Aza and oxo Diels–Alder reactions using cis-cyclohexadienediols of microbial origin: chemoenzymatic preparation of synthetically valuable heterocyclic scaffolds

Pazos, Mariana; Martínez, Sebastián; Vila, María Agustina; Rodríguez, Paola; Veiga, Nicolás; Seoane, Gustavo; Carrera, Ignacio

doi:10.1016/j.tetasy.2015.10.015

Cited by 13 publications

(14 citation statements)

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“…The synthetic strategy for the construction of conduritol C stereochemical patterns takes advantage of the enzymatic cis -dihydroxylation process from substituted arenes that generates two of the required stereocenters. This method, previously reported by our lab, produces the corresponding cis -diol by microbial oxidation using the mutant bacteria E. coli JM109 (pDTG601) with excellent enantiomeric excess (>99% ee) (see Scheme 1 ) [ 13 , 14 ].…”

Section: Resultsmentioning

confidence: 99%

“…Starting from methyl-cyclohexadienediol 1 (23 g/L from toluene) [ 14 ] ( Scheme 2 ), we recently reported the synthesis [ 15 ] of 5 in four steps with an overall 24% yield, and we also described its crystal structure ( Figure 1 a) [ 12 ]. We optimized the reported method as follows: The reaction of acetonide 2 under Prevost conditions [ 16 , 17 ] produced iodohydrin 3a as the major product, which, treated with an excess of aqueous KOH at reflux, generated diol 5 , without isolation of epoxide 4 .…”

Section: Resultsmentioning

confidence: 99%

“…Our general method leads to secured stereochemistry at all four stereogenic centers in the conduritol C derivatives. Bromo-cyclohexadienediol 7 (43 g/L) [ 14 ] ( Scheme 3 ), which was obtained by biotransformation of bromobenzene, established the absolute configuration of two stereogenic centers that we protected under the conventional protocol to the corresponding dioxolane 8 .…”

Section: Resultsmentioning

confidence: 99%

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General Method for the Synthesis of (−)-Conduritol C and Analogs from Chiral Cyclohexadienediol Scaffolds

et al. 2018

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An efficient and facile general method for the synthesis of conduritol C analogs, taking advantage of an enantioselective biocatalysis process of monosubstituted benzenes, is described. The absolute stereochemical patterns of the target molecules (−)-conduritol C, (−)-bromo-conduritol C, and (−)-methyl-conduritol C were achieved by means of chemoenzymatic methods. The stereochemistry present at the homochiral cyclohexadiene-cis-1,2-diols derived from the arene biotransformation and the enantioselective ring opening of a non-isolated vinylepoxide derivative permitted the absolute configuration of the carbon bearing the hydroxyl groups at the target molecules to be established. All three conduritols and two intermediates were crystallized, and their structures were confirmed by X-ray diffraction. The three conduritols and intermediates were isostructural. The versatility of our methodology is noteworthy to expand the preparation of conduritol C analogs starting from toluene dioxygenase (TDO) monosubstituted arene substrates.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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General Method for the Synthesis of (−)-Conduritol C and Analogs from Chiral Cyclohexadienediol Scaffolds

et al. 2018

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“…Further decorations may be carried out through the many possibilities of additions to the carbon-carbon double bonds of the diene substructures. This includes [4+2] cycloadditions to the dienes, which lead to bridged bicycles (Pazos et al 2015), molecules with a rigid three-dimensional core that have recently been shown to be interesting candidates for bioactivity screens (Birudukota et al 2016). As the double dioxygenation generates four new chiral centres, these metabolites are of particular interest for enantioselective syntheses (Hudlicky and Reed 2009).…”

Section: Applications Of Bis-dhdsmentioning

confidence: 99%

An aryl dioxygenase shows remarkable double dioxygenation capacity for diverse bis-aryl compounds, provided they are carbocyclic

Overwin

González

Méndez

et al. 2016

Appl Microbiol Biotechnol

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CitationAn aryl dioxygenase shows remarkable double dioxygenation capacity for diverse bis-aryl compounds, provided they are carbocyclic. 2016, 100 (18) AbstractThe bacterial dioxygenation of mono-or polycyclic aromatic compounds is an intensely studied field. However, only in a few cases has the repeated dioxygenation of a substrate possessing more than a single aromatic ring been described. We previously characterized the aryl-hydroxylating dioxygenase BphA-B4h, an artificial hybrid of the dioxygenases of the biphenyl degraders Burkholderia xenovorans LB400 and Pseudomonas sp. strain B4-Magdeburg, which contains the active site of the latter enzyme, as an exceptionally powerful enzyme. We now show that this dioxygenase possesses a remarkable capacity for the double dioxygenation of various bicyclic aromatic compounds, provided that they are carbocyclic. Two groups of biphenyl analogues were examined: series A compounds containing one heterocyclic aromatic ring and series B compounds containing two homocyclic aromatic rings. Whereas all of the seven partially heterocyclic biphenyl analogues were solely dioxygenated in the homocyclic ring, four of the six carbocyclic bis-aryls were converted into ortho,meta-hydroxylated bis-dihydrodiols. Potential reasons for failure of heterocyclic dioxygenations are discussed. The obtained bis-dihydrodiols may, as we also show here, be enzymatically re-aromatized to yield the corresponding tetraphenols. This opens a way to a range of new polyphenolic products, a class of compounds known to exert multiple biological activities. Several of the obtained compounds are novel molecules.

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“…The microbial oxidation product of toluene, and its acetonide derivative 1 , have been extensively used as dienes in DA and hetero DA reactions (see and references therein). As a consequence of the steric repulsion imparted by the isopropylidenedioxy group, the acetonide 1 generally reacts by the less hindered face of the diene (α face).…”

Section: Introductionmentioning

confidence: 99%

Diels‐Alder Reaction of Levoglucosenone with a Protected cis‐Cyclohexadienediol: Structural and Electronic Basis behind the Unexpected Stereoselectivity

et al. 2017

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Recently, we found that the Diels–Alder reaction between levoglucosenone and the acetonide of (1S,2R)‐3‐methylcyclohexa‐3,5‐diene‐1,2‐diol occurs through the most hindered face of the diene. This unexpected facial selectivity has no precedent for di‐O‐isopropylidene‐protected dienes, and the reasons behind it remain unclear. Here, we expand on our earlier findings, computationally assessing the structural and electronic factors responsible for this unforeseen stereoselectivity. The B3LYP/6‐31+G(d,p) results identify the three main adducts (β‐endo‐ortho:α‐endo‐meta:α‐exo‐ortho), giving a product ratio (63:9:28) that is in line with the experimental value (64:16:10). The β‐endo attack allows to maximize the electrostatic attraction between the reactants, giving rise to dipolar C−O⋅⋅⋅H−C interactions with the isopropylidene group at the transition state. The endo/exo preference can be rationalized through electrostatic repulsion and steric hindrance between the isopropylidene and methylene fragments. Finally, the non‐classical C=O⋅⋅⋅H−C hydrogen bonding stabilizes the ortho transition structures, making them more polar and asynchronous.

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Aza and oxo Diels–Alder reactions using cis-cyclohexadienediols of microbial origin: chemoenzymatic preparation of synthetically valuable heterocyclic scaffolds

Cited by 13 publications

References 73 publications

General Method for the Synthesis of (−)-Conduritol C and Analogs from Chiral Cyclohexadienediol Scaffolds

General Method for the Synthesis of (−)-Conduritol C and Analogs from Chiral Cyclohexadienediol Scaffolds

An aryl dioxygenase shows remarkable double dioxygenation capacity for diverse bis-aryl compounds, provided they are carbocyclic

Diels‐Alder Reaction of Levoglucosenone with a Protected cis‐Cyclohexadienediol: Structural and Electronic Basis behind the Unexpected Stereoselectivity

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