[Research progress on application of multi-enzyme-catalyzed cascade reactions in enzymatic synthesis of natural products].

As a biocatalyst, enzyme has the advantages of high catalytic efficiency, strong reaction selectivity, specific target products, mild reaction conditions, and environmental friendliness, and serves as an important tool for the synthesis of complex organic molecules. With the continuous development of gene sequencing technology, molecular biology, genetic manipulation, and other technologies, the diversity of enzymes increases steadily and the reactions that can be catalyzed are also gradually diversified. In the process of enzyme-catalyzed synthesis, the majority of common enzymatic reactions can be achieved by single enzyme catalysis, while many complex reactions often require the participation of two or more enzymes. Therefore, the combination of multiple enzymes together to construct the multi-enzyme cascade reactions has become a research hotspot in the field of biochemistry. Nowadays, the biosynthetic pathways of more natural products with complex structures have been clarified, and secondary metabolic enzymes with novel catalytic activities have been identified, discovered, and combined in enzymatic synthesis of natural/unnatural molecules with diverse structures. This study summarized a series of examples of multi-enzyme-catalyzed cascades and highlighted the application of cascade catalysis methods in the synthesis of carbohydrates, nucleosides, flavonoids, terpenes, alkaloids, and chiral molecules. Furthermore, the existing problems and solutions of multi-enzyme-catalyzed cascade method were discussed, and the future development direction was prospected.

Correction: Asymmetric synthesis of (-)-solanidine and (-)-tomatidenol.

Correction for 'Asymmetric synthesis of (-)-solanidine and (-)-tomatidenol' by Yun Wang et al., Org. Biomol. Chem., 2020, 18, 3169-3176, DOI: .

Asymmetric synthesis of (-)-solanidine and (-)-tomatidenol.

A concise asymmetric synthesis of two naturally occurring seco-type cholestane alkaloids (-)-solanidine and (-)-tomatidenol from (-)-diosgenin with a linear reaction sequence of 12 steps and 13 steps, respectively, is reported. The synthetic strategy includes the highly controlled establishment of highly functionalized octahydroindolizine ((-)-solanidine) and 1-oxa-6-azaspiro[4.5]decane ((-)-tomatidenol) cores with five stereocenters, respectively, from (-)-diosgenin, featuring two stereoselective cascade transformations including a modified cascade ring-switching process of furostan-26-acid to open the E-ring of (-)-diosgenin and a cascade azide reduction/intramolecular reductive amination to close the E- and F-rings of (-)-solanidine and (-)-tomatidenol. This work should enable further explorations of chemical and biological spaces based on solanidine, tomatidenol and related natural products.

Stereoselective Synthesis of (-)-Verazine and Congeners via a Cascade Ring-Switching Process of Furostan-26-acid.

An efficient synthetic strategy for three natural seco-type cholestane alkaloids isolated from the Veratrum plants, based on commercially available naturally occurring and abundant (-)-diosgenin (1), as exemplified in the concise asymmetric synthesis of (-)-verazine (4), (-)-veramiline (5) (proposed structure), and its 22-epimer, (-)-oblonginine (6), is presented. This work highlights the application of a cascade ring-switching process of (-)-diosgenin to achieve the E-ring opening and construction of chiral six-membered lactone challenges in seco-type cholestane alkaloid synthesis. This approach enables the synthesis of related natural and nature-like novel cholestane alkaloids, opening up opportunities for more extensive exploration of cholestane alkaloid biology.

Divergent Synthesis of Solanidine and 22-epi-Solanidine.

A divergent synthesis of solanidine and 22-epi-solanidine, two 25S natural steroidal alkaloids, from 25R-configured diosgenin acetate, is described. Initially, solanidine was synthesized through a series of transformations including a cascade ring-switching process of furostan-26-acid, an epimerization of C25 controlled by the conformation of six-membered lactone ring, an intramolecular Schmidt reaction, and an imine reduction/intramolecular aminolysis process. To address the epimerization issue during Schmidt reaction, an improved synthesis was developed, which also led to a synthesis of 22-epi-solanidine. In this synthesis, selective transformation of azido lactone to azido diol and amino diol was realized through a reduction relay tactic. The azido diol was transformed to solanidine via an intramolecular Schmidt reaction/N-alkylation/reduction process and to 22-epi-solanidine via an intramolecular double N-alkylation process.

Constructing 24(23→22)-abeo-Cholestane from Tigogenin in a 20(22→23)-abeo-Way via a PhI(OAc)2-mediated Favorskii Rearrangement.

Transforming tigogenin, a steroidal sapogenin, to a 24(23→22)-abeo-cholestane, which is an unusual structural feature shared by the aglycons of saundersiosides and candicanoside A, is described. The spiroketal of tigogenin was unfolded and the resulting C22-ketone was subjected to Favorskii rearrangement mediated by PhI(OAc)2/KOH/MeOH to squeeze out the C22 from the side chain, thus reaching the 24(23→22)-abeo-cholestane structure.

Synthesis of 12,12'-azo-13,13'-diepi-Ritterazine N.

A synthesis of the 12,12'-azo-analogue of ritterazine N from hecogenin is reported. Ring contraction of two 6/5 bicyclic ring systems, one trans-fused and another spiro, to 5/5 spiro ring systems is accomplished with excellent stereochemical control. Key transformations include an abnormal Baeyer-Villiger oxidation, a Norrish type I cleavage, an intramolecular dipolar [3 + 2] cycloaddition, and an intramolecular oxymecuration. Failing to uncover the ß-OH ketone from the isoxazoline ring, we end up with a synthesis of a cyclic analogue of ritterazine N.

Synthesis of Demissidine and Solanidine.

Demissidine and solanidine, two steroidal alkaloids, are synthesized in eight steps from tigogenin acetate and diosgenin acetate, respectively, which involve the replacement of three C-O bonds with C-N bonds. Key transformations include a cascade ring-switching process of furostan-26-acid, an epimerization of C25, an intramolecular Schmidt reaction, and an imine reduction/intramolecular aminolysis process.

Synthesis Toward and Stereochemical Assignment of Clathsterol: Exploring Diverse Strategies to Polyoxygenated Sterols.

Herein we describe a synthesis of the trisulfate derivative of clathsterol (1), a marine sterol endowed with impressive structural features and moderate inhibitory activity against HIV-1 reverse transcriptase. By synthesizing two possible isomers of the side chain, the stereochemistry of 1 is assigned. In creating chiral side chains from steroidal lactone, our strategies, including an addition/reduction procedure to give C22R-OH, an epoxide-opening reaction, and a [3.3]-rearrangement to induce the generation of C24S-Et and C24R-Et respectively, are highly flexible and complementary to each other.

Synthesis of the aglycon of aspafiliosides E and F based on cascade reactions.

A synthesis of C17α-OH-tigogenin, the aglycon of aspafiliosides E and F, is described. The main features of the synthesis are three cascade processes, which involve the iodo-lactonization of furostan-26-acid to open ring E, a cascade hydrolysis/intramolecular SN2 process to close ring E, and a cascade intramolecular redox-ketalization process to close ring F. This synthesis would enrich the strategies used for the manipulation of spiroketals in steroidal sapogenins and other substrates.

Concise synthesis of the core structures of saundersiosides.

A divergent synthesis of three core pentacyclic lactones of nine rearranged cholestane sapogenins, saundersiosides A-H (1-8) and candicanoside A (9), is reported. Key features include a one-flask CBS reduction/Brown hydroboration-oxidation, a SmI2-mediated intramolecular Reformatskii reaction, and an intramolecular transesterification. This synthesis provides a general strategy and key precursors for the collective synthesis of natural and designed saundersiosides. An efficient formal synthesis of candicanoside A is also achieved.

Synthesis of (6R,12R)-6,12-Dimethylpentadecan-2-one, the Female-Produced Sex Pheromone from Banded Cucumber Beetle Diabrotica balteata, Based on a Chiron Approach.

Herein we describe a synthesis of (6R,12R)-6,12-dimethylpentadecan-2-one (5), the female produced sex pheromone of banded cucumber beetle Diabrotica balteata Le Conte, from (R)-4-methyl-5-valerolactone, a methyl-branched chiron.

Highly efficient and scalable synthesis of clionamine D.

Herein we describe an efficient and scalable synthesis of clionamine D (4), a special member with autophagy bioactivity and an unprecedented spirobislactone side chain in the novel aminosteroid clionamines. This synthesis features a quick access to α-methylene-γ-lactone 8 and a Mn(OAc)3-mediated radical [3 + 2] reaction to assemble the unique spirobislactone unit. Clionamine D (4) can also serve as a key synthetic precursor to other clionamine members.

Total syntheses of (Sp)-(+)- and (Rp)-(-)-spiniferin-1, a pair of unusual natural products with planar chirality.

(S(p))-(+)-Spiniferin-1 and (R(p))-(-)-spiniferin-1, a pair of unusual marine natural products with planar chirality, were firstly synthesized via a polyfluoroalkanosulfonyl fluoride induced homoallylic carbocation rearrangement reaction. The chiral resolution and palladium-catalyzed ß-H elimination of allylic alcohol derivatives were considered as the key steps of these divergent syntheses.

Total synthesis of (±)-spiniferin-1 via a polyfluoroalkanosulfonyl fluoride induced homoallylic carbocation rearrangement reaction.

A facile total synthesis of marine natural product (±)-spiniferin-1 has been accomplished in eight steps with 28.9% overall yield, involving a rearrangement reaction initiated by polyfluoroalkanosulfonyl fluoride to construct the 1,6-methano[10]annulene core of the natural product as a key step.

Total synthesis of (+/-)-dihydrospiniferin-1 via a polyfluoro alkanosulfonyl fluoride induced tandem carbonium ion rearrangement reaction.

A novel polyfluoroalkanosulfonyl fluoride induced carbonium ion rearrangement reaction of gamma-hydroxymethyl cyclohexenone has been used for the total synthesis of (+/-)dihydrospiniferin 1.