Imines, diastereoselective allylation

In this chapter, recent applications of (W)-phcnylglycine amide (1) in asymmetric synthesis are presented (Figure 25.2). The first section deals with diastereoselective Strecker reactions for the preparation of a-amino acids and derivatives, whereas the second section focuses on diastereoselective allylation of imines for preparation of enantiomerically pure homoallylamines. This latter class of compounds is a well-known intermediate for the synthesis of, for example, many types of amines, amino alcohols, and P-amino acids. The final section describes reduction of imines providing enantiomerically pure amines. (S)-3,3-Dimethyl-2-butylamine and (S)-l-aminoindane will be presented as leading examples. The results described in this chapter originate from a longstanding cooperation in the field of chiral technology development between DSM Pharma Chemicals and Syncom B.V. 

The imines generated in situ from 2-pyridinecarboxaldehyde (or 2-quinolinecarboxaldehyde) and arylamines undergo indium-mediated Barbier allylation in aqueous media to provide homoallylic amines. Crotyl and cinnamyl bromides lead to diastereoselective allylation with diastereomeric ratios up to 98 2 (Equation (60)).260... 

Diastereoselective allylation of immobilized chiral imines has been carried out by employing a polymer-bound substrate bearing a pendant chiral auxiliary (Scheme 12.18) [13, 24]. The auxiliary was not directly attached to the resin. 

Diastereoselective allylation and crot-ylation of A-unsubstituted imines derived from ketones. 

The cyclic 2,4-dienoate 184, formed by the Pd-catalyzed cyclization of the 1,6-enyne 183, reacted with 154 to form the azulene derivative 185[118], The 3-methylenepyrrolidine 188 is formed by the reaction of the Zn reagent 186 with the chiral imine 187 with high diastereomeric excess. The structure of the allylic ethers is important for obtaining high diastereoselectivity[l 19],... 

Reactions with seven- to nine-membered cydic allylic carbonates or halides give the corresponding cydic allyltitanium compounds. These reagents add to aldehydes and imines with moderate to excellent diastereoselectivities [59]. The allyltitanium compound generated from 1-vinylcyclopropyl carbonate reacts regioselectively with aldehydes and ketones at the less substituted carbon atom to provide alkylidenecydopropane derivatives, as shown in Scheme 13.29 [60], The regiochemical outcome of the reaction can be rationalized by assuming an equilibrium between two allyltitanium spedes that favors the less strained tertiary structure. 

Grigg and co-workers described a novel three-component indium-palladium-mediated allylation reaction [67]. As exemplified by Eq. 14.16, 3,3-disubstituted oxi-ndole derivative 133 was obtained smoothly from phenyl iodide, the easily available isatin imine 132 and 1,2-propadiene (131). Excellent levels of diastereoselectivity were obtained in this cascade reaction employing imines derived from enantiopure sulfmamides. 

Additionally, 1,2-dihydroxyethylene dipeptide analogues without the C-terminal carboxylic acid have been used to obtain aspartyl proteases inhibitors.[641 These efforts include stereoselective alkylation of imines, one-pot reductive amination of epoxy ketones, ring opening of epoxides with sodium azide, diastereoselective dihydroxylation of allylic amines, and enzymatic resolution and stereocontrolled intramolecular amidation. 

Herein, we describe highly enantioselective and diastereoselective additions of diorganozincs to aldehydes, imines, and enones. Enantioselective cyclo-propanation of allylic alcohols will also be mentioned. 

The reaction can be applied to imines. Recently, the preparation of chiral allylglycines was effected by addition of allyl groups to the C=N bond in glyoxylic acid oximes modified as chiral sultams (Oppolzer chiral induction methodology).55 The yields (> 88%) and the diastereoselectivity (d.e. > 80 20) are excellent. 

Reactions of glycosyl imines derived from aliphatic aldehydes must be carried out at low temperature due to their higher sensibility towards anomerization. Yields and diastereoselectivity rank in the same region as those achieved for galactosyl homo-allylamines. The results of different stereoselective allylations, are summarized in Table 4.1. 

The following reactions proceed with the participation of the allylic boron system (i) allylboration and protolytic cleavage of organic compounds with multiple bonds, (ii) allylboron-alkyne condensation,598 599 (iii) reductive mono-and trans-a,a -diallylation of nitrogen aromatic compounds, (iv) disproportionation processes between tribut-2-enylborane and BX3 (X = C1, Br, OR, SR). Allylboration of carbonyl compounds, thioketones, imines, or nitriles leads to the homoallylic alcohols, thiols, or amines (Equations (136) and (137). It is most important that 1,2-addition to aldehydes and imines proceeds with high diastereoselectivity so that ( )-allylic boranes and boronates give the anti-products, while -products are formed preferentially from (Z)-isomers. 

Diastereoselective Barbier-type allylation of chiral imines bearing a hydroxyl group on the chiral auxiliary has been achieved in DMF (Equation (59)).257-259 The chelation between the nitrogen and the hydroxyl group of the imine with indium is crucial for the high stereoselectivity. The palladium-catalyzed indium-mediated allylation of imines also proceeds well with Ini prepared in situ from In and I2.259... 

Oxazolidine 144 obtained from amino alcohol 143 and ethyl trifluoropyruvate is also a synthetic intermediate for 2-amino-2-trifluoromethylpentanoic acid 145. Lewis acid-catalyzed allylation of 144 with allyl silane occurs in excellent yield with a moderate stereoselectivity. Meanwhile, O-tert-butyldimethylsilyl-protected imine 146 gives better diastereoselectivity although yield is poor (see Scheme 9.31) [57]. 

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