Chiral auxiliaries agents

Kolb and Barth 229) synthesized oc-substituted optically active amines or amino acids (223). Again the authors employed a derivative of naturally occurring (S)-proline, namely (—)-(S)-l-dimethoxymethyl-2-methoxymethyl-pyrrolidine (221) as chiral auxiliary agent. The metalation of the amidines (160) leads to azaallyl anions homologous with (222). After alkylation and hydrolysis, the desired a-substituted amines and amino acids, respectively, are obtained with some stereoselectivity. 

DDB, TMB, and DEB are far superior to other neutral chiral auxiliary agents used in the same reactions.3,10-13... 

In each case it is a matter of obtaining a diastereomeric environment around the nuclei whose resonances can then be distinguished. The ee is then calculated by integration of the peaks corresponding to each of the diastereomers. In reality, it is a diastereomeric excess that is calculated, but this can be converted into an ee if the chiral auxiliary agent used is itself enantiomerically pure. In order for the precision of the measurement to reach 5%, each peak area must be obtained with an accuracy of 1.25%. 

In order to depart to the third dimension to perform asymmetric synthesis in a way to obtain only or prevalently one enantiomer of the target molecule, there is a substantial prerequisite chiral information has to be present in the reaction system. This is materialized as a chiral catalyst, chiral auxiliary agent or even chiral solvent. Detailed discussion of stereoisomerism as an introduction to stereoselective reactions is presented in Chap. 3. We suggest detailed study of the following examples after reading this chapter. 

In conclusion, the asymmetric alkylation of chiral enolates and enamines can be completed with high stereoselectivity affording final products with high optical purity [17], The chiral economy of this and other noncatalytic methods that use chiral auxiliary agents in a stoichiometric quantity depends on their availability and effective recycling in the process. 

The 4-thiazolidinyl phosphonates 143 (Scheme 44) are known for their therapeutical properties, in particular as anti-inflammatory agents [5,89]. Their asymmetric synthesis by hydrophosphonylation of 3-thiazolines has been described using various chiral auxiliaries chiral phosphites such as (2S,4i )-2H-2-oxo-5,5-dimethyl-4-phenyl-l,3,2-dioxaphosphorinane (de = 2-8%) [90] or BINOL-phos-phite (de = 65-90%) [91] and also chiral catalyst such as titanium or lanthanide chiral complexes (ee = 29-98%) [92]. Hydrophosphonylation of C2-chiral3-thi-azolines has also been performed (de = 32-38%) [93]. 

Scheme 2.6 shows some examples of the use of chiral auxiliaries in the aldol and Mukaiyama reactions. The reaction in Entry 1 involves an achiral aldehyde and the chiral auxiliary is the only influence on the reaction diastereoselectivity, which is very high. The Z-boron enolate results in syn diastereoselectivity. Entry 2 has both an a-methyl and a (3-benzyloxy substituent in the aldehyde reactant. The 2,3-syn relationship arises from the Z-configuration of the enolate, and the 3,4-anti stereochemistry is determined by the stereocenters in the aldehyde. The product was isolated as an ester after methanolysis. Entry 3, which is very similar to Entry 2, was done on a 60-kg scale in a process development investigation for the potential antitumor agent (+)-discodermolide (see page 1244). 

NMR can be a powerful tool for determination of enantiomeric excess or absolute configuration of the optically active compounds, however, these processes require the use of some auxiliaries, for example, chiral lanthanide shift reagents or chiral derivatising agent. In many cases, the starting point for determination of enantiopurity of amines, amino acids or diols is the formation of chiral imines. 

Intramolecular C-H functionalizations were employed for the synthesis of a precursor to (—)-rhazinilam, an antitumor agent. Using a chiral auxiliary good ee s were achieved (Equation (202)).164... 

Hydride reductions of C = N groups are well known in organic chemistry. It was therefore obvious to try to use chiral auxiliaries in order to render the reducing agent enantioselective [88]. The chiral catalyst is prepared by addition of a chiral diol or amino alcohol, and the active species is formed by reaction of OH or NH groups of the chiral auxiliary with the metal hydride. A major drawback of most hydride reduction methods is the fact that stoichiometric or higher amounts of chiral material are needed and that the hydrolyzed borates and aluminates must be disposed of, which leads to increased costs for the reduction step. 

There are three types of chiral auxiliary that are used chiral derivatizing agents (CDAs), chiral lanthanide shift reagents (CLSRs) and chiral solvating agents (CSAs)75. Chiral derivatizing agents (CDAs), such as the enantiomers of o -methoxy-o -(trifluoromethyl)phenylacetic acid (MTPA, 83)76, require the separate formation of discrete... 

The optical yield was found to be very sensitive to structural modifications of the achiral agent. For example, use of the more bulky FV or Bu substituents in the 3,5-positions of phenol resulted in lower optical yields. In some cases a reversal of the sense of asymmetric induction was observed. Systematic variation of reaction conditions using the best achiral component, 3,5-xylenol, established that optimum results were obtained in ether solvent at about - 15°C. There was also a minor but definite influence of the rate of addition of ketone as well as an effect of concentration on optical yield, with a slower rate being advantageous. The results of reduction of aryl alkyl ketones are shown in Table 9, along with comparative results of reduction with similar chiral auxiliary reagents. 

Both the (2S,5S)- and the (27 ,5/ )-enantiomers of the trans-pyrrolidine auxiliary 1 are available in high diastereomeric purity and high enantiomeric excess via resolution of traw-l-benzyl-2,5-pyrrolidinedicarboxylic acid and subsequent functional group transformation (see Appendix)7,13, 14. The chiral auxiliaries so obtained are then acylated with the appropriate acylation agent, which yields the desired /rart.v-2,5-disubstituted 1-acylpyrrolidines 2. 

Optically pure or almost pure a-amino acids (glycine derivatives) can be obtained by reacting 3,6-dialkoxy-2,5-dihydropyrazines 1 (prepared from glycine and an appropriate optically pure amino acid as chiral auxiliary) with alkylating agents, followed by hydrolysis (see Table 1). 

---