Efficient Synthesis of Natural Products Aided by Automated Synthesizers and Microreactors

Fuse, Shinichiro; Machida, Kazuhiro; Takahashi, Takashi

doi:10.1002/9783527645824.ch2

Cited by 4 publications

(3 citation statements)

References 53 publications

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“…The use of retrosynthetic planning identified the pathway intermediate that could serve as the best starting material for semisynthesis of paclitaxel. SciFinder SciPlanner, Reaxys, ARChem, and published literature ,,− were utilized for this exercise.…”

Section: Methodsmentioning

confidence: 99%

Combining Metabolic Pathway Design and Retrosynthetic Planning for the Design of a Novel Semisynthetic Manufacturing Scheme for Paclitaxel

Yadav

2014

Org. Process Res. Dev.

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Using the example of paclitaxel, this paper expounds how retrosynthetic analysis can be combined with metabolic pathway design to devise novel semisynthetic schemes for manufacturing natural products. The analytical framework presented herein leverages the latest developments in chem-and bioinformatics, metabolic engineering, and retrosynthetic planning, and the proposed schemes commence with the microbially aided synthesis of an advanced intermediate that is then recruited for target-oriented synthesis (TOS). A technoeconomic analysis of the scheme devised using bioretrosynthetic analysis for manufacturing paclitaxel suggests that the new process competes favorably with the current route for producing paclitaxel. Additionally, since TOS can access precise regions of chemical space, either a single molecule or a small assortment of molecules exhibiting minor variations on a chemical theme, bioretrosynthesis also doubles as a tool for drug discovery.

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Section: Methodsmentioning

confidence: 99%

Combining Metabolic Pathway Design and Retrosynthetic Planning for the Design of a Novel Semisynthetic Manufacturing Scheme for Paclitaxel

Yadav

2014

Org. Process Res. Dev.

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“…While the use of advanced engineering and robotics can assist with such an approach, 38 this inherent lack of generality has limited the applications and widespread adoption of this approach. 39,40,41 …”

Section: Automation Of the Iterative Coupling Platformmentioning

confidence: 99%

“…Because small molecule syntheses typically employ strategies and purification methods that are highly customized for each target, efforts in automation have thus far focused on expanding the types of reactions and purification processes that can be implemented on a synthesizer. While the use of advanced engineering and robotics can assist with such an approach, this inherent lack of generality has limited applications and widespread adoption. − …”

Section: Automation Of the Iterative Coupling Platformmentioning

confidence: 99%

From Synthesis to Function via Iterative Assembly of N-Methyliminodiacetic Acid Boronate Building Blocks

2015

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Small molecules can powerfully benefit society, but the study and optimization of their function is too often impeded by the time-intensive and specialist-dependent process that is typically used to make them. In contrast, general and automated platforms have been developed for peptide, oligonucleotide, and increasingly oligosaccharide synthesis, resulting in on-demand access to these molecules, even for non-specialists. A more generalized and automated approach for making small molecules could similarly help shift the rate limiting step in small molecule science from synthesis to function. Targeting this goal, we have developed a fully automated and increasingly general platform for iterative coupling of boronate building blocks. Analogous to peptide synthesis, the process involves iterative coupling of haloboronic acids protected as the corresponding N-methyliminodiacetic acid (MIDA) boronates. This platform has enabled us and other groups to access many polyene natural products, including the polyene motifs in >75% of all polyene natural products. It further allowed us to derivatize and thereby understand the powerful but also highly toxic antifungal natural product amphotericin B, which has led to the development of less toxic derivatives currently under evaluation as drug candidates. We also discovered a stereocontrolled entry into chiral, non-racemic α-boryl aldehydes, which are versatile intermediates for the synthesis of many Csp3 boronate building blocks that are otherwise difficult to access. We have also expanded the scope of the platform to include Csp3-rich, polycyclic molecules using a linear-to-cyclized strategy, in which Csp3 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, 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, Csp3 cross-coupling methodologies, and cyclization strategies.

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Asymmetric Total Synthesis of ent‐Pyripyropene A

Fuse

Ikebe

Oosumi

et al. 2015

Chemistry A European J

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An asymmetric total synthesis of ent-pyripyropene A was achieved by a convergent synthetic route. We used our originally developed Ti(III) -catalyzed radical cyclization to construct an AB-ring portion that consisted of a trans-decalin skeleton with five contiguous stereogenic centers. The coupling between the AB-ring and the DE-ring portions, and a subsequent C-ring cyclization, led to the total synthesis of ent-pyripyropene A. An evaluation of the insecticidal activity of ent-pyripyropene A against two aphid species revealed that ent-pyripyropene A was 35-175 times less active than naturally occurring pyripyropene A. This result indicated that the biological target of pyripyropene A recognizes the absolute configuration of pyripyropene A.

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Efficient Synthesis of Natural Products Aided by Automated Synthesizers and Microreactors

Cited by 4 publications

References 53 publications

Combining Metabolic Pathway Design and Retrosynthetic Planning for the Design of a Novel Semisynthetic Manufacturing Scheme for Paclitaxel

Combining Metabolic Pathway Design and Retrosynthetic Planning for the Design of a Novel Semisynthetic Manufacturing Scheme for Paclitaxel

From Synthesis to Function via Iterative Assembly of N-Methyliminodiacetic Acid Boronate Building Blocks

Asymmetric Total Synthesis of ent‐Pyripyropene A

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