Stereochemistry enantiomers, biological

The title compound is a key C6 building block. Several labs have prepared novel a-amino acids, biological probes and other interesting compounds using the D-diepoxide as a key intermediate.3 An efficient route to the L-enantiomer provides a pathway to compounds with the opposite configuration, one not readily available from commercial sources, and a valuable probe of stereochemistry in biological systems and reaction mechanism. 

This simple compound 2 was needed by Novartis Pharma Inc. (Basel) for the preparation of a new class of anti-diabetic agents 1. Both enantiomers were needed on a large scale to explore the relationship between stereochemistry and biological activity.1... 

But all work on the stereospecificity of caimabinoid action had been done with (+) THC synthesized according to a procedure published by our group based on commercial a-pinene. And we knew that commercial pinene is not stereochemically pure, and therefore would lead to stere-ochemically impure products. Hence, the lack of stereospecificity could be due to the presence of varying amounts of the active (-) stereoisomer in the presumed pure (+) isomer. So we repeated the synthesis with stereochemically pure (+) a-pinene and tested the (-t) THC produced. It had no (-) THC-like activity, as expected. Then we evaluated the activity in the 11-hydroxy-dimethylheptyl series. As mentioned earlier (-) HU210, is very potent — at least 100 times more than THC. Its enantiomer, (-t) HU211, turned out to be many thousands of times less active than HU210 in a wide series of tests done in collaboration with my friends Billy Martin, Toby Jarbe, and Allyn Hewlett. The stereochemical hurdle was thus overcome. (For a review on the cannabinoid stereochemistry and biological activity, see Mechoulam et al., 1992). 

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

Divalent sulfur compounds are achiral, but trivalent sulfur compounds called sulfonium stilts (R3S+) can be chiral. Like phosphines, sulfonium salts undergo relatively slow inversion, so chiral sulfonium salts are configurationally stable and can be isolated. The best known example is the coenzyme 5-adenosylmethionine, the so-called biological methyl donor, which is involved in many metabolic pathways as a source of CH3 groups. (The S" in the name S-adenosylmethionine stands for sulfur and means that the adeno-syl group is attached to the sulfur atom of methionine.) The molecule has S stereochemistry at sulfur ana is configurationally stable for several days at room temperature. Jts R enantiomer is also known but has no biological activity. 

In general, the Henry reaction gives a mixture of diastereomers and enantiomers. The lack of selectivity is due to the reversibility of the reaction and the easy epimerization at the nitro-substituted carbon atom. Existing reviews have hardly mentioned the stereochemistry of the Henry reaction. Recently, Shibasaki has found that the modification of the Henry reaction can control the stereochemistry to give (3-nitro alcohols with high diastereo- and enantio-selectivity.6 In Section 3.3, the progress of the stereoselective Henry reaction and its application to biologically active compounds are discussed. 

Therefore, metabolic and regulatory processes mediated by biological systems are sensitive to stereochemistry, and different responses often can be observed upon comparing the activities of a pair of enantiomers. These differences can be expressed in distribution rates, in metabolism and excretion, in antagonistic actions relative to each other, or in toxicological properties. It is very... 

It has long been recognized that biological activity of certain chiral compounds varies and is related to their stereochemistry. Biological activity of certain enantiomers can vary dramatically and not only be biologically active but toxic as well. It is for these reasons that the separation of enantiomers is so important (see additional discussion in Chapter). There are two approaches to the separation of enantiomers by GC. 

Drug Activity and Stereochemistry The quantitative differences in biological activity between the two enantiomers of a compound are sometimes quite large. For example, the D isomer of the drug isoproterenol, used to treat mild asthma, is 50 to 80 times more effective as a bronchodilator than the l isomer. Identify the chiral center in isoproterenol. Why do the two enantiomers have such radically different bioactivity ... 

Two enantiomers of one molecule may be the same compound, but they are clearly different, though only in a limited number of situations. They can interact with biological systems differently, for example, and can form salts or compounds with different properties when reacted with a single enantiomer of another compound. In essence, enantiomers behave identically except when they are placed in a chiral environment. In Chapter 45, we will see how to use this fact to make single enantiomers of chiral compounds, but next we move on to three classes of reactions in which stereochemistry plays a key role substitutions, eliminations, and additions. 

Samples of (IK, 2R, 3R) and (IS, 25, 35) prephytoene alcohols have been chemically synthesized and only the (IK, 2K, 3K) enantiomer (91), as the pyrophosphate ester, is biologically active The absolute configuration of prephytoene pyrophosphate (89) is thus identical to that found for presqualene pyrophosphate (77) and the detailed stereochemistry of the formation of these compounds is probably identical. 

Furthermore, the chiral discrimination of monoterpenes has been recognized as one of the most important analytical techniques in flavor chemistry and pharmacology because the optically active stereoisomers have different sensory qualities and biological activities. HPLC offers powerful techniques for separation and quantification of enantiomers because of the progressive improvement of chiral chromatographic materials and chiral detectors such as optical rotatory dispersion (ORD) and circular dichroism (CD) detectors. In contrast, determination of chiral compounds by GC typically requires coinjection of the reference compound with known stereochemistry. An HPLC system equipped with a chiral detector, on the other hand, allows direct determination of the configuration of chiral compounds.84... 

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