From chemical synthesis to biosynthesis: trends toward total synthesis of natural products

doi:10.12211/2096-8280.2021-039

Abstract

Abstract:

The complexity and diversity of natural products have made them a rich source for drug and agrochemical discovery. To overcome the supplying limitation of natural resources, tremendous effort has been made by the academic and industrial communities during the past two centuries for the total artificial synthesis of natural products. In this regard, total chemical synthesis has achieved significant progress, and numerous highly complex natural products have been synthesized through different chemical processes. Despite these great achievements in total chemical synthesis, there are still many challenges including expensive chemical reagents, harsh reaction conditions, difficult control on stereoselectivity, long synthetic route, and low product yield. Notably, the development of synthetic biology has allowed more and more natural products to be produced through biological cell factories, which provides a new and complementary strategy for the synthesis of natural products at a large scale. This review critically comments on the representative advances in total chemical synthesis of natural products (Section 1), and then highlight major progress and trends in the biosynthesis of pharmaceutically important natural products (Sections 2 and 3). In Section 2.1, we selected the production of penicillin, erythromycin, and avermectin as examples to analyze the modification and optimization of natural product biosynthetic pathways. The discovery and utilization of secondary metabolites from microorganisms has been a continuous driving force in the field of natural products. Notably, significant progress has been made in the total biosynthesis of natural products from secondary metabolism via the genetic manipulation of microbial cells. In Section 2.2, we selected Vitamin B₁₂ and Tropane alkaloids as examples to demonstrate the use of heterologous expression and biological production for natural product synthesis. In recent years, on the basis of analyzing the structure of natural products in animals, plants, and microorganisms, great advances have emerged in exploring their biochemical reaction mechanisms and synthetic routes. More importantly, expressing and regulating the relative genes in heterologous microbial cells have enabled the complete biosynthesis of many natural products. Furthermore, in Section 3, human insulin, artemisinin, saframycin, azaphilone, kainic acid, and podophyllotoxin were selected as examples to showcase the power of merging chemical and biological processes for the total synthesis of natural products. Although there are still many challenges in the total synthesis of new and complex natural products, biosynthesis will ultimately play a significant role in the construction of natural molecules and their relative analogues. By taking advantage of the merits with organic chemistry, synthetic biology, and artificial intelligence, the development of highly efficient and automatic biosynthesis could be a trend in this field.

Key words: natural products, total synthesis, synthetic biology, biocatalysis, chemoenzymatic synthesis

摘要：

结构复杂而多样的天然产物是药物发现和创制的重要宝库。为了克服有限的自然资源，来自学术界和工业界的科学家近两个世纪一直不断尝试人工合成天然产物。化学全合成已经取得了巨大成就，众多高度复杂的天然产物已经被有机化学家成功制备；但本领域仍存在诸多挑战性问题，例如化学反应中涉及昂贵的化学试剂、苛刻的反应条件、难控的立体选择性、冗长的合成路线以及较低的总收率等。随着合成生物学的发展，越来越多天然产物可通过生物细胞工厂实现人工制备，从而提供全新而互补的全合成策略。本文简要概括天然产物化学全合成，围绕几种药物活性天然产物的生物合成介绍其相关进展，以青霉素、红霉素、阿维菌素为例分析总结了天然产物同源途径的改造与优化；以维生素B₁₂、莨菪烷碱为例概括评述了天然产物的异源表达与生物制造；并以人源胰岛素、青蒿素、沙弗拉霉素、嗜氮酮、卡英酸、鬼臼毒素为例重点介绍了生物与化学交叉融合策略在天然产物全合成中的应用。尽管在类天然产物新分子、立体复杂天然产物等的全合成中仍面临诸多挑战，但生物全合成对这些天然产物分子的构建将发挥越来越显著的作用；通过化学合成与生物合成优势互补，并借助当今蓬勃发展的人工智能技术，实现生物全合成的智能化、自动化、高效化将是本领域发展的新趋势。

关键词: 天然产物, 全合成, 合成生物学, 生物催化, 化学-酶法合成

CLC Number:

Faguang ZHANG, Ge QU, Zhoutong SUN, Jun′an MA. From chemical synthesis to biosynthesis: trends toward total synthesis of natural products[J]. Synthetic Biology Journal, 2021, 2(5): 674-696.

张发光, 曲戈, 孙周通, 马军安. 从化学合成到生物合成——天然产物全合成新趋势[J]. 合成生物学, 2021, 2(5): 674-696.

Figures/Tables 15

Fig. 1 Chemical structures of morphine, salicin, salicylic acid, and acetylsalicylic acid

Fig. 2 Molecular structures of several star natural products as pharmaceuticals

Fig. 3 Total synthesis of the anti-cancer natural product paclitaxel by Robert Holton (a) and its semi-synthesis by the Pierre Potier route (b)

Fig. 4 Biosynthetic pathway of penicillin

Fig. 5 Biosynthetic pathway of erythromycin A

Fig. 6 Biosynthetic pathway of avermectin

Fig. 7 De novo biosynthesis of vitamin B12

Fig. 8 Biosynthetic pathway of tropane alkaloids

Fig. 9 Heterologous biosynthesis of tropane alkaloids in yeast

Fig. 10 Biosynthesis of human insulin A and B chains, as well as their chemical linkage

Fig. 11 Total synthesis of artemisin via combining bio-synthesis and chemical synthesis

Fig. 12 Syntheses of saframycins through the chemo-enzymatic catalysis

Fig. 13 Stereodivergent and chemoenzymatic synthesis of azaphilone natural products

Fig. 14 Chemoenzymatic synthesis of kainic acid

Fig. 15 Two chemoenzymatic synthesis pathways of podophyllotoxin

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