Enzyme-catalyzed Hetero-Diels-Alder reactions

doi:10.12211/2096-8280.2023-015

Abstract

Abstract:

The Diels-Alder reaction is a chemical process where a conjugated diene reacts with a dienophile to form cyclohexene. This reaction can generate up to four adjacent chiral centers and two carbon-carbon bonds simultaneously, making it an effective method to form C—C bonds. Therefore, it has attracted wide attention. Hetero-Diels-Alder (HDA) reactions, which involve heteroatoms, are an important tool for synthesizing natural heterocyclic rings. HAD reaction types are classified according to the heteroatoms involved, with the most common types being oxa Diels-Alder reaction and aza Diels-Alder reaction. At present, non-enzyme catalysts have been successfully applied to catalyze HDA reactions, which are catalyzed by chemical catalysts such as Lewis acids, metal ions, and organic molecules can do. However, compared to chemical catalysis, enzyme-catalyzed HDA reactions are favored due to their green, mild, efficient, and highly selective properties. With the discovery of enzyme-catalyzed HDA reactions in natural product biosynthetic pathways, uncovering the stereoselectivity and substrate specificity of HDA-related enzymes promotes our understandings of the relationship between sequences and functions. Additionally, it lays the foundation for further mining and modification of enzymes. However, there are several challenges need to be tackled. Firstly, although a few HDA enzymes have been studied, the vast majority are remained to be isolated and characterized. Secondly, the catalytic mechanisms of most reported HDA enzymes are not clear, and more information about their structures, key residues and catalytic processes remains to be uncovered. Thirdly, all reported cases present rather narrow substrate spectra, and the stereoselectivity is rather poor. Here, we summarize the currently known enzyme-catalyzed HDA reactions in heterocyclic natural product biosynthetic pathways, focusing mainly on those involved in the biosynthesis of pyridines and indole alkaloids. By summarizing and analyzing the entire biocatalytic pathways and catalytic mechanisms, we expect to guide further research and engineering of HAD enzymes to improve their activity and selectivity. We also hope to inspire the development of new biocatalysts for the synthesis of non-natural heterocyclic products.

Key words: Hetero-Diels-Alder reaction, enzyme, heteroatom, pyranoids, indole alkaloids

摘要：

Diels-Alder反应被认为是合成复杂天然产物的最有效的方法之一，一直以来都深受化学家的关注。而杂原子参与的HDA（Hetero-Diels-Alder）反应是合成各种天然杂环的重要工具，其中以氧杂DA反应和氮杂DA反应最为常见。酶催化HDA反应以其绿色温和、高效、高选择性等优势受到人们广泛关注。随着杂环天然产物中酶催化HDA反应的不断发现，对HDA相关酶的立体选择性、底物特异性的研究也不断深入，有效促进了人们对这一类酶序列与功能关系的了解，为其挖掘和改造奠定了基础。本文集中对目前已知的酶催化HDA反应合成杂环天然产物的成果进行概述，主要包括吡喃类化合物和吲哚生物碱生物合成中涉及的酶促HDA反应，以期通过对途径和催化机理的分析，为发展新的相关生物催化剂用于合成非天然的杂环产物提供思路。

关键词: Hetero-Diels-Alder反应, 酶, 杂原子, 吡喃类化合物, 吲哚生物碱

CLC Number:

Cuizhen WANG, Tiao CHEN, Jianbo WANG. Enzyme-catalyzed Hetero-Diels-Alder reactions[J]. Synthetic Biology Journal, 2024, 5(1): 107-125.

王翠珍, 陈窕, 王健博. 酶催化杂Diels-Alder反应[J]. 合成生物学, 2024, 5(1): 107-125.

Figures/Tables 15

Fig. 1 Pyran compounds

Fig. 2 Products containing bicyclo[2.2.2] diazaoctane rings

Fig. 3 Classification of Diels-Alder reactionsEDG—Electron donating group; EWG—Electron withdrawing group

Fig. 4 Biosynthetic pathway of Leporin B (1)

Fig. 5 Biosynthetic pathway of Neosetophomone B (3) and Epolone B (4)

Fig. 6 Pathway for synthesizing the precursor Asperpyridone A (9) of Fusaricide (10)

Fig. 7 HDA reaction catalyzed by the artificial zinc metalloenzyme DA7

Fig. 8 Methyl 6-decanamido-2-fluoro-3-oxohexanoate (47)

Fig. 9 Biosynthetic pathway of Tetronasin (13)

Fig. 10 Biosynthetic pathway of Tetromadurin (14)

Fig. 11 Biosynthetic pathway of indole alkaloid malbrancheamides (17)

Fig. 12 Catalytic mechanism underlying the MalC/PhqE-catalysed Diels-Alder reaction

Fig. 13 Biosynthetic pathway of indole alkaloid (+)-Precitrinadin A (19)

Fig. 14 Catalytic mechanism underlying the CtdP-catalysed IEDDA reaction

Table 1 HDA enzymes and products

HDA酶基因簇	来源	HDA产物	晶体结构	催化机理
lep	Aspergillus flavus	1, 2	[56-59]	[54,56-57,59]
eupf	Penicillium janthinellum	3, 4, 5	－	[61]
pyc	Leptobacillium sp.	6, 36	－	[65]
epi	Epicoccum sorghinum FT1062^[66]	9, 10, 41	－	－
upi	Uncinocarpus reesii^[68]	9, 10, 41	－	－
hpi	Hymenoscyphus scutula^[68]	9, 10, 41	[68]	[68]
tsn	Streptomyces longisporoflavus	13	[85]	[85]
mad	Actinomadura verrucosospora^[86]	14	－	－
mal	Malbranchea aurantiaca^[89]	17, 18	[29,95]	[29,95]
ctd	Penicillium citrinum ATCC 9849^[97]	19, 20	[45,97]	[45,97-98]

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