Assembly-line synthesis of organic molecules with tailored shapes

• Published in: Nature (London) Vol. 513; no. 7517; pp. 183 - 188
• Main Authors: Burns, Matthew, Essafi, Stéphanie, Bame, Jessica R., Bull, Stephanie P., Webster, Matthew P., Balieu, Sébastien, Dale, James W., Butts, Craig P., Harvey, Jeremy N., Aggarwal, Varinder K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.09.2014; Nature Publishing Group
• Subjects: 639/638/403; Analytical chemistry; Binomial distribution; Biosynthesis; Boron; Carbon; Chemical research; Chemical Sciences; Chemical tests and reagents; Chemistry Techniques, Synthetic - methods; Chemistry Techniques, Synthetic - standards; Esters; Humanities and Social Sciences; Magnetic Resonance Spectroscopy; Molecular Conformation; multidisciplinary; Organic chemistry; Organic compounds; Physiological aspects; Polyketides - chemical synthesis; Polyketides - chemistry; Science; Stereoisomers; Synthesis; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13711

Molecular ‘assembly lines’, in which organic molecules undergo iterative processes such as chain elongation and functional group manipulation, are found in many natural systems, including polyketide biosynthesis. Here we report the creation of such an assembly line using the iterative, reagent-controlled homologation of a boronic ester. This process relies on the reactivity of α-lithioethyl tri-isopropylbenzoate, which inserts into carbon–boron bonds with exceptionally high fidelity and stereocontrol; each chain-extension step generates a new boronic ester, which is immediately ready for further homologation. We used this method to generate organic molecules that contain ten contiguous, stereochemically defined methyl groups. Several stereoisomers were synthesized and shown to adopt different shapes—helical or linear—depending on the stereochemistry of the methyl groups. This work should facilitate the rational design of molecules with predictable shapes, which could have an impact in areas of molecular sciences in which bespoke molecules are required. The iterative, reagent-controlled homologation of a boronic ester is used to create an ‘assembly line’ capable of synthesizing organic molecules that contain ten contiguous, stereochemically defined methyl groups and which have different shapes depending on the stereochemistry of those groups. Assembly-line synthesis of defined complex molecules Biological systems have evolved sophisticated machinery for organic synthesis resembling molecular assembly-line processes. Until now chemists have been able to mimic this type of approach only to synthesize peptides and oligonucleotides, creating simple amide (C–N) or phosphate (P–O) bonds. These authors emulate nature by creating a molecular assembly line through iterative reagent-controlled homologations of boronic esters. The process relies on the reactivity of α-lithioethyl tri-ispopropylbenzoate, which inserts into carbon–boron bonds with high fidelity and stereocontrol. Each chain-extension step generates a new boronic ester, which is immediately ready for further homologation. They use this method to generate several organic molecules that contain ten contiguous, stereochemically defined methyl groups. This work is a step towards the rational design and synthesis of complex molecules with predictable shape.