Simon Breitler

Formaldehyde N,N-Dialkylhydrazones as Neutral Formyl Anion Equivalents in Iridium-Catalyzed Asymmetric Allylic Substitution

The use of formaldehyde N,N-dialkylhydrazones as neutral C1-nucleophiles in the iridium-catalyzed substitution of allylic carbonates is described for two processes. Kinetic resolution or, alternatively, stereospecific substitution affords configurationally stable α,α-disubstituted aldehyde hydrazones in high enantiomeric excess and yield. This umpolung approach allows for the construction of optically active allylic nitriles and dithiolanes as well as branched α-aryl aldehydes. A catalyst-controlled reaction with Enders chiral hydrazone derivatives followed by diastereoselective nucleophilic addition to the hydrazone products constitutes a two-step stereodivergent synthesis of chiral amines.

Total Synthesis of (+)‐Crotogoudin

Fellowship of the ring: The first total synthesis of (+)-crotogoudin, a 3,4-seco-atisane diterpenoid natural product, is reported. Asymmetric access to the bicyclo[2.2.2]octane core is achieved through a desymmetrization of a meso-diketone with bakers yeast (LG=leaving group, PG=protecting group). A SmI2 -induced radical cyclopropane-opening/annulation/elimination cascade affords the suitably decorated tetracyclic structure of (+)-crotogoudin. The synthesis led to revision of the reported optical rotation of the natural product and to assignment of its absolute configuration as an ent-atisane (5R,10R).

Cationic Chiral Fluorinated Oxazaborolidines. More Potent, Second-Generation Catalysts for Highly Enantioselective Cycloaddition Reactions.

The coordination of chiral ligands to Lewis acid metal derivatives, a useful strategy for enantioselective, electrophilic catalysis, generally leads to a lower level of catalytic activity than that of the original uncomplexed compound. Activation by further attachment of a proton or strong Lewis acid to the complex provides a way to overcome the deactivating effect of a chiral ligand. The research described herein has demonstrated that further enhancement of catalytic activity is possible by the judicious placement of fluorine substituents in the chiral ligand. This approach has led to a new, second-generation family of chiral oxazaborolidinium cationic species which can be used to effect many Diels-Alder reactions in >95% yield and >95% ee using catalyst loadings at the 1-2 mol % level. The easy recovery of the chiral ligand makes the application of these new catalysts especially attractive for large-scale synthesis.

Acceleration of Enantioselective Cycloadditions Catalyzed by Second-Generation Chiral Oxazaborolidinium Triflimidates by Biscoordinating Lewis Acids

The activation of second-generation fluorinated oxazaborolidines by the strong acid triflimide (Tf2NH) in CH2Cl2 solution leads to highly active chiral Lewis acids that are very effective catalysts for (4 + 2) cycloaddition. We report herein that this catalytic activity can be further enhanced by the use of Tf2NH in combination with the biscoordinating Lewis acid TiCl4 or SnCl4 as a coactivator. The effective increase in acidity of an exceedingly strong protic acid is greater for biscoordinating TiCl4 and SnCl4 than for monocoordinating salts, even the strong Lewis acids AlBr3 and BBr3 in CH2Cl2 or CH2Cl2/toluene. The increase in the effective acidity of Tf2NH can be understood in terms of a stabilized cyclic anionic complex of Tf2N(-) and TiCl4, which implies a broader utility than that described here. The utility of Tf2NH-TiCl4 activation of fluorinated oxazaborolidines is documented by examples including the first enantioselective (4 + 2) cycloaddition to α,β-unsaturated acid chlorides.

Total Syntheses of Ampelopsin D, Pallidol, and Quadrangularin A

Significance: The polyphenols quadrangularin A, ampelopsin D and pallidol consist of two resveratrol units. Considering the impressive biological activity of the monomer, these natural products are considered promising targets for further investigations. Klotter and Studer describe a highly modular approach that offers the possibility to introduce differently substituted aryl groups at will, allowing for the preparation of various analogues for biological investigations. The flexibility of the route is demonstrated by the short syntheses of racemic quadrangularin A, ampelopsin D and pallidol. Comment: The approach is centered on two consecutive palladium-catalyzed coupling reactions. Decarboxylative arylation of indene carboxylic acid C, accessible in eight steps from cinnamic acid derivative A, gave indenes D and E depending on the aryl iodide employed. Oxidative Heck reactions with aryl boronic acids F or H afforded, after deprotection, quadrangularin A and ampelopsin D from D and E, respectively. Hydroboration, oxidation, and deprotection of intermediate G allowed for the preparation of pallidol. CO2H

Total Synthesis of Cardamom Peroxide

Significance: In the wake of the success of artemisinin for the treatment of chloroquine-resistant malaria, enormous interest has been placed in naturally occurring organic peroxides as potential leads for medicinal chemistry. Cardamom peroxide, a diterpenoid containing a seven-membered cyclic peroxide, was isolated from Siam cardamom in 1995 by Clardy and co-workers and, although it has been shown to be highly active against Plasmodium falciparum, has only now succumbed to total synthesis. Hu and Maimone identified a non-obvious symmetry and hypothesized that cardamom peroxide could be stitched together by two monoterpenes and molecular oxygen. Brilliantly executing this plan, they were able to synthesize the target compound in only four steps from (–)-myrtenal. Comment: Following the biosynthetic hypothesis, the authors settled on (–)-myrtenal as the monoterpenoid starting material. McMurry coupling led to triene A which underwent a [4+2] cycloaddition with singlet oxygen. The resulting peroxide was not isolated but treated with DBU, leading to a Kornblum–DeLaMare rearrangement to give dienone D. Oxidation to the diketone E then set the stage for the crucial oxidation reaction. Extensive experimentation identified a manganese-catalyzed radical hydroperoxidation which leads to regioselective functionalization of the doubly activated olefin. Following 7-endo cyclization, trapping with oxygen gave the corresponding α-hydroperoxyketone which was reduced using Ph3P to afford cardamom peroxide. Using this highly efficient strategy, the natural product was constructed in 18% yield over four steps. O O O

Total Synthesis of (±)-Alstilobanine A

Significance: Monoterpene indole alkaloids usually consist of a tryptamine residue attached to a monoterpenoid unit. (±)-Alstilobanine A, however, features an intriguing rearranged skeleton. The authors based their concise synthesis on the conjugate addition of ester enolate F to an in situ-generated nitrosoalkene and the formation of β-lactam L via an intramolecular formal ketene–ketone [2+2] cycloaddition developed by Romo and coworkers (Org. Lett. 2006, 8, 4363). Comment: The intermolecular conjugate addition of ester enolate F onto nitrosoalkene G, generated in situ from α-chlorooxime E, proceeded efficiently to give H. This transformation highlights an interesting method to construct 1,4-dicarbonyl frameworks. Both C16-diastereomers could be used to access I, which then underwent a formal [2+2] cycloaddition to afford the desired syn-2-azadecalin L in excellent yield and diastereoselectivity. The synthesis was completed in eight steps from L to generate the natural product in an impressive 14% overall yield. N H CO2Me

Total Synthesis of (+)-Hyperforin

Significance: Hyperforin, a constituent of St. John’s wort, is a member of the polycyclic polyprenylated acylphloroglucinol natural product family. Its well-studied antidepressant activity, along with the structural complexity, renders it an attractive target for total synthesis. To date, only one total synthesis has been reported with an overall length of 51 steps (Angew. Chem. Int. Ed. 2010, 49, 1103; Synfacts 2010, 510). This synthesis by Shair and co-workers is significantly shorter, utilizing an epoxide-opening cyclization to set four stereocenters in one step, thus affording (+)-hyperforin in only 18 steps. Comment: Intramolecular Lewis acid mediated opening of epoxide C by only one of the diastereotopic enol ethers furnished the key bicyclo[3.3.1]nonane core as the methyl ketal E. In this impressive display of stereocontrol, four stereocenters, including two quaternary ones, were set in good yield from an enantiopure epoxide. The subsequent allylic oxidation proceeded in a highly chemoselective fashion to furnish ketone F which was then transformed into (+)-hyperforin in ten further steps. OMe OMe

Total Synthesis of (±)-Goniomitine

Significance: Goniomitine, a monoterpene indole alkaloid belonging to the aspidosperma family, has been a popular target for total synthesis with five successful endeavors so far. While most strategies rely on the early-stage construction of the 2,3-difunctionalized indole structure, Zhu and coworkers start with a newly developed decarboxylative vinylation. The indole is formed together with the saturated rings late in the synthesis during an impressive one-pot reaction, affording the natural product in only seven steps. Comment: The authors employ a novel palladiumcatalyzed decarboxylative vinylation of a potassium acetate D with a vinyl triflate B to quickly access nitroarene F. After conversion into azide G, an intriguing reaction cascade is triggered. In a single pot, oxidative cleavage of the cyclopentene, followed by simultaneous reduction of the nitro and the azide group and subsequent triple cyclization yields the protected natural product as a single diastereomer with excellent yield. OEt OTf TBSO

Total Synthesis of (–)-Lycoposerramine-S

Significance: Fukuyama and co-workers report the first total synthesis of the caged tetracyclic Lycopodium alkaloid (–)-lycoposerramine-S. The enantioselective synthesis is centered around an impressive 1,3-dipolar cycloaddition which diastereoselectively constructs the central pentasubstituted pyrrolidine ring utilizing a chiral morpholinone. A radical cyclization and alkylative ring closure of the nine-membered ring using a 4-nitrobenzenesulfonyl amide leads to the synthesis of the natural product in only 14 steps. Comment: In a striking intramolecular 1,3-dipolar cycloaddition, condensation of aldehyde D with morpholinone E led to the diastereoselective formation of pyrrolidine G containing four newly constructed contiguous stereocenters in excellent yield. The formation of the 2,5-cis relationship is thought to arise from preferential formation of Z-azomethine ylide F. Exhaustive reduction, selective elimination of the resulting secondary alcohol followed by a radical annulation led to tricycle J. Finally, the medium-sized ring was assembled by use of alkylative nosyl amide chemistry previously developed by the Fukuyama group. I