Part I: synthesis and cross-coupling of the C1-C12 primary organoborane building block of amphotericin B; Part II: site- and stereoretentive cross-coupling of unactivated secondary boronic acids inspired by amphotericin B
|Institution:||University of Illinois – Urbana-Champaign|
|Full text PDF:||http://hdl.handle.net/2142/46571|
In contrast to peptides, oligonucleotides, and increasingly oligosacharides, which can be rapidly and flexibly assembled in a systematic fashion from pre-fabricated building blocks, the synthesis of small molecules has remained a relatively slow, complex, and unsystematized process. With the potential of addressing these limitations, an analogous building block-based approach for making small molecules has been proposed in our group. In the idealized limit, a collection of off-the-shelf boronic acid-based building blocks having all of the required functional groups pre-installed in the correct oxidation states and with the desired stereochemical relationships are readily assembled using only a single cross-coupling reaction repeatedly. Such an iterative cross-coupling (ICC) strategy has been applied in our proposed total synthesis of clinically valuable polyene natural product amphotericin B (AmB). In our retrosynthetic analysis, AmB is disconnected into four bifunctional building blocks and these building blocks are assembled via an iterative deprotection/cross-coupling fashion. Boronic acid-based cross-coupling reactions (Suzuki-Miyaura reaction) are most commonly executed to form Csp2-Csp2 bond. In practice, due to the lack of consecutive Csp2 centers on C1-C19 AmB skeleton, Csp3-Csp2 cross-coupling is required to assemble the polyol subunit BB1. The synthesis of BB1 turned out to be challenging. Moreover, a Csp3-Csp2 cross-coupling reaction was not readily available for the connection of BB1 and the rest of the molecule. Three generations of syntheses were developed and finally we reached a modular and efficient solution of the synthesis and assembly of BB1. Our total synthesis of the doubly-C13 labeled protected AmB is a good example to showcase the power of the ICC approach to small molecule synthesis. Also from the synthesis, it is clear that building block scopes for ICC are currently restricted to primarily Csp2 organoborons. Unactivated Csp3 organoborons are often unstable and methods to access these building blocks are limited. In addition, at present, unactivated Csp3 organoborons cannot be cross-coupled with the same levels of efficiency that is now accessible with many of their Csp2 and activated Csp3 hybridized counterparts. In order to address these challenges, in my thesis research, I developed three novel methods to make Csp3 organo-N-methyliminodiacetic acid (MIDA) boronate building blocks that are indefinitely bench-top stable. Additionally, inspired by our ongoing total synthesis of AmB, I discovered a solution to the long-standing problem of site-, and stereoretentive cross-coupling of unactivated secondary Csp3 boronic acids.