Imines stereochemistry

For methyl ketimines good regiochemical control in favor of methyl deprotonation, regardless of imine stereochemistry, is observed using LDA at -78° C. With larger A-substituents, deprotonation at 25° C occurs anti to the nitrogen substituent.115... 

Figure 12.48 Effects of imine stereochemistry on the C-C coupling constants.

A wide variety of /3-lactams are available by these routes because of the range of substituents possible in either the ketene or its equivalent substituted acetic acid derivative. Considerable diversity in imine structure is also possible. In addition to simple Schiff bases, imino esters and thioethers, amidines, cyclic imines and conjugated imines such as cinnamy-lidineaniline have found wide application in the synthesis of functionalized /3-lactams. A-Acylhydrazones can be used, but phenylhydrazones and O-alkyloximes do not give /3-lactams. These /3-lactam forming reactions give both cis and /raMS-azetidin-2-ones some control over stereochemistry can, however, be exercised by choice of reactants and conditions. 

At Smith Kline French a general approach to cephalosporin and penicillin nuclear analogs was developed that utilizes a monocyclic /3-lactam (59) with the correct cis stereochemistry as a key intermediate. This is prepared by reaction of the mixed anhydride of azidoacetic acid and trifluoroacetic acid with imine (58) followed by oxidative removal of the dimethoxybenzyl group. This product could be further elaborated to intermediate (60) which, on reaction with a -bromoketones, provides isocephalosporins (61). These nuclear analogs displayed antibacterial properties similar to cephalosporins (b-79MI51000). 

Fischer s original method for conversion of the nitrile into an aldehyde involved hydrolysis to a carboxylic acid, ring closure to a cyclic ester (lactone), and subsequent reduction. A modern improvement is to reduce the nitrile over a palladium catalyst, yielding an imine intermediate that is hydrolyzed to an aldehyde. Note that the cyanohydrin is formed as a mixture of stereoisomers at the new chirality center, so two new aldoses, differing only in their stereochemistry at C2, Tesult from Kiliani-Fischer synthesis. Chain extension of D-arabinose, for example, yields a mixture of D-glucose and o-mannose. 

In the course of investigations on the synthesis of ( + )-biotin (7) the addition of isothiocyana-toacetate enolates 8 to 1,3-thiazolines 9 has been studied16 17. The diastereofacial selectivity of these reactions is controlled by attack of the enolate on the imine face opposite the 5-pentyl group and correctly establishes the relative stereochemistry at C-l and C-2 of biotin. 

This contrary stereochemistry in the Bucherer - Bergs reaction of camphor has been attributed to steric hindrance of e.w-attack of the cyanide ion on the intermediate imine. Normally, equatorial approach of the cyanide ion is preferred, giving the axial (t>Mr/o)-amino nitrile by kinetic control. This isomer is trapped under Bucherer-Bergs conditions via urea and hydan-toin formation. In the Strecker reaction, thermodynamic control of the amino nitrile formation leads to an excess of the more stable compound with an equatorial (e.w)-amino and an axial (endo)-cyano (or carboxylic) function13-17. 

The diastereofacial selectivity of this asymmetric [3C+2S] process is explained following a model similar to that described in Sect. 2.6.4.4 for the reaction of chiral alkenylcarbene complexes and 1,3-dienes. Thus, the proposed mechanism that explains the stereochemistry observed assumes a [4+2] cycloaddition reaction between the chromadiene system and the C=N double bond of the imine. The necessary s-cis conformation of the complex makes the imine... 

Tables XXVIII and XXIX, respectively. Excellent correlations were obtained for all three sets. The stereochemistry of the sy -methyl ketoximes is discussed by Charton and Charton (73). The values of pj obtained for the trans-heterovinylene sets are not in good agreement with each other. Two sets gave values of 54 and 55, respectively, and the third set gave a value of 35. The difference in pj values cannot be accounted for. A value of 54 to 55 for pj suggests the possibility of some exaltation between substituent and reaction site such as that which occurs in para-substituted phenols and anilines. To demonstrate this with certainty requires that the value of pj be determined for a set of imines bearing a reaction site on the nitrogen which will not interact strongly with substituents. No such set of data is extant in the literature at the present time.

Amine (1) was needed to study the stereochemistry of alkylation reactions. The primary alkyl group had best come from an amide or an Imine while the secondary alkyl group must come from an imine. The disconnections may be carried out in any order. 

A mechanistic rationale for the observed cw-selectivity has been proposed based on preorganisation of the Breslow-type intermediate and imine through hydrogen bonding 253, with an aza-benzoin oxy-Cope process proposed. Reaction via a boat transition state delivers the observed cw-stereochemistry of the product (Scheme 12.57). Related work by Nair and co-workers (using enones 42 in place of a,P-unsaturated sulfonylimines 251, see Section 12.2.2) generates P-lactones 43 with fran -ring substituents, while the P-lactam products 252 possess a cw-stereo-chemical relationship. 

The discussion of the activation of bonds containing a group 15 element is continued in chapter five. D.K. Wicht and D.S. Glueck discuss the addition of phosphines, R2P-H, phosphites, (R0)2P(=0)H, and phosphine oxides R2P(=0)H to unsaturated substrates. Although the addition of P-H bonds can be sometimes achieved directly, the transition metal-catalyzed reaction is usually faster and may proceed with a different stereochemistry. As in hydrosilylations, palladium and platinum complexes are frequently employed as catalyst precursors for P-H additions to unsaturated hydrocarbons, but (chiral) lanthanide complexes were used with great success for the (enantioselective) addition to heteropolar double bond systems, such as aldehydes and imines whereby pharmaceutically valuable a-hydroxy or a-amino phosphonates were obtained efficiently. 

The complete interpretation of regiochemistry and stereochemistry of imine deprotonation also requires consideration of the state of aggregation and solvation of the... 

Imines, on the contrary, proved particularly reactive under these conditions (Fig. 4.34). For example, Jones and Selenski report that the introduction of one equivalent of methyl magnesium bromide to benzaldehyde 5 stirring at —78 °C in the presence of one and half equivalents of the imine that is derived from the condensation of benzyl amine and benzaldehyde proceeds immediately to the aminal 65 in 94% yield.27 Only the trans isomer is observed from this low-temperature cycloaddition. While the relative stereochemistry appears to be result of an exo transition state, we suspect that initial cis adduct from and endo addition may epimerize under these conditions. 

Stereochemistry was controlled by the stereodirecting phenyl group at position 3 and by the ortho-substituents of the aromatic ring at position 10 in the azomethine imines (Equation 101) <2007T991>. 

A Lewis acid-induced aza-Diels-Alder reaction between the /3-lactam-imine 295 and 3,4-di hydro-2//-pyran gives the two diastereomeric pyranoquinolines 296 and 297. Under basic conditions, these products rearrange to the amino-substituted pyranoindolizinones, 298 and 299, respectively, with retention of stereochemistry (Scheme 74) <2003CEJ3415>. 

Scheme 6.8) the substituent (R) on the nitrogen should point as far away as possible from the indenyl ligand. This model predicts that hydrogenation of syn- and cwti-imines give rise to enantiomers of opposite stereochemistry as observed experimentally. The model also predicts that if one takes into consideration the influence of Rs and RL substituents, the energy difference of the two possible pathways should be lower for the syn imines, giving rise to lower enan-tioselectivities. 

In contrast to the allyltitaniums derived from acrolein cyclic acetals, such as 1,2-dicyclo-hexylethylene acetal shown in Scheme 9.8, those derived from acrolein acyclic acetals react with ketones and imines exclusively at the y-position. As shown in Eq. 9.29, the reaction with chiral imines having an optically active 1-phenylethylamine moiety proceeds with high diastereoselectivity, thus providing a new method for preparing optically active 1-vinyl-2-amino alcohol derivatives with syn stereochemistry [53], The intermediate allyltita-nium species has also found use as a starting material for a carbozincation reaction [54],... 

The reactions of allylmetal reagents with carbonyl compounds and imines have been extensively investigated during the last two decades [1], These carbon—carbon bondforming reactions possess an important potential for controlling the stereochemistry in acyclic systems. Allylmetal reagents react with aldehydes and ketones to afford homo-allylic alcohols (Scheme 13.1), which are valuable synthetic intermediates. In particular, the reaction offers a complementary approach to the stereocontrolled aldol process, since the newly formed alkenes may be readily transformed into aldehydes and the operation repeated. 

The heteroatom version of the vinylcyclopropane rearrangement serves to facilitate alkaloid construction. Scheme 13 outlines a strategy for the pyrrolizidine alkaloid isoretronecanol 211 90). Use of a carboxaldehyde (i.e. 213) as a synthon for the primary alcohol provides an ability to adjust stereochemistry. It also sets up formation of the pyrrolidine ring bearing the aldehyde by an aldol-type condensation of an enol of the aldehyde onto an imine derived from 214. Because of the lability of such systems, introduction of X=PhS imparts stability. The resultant azacyclopentene translates to an imine 215 using the iminocyclopropane rearrangement methodology. Simple condensation of the primary amine 216 with aldehyde 37a then initiates this... 

---