A general synthetic approach to the amnesic shellfish toxins: total synthesis of (-)-isodomoic acid B, (-)-isodomoic acid E and (-)-isodomoic acid F

The alkynylpyrrolidine 4 was made via a dearomatising cyclisation of an aromatic amide, and was elaborated by stannylcupration and palladium-catalysed coupling to achieve the first total synthesis of three members of the isodomoic acid family; the same alkyne can be envisaged as a precursor to several more of this class of amnesic shellfish toxins.     

Total synthesis of (-)-tirandamycin C

Tirandamycin C is a newly isolated member of the tetramic acid family natural products. We described herein the first enantioselective synthesis of natural (-)-tirandamycin C, the postulated biosynthetic precursor of other members of this family. The highly stereoselective (>15:1) mismatched double asymmetric γ-stannylcrotylboration reaction of aldehyde 8 with crotylborane reagent (R)-E-9 was utilized to access the key anti,anti-stereotriad 18.     

Enantioselective synthesis of (-)-cis-clavicipitic acid

An enantioselective synthetic method for (-)-cis-clavicipitic acid (1) was reported. 1 was obtained in 10 steps (99% ee and 20% overall yield) from 1H-indole-3-carboxylic acid methyl ester (9) via asymmetric phase-transfer catalytic alkylation and diastereoselective Pd(II)-catalyzed intramolecular aminocyclization as key steps.     

Enantioselective synthesis of (-)-roccellaric acid

[reaction in text] A new strategy for the synthesis of anti-4,5-disubstituted gamma-butyrolactones starting from inexpensive furan-2-carboxylic methyl ester was developed. By applying this methodology, the enantioselective synthesis of (-)-roccellaric acid ((-)-17) was accomplished using a copper(I)-catalyzed asymmetric cyclopropanation, a tin(IV)-catalyzed retroaldol/lactonization sequence of cyclopropanols, and a ruthenium-catalyzed intermolecular metathesis reaction as key steps.     

Stereoselective synthesis of (-)-acanthoic acid

[reaction: see text] The first stereoselective synthesis of (-)-acanthoic acid (1) has been designed and accomplished. Our synthetic plan departs from (-) Wieland-Miesher ketone (7) and calls upon a Diels-Alder cycloaddition reaction for the construction of the C ring of 1. The described synthesis confirms the proposed stereochemistry of 1 and represents an efficient entry into an unexplored class of biologically active diterpenes.     

Enantiospecific synthesis of (-)-trachyspic acid

The enantiospecific synthesis of (-)-trachyspic acid () is presented. This has allowed for the assignment of the absolute configuration of natural (+)-trachyspic acid as 3S,4S,6S.     

Total synthesis of (-)-sessilifoliamide C and (-)-8-epi-stemoamide

A convergent route featuring [3,3]-sigmatropic rearrangements of a linchpin azepinopyrrolidine served to install two of the four contiguous stereocenters present in the tricyclic Stemona alkaloids sessilifoliamide and stemoamide. In addition to the first total synthesis of (-)-sessilifoliamide C, a potential biosynthetic relationship between the sessilifoliamides and previously reported Stemona alkaloids is presented.     

Total synthesis of (-)-senepodine G and (-)-cermizine C

An efficient, stereospecific synthesis of the alkaloids senepodine G (2) and cermizine C (1) has been completed using the BF3.Et2O-promoted stereospecific addition of Me2CuLi to alpha,beta-unsaturated lactam 6 to provide lactam 3, the addition of MeMgBr followed by HCl to convert 3 to senepodine G (2) (six steps, 40% overall yield), and the stereospecific NaBH4 reduction of 2 to give cermizine C (1) (seven steps, 40% overall yield).     

An efficient enantioselective synthesis of (S)-(-)-acromelobic acid

[reaction: see text] A highly efficient enantioselective synthesis of (S)-(-)-acromelobic acid (1) was achieved via asymmetric hydrogenation of dehydroamino acid derivative (3) using (R,R)-[Rh(DIPAMP)(COD)]BF(4) catalyst followed by removal of protective groups in >98% ee and good over all yield. The key intermediate (3) was prepared from the commercially available citrazinic acid (4) in six steps.     

Stereocontrolled total synthesis of (-)-eudistomin C

A stereocontrolled total synthesis of (-)-eudistomin C was accomplished in 18-step sequence with an overall yield of 7.7%. The synthesis features the diastereoselective Pictet-Spengler reaction of a tryptamine derivative and the Garner aldehyde catalyzed by Bronsted acids, and the unprecedented construction of the unusual oxathiazepine ring by intramolecular alkylation.     

Total synthesis of (-)-disorazole C1

The antimitotic natural product disorazole C1 was isolated in 1994 from the fermentation broth of the myxobacterium Sorangium cellulosum. We have developed a highly convergent and stereoselective total synthesis of this compound which establishes its relative and absolute configuration. Key features of our synthesis include a highly convergent strategy and selective functional group manipulations that minimize decomposition of the sensitive polyene macrodiolide.     

Total synthesis of (-)- and (+)-membrenone C

[reaction: see text] A synthesis of the polypropionate marine defense substance (+)-membrenone C and its enantiomer that starts from (S)-2-methyl-3-(tert-butyldimethylsilyloxy)propanal is described. Key steps include (1) additions of chiral allenylmetal reagents to effect both chain homologation and the concomitant introduction of four stereo centers, (2) a bis-intramolecular hydrosilylation-oxidation sequence to install beta-hydroxy ketone subunits, and (3) a bis-intramolecular aldol reaction to construct the two dihydropyrone termini.     

Total synthesis of (-)-pseudolaric acid B

We report a full account of our work toward the total synthesis of pseudolaric acid B (1a), a diterpene acid isolated from the bark of Pseudolarix kaempferi Gordon (pinaceae). Compound 1a is an antifungal and antifertility agent. Furthermore, its capacity for inhibiting tubulin polymerization makes it a potential lead for cancer therapy. Herein, we describe the use of a Ru- or Rh-catalyzed [5 + 2] intramolecular cycloaddition reaction of an alkyne and a vinylcyclopropane for the construction of the polyhydroazulene core of the molecule. Our first unsuccessful strategy for the introduction of the quaternary center based on an epoxide opening with cyanide led to the discovery of a new TBAF-mediated isomerization of a 1,4-diene to a 1,3-diene and a vinylogous eliminative opening of an epoxide to form a dienol. Our second strategy, based on the cyclization of an alkoxycarbonyl radical upon a diene system, succeeded in forming the quaternary center. Detailed studies showed the dependence of this underutilized approach for the synthesis of lactones on substrate structure and reaction conditions. In the late stage of the synthesis, the unique capacity of cerium organometallic reagents to add to a sensitive, sterically hindered ketone was demonstrated. The easy formation of an oxo-bridged derivative was the major hurdle to the completion of the synthesis and showcased the intriguing reactivity of the complex core of the pseudolaric acids.     

The enantioselective total synthesis of a beta-carboline alkaloid, (S)-(-)-dichotomine C

The first enantioselective synthesis of a beta-carboline alkaloid, dichotomine C, possessing antiallergic effects, was achieved by constructing a beta-carboline framework based on the microwave-assisted thermal electrocyclic reaction of a 1-azahexatriene system, followed by the Sharpless asymmetric dihydroxylation.     

Enantioselective total synthesis of (-)-kibdelone C

The kibdelones are aromatic polyketide natural products featuring isoquinolinone and tetrahydroxanthone ring systems. They display potent cytotoxicity toward a range of human cancer cell lines. Here, we present an enantioselective total synthesis of kibdelone C that utilizes a Shi epoxidation to establish the absolute and relative stereochemistry, an acid-catalyzed cyclization to form the tetrahydroxanthone, and a C-H arylation to complete the hexacyclic skeleton.     

Total synthesis of (-)-N-methylwelwitindolinone C isothiocyanate

We report the first total synthesis of (-)-N-methylwelwitindolinone C isothiocyanate. Our route features a number of key transformations, including an indolyne cyclization to assemble the [4.3.1]-bicyclic scaffold, as well as a late-stage intramolecular nitrene insertion to functionalize the C11 bridgehead carbon en route to the natural product.     

A straightforward synthesis of (-)-phaseolinic acid

A concise approach to (-)-phaseolinic acid starting from commercially available (S)-oct-1-yn-3-ol is disclosed. The key steps are a ring-closing metathesis reaction to prepare a C(2)-symmetrical allylic diol and its desymmetrization to a gamma-butyrolactone by using an Ireland-Claisen rearrangement. The 2S,3S,4S configuration of the levogyre natural product has been confirmed.     

A practical synthesis of (-)-kainic acid

A highly practical stereoselective total synthesis of (-)-kainic acid is described. This synthesis features the stereoselective alkylation of an iodolactone intermediate that was efficiently prepared from (+)-carvone and introduction of carboxylic acid by hydrolysis of a nitrile accompanied by epimerizaion. This synthetic route enabled us to obtain 14.6 g of (-)-kainic acid.     

Stereocontrolled total synthesis of (-)-kainic acid

[reaction: see text] A stereocontrolled total synthesis of (-)-kainic acid is described. A fully functionalized trisubstituted pyrrolidine ring was constructed by ring-closing metathesis of an acrylate derivative followed by an intramolecular Michael addition of the resultant alpha,beta-unsaturated lactone with high diastereoselectivity. Two alternative protocols for the construction of the alpha,beta-unsaturated lactone were also developed.