C(21)−C(40) of Tetrafibricin <i>via</i> Metal Catalysis: Beyond Stoichiometric Chiral Reagents, Auxiliaries, and Premetalated Nucleophiles

Kumpulainen, Esa T. T.; Kang, Bongkoo; Krische, Michael J.

doi:10.1021/ol200735r

Cited by 15 publications

(11 citation statements)

References 34 publications

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“…In the past few years, several strategies have emerged to specifically target the chiral 1,5-diols present in tetrafibricin and related targets. − Some limitations and disadvantages inherent to the prior art include the use of cumbersome reaction conditions (e.g., toxic metals or high pressures), expensive chiral reagents used in stoichiometric quantities, and different reagents required for different stereoisomers. In many cases, assigning the new configuration of each remotely generated alcohol stereogenic center also adds extra steps to the workflow.…”

Section: Introductionmentioning

confidence: 99%

Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Enantioselective Preparation of γ-Sulfonyl-α-silyloxyaldehydes and Iterative Julia–Kocienski Coupling

et al. 2018

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Diverse classes of natural products contain chiral 1,5-polyols, within which may be stereochemical triads of 1,5,9- and 1,5,7-triols. Biological activities associated with compounds containing these motifs warrant targeted synthetic strategies to access all stereoisomers of a 1,5-polyol family from cheap and easily accessible reagents while avoiding the need to determine configurations at each alcohol stereocenter. Here, we address these problems via design and implementation of an iterative configuration-encoded strategy to access 1,5-polyols with unambiguous stereocontrol; the coupling event exploits Julia–Kocienski reactions of enantiopure α-silyloxy-γ-sulfononitriles. These building blocks, bearing sulfone at one terminus and α-silyloxyaldehyde (in latent form) at the other, were prepared via asymmetric catalysis. An efficient scalable route to these building blocks was developed, leading to enantiopure samples in multigram quantities. Preliminary studies of acetals as the latent aldehyde functionality in the α-silyloxyaldehyde showed that Julia–Kocienski coupling of these building blocks was effective, but iterative application was thwarted during acetal hydrolysis, leading to use of nitrile to perform the latent aldehyde function. A variety of 1,5-polyols, including a 1,5,9,13-tetraol and a differentially protected 1,5,9-triol, were prepared, validating the approach. The accompanying paper describes the application of this configuration-encoded 1,5-polyol synthesis to 1,5,9- and 1,5,7-triols found in tetrafibricin.

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Section: Introductionmentioning

confidence: 99%

Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Enantioselective Preparation of γ-Sulfonyl-α-silyloxyaldehydes and Iterative Julia–Kocienski Coupling

et al. 2018

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“…Moreover, for strategies that generate 1,5-diol stereochemistry in coupling events, there is a significant analytical problem associated with determining the configuration of each newly generated stereogenic center. Despite these hurdles, several notable synthetic efforts toward tetrafibricin have led to a synthesis of N -acetyldihydrotetrafibricin methyl ester (Roush), methods to prepare various polyol subunits (Krische and Cossy), and synthetic studies advancing to late-stage fragment coupling (Curran).…”

Section: Introductionmentioning

confidence: 99%

“…The [M − 57] + peak is a diagnostic proxy for molecular weight in mass spectrometry of TBS ethers 45. (2S,4S)-2-Hydroxy-4-((4-methoxybenzyl)oxy)pentanenitrile(9). A mixture of ligand (R)-819 (0.501 g, 1.42 mmol) and Ti(O-i-Pr) 4 (0.42 mL, 1.42 mmol) in CH 2 Cl 2 (19 mL) was stirred for 1 h at room temperature.…”

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confidence: 99%

Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Preparation and Coupling of C15–C25 and C26–C40 Fragments of Tetrafibricin

et al. 2018

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Diverse classes of natural products contain chiral 1,5,9-and 1,5,7-triol stereotriads, including the novel fibrinogen receptor antagonist tetrafibricin. Biological activities associated with compounds containing these motifs warrant targeted synthetic strategies to 1,5-polyol families from cheap and easily accessible reagents while avoiding the need to determine configurations at each alcohol stereocenter. In the accompanying paper, we present a solution to these problems via an iterative configuration-encoded strategy that exploits Julia−Kocienski couplings of enantiopure α-silyloxy-γ-sulfononitrile building blocks. The stereocontrol is unambiguous, and the building blocks are available in multigram quantities via asymmetric catalysis. This approach efficiently accessed a C26−C40 subunit of tetrafibricin that contains a syn,syn-1,5,9-triol and all of the stereochemistry and functionality needed to advance toward tetrafibricin. A modification afforded the anti,syn-1,5,7-triol within the C15−C25 fragment of tetrafibricin by merging 1,5-polyol synthesis with diastereoselective intramolecular conjugate addition. The union of the C15−C25 and C26−C40 fragments was achieved via a BF 3 •OEt 2 -mediated Mukaiyama aldol construction with high 1,3-anti stereoinduction, revealing some unexpected insights on the impact of silyl protecting groups on 1,3-anti diastereocontrol by a β-siloxyaldehyde aldol acceptor. Directed 1,3-anti reduction completed the stereostructure of the C15−C40 portion of tetrafibricin, with configurations established by a combination of NMR experiments.

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“…Inspired by the unanswered synthetic challenges posed by tetrafibricin, a 12 step route to the C21-C40 segment was devised using iridium catalyzed alcohol C-H allylation developed in our laboratory. 10,14 Here, we report a 10 step synthesis of the C9-C20 substructure of tetrafibricin featuring enantioselective methods for ruthenium catalyzed alcohol C-H syn -crotylation 15 and iridium catalyzed alcohol C-H allylation. 14 …”

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confidence: 99%

Asymmetric Alcohol C–H Allylation and syn-Crotylation: C9–C20 of Tetrafibricin

et al. 2014

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C(21)−C(40) of Tetrafibricin via Metal Catalysis: Beyond Stoichiometric Chiral Reagents, Auxiliaries, and Premetalated Nucleophiles

Cited by 15 publications

References 34 publications

Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Enantioselective Preparation of γ-Sulfonyl-α-silyloxyaldehydes and Iterative Julia–Kocienski Coupling

Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Enantioselective Preparation of γ-Sulfonyl-α-silyloxyaldehydes and Iterative Julia–Kocienski Coupling

Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Preparation and Coupling of C15–C25 and C26–C40 Fragments of Tetrafibricin

Asymmetric Alcohol C–H Allylation and syn-Crotylation: C9–C20 of Tetrafibricin

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