Synthesis of the [6-6-7-5-5] Pentacyclic Core of Calyciphylline N.

A new approach for the concise 11-step synthesis of the [6-6-7-5-5] BCDEF pentacyclic core of calyciphylline N is described. A type II [5 + 2] cycloaddition was employed to construct the strained BCD skeleton, which encompasses the challenging bicyclo[2.2.2] and bicyclo[4.3.1] ring systems. With a regio- and diastereoselective Lu's [3 + 2] cycloaddition, followed by intramolecular aldol cyclization and elimination, the desired [5-5]-fused EF ring system has been successfully installed, resulting in the complete carbocyclic skeleton of calyciphylline N.

Asymmetric Total Synthesis of Pedrolide.

The asymmetric total synthesis of pedrolide (>200 mg) with an unprecedented [5-5-5-6-6-3] hexacyclic core (pedrolane) was achieved. Its unique bicyclo[2.2.1]heptane ring system was efficiently constructed via an enantioselective ene reaction of cyclopentadiene followed by a Wittig reaction, isomerization, and a diastereoselective intramolecular Diels-Alder reaction cascade. The highly oxygenated carane [6-3] ring system was synthesized via a ring-closing metathesis reaction followed by an unusual free carbene cyclopropanation. Furthermore, the 12 contiguous stereocenters of pedrolide were installed diastereoselectively.

Asymmetric Synthesis of the epi-Vinigrol Tricyclic Core Enabled by a Wolff Rearrangement Strategy and Formal Total Synthesis of (-)-Vinigrol.

A new approach to construct the tricyclic framework of the diterpenoid vinigrol is described. The challenging 1,5-butanodecahydronaphthalene core was established efficiently and diastereoselectively through a combination of type II [5 + 2] cycloaddition and Wolff rearrangement. In addition, a formal total synthesis of (-)-vinigrol was achieved in 12 steps, in which Baran's intermediate was efficiently produced from a known compound by a two-step sequence involving a stereoselective α-hydroxylation and a diastereoselective α-ketol rearrangement.

Total Synthesis of abeo-Steroids via Cycloaddition Strategy.

ConspectusSteroids continue to play a significant role in organic chemistry, medicinal chemistry, and drug discovery due to their important biological activities and diverse intriguing structures. Although synthetic organic chemists have successfully constructed and elaborated the classical [6-6-6-5] tetracyclic steroid skeleton for nearly a century, synthesis of the unusual rearranged steroids, particularly abeo-steroids with a medium-sized ring, remains a challenge in the synthetic community. Furthermore, the structures of abeo-steroids are complex and diverse, containing a seven-membered ring embedded in the fused or bridged A/B ring system and possessing numerous stereogenic centers. Besides their structural complexity, various abeo-steroids have shown remarkable biological activities. However, the relative scarcity of abeo-steroids in natural sources has impeded the systematic evaluation of their biological activities. In addition, direct strategies to build the core structures of abeo-steroids are very rare, partially because of the high ring-strain energies of their rearranged A/B ring systems. Therefore, the development of direct and efficient synthetic approaches to these complex molecules is highly desired.Our long-standing interest in the total synthesis of abeo-steroids and the development of new cycloaddition reactions for streamlining complex molecule synthesis have led us to develop a series of unique and powerful intramolecular cycloaddition strategies to access a diverse array of highly strained abeo-steroids. These strategies include Ru-catalyzed [5 + 2] cycloaddition, acid-promoted type I [5 + 2] cycloaddition, Rh-catalyzed [2 + 2 + 1] cycloaddition, and type II [5 + 2] cycloaddition. Since 2018, we have accomplished the first total syntheses of five synthetically challenging abeo-steroids, i.e., bufogargarizins A and B, phomarol, bufospirostenin A, and cyclocitrinol, thus facilitating the evaluation of their pharmacological potentials. In this Account, we summarize our laboratory's systematic efforts in the total synthesis of these abeo-steroids via cycloaddition strategies. We highlight the efficiency and versatility of each cycloaddition strategy for constructing structurally complex abeo-steroid cores by forming the A/B ring system. The evolution of each strategy and key lessons learned from the synthetic journey are also discussed. We believe that our unique perspective in this field will promote advances in the total synthesis of abeo- and related steroids.

Total Synthesis of (±)- and (-)-Daphnillonin B.

The first total synthesis of (±)- and (-)-daphnillonin B, a daphnicyclidin-type alkaloid with a new [7-6-5-7-5-5] A/B/C/D/E/F hexacyclic core, has been achieved. The [6-5-7] B/C/D ring system was efficiently and diastereoselectively constructed via a mild type I intramolecular [5+2] cycloaddition, followed by a Grubbs II catalyst-catalyzed radical cyclization. The [5-5] fused E/F ring system was synthesized via a diastereoselective intramolecular Pauson-Khand reaction. Notably, the synthetically challenging [7-6-5-7-5-5] hexacyclic core was reassembled by a unique Wagner-Meerwein-type rearrangement from the [6-6-5-7-5-5] hexacyclic framework found in calyciphylline A-type Daphniphyllum alkaloids.

Strategies and Lessons Learned from Total Synthesis of Taxol.

Taxol (paclitaxel), the most well-known taxane diterpenoid, is the best-selling natural-source anticancer drug ever produced and one of the most common prescriptions in the treatment of breast, lung, and ovarian cancers, saving countless lives around the world. Structurally, Taxol possesses a highly oxygenated [6-8-6-4] core bearing 11 stereocenters, seven of which are contiguous chiral centers. Moreover, the extremely strained bicyclo[5.3.1] undecane ring system with a bridgehead double bond is a unique structural feature. All these features make Taxol a highly challenging synthetic target. Tremendous synthetic efforts from more than 60 research groups around the world have already culminated in ten total syntheses and three formal syntheses, as well as more than 60 synthetic model studies of Taxol. This review is intended to provide a long-overdue appraisal of the great achievements in the total syntheses of Taxol reported in the last few decades. In doing so, we summarize the development of synthesis toward Taxol from 1994 to 2022, including the evolution of synthetic strategy for accessing this complex molecular scaffold and key lessons learned from such endeavors. Finally, we briefly discuss the future of the research in this area.

Synthesis of Spirotricyclic Core of Bonnadiene.

We herein describe a new approach for the efficient synthesis of the tricyclic core of diterpene bonnadiene. The synthetically challenging and unusual [6-7-5] spirotricyclic skeleton including the all-carbon quaternary stereocenter, was installed diastereoselectively via a type II [5 + 2] cycloaddition, followed by a unique vinylogous semipinacol rearrangement. The described chemistry demonstrates the feasibility of making the [6-7-5] spirotricyclic skeleton of the final product from the strained bridged [7-8-5] ring system.

Asymmetric Total Synthesis of Twin Bufogargarizins A and B.

The first and asymmetric total synthesis of bufogargarizins A and B, two unusual and highly oxygenated twin steroids with rearranged A/B rings, was achieved. The synthetically challenging [7-5-6-5] tetracyclic ring system of bufogargarizin A was efficiently constructed by the first intramolecular Ru-catalyzed [5 + 2] cycloaddition reaction of a vinyl ether cyclopropane-yne. Notably, the interesting [5-7-6-5] tetracyclic skeleton of bufogargarizin B was diastereoselectively reassembled by unique retro-aldol/transannular aldol cascade reactions from the [7-5-6-5] tetracyclic framework.

Total Synthesis of Yuzurine-type Alkaloid Daphgraciline.

The first total synthesis of daphgraciline has been achieved, which also represents the first example of the synthesis of Daphniphyllum yuzurine-type alkaloids (∼50 members). The unique bridged azabicyclo[4.3.1] ring system in the yuzurine-type subfamily was efficiently and diastereoselectively assembled via a mild type II [5+2] cycloaddition for the first time. The compact tetracyclic [6-7-5-5] skeleton was installed efficiently via an intramolecular Diels-Alder reaction, followed by a benzilic acid-type rearrangement. The synthetically challenging spiro tetrahydropyran moiety in the final product was installed diastereoselectively via a TiIII-mediated reductive epoxide coupling reaction. Potential access to enantioenriched daphgraciline is presented.

Neferine Suppresses Experimental Colitis-Associated Colorectal Cancer by Inhibition of NF-[Formula: see text]B p65 and STAT3.

Colitis is an important risk factor for the development of colorectal cancer (CRC). The inhibitory effect and the underlying mechanism of neferine on colitis-associated colorectal cancer (CA-CRC) were investigated using an azoxymethane (AOM)/dextran sulfate sodium (DSS) triggered mice model. Compared with the CA-CRC model, oral treatment of neferine (2.5 and 5.0 mg/kg) significantly inhibited the DAI scores, decreased the tumor number, and reduced the tumor size. Neferine decreased inflammatory cell infiltration and epithelial hyperplasia in colon tissues. The levels of tumor necrosis factor-[Formula: see text] (TNF-[Formula: see text], interleukin-1beta (IL-1[Formula: see text], and interleukin 6 (IL-6) in colon tissues were decreased by neferine. Furthermore, neferine significantly decreased protein expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), p-p65, and p-STAT3 in both tumor and non-tumor tissues. In addition, neferine inhibited LPS and IL-6-induced phosphorylation of both NF-[Formula: see text]B p65 and STAT3. Molecular docking demonstrated the interactions of neferine with both NF-[Formula: see text]B p65 and STAT3. In conclusion, these results suggested that neferine inhibited CA-CRC carcinogenesis possibly by regulating NF-[Formula: see text]B and STAT3. Neferine might be a lead compound for the chemoprevention of CA-CRC.

Asymmetric Total Syntheses of Hypoestin A, Albolic Acid, and Ceroplastol II.

The first asymmetric total synthesis of bioactive diterpenoid hypoestin A with an unprecedented [5-8-5-3] tetracyclic skeleton is accomplished in 15 steps from commercially available (R)-limonene. Furthermore, the second asymmetric total syntheses of sesterterpenoids albolic acid and ceroplastol II in 21 steps are also reported. The synthetically challenging and highly functionalized [X-8-5] (X = 5 or 7) tricarbocyclic ring systems found in hypoestin A, albolic acid, ceroplastol II, and schindilactone A, as well as other natural products, are efficiently and directly constructed via a unique intramolecular Pauson-Khand reaction of an allene-yne. This work represents the first reported use of the Pauson-Khand reaction to access synthetically challenging eight-membered-ring systems in natural product synthesis.

Synthesis of Various Bridged Ring Systems via Rhodium-Catalyzed Bridged (3+2) Cycloadditions.

Here, we describe the rhodium-catalyzed bridged (3+2) cycloaddition cascade reactions of N-sulfonyl-1,2,3-triazoles, which allowed the efficient diastereoselective construction of various functionalized and synthetically challenging bridged ring systems. This simple, direct transformation had a broad substrate scope and excellent functional group tolerance. The highly strained polycyclic bicyclo[2.2.2]octa[b]indole core of fruticosine was synthesized efficiently using this methodology.

Asymmetric Total Synthesis of Taxol.

Taxol is one of the most famous natural diterpenoids and an important anticancer medicine. Taxol represents a formidable synthetic challenge and has prompted significant interest from the synthetic community. However, in all the previous syntheses of Taxol, there have been no reports of closing the desired eight-membered ring through C1-C2 bond formation. Furthermore, the existence of Taxol-resistant tumors and side effects of Taxol make the development of new approaches to synthesize Taxol and its derivatives highly desirable. Here, we report the asymmetric total synthesis of Taxol using a concise approach through 19 isolated intermediates. The synthetically challenging eight-membered ring was constructed efficiently by a diastereoselective intramolecular SmI2-mediated pinacol coupling reaction to form the C1-C2 bond. The unique biomimetic oxygen ene reaction and the newly developed facile tandem C2-benzoate formation and C13 side chain installation improved the efficiency of the synthesis. The mild oxygen ene reaction under light conditions would be an alternative reaction involved in Taxol biosynthesis. This new convergent approach will allow the diverse creation of Taxol derivatives to enable further biological research.

Synthesis of the Bridged [5-7-7] Tricyclic Core of Eurifoloid A.

We herein describe a new approach for the efficient and asymmetric construction of the tricyclic core of eurifoloid A, which possesses a unique and highly strained bicyclo[4.4.1] ring system. A rhodium-catalyzed intramolecular [3 + 2] dipolar cycloaddition was developed to install synthetically challenging bridged bicyclo[4.3.1] ring systems. The reported chemistry shows the feasibility of constructing the eurifoloid A framework using a diastereoselective intramolecular [3 + 2] cycloaddition and a ring enlargement.

Facile generation of bridged medium-sized polycyclic systems by rhodium-catalysed intramolecular (3+2) dipolar cycloadditions.

Bridged medium-sized bicyclo[m.n.2] ring systems are common in natural products and potent pharmaceuticals, and pose a great synthetic challenge. Chemistry for making bicyclo[m.n.2] ring systems remains underdeveloped. Currently, there are no general reactions available for the single-step synthesis of various bridged bicyclo[m.n.2] ring systems from acyclic precursors. Here, we report an unusual type II intramolecular (3+2) dipolar cycloaddition strategy for the syntheses of various bridged bicyclo[m.n.2] ring systems. This rhodium-catalysed cascade reaction provides a relatively general strategy for the direct and efficient regioselective and diastereoselective synthesis of highly functionalized and synthetically challenging bridged medium-sized polycyclic systems. Asymmetric total synthesis of nakafuran-8 was accomplished using this method as a key step. Quantum mechanical calculations demonstrate the mechanism of this transformation and the origins of its multiple selectivities. This reaction will inspire the design of the strategies to make complex bioactive molecules with bridged medium-sized polycyclic systems.

Synthesis of natural products containing highly strained trans-fused bicyclo[3.3.0]octane: historical overview and future prospects.

Owing to high strain energy, molecules with trans-fused bicyclo[3.3.0]octane ring systems are very difficult to synthesize, and there are very few approaches to access them. Recently, a number of natural products with such ring systems have been made by the synthetic community. However, there has been no review in this field before. This review provides a systematic and comprehensive discussion on the synthesis of natural products containing trans-fused bicyclo[3.3.0]octanes and the historical context of this work. The prospects for future research in this field are also discussed. Covering the literature before 2021, this review aims to offer a helpful reference for total synthesis of highly strained natural products containing trans-fused bicyclo[3.3.0]octane ring systems.

Rhodomentosones A and B: Two Pairs of Enantiomeric Phloroglucinol Trimers from Rhodomyrtus tomentosa and Their Asymmetric Biomimetic Synthesis.

Rhodomentosones A and B (1 and 2), two pairs of novel enantiomeric phloroglucinol trimers featuring a unique 6/5/5/6/5/5/6-fused ring system were isolated from Rhodomyrtus tomentosa. Their structures with absolute configurations were elucidated by NMR spectroscopy, X-ray crystallography, and ECD calculation. The bioinspired syntheses of 1 and 2 were achieved in six steps featuring an organocatalytic asymmetric dehydroxylation/Michael addition/Kornblum-DeLaMare rearrangement/ketalization cascade reaction. Compounds 1 and 2 exhibited promising antiviral activities against respiratory syncytial virus (RSV).

Enantioselective Total Synthesis of Cerorubenic Acid-III via Type II [5+2] Cycloaddition Reaction.

The first enantioselective total synthesis of cerorubenic acid-III is described in detail. Different strategies and attempts, based on a type II [5+2] cycloaddition reaction, leading to the bicyclo[4.4.1] ring system with a strained bridgehead double bond, are depicted. Furthermore, sodium naphthalenide was found to be efficient in the chemoselective reduction of 8-oxabicyclo[3.2.1]octene, with three transformations completed in one operation. An unusual SN1 transannular cyclization reaction was applied to construct the synthetically challenging vinylcyclopropane moiety. This strategy enabled the total synthesis of cerorubenic acid-III in 19 steps.

Stable Axially Chiral Isomers of Arylnaphthalene Lignan Glycosides with Antiviral Potential Discovered from Justicia procumbens.

Arylnaphthalene lignans (ANLs) were known to have axial chirality due to the biphenyl skeleton with hindered rotation at the single bond. However, the stable ANL atropisomers have not been isolated from nature until the present study. Phytochemical separation of the methanol extract of the stems and barks of Justicia procumbens led to the isolation of 11 ANL glycosides including four pairs of new atropisomers with stable confirmations at room temperature. Their structures were deduced from elucidation of the extensive spectral data, and their absolute configurations were determined by the circular dichroism, electronic circular dichroism, and X-ray methods as well as the total synthesis of one pair of the atropisomers. The ANL compounds were evaluated for their antiviral potential, and it was found that they displayed great antiviral activity discrepancy between a pair of atropisomers due to the geometric orientation. The 1'P-oriented atropisomers showed much more significant antiviral potency than their corresponding 1'M-oriented counterparts. The biological activity discrepancy caused by the axial chirality will not only inspire synthetic design of novel ANL atropisomers to enrich the structural diversity, but also provide important hints to direct the synthetic approaches toward the antiviral drug development of ANL compounds.

Recent advances in total syntheses of natural products containing the benzocycloheptane motif.

Covering: 2010 to 2020Benzocycloheptane is a fundamental and unique structural motif found in pharmaceuticals and natural products. The total syntheses of natural products bearing the benzocycloheptane subunit are challenging and there are only a few efficient approaches to access benzocycloheptane. Thus, new methods and innovative strategies for preparing such natural products need to be developed. In this review, recent progress in the total syntheses of natural products bearing the benzocycloheptane motif is presented, and key transformations for the construction of benzocycloheptane are highlighted. This review provides a useful guide for those engaged in the syntheses of natural products containing the benzocycloheptane motif.