| Neristatin 1 is a macrolide isolated from the marine organism Bugula neritina.It possesses 11 chiral centers,two tetrahydropyran and a fused bis-tetrahydrofuran ring moieties.Bioactivity studies revealed that Neristatin 1 has a high affinity for protein kinase C with a inhibitory effect of 21.2+1.3 nM,and exhibited significant anticancer activity with an IC500 of 1.58+0.23 nM for Toledo cells.However,its total synthesis has not been reported since its isolation in 1991.Therefore,total synthesis of Neristatin 1 is of great importance to facilitate studies on its anticancer mechanism and structure-activity relationship（SAR）.The northern portion of Neristatin 1 is the study object of this thesis.We completed the synthesis of the northern portion of Neristatin 1 by referencing the published synthetic routes of Bryostatins which have the same northern portion as Neristatin 1does.In initial route,C1-C11 fragment of Neristatin 1 was constructed via the Mukaiyama aldol reaction mediated by dichlorotitanium diisopropoxide and allylation reaction mediated by dimethylaluminum chloride.However,pivalation of the secondary alcohol at C7 could not be realized.Thus a second route was developed,where the C1-C11 fragment of Neristatin 1 was assembled via chlorodiisopinocamphoryl borane mediated Mukaiyama aldol reaction as the key step,and the C7 secondary alcohol was protected by TBS.A third route was designed employing Lewis acids mediated Mukaiyama aldol reaction,Leighton asymmetric allylation and Nicolaou hydrolysis of the ester to construct the northern portion of Neristatin 1.While the diastereoisomers produced by aldol reaction are inseparable,we plan to alter the protecting groups on aldehyde and ketone in order to fine tune the polarity of product and finally obtain the desired diastereoisomer.These studies provided theoretical and practical basis for synthetic research on the northern portion of Neristatin 1,which laid a solid foundation for the total synthesis of this molecule. |
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