Total Synthesis and Cytotoxicity Evaluation of Pareitropone and Analogues.

A concise synthesis of pareitropone by oxidative cyclization of a phenolic nitronate is delineated. The use of TMSOTf as an additive to promote the facile formation of a strained norcaradiene intermediate provides convenient access to highly condensed multicyclic tropones in high yields. This synthesis is modular, efficient, and scalable, highlighting the synthetic utility of radical anion coupling reactions in annulation reactions. This work is discussed in the context of total syntheses of the tropoloisoquinoline alkaloids. Also included are the preparation of several congeners and a brief description of their biological activities.

Synthesis of Indoles from o-Haloanilines.

A convenient method for the synthesis of indoles has been developed by the sequential orchestration of the cross-coupling reaction of o-haloaniline and PIFA oxidation of the resulting 2-alkenylanilines. A highlight of this two-step indole synthesis is a modular strategy which is applicable to both acyclic and cyclic starting materials. Particularly noteworthy is the regiochemistry that is complementary to the Fischer indole synthesis and related variants. Direct preparation of N-H indoles with no N-protecting group is also advantageous.

Acyclic Remote 1,6-Stereoselection.

Stereochemical communication in homopropargylation and homoallylation of aldehydes was achieved by the Ti-O temporary linker strategy. Propargylic and allylic alcohol derivatives were employed as convenient pronucleophiles, obviating prefabrication of propargylation/allylation reagents. It was surprising that 1,6-diastereoselectivity was affected by not only the Grignard reagent but also the reaction solvent.

Cu-Mediated Rearrangements of Allenylcyclopropanols to Cyclopentenones: Two Divergent Pathways.

Two CuCN-mediated rearrangement reactions of allenylcyclopropanols to cyclopentenones have been achieved by means of Et2Zn/CuCN·2LiCl or CuCN·2LiCl to afford 5-alkyl or 4-alkyl cyclopentenone regioisomers: the former conditions afford 5-alkyl substituted cyclopentenones via ß-carbon elimination, whereas the latter result in the 4-alkyl substituted regioisomers with concomitant oxidation at the γ-position, via a free radical mechanism.

Mechanism of Ru(II)-Catalyzed Rearrangements of Allenyl- and Alkynylcyclopropanols to Cyclopentenones.

A comparison study of the Ru(II)-catalyzed rearrangements of allenyl- and alkynylcyclopropanols to the corresponding cyclopentenones has been undertaken with the aid of an alkyl substituent on the three-membered ring. These ring expansion reactions proceed with exceptional regioselectivity irrespective of the cis/trans stereochemistry of the substituents on the three-membered ring. ß-Carbon elimination is the common feature in the absence of a chelating group at the 4'-position in the alkyne chain.

Construction of Seven-Membered Carbocycles via Cyclopropanols.

A new method for seven-membered ring annulation has been devised by an intramolecular cross-coupling of cyclopropanols and aryl/alkenyl halides. This cyclization reaction is broad in scope and provides easy access to not only fused but also bridged bicyclic compounds.

C-Alkynylation of Cyclopropanols.

Alkynylation of cyclopropanols with 1-bromo-1-alkynes has been devised for easy access to synthetically useful alk-4-yn-1-ones. This method broadens the utility of attractively functionalized cyclopropanols as a new class of homoenolate equivalent in C-C bond formation.

Concise synthesis of alkaloid (-)-205B.

Described herein is a short total synthesis of alkaloid (-)-205B (1) by means of an anti-selective SN2' alkylation of an attractively functionalized cyclopropanol and diastereoselective cyclization of the resulting aminoallene adduct for bicyclic ring formation. The synthesis features a general route to cis- or trans-2,6-disubstituted piperidines by lithium aluminum hydride reduction of the imine intermediate by an appropriate choice of solvent and cis- or trans-2,5-disubstituted pyrrolidines by an exceptional level of chirality transfer from a pendant allene. Particularly noteworthy are the brevity and convergence made possible by a segment-coupling strategy.

Cross-coupling of cyclopropanols: concise syntheses of indolizidine 223AB and congeners.

A new synthetic method for indolizidine or pyrrolizidine alkaloids based on readily available and attractively functionalized cyclopropanols, as exemplified in concise syntheses of indolizidine (-)-223AB, its 3-epimer, (-)-indolizidine 239AB, and (-)-indolizidine 239CD, is reported. This work highlights the applications of SN2' alkylation and C-acylation of cyclopropanols to meet stereochemical challenges in natural product synthesis. Also included is diastereoselective cyclization of the resulting aminoallene adduct for bicyclic ring formation.

C-acylation of cyclopropanols: preparation of functionalized 1,4-diketones.

A convenient method for preparing attractively functionalized 1,4-diketones has been devised by palladium-catalyzed cross-coupling of cyclopropanols and acyl chlorides. The utility of this method has been demonstrated in an enantioselective synthesis of (+)-myrmicarin 217.

Stereoselective synthesis of 2,6-trans-tetrahydropyrans.

A stereoselective route to the thermodynamically unfavorable 2,6-trans-tetrahydropyrans has been developed from coupling of hydroxyethyl-tethered cyclopropanols and aliphatic aldehydes. Noteworthy is high convergency from direct coupling of two segments.

Total synthesis of pareitropone via radical anion coupling.

A concise (9-step) synthesis of the tropoloisoquinoline alkaloid pareitropone has been achieved starting from 2-bromoisovanillin. The key step features oxidative cyclization of a readily available phenolic nitronate for the convenient construction of the fused tropone ring. This work underscores the synthetic utility of intramolecular oxidative coupling reactions of phenolic nitronates.

Stereoselective cross-coupling between allylic alcohols and aldimines.

A cross-coupling reaction between an allylic alcohol and an imine is described for stereoselective allylation of aromatic and aliphatic imines. This method provides operationally simple, enantioselective access to functionalized homoallylic amines. Particularly noteworthy is direct use of a functionalized allylic alcohol as an allylating reagent without prederivatization, which obviates the use of preformed organometallic reagents or activated imine derivatives.

Total synthesis of cyathin A(3) and cyathin B(2).

A stereoselective synthesis of cyathin A(3) and cyathin B(2) has been achieved by a Prins-type reaction of a cycloalkenyl cyclopropanol. Particularly noteworthy is the use of a spirocyclobutanone moiety as a convenient scaffold for an efficient ring-closing metathesis to stereoselectively construct a suitably functionalized seven-membered ring (see scheme).

Low-valent titanium-mediated stereoselective alkylation of allylic alcohols.

We have developed low-valent titanium-mediated 1,3-transpositive cross-coupling reactions of acyclic and cyclic allylic alcohols for the stereoselective introduction of ethyl, 2-silylethyl, 2-phenethyl, and alkenyl groups. Cross-coupling of an allylic alcohol with a vinylsilane or styrene derivative is particularly noteworthy, as an efficient cross-selective coupling of two alkenes has been elusive. The stereochemistry of the cross-coupling alkylation is consistent with syn addition/beta-elimination.

Olefin Exchange-Mediated Cyclopropanation of Nitriles with Homoallylic Alcohols.

We report herein olefin exchange-mediated cyclopropanation of nitriles with homoallylic alcohols. The use of homoallylic alcohols is central to the successful implementation.

Acid- and Pd(0)-catalyzed ring opening of 1-(1-cycloalkenyl)cyclopropyl sulfonates.

We report herein facile acid-catalyzed isomerization of 1-(1'-cycloalkenyl)cyclopropyl sulfonates under mild conditions. The remarkable ease of ring opening is attributed to the presence of a 1'-alkyl substituent. Also included is a palladium-catalyzed ring opening reaction of 1-(1'-cycloalkenyl)cyclopropyl tosylates for convenient preparation of substituted 1,3-dienylamines, which complements previously reported nucleophilic substitution reactions of (1-vinyl)cyclopropyl tosylates.

Diastereoselective Prins-type reaction of cycloalkenylcyclopropanol silyl ethers and alpha,beta-unsaturated aldehyde acetals.

Electrophilic addition of 1-(1-cyclohexenyl)-1-cyclopropanol trimethylsilyl ether to alpha,beta-unsaturated aldehyde acetals under Lewis acidic conditions proceeds with good to excellent diastereoselectivity to afford spirocyclobutanones containing three contiguous stereocenters. A convenient entry to enantioselective syntheses is available by use of a nonracemic C2-symmetric acetal. Elaboration of the resulting adducts provides ready access to medium-sized carbocycles.