Single-enantiomer compounds

Know the primary methods for obtaining single enantiomer compounds... 

From January 2004 to June 2006, approximately 66% of all drugs approved by the U.S. Food and Drug Administration (FDA) were single enantiomer compounds (Figure 13.10).11 Only 7% of the approved drugs were mixtures of stereoisomers. 

Therefore, techniques for preparing single enantiomer compounds are of vital importance for both medicinal and process chemists. 

Approaches to single enantiomer compounds can be divided into two categories. One, the product may be formed as a racemic mixture with the desired enantiomer being separated afterward. This is a resolution approach. Two, a synthetic route may be designed to prepare mostly, if not exclusively, a single enantiomer. This technique is called asymmetric synthesis. 

Issues related to prior art enablement, prima facie obviousness and secondary considerations of nonobviousness often intertwine in obvious determinations during patent prosecution and litigation since their definitional boundaries are often not well demarcated. In the case Sterling Drug Inc. v. Watson,69 the USPTO rejected claims to various single enantiomer compounds,70 and this decision was appealed to the U.S. District Court for the District of Colombia. The claims in question—10,12, and 14—are presented in Figure 8.18 together with the claimed structures (L-arterenol is the neurotransmitter norepinephrine).71... 

Strictly speaking, the availability of single-enantiomer compounds is not a future trend since some of them have already made an entry into clinical medicine. However, this technique s full potential is still unrealized, and it may lead to increased availability of many better and safer medications. The field of stereochemistry, which deals with the three-dimensional structure of molecules, teaches us that chemical compounds, medications included, can occur as a mixture of molecules whose structures are mirror images of each other. This means that two molecules that are otherwise identical may be spatially oriented in opposite directions, say, one to the right, the other to the left. Molecules so characterized are called enantiomers. 

Schemes Gelators that gel as a single enantiomer. Compounds 13-21 are described in references [23-31], respectively...

Of the two thousand or so drug substances currently marketed worldwide, over 70% are synthetic. The remainder are derived either directly, or by semi-synthesis, from natural sources. Those in the latter category, perhaps not surprisingly, are overwhelmingly single enantiomer compounds. Examples include naturally occurring substances such as quini-dine/quinine and the semi-synthetic beta lactam antibiotic ampicillin. 

Although in the past many of these compounds have been used in racemic form, the current trend in the pharmaceutical industry is toward enantiomerically pure drugs. The enantioselective synthesis or the chiral separation of racemic mixtures is often difficult, and synthetic chemistry is increasingly looking toward the use of enzymes for the preparation of single enantiomer compounds to be used for the generation of p-substituted pharmaceutical intermediates [9, 10], an area that our group has also focused on [11, 12]. 

Strategy Problem 7 Synthesis of a single enantiomer. Many compounds such as pharmaceuticals, flavourings, and insect control chemicals must not only have the right relative stereochemistry but must be optically active too if tliey are to be of any use. Consider the strategy of synthesising one enantiomer ... 

A -sulfinyl chiral auxiliaries have been used to prepare enantiopure tetrahydro-P-carbolines and tetrahydroisoquinolines in good yields under mild reaction conditions. Both enantiomers of V-p-toluenesulfinyltryptamine 46 could be readily prepared from the commercially available Andersen reagents.Compound 46 reacted with various aliphatic aldehydes in the presence of camphorsulfonic acid at -78 °C to give the A-sulfinyl tetrahydro-P-carbolines 47 in good yields. The major diastereomers were obtained after a single crystallization. Removal of the sulfinyl auxiliaries under mildly acidic conditions produced the tetrahydro-P-carbolines 48 as single enantiomers. 

The enantioselectivity a is defined as the distribution ratio of one single enantiomer over the two chiral phases and has been determined experimentally for a variety of compounds (Table 5-1). It has been known from work by Prelog [66, 67] that tartaric acid derivatives show selectivities towards a-hydroxyamines and amino acids. However, from Table 5-1 it is obvious that tartaric acid derivatives show selectivity for many other compounds, including various amino bases (e.g. mirtazapine (10)) and acids (e.g. ibuprofen (11)). The use of other chiral selectors (e.g. PLA)... 

The development of a single enantiomer as a new active substance should be described in the same manner as for any other new chemical entity. Studies should be carried out with the single enantiomer, but if development began with the race-mate then these studies may also be taken into account. Chiral conversion should be considered early on so that enantiospecific bioanalytical methods may be developed. These methods should be described in chemistry and pharmacy part of the dossier. If the opposite enantiomer is formed in vivo, then it should be evaluated in the same way as other metabolites. For endogenous human chiral compounds, enantiospecific analysis may not be necessary. The enantiomeric purity of the active ingredient used in preclinical and clinical studies should be stated. 

In a special case of this type of asymmetric synthesis, a compound (47) with achiral molecules, but whose crystals are chiral, was converted by UV light to a single enantiomer of a chiral product (48). ... 

The above described DKR allows generation of a single enantiomer and dias-tereoisomer of a compound from a racemic starting material, and, as such, is a very powerful transformation. There are a number successful implementations documented, and here we outline two recently published examples also... 

---