Total Synthesis of (+)-Lycoricidine and Conduramine B-1, ent-C-1, C-4, D-1, ent-F-1, and ent-F-4, and Formal Synthesis of (-)-Laminitol: a C2-Symmetric Chiral-Pool-Based Flexible Strategy.

A facile and diversity-oriented synthetic strategy toward aminocyclitol natural products from inexpensive C2-symmetric l-tartaric acid was developed. The pivotal epoxide was used as a common intermediate to accomplish eight diverse target molecules in six to eleven steps. Various allyl-amine-type conduramines were synthesized in a diastereoselective manner. Heck arylation was explored to construct a phenanthridone ring in a concise synthesis of (+)-lycoricidine. In addition, a highly efficient formal synthesis of (-)-laminitol was developed.

A C2-symmetric chiral pool-based flexible strategy: synthesis of (+)- and (-)-shikimic acids, (+)- and (-)-4-epi-shikimic acids, and (+)- and (-)-pinitol.

Via combination of a novel acid-promoted rearrangement of acetal functionality with the controlled installation of the epoxide unit to create the pivotal epoxide intermediates in enantiomerically pure form, a simple, concise, flexible, and readily scalable enantiodivergent synthesis of (+)- and (-)-shikimic acids and (+)- and (-)-4-epi-shikimic acids has emerged. This simple strategy not only provides an efficient approach to shikimic acids but also can readily be adopted for the synthesis of (+)- and (-)-pinitols. These concise total syntheses exemplify the use of pivotal allylic epoxide 14 and its enantiomer ent-14. A readily available inexpensive C2-symmetric L-tartaric acid (7) served as key precursor. In general, the strategy here provides a neat example of the use of a four-carbon chiron and offers a good account of the synthesis of functionalized cyclohexane targets.

New, general, and practical preparation of methyl ketones via the direct coupling of amides with CH2Cl2 promoted by TiCl4/Mg.

The direct coupling of a variety of amides with CH2 Cl2 or CD2 Cl2 promoted by TiCl 4/Mg/THF provides an extremely simple, practical, selective, and efficient approach for the construction of methyl ketones. The efficiency and practicability of this chemistry is illustrated by the very simple synthesis of deuterated methyl ketones.

Unusual ambiphilic carbenoid equivalent in amide cyclopropanation.

[reaction: see text] The titanium-methylene complexes derived from the TiCl(4)-Mg-CH(2)Cl(2) system serve as a novel class of ambiphilic carbenoid equivalents, which not only efficiently effect cyclopropanations of a variety amides but also exhibit high chemoselectivity.

New, general, and practical enamine cyclopropanation using dichloromethane.

[reaction: see text] Dichloromethane serves as a novel electrophilic carbene equivalent which adds to an enamine double bond. The presence of other alkene moieties in the enamine partner is well tolerated. Even enamines derived from sterically hindered ketones react readily with dichloromethane promoted by TiCl(4)-Mg.

Exceedingly Concise and Elegant Synthesis of (+)-Paniculatine, (-)-Magellanine, and (+)-Magellaninone.

Starting from inexpensive (+)-pulegone as the chiral building block, a highly convergent synthesis of the unusual diquinane-based structures of (+)-paniculatine (1), (-)-magellanine (2), and (+)-magellaninone (3), has been achieved. This approach is based upon a tandem acylation-alkylation of ketoester 8 and palladium-catalyzed olefin insertion, oxidation, and hydrogenation for construction of the tetracyclic framework. This exceedingly concise strategy, requiring only 12-14 steps, is the shortest to date.

Dichloromethane activation. Direct methylenation of ketones and aldehydes with CH2Cl2 promoted by Mg/TiCl4/THF.

[reaction: see text] This Mg-TiCl4-promoted CH2-transfer reaction of CH2Cl2 represents an extremely simple, practical, and efficient methylenation of a variety of ketones and aldehydes, especially in enolizable or sterically hindered ketones such as 2,2-dimethylcyclohexanone, camphor, and fenchone.

Dichloromethane as an unusual methylene equivalent. A new entry of highly nucleophilic and selective titanium-methylene complexes for ester methylenation.

[reaction: see text] The successful application of CH2Cl2-Mg-TiCl4-system mediated methylenation of various esters such as tert-butyl ester and 2,5-cyclohexadiene-1-carboxylate highlights the extraordinary reactivity, selectivity, and the nonbasic nature of this new methylene-carbenoid, which serves as a practical reagent applicable to large-scale synthesis.

Bromoform activation. TiCl4-Mg-promoted CHBr2- and CBr3- transfer to a variety of aldehydes and ketones.

TiCl4-Mg can mediate addition of CHBr3 to a variety of aldehydes and ketones to form dibromomethyl carbinols and also be used to effect CBr3 transfer to carbonyl groups to form tribromomethyl carbinols. The successful application of TiCl4-Mg-promoted coupling of CHBr3 with various carbonyl compounds, especially in the case of highly enolizable ketones such as 2-indanone and ß-tetralone, highlights the extraordinary reactivity and selectivity and the weakly basic nature of this system.

Chiral pool based efficient synthesis of the aminocyclitol core and furanoside of (-)-hygromycin A: formal total synthesis of (-)-hygromycin A.

A chiral pool based synthetic strategy that leads from the readily available and inexpensive C(2)-symmetric tartaric acids to the chiral O-isopropylidenebenzooxazole--a convenient precursor to the aminocyclitol core of hygromycin A as well as the chiral γ-disilyloxybutyrolactone--a pivotal intermediate to approach to the furanoside of hygromycin A.

A flexible strategy based on a C2-symmetric pool of chiral substrates: concise synthesis of (+)-valienamine, key intermediate of (+)- pancratistatin, and conduramines A-1 and E.

A new strategy invoking a new application of the [3,3] sigmatropic rearrangement of allylic azides and the presence of a C(2) symmetry element within a pool of chiral substrates was evolved. Not only does this simple flexible strategy provide a concise approach to (+)-valienamine, but it also can readily be adopted for the synthesis of conduramines A-1 and E and the enantiopure azido carbonate 4, a key intermediate of (+)-pancratistatin.

A new entry to 1,5-keto esters and their 4,4-dideuterio derivatives via methylene chloride as "methylene dianion" equivalents.

This TiCl 4-Mg promoted multicomponent coupling of various amides with CH(2)Cl(2) and methyl acrylate represents an extremely simple and practical synthesis of 1,5-keto esters. The efficiency of this chemistry is illustrated by the very simple preparation of unusual 4,4-dideuterio-1,5-keto esters.

Novel ambiphilic dichlorocarbenoid equivalent in alkene cyclopropanation and carbonyl olefination.

The Ti-Mg-dichloromethylene complexes derived from the oxidative addition of CCl4 to the Mg-TiCl4 bimetallic species serve as a novel class of ambiphilic dichlorocarbenoid equivalents. Not only is Ti-Mg-dichlorocarbenoid highly selective but also it seems highly reactive in both alkene cyclopropanations and carbonyl dichloromethylenations.

New highly nucleophilic and practically accessible chlorocarbenoids for carbonyl olefination.

[reaction: see text] Direct oxidative addition of CHCl3 to the Mg-TiCl4 bimetallic species resulted in the generation of a highly nucleophilic and practically convenient chloromethylenetitanium complex, which efficiently effected condensation even with enolizable or inert carbonyl compounds, such as sterically congested ketones, to provide vinyl chloride compounds.

A short synthesis of (+)-narciclasine via a strategy derived from stereocontrolled epoxide formation and SnCl(4)-catalyzed arene-epoxide coupling.

A facile construction of the typical framework of narcissus alkaloids has been realized by virtue of the development of a practical route involving stereocontrolled epoxide formation and SnCl(4)-catalyzed arene-epoxide coupling. To achieve this goal, it proved to be necessary to devise a strategy that would enable chemical transformations to install an epoxy moiety in a congested environment. The successful preparation of a hindered epoxide from O-isopropylidene-protected 4-aminocyclohexenol required three steps consisting principally of controlled bromohydration and base-promoted closure and N-alkylation. It was found that a catalytic amount of SnCl(4) not only maintained the catalytic cycle but also effected clean arylation to form a fused BC ring system. Several tactics that ultimately proved to be unsatisfactory are also discussed in an effort to set important boundary limits on arene-epoxide coupling. The requisite enantiopure 4-aminocyclohexenol was available via an asymmetric cycloaddition of diene to camphor-based chloronitroso. The total synthesis of (+)-narciclasine was realized in nine steps with an overall yield of 19%.