Formal Total Synthesis of Manzacidin C Based on Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Imines

Tong, Thu Minh Thi; Soeta, Takahiro; Suga, Tetsuya; Kawamoto, Keisuke; Hayashi, Yoshihito; Ukaji, Yutaka

doi:10.1021/acs.joc.6b02816

Cited by 22 publications

(5 citation statements)

References 43 publications

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“…Conversion of 22 to manzacidin C is well-documented in the literature, proceeding in two facile steps . Overall, our approach constitutes a five-step formal synthesis of manzacidin C, and compares favorably to previous approaches to this alkaloid . More importantly, we showed that incorporation of enzymatic methods into the precepts of C–H functionalization logic can dramatically simplify a synthesis design.…”

Section: Resultsmentioning

confidence: 57%

Remote C–H Hydroxylation by an α-Ketoglutarate-Dependent Dioxygenase Enables Efficient Chemoenzymatic Synthesis of Manzacidin C and Proline Analogs

2018

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Selective C-H functionalization at distal positions remains a highly challenging problem in organic synthesis. Though Nature has evolved a myriad of enzymes capable of such feat, their synthetic utility has largely been overlooked. Here, we functionally characterize an α-ketoglutarate-dependent dioxygenase (Fe/αKG) that selectively hydroxylates the δ position of various aliphatic amino acids. Kinetic analysis and substrate profiling of the enzyme show superior catalytic efficiency and substrate promiscuity relative to other Fe/αKGs that catalyze similar reactions. We demonstrate the practical utility of this transformation in the concise syntheses of a rare alkaloid, manzacidin C, and densely substituted amino acid derivatives with remarkable step efficiency. This work provides a blueprint for future applications of Fe/αKG hydroxylation in complex molecule synthesis and the development of powerful synthetic paradigms centered on enzymatic C-H functionalization logic.

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Section: Resultsmentioning

confidence: 57%

Remote C–H Hydroxylation by an α-Ketoglutarate-Dependent Dioxygenase Enables Efficient Chemoenzymatic Synthesis of Manzacidin C and Proline Analogs

2018

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“…A telescoped hydrogenation/dual Boc protection/selective lactonization procedure then afforded lactone 10 in 41% yield over two steps (Figure B). Given the aforementioned two-step elaboration of 10 to the natural product, our route represents a five-step formal synthesis of manzacidin C and a drastic improvement in step economy over prior approaches . This improvement, coupled with absolute regio- and stereocontrol, underscores the capability of enzymatic C–H functionalization to streamline synthetic efforts.…”

Section: Amino Acid Functionalizationmentioning

confidence: 96%

Reinvigorating the Chiral Pool: Chemoenzymatic Approaches to Complex Peptides and Terpenoids

Stout

Renata

2021

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Biocatalytic transformations that leverage the selectivity and efficiency of enzymes represent powerful tools for the construction of complex natural products. Enabled by innovations in genome mining, bioinformatics, and enzyme engineering, synthetic chemists are now more than ever able to develop and employ enzymes to solve outstanding chemical problems, one of which is the reliable and facile generation of stereochemistry within natural product scaffolds. In recognition of this unmet need, our group has sought to advance novel chemoenzymatic strategies to both expand and reinvigorate the chiral pool. Broadly defined, the chiral pool comprises cheap, enantiopure feedstock chemicals that serve as popular foundations for asymmetric total synthesis. Among these building blocks, amino acids and enantiopure terpenes, whose core structures can be mapped onto several classes of structurally and pharmaceutically intriguing natural products, are of particular interest to the synthetic community.In this Account, we summarize recent efforts from our group in leveraging biocatalytic transformations to expand the chiral pool, as well as efforts toward the efficient application of these transformations in natural products total synthesis, the ultimate testing ground for any novel methodology. First, we describe several examples of enzymatic generation of noncanonical amino acids as means to simplify the synthesis of peptide natural products. By extracting amino acid hydroxylases from native biosynthetic pathways, we obtain efficient access to hydroxylated variants of proline, lysine, arginine, and their derivatives. The newly installed hydroxyl moiety then becomes a chemical handle that can facilitate additional complexity generation, thereby expanding the pool of amino acidderived building blocks available for peptide synthesis. Next, we present our efforts in enzymatic C−H oxidations of diverse terpene scaffolds, in which traditional chemistry can be combined with strategic applications of biocatalysis to selectively and efficiently derivatize several commercial terpenoid skeletons. The synergistic logic of this approach enables a small handful of synthetic intermediates to provide access to a plethora of terpenoid natural product families. Taken together, these findings demonstrate the advantages of applying enzymes in total synthesis in conjunction with established methodologies, as well as toward the expansion of the chiral pool to enable facile incorporation of stereochemistry during synthetic campaigns.

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“…The versatile reactivities of N,N -cyclic azomethine imines have been consistently explored, allowing the facile construction of a variety of dinitrogen-fused heterocyclic systems. Thus, owing to their inherent dipolar character, a range of dipolarophiles including olefins [11], alkynes [12], enones [13], isocyanides [14], and allenes [15] were subjected to [3 + n] dipolar cyclization with N,N -cyclic azomethine imines to derive a range of fused dinitrogen-containing heterocycles. Interestingly, dimerization of N,N -cyclic azomethine imine under the UV-irradiation was observed by Rodina and Geissler et al, leading to the formation of a 1,5-diazabicycle [16,17].…”

Section: Introductionmentioning

confidence: 99%

Eosin Y-Catalyzed Visible-Light-Mediated Aerobic Transformation of Pyrazolidine-3-One Derivatives

et al. 2020

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By utilizing an underexplored reactivity of N1-substituted pyrazolidine-3-ones, we developed a visible-light-induced aerobic oxidation of N1-substituted pyrazolidine-3-one derivatives yielding the corresponding azomethine imines. The resulting azomethine imines can be further reacted with ynones in situ under copper catalyzed [3 + 2] cycloaddition reaction conditions yielding the corresponding pyrazolo[1,2-a]pyrazoles in good yields. The methodology can be extended to other 1-aryl-substituted pyrazolidinones which undergo endocyclic oxidation deriving the corresponding pyrazolones as single products.

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Formal Total Synthesis of Manzacidin C Based on Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Imines

Abstract: An enantioselective formal total synthesis of (+)-manzacidin C is described. A key feature of the synthesis is the construction of two chiral centers via the asymmetric 1,3-dipolar cycloaddition of an azomethine imine to methallyl alcohol by the use of (S,S)-DIPT as a chiral auxiliary.

Cited by 22 publications

References 43 publications

Remote C–H Hydroxylation by an α-Ketoglutarate-Dependent Dioxygenase Enables Efficient Chemoenzymatic Synthesis of Manzacidin C and Proline Analogs

Remote C–H Hydroxylation by an α-Ketoglutarate-Dependent Dioxygenase Enables Efficient Chemoenzymatic Synthesis of Manzacidin C and Proline Analogs

Reinvigorating the Chiral Pool: Chemoenzymatic Approaches to Complex Peptides and Terpenoids

Eosin Y-Catalyzed Visible-Light-Mediated Aerobic Transformation of Pyrazolidine-3-One Derivatives

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