A regiospecific radical annulation strategy to functionalised chiral bicyclo[3.3.l]nonanes

A radical annulation, i.e. an intermolecular radical Michael addition followed by an intramolecular Michael addition of the resultant radical (radical cyclisation) has been employed for the construction of chiral functionalised bicyclo[3.3,1]-nonanes. Thus reaction of carvone hydrohalides 7 with (n)Bu(3)SnH and AIBN in the presence of excess of radicophiles 4 furnished, regiospecifically bicyclo[3.3.1]nonanes 8-14, introducing three new chiral centres in a stereoselective manner. Analogously the bromide 18 generated the bridgehead substituted bicyclo[3.3.1]-nonanes 19-21.

Synthesis based on cyclohexadienes. Part 15. Total synthesis of (±)-prezizaene, (±)-prezizanol and (±)-jinkohol II

A new methodology for the synthesis of the complex ring system tricyclo[6.2.1.0(1.5)]undecane. present in the zizaene group of sesquiterpenes, is described. Acid-catalysed rearrangement of the endo alcohol 20 afforded the enone 12, which was transformed stereoselectively into the key intermediate. (+/-)-norprezizanone 10. The features of the synthesis are the transformation of a bicycle[2.2.2] octane framework into a bicycle[3.2.1] octane system by an acid-catalysed rearrangement and a stereoselective conjugate addition of a methyl group on an alpha,beta-unsaturated keto ester at -100 degrees C. Norprezizanone was converted into the sesquiterpenes (+/-)-prezizanol 5 and(+/-)-prezizaene 4. The first total synthesis of (+/-)-jinkohol II 6 is also presented.

Total synthesis of the novel sesquiterpenes of Eremophila georgei Diels

The first stereoselective total synthesis of the natural sesquiterpenes 4 and 5, having the tricyclo[6.2.1.0(1,5)]undecane skeleton with a bridgehead methyl group, is reported via the intermediate 9, which was obtained by the acid catalysed rearrangement of the alcohols 7 and 8.

Asymmetric Diels-Alder Reactions of Chiral Acrylates of Cholic Acid Derivatives

New steroid-based chiral auxiliaries 6, 9, and 12 have been synthesized from readily available cholic acid. These new chiral auxiliaries place the reactive and the shielding sites in a 1,5 relationship to each other. Diels-Alder reaction of cyclopentadiene with corresponding acrylate esters (7, 10, and 13) have been examined. Acrylates 7 and 10 yielded cycloadducts with 29-88% diastereomeric excess with excellent endo selectivity in the presence of an excess of Lewis acids such as AlCl3, BF3.OEt(2), FeCl3, SnCl4, TiCl4, and ZnCl2. Treatment of acrylate 7 with cyclopentadiene in the presence of BF3.OEt(2) at -80 degrees C gave the endo adduct (>99%) with 88% de. Lewis acid catalyzed and uncatalyzed reactions of acrylates 7 and 10 with cyclopentadiene yielded cycloadducts with opposite stereochemistry. The chiral auxiliary was recovered in a nondestructive manner only via iodolactonization. Acrylate ester of alcohol 12 did not show any selectivity in either catalyzed and uncatalyzed reactions with cyclopentadiene. The presence of a flat aromatic surface at C-7 of the steroid was found to be essential to effect high diastereoselection.

1,3-Dipolar cycloaddition reaction of ?,?-unsaturated esters and lactones with diazomethane

1,3-Dipolar cycloaddition of diazomethane to the alpha,beta-unsaturated esters and lactones such as 2-4, 6-8, 10 and 13 occurs in a stereoselective manner affording conjugated Delta(2)-pyrazolines. E and Z isomers of D-mannitol lead to identical product which was cyclised to investigate the absolute stereochemistry of the product. The regiospecificities of all the reactions are consistent with FMO coefficients obtained through AM1 calculations.

Synthesis based on cyclohexadienes. Part 17. Total synthesis of the sesquiterpenes of Eremophila georgei diels

The first stereoselective total synthesis of the novel sesquiterpenes 1 and 2 is described. The preparation of the key intermediate 27 involved a rearrangement of a bicyclo[3.2.1] octane framework to an isomeric bicyclo[3.2.1]octane skeleton via a bicyclo[2.2.2]octane derivative.

Synthesis based on cyclohexadienes .23. Total synthesis of 5-epi-pupukean-2-one

A new strategy for the construction of the isotwistane skeleton is reported from easily available cyclohexadienes which involves stereoselective alkylation of a bicyclooctenone derivative and a decarboxylative 5-exo-trig radical cyclisation as the key steps in the total synthesis of 5-epi-pupukean-2-one.

Enantiodivergent total synthesis of microcarpalide from L-tartaric acid

Stereoselective approach for the synthesis of both enantiomers of bio-active decanolactone microcarpalide is described from L-tartaric acid. The synthesis of the key intermediates en route to the natural product is achieved from L-tartaric acid involving the elaboration of gamma-hydroxy amide derived from tartaric acid and ring opening of an epoxide derived from tartaric acid. (C) 2011 Elsevier Ltd. All rights reserved.

Total Synthesis of Gabosine H

Stereoselective total synthesis and assignment of the absolute configuration of the keto carba sugar gabosine H is presented. Pivotal reactions in the sequence include desymmetrization of the dimethylamide of tartaric acid and ring-closing metathesis.

Reactivity switching and selective activation of C-1 or C-3 in 2,3-unsaturated thioglycosides

Reactivity switching and selective activation of C-1 or C-3 in 2,3-unsaturated thioglycosides, namely, 2,3-dideoxy-1-thio-D-hex-2-enopyranosides are reported. The reactivity switching allowed activation of either C-1 or C-3, with the use of either N-iodosuccinimide (NIS)/triflic acid (TfOH) or TfOH alone. C-1 glycosylation with alcohol acceptors occurred in the presence of NIS/TfOH, without the acceptors reacting at C-3. On the other hand, reaction of 2,3-unsaturated thioglycosides with alcohols mediated by triflic acid led to transposition of C-1 ethylthio-moiety to C-3 intramolecularly, to form 3-ethylthio-glycals. Resulting glycals underwent glycosylation with alcohols to afford 3-ethylthio-2-deoxy glycosides. However, when thiol was used as an acceptor, only a stereoselective addition at C-3 resulted, so as to form C-1, C-3 dithio-substituted 2-deoxypyranosides. (C) 2011 Elsevier Ltd. All rights reserved.

Total Synthesis of (-)-Anamarine

Total synthesis of polyhydroxy delta-pyranone natural product (-)-anamarine is accomplished from D-(-)-tartaric acid. The main feature of the synthesis is the utility of hitherto unexplored beta-keto phosphonate derived from tartaric acid amide and further elaboration involving stereoselective reduction.

Total Synthesis of (+)-Cladospolide A

A stereoselective total synthesis of (+)-cladospolide A from D-ribose is described. Key features of the synthesis include olefin cross metathesis and Yamaguchi lactonization.

Electrophile-Induced C-C Bond Activation of Vinylcyclopropanes for the Synthesis of Z-Alkylidenetetrahydrofurans

We present a detailed study on the behavior of vinylcyclopropanes as masked donor acceptor system toward the stereoselective synthesis of Z-alkylidenetetrahydrofurans. Results of bromenium catalyzed indirect activation of C-C bond of vinylcyclopropanes and concomitant cyclization to alkylidenetetrahydrofuran and other heterocycles have been discussed. The stereoselective formation of the Z-isomer is strongly controlled by the extent of destabilization of one of the gauche conformers of the vinylcyclopropane. The ring-opening/cyclization step was found to be stereospecific as in the case of DA cyclopropanes. The activation of the C-C bond leads to a tight-carbocation intermediate, which is evident from the complete retention of the stereochemistry. The retention of configuration has been established by a necessary control experiment that rules out the possibility of a double inversion pathway. The present results serve as direct stereochemical evidence in support of a tight ion-pair intermediate versus the controversial S(N)2 pathway. A 2D potential energy scan has been carried out at B3LYP/6-31G(d) level theory to obtain the relative energies of the conformers. The Z-selectivity observed has been explained on the basis of the relative population of the conformers and modeling the intermediate and transition state involved in the reaction at M06-2x/6-31+G(d) level. Energy profile for the cyclization step was modeled considering various possible pathways through which cyclization can happen. The methodology has been successfully demonstrated on vinylcyclobutanes as well.

Structural insights into the role of Bacillus subtilis YwfH (BacG) in tetrahydrotyrosine synthesis

The synthesis of the dipeptide antibiotic bacilysin involves the sequential action of multiple enzymes in the bac operon. YwfH (also referred to as BacG) catalyzes the stereoselective reduction of dihydro-hydroxyphenylpyruvate (H2HPP) to tetrahydro-hydroxyphenylpyruvate (H4HPP) in this biosynthetic pathway. YwfH is an NADPH-dependent reductase that facilitates the conjugate addition of a hydride at the C4 olefin terminus of H2HPP. Here, the structure of YwfH is described at three conformational steps: the apo form, an apo-like conformation and the NADPH complex. YwfH is structurally similar to other characterized short-chain dehydrogenase/reductases despite having marginal sequence similarity. The structures of YwfH in different conformational states provide a rationale for the ping-pong reaction mechanism. The identification and role of the residues in the catalytic tetrad (Lys113Tyr117Ser155Asn158) in proton transfer were examined by mutational analysis. Together, the structures and biochemical features revealed synchronized conformational changes that facilitate cofactor specificity and catalysis of H4HPP formation en route to tetrahydrotyrosine synthesis.

Formal Synthesis of Actin Binding Macrolide Rhizopodin

Formal synthesis, of an actin binding macrolide rhizopodin was achieved in 19 longest linear steps. The key features of the synthesis include a stereoselective Mukaiyama aldol reaction, dual role of a Nagao auxiliary (first, as a chiral auxiliary of choice for installing hydroxy centers and, later, as an acylating agent to form an amide bond with an amino alcohol), late stage oxazole formation, and Stille coupling reactions.