Fragment Coupling Reactions in Total Synthesis That Form Carbon–Carbon Bonds via Carbanionic or Free Radical Intermediates

Tomanik, Martin; Hsu, Ian Tingyung; Herzon, Seth B.

doi:10.1002/anie.201913645

Cited by 47 publications

(28 citation statements)

References 361 publications

(245 reference statements)

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“…10 Herein we report the first total synthesis of clionastatins, which was accomplished asymmetrically via a convergent approach 11,12 involving radical fragment coupling. [13][14][15][16] Moreover, our synthetic studies resulted in revision of the originally proposed structures of these natural products.…”

Section: Scheme 1 Synthetic Challenge and Retrosynthetic Analysis Of Clionastatins A And Bmentioning

confidence: 99%

Asymmetric Total Synthesis of Clionastatins A and B

Wang

Tian

et al. 2021

Preprint

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Herein we report the first total synthesis of polychlorinated steroids clionastatins A and B, which was accomplished asymmetrically by means of a convergent, radical fragment coupling approach. Key features of the synthesis include an Ireland-Claisen rearrangement to introduce the C5 stereocenter (which was ultimately transferred to the C10 quaternary stereocenter of the clionastatins via a traceless stereochemical relay), a regioselective acyl radical conjugate addition to join the two fragments, an intramolecular Heck reaction to install the C10 quaternary stereocenter, and a diastereoselective olefin dichlorination to establish the synthetically challenging pseudoequatorial dichlorides. This work also enabled us to determine that the true structures of clionastatins A and B are in fact C14 epimers of the originally proposed structures.Chlorinated steroid drugs, such as the corticosteroids Temovate and Nasonex (Figure 1), are an important class of synthetic steroids

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Section: Scheme 1 Synthetic Challenge and Retrosynthetic Analysis Of Clionastatins A And Bmentioning

confidence: 99%

Asymmetric Total Synthesis of Clionastatins A and B

Wang

Tian

et al. 2021

Preprint

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“…We envisioned devising a new convergent strategy for the total synthesis of 1 because it is generally more suited for a shorter route than the linear counterpart, which involves stepwise manipulations from a simple starting material . In particular, our continued interest in developing radical-based strategies motivated us to integrate a powerful radical coupling reaction into the synthesis. , Herein, we detail the development of a novel radical-based route to hikizimycin ( 1 ) from four simple components in 17 steps as the longest linear sequence. The densely functionalized hikosamine structure was convergently built by a newly developed radical coupling reaction between an α-alkoxy radical and an aldehyde.…”

Section: Introductionmentioning

confidence: 99%

Convergent Total Synthesis of Hikizimycin Enabled by Intermolecular Radical Addition to Aldehyde

et al. 2020

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Hikizimycin (1), which exhibits powerful anthelmintic activity, has the most densely functionalized structure among nucleoside antibiotics. A central 4-amino-4-deoxyundecose of 1 possesses 10 contiguous stereocenters on a C1–C11 linear chain and is decorated with a cytosine base at C1 and a 3-amino-3-deoxyglucose at C6-OH. These distinctive structural features of 1 make it an extremely challenging target for de novo construction. Herein, we report a convergent total synthesis of 1 from four known components: 3-azide-3-deoxyglucose derivative 4, bis-TMS-cytosine 5, d-mannose 9, and d-galactose derivative 10. We first designed and devised a novel radical coupling reaction between multiply hydroxylated aldehydes and α-alkoxyacyl tellurides. The generality and efficiency of this process was demonstrated by the coupling of 7c and 8, which were readily accessible from two hexoses, 9 and 10, respectively. Et3B and O2 rapidly induced decarbonylative radical formation from α-alkoxyacyl telluride 8, and intermolecular addition of the generated α-alkoxy radical to aldehyde 7c yielded 4-amino-4-deoxyundecose 6-α with installation of the desired C5,6-stereocenters. Subsequent attachments of the cytosine with 5 and of the 3-azide-3-deoxyglucose with 4 were realized through selective activation of the C1-acetal and selective deprotection of the C6-hydroxy group. Finally, the 3 amino and 10 hydroxy groups were liberated in a single step to deliver the target 1. Thus, the combination of the newly developed radical-coupling and protective-group strategies minimized the functional group manipulations and thereby enabled the synthesis of 1 from 10 in only 17 steps. The present total synthesis demonstrates the versatility of intermolecular radical addition to aldehyde for the first time and offers a new strategic design for multistep target-oriented syntheses of various nucleoside antibiotics and other bioactive natural products.

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mentioning

confidence: 99%

Asymmetric Total Synthesis of Clionastatins A and B

Wang

Tian

et al. 2021

Preprint

View full text Add to dashboard Cite

Herein we report the first total synthesis of polychlorinated steroids clionastatins A and B, which was accomplished asymmetrically by means of a convergent, radical fragment coupling approach. Key features of the synthesis include an Ireland–Claisen rearrangement to introduce the C5 stereocenter (which was ultimately transferred to the C10 quaternary stereocenter of the clionastatins via a traceless stereochemical relay), a regioselective acyl radical conjugate addition to join the two fragments, an intramolecular Heck reaction to install the C10 quaternary stereocenter, and a diastereoselective olefin dichlorination to establish the synthetically challenging pseudoequatorial dichlorides. This work also enabled us to determine that the true structures of clionastatins A and B are in fact C14 epimers of the originally proposed structures.

show abstract

Fragment Coupling Reactions in Total Synthesis That Form Carbon–Carbon Bonds via Carbanionic or Free Radical Intermediates

Cited by 47 publications

References 361 publications

Asymmetric Total Synthesis of Clionastatins A and B

Asymmetric Total Synthesis of Clionastatins A and B

Convergent Total Synthesis of Hikizimycin Enabled by Intermolecular Radical Addition to Aldehyde

Asymmetric Total Synthesis of Clionastatins A and B

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