Mingji Dai

We report herein an enantioselective total synthesis of (−)-methyl gummiferolate, a complex diterpene natural product with a tetracyclic ent-atisane core including a bicyclo[2.2.2]octane subunit and three all-carbon quaternary centers. Gummiferolic acid has demonstrated potent plant growth-regulatory activity similar or superior to gibberellic acid. Using pattern recognition analysis, the tetracyclic ent-atisane core of (−)-methyl gummiferolate was retrosynthetically traced back to chiral pool molecule (S)-perillaldehyde and a six-membered ring containing starting material which can be accessed using an enantioselective Diels–Alder reaction with the Rawal diene. Our forward synthesis features a substrate-controlled stereoselective MHAT-initiated Baran reductive olefin cross coupling (BROC), a powerful radical cyclization approach, to close the six-membered B ring and an intramolecular alkylation to build the bicyclo[2.2.2]octane subunit. The BROC precursor was assembled in a convergent manner using a 1,2-addition of an alkyl lithium to a Weinreb amide derived from (S)-perillaldehyde. The alkyl lithium precursor was prepared from a known cyclohexenone (12) using key steps including CBS reduction, 2,3-Wittig–Still rearrangement, and Appel iodination. Overall, (−)-methyl gummiferolate was prepared in 18 steps from 12.

We report herein the first total synthesis of (±)-stemocurtisine, a rare insecticidal Stemona alkaloid natural product possessing a cage-like polycyclic skeleton with five O/N-heterocycles including a characteristic pyrido[1,2-a]azepine ring system and a highly oxidized tetrasubstituted double bond. Our synthesis features a palladium-catalyzed cyclopropanol ring-opening carbonylative lactonization to build a fused bicyclic lactone as a platform to construct the rest of the ring systems and an unusual bis(iodozincio)methane-mediated cyclopropanation of an α,β-epoxyketone to prepare the key cyclopropanol substrate. Two complementary approaches were developed to build the pyrido[1,2-a]azepine ring system. The first one is based on conventional nitrogen alkylation chemistry using SN2 reactions. The second one features modern transition metal-catalyzed borrowing hydrogen chemistry to form two C–N bonds intramolecularly between a free amine and two primary alcohols under redox neutral conditions, which is more concise and atom-economical. Lastly, the tetrasubstituted double bond was installed using a Horner–Wadsworth–Emmons olefination protocol followed by oxidation state adjustment. Overall, these enabling transformations led to (±)-stemocurtisine in 15 or 17 steps from two known and readily available starting materials.

Skeletal editing is rapidly reshaping synthetic chemistry by enabling precise, atom-level modifications to complex molecular frameworks. Despite recent advances in methodology development, skeletal editing has yet to realize its full impact on complex molecule synthesis. In this Perspective, we highlight the power of single-atom skeletal editing transformations in enabling efficient syntheses of various complex natural products and advocate for the development of new methods and novel applications. We present guidelines rooted in historical precedent along with modern case studies that highlight when skeletal edits enable efficient synthesis, and where reactivity gaps still limit broader adoption. By analyzing the existing literature, we aim to inspire novel retrosynthetic disconnections, and steer new method development, which, collectively, will advance the fields of total synthesis and skeletal editing.

We report herein a total synthesis of conidiogenone B, a complex cyclopiane diterpene exhibiting potent antibacterial activity against multidrug-resistant pathogens. Conidiogenone B and its natural congeners feature a congested 6/5/5/5 (A/B/C/D) tetracyclic carbon framework and multiple stereocenters, including four all-carbon quaternary centers. The challenge of conidiogenone total synthesis lies in how to efficiently construct the tetracyclic carbon framework, especially the A/B hydrindane moiety with two vicinal all-carbon quaternary centers at the ring junction. We developed an efficient strategy with a metal-hydride hydrogen atom transfer (MHAT)-initiated reductive olefin-nitrile radical cyclization to close the six-membered A ring and construct the angular methyl containing all-carbon quaternary center adjacent to an existing one, which was formed via a stereoselective Johnson-Claisen rearrangement. Two approaches were investigated to form the B ring. The first one involves a four-step sequence featuring an intramolecular aldol condensation to close the B ring. The second one-step approach utilizes a doubly activated cyclopropane derivative (1-(ethoxycarbonyl)cyclopropyl)triphenylphosphonium tetrafluoroborate as a formal 1,3-dipole in a one-pot stepwise (3 + 2) annulation, namely, α-alkylation followed by Wittig olefination, to construct the B ring. In addition, a MHAT-initiated Baran reductive olefin-enone cyclization (BROC) was employed to form the D ring, and a Stork-Danheiser alkylation transposition protocol was used to produce the BROC precursor. Overall, these enabling transformations delivered conidiogenone B in only 7 steps without using any protecting groups by maximizing C–C bond-forming events and minimizing individual functional group manipulation steps to achieve high efficiency and 100% ideality in terms of strategic step count.

In this review, we summarize and compare four total syntheses of complanadine A, a complex and pseudo-dimeric lycopodium alkaloid with promising neurotrophic activity and potential for pain management. These four total syntheses are from the groups of Siegel, Sarpong, Tsukano, and Dai. Each of the four total syntheses contains innovative strategies and creative tactics, reflecting how emerging synthetic capabilities and concepts can positively impact natural product total synthesis.

Vitamin D receptor (VDR) activation has demonstrated beneficial effects on psoriasis. However, its crucial role in calcium metabolism limits clinical applications due to the risk of health-threatening dysregulation in serum calcium. In the present study, we have designed, synthesized, and biologically tested highly potent light-controllable VDR agonists containing a photoswitchable azobenzene moiety in the drug scaffold. The optimized molecule PhotoVDRM is inactive in the dark and can be selectively activated with light using specific wavelengths, including nonphototoxic visible blue light and UVB that is currently used in skin treatments. We used a modified hydrogen/deuterium exchange method to identify the binding site and study VDR dynamics upon ligand binding. Importantly, testing PhotoVDRM in a psoriasis mouse model demonstrates that it can spatiotemporally activate VDR in localized diseased areas. Strikingly, this targeted activation results in a robust therapeutic effect without systemic hypercalcemia, thereby addressing at the preclinical level a major historic impediment to VDR agonist treatments in clinical trials. This photopharmacology-based strategy enables the discovery of innovative targeted medicines using light-controlled agonists to spatiotemporally activate the VDR at pathological sites.

Guaianolide sesquiterpene natural products are of great biological and synthetic importance. Among them, phaeocaulisin A with a unique tetracyclic skeleton was isolated in 2013 and found to exhibit anticancer cell proliferation activity and anti-inflammatory activity. The first total synthesis of ( − )-phaeocaulisin A was achieved by Procter and coworkers in 2022. Two years later, we reported a total synthesis of ( ± )-phaeocaulisin A. The key steps of our total synthesis include a novel palladium-catalyzed cyclopropanol ring-opening carbonylative esterification to access a key γ-ketoester, a regio- and stereo-selective aldol cyclization to build the 7-membered carbocycle, and a cascade ketalization/lactonization to construct the tetracyclic skeleton. This Synpact article reflects our journey toward ( ± )-phaeocaulisin A, which also led to the discovery of an analogue with potent anticancer activity against triple negative or HER2+ breast cancer.

We report herein an enantioselective total synthesis of (-)-psathyrin A, an antibacterial diterpene natural product possessing a unique 6/4/5/5 tetracyclic carbon skeleton and seven contiguous stereocenters, including three adjacent all-carbon quaternary centers. Our synthesis begins with commercially available 2-methyl-2-cyclopenten-1-one, which was subjected to an enantioselective copper/NHC-catalyzed conjugate addition, followed by trapping the resulting enolate with 1-bromo-2-butyne to set up the first two stereocenters, including one all-carbon quaternary center. A Suzuki-Miyaura cross coupling introduces an aromatic ring as the six-membered ring precursor, and a gold(I)-catalyzed Conia-ene reaction constructs the 5/5-fused bicyclic ring system and the second all-carbon quaternary center. Following Birch reduction of the aromatic ring, hydrolysis, and double bond isomerization, a Baran reductive olefin coupling, namely, MHAT-initiated olefin-enone radical cyclization, was employed to construct the four-membered ring and establish the third all-carbon quaternary center. This enabling radical cyclization completed the tetracyclic carbon framework for subsequent peripheral decorations, achieving the first total synthesis of (-)-psathyrin A in 19 steps.

N-Cyano amides are pivotal in agrochemicals, biologically active compounds, and nitrogen-containing heterocycles synthesis. Here, we present an umpolung cyanation strategy for the synthesis of N-cyano amides. By applying the readily accessible O-tosyl hydroxamates as nitrogen electrophiles, direct nucleophilic cyanation can be achieved with trimethylsilyl cyanide (TMSCN) under mild and transition metal-free conditions. This protocol features excellent functional group tolerance, easy scalability, and broad substrate scope (over 70 examples). Moreover, preliminary experimental studies and density functional theory (DFT) calculations support an S_N2-type mechanism of this reaction. Our work not only provides efficient, robust, and practical approaches to a variety of useful and complex N-cyano amide molecules but also expands the concept and scope of S_N2-type reaction at the non-anomeric amide electrophilic nitrogen center.

We report an asymmetric total synthesis of (-)-neocucurbol C, a diterpene natural product possessing a unique and complex 6/6/5/5/6 polycyclic skeleton and nine stereocenters. Pattern-recognition analysis led us to the chiral pool molecule (+)-nootkatone as the starting material, already containing the AB ring system and two key stereocenters encoded by the target molecule. The extra isopropenyl group of (+)-nootkatone was removed by Kwon's hydrodealkenylative bond fragmentation. Other key steps include a Suzuki-Miyaura cross coupling to introduce an aromatic ring as the E ring precursor, an oxidative dearomatization cyclization to form the key oxa-bridge, and a metal-catalyzed hydrogen atom transfer (MHAT)-initiated reductive radical cyclization to complete the entire framework for subsequent peripheral decorations, which eventually delivered (-)-neocucurbol C in 24 steps for the first time. In addition, the cytotoxicity evaluation of (-)-neocucurbol C and its synthetic intermediates against multiple cancer cell lines identified new lead compounds with promising anticancer activity for further development.