Et3Al/Light-Promoted Radical-Polar Crossover Reactions of α-Alkoxyacyl Tellurides.

Here, we report new radical-polar crossover reactions of α-alkoxy carbon radicals for constructing highly oxygenated molecules with contiguous stereocenters. The method employs a 370 nm UV light-emitting diode (LED) for the photoexcitation of α-alkoxyacyl telluride, and Et3Al as the radical initiator and terminator. First, Et3Al and UV LED promoted radical coupling between the α-alkoxyacyl telluride and cyclopentenone via C-Te bond homolysis, CO expulsion, and C-C bond formation. Second, Et3Al converted the radical species to the corresponding aluminum enolate. Third, the second C-C bond formation occurred via a polar mechanism: intermolecularly with aldehydes/ketones and intramolecularly with epoxide, producing aldol and SN2 adducts, respectively. The present coupling reactions increase the molecular complexity in a single step by stereoselective formation of the two hindered C-C bonds. The devised method is expected to be useful for the expeditious assembly of densely oxygenated natural products.

Total Syntheses of Hikosamine and Hikizimycin.

Hikizimycin (1) is a potent anthelmintic and antibacterial natural product. The core 4-amino-4-deoxyundecose sugar (hikosamine) of 1 consists of an 11-carbon linear chain substituted with one amino group and 10 hydroxy groups. The C1 and C6O positions of the 10 contiguous stereocenters are further appended by a cytosine base and a 3-amino-3-deoxyglucose sugar (kanosamine), respectively. Since the structural determination in the early 1970s, synthetic chemists have been attracted by this exceedingly complex structure and have investigated the full chemical construction of 1. These synthetic efforts culminated in four syntheses of the protected hikosamines and two total syntheses of 1. In this Perspective, we summarize the strategies and tactics utilized in these syntheses to showcase the evolution of modern natural product synthesis.

A new anti-austerity agent, 4'-O-methylgrynullarin from Derris scandens induces PANC-1 human pancreatic cancer cell death under nutrition starvation via inhibition of Akt/mTOR pathway.

An ethanolic extract of Derris scandens flowers showed potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrient-deprived condition, with a PC50 value of 0.7 µg/mL. Phytochemical investigation of this active extract led to the isolation of four prenylated isoflavones (1-4) including a new compound named 4'-O-methylgrynullarin (1). The structure elucidation of the new compound was achieved by HRFABMS and NMR spectroscopic analysis. The isolated compounds exhibited potent anti-austerity activity against four different human pancreatic cancer cell lines under nutrient-deprived conditions. The new compound 4'-O-methylgrynullarin (1) was also found to inhibit PANC-1 cell migration and colony formation under nutrient-rich condition. Mechanistically, compound 1 inhibited key survival proteins in the Akt/mTOR signaling pathway. Therefore, 4'-O-methylgrynullarin (1) can be considered as a potential lead compound for the anticancer drug development based on the anti-austerity strategy.

Convergent Total Synthesis of Hikizimycin Enabled by Intermolecular Radical Addition to Aldehyde.

Hikizimycin (1), which exhibits powerful anthelmintic activity, has the most densely functionalized structure among nucleoside antibiotics. A central 4-amino-4-deoxyundecose of 1 possesses 10 contiguous stereocenters on a C1-C11 linear chain and is decorated with a cytosine base at C1 and a 3-amino-3-deoxyglucose at C6-OH. These distinctive structural features of 1 make it an extremely challenging target for de novo construction. Herein, we report a convergent total synthesis of 1 from four known components: 3-azide-3-deoxyglucose derivative 4, bis-TMS-cytosine 5, d-mannose 9, and d-galactose derivative 10. We first designed and devised a novel radical coupling reaction between multiply hydroxylated aldehydes and α-alkoxyacyl tellurides. The generality and efficiency of this process was demonstrated by the coupling of 7c and 8, which were readily accessible from two hexoses, 9 and 10, respectively. Et3B and O2 rapidly induced decarbonylative radical formation from α-alkoxyacyl telluride 8, and intermolecular addition of the generated α-alkoxy radical to aldehyde 7c yielded 4-amino-4-deoxyundecose 6-α with installation of the desired C5,6-stereocenters. Subsequent attachments of the cytosine with 5 and of the 3-azide-3-deoxyglucose with 4 were realized through selective activation of the C1-acetal and selective deprotection of the C6-hydroxy group. Finally, the 3 amino and 10 hydroxy groups were liberated in a single step to deliver the target 1. Thus, the combination of the newly developed radical-coupling and protective-group strategies minimized the functional group manipulations and thereby enabled the synthesis of 1 from 10 in only 17 steps. The present total synthesis demonstrates the versatility of intermolecular radical addition to aldehyde for the first time and offers a new strategic design for multistep target-oriented syntheses of various nucleoside antibiotics and other bioactive natural products.

The Total Synthesis of Chalcitrin.

The first total synthesis of the yellow pigment chalcitrin, a structurally distinct pulvinic acid dimer obtained from Chalciporous piperatus, has been achieved in 17 linear steps from commercially available materials. Key elements of the design include the use of a Au(I)-catalyzed Conia ene reaction and an N-heterocyclic carbene-mediated acyloin addition to rapidly fashion its unique polycyclic core, with the two high oxidation state side chains introduced in a single step via a late-stage double Stille coupling. Of note, many alternate designs based on differential final couplings failed, likely because of the hindered nature of the core. In addition, significant challenges in final natural product characterization in terms of matching NMR spectra were experienced; our studies reveal that the originally characterized material was its carboxylate salt form not its free acid.

Unified Total Synthesis of Polyoxins†J, L, and Fluorinated Analogues on the Basis of Decarbonylative Radical Coupling Reactions.

Polyoxins J (1 a) and L (1 b) are important nucleoside antibiotics. The complex and densely functionalized dipeptide structures of 1 a and 1 b contain thymine and uracil nucleobases, respectively. Herein we report the unified total synthesis of 1 a, 1 b, and their artificial analogues 1 c and 1 d with trifluorothymine and fluorouracil structures. Decarbonylative radical coupling between α-alkoxyacyl tellurides and a chiral glyoxylic oxime ether led to chemo- and stereoselective construction of the ribonucleoside α-amino acid structures of 1 a-d without damaging the preinstalled nucleobases. The high applicability of the radical-based methodology was further demonstrated by preparation of the trihydroxynorvaline moiety of 1 a-d. The two amino acid fragments were connected and elaborated into 1 a-d (longest linear sequence: 11 steps). Compounds 1 a and 1 b assembled in this way exhibited potent activity against true fungi, while only 1 d was active against Gram-positive bacteria.

Decarbonylative radical coupling of α-aminoacyl tellurides: single-step preparation of γ-amino and α,ß-diamino acids and rapid synthesis of gabapentin and manzacidin†A.

A new radical-based coupling method has been developed for the single-step generation of various γ-amino acids and α,ß-diamino acids from α-aminoacyl tellurides. Upon activation by Et3 B and O2 at ambient temperature, α-aminoacyl tellurides were readily converted into α-amino carbon radicals through facile decarbonylation, which then reacted intermolecularly with acrylates or glyoxylic oxime ethers. This mild and powerful method was effectively incorporated into expeditious synthetic routes to the pharmaceutical agent gabapentin and the natural product (-)-manzacidin A.

Et3 B/Et2 AlCl/O2 -Mediated Radical Coupling Reaction between α-Alkoxyacyl Tellurides and 2-Hydroxybenzaldehyde Derivatives.

A newly devised radical-based strategy enabled coupling between multiply oxygenated α-alkoxyacyl tellurides and 2-hydroxybenzaldehyde derivatives. A reagent combination of Et3 B, Et2 AlCl, and O2 promoted the formation of the α-alkoxy carbon radical from the α-alkoxyacyl telluride and the addition of the radical to the carbonyl group of 2-hydroxybenzaldehyde. The reaction chemo- and stereoselectively forged the hindered C-C bond between two oxygen-functionalized carbons at ambient temperature. The method was applied to the preparation of 12 coupling adducts with three to six contiguous stereocenters and to the concise synthesis of an antitumor compound, LLY-283.