Concise Total Synthesis of Nannocystin A

Nannocystin A, a structurally unique 21‐membered macrocyclic depsipeptide with low nanomolar inhibitory activity against elongation factor 1A, was synthesized according to a strategy involving the vinylogous Mukaiyama aldol reaction, Sharpless epoxidation, olefin metathesis, the Mitsunobu reaction, and a palladium‐catalyzed intramolecular Suzuki coupling of a highly complex cyclization substrate. The overall synthesis is efficient and paves the way for preparation of analogues for drug development efforts.     

Total Synthesis and Biological Evaluation of the Glycosylated Macrocyclic Antibiotic Mangrolide A

The macrocyclic antibiotic mangrolide A has been described to exhibit potent activity against a number of clinically important Gram‐negative pathogens. Reported is the first enantioselective total synthesis of mangrolide A and derivatives. Salient features of this synthesis include a highly convergent macrocycle preparation, stereoselective synthesis of the disaccharide moiety, and two β‐selective glycosylations. The synthesis of mangrolide A and its analogues enabled the re‐examination of its activity against bacterial pathogens, and only minimal activity was observed.     

Total Synthesis and Biological Evaluation of Siladenoserinol A and its Analogues

The total synthesis of siladenoserinol A, an inhibitor of the p53–Hdm2 interaction, has been achieved. AuCl₃‐catalyzed hydroalkoxylation of an alkynoate derivative smoothly and regioselectively proceeded to afford a bicycloketal in excellent yield. A glycerophosphocholine moiety was successfully introduced through the Horner–Wadsworth–Emmons reaction using an originally developed phosphonoacetate derivative. Finally, removal of the acid‐labile protecting groups, followed by regioselective sulfamate formation of the serinol moiety afforded the desired siladenoserinol A, and benzoyl and desulfamated analogues were also successfully synthesized. Biological evaluation showed that the sulfamate is essential for biological activity, and modification of the acyl group on the bicycloketal can improve the inhibitory activity against the p53–Hdm2 interaction.     

Conformation‐Enabled Total Syntheses of Ohmyungsamycins A and B and Structural Revision of Ohmyungsamycin B

The first total syntheses of the bioactive cyclodepsipeptides ohmyungsamycin A and B are described. Key features of our synthesis include the concise preparation of a linear cyclization precursor that consists of N‐methyl amides and non‐proteinogenic amino acids, and its macrolactamization from a bent conformation. The proposed structure of ohmyungsamycin B was revised based on its synthesis. The cyclic core of the ohmyungsamycins was shown to be responsible for the excellent antituberculosis activity, and ohmyungsamycin variants with truncated chains were evaluated for their biological activity.     

Total Synthesis and Biological Assessment of Mandelalide A

A new convergent total synthesis of the marine macrolide mandelalide A ( 1 ) has been developed that is based on macrocyclic ring closure by a Shiina‐type macrolactonization and the construction of the requisite precursor seco acid by a highly efficient Sonogashira cross‐coupling reaction between two fragments of comparable complexity. Key steps in the elaboration of the acid building block were the enantioselective, catalytic addition of a protected acetylene to crotonaldehyde and the construction of the tetrahydropyran unit that is embedded in the macrocycle by means of an acid‐catalyzed Prins reaction. The synthesis of the alcohol fragment features the formation of the trisubstituted tetrahydrofuran ring through an acetal cleavage/epoxide opening cascade reaction and a rarely used radical alkynylation of a primary alkyl iodide. Intriguingly, the dihydroxylation of a terminal double bond as part of the synthesis of this building block gave the same major product for both the α‐ and β‐AD‐mix reagents, albeit with moderate or low selectivity. Synthetic mandelalide A ( 1 ) was a potent proliferation inhibitor of A549, HT460, and H1299 human lung cancer cells in vitro, but not of SK‐N‐SH neuroblastoma cells. However, in no case did we observe complete cell kill even at the highest compound concentration tested (5 μm ).     

Total Synthesis and Biological Evaluation of Rakicidin A and Discovery of a Simplified Bioactive Analogue

We report a concise asymmetric synthesis of rakicidin A, a macrocyclic depsipeptide that selectively inhibits the growth of hypoxic cancer cells and stem‐like leukemia cells. Key transformations include a diastereoselective organocatalytic cross‐aldol reaction to build the polyketide portion of the molecule, a highly hindered ester fragment coupling reaction, an efficient Helquist‐type Horner—Wadsworth—Emmons (HWE) macrocyclization, and a new DSC‐mediated elimination reaction to construct the sensitive APD portion of rakicidin A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia‐selective activity.     

Synthesis and Biological Evaluation of Bromo‐ and Fluorodanicalipin A

We disclose the syntheses of (+)‐bromodanicalipin A as well as (±)‐fluorodanicalipin A. The relative configuration and ground‐state conformation in solution of both molecules was secured by J‐based configuration analysis which revealed that these are identical to natural danicalipin A. Furthermore, preliminary toxicological investigations suggest that the adverse effect of danicalipin A may be due to the lipophilicity of the halogens.     

A Total Synthesis of Norhalichondrin B

Four corners : The syntheses of four key building blocks for the total synthesis of norhalichondrin B (see structure) are described. The assembly of these subunits into the natural product is also reported. Key features of the synthesis are the use of the Achmatowicz oxidation/ionic hydrogenation for the synthesis of pyrans and pyranopyrans, and the application of tandem metathesis for the synthesis of pyranopyrans.

     

Solid‐phase Total Synthesis of (−)‐Apratoxin A and Its Analogues and Their Biological Evaluation

Two approaches for the solid‐phase total synthesis of apratoxin A and its derivatives were accomplished. In synthetic route A, the peptide was prepared by the sequential coupling of the corresponding amino acids on trityl chloride SynPhase Lanterns. After cleavage from the polymer‐support, macrolactamization of 10 , followed by thiazoline formation, provided apratoxin A. This approach, however, resulted in low yield because the chemoselectivity was not sufficient for the formation of the thiazoline ring though its analogue 33 was obtained. However, in synthetic route B, a cyclization precursor was prepared by solid‐phase peptide synthesis by using amino acids 13 – 15 and 18 . The final macrolactamization was performed in solution to provide apratoxin A in high overall yield. This method was then successfully applied to the synthesis of apratoxin analogues. The cytotoxic activity of the synthetic derivatives was then evaluated. The epimer 34 was as potent as apratoxin A, and O‐methyl tyrosine can be replaced by 7‐azidoheptyl tyrosine without loss of activity. The 1,3‐dipolar cycloaddition of 38 with phenylacetylene was performed in the presence of a copper catalyst without affecting the thiazoline ring.     

Total Synthesis of Hopeahainol A and Hopeanol

Similar, but different : Possessing almost the same but not identical structures, the recently discovered natural products hopeahainol A ( 1 ) and hopeanol ( 2 ) exhibit important but differing biological properties (see structures). Their first total synthesis has now been achieved through a series of novel cascade reactions and skeletal rearrangements.

     

Stereocontrolled Total Synthesis of Polygalolide A

The total synthesis of polygalolide A, a secondary metabolite that was isolated from a Chinese medicinal plant, is reported. A key issue in this synthesis was construction of an oxabicyclo[3.2.1] skeleton, which was solved by the development of an intramolecular Ferrier‐type C‐glycosylation of a glucal with siloxyfuran as an internal nucleophile. The substrate was prepared from D ‐glucal by the introduction of trimethylsilylacetylene and siloxyfuran groups. Although C‐glycosylation did not occur under the conditions found from model experiments, further examination revealed that the combination of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,4,6‐collidine successfully afforded the desired product as a single diastereomer. The siloxy group at the C3 position played a crucial role in the stereocontrol of this reaction. The product was further transformed into a tetracyclic compound as follows: The vinyl ether and acetylenic moieties were reduced and the siloxy group was removed with a Barton–McCombie reaction. The construction of the six‐membered ether and the γ‐lactone provided the tetracyclic compound. Finally, a phenolic moiety was introduced by using a Mukaiyama aldol reaction to furnish polygalolide A.     

Total Synthesis and Biological Evaluation of Heliolactone

Strigolactones are phytohormones, which affect diverse aspects of plant growth and development with potential application in modern agriculture. Recently, heliolactone has been isolated as a non‐canonical type of strigolactone from the root exudates of sunflower, and it could be involved in signaling in the rhizosphere as well as in planta. However, its biological activity is yet to be evaluated, due to its relative chemical instability and its low natural abundance. Herein, we describe the gram‐scale synthesis of heliolactone and its derivatives by using Stille cross‐coupling as the key bond‐forming reaction, and we disclose some of their biological activities (soil stability, binding ability to strigolactone receptor, corn germination, sunflower germination, Orobanche cumana germination and leaf senescence) in comparison with other canonical and non‐canonical strigolactones.     

Total Synthesis of Leucosceptroids A and B

Leucosceptroids A and B are sesterterpenoids with potent antifeedant and antifungal activities. A more efficient gram‐scale total synthesis of leucosceptroid B and the first total synthesis of leucosceptroid A are presented. The key transformations include an aldol reaction between a substituted dihydrofuranone and an (S)‐citronellal‐derived aldehyde, a SmI₂‐mediated intramolecular ketyl–olefin radical cyclization, and final‐stage alcohol oxidation.     

Total Synthesis of Diterpenoid Steenkrotin A

A concise and diastereoselective total synthesis of the diterpenoid (±)‐steenkrotin A is described for the first time. The strategy mainly features three key ring formations: 1) a rhodium‐catalyzed O? H bond insertion followed by an intramolecular carbonyl‐ene reaction to build up the tetrahydrofuran subunit; 2) sequential SmI₂‐mediated Ueno–Stork and ketyl–olefin cyclizations to construct the [5,7] spirobicyclic skeleton; and 3) an intramolecular aldol condensation/vinylogous retro‐aldol/aldol sequence to form the final six‐membered ring with inversion of the relative configuration at the C7 position.