be reviewed. 

The use of enantioselective lithiation to generate axial chirality directly is in its infancy. However, several strategies are available for the conversion of planar or... 

Widdowson has exploited the asymmetric deprotonation of 183 in a synthesis of a protected version 191 of the biaryl component of vancomycin, actinoidinic acid (Scheme 48) [110, 111]. One of the rings derives from an arenechromiiun tricarbonyl with stereochemistry controlled by asymmetric lithiation. The most readily lithiated position of 183, between the two methoxy groups, first needed blocking. Enantioselective lithiation and chlorination of 184 gave 186 (TMEDA was needed to displace sparteine from 185 and restore reactivity towards a poor electrophile). Suzuki coupling of 187 with the boronic acid 188 transfers planar... 

Principal among these are amides either benzamides, exemplified by 197, or anilides, exemplified by 200 (Scheme 50). Given the known lithiation directing ability of amide groups [ 1,114], these compounds are clearly prime candidates for asymmetric synthesis using enantioselective lithiation. 

As with atropisomeric biaryls, axial chirality in atropisomeric amides maybe introduced by stereochemical control in the atroposelective reactions of planar chiral complexes [115]. Enantioselective lithiation was reported in this context by Uemura, who showed that the achiral complexes 195,198,201 and 204 are de-protonated enantioselectively by treatment with chiral lithium amide bases (Scheme 50) [116-118]. The stereogenic C-C and C-N axes in these compounds are orientated such that the larger NR2 and acyl groups, respectively, are directed away from the chromium. A range of chiral lithium amides was investigated, and by careful selection it was possible to obtain products 196,199,202 and 205... 

Note added in proof. The diastereoselective lithiation of N,N-dimethylferrocenylethylamine) 9 (Scheme 2) and sparteinemediated enantioselective lithiation of (diisopropylamido)fer-rocene 84 (Scheme 21) using MeLi were modeled through an assumed reversible adduct for-... 

In 2010 Bolm et al. and Christmann, Strohmann et al. independently reported the preparation and use of 2-silyl-pyrrolidines (S)-35 in organoca-talytic transformations. Catalysts 35 were efficiently obtained exploiting the Beak s enantioselective lithiation protocol of AI-Boc pyrrolidine in the presence of (-)-sparteine (Scheme 11.33). ... 

Scheme 11.33 Beak s enantioselective lithiation for the preparation of pyrrolidines (S)-35.

In short, the sequence enantioselective lithiation-electrophilic trapping-reductive elimination represents an enantioselective demethylation of 4 to produce optically pure 9. As seen through this book, secondary phosphine boranes are versatile synthons in P-stereogenic chemistry. In this case, they were alkylated with 2-(chloromethyl)benzothiophene providing phosphine boranes 10 in good yields, which were used in HPLC analysis to evaluate the optical purity of 9. 

---