Total Synthesis of (+)-Neopeltolide by the Macrocyclization/Transannular Pyran Cyclization Strategy

Nakazato, Kazuki; Oda, Mami; Fuwa, Haruhiko

doi:10.1021/acs.orglett.2c01429

Cited by 17 publications

(8 citation statements)

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“…A much more challenging test is exemplified by the synthesis of the macrocyclic core of (+)-Neopeltolide ( 10 ), a highly cytotoxic marine macrolactone with prominent anticancer properties . The complex structure of this macrolactone, with six stereocenters and a number of oxygen-containing functional groups, represents an appealing target for synthesis. , Previously, we reported the application of (allyl)tributylstannane 2b as a synthetic equivalent of a C5-bipolar isoprenoid synthon in the synthesis of the C7–C16 building block of (+)-Neopeltolide ( 11 ) (Scheme b) . We anticipated utilizing the same bifunctional building block 2b for the assembly of 2,6- cis -4-hydroxy-THP unit in 10 , thus implementing an iterative biomimetic strategy similar to the biosynthesis of terpenoids.…”

Section: Results and Discussionmentioning

confidence: 99%

Stereodivergent Assembly of 2,6-cis- and -trans-Tetrahydropyrans via Base-Mediated Oxa-Michael Cyclization: The Key Role of the TMEDA Additive

et al. 2022

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The stereodivergent synthesis of cis- and trans-2,6-disubstituted tetrahydropyrans (THPs) via sodium hexamethyldisilazide-promoted oxa-Michael cyclization of (E)-ζ-hydroxy α,β-unsaturated esters is presented. The cyclization affords the kinetically favored trans-THPs with high stereoselectivity (dr up to 93:7) at a low temperature (−78 °C), while the room-temperature reaction does not produce the thermodynamically preferred cis-THPs as major products and occurs with poor stereocontrol. The addition of tetramethylethylenediamine (TMEDA) significantly improves the stereochemical outcome of the room-temperature cyclization and allows attaining high cis-selectivity (dr up to 99:1). The remarkable effect of TMEDA indicates that the sodium cation plays an important role in controlling the stereoselectivity of the thermodynamically driven process, that is, complexation of the cation with the cyclization products results in diminished selectivity. DFT calculations support this conclusion, indicating a greater difference in Gibbs energies of sodium-free cis- and trans-enolates compared to the respective sodium chelate complexes. The synthetic utility of the method has been demonstrated by the formal syntheses of (+)-Neopeltolide and (−)-Diospongin B and the total synthesis of (−)-Diospongin A.

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Section: Results and Discussionmentioning

confidence: 99%

Stereodivergent Assembly of 2,6-cis- and -trans-Tetrahydropyrans via Base-Mediated Oxa-Michael Cyclization: The Key Role of the TMEDA Additive

et al. 2022

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“…Then, the absolute stereochemistry of 1 was stablished after the first total synthesis of 1 reported independently by the groups of Panek [13] and Scheidt [14] in 2007 and 2008, respectively. The total synthesis of (+)-neopeltolide (1) was reported recently, in 2022, by Fuwa et al [15]. Neopeltolide ( 1) is an inhibitor of the in vitro proliferation of the A-549 adenocarcinoma of the human lung (IC 50 = 1.2 nM), the NCI-ADR-RES human ovary sarcoma (IC 50 = 5.1 nM), and the P388 murine leukemia cell lines (IC 50 = 0.56 nM).…”

Section: Introductionmentioning

confidence: 91%

Extraction, Isolation, Characterization, and Bioactivity of Polypropionates and Related Polyketide Metabolites from the Caribbean Region

Rodríguez-Berríos,

Ríos-Delgado,

Perdomo-Lizardo

et al. 2023

Antibiotics

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The Caribbean region is a hotspot of biodiversity (i.e., algae, sponges, corals, mollusks, microorganisms, cyanobacteria, and dinoflagellates) that produces secondary metabolites such as polyketides and polypropionates. Polyketides are a diverse class of natural products synthesized by organisms through a biosynthetic pathway catalyzed by polyketide synthase (PKS). This group of compounds is subdivided into fatty acids, aromatics, and polypropionates such as macrolides, and linear and cyclic polyethers. Researchers have studied the Caribbean region to find natural products and focused on isolation, purification, structural characterization, synthesis, and conducting biological assays against parasites, cancer, fungi, and bacteria. These studies have been summarized in this review, including research from 1981 to 2020. This review includes about 90 compounds isolated in the Caribbean that meet the structural properties of polyketides. Out of 90 compounds presented, 73 have the absolute stereochemical configuration, and 82 have shown biological activity. We expect to motivate the researchers to continue exploring the Caribbean region’s marine environments to discover and investigate new polyketide and polypropionate natural products.

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“…1,2 The high reactivity of the three-membered ring provides the use of ECH to obtain di-and trifunctional organic compounds, polyfunctional polymers, and composites based on them 2,3 to develop effective methods for the synthesis of new heterocyclic and macrocyclic molecules. [4][5][6][7][8][9] The reactions of epichlorohydrin with proton-containing reagents (carboxylic acids, alcohols, phenols) are widely used for the synthesis of biologically active substances that exhibit antibacterial, antituberculous, and antimalarial properties, act as antioxidants and enzyme inhibitors, and are included to hypoglycemic drugs. 1,[10][11][12] The oxirane ring opening by carboxylic acids occurs to form two regioisomeric chlorohydrin esters (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Finding the right balance between tertiary amine steric effect and solvent polarity for the regioselectivity and kinetics of epichlorohydrin acetolysis

Yutilova,

Tkach,

Tarasenko

et al. 2023

J of Physical Organic Chem

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The asymmetric oxirane ring‐opening reaction leading to the formation of regioisomeric chlorohydrin esters was studied in the reaction series “acetic acid–epichlorohydrin–tetrahydrofuran (nitrobenzene)–trialkylamine” by kinetic methods and FT‐IR spectroscopy. The effect of solvent polarity and the structure of tertiary amines on the regioselectivity and reaction rate were studied. Tertiary amines with comparable basicity but different nucleophilicity and spatial structure were chosen as catalysts. It was shown that in solvents of different polarity, the components of the initial reaction system are present both as hydrogen‐bonded complexes and as individual substances. The reaction orders with respect to acid and amine in solvents of different polarity were established. Correlations between the reaction rate and the parameters of nucleophilicity and structure of amines as well as the polarity of the solvent were established. The regioselectivity of the reaction was studied by 1H NMR spectroscopy using the ratio of regioisomeric reaction products. It was shown that the regioselectivity and rate of catalytic acetolysis of epichlorohydrin are effectively controlled by the structure of tertiary amines and the polarity of the solvent. The scheme of reaction regio‐flows was detailed.

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Total Synthesis of (+)-Neopeltolide by the Macrocyclization/Transannular Pyran Cyclization Strategy

Cited by 17 publications

References 51 publications

Stereodivergent Assembly of 2,6-cis- and -trans-Tetrahydropyrans via Base-Mediated Oxa-Michael Cyclization: The Key Role of the TMEDA Additive

Stereodivergent Assembly of 2,6-cis- and -trans-Tetrahydropyrans via Base-Mediated Oxa-Michael Cyclization: The Key Role of the TMEDA Additive

Extraction, Isolation, Characterization, and Bioactivity of Polypropionates and Related Polyketide Metabolites from the Caribbean Region

Finding the right balance between tertiary amine steric effect and solvent polarity for the regioselectivity and kinetics of epichlorohydrin acetolysis

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