From synthesis to function via iterative assembly of N-methyliminodiacetic acid boronate building blocks

Abstract

The study and optimization of small molecule function is often impeded by the time-intensive and specialist-dependent process that is typically used to make such compounds. In contrast, general and automated platforms have been developed for making peptides, oligonucleotides, and increasingly oligosaccharides, where synthesis is simplified to iterative applications of the same reactions. Inspired by the way natural products are biosynthesized via the iterative assembly of a defined set of building blocks, we developed a platform for small molecule synthesis involving the iterative coupling of haloboronic acids protected as the corresponding N-methyliminodiacetic acid (MIDA) boronates. Here we summarize our efforts thus far to develop this platform into a generalized and automated approach for small molecule synthesis. We and others have employed this approach to access many polyene-based compounds, including the polyene motifs found in >75% of all polyene natural products. This platform further allowed us to derivatize amphotericin B, the powerful and resistance-evasive but also highly toxic last line of defense in treating systemic fungal infections, and thereby understand its mechanism of action. This synthesis-enabled mechanistic understanding has led us to develop less toxic derivatives currently under evaluation as improved antifungal agents. To access more Csp(3)-containing small molecules, we gained a stereocontrolled entry into chiral, non-racemic α-boryl aldehydes through the discovery of a chiral derivative of MIDA. These α-boryl aldehydes are versatile intermediates for the synthesis of many Csp(3) boronate building blocks that are otherwise difficult to access. In addition, we demonstrated the utility of these types of building blocks in accessing pharmaceutically relevant targets via an iterative Csp(3) cross-coupling cycle. We have further expanded the scope of the platform to include stereochemically complex macrocyclic and polycyclic molecules using a linear-to-cyclized strategy, in which Csp(3) boronate building blocks are iteratively assembled into linear precursors that are then cyclized into the cyclic frameworks found in many natural products and natural product-like structures. Enabled by the serendipitous discovery of a catch-and-release protocol for generally purifying MIDA boronate intermediates, the platform has been automated. The synthesis of 14 distinct classes of small molecules, including pharmaceuticals, materials components, and polycyclic natural products, has been achieved using this new synthesis machine. It is anticipated that the scope of small molecules accessible by this platform will continue to expand via further developments in building block synthesis, Csp(3) cross-coupling methodologies, and cyclization strategies. Achieving these goals will enable the more generalized synthesis of small molecules and thereby help shift the rate-limiting step in small molecule science from synthesis to function.

Figure 1

The iterative coupling platform for small molecule synthesis from MIDA boronate building blocks is analogous to peptide synthesis from protected amino acids. D = deprotection, C = coupling

Figure 2

Synthesis of the polyene motifs found in >75% of polyene natural products from 12 MIDA boronate building blocks.

Figure 3

A) Structures of amphotericin B, ergosterol, and cholesterol. B) In the presence of ergosterol or cholesterol, AmB spontaneously forms ion channels in lipid membranes. C) AmB kills yeast by simply sequestering ergosterol.

Figure 4

A) C35deOAmB retains the capacity to bind ergosterol. B) C35deOAmB is unable to permeabilize yeast while AmB can. C) C35deOAmB retains potent antifungal activity.

Figure 5

Structures of natural products or derivatives synthesized by other groups using MIDA boronates. Portions highlighted in red come from MIDA boronate building blocks.

Figure 6

Leveraging the enforced proximity between the chiral R* group and the organic group bound to boron to achieve highly diastereoselective reactions.

Figure 7

Highly diastereoselective epoxidations of alkenyl PIDA boronates. Numbers in parentheses indicate isolated yields.

Figure 8

Examples of new types of Csp³ boronates that can be derived from α-boryl aldehydes.

Figure 9

A catch-and-release purification protocol for MIDA boronate intermediates.

Figure 10

Photograph of the small molecule synthesizer and the three modules for deprotection, coupling, and purification.

Figure 11

Natural products, pharmaceuticals and materials made on the synthesizer.

Figure 12

Semi-automated synthesis of Csp³-rich macro- and polycyclic natural products and natural product-like cores using the linear-to-cyclized strategy.

Scheme 1

Total synthesis of ratanhine via an iterative coupling approach.

Scheme 2

Completely stereocontrolled synthesis of (−)-peridinin via ICC.

Scheme 3

Synthesis of C35deOAmB through ICC.

Scheme 4

Determining the migrating group by A) probing the stereochemical outcome of the rearrangement and B) deuterium labeling.

Scheme 5

Iterative Csp³-Csp² cross-coupling for the modular synthesis of 31.

Scheme 6

The linear-to-cyclized approach for the synthesis of the secodaphnane core 38.