Chemistry and Biology of Biosynthetic Diels–Alder Reactions

Stocking, Emily M.; Williams, Robert M.

doi:10.1002/anie.200200534

Cited by 427 publications

(193 citation statements)

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“…[13] This reaction type is of great relevance in organic chemistry, [14] and candidates for catalyzing the Diels-Alder reaction in nature are currently under intensive investigation. [15][16][17] This ribozyme was the first RNA enzyme to catalyze a bond-forming reaction enantioselectively, [18] and substrate-specificity studies suggested a simple and convincing structural model for the stereoselectivity (Figure 1b). [19] The size of the diene's substituent was identified as the major determinant of stereoselectivity (see the table in Figure 1), and the diene was thought to enter the catalytic pocket with the sterically less demanding edge first, then react with the maleimide bound in one fixed orientation (Figure 1b, left model), while the opposite orientation of the anthracene (right model) was found to be disfavored.…”

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confidence: 98%

Control of Stereoselectivity in an Enzymatic Reaction by Backdoor Access

et al. 2006

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The ability of biopolymers to discriminate between optical isomers is vital for living systems, and the selective formation of only one product stereoisomer from achiral substrates is one of the most sophisticated tasks for enzymes. Using a Diels-Alder ribozyme as an example, we demonstrate here that by a simple strategy a biocatalyst can be used to selectively synthesize both product stereoisomers in one catalytic pocket, namely, by controlling access to the active site from opposite directions through different "doors". While substrates tethered to the catalyst were used to observe this phenomenon, we propose ** We gratefully acknowledge support by the Bundesministerium für Bildung und Forschung (BioFuture program), the Deutsche Forschungsgemeinschaft, and the Human Frontiers Science Program (A.J.), and by the NIH, the DeWitt Wallace Foundation, and the Abby Rockefeller Mauze Trust (D.J.P.).

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confidence: 98%

Control of Stereoselectivity in an Enzymatic Reaction by Backdoor Access

et al. 2006

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“…Although putative enzymes for unimolecular [4+2] cycloadditions have been reported (1)(2)(3)(4), no naturally occurring enzyme is known to catalyze a bimolecular Diels-Alder reaction (5,6). The generation of artificial Diels-Alderases has therefore been a longstanding and alluring goal for protein engineers.…”

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confidence: 99%

Impact of scaffold rigidity on the design and evolution of an artificial Diels-Alderase

Preiswerk

Beck

Schulz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

101

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By combining targeted mutagenesis, computational refinement, and directed evolution, a modestly active, computationally designed DielsAlderase was converted into the most proficient biocatalyst for [4+2] cycloadditions known. The high stereoselectivity and minimal product inhibition of the evolved enzyme enabled preparative scale synthesis of a single product diastereomer. X-ray crystallography of the enzyme-product complex shows that the molecular changes introduced over the course of optimization, including addition of a lid structure, gradually reshaped the pocket for more effective substrate preorganization and transition state stabilization. The good overall agreement between the experimental structure and the original design model with respect to the orientations of both the bound product and the catalytic side chains contrasts with other computationally designed enzymes. Because design accuracy appears to correlate with scaffold rigidity, improved control over backbone conformation will likely be the key to future efforts to design more efficient enzymes for diverse chemical reactions.biocatalysis | computational enzyme design | Diels-Alder reaction | laboratory evolution | enzyme mechanism

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“…Diels-Alder reactions have been proposed as key steps in the biogenesis of several natural products, including lovastatin, solanapyrone, nargenicin, and ikarugamycin (12). Kirst et al (3) suggested that the biosynthesis of spinosyn A may involve a transannular Diels-Alder (TDA) (13) reaction of a macrocyclic pentaene to form the C(4)OC (12) and C(7)OC (11) bonds (see 4 3 3; Scheme 1).…”

Section: Synthetic Strategymentioning

confidence: 99%

“…Kirst et al (3) suggested that the biosynthesis of spinosyn A may involve a transannular Diels-Alder (TDA) (13) reaction of a macrocyclic pentaene to form the C(4)OC (12) and C(7)OC (11) bonds (see 4 3 3; Scheme 1). Kirst also suggested that a transannular cyclization of a 1,3-dicarbonyl nucleophile may generate the C(3)OC (14) bond (3).…”

Section: Synthetic Strategymentioning

confidence: 99%

Total synthesis of (–)-spinosyn A

Mergott

Frank

Roush

2004

Proc. Natl. Acad. Sci. U.S.A.

127

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A convergent, highly stereoselective total synthesis of (؊)-spinosyn A (1) is described. Key features of the synthesis include the transannular Diels-Alder reaction of macrocyclic pentaene 11 and the transannular Morita-Baylis-Hillman cyclization of 12 that generates tetracycle 26. The total synthesis of (؊)-spinosyn A was completed by a sequence involving the highly ␤-selective glycosidation reaction of 13 and glycosyl imidate 30.T he spinosyns are a family of polyketide natural products that possess extraordinary insecticidal activity. The biosynthetic mixture, generated by Saccharopolyspora spinosa, comprises mostly spinosyn A (1) (Scheme 1) (Ϸ85%) and spinosyn D (Ϸ10-15%) (1-8). This mixture is currently marketed for use as an insecticide against a variety of insects (6). Total syntheses of spinosyn A have been reported by Evans and Black (9) and Paquette et al. (10,11). Synthetic StrategyDiels-Alder reactions have been proposed as key steps in the biogenesis of several natural products, including lovastatin, solanapyrone, nargenicin, and ikarugamycin (12). Kirst et al. (3) suggested that the biosynthesis of spinosyn A may involve a transannular Diels-Alder (TDA) (13) reaction of a macrocyclic pentaene to form the C(4)OC(12) and C(7)OC (11) bonds (see 4 3 3; Scheme 1). Kirst also suggested that a transannular cyclization of a 1,3-dicarbonyl nucleophile may generate the C(3)OC (14) bond (3). Alternatively, we speculated that the C(3)OC(14) bond may be formed by a vinylogous Morita-Baylis-Hillman (MBH) reaction mediated by an enzymatic nucleophile (compare 3 3 1; Scheme 1). Based on these biosynthetic considerations, we sought to assemble spinosyn A (1) via a TDA and MBH cyclization sequence of an appropriately functionalized macrocyclic pentaene 4.Diastereoselectivity of the Diels-Alder Reaction. Paramount to the success of this synthetic strategy is the control of the diastereoselectivity of the TDA reaction (4 3 3). It is known from the work of Evans and Black (9) that the intrinsic diastereofacial selectivity of the intramolecular Diels-Alder (IMDA) reaction of 5a favors the incorrect C(7)OC(11) trans-fused diastereomer 6a with 6:1 selectivity (Scheme 2). Although Evans and Black (9) addressed this issue by incorporating a chiral auxiliary (13) in the dienophile (see 5b 3 7b), we would not have recourse to this strategy for the TDA cyclization of 4. Thus, some means for controlling the stereochemistry at the C(7)OC(11) ring fusion relative to the C(9)Oalkoxy substituent in the Diels-Alder reaction was required.We initially hoped to use the steric directing-group strategy to control the diastereoselectivity of the Diels-Alder reaction (15-17), which could involve appending a bromine steric directing group at C(6) of the IMDA or TDA substrate to control the stereochemical outcome of the cycloaddition, leading to the desired C(7)OC(11) trans-fused diastereomer. It was anticipated that TS2, which leads to the undesired C(7)OC(11) trans-fused isomer 10 and is favored in the absence of the C(6)OBr steric direct...

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Chemistry and Biology of Biosynthetic Diels–Alder Reactions

Cited by 427 publications

References 214 publications

Control of Stereoselectivity in an Enzymatic Reaction by Backdoor Access

Control of Stereoselectivity in an Enzymatic Reaction by Backdoor Access

Impact of scaffold rigidity on the design and evolution of an artificial Diels-Alderase

Total synthesis of (–)-spinosyn A

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