2017
DOI: 10.1038/nature23882
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Abstract: Pericyclic reactions are among the most powerful synthetic transformations to make multiple regioselective and stereoselective carbon-carbon bonds1. These reactions have been widely applied for the synthesis of biologically active complex natural products containing contiguous stereogenic carbon centers2–6. Despite the prominence of pericyclic reactions in total synthesis, only three naturally existing enzymatic examples, intramolecular Diels-Alder (IMDA) reaction7, Cope8 and Claisen rearrangements9, have been… Show more

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Cited by 155 publications
(178 citation statements)
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“…Initially annotated as SDRs, the MKP IMDAases MalC and PhqE perform an initial reduction prior to controlling the selective [4 + 2] cycloaddition reaction. This is an example of the only characterized Diels–Alder enzyme that retains its ancestral functionality [44,81]. Interestingly, DFT calculations suggest that the syn ‐/ anti ‐diastereospecificity of the IMDA reaction can be substrate‐driven based on the oxidation state of the indole ring, where the presence of the FMO‐derived spirooxindole moiety reverses the intrinsic diastereospecificity.…”
Section: Discussionmentioning
confidence: 99%
“…Initially annotated as SDRs, the MKP IMDAases MalC and PhqE perform an initial reduction prior to controlling the selective [4 + 2] cycloaddition reaction. This is an example of the only characterized Diels–Alder enzyme that retains its ancestral functionality [44,81]. Interestingly, DFT calculations suggest that the syn ‐/ anti ‐diastereospecificity of the IMDA reaction can be substrate‐driven based on the oxidation state of the indole ring, where the presence of the FMO‐derived spirooxindole moiety reverses the intrinsic diastereospecificity.…”
Section: Discussionmentioning
confidence: 99%
“…Ar emarkably similar ambimodal pericylic transition state has also been proposedf or the LepI cyclase, though in this instance the energy landscape, which includes as table intermediate, allows the system to be more experimentally tractable. [70] The biosynthesis of leporin C( 25), ac ytotoxic hybrid PKS-NRPS natural product from Aspergillus,i nvolves pericyclic steps catalysed by the stand-alone enzyme LepI. [70] Formation of as table ketonei ntermediate by LepA, Ga nd Hi sf ollowed by reductionc atalysed by LepF,as hort-chain dehydrogenase, generating as econdary alcohol.…”
Section: Leporin Cb Iosynthesismentioning
confidence: 99%
“…The products of both lepA (PKS-NRPS) and lepG (enoyl reductase) are responsible for fusion of phenylalanine with a hexaketide and subsequent release of the stable tetramic acid precursor, pre-leporin C. The putative cytochrome P450, LepH, an enzyme demonstrating significant homology to the ring expansion cytochrome P450s found in the 2-pyridones, tenellin and bassianin, was shown to be required for the ring expansion step. LepF, a putative short chain dehydrogenase/ reductase, was hypothesized to reduce the acyl carbonyl to an alcohol 143) . Interestingly, although lepI was predicted to encode a putative methyltransferase, elegant in vitro studies by Tang and coworkers 143) showed that LepI catalyzed an Sadenosyl-L-methionine (SAM)-dependent inverse electron demand hetero-Diels-Alder (HDA) reaction forming leporin C. In addition to the HDA reaction, LepI was shown to possess retro-Claisen activity, which allows the enzyme to convert a byproduct of the Diels-Alder reactions to leporin C. Leporin C is then further oxidized by the N-hydroxylase, LepD, to form leporin B.…”
Section: -2 Leporin Clustermentioning
confidence: 99%
“…LepF, a putative short chain dehydrogenase/ reductase, was hypothesized to reduce the acyl carbonyl to an alcohol 143) . Interestingly, although lepI was predicted to encode a putative methyltransferase, elegant in vitro studies by Tang and coworkers 143) showed that LepI catalyzed an Sadenosyl-L-methionine (SAM)-dependent inverse electron demand hetero-Diels-Alder (HDA) reaction forming leporin C. In addition to the HDA reaction, LepI was shown to possess retro-Claisen activity, which allows the enzyme to convert a byproduct of the Diels-Alder reactions to leporin C. Leporin C is then further oxidized by the N-hydroxylase, LepD, to form leporin B. The function of LepA, G, H, F, I and D were confirmed by heterologous reconstitution in A. nidulans; the function of LepF and LepI were investigated in vitro using recombinant protein expressed from S. cerevisiae and E. coli, respectively 143) .…”
Section: -2 Leporin Clustermentioning
confidence: 99%