Diastereomers biological activity

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. 

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. 

Some pyranoindolizine-containing alkaloids have been isolated from plants of the genus Daphniphyllum. These are calyciphylline B, 292, an iV-oxide, and the two diastereomers, deoxycalyciphylline B, 293, and deoxyisocalyciphylline B, 294. Biosynthetic pathways for these molecules have been proposed however, little has been mentioned of any biological activity <2003OL2895, 2003JOC7961, 2005HCA854>. 

N5,N10-methenyltetrahydrofolate (with ascorbic acid) was adjusted to neutral pH, autoclaved, and stored at -20° C prior to column purification on DEAE and G-15 Sephadex. These labeled products are the biologically active diastereomers, and they are used to study the metabolism of folinic acid in cells, tissues, and animals. 

Biological activities such as enzyme reactions and metabolic changes are highly stereospecific, hence enantiomers and diastereomers may have entirely different... 

The cyclic ammonium ylide/[l,2]-shift approach has been successfully applied by West and Naidu to a key step in the total synthesis of (—)-epilupinine, one of the biologically active lupin alkaloids. Cu(acac)2-catalyzed diazo decomposition of enantiomeric pure diazoketone 160 in refluxing toluene generates a spiro ammonium ylide 161 and 162, which then undergoes [l,2]-shift to give rise to a quinolizidine skeleton as a mixture of diastereomers (95 5) (Scheme Major diastereomer 164 has enantiomeric purity of 75% ee. The partial retention of stereo-... 

Having identified the (+)-stereoisomer as the biologically active isomer, several independent enantioselective syntheses of this stereoisomer were developed. The initial synthesis developed in discovery chemistry employed the diastereoselective aldol condensation pioneered by Braun as the key component. Thus, treatment of aldehyde 13 from the racemic synthesis with the magnesium enolate of (5)-(+)-2-acetoxy-l,l,2-triphenylethanol at -70 °C, afforded 17 in 60% yield as a 97 3 mixture of the / ,5 5,5-diastereomers by HPLC (Scheme 3). Ester exchange employing sodium methoxide provided the methyl ester in quantitative yield. Reaction of this ester with three equivalents of lithio-f-butylacetate at -40 °C afforded the nearly enantiomerically pure r-butyl ester analog of racemic 14 in 75% yield. 

This series of KCAs, developed originally from a study of potential K /H ATPase inhibitors resulted in the lead compound RP 49356 (4), and its biologically active IR,2R enantiomer, aprikalim (5) (see Figure 9.1) [41]. The precursor sulphide of (4) was inactive in vitro, but careful observation of its effect in SHR identified a delayed onset in antihypertensive activity that led to the identification of the trans sulphoxide as its active metabolite. In contrast, the cis diastereomer was significantly less active. 

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