Chiral Synthesis of Bio-active Compounds by the Asymmetric Cycloaddition Based on the Unique Molecular Design

利用(R) s-2-甲基-3-（对甲基亚砜基）对苯甲酸酯(A)和（2-吡啶基亚砜基）丙烯酸甲酯(B)与环戊二烯的Diels-Alder反应得到的环加合物，手性合成了(+)-外- β -santalene（文献1）、(-)-马马霉素和(-)-neplanocin A（文献3）。此外，从二亲酚B和呋喃的环加成得到的加合物开始，手性合成了(-)-莽草酸和外延莽草酸（参考文献2和6）。通过B与环己二烯的D-A反应，得到了合成多环戊二醇类化合物的重要中间体（参考文献4）。另一方面，从二甲基乙炔二羧酸酯和1-巯基异龙脑开始，设计并非对映选择性地得到了二甲基(R) s-2-（异龙脑-10-亚砜基）丙烯酸酯(C)。在Lewis酸催化剂的存在下，二亲试剂C与环戊二烯的D-A反应以高度立体和非对映选择性的方式进行，生成单个加合物，该加合物有效地转化为Ohno的半酯（参考文献5）。由于大野半酯已转化为各种碳环核苷，因此本文的合成构成了这些碳环核苷的正式合成，具有广泛的应用前景。在这项研究中，我们发现10-巯基异龙脑通常是合成光学活性烷基亚砜的良好手性助剂（参考文献10）。硫醇也被证明是合成光活性有机磷化合物的优良手性助剂（参考文献9）。同时，研究了1-甲基-3-氧化吡啶与各种亚砜的环加成反应。加合物可以有效地以外消旋和旋光形式转化为2 - -tropanol衍生物（参考文献7,8）。

Utilizing cycloadducts which were obtained by the Diels-Alder reaction of (R)_s-2-methyl-3-( p-tolylsulfinyl )p ropenoate (A) and menthyl 3-(2-pyridylsulfinyl) acrylate (B) with cyclopentadiene, chiral synthesis of (+)-epi-beta-santalene (ref 1) , (-)-aristeromycin and (-)-neplanocin A (ref 3) were accomplished. Furthermore, starting from the adduct obtained from the cycloaddition of dienophile B and furan , chiral synthesis of (-)-shikimic acid and epi-shikimic acid were achieved (ref. 2 & 6). An important key intermediate for the synthesis of polycyclopenatano ids have been obtained by the D-A reaction of B and cyclohexadiene (ref. 4)On the other hand, dimethyl (R)_s-2-(isoborneol-10-sulfinyl) acrylate (C) has been designed and obtained diastereoselectively starting from dimethyl acetylenedicarboxylate and 1-mercapto- isoborneol. Under the presence of Lewis acid catalyst, the D-A reaction of the dienophile C with cyclopentadiene proceeded highly stereo- and diastereoselective manner to afford a single adduct, which was effectively converted to Ohno's half ester (ref. 5). Since the Ohno's half ester have been transformed into various carbocyclic nucleosides, the present synthesis constitutes the formal synthesis of those carbocyclic nucleosides and would find wide applications.During this investigation, we found 10-mercaptoisoborneol could be a good chiral auxiliary for the synthesis of optically active alkyl sulfoxides, in general (ref. 10). The thiol also turned out to be an excellent chiral auxiliary for the synthesis of optically active organophosphorus compounds (ref 9).Meanwhile, the cycloaddition of 1-methyl-3-oxidopyridinium with various sulfinyl ethenes has been studied. The adducts were effectively converted to 2alpha-tropanol derivatives both in racemic and optically active forms (ref. 7, 8).