Lithium-substitution methodology

Because 3-substituted 1,2-amino alcohols and even P-alkyl-y-hydroxy-5-amino esters are potentially precursors to pharmacologically interesting materials, further investigations have been carried out to extend the methodology in this direction. Thus, the reduction of the ketone moiety of 56 by applying L-selectride or lithium tri-t-butoxyaluminum hydride opened access to the cis-amino lactones 58 (45-54% yield de = 90-94%) and the trans-amino lactones 58 (67-76% yield de > 98%), respectively (Scheme 1.1.16). Monodebenzylation with cerium ammoni-... 

An interesting variation of this methodology was developed whereby zinc enolates 127 were employed giving 2-ester-substituted pyrrolidines 128-13060c. The enolates 127 were obtained via transmetallation of lithium ester enolates 126 with ZnBr2 (equation 59). 

Cyclopropanations of a,/i-unsaturated ketones with sulfur-substituted methylenes have been achieved in several ways using this methodology. Sequential treatment of conjugated enones with (PhS)3CLi,. s-BuLi and electrophiles produces phenylthiocyclopropanes (equation 128)275. Generation of lithium bicyclofl. 1,0]butane-2-olates as intermediates has... 

P-Hydroxy sulfoximines are thermally labile and revert to their starting carbonyl compound and sulfoximine on mild thermolysis. This property has been exploited effectively as a method for the resolution of racemic chiral cyclic ketones.65 For example, the addition of the lithium salt of (+)-(S)-2b (99% ee) under kinetically controlled conditions (-78 °C) to racemic menthone gave three of the four possible diastereomeric adducts. The major two adducts resulted from attack on the menthone from the equatorial direction. These diastereomeric adducts could be readily separated by column chromatography. Thermolysis of the individual two major diastereomeric carbinols at 140 °C gave d- and /-menthone, respectively, in high enantiomeric purities (90-93% ee). This methodology has been successfully applied to the resolution of other 2-substituted cyclohexanones as well as other chiral ketones that have served as advanced synthetic intermediates for the synthesis of natural products.66-69... 

The Michael-aldol process with methacrylates described in Section II.B can be also applied to the synthesis of substituted tetrahydrofurans, 245. If the reaction is carried out in THF, the yield and selectivity of the sequence decrease. It was proposed that the lithium coordination with THF molecules hinders the formation of the product 245. The authors concluded that the Lewis acidity of naked lithium cation is the key driving force for the reaction to proceed successfully. The tandem reaction with lithium thiophenolate, fumarate ester and benzaldehyde constitutes an useful methodology for the preparation of y-butyrolactone (Scheme 75)89,90. 

The cascade sequence that affords bicyclic systems fails with the lithium derivatives of 2-bromo-iV,iV-diallylaniline. The methodology is useful for the synthesis of 3-substituted indolines and indoles, but the substrate undergoes only one anionic cyclization. Alkenyl vinyllithiums and alkenyl aryllithiums have also been employed in the preparation of alkylidenecyclopentanes and indanes. The intramolecular addition of vinyllithium reagents... 

Using the methodology previously developed by Stella and coworkers22 and by Wald-mann and Braun23 to synthesize 2-substituted aza-norbornanes (see Section II.C), Ander-sson and coworkers prepared chiral lithium amide 1824,25. This chiral base has been reported to rearrange several epoxides in up to 98% ee in the absence or presence of high concentrations of DBU (Scheme 13). 

In a nice illustration of the impact of metal coordination upon the reactivity of phospholes, a methodology for the functionalization of these heterocycles in the /3-position has been described (see also Scheme 22) <2001JOM105>. Here, coordination of both the P-lone pair and the cyclic diene system was undertaken. The resulting multimetallic complex 79 was treated with lithium diisopropylamide (LDA) to afford the lithium salt 350 (Scheme 118). This readily undergoes nucleophilic substitution with a variety of electrophiles to afford the corresponding substituted phosphole complexes 351-353. The free phospholes can be isolated following decomplexation with cerium(iv) ammonium nitrate (CAN). 

Chiral Auxiliary. (/ ,/ )-( ) has been used as a chiral auxiliary to direct the stereochemistry of addition of a nucleophile to an acrylate moiety. Almost complete stereoselectivity is achieved in the addition of cyclopentanecarboxylic acid lithium dianion to the a-substituted acrylate substrate (eq 14). This methodology allows stereochemical control at the a-position of a p-amino ester and thus complements the methodology described above for the stereoselective formation of p-substituted p-amino esters. 

Alkylamines are generally accessible via the reduction of nitroalkenes with lithium aluminum hy-dride. Substituted thienylethylamines can also be obtained using this methodology (equation 30). 

Deoxygenation of phenols may be achieved by reduction of aryl diethyl phosphates with lithium or sodium in liquid ammonia." A recent application of the methodology is outlined in Scheme 43." The reaction works well with a variety of substituted phenols, but not with dihydric phenols or naphthols. The alternative reduction of aryl sulfonates has also been examined, but the limited solubility of these derivatives can present difficulties. 

As mentioned above, one major drawback of the Trost methodology is its restriction to the parent compound. It was the Cohen group who found an alternative approach to phenylthiocyclopropyl lithium chemistry by using a reductive lithiation of readily accessible cyclopropanone dithioketals which also works for alkyl-substituted cyclopropanes. The anions obtained by reduction with two equivalents of lithium naphthalene or preferably lithium l-(dimethylamino)naphthalene (LDMAN) can effectively be trapped by apt electrophiles (equation 112). 

The a-iodoalkyltin compounds described above react readily with a variety of nucleophiles (alcohols, phenols, thiols, amides etc.) to give further types of a-functionally-substituted compounds R 3SnCHRX (Scheme 6-1).11 26 These will then react with butyl-lithium to give the reagents LiCHRX (Section 22.1) which will react in turn with carbon electrophiles to extend the carbon chain, and this methodology has been exploited extensively in organic synthesis. 

---