Paultheo von Zezschwitz

New cascade and multiple cross-coupling reactions for the efficient construction of complex molecules

Multiple palladium-catalyzed cross-coupling reactions of the Heck, Suzuki and Stille types on oligofunctionalized cycloalkenes and arenes can be performed in very high yields. While Heck type reactions on 1,2-dibromocycloalkenes or 2-bromocyclohexenyl triflates lead only to the twofold coupling products, the Stille coupling of the latter substrates occurs chemoselectively at the site of the triflate leaving group to give bromobutadienes which readily undergo subsequent Heck reactions. The thus obtained 1,3,5-hexatrienes undergo thermal 6π-electrocyclizations to furnish bicyclic skeletons, among others cyclohexenone-annelated systems after acidic work-up. Cascades of carbopalladation, rearrangement and [4+2] cycloaddition with bicyclopropylidene, aryl iodides and dienophiles constitute a new class of three-component reactions with a remarkable combinatorial potential, especially since they can be performed on the solid phase using the triazene linker. With nucleophiles instead of dienophiles yet another domino reaction consisting of carbopalladation, rearrangement and nucleophilic substitution can be performed with bicyclopropylidene, aryl or alkenyl iodides and C-, O- and N-centered nucleophiles to give a wide variety of interesting compounds. Under properly adjusted conditions even sixfold coupling reactions on hexabromoarenes can be achieved. When using Heck type reactions the initially formed intermediates en route to hexaalkenylarenes undergo intramolecular ring closures to yield multi-component mixtures of isomers of the expected products, but sixfold Stille and Suzuki couplings give pure hexaalkenylarenes in up to 73% yield. Crystal structure analyses reveal that depending on the nature of the alkenyl groups the six arms are positioned either on the same side of the central ring making it an interesting cup-shaped molecule or alternating above and below the central plane.

A One‐Pot Sequence of Stille and Heck Couplings: Synthesis of Various 1,3,5‐Hexatrienes and Their Subsequent 6π‐Electrocyclizations

Palladium-catalyzed cross-coupling reactions of 2-bromocyclohex-1-enyl triflates 7 and 11 with a variety of alkenylstannanes occurred chemoselectively at the site of the triflate leaving group to give bromobutadienes which readily underwent Heck reactions with acrylates and styrene. Both steps could be performed in the same flask to give differentially functionalized hexatrienes in up to 88% overall yield. With simple stannanes, the same catalyst precursor could be used for both coupling steps making it possible to perform the whole sequence with only one portion of catalyst. For some of the functionally substituted stannanes, specifically adjusted catalyst systems had to be used. The 1,3,5-hexatrienes obtained were further transformed, in particular the methoxy-substituted compounds 14a-c were converted to bicyclo[4.4.0]decenones 30 (71-97%), bicyclo[4.3.0]nonenones 35 (74-93%), cyclodecynone 37a (47%), and cyclononynone 39a (15%). Thermal electrocyclizations of the other hexatrienes gave tetrahydronaphthalines 31 (60-61%), the tricyclic lactone 32 (72-75%) and decahydrophenanthrene 33 (75 %) in good yields.

The Twofold Heck Reaction on 1,2-Dihalocycloalkenes and Subsequent 6π-Electrocyclization of the Resulting (E, Z, E)-1,3,5-Hexatrienes: A New Formal {2+2+2}-Assembly of Six-Membered Rings

1,6-Disubstituted (E,Z,E)-1,3,5-hexatrienes (4 and 5) were prepared by vicinal twofold Heck coupling reactions from 1,2-dibromocyclopentene (1), 1,2-dibromocyclohexene (2), 1,2-diiodocyclopentene (8), 1,2-diiodocyclohexene (9), 1-bromo-2-trifluoromethanesulfonyloxycyclohex-1-ene (11), or 1-chloro-2-nonafluorobutanesulfonyloxycyclohex-1-ene (19) with alkenes 3, e. g. methyl, tert-butyl, menthyl, 8-phenylmenthyl acrylate, styrene, and alkenylsilanes, respectively, in moderate to mostly good and very good yields (20-92 %). The coupling of alkenylsilanes 3f-k could only be achieved with the 1,2-diiodocycloalkenes 8 and 9, respectively. The corresponding hexatrienes 5 with two different substituents in the 1- and 6-positions were prepared by a sequence of two coupling reactions with different alkenes from 1-chloro-2-nonafluorobutanesulfonyloxycyclo-hex-1-ene (19) or by Wittig-Horner-Emmons olefination of 2-bromocyclohexene-1-carbaldehyde (24) and subsequent Heck reaction of the resulting (E,Z)-bromodienes 25. Several of the hexatrienes (4aa, ee, 5aa, ee, al, am, el) readily underwent a 6-electrocyclization upon heating in an inert atmosphere to give the 5- or 6-ring-annelated cis-5,6-disubstituted cyclohexadienes 26, 27 (50-95 %). Starting from 5am 2,3-disubstituted tetrahydronaphthalene 28am was formed under oxidative conditions (air) in the reaction and in the work-up procedure. The bissilyl-substituted derivatives 4ff, jj, 5ff did not cyclize under thermal conditions, apparently due to the steric demand of the two silyl substituents which would have to end up cis with respect to each other in the cyclohexadiene products.

Archazolid A Binds to the Equatorial Region of the c-Ring of the Vacuolar H+-ATPase

The macrolactone archazolid is a novel, highly specific V-ATPase inhibitor with an IC50 value in the low nanomolar range. The binding site of archazolid is presumed to overlap with the binding site of the established plecomacrolide V-ATPase inhibitors bafilomycin and concanamycin in subunit c of the membrane-integral VO complex. Using a semi-synthetic derivative of archazolid for photoaffinity labeling of the V1VO holoenzyme we confirmed binding of archazolid to the VO subunit c. For the plecomacrolide binding site a model has been published based on mutagenesis studies of the c subunit of Neurospora crassa, revealing 11 amino acids that are part of the binding pocket at the interface of two adjacent c subunits (Bowman, B. J., McCall, M. E., Baertsch, R., and Bowman, E. J. (2006) J. Biol. Chem. 281, 31885–31893). To investigate the contribution of these amino acids to the binding of archazolid, we established in Saccharomyces cerevisiae mutations that in N. crassa had changed the IC50 value for bafilomycin 10-fold or more and showed that out of the amino acids forming the plecomacrolide binding pocket only one amino acid (tyrosine 142) contributes to the binding of archazolid. Using a fluorescent derivative of N,N′-dicyclohexylcarbodiimide, we found that the binding site for archazolid comprises the essential glutamate within helix 4 of subunit c. In conclusion the archazolid binding site resides within the equatorial region of the VO rotor subunit c. This hypothesis was supported by an additional subset of mutations within helix 4 that revealed that leucine 144 plays a role in archazolid binding.

Rhodium-catalyzed enantioselective addition of organoaluminum reagents to N-tosyl ketimines.

Rhodium(I)/Binap complexes catalyze highly enantioselective additions of methyl- and arylaluminum reagents to cyclic α,β-unsaturated N-tosyl ketimines. Depending on the solvent and substituents at the ring, the reaction occurs either in a 1,2-manner to deliver α-tertiary allylic amines or in a 1,4-manner to yield, after subsequent reduction, 3-substituted cycloalkyl amines. Well known in the case of the respective cycloalkenones, these first transformations of the aza-analogues enable the synthesis of amine structures of pharmaceutical and biochemical interest.

The Binding Site of the V-ATPase Inhibitor Apicularen Is in the Vicinity of Those for Bafilomycin and Archazolid.

Background: Apicularen is a specific V-ATPase inhibitor that binds to the VO complex of the holoenzyme. Results: Apicularen binds at the interface of the VO subunits a and c. Conclusion: The binding site for apicularen is in the vicinity of those for bafilomycin and archazolid. Significance: We propose the first model of binding site arrangement for these three classes of V-ATPase inhibitors. The investigation of V-ATPases as potential therapeutic drug targets and hence of their specific inhibitors is a promising approach in osteoporosis and cancer treatment because the occurrence of these diseases is interrelated to the function of the V-ATPase. Apicularen belongs to the novel inhibitor family of the benzolactone enamides, which are highly potent but feature the unique characteristic of not inhibiting V-ATPases from fungal sources. In this study we specify, for the first time, the binding site of apicularen within the membrane spanning VO complex. By photoaffinity labeling using derivatives of apicularen and of the plecomacrolides bafilomycin and concanamycin, each coupled to 14C-labeled 4-(3-trifluoromethyldiazirin-3-yl)benzoic acid, we verified that apicularen binds at the interface of the VO subunits a and c. The binding site is in the vicinity to those of the plecomacrolides and of the archazolids, a third family of V-ATPase inhibitors. Expression of subunit c homologues from Homo sapiens and Manduca sexta, both species sensitive to benzolactone enamides, in a Saccharomyces cerevisiae strain lacking the corresponding intrinsic gene did not transfer this sensitivity to yeast. Therefore, the binding site of benzolactone enamides cannot be formed exclusively by subunit c. Apparently, subunit a substantially contributes to the binding of the benzolactone enamides.

Kinetic Resolution of Chiral Cyclohex-2-enones by Rhodium(I)/binap-Catalyzed 1,2- and 1,4-Additions

The feasibility of kinetic resolutions of racemic monosubstituted cyclohex-2-enones by Rh/binap-catalyzed reactions was investigated. 1,2-Addition of AlMe(3) to the 5-substituted derivatives furnished allylic alcohols in the matched case, while the less reactive enantiomers were either left over or transformed into trans-3,5-disubstituted cyclohexanones in parallel or sequential 1,4-additions. Altogether, these represent regiodivergent reactions on racemic mixtures. In contrast, 1,4-addition of aryl groups led to inferior results since either catalyst or substrate control dominated.

Enantioselective Synthesis of 3,4-Disubstituted cis- and trans-1,2,5-Thiadiazolidine-1,1-dioxides as Precursors for Chiral 1,2-Diamines

Both, cis- and trans-3,4-disubstituted thiadiazolidines 5 and 6 can enantioselectively be obtained from thiadiazoles 2 which, in turn, are efficiently prepared from the respective 1,2-diketone by an improved protocol. An asymmetric ruthenium-catalyzed transfer hydrogenation followed by a diastereoselective hydride addition furnishes exclusively the cis-isomers 5 which, under acidic conditions, undergo a novel isomerization into the trans-isomers 6. These cyclic sulfamides can be transformed into 1,2-diamines as well as 2,3-diamino acids.

Organoaluminum Couplings to Carbonyls, Imines, and Halides

While the stereoselective addition of zinc organyls to carbonyl compounds is nowadays an established synthetic method, the use of aluminum reagents is less common, even though they offer distinct advantages. This chapter presents an overview of the current status of catalytic asymmetric additions to aldehydes, ketones, and imines, as well as the difficulties and the limitations of such transformations, respectively. Certain combinations of substrate types and carbon nucleophiles were so far only achieved using stoichiometric systems under substrate or auxiliary control. These examples are also included, as well as aspects of cross-coupling reactions of aluminum organyls with organic halides.