Induced asymmetry

A synthesis of optically active citroneUal uses myrcene (7), which is produced from P-piaene. Reaction of diethylamine with myrcene gives A/,A/-diethylgeranyl- and nerylamines. Treatment of the aHyUc amines with a homogeneous chiral rhodium catalyst causes isomerization and also induces asymmetry to give the chiral enamines, which can be readily hydrolyzed to (+)-citroneUal (151). 

E. (+)-2-Butanol from c/.s-2-Butene The Use of Diisopinocampheylborane to Induce Asymmetry (i)... 

Reductive alkylation with chiral substrates may afford new chiral centers. The reaction has been of interest for the preparation of optically active amino acids where the chirality of the amine function is induced in the prochiral carbonyl moiety 34,35). The degree of induced asymmetry is influenced by substrate, solvent, and temperature 26,27,28,29,48,51,65). Asymmetry also has been obtained by reduction of prochiral imines, using a chiral catalyst 44). Prediction of the major configurational isomer arising from a reductive alkylation can be made usually by the assumption that amine formation comes via an imine, not the hydroxyamino addition compound, and that the catalyst approaches the least hindered side (57). 

The interest in asymmetric synthesis that began at the end of the 1970s did not ignore the dihydroxylation reaction. The stoichiometric osmylation had always been more reliable than the catalytic version, and it was clear that this should be the appropriate starting point. Criegee had shown that amines, pyridine in particular, accelerated the rate of the stoichiometric dihydroxylation, so it was understandable that the first attempt at nonenzymatic asymmetric dihydroxylation was to utilize a chiral, enantiomerically pure pyridine and determine if this induced asymmetry in the diol. This principle was verified by Sharpless (Scheme 7).20 The pyridine 25, derived from menthol, induced ee s of 3-18% in the dihydroxylation of /rcms-stilbene (23). Nonetheless, the ee s were too low and clearly had to be improved. 

Epoxides bearing electron-withdrawing groups have been most commonly synthesized by the Darzens reaction. The Darzens reaction involves the initial addition of an ct-halo enolate 40 to the carbonyl compound 41, followed by ring-closure of the alkoxide 42 (Scheme 1.17). Several approaches for inducing asymmetry into this reaction - the use of chiral auxiliaries, reagents, or catalysts - have emerged. 

Table 1.8 Use of 8-phenylmenthyl esters to induce asymmetry in the Darzens reaction.

Ohkata [30, 31] and co-workers have employed an 8-phenylmenthyl ester to induce asymmetry in the Darzens reaction (Table 1.8). Moderate to high diaster-... 

The complex obtained from commercially available chiral a-amino acids (AA) with Cu + ion induces asymmetry in the Diels-Alder reaction of 31 (R = H) with 32. By using 10% Cu(II)-AA (AA = L-abrine) the cycloaddition occurs e/iJo-stereoselectively in 48 h at 0°C with high yield and with acceptable enantioselectivity ee = 1A%). This is the first example of enantioselective Lewis-acid catalysis of an organic reaction in water [9b]. 

It is often possible to convert an achiral compound to a chiral compound by (1) addition of a chiral group (2) running an asymmetric synthesis, and (3) cleavage of the original chiral group. An example is conversion of the achiral 2-pentanone to the chiral 4-methyl-3-heptanone (50). In this case, >99% of the product was the (5) enantiomer. Compound 49 is called a chiral auxiliary because it is used to induce asymmetry and then is removed. 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

Ever since Pasteur s work with enantiomers of sodium ammonium tartrate, the interaction of polarized light has provided a powerful, physical probe of molecular chirality [18]. What we may consider to be conventional circular dichroism (CD) arises from the different absorption of left- and right-circularly polarized light by target molecules of a specific handedness [19, 20]. However, absorption measurements made with randomly oriented samples provide a dichroism difference signal that is typically rather small. The chirally induced asymmetry or dichroism can be expressed as a Kuhn g-factor [21] defined as ... 

More than sixty years ago, Criegee reported that the dihydroxylation of olefins by osmium tetroxide was accelerated by the addition of a tertiary amine.165 166 Later, this discovery prompted the study of asymmetric dihydroxylation, because the use of an optically active tertiary amine was expected to increase the reaction rate (kc > k0) and to induce asymmetry (Scheme 41).167... 

The extent of asymmetric induction was low. L 1 was the most effective to induce asymmetry in the adduct of a-methylstyrene and methyl-... 

The H-bond-induced asymmetries in C—H bonds are also apparent in the forms oftheNBOs ... 

In an asymmetric reaction, substrate and reagent combine to form diaster-eomeric transition states. One of the two reactants must have a chiral element to induce asymmetry at the reaction site. Most often, asymmetry is created upon conversion of trigonal carbons to tetrahedral ones at the site of the functionality. Such asymmetry at carbon is currently a major area of interest for the synthetic organic chemists. 

S. F. Scarlata and C. A. Royer, Ligand-induced asymmetry as observed through fluorophore rotations and free energy couplings Application to neurophysin, Biochemistry 25, 4925 4929 (1986). 

The most common method for inducing asymmetry in 1,3-dipolar cycloadditions is by the application of chiral 1,3-dipoles, chiral dipolarophiles, or both, the latter always being the case for intramolecular reactions (5). First the reaction of chiral 1,3-dipoles will be described, then the reactions of chiral dipolarophiles, and finally the intramolecular reactions. In this chapter we have chosen to treat the diaster-eoselective reactions employing chiral auxiliaries separately in Section 12.3. 

III.C.3) and the use of special sampling methods to gain the rapid-convergence advantage of point-successive iteration without inducing asymmetry (Section III.C.2). 

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