Lithium diisopropylamide auxiliaries

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Oxo esters are accessible via the diastereoselective 1,4-addition of chiral lithium enamine 11 as Michael donor. The terr-butyl ester of L-valine reacts with a / -oxo ester to form a chiral enamine which on deprotonation with lithium diisopropylamide results in the highly chelated enolate 11. Subsequent 1,4-addition to 2-(arylmethylene) or 2-alkylidene-l,3-propanedioates at — 78 °C, followed by removal of the auxiliary by hydrolysis and decarboxylation of the Michael adducts, affords optically active -substituted <5-oxo esters232 (for a related synthesis of 1,5-diesters, see Section 1.5.2.4.2.2.1.). In the same manner, <5-oxo esters with contiguous quaternary and tertiary carbon centers with virtually complete induced (> 99%) and excellent simple diastereoselectivities (d.r. 93 7 to 99.5 0.5) may be obtained 233 234. 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

Stereoselective Aldol Reactions. The (R)- and (S)-2-hydroxy-1,2,2-triphenylethyl acetates (HYTRA) offer a simple soludon for a stereoselecdve aldol addition of a-unsubstituted enolates. When a suspension of HYTRA is treated in THF with 2 equiv of Lithium Diisopropylamide, a clear soludon of the enolate forms (eq 1). Subsequent dilution with 2-methylbutane followed by the addition of 2-methylpropanal affords predominantly the (R,R)-diastereomeric adduct. Alkaline hydrolysis not only delivers (/ )-3-hydroxy-4-methylpentanoic acid in 86-94% ee but also liberates the optically pure auxiliary reagent (/ )-1,2,2-triphenylethane-1,2-diol, which can be removed and reused (eq 1). - ... 

The synthesis of (-)-Cio-desmethyl arteannuin B, a structural analog of the antimalarial artemisinin, was developed by D. Little et a. In their approach, the absolute stereochemistry was introduced early in the synthesis utilizing the Enders SAMP/RAMP hydrazone alkylation method. The sequence begins with the conversion of 3-methylcyclohexenone to the corresponding (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone. Deprotonation with lithium diisopropylamide, followed by alkylation in the presence of lithium chloride at -95 °C afforded the product as a single diastereomer. The SAMP chiral auxiliary was removed by ozonolysis. 

Chiral enolates in which the auxiliary is in the ester portion provide still another route to optically active lactams. Early results indicated that little asymmetric induction was obtained with menthyl enolates. Use of the enolate obtained from 24 did lead to high levels of asymmetric induction. Treatment of 24 with lithium diisopropylamide in tetrahydrofuran, followed by addition of imine 25, gives cf -/(-lactam 26 in 79% yield and 91%ee98. Optically active /3-lactams can be prepared by addition of chiral iron enolates (see Section D.l. 1.1.3.2.) to imines99-101. Addition of aluminum enolate 27 to imine 28, followed by oxidative cyclization with iodine and an amine, affords /(-lactam 29 in 54% yield and >95% ee. 

The ketone 18 forms a hydrazone 19 with SAMP. Due to asymmetric induction by the chiral auxiliary, the subsequent alkylation (a-metalation with lithium diisopropylamide in diethyl ether, followed by 1-iodopropane at —110°C) occurs stereoselectively with formation of the diastereomer 20. In the final step, the auxiliary SAMP is removed from 20 by hydrolysis and the a-alkylated ketone 21 is obtained with ee = 99.5%. The use of RAMP as auxihary produces the (R)-enantiomer of 21. 

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