Ynamide-mediated Macrolactonization

Macrolactones are widely found in a broad range of drug molecules and natural products,and are essential structural characters for their intriguing biological activities.Then,how can we construct it? Due to entropic and enthalpic factors,direct cyclization is generally not possible without activation of either the alcohol or the carboxylic acid terminal group.Consequently,a plethora of macrolactonization strategies have been developed over the past few decades.However,the application of these methods is limited to special cases because of the difficult availability of their ring closing precursors and the harsh reaction conditions and transition mental catalysis sometime required to carry out these transformations.The racemization/epimerization associated with seco-acids containing ?-chiral center makes total synthesis of the macrolactonization of drug molecules and natural products more complicated.Therefore,it has always been a long-standing challenge for organic chemists to develop an efficient macrolactonization strategy which the racemic isomerization or epimerization can be suppressed.This paper is based on the ynamide,developed by our group,which can efficiently construct macrolactones through simple and green operation process,and can accomplish the total synthesis of complex natural products.This paper mainly consists of two parts:(1)In this paper,the reaction conditions of template macrolactonization were determined under mild reaction conditions.Various macrolactones from medium to large ring size could be prepared in good to excellent yields with little or no diolide side products.The notorious racemization/epimerization issue of the seco-acids containing ?-chiral center can be well suppressed.It should be noted that the ynamide-mediated macrolactonizations could be performed in a two-step,one-pot manner.(2)We had made a comparative study test between ynamide and the traditional macrolactonizition coupling reagents,and the natural product Dehydroxy LI-F04 a was finished.The problem of ?-containing chiral center or ?,?-unsaturated seco acid Z/E isomerization has been proved by comparative experiments that our method can easily solve the problem of racemization or epimerization,which is often observed in the process of ring closing of traditional large ring esterification reagents...