Stereoselective Total Synthesis Research Articles

Synthetic Studies of the Rubellin Natural Products: Development of a Stereoselective Strategy and Total Synthesis of (+)-Rubellin C.

This manuscript describes our studies of the class of natural products known as the rubellins, culminating in the total synthesis of (+)-rubellin C. These anthraquinone-based natural products contain a variety of stereochemical and architectural motifs, including a 6-5-6-fused ring system, 5 stereogenic centers, and a central quaternary center. Herein, we report our development of a strategy to target the stereochemically dense core and anthraquinone nucleus, including approaches such as a bifunctional allylboron and vinyl triflate reagent, an anthraquinone benzylic metalation strategy, and a late-stage anthraquinone introduction strategy. Our studies culminate in a successful route to highly functionalized anthraquinone-based natural product scaffolds and a stereoselective total synthesis of (+)-rubellin C. These strategies and outcomes will aid in synthetic planning toward anthraquinone-based natural products of high interest.

Stereodivergent Total Syntheses of (+)‐Monomorine I and (+)‐Indolizidine 195B

AbstractA simple and efficient stereoselective total syntheses of two natural products (+)‐monomorine I and (+)‐indolizidine 195B in high yields starting from a readily available alcohol is described. The key step in this synthetic route exploits the judicious use of solvent to enable a closed or open transition state in a nucleophilic addition of Grignard reagent to sulfinimine, giving selective access to two distinct diastereomers required for the formation of the two target natural products.

Total Synthesis of the Proposed Structure of Uncarialin A.

The stereoselective total synthesis of the proposed structure of a potent serotonin 5-HT1A receptor agonist uncarialin A (1) is described. By employing the readily available meroquinene tert-butyl ester as the chiral synthon, the target structure has been prepared in a six-step linear sequence with a 17% overall yield. In comparison to the sample isolated from natural sources, the synthetic product shows significant spectral differences, strongly suggesting that the structure of the natural product should be revised.

Stereoselective Total Synthesis of Siladenoserinols A and D.

The stereoselective total synthesis of siladenoserinols A and D has been accomplished using carbohydrate as a chiral template. The feature of this work is to build the medicinally privileged 6,8-DOBCO scaffold through a cascade reaction of hydrogenation/deacetalization/ketalization in a one-pot process, that is, to take advantage of a thermodynamically controlled bicyclization of polyhydroxyketone under HCl/MeOH reaction conditions. The current cost-effective synthetic strategy could facilitate the bioactivity investigation of siladenoserinols.

1-Alkoxyvinyl Ester as an Excellent Acyl Donor: Efficient Macrolactone Synthesis.

Ketene acetal derivatives, such as 1-alkoxyvinyl esters and O-silyl ketene acetals, belong to the category of O-substituted enols of esters, which easily react with various types of nucleophiles, Nu-H, under neutral conditions to give the corresponding acylated and silylated products in excellent yields only by evaporation of the generated volatile esters. Silyl ketene acetals can be easily synthesized by various simple procedures, whereas 1-alkoxyvinyl esters require an equimolar or catalytic amount of a mercury salt to synthesize them. This drawback prevented the advancement of the chemistry of 1-alkoxyvinyl esters. In 1993, we developed a useful synthetic method of 1-alkoxyvinyl esters using a small amount (0.5-1 mol %) of a ruthenium catalyst. Encouraged by this discovery, we subsequently developed various reactions and applied them to the synthesis of natural products. It is noteworthy that the stereoselective total synthesis of fredericamycin A was achieved by the combined use of these reactions. Macrocyclization was variously utilized for the synthesis of natural macrolides by two types of approaches: direct macrolactonization of α,ω-hydroxy acids or intermolecular esterification between an acid and alcohol followed by a ring-closure step. Additionally, several new reactions using 1-alkoxyvinyl esters or their analogs as key intermediates on the basis of our methods were recently reported. In this paper, we introduce our efforts from the synthesis of 1-alkoxyvinyl esters to the application such as natural product syntheses and recent advancements.

Synthetic Studies toward Leucosceptroid Family of Natural Products.

Leucosceptroids are sesterterpenoids with potent antifeedant and antifungal activities. In this paper, efforts on two synthetic strategies toward stereoselective total synthesis of the leucosceptroid family of natural products are reported. Intramolecular addition cyclization strategy could lead to a stereochemically mismatched core structure, while intermolecular addition/ring-closing metathesis cyclization strategy successfully furnished an advanced common intermediate bearing eight contiguous stereogenic centers, including three tetra-substituted ones, which fully matches all the stereochemistry on the tricyclic framework in leucosceptroid H. Late-stage transformation of this intermediate to leucosceptroid H encountered difficulty in oxidizing the secondary hydroxyl group to a carbonyl group in the target. Instead of the desired oxidation, an interesting tricyclic spiral product originating from a C-C bond cleavage was observed.

Stereoselective total synthesis of (±)-vindeburnol and (±)-16-epi-vindeburnol.

A concise stereoselective total synthesis of (±)-vindeburnol and its epimer (±)-16-epi-vindeburnol is presented. This synthetic work features the utilization of Baeyer-Villiger oxidation to install different types of lactone substrate, and a sequence of aminolysis, aldimine condensation and acyl-Pictet-Spengler to deliver the crucial trans-fused indoloquinolizidine scaffold with high-level diastereocontrol.

Stereoselective total synthesis of obolactones and 7′,8′-dihydroobolactones

A concise stereoselective total synthesis of two diastereomeric obolactones and 7′,8′-dihydroobolactones has been achieved using a metal-free catalytic δ-hydroxyalkynone rearrangement and ring-closing metathesis.

Asymmetric Synthesis of Catechol Pyran Isolated from Plectranthus sylvestris by δ‐Hydroxyalkynone Rearrangement

AbstractA highly efficient atom‐economic and metal‐free rearrangement of δ‐hydroxyalkynone to 2,3‐dihydro‐4H‐pyran‐4‐one‐based strategy has been employed in the stereoselective total synthesis of either enantiomers of catechol pyran natural product isolated from Plectranthus sylvestris. The desired δ‐hydroxyalkynone substrates for rearrangement were prepared via the enantioselective Jacobsen kinetic resolution and the rearrangement was effected with cheaply available Brønsted acid para‐toluene sulfonic acid (p‐TsOH at 10 mol%). The strategy is concise and easily adoptable for synthesis of various 4‐hydroxy or 4‐keto‐2,6‐disubstituted pyran‐based natural products.

First stereoselective total synthesis of (−)-Inohanalactone

The first stereoselective total synthesis of (−)-Inohanalactone is reported. The salient features of this synthesis are highly Z-selective Wittig olefination and chemoselective oxidation of 1,4 diol to the γ-butyrolactone. The synthesis was accomplished from readily available 2,3-O-isopropylidene-l-erythrose derived from d-ribose in eight steps with 32% overall yield.

First Stereoselective Total Synthesis of Modiolin

The first stereoselective total synthesis of the linear pentaketide Modiolin has been performed via Jacobsen’ hydrolytic kinetic resolution and 2C-Wittig homologation as key steps.

Total Synthesis of Surinamensinols A and B

AbstractAn efficient total synthesis of the naturally occurring anti-inflammatory and antitumour 8-O-4′-neolignans, surinamensinols A and B, has been accomplished from commercially available allyl alcohol and (S)-ethyl lactate. The synthetic sequence involves a palladium-catalysed Suzuki–Miyaura cross-coupling reaction followed by a chiral Mitsunobu­ reaction as the key steps. This is the first report of the simultaneous stereoselective total synthesis of surinamensinols A and B through a single approach involving only six steps.

Stereoselective total synthesis of diplodialide A

An efficient stereoselective total synthesis of Diplodialide A has been achieved from inexpensive and commercially available starting material (R)-propylene oxide. This linear synthesis utilizes Wittig reaction, alkylation of 1,3-dithiane and Yamaguchi macrolactonization as key steps.

Stereoselective total synthesis of (S)- and (R)-nuciferine using benzyne chemistry

Total syntheses of (S)- and (R)-nuciferine were accomplished through approach involving diastereoselective reaction between a chiral dihydroisoquinoline enamide and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate promoted by CsF, affording a separable mixture of diastereoisomers, which provided (S)- and (R)-nuciferine via simple and efficient transformations.

Synthetic Study on Lactonamycins, Part 2: Stereoselective Access to ABCD-Ring System

Toward a stereoselective total synthesis of the lactonamycins, we recently reported an approach to the DEF-ring system. Here we report a model study for constructing the ABCD-ring system, revealing a viable approach through (1) construction of the C-ring by asymmetric benzoin cyclization, (2) introduction of an angular hydroxy group through oxidation of an isoxazolium salt, and (3) construction of the AB rings through a ring-opening/closing sequence.

An Improved First‐Generation Synthesis of ent‐Oxycodone

AbstractAn improvement in the stereoselective total synthesis of unnatural (+)‐oxycodone from phenethyl acetate is described. The total step count was reduced by conducting some chemical transformations in “one‐pot” and a change in the sequence of chemical operations was implemented, in comparison with the previously published first‐generation synthesis. The synthesis of (+)‐oxycodone was completed in a total of 12 operations (17 steps) and an overall yield of 1.6%, in comparison to our previous synthesis (13 operations, 19 steps, 1.5% yield) Experimental and spectral data are provided for all new compounds.

Enantioselective Total Syntheses of (-)-20-epi-Vincamine and (-)-20-epi-Eburnamonine by Ir-Catalyzed Asymmetric Imine Hydrogenation/Lactamization Cascade.

The Eburnamine-Vincamine alkaloids have been studied intensively over the past six decades for their outstandingly potent vasorelaxation activity. Stereocontrolled assembly of the C20/C21 adjacent chiral centers has been a formidable challenge in the synthesis of this family. Herein, we report a concise stereoselective total synthesis of two trans-ring-fused non-natural analogues, (-)-20-epi-Vincamine and (-)-20-epi-Eburnamonine, that features the following key steps: a) a continuous-flow oxidation/lactam alcoholysis cascade producing the symmetrical dihydro-β-carboline diester precursors, and b) a highly stereoselective Ir/f-Binaphane-catalyzed hydrogenation/lactamization cascade leading to the privileged trans-(20R, 21S) lactam ester scaffold with high-level enantio- and diastereocontrol.

Stereoselective total synthesis of all the stereoisomers of (+)- and (−)-febrifugine and halofuginone

A convenient method for the total synthesis of all the stereoisomers of febrifugine and halofuginone using D-arabinose and L-arabinose as the key starting materials is reported. Apart from the inherent stereocenters in these pentose sugars, the method utilizes the selective hydrogenolysis of the anomeric O-benzyl group, stereoselective Grignard reaction and Wacker oxidation as the key steps to obtain the important precursors for the total synthesis.

Stereoselective total synthesis of (−)-galantinic acid and 1-deoxy-5-hydroxysphingolipids via prins cyclization

The stereoselective total synthesis of (−)-galantinic acid 1 and 1-deoxy-5-hydroxysphingolipids 4 is described via Prins cyclization protocol followed by reductive ring opening sequence of substituted pyrenol derivative 6. The target molecules were synthesized using a common synthetic intermediate epoxide 5. Besides, we also proposed synthetic pathways to achieve other structural analogues using common intermediates.

Recent Advances in the Stereoselective Total Synthesis of Natural Pyranones Having Long Side Chains.

Pyranone natural products have attracted great attention in recent years from chemists and biologists due to their fascinating stereoisomeric structural features and impressive bioactivities. A large number of stereoselective total syntheses of these compounds have been described in the literature. The natural pyranones with long side chains have recently received significant importance in the synthetic field. In the present article, we aim to review the modern progress of the stereoselective total syntheses of these natural pyranones containing long-chain substituents.