Automation has fuelled dramatic advances in fields such as proteomics and genomics (e.g., in preparation of proteins and nucleic acids), 1,2 enabling non-experts to prepare, test and analyse complex biological molecules. However, the field of automated organic synthesis lags far behind, partly because of the complexity and variety of organic molecules. As a result, only a handful of relatively simple organic molecules, requiring a small number of synthetic steps, have been made in an automated fashion. Herein, we report an automated assembly-line synthesis that allows iterative, stereocontrolled formation of C(sp 3 )-C(sp 3 ) bonds with high stereochemical fidelity and reproducibility, enabling access to complex organic molecules even by non-synthesis experts. This was achieved on a commercially available robotic platform capable of handling air sensitive reactants and performing low temperature reactions, which enabled six sequenced one-carbon homologations of organoboron substrates to be performed iteratively without human intervention. Together with other automated functional group manipulations, this methodology has been exploited to rapidly build the core fragment of the natural product (+)-kalkitoxin, thus leading the way towards automated organic synthesis.

Ab road range of acyclic primary and secondary 2,4,6-triisopropylbenzoate( TIB) esters have been used in lithiation-borylation reactions,b ut cyclic TIB esters have not. We have studied the use of cyclic TIB esters in lithiationborylation reactions and looked at the effect of ring size (3-! 6-membered rings) on the three key steps of the lithiationborylation protocol:deprotonation, borylation and 1,2-metalate rearrangement. Although all rings sizes could be deprotonated, the cyclohexyl case was impractically slow,a nd the cyclopentyl example underwent a-elimination faster than deprotonation at À78 8 8Ca nd so could not be used. Both cyclobutyl and cyclopropyl cases underwent rapid borylation, but only the cyclobutyl substrate underwent 1,2-metalate rearrangement. Thus,t he cyclobutyl TIB ester occupies a" Goldilocks zone," being small enough for deprotonation and large enough to enable 1,2-migration. The generality of the reaction was explored with ab road range of boronic esters.

Dysoxylactam A is a 17‐membered macrocyclic lipid which has been found to dramatically reverse multidrug resistance in cancer cells. Three previous syntheses have been reported in 15–17 steps. Using iterative lithiation‐borylation reactions as the key C−C bond forming and stereocontrolling steps, we now describe an 11‐step synthesis of dysoxylactam A. The complete sequence only required a total of five chromatographic purifications and used minimal protecting groups making it both rapid and efficient.

The catalytic reductive transformation of carboxylic esters into α-branched ethers is described. The procedure pivots on the chemoselective iridium-catalyzed hydrosilylation of ester and lactone functionality to afford a silyl acetal intermediate. Upon treatment with a Lewis acid, these hemilabile intermediates dissociate to form reactive oxocarbenium ions, which can be intercepted by allyltributyltin nucleophiles, resulting in the formation of valuable α-branched alkyl–alkyl ether derivatives. This reductive allylation procedure was found to be amenable to a range of carboxylic ester starting materials, and good chemoselectivity for ethyl over tert-butyl esters was demonstrated. Furthermore, downstream synthetic manipulation of α-amino acid-derived products led to the efficient formation of pyrrolidine, piperidine, and azepane frameworks.

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