Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization.

Chemoenzymatic strategies that combine synthetic and enzymatic transformations offer efficient approaches to yield target molecules, which have been increasingly employed in the synthesis of bioactive natural products. In the biosynthesis of macrocyclic nonribosomal peptides, polyketides, and their hybrids, thioesterase (TE) domains play a significant role in late-stage macrocyclization. These domains can accept mimics of native substrates in vitro and exhibit potential for use in total synthesis. This review summarizes the recent advances of TE domains in the chemoenzymatic synthesis for these natural products that aim to address the common issues in classical synthetic approaches and increase synthetic efficiencies, which have the potential to facilitate further pharmaceutical research.

Tumor-derived OBP2A promotes prostate cancer castration resistance.

Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa); although most patients initially respond to ADT, almost all cancers eventually develop castration-resistant PCa (CRPC). Currently, most research focuses on castration-resistant tumors, and the role of tumors in remission is almost completely ignored. Here, we report that odorant-binding protein (OBP2A) released from tumors in remission during ADT catches survival factors, such as CXCL15/IL8, to promote PCa cell androgen-independent growth and enhance the infiltration of myeloid-derived suppressor cells (MDSCs) into tumor microenvironment, leading to the emergence of castration resistance. OBP2A knockdown significantly inhibits CRPC and metastatic CRPC development and improves therapeutic efficacy of CTLA-4/PD-1 antibodies. Treatment with OBP2A-binding ligand α-pinene interrupts the function of OBP2A and suppresses CRPC development. Furthermore, α-pinene-conjugated doxorubicin/docetaxel can be specifically delivered to tumors, resulting in improved anticancer efficacy. Thus, our studies establish a novel concept for the emergence of PCa castration resistance and provide new therapeutic strategies for advanced PCa.

Remote B-Ring Oxidation of Sclareol with an Engineered P450 Facilitates Divergent Access to Complex Terpenoids.

Though chiral pool synthesis is widely accepted as a powerful strategy in complex molecule synthesis, the effectiveness of the approach is intimately linked to the range of available chiral building blocks and the functional groups they possess. To date, there is still a pressing need for new remote functionalization methods that would allow the installation of useful chemical handles on these building blocks to enable a broader spectrum of synthetic manipulations. Herein, we report the engineering of a P450BM3 variant for the regioselective C-H oxidation of sclareol at C6. The synthetic utility of the resulting product was demonstrated in a formal synthesis of ansellone B, the first total synthesis of the 2,3-seco-labdane excolide B, and a model study toward (+)-pallavicinin.

A Chiral-Pool-Based Strategy to Access trans-syn-Fused Drimane Meroterpenoids: Chemoenzymatic Total Syntheses of Polysin, N-Acetyl-polyveoline and the Chrodrimanins.

trans-syn-Fused drimane meroterpenoids are unique natural products that arise from contra-thermodynamic polycyclizations of their polyene precursors. Herein we report the first total syntheses of four trans-syn-fused drimane meroterpenoids, namely polysin, N-acetyl-polyveoline, chrodrimanin C, and verruculide A, in 7-18 steps from sclareolide. The trans-syn-fused drimane unit is accessed through an efficient acid-mediated C9 epimerization of sclareolide. Subsequent applications of enzymatic C-H oxidation and contemporary annulation methodologies install the requisite C3 hydroxyl group and enable rapid generation of structural complexity to provide concise access to these natural products.

Stereoselective Synthesis of ß-Branched Aromatic α-Amino Acids by Biocatalytic Dynamic Kinetic Resolution*.

ß-Branched noncanonical amino acids are valuable molecules in modern drug development efforts. However, they are still challenging to prepare due to the need to set multiple stereocenters in a stereoselective fashion, and contemporary methods for the synthesis of such compounds often rely on the use of rare-transition-metal catalysts with designer ligands. Herein, we report a highly diastereo- and enantioselective biocatalytic transamination method to prepare a broad range of aromatic ß-branched α-amino acids. Mechanistic studies show that the transformation proceeds through dynamic kinetic resolution that is unique to the optimal enzyme. To highlight its utility and practicality, the biocatalytic reaction was applied to the synthesis of several sp3 -rich cyclic fragments and the first total synthesis of jomthonic acid A.

Merging chemoenzymatic and radical-based retrosynthetic logic for rapid and modular synthesis of oxidized meroterpenoids.

Meroterpenoids are natural products of hybrid biosynthetic origins-derived from both terpenoid and polyketide pathways-with a wealth of biological activities. Given their therapeutic potential, a general strategy to access these natural products in a concise and divergent fashion is highly desirable. Here, we report a modular synthesis of a suite of oxidized meroterpenoids using a hybrid synthetic strategy that is designed to harness the power of both biocatalytic and radical-based retrosynthetic logic. This strategy enables direct introduction of key hydroxyl groups and rapid construction of key bonds and stereocentres, facilitating the development of a concise route (7-12 steps from commercial materials) to eight oxidized meroterpenoids from two common molecular scaffolds. This work lays the foundation for rapid access to a wide range of oxidized meroterpenoids through the use of similar hybrid strategy that combines two synthetic approaches.

Enzymatic CH functionalizations for natural product synthesis.

Direct functionalization of CH bond is rapidly becoming an indispensible tool in chemical synthesis. However, due to the ubiquity of CH bonds, achieving site-selective functionalization remains an arduous task, especially on advanced synthetic intermediates or natural products. In contrast, Nature has evolved a multitude of enzymes capable of performing this task with extraordinary selectivity, and the use of these enzymes in organic synthesis may provide a viable solution to contemporary challenges in site-selective functionalization of complex molecules. This review covers recent applications of enzymatic CH functionalization strategies in natural product synthesis, both in the context of key building block preparation and late-stage functionalization of advanced synthetic intermediates.

Bioinspired Asymmetric Synthesis of Hispidanin†A.

The first enantiospecific synthesis of hispidanin A (4), a dimeric diterpenoid from the rhizomes of Isodon hispida, was achieved with a longest linear sequence of 12 steps in 6.5 % overall yield. A key component is the use of the abundant and naturally occurring diterpenoids (+)-sclareolide and (+)-sclareol as starting materials, which enables the gram-scale preparation of the key intermediates totarane (1) and s-trans-12E,14-labdadien-20,8ß-olide (2). Subsequently a thermal or an erbium-catalyzed intermolecular Diels-Alder reaction of totarane (1) with labdadienolide (2) provide convergent and rapid access to the natural product hispidanin A (4). The synthetic studies have offered significant impetus for the efficient construction of these architecturally complex natural products.

A chiral pool approach for asymmetric syntheses of (-)-antrocin, (+)-asperolide C, and (-)-trans-ozic acid.

Ozonolysis of aromatic abietane (+)-carnosic acid (4) is used to create an important intermediate in an enantiomerically pure form, resulting in a simple, concise, readily scalable, and asymmetric synthesis of (-)-antrocin (1). This strategy not only provides an efficient approach to (-)-antrocin (1) synthesis but can also be readily adopted for the syntheses of optically pure (+)-asperolide C (2) and (-)-trans-ozic acid (3) from the naturally abundant aromatic abietanes (+)-podocarpic acid (5) and (+)-dehydroabietic acid (6). The strategy presented here is an example of the use of naturally occurring aromatic abietanes as a chiral pool and offers an account of the asymmetric synthesis of terpenoids.

Asymmetric Total Synthesis of (-)-Maoecrystal†V.

The asymmetric total synthesis of (-)-maoecrystal V, a novel cytotoxic pentacyclic ent-kaurane diterpene, has been accomplished. Key steps of the current strategy involve an early-stage semipinacol rearrangement reaction for the construction of the C10 quaternary stereocenter, a rhodium-catalyzed intramolecular O-H insertion reaction, and a sequential Wessely oxidative dearomatization/intramolecular Diels-Alder reaction to forge the pentacyclic framework of maoecrystal V.

Palladium-catalyzed carbonylative cyclization of aryl alkenes/alkenols: a new reaction mode for the synthesis of electron-rich chromanes.

The Pd(II)-catalyzed intramolecular carbonylative cyclization reaction of aryl alkenes and aryl alkenols is reported for the synthesis of structurally diverse chromanes. PdCl2(CH3CN)2 was used as the catalyst and CuCl2 as the oxidant under the balloon pressure of CO. The reaction is conducted under mild conditions, and chromane-type esters and lactones can be generated in a highly regio- and stereoselective manner.

Collective synthesis of humulanolides using a metathesis cascade reaction.

A new method has been developed for the concise and asymmetric synthesis of seven humulanolides in 5-7 steps without the need for protecting groups. Notably, the challenging 11-membered ring and bridged butenolide moieties in asteriscunolide D and 6,7,9,10-tetrahydroasteriscunolide were introduced in one step using a ring-opening/ring-closing metathesis cascade reaction. Asteriscunolide D was used as a versatile synthetic precursor to prepare asteriscunolides A-C via a photoinduced isomerization reaction, asteriscanolide via a unique transannular Michael reaction, and 6,7,9,10-tetradehydroasteriscanolide via a transannular Morita-Baylis-Hillman-type reaction. The unique bicyclo[6.3.0]undecane core was introduced diastereoselectively.