3-Pinanone

Ethyl (bornylideneamino)acetate (2) and the imines of (-)-(lf ,2, 5 )-2-hydroxy-3-pinanone and glycine, alanine and norvaline methyl esters were particularly successful as Michael donors. The chiral azaallyl anions, derived from these imines by deprotonation with lithium diisopropylamide in THF at — 80 C, add to various a,/i-unsaturated esters with modest to high diastereoselectivity (see Section 1.5.2.4.2.2.5.). Thus, starting with the imine 2, (R1 = CH,) and ethyl ( )-2-butcnoate, the a,/i-dialkylated glutamate derivative 3 is obtained as a single diastercomer in 90% yield91-92. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

Therefore, in principal, condensation of a primary amine with an enantiomerically pure ketone should allow asymmetric synthesis of a-substituted primary amines. This approach has been applied to the synthesis of a-amino acids, for example, using the imine prepared from a-amino esters and (l.S, 2,S ,5,S )-2-hydroxy-3-pinanone, via an amino-substituted ester enolate anion with some success39 40. Application of this approach to simple primary amines has seldom been reported. 

Really excellent stereoselectivities were reported using 2-hydroxy-3-pinanone, easily available in both enantiomeric forms by oxidation of the corresponding naturally occurring a-pinenes50, as the chiral auxiliary. 

Following the same procedure, formation of the imine 6D and subsequent deprotonation with two equivalents of butyllithium followed by alkylation, either enantiomer of the a-substituted benzylamines could he obtained with nearly complete stereocontrol. Unfortunately only poor yields are obtained51,52,53. The (-)-(15,25, 55)-2-hydroxy-3-pinanone derived from ( + )-a-pinene resulted in the formation of the R-configurated benzylamines, conversely the ( + )-2-hy-droxy-3-pinanone derivative led to the (S )-benzylamine product. It has been shown that the high stereocontrol occurs within the alkylation step. The chiral auxiliary can be recovered without racemization from the oxime with aqueous titanium(III) chloride. 

A synthesis of a-arylamino acids has been reported using Schiff-base anions 61 derived from amino esters, which are arylated with fluorobenzene complex la to give a-aryl imino esters 62 in 48-76 % yield (R = H, Me, CH2Ph) [49]. Using the same procedure, these authors reported a convenient synthesis of optically pure a-aryl amino acid precursors 64 by enantioselective substitution of fluorobenzene complex la using the Schiff base of L-alanine methyl ester with f 1 R.2R.5 R -2-hydroxy-3-pinanone 63 in the presence of LDA (Scheme 30) [50]. 

Chiral auxiliaries may be applied to a-amino acid esters by forming imine derivatives. Enolates from 2-hydroxy-3-pinanone glycinate esters have been alkylated to produce mono- and di-substituted o-amino acids in good optical yields after hydrolysis. Recently, McIntosh et al reported the results of alkylations of the enolate (139) derived from the (+)-camphor imine of r-butyl glycinate with a variety of... 

Alkylation of the Schiff base of glycine with 2-hydroxy-3-pinanone proceeds in an extremely diastereoselective manner. Thus, fluoro-functionalization on the a-carbon of the Schiff base followed by hydrolysis provides fluorinated a-amino acids in a highly enantiomerically enriched form. 2-Fluoroethylation and 2-fluoroallylation of 157 (see Scheme 9.35) and bromodifluoromethylation of 161 (see Scheme 9.36) give the desired adducts 158 and 162, respectively, with excellent diastereoselectivities. Lithium enolate dimer 160 has been proposed as a reactive intermediate for the stereocontrolled alkylation [61]. The adducts 158 and 162 were transformed to 4-fluoro-2-amino acids (>96% ee) 159 [61] and 3,3-difluoroglutamine 164 [62], respectively. 

Laue, K. W., Kroger, S., Wegelius, E. ad Haufe, G. (2000) Stereoselective synthesis of "/-fluorinated a-amino acids using 2-hydroxy-3-pinanone as an auxiliary. Eur. J. Org. Chem., 3737-3743. 

The alkylation of diethyl (aminomethyl)phosphonate Schiff bases e.g. (217 R =H or Ph, R =Ph), with (218 Y=C1, OAc, or 0C02Et) is catalyzed by Pd(0). The alkylation of the Schiff base (219) ( from diethyl (aminomethyl)phosphonate and either (IR,2R,5R)-(+)- or (IS,2S,5S)-(-)-2-hydroxy-3-pinanone) followed by separation of the diastereoisomeric products (220) and their subsequent acidolysis, afforded the resolved esters (221) Amongst the various compounds so prepared was the optically... 

Controlled oxidation of the a-pinenes with potassium permanganate leads to the enantiomeric 2-hydroxy-3-pinanones 38 29-31, while under forcing conditions, ring cleavage occurs, leading to cyclobutane derivatives 39. The hydroxy ketones 38 are useful auxiliaries forming imines with benzylic amines or glycine esters which can be alkylated enantioselectively via the enolates (Sections D.l. 1.1.1.3.2., D. 1.1.1.4.1. and D.I.5.2.4.). 

FIGURE 11.7.sfroc The structure of 2-hydroxy-3-pinanone (with numbering). 

FIGURE 11.7The2-D H- C gHSQC NMR spectrum of 2-hydtoxy-3-pinanone in CDCI3. 

I FIGURE WJ.ghmbc The 2-D gHMBC NMRspectrum of 2-hydroxy-3-pinanone in CDCI3. 

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