Exocyclic stereocenter

The 1,4-addition of the anion of a racemic /1-oxo sulfoxide to racemic 2-cyclopentenone was reported to give a single diastereomeric adduct resulting from addition opposite to the y-ace-toxy group20, t he relative configuration of the exocyclic stereocenter was not determined. 

Double asymmetric induction is observed30 in the alkylation of 3-(2-hydroxyalkyl)-substituted 4,5-dihydroisoxazoles, e.g., 12. The stereoselectivity is controlled by both the C4-substituent and the exocyclic stereocenter. Thus, in the matched case, alkylation of the chelated Z-azaenolate occurs preferentially anti to the C4-substituent and the phenyl group. 

In studies using tetrahydropyran formation as part of a synthesis of frenolicin and other naphthoquinone antibiotics50 53, this reaction proceeds with high stereoselectivity. Thus, palladium-catalyzed intramolecular alkoxycarbonylation of various 6-hydroxyaIkenes (e.g., 1) leads to 2,6-disubstituted tetrahydropyrans 2 with up Lo 97 % diastereoselectivity. The configuration of the exocyclic stereocenter depends on the E or Z geometry of the substrate double bond34... 

Stereocenters in a ring which can be severed by a disconnective transform, but which are not part of the retron, can be eliminated prior to disconnection if they are clearable. Removal of such stereocenters may convert a non-strategic bond into a strategic one. Stereocenters should also be cleared if that sets up the retron for a disconnective transform. Such strategic stereocenter eliminations commonly involve transforms which remove a 3 ° or 4 ° stereocenter to generate C=C (endo- or exocyclic), C=0 or C=N. Elimination of two clearable vicinal stereocenters to generate C=C retrosynthetically is strategically indicated whether or not that leads to a disconnectable retron. 

Substrates bearing a propargylic stereocenter exhibited perfect 1,4-stereoinduction (entry 4). No specific model was proposed to account for different product olefin isomers (endocyclic versus exocyclic) obtained from different substrate structures. 

Aliphatic enamine derivatives 198 linked to a chiral oxazolidone allow an almost totally diastereoselective [2 + 2] photocycloaddition of 102 (Scheme 53). This efficiency was attributed to a selective shielding of the lower face by the R substituents in the preferred conformation of the chiral oxazilidone enecarbamate. Interestingly, the de of 199 did not depend on the configuration of the stereocenter on the exocyclic appendage [122]. 

Stercocontrol in the addition of formaldehyde to a double bond exocyclic to a five-membered ring has also been demonstrated, forming one new stereocenter with control lower than in the previous example76. The i-isomer of the starting material afforded mainly the 1,2-disubstitut-ed cyclopentene derivative 9. 

Our initial approach centered on the use of a strategic Wessely oxidation reaction to transform an appropriately decorated resorcinol precursor into a tricyclic cage architecture formed by an in situ intramolecular Diels-Alder cycloaddition reaction (Scheme 1). From there we envisioned a 6-exo-type cyclization to form the tetracyclic core, which in the best case scenario would also set the C9-methyl stereocenter. Manipulation of the functional groups on the tetracyclic core would then be followed by a late-stage C—C bond fragmentation reaction to access the vinigrol core. Conversion of the exocyclic methyl ketone group was expected to afford the desired isopropyl moiety. 

Following this spate of disconnections, one of the rings from the central tricyclic core of resiniferatoxin (1) and two of its perplexing stereocenters have been successfully excised. Several challenging elements still remained for consideration. As shown in Scheme 4, though, if the exocyclic C—C double bond of the a,P-unsaturated system in 10 were modified to an endocyclic variant (15), then the majority of the remaining complexity could be dealt with in one fell swoop as this new adduct could conceivably result from an intramolecular 1,3-dipolar cycloaddition of an alkene and a tethered 3-oxidopyrylium motif (16). This compound, in turn, could be obtained from pyranone 17. 

The second generation of synthetic analogs isomerized an alkene, which led to the development of clinprost (3 Fig. 2) and its active metabolite isocar-bacyclin (4), both of which were found to be more stable than prostacyclin (1). In addition to vasodilation, isocarbacyclin and its methyl ester, clinprost, were found to have neuroprotective activity in animal models following ischemic stroke. Isocarbacyclin possesses a bicyclo[3.3.0]octene system with four stereocenters and a side chain connected to the exocyclic alkene, which is called the m-side chain, and another a-side chain that cmitains the carboxylic acid moiety. The R, and nomenclature derives from the a and co parts of arachidonic acid, which is the biosynthetic precursor for prostacyclin (1). 

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