Alcohols resolving agents

Practical advantage of the method is that it does not require dry solvents. The resolving agent can be prepared by simple solution of DBTA monohydrate and half an equivalent amount of calcium oxide in hot 95 % ethyl alcohol. Crystallization of the diastereoisomeric coordination complex can be achieved by cooling and addition of cosolvents (e.g. acetone, toluene, ethyl acetate, etc.) or change ethyl alcohol to an ester type solvent. The enantiomers can be liberated from the crystalline complex by simple acidic workup procedure. [23]... 

Coordination complex formation of alkoxyalcohols (8, 9, 10, 14), 2-butanol (15) and 1,3-butanediol (16, Scheme 7) with the zinc salt of DBTA was investigated, too. [25] The resolving agent (DBTAZn) was prepared again from DBTA monohydrate and zinc oxide or zinc acetate in aqueous ethyl alcohol solution. 

Rate of complex formation between chiral alcohols and DBTA monohydrate in hexane suspension is quite slow (see Figure 1) and numerous separation steps are necessarry for isolation of the alcohol isomers (filtration of the diastereoisomeric complex then concentration of the solution, decomposition of the complex, separation of the resolving agent and the enantiomer, distillation of the product). To avoid these problems, alternative methods have been developed for complex forming resolution of secondary alcohols. In a very first example of solid phase one pot resolution [40] the number of separation steps was decreased radically. Another novel method [41] let us to increase the rate of complex forming reaction in melt. Finally, first examples of the application of supercritical fluids for enantiomer separation from a mixture of diastereoisomeric complexes and free enantiomers [42, 43] are discussed in this subchapter. 

The racemic alcohol is esterified with an optically active acid. The acid is chosen, if possible, so that the two resulting diastereoisomeric esters are solids capable of separation. After the separation, the active alcohol and resolving agent are recovered from either (or both) of the pure active esters, usually by alkaline hydrolysis. 

Frankland and Price 17 were the first to attempt the resolution of alcohols (and acids) by fractional crystallization of their solid esters. The isomeric solid esters formed from Z-s-butylcarbinol and di-dibenzoyl-glyceric acid failed to separate on crystallization the corresponding di-alcohol-i-acid ester was liquid. Marckwald and McKenzie 18-19 effected partial resolutions of dl-mandelic acid and related acids with 1-menthol and d-bomeol, and of di-2-octanol with d-tartaric acid, but did not develop a satisfactory method for resolving alcohols. Later investigators, however, have employed the following resolving agents in several more or less successful resolutions of certain alcohols (a) i-menthyl isocyanate, (6) d-camphoric acid, (c) d- or i-mandelic acid, (d) d- or... 

Z-Menthyl Isocyanate. Pickard and Littlebury 20-21 found that Z-menthyl isocyanate forms crystalline esters (urethanes) with many alcohols and phenols. The two diastereoisomeric urethanes from cZZ-l-phenyl-1-p-hydroxyphenylethane and from dZ-oc-tetrahydro-/3-naphthol were separated readily.2 The method has not been applied widely. Z-Men-thyl isocyanate is the most readily available resolving agent of this type but is difficult to prepare. The urethanes are not easily hydrolyzed, and the isocyanate is not recovered in the hydrolysis but is converted to the amine. 

In this method the alcohol is converted to an acid ester, usually the sulfate, phthalate, or succinate. The acid ester is then resolved by crystallization of its salts with active bases, and the active esters are recovered from the salts and saponified to yield the corresponding active alcohols. The method has been by far the most generally applicable. It was developed because of the relative ease and certainty with which racemic acids may be resolved by means of their salts with active bases. Basic resolving agents are sufficiently numerous and accessible so that it usually is possible to find some combination of active base and solvent that will yield separable crystalline salts with nearly any type of acid. A list of basic resolving agents is given later (p. 394). 

The amino alcohol cis-1-ami no-2-i ndanoI (1) has been shown to be an extremely versatile reagent in asymmetric synthesis. It has been used as a chiral auxiliary. This chemistry and the synthesis of 1 and its uses in biologically active agents are discussed in Chapter 24. Reactions where the amino alcohol 1 is used as a ligand in catalytic reactions will be found in Chapter 17. This chapter discusses reactions where 1 is used as a resolving agent. Other resolution methods can be found in Chapters 6 and 7. 

Let s consider how we might resolve a racemic mixture of (R)- and (,S )-bu(an-2-ol. We need a resolving agent that reacts with an alcohol and that is readily available in an enantiomerically pure state. A carboxylic acid combines with an alcohol to form an ester. Although we have not yet studied the chemistry of esters (Chapter 21), the following equation shows how an acid and an alcohol can combine with the loss of water to form an ester. 

The diastereomers of 2-butyl tartrate have different physical properties, and they can be separated by conventional distillation, recrystallization, or chromatography. Separation of the diastereomers leaves us with two flasks, each containing one of the diastereomeric esters. The resolving agent is then cleaved from the separated enantiomers of butan-2-ol by the reverse of the reaction used to make the ester. Adding an acid catalyst and an excess of water to an ester drives the equilibrium toward the acid and the alcohol ... 

Problem 20.9 Alcohols are the class of compounds most commonly resolved (Sec. 7.9), despite the fact that they are not acidic enough or basic enough to form (stable) salts. Outline all steps in a procedure for the resolution of sec-butyl alcohol, using as resolving agent the base (-)-B. 

Chromatography of radiochemically homogeneous terpenoids has been reviewed useful gas-chromatographic techniques reported include the use of polyphenyl ether in g.c.-m.s. of 23 monoterpenoid hydrocarbons,the use of 3,4,5-trimethoxybenzylhydrazine for pre-column removal of aldehydes and ketones, and the resolution of some bicyclic alcohols and ketones by co-injection with a volatile chiral resolving agent. 

The resolving agent must now be removed by hydrolysis of the amide. This is a risky business as enolisation would destroy the newly formed stereogenic centre, and a cunning method was devised to rearrange the amide 30 into a more easily hydrolysed ester by acyl transfer from N to O. The rest of the synthesis is as before. By this means the alcohol 28 was obtained almost optically pure, <0.4% of the other enantiomer being present. No further reactions occur at the newly formed stereogenic centre, so the absolute chirality of 22 is as shown. 

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