Stereospecific reactions quaternary

Enol lactones are assumed to form from iV-methylisoquinolinium salts as a result of a Hofmann-type degradation process. This P elimination is a highly stereospecific reaction in which Z isomers are produced from precursors of erythro configuration and isomers from threo diastereomers(5,97). This fact seems to suggest that syn rather than the more usual anti elimination takes place. Examination of models indicates, however, that there is a preferred conformation in which the C-8 hydrogen is in the syn and coplanar position to the quaternary nitrogen. This hypothesis was proved correct in experiments carried out in vitro (5,14,15,91-94). 

Mortko, C.J. and Garcia-Garibay, M.A. (2006) Engineering stereospecific reactions in crystals synthesis of compounds with adjacent stereogenic quaternary centers by photodecarbonylation of crystalline ketones, in Topics in Stereochemistry, Vol. 25 (eds S.E. Denmark and J.S. Siegel), John Wiley Sons, Hoboken, NJ, pp. 205—253. 

Pyranopyrroloimidazoles have been prepared stereospecifically by an intramolecular 1,3-dipolar cycloaddition reaction. Either enantiomer of the imidazoline derivative 176 (the -enantiomer is shown) may react with the bromoacetyl-containing acrylate dipolarophile 177, in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), to give the diastereomerically pure tricyclic product 178 in moderate yield (Equation 15). This reaction involves quaternization of the imidazole N, reaction of the quaternary salt with base to give the 1,3-dipole, which can then react, intramolecularly and stereospecifically, with the tethered dipolarophile <1997TL1647>. 

Typically, the stereospecific formation of quaternary centers is as problematic as selective nucleophilic attack at the more substituted carbon of aziridines. Interestingly, a copper mediated methodology has been reported that does both <060L5105>. Although N-tosyl aziridines show favorable results, A-nosyl aziridines gave the best results. The reaction of 89 with a variety of phenols yielded 90 in moderate yields. 

The quaternary center was constructed stereospecifically by Claisen rearrangement (Scheme 46). The necessary enol ether was obtained by reaction of the secondary alcohol of 399 with ethyl vinyl ether and mercuric acetate. To change the polarity of the endocyclic double bond, the unsaturated ketone was reduced with lithium aluminum hydride to the allylic alcohol, 400, at low temperature. Then, prolonged heating with xylene led to the aldehyde, 401. Protection of the secondary alcohol was achieved by bromoether formation with W-bromosuccinimide in acetonitrile before the aldehyde of 402 was reacted with methyllithium. The epimeric mixture of secondary alcohols was protected as acetates 403. Then, the cyclic ketone... 

When the alkene is cyclic, or the insertion step forms a quaternary center, a substitution product is not obtained. For example, stereospecific syn addition of an arylpalladium halide 13 to cyclohexene generates cyclohexylpalladium(II) intermediate 14 (Scheme 6-3). The C—Pd cr-bond in this intermediate is anti to H and syn elimination to form a substitution product is not possible. However, elimination of cis hydrogen H is possible and generates allylic product 15. This pathway of the Heck reaction is particularly important in complex molecule construction since a new stereogenic center is produced. 

The second reaction creates a lithium enolate and alkylates it. It is again stereospecific at the unchanged chiral centre but stereoselective at the newly created quaternary centre. Finally, acetal hydrolysis preserves the new quaternary centre unchanged (stereospecific) by a mechanism that is the reverse of the first step... 

Consider, for example, the rapid and efficient construction of the perhydrophenanthrene skeleton 119 as exemplified by the conversion illustrated next [34]. The reaction is stereospecific, leading to the trans-anti-trans ring fused adduct in a 65% to 72% yield. Furthermore, C-C bond formation occurred despite the fact that in so doing, a very crowded environment consisting of vicinal quaternary carbon centers, is produced. There are very few methods that provide such scope. It takes little thought to imagine the application of this powerful transformation to the synthesis of steroids. Yet, the opportunity to apply the methodology to natural product synthesis has not been realized. 

The stereoselective synthesis of (+)-trichodiene was accomplished by K.E. Harding and co-workers. The synthesis of this natural product posed a challenge, since it contains two adjacent quaternary stereocenters. For this reason, they chose a stereospecific electrocyclic reaction, the Nazarov cyclization, as the key ring-forming step to control the stereochemistry. The cyclization precursor was prepared by the Friedel-Crafts acylation of 1,4-dimethyl-1-cyclohexene with the appropriate acid chloride using SnCU as the catalyst. The Nazarov cyclization was not efficient under protic acid catalysis (e.g., TFA), but in the presence of excess boron trifluoride etherate high yield of the cyclized products was obtained. It is important to note that the mildness of the reaction conditions accounts for the fact that both of the products had an intact stereocenter at C2. Under harsher conditions, the formation of the C2-C3 enone was also observed. 

Yamauchi, Y., Kawate, T., Katagiri, T. and Uneyama, K. (2003) Generation and reactions of a-trifluoromethyl stabilized aziridinyl anion, a general synthetic precursor for stereospecific construction of a-amino-a-trifluoromethylated quaternary carbon. Tetrahedron Lett., 44, 6319-6322. 

Addition of vinyllithium to 441 gives 442 as a mixture of syn and anti diols. The beauty of this synthesis is that both the syn and the -diol stereoisomers rearrange to the same tetra-hydrofuran product. Thus, acetal 443 undergoes a Prins pinacol rearrangement to tetra-hydrofuran 444 upon treatment with SnCU in nitromethane. The transformation proceeds with complete preservation of enantiomeric purity. Baeyer—Villiger reaction stereospecifically introduces the 3-hydroxy substituent, and conversion to the quaternary ammonium salt completes the target molecule 446. 

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