Medium-sized lactones and lactams (eight to eleven-membered rings) are important components in natural products with a diverse set of biological activities. In the last few decades, the efficient formation of these medium-sized lactones and lactams has attracted considerable attention in organic synthesis. A variety of methods have been developed, which are summarized in chapter I. Moreover, medium-sized lactones and lactams have widespread application in the synthesis of natural products, pharmaceuticals, agrochemicals, and functional organic materials. Several selected examples of the application of medium-sized lactones and lactams are also included in Chapter I.

In this thesis, two new strategies for the synthesis of lactones and one new approach for the formation of lac...[ Read more ]

Medium-sized lactones and lactams (eight to eleven-membered rings) are important components in natural products with a diverse set of biological activities. In the last few decades, the efficient formation of these medium-sized lactones and lactams has attracted considerable attention in organic synthesis. A variety of methods have been developed, which are summarized in chapter I. Moreover, medium-sized lactones and lactams have widespread application in the synthesis of natural products, pharmaceuticals, agrochemicals, and functional organic materials. Several selected examples of the application of medium-sized lactones and lactams are also included in Chapter I.

In this thesis, two new strategies for the synthesis of lactones and one new approach for the formation of lactams have been developed.

Chapter II describes the development of trifluoromethanesulfonimide (HNTf₂)-catalyzed intermolecular [6+2] cyclization of amphoteric molecules with siloxy alkynes. The molecules containing an oxetane and an aldehyde connected by a two-atom linker group were used as amphoteric molecules. A variety of eight-membered lactones were produced through this [6+2] cyclization. Unlike the conventional intramolecular approaches, such as lactonization and ring-closing metathesis, our method represents the first intermolecular reaction for the eight-membered lactone synthesis. Preliminary mechanistic analysis suggested that this unusual process involved a sequence of several selective ring-opening/ring-closing events with concomitant bond formation and cleavage.

Chapter III introduces a new ring expansion strategy for the formation of lactones of different ring sizes, including seven, eight, nine, ten and eighteen membered rings. The strategy does not require higher concentration or slow addition, which are usually required to achieve high efficiency in traditional strategies, such as lactonization and ring closing metathesis. Iterative ring expansion was also demonstrated to synthesize different sized lactones rapidly from simple starting materials. In principle, our protocol is capable of assembling medium and large lactones of all sizes starting from a small ring acetal or ketal. Preliminary mechanistic studies showed that four-membered oxocarbenium oxetene intermediates are involved in this process.

Chapter IV describes the catalytic medium-sized lactam formation from N,O-acetals and siloxy alkynes. Catalytic methods for the synthesis of medium-sized lactams are attractive due to their high efficiency and atom economy. However, it is challenging to develop catalytic approaches because the direct cyclization of amino acids is very difficult without large amount of activating reagents. In this chapter, a range of N,O-acetals and siloxy alkynes can successfully participate in this process to give different sized lactams in moderate to high yields in the catalytic amount of HNTf₂. This process is now added to the limited number of catalytic strategies available for the synthesis of medium-sized lactams, and is expected to find application in organic synthesis in the future. Mechanistic studies are also presented.