Racemization suppressing agents

The amount of racemization during activation is generally low, even when no racemi-zation-suppressing agents are added. Anderson and Paul found in the sensitive coupling of... 

Atropiae (41), isolated from the deadly nightshade Airopa belladonna L.) is the racemic form, as isolated, of (—)-hyoscyamine [which is not isolated, of course, from the same plant but is typically found ia solanaceous plants such as henbane (HyosQiamus mgerl. )]. Atropiae is used to dilate the pupil of the eye ia ocular inflammations and is available both as a parasympatholytic agent for relaxation of the intestinal tract and to suppress secretions of the saUvary, gastric, and respiratory tracts. In conjunction with other agents it is used as part of an antidote mixture for organophosphorus poisons (see Chemicals in war). 

Sotalol (13) is a racemic mixture, and its two enantiomers have been studied extensively [47-51]. As expected from studies with other ff-blocking agents, the Class II activity resides predominantly in only one enantiomer [(-)-sotalol] while the Class III activity can be found equally in both enantiomers. Therefore, the (-I-)-enantiomer, which is essentially devoid of P-blocking activity, has been studied as one of the few early examples of a selective Class III agent. Both sotalol [52-55] and its enantiomer, (-l-)-sota-lol [56-58], have been shown to be clinically effective in the prevention of ventricular arrhythmias. The efficacy rate for suppression of inducible ventricular tachycardia during programmed electrical stimulation for both... 

There have been few alternative syntheses of bortezomib (1) published in the literature. A more convergent route was proposed by Ivanov et al. employing N-pyrazinyl-Z-phenylalanine (28) as a coupling partner to amino boronic ester 20.31 The use of TBTU as coupling agent was shown to suppress racemization in the reaction. Despite a convergent approach being considered by Millennium, the linear approach was ultimately adopted for synthesis on scale. 

The examples provided above indicate that single enantiomers are not always better alternatives to their respective racemates. Another interesting example is 5-dimethyl-sulphamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxilic acid, a racemic diuretic whose diuretic activity is attributed to the S(—)-enantiomer, while theR(+)-enantiomer has uricosuric properties that suppress the S-enantiomer-induced side-effect of elevated blood uric acid (21). It is not known if marripulation of the S R ratio of this drug, as is seen for indocrinone (below), results in a better diuretic agent. 

In the mid-1980s researchers in the pharmaceutical industry demonstrated that single enantiomers of pharmaceutical compounds often functioned better as therapeutic agents than racemic mixtures. There are many examples for which one particular chiral form (enantiomer) of a compound demonstrated therapeutic efficacy, while the other chiral form was ineffective or produced deleterious effects. (For example, dextro-methorpan is commonly used as a cough suppressant, while its enantiomer, levomethorphan, is a powerful narcotic.) By 2002 annual sales of the top 10 singleenantiomer drugs totaled 34.2 billion. ... 

Suppression of aldehyde product racemization under the reaction conditions can be achieved with ethyl orthoformate21-45, l34,158. Thus, nearly quantitative induction is observed when a BPPM-modified platinum catalyst is used for styrene hydroformylation in the presence of orthoformate as the trapping agent for the chiral aldehyde formed125-, 58. These results, however, are reported to be not reproducible48, S3-177. 

Addition of trapping agents such as N-Hydroxysuccinimide and 1-Hydroxybenzotriazole (HOBt) reduce the extent of many side reactions, especially A-acylurea formation. Also, racemization is suppressed when these additives are present. The latter reagent eliminates the intramolecular dehydration of m-amides of asparagine and glutamine that occurs with carbodiimides (eq 2). - ... 

---