A Convenient Large Scale Synthesis of 2-Hydroxy-3-pinanone

A convenient large scale synthesis of 2-hydroxy-3-pinanone from readily available α-pinene has been developed. This two step method involves the diastereoselective dihydroxylation of α-pinene and subsequent oxidation of pinanediol to the hydroxyketone. The key advantages of this method, which allows access to large quantities of this important chiral auxiliary, are high yield and ease of operation.     

An Enantiospecific Synthesis of Jiadifenolide

A Robinson annulation, van Leusen homologation, and a desymmetrizing C? H oxidation enabled an enantiospecific synthesis of the neurotrophic natural product jiadifenolide. From a pulegone‐derived building block, a key propellane intermediate was constructed through the use of simple reagents in a highly diastereoselective fashion. A short series of oxidations of this tricylic framework allowed progression to the natural product.     

Synthesis of 7-oxa-phomopsolide E and its C-4 epimer

A flexible, enantioselective route to highly functionalized α,β-unsaturated δ-lactones has been applied to the synthesis of 7-oxa-phomopsolide E and its C-4 epimer. This approach relies on the application of the Noyori asymmetric hydrogenation of furyl ketone to produce the secondary furyl alcohol in high enantioexcess, which can be stereoselectively transformed into α,β-unsaturated-δ-lactones by a short, highly diastereoselective oxidation and reduction sequence. DCC and Mitsunobu coupling were used to introduce the side chains of the two natural product analogs.     

Stereoselective synthesis of (−)-centrolobine

The stereoselective synthesis of (−)-centrolobine has been accomplished starting from d-glyceraldehyde acetonide by a combination of chelation-controlled diastereoselective alkylation and ring-closing metathesis. A high degree of 1,3-asymmetric induction has been realized in an ether system.     

Diastereoselective Synthesis of Novel Benzofuran Derivatives by Euparin as a Natural Compound with DMAD in the Presence of Trialkyl Phosphite

An efficient, simple, and diastereoselective synthesis of novel benzofuran phosphonato ester derivatives has been achieved via a one‐pot three‐component reaction of euparin as a natural product, trialkyl phosphate, and dimethyl acetylenedicarboxylate (DMAD) in diethyl ether without using any catalyst at room temperature. NMR spectroscopic data and X‐ray crystallography analysis are in agreement with the anti arrangement for the two vicinal protons in the structures, and only one diastereoisomer (2S,3R) or (2R,3S) was obtained for the products. The advantage of our research is that this is the first report for the diastereoselective synthesis of phosphonato ester derivatives from a green natural product. This one‐pot reaction occurs in high yields with easy work‐up under mild conditions. All pure products were obtained by recrystallization from ethanol, and there was no need for column chromatography.     

Single‐Electron/Pericyclic Cascade for the Synthesis of Dienes

The highly efficient and diastereoselective synthesis of E dienes has been accomplished through radical cyclization of bromoallyl hydrazones. This methodology has been further extended to generate these products through a one‐pot condensation/radical cyclization/cycloreversion cascade from simple aldehyde starting materials in high yields (>75 %) and high diastereoselectivities (>95:5). Mechanistic investigations suggest that the cascade reaction proceeds through a cyclic diazene intermediate prior to the cycloreversion.     

Synthesis of (+)-1-epiaustraline

A highly efficient total synthesis of (+)-1-epiaustraline ((+)-1), a tetrahydroxypyrrolizidine alkaloid of the alexine/australine subclass, is described. The key step is a tandem intramolecular [4 + 2]/intermolecular [3 + 2] nitroalkene cycloaddition involving dienylsilyloxy nitroalkene 3 and chiral vinyl ether 4, which establishes four of the five stereocenters present. The final center was installed by a diastereoselective dihydroxylation. Hydrogenolytic unmasking of the nitroso acetal tosylate 17 containing the silyl ether linkage was thwarted by a slow alkylation and an undesired Peterson-type elimination. Prior removal of the silicon moiety by Tamao-Fleming oxidation proceeded in excellent yield and provided a substrate suitable for hydrogenolysis and deprotection. The complete synthesis required only 10 steps to deliver the (+)-1-epiaustraline in 7.0% overall yield.     

Total Synthesis of Metaphanine and Oxoepistephamiersine

Herein, we report a concise and divergent synthesis of the complex hasubanan alkaloids metaphanine and oxoepistephamiersine from commercially available and inexpensive cyclohexanedione monoethylene acetal. Our synthesis features a palladium-catalyzed cascade cyclization reaction to set the tricyclic carbon framework of the desired molecules, a regioselective Baeyer–Villiger oxidation followed by a MeNH₂ triggered skeletal reorganization cascade to construct the benzannulated aza[4.4.3]propellane, and a strategically late-stage regio-/diastereoselective oxidative annulation of sp³ C−H bond to form the challenging THF ring system and hemiketal moiety in a single step. In addition, a highly enantioselective alkylation of cyclohexanedione monoethylene acetal paved the way for the asymmetric synthesis of target molecular.     

Enantioselective Total Synthesis of Cymoside through a Bioinspired Oxidative Cyclization of a Strictosidine Derivative

The first total synthesis of the caged monoterpene indole alkaloid cymoside is reported. This natural product displays a unique hexacyclic‐fused skeleton whose biosynthesis implies an early oxidative cyclization of strictosidine. Our approach to the furo[3,2‐b]indoline framework relied on an unprecedented biomimetic sequence which started by the diastereoselective oxidation of the indole ring into a hydroxyindolenine which triggered the addition of an enol ether and was followed by the trapping of an oxocarbenium intermediate.     

The first total synthesis of (+/-)-ingenol

The first total synthesis of (+/-)-ingenol has been achieved. The key features of the synthesis include the use of a highly diastereoselective Michael reaction to fix the C-11 methyl stereochemistry and the incorporation of the dimethylcyclopropane via diastereoselective carbene addition to the Delta13,14 olefin. The intramolecular dioxenone photoaddition-fragmentation sequence leads to the establishment of the critical C-8/C-10 trans intrabridgehead stereochemistry, a central challenge in the synthesis of ingenanes. The completion of the synthesis proceeds using the C-6alpha hydroxymethyl group as the sole handle for oxidation of seven contiguous carbon centers.     

Natural p‐Menthene Monoterpenes: Synthesis of the Enantiomeric Forms of Wine Lactone,Epi‐wine Lactone,Dill Ether,and Epi‐dill Ether Starting from a Common Intermediate

A concise synthesis of the enantiomeric forms of wine lactone ( 5 ), epi‐wine lactone ( 14 ), dill ether ( 6 ), and epi‐dill ether ( 15 ) was accomplished starting from the enantiomeric forms of p‐mentha‐1,8(10)‐diene‐3,9‐diol ( 8 ) (Scheme 3). The latter compounds were previously prepared in high optical purity by means of lipase‐mediated kinetic resolution, and they were the common building blocks for this divergent synthesis. The key steps were a number of chemo‐ and diastereoselective reactions of which the oxidation of 8 to the lactone 7 (see Table 1), the diastereoselective reduction of 7 to the lactones 14 and 5 (see Table 2), and the reduction of enol‐ether 16 to ether 15 were studied comprehensively. The effectiveness of this new synthetic approach allows the preparation of the title p‐menthane monoterpenes, which are of considerable interest to the perfume industry, in high yield and in a few simple experimental steps.     

Utilization of 1-oxa-2,2-(dimesityl)silacyclopentane acetals in the stereoselective synthesis of polyols

We have developed a route for the stereoselective synthesis of 1-oxa-2,2-(dimesityl)silacyclopentane acetals, intermediates in the synthesis of highly functionalized 1,3-diols. This route involves a diastereoselective conjugate addition reaction of a hydrosilyl anion, a subsequent diastereoselective enolate alkylation, and a fluoride-catalyzed intramolecular hydrosilylation reaction to afford the oxasilacyclopentane acetal. A highly selective nucleophilic substitution reaction, followed by oxidation of the C-Si bond, leads to the desired polyol.     

Enantioselective Syntheses of Rigidiusculamides A and B: Revision of the Relative Stereochemistry of Rigidiusculamide A

The first enantioselective synthesis of cytotoxic natural products rigidiusculamides A (ent‐ 21 ) and B ( 8 ) has been achieved by two synthetic routes. The first one is convergent based on the common intermediate 11 , obtained through a high yielding SmI₂‐mediated Reformatsky‐type reaction. A highly diastereoselective one‐pot Dess–Martin periodinane‐mediated bis‐oxidation allowed the direct conversion of the diastereomeric mixture of 11 into rigidiusculamide B ( 8 ). Isolation of minor diastereomer 21 , in combination with computational work, allowed us to suggest the structure of the natural rigidiusculamide A to be 21 , as synthesized by the second route. Four diastereomers ( 7 , 7 , 22a , and 22b ) and an enantiomer ( 21 ) of rigidiusculamide A ( 21 ) have been synthesized. On the basis of literature precedents and computational work, a biosynthetic pathway for rigidiusculamides A and B was proposed to account for the opposite configuration at C‐5 of those two congeners.     

Formal Total Synthesis of Fostriecin by 1,4‐Asymmetric Induction with an Alkyne–Cobalt Complex

The synthesis of a protected dephosphofostriecin, and thereby a formal synthesis of fostriecin, has been accomplished. The synthetic challenges were the construction of four stereogenic centers and the conformationally labile cis‐cis‐trans‐triene moiety. Previous total syntheses have employed at least two asymmetric reactions that required the use of an external chiral auxiliary. Although remote stereoinduction in a 1,4‐relationship is considered difficult, we have developed a notable 1,4‐asymmetric induction that utilizes an alkyne–cobalt complex for the control of C5 stereochemistry by the C8 stereogenic center. The stereochemistry at C11 was established by 1,3‐asymmetric induction with a higher‐order alkynyl‐zinc reagent. Thus, only one asymmetric reaction requiring an external chiral auxiliary was employed in this route. The labile cis‐cis‐trans‐triene unit was constructed at a late stage of the synthesis by diastereoselective coupling of a dienyne and an aldehyde unit, followed by reduction.     

Approach to the hyacinthacines: first non-chiral pool synthesis of (+)-hyacinthacine A1

The first non-chiral pool total synthesis of (+)-hyacinthacine A(1) is described. This synthesis is based on an effective [2 + 2] cycloaddition of dichloroketene to a Stericol-based enol ether, a diastereoselective dihydroxylation, and an efficient Tamao-Fleming oxidation.     

Stereoselective Total Synthesis of Eburnane‐Type Alkaloids Enabled by Conformation‐Directed Cyclization and Rearrangement

Controlling the cis C20/C21 relative stereochemistry remains an unsolved issue in the synthesis of eburnane‐type indole alkaloids. Provided herein is a simple solution to this problem by developing a unified and diastereoselective synthesis of four representative members of this class of natural products, namely, eburnamonine, larutensine, terengganensine B, and melokhanine E. The synthesis features the following key steps: a) an α‐iminol rearrangement transforming the 3‐hydroxyindolenine into spiroindolin‐3‐one, b) a highly diastereoselective conformation‐directed cyclization leading to the melokhanine skeleton with the desired C20/C21 cis stereochemistry, and c) either an aza‐pinacol or an unprecedented α‐aminoketone rearrangement converting spiroindolinone back into the indole skeleton.     

Development of the enantioselective addition of ethyl diazoacetate to aldehydes: asymmetric synthesis of 1,2-diols

A novel synthetic strategy toward the asymmetric synthesis of vicinal diols bearing a tertiary center is presented. The method encompasses the dinuclear Mg-catalyzed asymmetric addition of ethyl diazoacetate into several aldehydes, oxidation of the diazo functionality, and diastereoselective alkyl transfer of various organometallics into the resulting chiral β-hydroxy-α-ketoesters to afford a diverse range of 1,2-diols in high yield, diastereoselectivity, and chirality transfer.     

Synthesis and stereoselective oxidation of α-thio-β-chloropropenyloxazolidin-2-ones

The investigation of the stereoselective reaction of α-thiopropanoyloxazolidin-2-ones with NCS to yield α-thio-β-chloropropenyloxazolidin-2-ones is described. Diastereoselective sulfur oxidation of the resulting α-thio-β-chloropropenyloxazolidin-2-ones shows modest diastereocontrol. However, via a combination of diastereoselective oxidation and subsequent kinetic resolution in the sulfoxide oxidation, diastereoselectivities of up to 94% de have been achieved.     

Synthesis of Pyridines by Anodic Oxidation of 1,4-Dihydropyridines

Anodic oxidation of a series 1,4-dihydropyridines were performed in acetonitrile-tetrabutylammonium perchlorate electrolyte solution at platinum electrode using controlled potential electrolysis. On the bases of electroanalytical results the electrochemical oxidation mechanism of 1,4-dihydropyridines could be designed ECEC process. As a result of two-electron oxidation corresponding pyridines were obtained in yields ranging from 85%–92%. The advantages of electrochemical synthesis of pyridine derivatives are simple reaction condition, low cost and of high purity products.     

An Asymmetric Synthesis of Isoindolinones

Recently, the results from this laboratory showed that the reductive alkylation of protected (S)-malimide could be achieved in a high regio- and diastereoselective manner. The substituted 2-pyrrolidinones thus formed are versatile chiral building blocks which can be used in the asymmetric synthesis of pyrrolidines^[1,2],2-pyrrolidinones^[3,4] and β-hydroxy-γ-amino acids^[5,6]. As an extension of this work, and in combination with the current interest in the synthesis of isoindolin-1-ones, a study on the asymmetric reductive alkylation of phthalimide derived from (R)-phenylglycinol was undertaken.