Systematic Search for Transition States in Complex Molecules: Computational Analyses of Regio- and Stereoselective Interflavan Bond Formation in Flavan-3-ols

Urabe, Daisuke; Fukaya, Keisuke

doi:10.3987/rev-20-943

Cited by 3 publications

(4 citation statements)

References 89 publications

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“…In general, theoretical analysis favors modeling only the smallest molecular structure around the reactive site to reduce computational costs and simplify the analysis. However, we have shown in our previous reports the importance of modeling complex structures as they are, albeit at increased computational cost, since bonding/nonbonding interactions of multiple structural motifs could affect the energy and geometry of complex molecules . Such a computational approach is becoming feasible with modern computing power and is suitable for theoretical calculations of complex intermediates in natural product synthesis.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Macrolactone Core of ent-Formosalide A via Regioselective Ether Cyclization

Mozumi,

Fukaya,

Ito

et al. 2024

J. Org. Chem.

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Formosalide A is a cytotoxic macrolide isolated from the dinoflagellate Prorocentrum sp, whose structure is characterized by functionalized 5-and 6-membered ether rings embedded in the macrolactone and an all cis-tetraene side chain. Here, we report the synthesis of the macrolactone core of entformosalide A. Our approach is highlighted by the Au-mediated 6exo-dig cyclization for the synthesis of the 6-membered ether ring, which proceeded in a highly regioselective manner. Control experiments demonstrated that the acyclic protecting group of the C9,C10-diol was crucial for the desired 6-exo-dig cyclization. Theoretical studies were performed focusing on structural component analysis, which suggested that the C8−C9−C10-C11 dihedral angle induced by the protecting group controlled the regioselectivity. An additional 6 steps including Shiina macrolactone formation from the 6-membered ether ring completed the synthesis of the macrolactone core of ent-formosalide A.

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Section: Resultsmentioning

confidence: 99%

Synthesis of Macrolactone Core of ent-Formosalide A via Regioselective Ether Cyclization

Mozumi,

Fukaya,

Ito

et al. 2024

J. Org. Chem.

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“…Because the structures in enantiomeric relationships can be omitted, the (1S,6R) and (1S,6S)-bond formations for TS-Aa and TS-Bb were the subject of the computations in subsequent calculations. A conformationally comprehensive protocol 5 was employed to obtain the transition-state structures TS-Aa and TS-Ab for the C−C bond formation. First, the initial geometries were generated by a conformational search by the Monte Carlo multiple minimum (MCMM) method using the OPLS4 forcefield with the distance between C1 and C6 constrained to 2.2 Å.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…A conformationally comprehensive protocol was employed to obtain the transition-state structures TS-Aa and TS-Ab for the C–C bond formation. First, the initial geometries were generated by a conformational search by the Monte Carlo multiple minimum (MCMM) method using the OPLS4 force-field with the distance between C1 and C6 constrained to 2.2 Å.…”

Section: Resultsmentioning

confidence: 99%

Computational Study Focusing on a Comprehensive Conformational Analysis of Transition States for Aza-Spiro Ring Formations with N-Alkoxyamides

Fukaya,

Sato,

Chida

et al. 2023

J. Org. Chem.

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An accurate understanding of conformations in transition states is a critical piece in the theoretical analysis of complex molecular reactions. In this study, we investigated conformationally diverse transition states during intramolecular aza-spiro ring formation with an allylsilane moiety and N-alkoxy iminium ion, a key reaction in the synthesis of fasicularin by Sato and Chida et al., and identified the origins of stereoselectivity of the cyclization. A large number of conformational isomers with forming C–C bonds were comprehensively analyzed using Cremer–Pople puckering parameters. It was found that the conformations of the transition states had different puckering preferences depending on the reactant’s double-bond geometry and the product’s stereochemical configuration. Furthermore, an asymmetric aza-spiro cyclization with a tolyl group as a chiral auxiliary was investigated, showing that conformational anchoring by both a CH–O hydrogen bond and the CH−π interaction was critical for the asymmetric induction.

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“…Transition states TS-0-A and TS-0-B leading to 27a and 27b were generated using a previously reported method that incorporates a conformational search to exhaustively locate transition states. 15 The calculated transition states contain multiple possible Li−O interactions other than covalent Lialkoxide bonds, where the distance is within 2.3 Å. 16 In both TS-0-A and TS-0-B, the Li-chelated 6-membered ring between the alkoxide and aldehyde is formed as assumed in Scheme 1B.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Stereocontrolled Synthesis of C20S-C26 and C20R-C26 Fragments of Amphidinolide L

et al. 2022

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Amphidinolide L is a cytotoxic macrolide isolated from marine symbiotic dinoflagellates of the genus Amphidinium. While its planar structure and the absolute stereochemistry of the C21–C26 part have been determined, six stereocenters have remained unassigned. Aiming at structure determination, we have developed a synthetic route to the C20S-C26 and C20R-C26 fragments via the Li-mediated stereocontrolled aldol reaction. Two aldehydes, 16 with the C22-hydroxy group and 19 with the C22-TES ether, were synthesized from lactone 4. The aldol reactions using the Li-enolate of 4-methyl-2-pentanone in THF provided the C20S-C26 fragment 20 from 16 and a 1:3.5 mixture of the C20–C26 fragment 22 favoring the C20R-isomer. Mechanistic studies based on an extensive search of transition states in explicit solvents indicated that the C20S-isomer would be generated via a tri-solvated transition state, while the C20R-isomer would be formed via a di-solvated transition state. The calculation emphasizes the importance of the coordination network as a higher-order complex composed of solvent molecules, aldehyde, enolate, and Li atoms in the reaction of 16 to minimize steric interactions but maximize the stabilizing effect by the coordination of solvents. The presence of the rotationally free aldehyde in the reaction of 19 results in moderate diastereoselectivity.

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Systematic Search for Transition States in Complex Molecules: Computational Analyses of Regio- and Stereoselective Interflavan Bond Formation in Flavan-3-ols

Cited by 3 publications

References 89 publications

Synthesis of Macrolactone Core of ent-Formosalide A via Regioselective Ether Cyclization

Synthesis of Macrolactone Core of ent-Formosalide A via Regioselective Ether Cyclization

Computational Study Focusing on a Comprehensive Conformational Analysis of Transition States for Aza-Spiro Ring Formations with N-Alkoxyamides

Stereocontrolled Synthesis of C20S-C26 and C20R-C26 Fragments of Amphidinolide L

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