Sparteine, mediation

Scheme 12 (-)-Sparteine-mediated addition of a-amino organometallic reagents to imines...

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. 

The (-)-sparteine-mediated lithiation of achiral propargyl carbamates with wBuLi and allene synthesis has already been described in Section 4.2.7 [84],... 

In recent years, Hoppe s group has considerably extended the isomerization-addition methodology, especially for the highly regio- and stereoselective synthesis of 1,2-alkadienyl carbamates. It involves deprotonation of alkynyl carbamates, transme-talation into a titanium species and subsequent reaction with carbonyl compounds [26-30]. This group recently described the preparation of enantiomerically enriched 4-hydroxyallenyl carbamates 22 by sparteine-mediated lithiation of alkynyl carbamates 20 [29]. Impressive examples of these transformations are summarized in Scheme 8.8. 

If kepi, k-epi are much larger than the rates k, ki of substitution, the enantiomeric ratio Hepi-1 is similar to kxjk (path C, dynamic kinetic resolution . Both mechanisms are performing when the rates of the two steps are similar. Since rates and equilibrium are temperature-dependent, enhancement of stereoselectivities can be achieved by sophisticated protocols (see Section m.E). The equilibrium 6/epi-6 is determined by the difference of free energy A AG. This effective energy difference is enlarged if it can be coupled with a second order transformation such as the selective crystallization of one diastere-omer dynamic thermodynamic resolution ). In fact, this applies to the first successful (—)-sparteine-mediated deprotonation (Section FV.C.l). 

The asymmetric (—)-sparteine-mediated deprotonation of alkyl carbamates was unprecedented until discovered in 1990 °. For the first time, protected 1-alkanols could be transformed generally to the corresponding carbanionic species by a simple deprotonation protocol. Moreover, an efficient differentiation between enantiotopic protons in the substrate took place and the extent of stereoselection could be stored in a chiral ion pair, bearing the chiral information at the carbanionic centre. 

In (—)-sparteine-mediated deprotonation and electrophilic substitution reactions, the minor enantiomer is close to the limits of exact determination. Therefore, the influence of the alkyl residue on selectivity was investigated for less efficient (/ ,/ )- ,2-bis(dimethyl-amino)cyclohexane/i-BuLi (equation 11)°. On the base of the isolated corresponding... 

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). 

Astonishingly enough, enantioenriched lithiated cyclooctene oxides 142, originating from (—)-sparteine-mediated lithiation of 124 by i-BuLi/(—)-sparteine (11), could be trapped by external electrophiles, resulting in substituted epoxides 143 (equation 31) ° . Again, the use of i-PrLi furnished better enantioselectivities (approx. 90 10). Lithiated epoxides, derived from tetrahydrofurans and A-Boc-pyrrolidines, undergo an interesting elimination reaction . ... 

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)" " . 

Only few configurationally stable, enantioenriched a-thioalkyUithium compounds are known today (178 , 179, 181 ) Scheme 4 includes also those which are meso-mericaUy stabilized (180, 182 ° , 183 ). No example of a preparation by efficient (—)-sparteine-mediated deprotonation has been published. 

The (—)-sparteine-mediated double deprotonation of 3-arylthio-Af-methylpropanamides 187 to dilithiated arylsulphides 188, followed by aldehyde addition, also provided low, strongly varying enantiomeric excesses of the resulting products 189 (equation 43). ... 

If no complexing substituents are in the vicinity, the deprotonation at benzylic methyl groups is a rather slow reaction. The first recorded attempt of (—)-sparteine-mediated lithiation by Nozaki and coworkers has already been mentioned in Section I.A.l. Ras-ton and coworkers obtained by dilithiation of 2,2, 6,6 -tetramethylbiphenyl followed by bismethylation one of the atropoisomers of 2,2 -diethyl-6,6 -dimethylbiphenyl with 40%... 

Allylic chloride survives the (—)-sparteine-mediated deprotonation of allylic carbamates by w-BuLi. When the ( , )-9-chloro-2,7-nonadienyl carbamate ( , )-319 was treated with two equivalents of n-BuLi/(—)-sparteine (11) at —90°C in toluene, the cis-divinylcyclopentane 321 was formed with an enantiomeric ratio of 90 10 (equation 85). The epimerization to form (/ )-320 (which leads to ent-321) is much slower than the cycloalkylation step under the reaction conditions. 321 was converted in few steps into (- -)-(3/ ,4/ )-dihydromultiliden . ... 

Early attempts atintrodncing axial chirality to allenes (viacarbenerearrangement) or to biaryls [throngh (—)-sparteine-mediated deprotonation of 2,2, 6,6 -tetramethylbiphenyl] proved less snccessfnl. 

Several further publications report on the (—)-sparteine-mediated addition of alkyl-or aryllithium onto imines or the C=N bond of isoquinolines . Usually, the achieved enantiomeric excesses are low and, sometimes, other chiral ligands serve better. As reported by Muller and coworkers, the nucleophilic substitution of arenecarbaldehyde dialkyl acetals by o-substituted aryllithium reagents is an alternative . 

Oeeasionally, very good enantioselectivities were achieved in the (-)-sparteine-mediated carbolithiation of 6-dimethylaminofulvene (470) by ort/zo-substituted aiyllithiums 471 (equation 129) . Here, (—)-sparteine (11) turned out the best chiral additive. The lithium cyclopentadienides 472 were converted to the corresponding Rh(l)-norbornadiene complexes 473. 

Beak and co-workers have also produced the key alcohol intermediate 74 by the sparteine-mediated lithiation and conjugate addition of allylamines to nitroalkenes to give Z-enecarbamates in good yields with high enantio- and diastereoselectivty (Scheme 16). Thus treatment of the allylamine 87 with n-BuLi in the presence of (-)-sparteine followed by conjugate addition to nitroalkene 88 gave the desired enecarbamate 89 in... 

Scheme 16. Synthesis of (-)-paroxetine utilizing a sparteine-mediated lithiation and conjugate addition reaction.

Laqua, H. Frohlich, R. Wibbeling, B. Hoppe, D. Synthesis of enantioenriched indene-de-rived bicyclic alcohols and tricyclic cyclopropanes via (-)-sparteine-mediated lithiation of a racemic precursor and kinetic resolution during the cyclocarbolithiation. J. Organomet. Chem. 2001, 624, 96-104. 

Hoppe, D. Woltering, M. J. Oestreich, M. Frohlich, R. (-)-Sparteine-mediated asymmetric intramolecular carbolithiation of alkenes synthesis of enantiopure cyclopentanes with three consecutive stereogenic centers. Helv. Chim. Acta 1999, 82, 1860-1877. 

Asymmetric synthesis relied upon the use of (-)-sparteine in the final annelation step leading to 40 (Fig. 15.15). Mechanistic studies revealed that (-(-sparteine-mediated stereoinduction was associated with kinetic resolution in the incomplete formation of dilithiated intermediate 30-Li2 and the reaction of diaster-eomeric complexes of 30-Li2 with bis (phenyl sulfonyl) sulfide [85]. The absolute... 

Fig. 15.16 Structures of trithiophene 42, [5]helicene 43, [7]heli-cene 44, [1 ljhelicene 45 and (-)-sparteine-mediated asymmetric synthesis of [1 ljhelicene 45. LDA (mono- and triannelation) and n-BuLi (diannelation) were used as bases.

A. Rajca, H. Wang, P. Bolshov, S. Rajca, Greek Cross Dodecaphenylene Sparteine-mediated Asymmetric Synthesis of Chiral D2-Symmetric Jt-Conjugated Tetra-o-phenylenes, Tetrahedron 2001,... 

Tab. 34. Sparteine-mediated electrocatalytic asymmetric oxidative dimerization of 2-naphthol and...

On the basis that a wide variety of (S)-configurated (a-carbamoyloxy)alkyllithium derivatives are accessible by (—)-sparteine-mediated deprotonation30, Hoppe and coworkers have described the synthesis of enantiomerically and diastereomerically pure cyclopen-tanols 38 by asymmetric cyclocarbolithiation reaction of 5-alkenyl carbamates like 36. Its deprotonation with s-BuLi/(—)-sparteine gives a chiral organolithium which cyclizes to benzyllithium 37 via 5-exo-trig and again with retention of configuration at the carbanionic... 

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