Quaternary center, stereocontrolled

The marine alkaloid (-)-norzoanthamine 3 suppresses bone loss in ovariectomized mice, and so is of interest as a lead to antiosteoporotic drugs. A substantial challenge in the assembly of 3 is the stereocontrolled construction of the C ring, with its three all-carbon quaternary centers. In the synthesis of 3 by Masaaki Mayashita of Hokkaido University (Science 2004,305,495), the and C rings were built and two of the three needed quaternary centers were set by the intramolecular Diels-Alder cyclization of 1 to 2. 

Enantiomerically-pure sulfoxides are readily available. Ilan Marek of Technion-Israel Institute of Technology reports (1. Am. Chem. Soc. 125 11776, 2003) that alkyne-derived sulfoxides such as 8 can be used to direct the addition of an allylic organometallic, prepared in situ, to an aldehyde 9. Both the secondary alcohol, from the aldehyde, and the adjacent quaternary center of 10 are formed with >99% stereocontrol. 

Larry Overman also used (J. Am. Chem. Soc. 2004,126, 14043) a chiral pool starting material, but in a different way. The prochiral enolate 12 showed substantial diastereoselectivity in its reaction with the bis-triflate 13, almost 10 1. Through the power of algebra, it followed that the three diastereomers of 14 were formed in a ratio of 90 9 1. The crystalline 14 was easily isolated in diastereomerically-pure form, and carried on to phenserine 15. This is a new method for the stereocontrolled construction of chiral quaternary centers. 

Alternatively, a diastereocontroUed formation of quaternary centers could be achieved by the use of an enantiomericaUy pure electrophile with a stereodefined allylmetal species [108]. In this case, a preassociation of the metal with polarized functional groups is supposed to influence the stereochemical outcome. Thus, the stereocontrolled carbocupration of unfunctionalized alkynes followed by homologation and reaction with chiral sulfinyUmines resulted in diastereomerically pure adducts 374 that can be easily deprotected to provide enantiomericaUy enriched homoallylic primary amines possessing an all-carbon quaternary stereocenter (Scheme 10.128). 

Addition of n-BuLi to 2 regenerated the enolate. There were two issues in the addition of that enolate to the aldehyde 7 syn vs. anti stereocontrol, and control of the configuration of the newly formed ternary center on the ring relative to the abeady-estahUshed quaternary center. Inclusion of Et,B in the reaction mixture assured anti aldol formation, hut there was... 

TABLE 2.8 Stereocontrol of Quaternary Centers by Diastereoselective Alkylation of Pseudophenamine Amides... 

Cell-surface sialic acid residues play important roles in diverse biological processes [86]. Sialic acids are usually found in terminal positions linked through an a-glyco-sidic linkage. The stereoselective synthesis of a-sialosides remains a challenge because the glycosides have the thermodynamically unfavorable equatorial orientation and the anomeric carbon is a very hindered quaternary center [4]. Enzymatic sialylation is, therefore, an attractive alternative means of preparation of a-sialosides in an efficient and stereocontrolled manner. 

Successful applications of these stereocontrolled conjugate additions have led to asymmetric syntheses of several natural products such as (-I-)-cuparenone (39) which involves formation of a quaternary carbon center (- )-iS-vetivone (40) ° and steroidal equilenin 41 the wavy lines in these structures indicate that C—C bond formed stereoselectively under the influence of a temporarily-attached stereogenic sulfoxide auxiliary group. 

A well-developed concept to achieve high stereocontrol in the formation of a quaternary chiral center has been introduced by Fraser-Reid, using the Claisen rearrangement along two lines. In the first approach a type III branched-chain sugar is prepared by Wittig... 

Based on preliminary results in the model studies, we turned our attention to the synthesis of zizaene sesquiterpenes such as d/-zizaene, /-isokhusimone, and d/-khusimone. To construct the zizaene skeleton via the consecutive carbon-carbon bond formation approach, the disconnection of two bonds of the four bonds at the quaternary carbon center of the ring junction should be possible as shown in Figure 12. Approaches d and e are not promising due to the involvement of 8-and 10-membered ring intermediates, whereas approach c requires stereocontrol at three stereogenic centers. In approach b, difficulty in... 

This was followed shortly by a stereo- and enantiocontrolled synthesis of (—)-chimonanthine (154) and calycanthine (150) as well as a second route to meso-chimonanthine (152). The central step in this synthesis features the use of a double Heck cyclization to create vicinal quaternary carbon centers in high yields and with complete stereocontrol 124). The synthesis commenced with a double alkylation of the lithium dienolate of dimethyl succinate 194 and tartrate-derived diiodide 195 to give a diastereomeric mixture of the saturated diesters. Subsequent oxidation of the diesters, followed in succession by aminolysis, A-benzylation, removal of the benzyl ethers, and silylation, provided the cyclization substrate 197, which on Heck cyclization yielded a single product, 198, a pentacyclic bisoxindole, subsequently shown to have the meso relationship of the two oxindole groups. Further manipulations of 198 led eventually to the diazide derivative 199, which can be processed to we.so-chimonanthine (152), following the procedure established in the preceding synthesis (Scheme 14). 

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