Relative stereoselection

A new noncarbohydrate-based enantioselective approach to (—)-swainsonine was developed in which the key step was an aqueous intramolecular asymmetric hetero-Diels-Alder reaction of an acylni-troso diene (Eq. 12.57).128 Under aqueous conditions there was significant enhancement of the trans stereoselectivity relative to the reaction under conventional nonaqueous conditions. 

Molecular mechanics analyses of the kind described in previous sections are able to rationalize not only the stereoselectivity (and stereospecificity) of regioregular primary insertion steps but also the stereoselectivities relative to occasional secondary monomer insertions as well as relative to primary insertions following these secondary insertions.37d... 

Several detailed investigations of transannular IMDA cycloadditions have appeared in recent years. This transformation promises to become an important synthetic method owing to the potential for the rapid efficient construction of complex polycyclic ring systems. Other potenti strategic benefits include increased reactivity due to diminished entropic requirements (AS ). This is nicely illustrated by the facile cyclization of (101) with a tetrasubstituted dienophile, compared with the unsuccessful IMDA reaction of (102) (Figure 27). Although the cyclization of (101) proceeds with only moderate diastereoselection, many other examples have been reported that exhibit outstanding selectivity, e.g. cyclization of (103). It is conceivable that conformational constraints imposed by the macrocyclic system may lead to improved IMDA stereoselectivity relative to conventional acyclic trienes, but this point has not yet been demonstrated in any published examples. 

As for stereoselectivity, relatively little is known as yet, except that the natural R configuration in the cysteine residue is a prerequisite for a cysteine conjugate to be a substrate of p-lyase. This fact has been used as a tool to ascertain the role of p-lyase in the development of nephrotoxicity by cysteine conjugates. No data are presently available with regard to the substrate-stereoselective effects of the noncysteine part of the thioether substrates of p-lyase (Commandeur and Vermeulen, 1990). Such stereoselective effects may be anticipated, however, since, for example, the regioisomeric 1,2- and 2,2-dichlorovinyl-LrCysteine conjugates have also... 

On the other hand, ambient water at low pressure also influences stereoselectivity. A large increase in stereoselectivity relative to organic solvents is found due to the so-called hydrophobic effect in ambient water [44, 45]. The hydrophobic effect is the tendency of non-polar molecules and molecular segments in aqueous solution to avoid contact with water molecules [46]. 

Table 14). A subsequent study [85] after the multiple dose administration of the racemate, however, showed an opposite stereoselectivity relative to that found after the administration of the single doses of the enantiomers separately [84] the plasma concentrations of S-propafenone were higher than those of its antipode when the racemate was administered. Further studies [133] after the administration of the separate enantiomers or the racemate to the same subjects demonstrated that the oral clearance of the R enantiomer is almost the same whether the administered drug is the enantiomer or the racemate. However, the oral clearance of the S enantiomer is significantly reduced in the presence of the other isomer (Table 14). This was attributed to an enantiomer-enantiomer interaction at the level of metabolism where R-propafenone reduces the metabolism of the S enantiomer [85]. 

The Nakai conditions in some cases can lead to greatly increased stereoselectivities relative to the Ireland conditions. Welch et al. found that use of sUyl triflates could lead to significantly improved diastereoselectivities and/or yields in the rearrangement of allyl fluoroacetates (Scheme 4.51) [53]. Rearrangement of the Z-crotyl fluoroacetate under the Nakai conditions proceeded via the Z-silyl ketene acetal and afforded excellent yield and high diastereoselectivity for the anti isomer Treat-... 

Very recently, Padwa reported a total synthesis of strychnine based on an intramolecular Diels-Alder reaction/rearrangement cascade, which was previously developed in his group to assemble the tetracyclic core ring system of indole alkaloids (Scheme 16) (174-178). Intramolecular cycloaddition reactions often benefit from higher reactivity and greater control of stereoselectivity relative to their intermolecular counterparts. Unlike Bodwell s lEDDA reaction (Scheme 13), the reaction of an electron-rich furan moiety with an N-acyl indole moiety required only a single tether. His synthesis also involved... 

Note that the relative spatial arrangement of the phenyl, amine, and hydroxyl functionahties are identical for (R)-alprenolol and (5)-sotalol. In addition to P-blocking activities, some of these compounds also possess potent local anaesthetic activity (see Anesthetics). The membrane stabilizing activity, however, is not stereoselective and correlates directly with the partition coefficient (hydrophobicity) of the compound. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

In further modifications of these norprogestins, reaction of norethindrone with acetic anhydride in the presence of p-toluene-sulfonic acid, followed by hydrolysis of the first-formed enol acetate, affords norethindrone acetate (41). This in turn affords, on reaction with excess cyclopentanol in the presence of phosphorus pentoxide, the 3-cyclopentyl enol ether (42) the progestational component of Riglovic . Reduction of norethindrone affords the 3,17-diol. The 33-hydroxy compound is the desired product since reactions at 3 do not show nearly the stereoselectivity of those at 17 by virtue of the relative lack of stereo-directing proximate substituents, the formation of the desired isomer is engendered by use of a bulky reducing agent, lithium aluminum-tri-t-butoxide. Acetylation of the 33,173-diol iffords ethynodiol diacetate, one of the most potent oral proves tins (44). ... 

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