Assembly-line synthesis of organic molecules with tailored shapes

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.

doi:10.1038/nature13711

Cited by 265 publications

(164 citation statements)

References 57 publications

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“…In a one pot procedure, a boronic ester was subjected to a series of six homologations, installing three methylene spacer units as well as three methyl-bearing stereocenters derived from the requisite enantiomerically-pure lithiated benzoates. 86 Amination followed by amide formation furnished the core of (+)-kalkitoxin in an overall 52% yield. This same approach has been used to synthesize baulamycin A, 87 tatanan A, 88 fluorohexestrol, 89 and C30 botryococcene 90 and many other targets.…”

Section: Many Customized Iterative Synthesis Methods Have Already Beementioning

confidence: 99%

“…This can be seen in Aggarwal’s assembly-line production method of hydrocarbons with tailored shapes. 86 …”

Section: Many Customized Iterative Synthesis Methods Have Already Beementioning

confidence: 99%

“…In contrast, divergent approaches to a iterative synthesis have the greatest potential to accelerate discovery of new function. It is evident from several divergent iterative synthesis methods 59, 76, 81, 86, 117 that the greater the potential for structural variation in the building blocks, the greater the scope of possible products. Given the arguments that most small molecules could be made from a defined set of molecular building blocks, is it possible to develop a suitably general iterative synthesis method?…”

Section: Many Customized Iterative Synthesis Methods Have Already Beementioning

confidence: 99%

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Towards the generalized iterative synthesis of small molecules

2018

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Small molecules have extensive untapped potential to benefit society, but access to this potential is too often restricted by limitations inherent to the customized approach currently used to synthesize this class of chemical matter. In contrast, the “building block approach”, i.e., generalized iterative assembly of interchangeable parts, has now proven to be a highly efficient and flexible way to construct things ranging all the way from skyscrapers to macromolecules to artificial intelligence algorithms. The structural redundancy found in many small molecules suggests that they possess a similar capacity for generalized building block-based construction. It is also encouraging that many customized iterative synthesis methods have been developed that improve access to specific classes of small molecules. There has also been substantial recent progress toward the iterative assembly of many different types of small molecules, including complex natural products, pharmaceuticals, biological probes, and materials, using common building blocks and coupling chemistry. Collectively, these advances suggest that a generalized building block approach for small molecule synthesis may be within reach.

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Section: Many Customized Iterative Synthesis Methods Have Already Beementioning

confidence: 99%

“…This can be seen in Aggarwal’s assembly-line production method of hydrocarbons with tailored shapes. 86 …”

Section: Many Customized Iterative Synthesis Methods Have Already Beementioning

confidence: 99%

Section: Many Customized Iterative Synthesis Methods Have Already Beementioning

confidence: 99%

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Towards the generalized iterative synthesis of small molecules

2018

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“…This renders fluorine a weak hydrogen-bonding acceptor, so organofluorines are poorly solvated in water, possessing 'polar hydrophobic' properties 5 . In linear alkanes carrying fluoromethylene carbons (CHF), C-F bonds positioned on alternate carbons tend to orientate away from each other to minimize dipolar repulsion, an aspect that compromises the overall molecular dipole moment 6,7 . However, if such 1,3-alignments could be maintained, polar organic molecules would result.…”

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confidence: 99%

All-cis 1,2,3,4,5,6-hexafluorocyclohexane is a facially polarized cyclohexane

et al. 2015

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The highest-energy stereoisomer of 1,2,3,4,5,6-hexafluorocyclohexane, in which all of the fluorines are 'up', is prepared in a 12-step protocol. The molecule adopts a classic chair conformation with alternate C-F bonds aligned triaxially, clustering three highly electronegative fluorine atoms in close proximity. This generates a cyclohexane with a high molecular dipole (μ = 6.2 D), unusual in an otherwise aliphatic compound. X-ray analysis indicates that the intramolecular Fax···Fax distances (∼2.77 Å) are longer than the vicinal Fax···Feq- distances (∼2.73 Å) suggesting a tension stabilizing the chair conformation. In the solid state the molecules pack in an orientation consistent with electrostatic ordering. Our synthesis of this highest-energy isomer demonstrates the properties that accompany the placement of axial fluorines on a cyclohexane and the unusual property of a facially polarized ring in organic chemistry. Derivatives have potential as new motifs for the design of functional organic molecules or for applications in supramolecular chemistry design.

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“…We recently reported an iterative strategy for the homologation of boronic esters that notably does not require any functional-group manipulations between chain-extension steps. [4,5] Theprocess involves the repeated addition of chiral lithiated carbamates or triisopropylbenzoate (TIB) esters and leads to carbon chains bearing multiple contiguous methylsubstituted stereogenic centers ( Figure 1A). This approach enabled the generation of extended chains of vicinal stereocenters (up to 10) with complete control over the relative and absolute stereochemistry and applications to complex natural products have also been reported.…”

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confidence: 99%

Short Enantioselective Total Synthesis of Tatanan A and 3‐epi‐Tatanan A Using Assembly‐Line Synthesis

2016

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Short and highly stereoselective total syntheses of the sesquilignan natural product tatanan Aa nd its C3 epimer are described. An assembly-line synthesis approach,using iterative lithiation-borylation reactions,w as applied to install the three contiguous stereocenters with high enantio-and diastereoselectivity.One of the stereocenters was installed using aconfigurationally labile lithiated primary benzyl benzoate,r esulting in high levels of substrate-controlled (undesired) diastereoselectivity.However,reversal of selectivity was achieved by using an ovel diastereoselective Matteson homologation. Stereospecific alkynylation of ah indered secondary benzylic boronic ester enabled completion of the synthesis in at otal of eight steps.Iterative strategies are highly attractive for the synthesis of complex molecules, [1] particularly when minimal or no functional-group manipulations between chain-extension steps are required. [2,3] Iterative aldol reactions provide one such strategy, [3] but if the target molecule is devoid of appropriate functional-group handles,a lternative methodologies are required. We recently reported an iterative strategy for the homologation of boronic esters that notably does not require any functional-group manipulations between chain-extension steps. [4,5] Theprocess involves the repeated addition of chiral lithiated carbamates or triisopropylbenzoate (TIB) esters and leads to carbon chains bearing multiple contiguous methylsubstituted stereogenic centers ( Figure 1A). This approach enabled the generation of extended chains of vicinal stereocenters (up to 10) with complete control over the relative and absolute stereochemistry and applications to complex natural products have also been reported. [6] Thepower of iterative homologation of boronic esters lies in its versatility since other alkyl groups can be easily incorporated simply by varying the groups on the lithiated benzoate reagent. In extending the reach of this method, we sought to introduce aryl substituents as this would enable access to an even broader array of targets,f or example tatanan A( 1)a nd iryantherin K( 2)( Figure 1B). [7,8] We targeted the sesquilignan tatanan A( 1)a st his structurally unique molecule had been reported to display potent glucokinase-activating properties,t hereby having implications for the development of antihyperglycemic drugs, although its bioactivity has since been questioned by Zakarian, who also reported its first synthesis. [9] Thes ynthesis of such am olecule would require homologation with am ixture of alkyl-and aryl-substituted lithiated benzoates.W hilst alkyl-substituted lithiated benzoates were known to be effective in assembly-line synthesis,l ittle was known about the aryl-substituted lithiated benzoates. [10,11] Such species present additional challenges in that, unlike the alkylsubstituted lithiated benzoates,t hey are configurationally

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Assembly-line synthesis of organic molecules with tailored shapes

Cited by 265 publications

References 57 publications

Towards the generalized iterative synthesis of small molecules

Towards the generalized iterative synthesis of small molecules

All-cis 1,2,3,4,5,6-hexafluorocyclohexane is a facially polarized cyclohexane

Short Enantioselective Total Synthesis of Tatanan A and 3‐epi‐Tatanan A Using Assembly‐Line Synthesis

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