Total Synthesis of (+)-Roxaticin via C−C Bond Forming Transfer Hydrogenation: A Departure from Stoichiometric Chiral Reagents, Auxiliaries, and Premetalated Nucleophiles in Polyketide Construction

Han, Soo Bong; Hassan, Abbas; Kim, In Su; Krische, Michael J.

doi:10.1021/ja1082798

Cited by 125 publications

(51 citation statements)

References 74 publications

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“…69 Application of this iterative strategy in a two-directional manner expedited construction of the key polyol portion of (+)-roxaticin (Figure 2d). 70 This methodology has proven to be highly versatile and readily scalable, enabling practical gram scale access to stereochemically complex building blocks for a wide range of highly complex polyketide natural products. 71–73 This efficiency has further enabled practical synthesis and testing of bryostatin derivatives, shedding new light on the relationship between potency and biological activity.…”

Section: Many Customized Iterative Synthesis Methods Have Already Beementioning

confidence: 99%

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%

Towards the generalized iterative synthesis of small molecules

2018

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“…31 Through iterative two-directional chain elongation of 1,3-propanediol, a total synthesis of the oxo-polyene macrolide (+)-roxaticin was achieved in 20 steps. 32 Corresponding double crotylations of 2-methyl-1,3-propanediol result in the generation of pseudo - C 2 -symmetric polypropionate stereoquintets, which appear as substructures in diverse polyketide natural products. Using the chromatographically isolated iridium catalyst modified by ( R )-SEGPHOS, 1 of 16 possible stereoisomers is formed predominantly.…”

Section: C-c Bond Forming Transfer Hydrogenationmentioning

confidence: 99%

Unlocking Hydrogenation for C–C Bond Formation: A Brief Overview of Enantioselective Methods

Hassan

Krische

2011

Org. Process Res. Dev.

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121

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Hydrogenation of π-unsaturated reactants in the presence of carbonyl compounds or imines promotes reductive C-C coupling, providing a byproduct-free alternative to stoichiometric organometallic reagents in an ever-increasing range of C=X (X = O, NR) additions. Under transfer hydrogenation conditions, hydrogen exchange between alcohols and π-unsaturated reactants triggers generation of electrophile-nucleophile pairs, enabling carbonyl addition directly from the alcohol oxidation level, bypassing discrete alcohol oxidation and generation of stoichiometric byproducts.

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“…The concise nature of this approach can be attributed to the rapid assembly of key fragments A and B , as availed through application of C-C bond forming hydrogenations developed in our laboratory 12 – a technology that has enabled dramatic simplification in the synthesis of other polyketide natural products. 33 This work serves as a prelude to even shorter routes to the bryostatins and simplified functional analogues. More broadly, the merged redox-construction events central to this study speak to an emerging retrosynthetic paradigm, wherein C-C bond construction is accompanied by withdrawal of hydrogen.…”

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confidence: 99%