Deprotonation sparteine-mediated

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). 

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. 

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... 

T(2-Alkylcycloalk-l-enyl)methyl carbamates of type 56 are useful 1,2-dianion synthons that can be combined with two aldehydes in adjacent positions to provide a versatile synthesis of [fjannulated tetrahydrofurans (Scheme 81). At first, a carbanion of carbamate 56, which exhibits considerable configurational stability, is generated by (—)-sparteine-mediated deprotonation this is then converted to an optically active homoaldol product 57 with up to %% ee. An (it)-oxonium ion, which is subsequently formed under the influence of BF3, undergoes an intramolecular Mukaiyama-type addition of the enolic moiety onto the carbonyl group of a second aldehyde in the least-hindered conformation. Finally, the carhamoyl group is extmded, and after aqueous workup, diastereomerically pure tetrahydrofurans can be isolated <2005ASC1621>. 

Nevertheless, there are two important issues that can arise following the use of sparteine in any particular transformation. Firstly, although (-h)-sparteine also occurs naturally it is much less easily obtained and so for a specific application if (-)-sparteine leads to the undesired enantiomer, then it is currently difficult, even despite an impressive recent total synthesis of (-h)-sparteine [66], to find a substitute for (-)-sparteine that will allow access to the desired enantiomer. A recent example is found in work by Clarke and Travers towards insecticidal 4-alkynyloxazohnes, which used a novel sparteine-mediated enantioselective deprotonation-alkylation of propargyhc amide systems (Scheme 20), and unfortunately did not lead to the biologically relevant enantiomer [67]. 

Chiral, Non-Racemic l-Oxy-2-Alkenyllithium Compounds by Sparteine-Mediated Deprotonation and Stereochemical... 

The presence of 2- and 3-dibenzylamino [63,67,68,95] and as well 3- or 4-OCby [78,96] or 4- or 5-TBSO groups [97,98] (compounds 155a - 159a) does not interfere. The presence of a remote dibenzylamino group at a stereogenic center in combination with an co-carbamoyloxy group in the dicarbamate 160a does not decrease the pro-S selectivity in the (-)-sparteine-mediated deprotonation step [75,77,99]. 

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. 

The (-)-sparteine-mediated enantioselective carboHthiation of phenyl-substituted alkenes has been performed intramolecularly to prepare enantioenriched cyclopentanes [55]. Scheme 33 shows that the (S)-configured (a-carbamoy-loxy)-alkyllithium, made by enantioselective deprotonation, still undergoes a syn addition, followed first by epimerization of the intermediate benzylHthium, and then by the electrophilic attack of the latter with inversion of configuration three stereogenic centers have been created. A similar stereoselective cycHza-tion has been used to transform piperidine-derived substrates into indoHzidines [56].The reaction proceeds equally well, if the styryl moiety, present here, is replaced by a 1-phenylbutadienyl or a l-phenylbut-l-yn-3-enyl moiety [57]. 

Mizaikoff, B. Lendl, B. (2002). Sensor Systems Based on Mid-infrared Transparent Fibers, In Handbook of Vibratkmal Spectroscopy, J. M. Chalmers P. R. Griffiths (Eds.), John Wiley Sons Ltd., ISBN 0471988472, Chichester Pippel, D. J. Weisenburger, G. A. Faibish, N. C. Beak, P. (2001). Kinetics and Mechanism of the (-)-Sparteine-Mediated Deprotonation of (E)-N-Boc-N-(p>-methoxyphenyl)-3-cyclohexylallylamine. Journal of the American Chemical Society Vol.123, pp. 4919-4927, ISSN 0002-7863... 

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