Intramolecular Alkyne-de Mayo Reaction Using the Enol Methylene Acetal Linker: Experimental Implementation and Computational Simulation.

The enol-linked intramolecular alkyne-de Mayo reaction is a photochemically triggered cascade reaction suitable for the synthesis of substituted dihydrotropones by two-carbon ring expansion of enol ethers of cyclopentane-1,3-dion. We report on the implementation of the methylene acetal linker and the isolation of the initial (2 + 2) photocycloadduct in substances. We have investigated in depth the modus operandi of the ring-opening of the π-donor-π-acceptor cyclobutene derivatives by computational chemistry.

Total Synthesis and Structural Assignment of (-)-Fusaequisin A.

(-)-Fusaequisin A is an irregularly assembled polyketide isolated from the ascomycete Fusarium equiseti. Fusaequisin A shares a carbon backbone with curvicollide C from the ascomycete Podospora curvicolla but its absolute configuration remained hitherto unsettled. Herein, we document the total synthesis of (-)-fusaequisin A and its 4-O-desmethyl derivative following a central-to-lateral building block strategy. Catalytic asymmetric Claisen rearrangement, Julia-Kocienski olefination and olefin cross-metathesis served as key C/C-connecting transformations. The constitution and absolute configuration of (-)-fusaequisin A was deduced and the original structural assignment was adjusted.

Photochemical Approach to the Cyclohepta[b]indole Scaffold by Annulative Two-Carbon Ring-Expansion.

We report on the implementation of the concept of a photochemically elicited two-carbon homologation of a π-donor-π-acceptor substituted chromophore by triple-bond insertion. Implementing a phenyl connector between the slide-in module and the chromophore enabled the synthesis of cylohepta[b]indole-type building blocks by a metal-free annulative one-pot two-carbon ring expansion of the five-membered chromophore. Post-irradiative structural elaboration provided founding members of the indolo[2,3-d]tropone family of compounds. Control experiments in combination with computational chemistry on this multibond reorganization process founded the basis for a mechanistic hypothesis.

Development of an Alkyne Analogue of the de†Mayo Reaction: Synthesis of Medium-Sized Carbacycles and Cyclohepta[b]indoles.

Embedded medium-sized carbacycles and cyclohepta[b]indoles occur frequently as scaffold elements in natural products and bioactive compounds. Described herein is a conceptionally novel photochemically triggered cascade process to these scaffolds. Key to the cascading ring-expansion process is an unprecedented intramolecular alkyne analogue of the de Mayo reaction.

Synthesis of Homoverrucosanoid-Derived Esters and Evaluation as MDR Modulators.

The synthesis of the A-B-cis,B-C-trans-annulated cyclohepta[e]hydrindane core of a gagunin E analogue is reported in detail. The tricarbocyclic scaffold was assembled starting from an easily accessible A ring building block by a (4 + 2)-cycloaddition for annulation of the B ring. A ring-closing metathesis served for construction of the seven-membered C ring. The angular methyl groups were attached by electrophilic cyclopropanation-ring opening. A library based on the most active lead compound was made accessible by esterification of the terpenols with commercially available acids. A transannular etherification reaction gave access to tetracyclic derivatives of the synthetic inhibitors. The members of the compound library of non-natural homoverrucosanoid-derived esters were examined as modulators of the membrane transporter proteins ABCB1 (P-gp), ABCG2 (BCRP), and ABCC1 (MRP1), which are involved in the formation of multidrug resistance (MDR) in cancer chemotherapy.

Catalytic asymmetric Claisen rearrangement of Gosteli-type allyl vinyl ethers: total synthesis of (-)-9,10-dihydroecklonialactone B.

The enantioselective synthesis of (-)-9,10-dihydroecklonialactone B is described. The catalytic asymmetric Claisen rearrangement of a Gosteli-type allyl vinyl ether was utilized to afford an acyclic α-keto ester building block endowed with functionality amenable to the preparation of the carbocyclic target molecule by suitable postrearrangement transformations: A highly diastereoselective Corey-Bakshi-Shibata reduction of a ß-chiral α-keto ester and a reductive homologation of an α-hydroxy ester. A transprotection tactic by a chemoselective intramolecular 6-exo-trig iodoetherification enabled regioselective ring-closing alkene metatheses to afford the 5- as well as the 14-membered ring, however, with mixed success in terms of E/Z selectivity.

Palladium(II)-catalyzed cycloisomerization of substituted 1,5-hexadienes: a combined experimental and computational study on an open and an interrupted hydropalladation/carbopalladation/ß-hydride elimination (HCHe) catalytic cycle.

The Pd(II)-catalyzed cycloisomerization of 3-alkoxycarbonyl-3-hydroxy-substituted 1,5-hexadienes has been studied experimentally and computationally. Experimentally, the reaction is characterized by a rapid room temperature formation of monomeric as well as dimeric cycloisomerization products using the commercially available precatalyst [(CH(3)CN)(4)Pd](BF(4))(2). In situ NMR measurements indicate the initial kinetic advantage of the desired cycloisomerization pathway to methylene cyclopentanes; however, double bond isomerization, elimination, and dimer formation are competitive undesired pathways. Evaluation of the obtained product structures by NMR spectroscopy and X-ray crystallography indicates that the sole determinant for the monomer/dimer ratio is the regioselectivity of the initial hydropalladation in favor of the allylic (monomer formation) or the homoallylic double bond (dimer formation). In order to account for the experimental results, we propose the coexistence of two product-forming catalytic cycles, an open, monomer generating, as well as an interrupted and redirected, dimer generating, hydropalladation/carbopalladation/ß-hydride elimination (HCHe) process. Results from computational studies of the proposed competing catalytic cycles are supportive to our mechanistic hypothesis and pinpoint the pivotal importance of Pd(II)-hydroxo-chelate complexes for the reactivity-stability interplay of on- and off-pathway intermediates.

(4R)-4-Benzyl-3-{(4S)-4-chloro-4-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]butano-yl}-1,3-oxazolidin-2-one.

The title compound, C(19)H(24)ClNO(5), was synthesized and subsequently employed in an Evans alkyl-ation. The purpose was to prove the absolute configuration in the projected synthesis of the side chain of (-)-Lytophilippine A. The oxazolidinone and the isopropylidene acetal rings have twisted conformations. The oxazolidinone and side-chain carbonyl groups are orientated in an anti-periplanar arrangement to minimize van der Waals repulsions. Furthermore, the Cl atom and the acetonide-protected secondary alcohol are also in an anti-periplanar arrangement with a torsion angle of 173.64 (14)°. The absolute configuration was determined and agrees with the configuration of the used chiral auxiliary.

Triphen-yl(prop-2-yn-1-yl)silane.

In the title compound, C(21)H(18)Si, the coordination geometry around the Si atom is a slightly distorted tetra-hedron with C-Si-C angles in the range 106.05 (11) to 110.58 (10) ° and Si-C bond lengths in the range 1.855 (2) to 1.883 (3) Å. The alkyne C-C bond length is 1.167 (4) Å. The dihedral angles between the three phenyl rings are 63.89 (7), 86.38 (7) and 70.51 (8)°. In the crystal, mol-ecules inter-act only by van der Waals forces.

Integration of catalysis and analysis is the key: rapid and precise investigation of the catalytic asymmetric Gosteli-Claisen rearrangement.

The kinetics of the Cu(II)(bisoxazoline)-catalyzed diastereo- and enantioselective Gosteli-Claisen rearrangement of 2-alkoxycarbonyl-substituted allyl vinyl ethers has been investigated by enantioselective on-column reaction gas chromatography (ocRGC). Enantioselective ocRGC integrates (stereoselective) catalysis and enantioselective chromatography in a single microcapillary, which is installed in a GC-MS for direct analysis of conversion and selectivity. Thus, this technique allows direct differentiation of thermal and stereoselectively catalyzed reaction pathways and determination of activation parameters and selectivities of the individual reaction pathways starting from stereoisomeric reactants with high precision. Two modes of operation of enantioselective ocRGC are presented to investigate noncatalyzed, i.e., conversion of isopropyl-2-(allyloxy)but-2Z-enoate 1 to isopropyl-3R,S-methyl-2-oxy-hex-5-enoate (±)-2 and the [Cu{(R,R)-Ph-box}](SbF(6))(2)-catalyzed Gosteli-Claisen rearrangement, i.e., conversion of isopropyl-2-(but-2'E-en-1-yloxy)but-2Z-enoate (E,Z)-3 to isopropyl-3S,4S-dimethyl-2-oxy-hex-5-enoate 4b. Eyring activation parameters have been determined by temperature-dependent measurements: Uncatalyzed rearrangement of 1 to (±)-2 gives ΔG(‡) (298 K) = 114.1 ± 0.2 kJ·mol(-1), ΔH(‡) = 101.1 ± 1.9 kJ·mol(-1), and ΔS(‡) = -44 ± 5 J·(K·mol)(-1), and catalyzed rearrangement of (E,Z)-3 to 4b gives ΔG(‡)(298 K) = 101.1 ± 0.3 kJ·mol(-1), ΔH(‡) = 106.1 ± 6.6 kJ·mol(-1), and ΔS(‡) = 17 ± 19 J·(K·mol)(-1).

Total synthesis of natural and non-natural Δ(5,6)Δ(12,13)-jatrophane diterpenes and their evaluation as MDR modulators.

We report the details of the total synthesis of natural and non-natural jatropha-5,12-dienes. The successful tactic for the assembly of the strained trans-bicyclo[10.3.0]pentadecane scaffold employed a B-alkyl Suzuki-Miyaura cross-coupling for the formation of the C5/C6 double bond and a ring-closing metathesis for the construction of the C12/C13 double bond. The key step of the synthesis of the cyclopentane fragment, an uncatalyzed intramolecular carbonyl-ene reaction, was studied computationally by DFT calculations. The members of the ensemble of synthetic natural and non-natural jatrophanes were subsequently examined as modulators for the ABCB1, ABCG2, and ABCC1 efflux proteins, which are associated with multidrug resistance in cancer chemotherapy.

1-Phenyl-5-{[2-(trimethyl-sil-yl)eth-yl]sulfon-yl}-1H-tetra-zole.

The title compound, C(12)H(18)N(4)O(2)SSi, was synthesized to be employed in a Julia-Kocienski olefination. In the mol-ecule, the dihedral angle between the phenyl ring and the tetra-zole ring is 41.50 (5)°. The significantly longer Si-C(methyl-ene) bond [1.8786 (13) Å] and the shortened adjacent C-C bond [1.5172 (18) Å], as well as the significant deviation of the corresponding Si-C-C angle [114.16 (9)°] from the ideal tetra-hedral angle, can be attributed to the ß-effect of silicon. In the crystal, mol-ecules are held together by van der Waals inter-actions.

(2R,4S,5S)-5-Meth-oxy-4-methyl-3-oxohept-6-en-2-yl benzoate.

The title compound, C16H20O4, was synthesized in the course of the total synthesis of fusaequisin A in order to verify and confirm the configurations of the stereogenic centers and to exclude the possibility of epimerization during the methyl-ation process. The crystal structure of the title compound at 100 K has ortho-rhom-bic (P212121) symmetry. The absolute configuration was determined by anomalous dispersion and agrees with the configuration of the allylic alcohol used in the synthesis.

(2SR,3SR)-Isopropyl 3-{[dimeth-yl(phenyl)-sil-yl]meth-yl}-2-hy-droxy-2-vinyl-pent-4-enoate.

The relative configuration of the title compound, C(19)H(28)O(3)Si, which was synthesized using a dienolate-[2,3]-Wittig rearrangement, was corroborated by single-crystal X-ray diffraction analysis. The Si-C bond distances are in the range 1.858 (2)-1.880 (2) Šand an intra-molecular O-H⋯O hydrogen bond helps to stabilize the mol-ecular conformation.

{2,2-Bis[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]propane}-bis-(N,N-dimethyl-formamide)-copper(II) bis-[hexa-fluoridoanti-monate(V)].

In the title compound, [Cu(C(15)H(26)N(2)O(2))(C(3)H(7)NO)(2)][SbF(6)](2), which is a potential catalyst in the catalytic asymmetric Gosteli-Claisen rearrangement, the central Cu(II) atom is in a nearly square-planar cis-N(2)O(2) environment in the cation arising from its coordination by an N,N-bidentate 2,2-bis-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]propane ligand and two O-bonded N,N-dimethyl-formamide mol-ecules. Two SbF(6) (-) anions are positioned on opposite sides of the plane through the CuN(2)O(2) unit, generating an axially distorted CuN(2)O(2)F(2) octa-hedral geometry for the metal ion.

Gosteli-Claisen rearrangement: DFT study of substituent-rate effects.

The uncatalyzed Gosteli-Claisen rearrangement of four double bond isomeric allyl vinyl ethers has been studied at the B3LYP/6-31G* and B3LYP/6-31G*+PCM levels of theory. The experimentally determined structure-reactivity relationship was successfully reproduced; the relative reactivity of the (E,E)-, (E,Z)-, (Z,E)-, and (Z,Z)-configured allyl vinyl ethers can be attributed to unfavorable interactions caused by pseudoaxial substituents within the chairlike transition-state structures. As expected, the isolated assessment of the calculated ground-state or transition-state stabilities is not suitable to explain the experimentally observed structure-reactivity relationship.

Synthetic studies toward jatrophane diterpenes from Euphorbia characias. Enantioselective synthesis of (-)-15-O-acetyl-3-O-propionyl-17-norcharaciol.

The enantioselective synthesis of (+)-17-norcharaciol is described. An uncatalyzed intramolecular carbonyl-ene reaction and a ring-closing metathesis were used as key C/C-connecting transformations to assemble the trans-bicyclo[10.3.0]pentadecane norditerpenoid core. We also report the evolution of our synthetic strategy toward the fully substituted characiol skeleton and the experiences from this venture.

Gosteli-Claisen rearrangement: substrate synthesis, simple diastereoselectivity, and kinetic studies.

The results of kinetic studies on the uncatalyzed [3,3]-sigmatropic rearrangement of 2-alkoxycarbonyl-substituted allyl vinyl ethers are reported. Apparently first reported by Gosteli in 1972, this variation of a Claisen rearrangement enjoyed a shadowy existence for three decades until its potential for the development of a catalytic asymmetric Claisen rearrangement was discovered. Inspired by this development, we have studied substituent and solvent rate effects, and we provide evidence that a chairlike transition state is highly favorable for the uncatalyzed Gosteli-Claisen rearrangement.

(3R,4R,5S)-4-Hydr-oxy-3-methyl-5-[(2S,3R)-3-methyl-pent-4-en-2-yl]-4,5-dihydro-furan-2(3H)-one.

The relative configuration of the title compound, C(11)H(18)O(3), which was synthesized using a catalytic asymmetric Gosteli-Claisen rearrangement, a diastereoselective reduction with K-Selectride and an Evans aldol addition, was corroborated by single-crystal X-ray diffraction analysis. The five-membered ring has an envelope conformation with a dihedral angle of 29.46 (16)° between the coplanar part and the flap (the hydr-oxy-bearing ring C atom). In the crystal, mol-ecules are connected via bifurcated O-H⋯(O,O) hydrogen bonds, generating [010] chains.

{2,2-Bis[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]propane}bis-(N,N-di-methyl-formamide)copper(II) bis-(hexa-fluoridoantimonate).

In the title compound, [Cu(C(17)H(30)N(2)O(2))(C(3)H(7)NO)(2)][SbF(6)](2), which is a potential catalyst in the asymmetric Gosteli-Claisen rearrangement, the Cu atom adopts a distorted cis-CuN(2)O(2) square-planar geometry arising from N,N'-bidentate coordin-ation by the chiral ligand and two O-bonded dimethyl-formamide mol-ecules. Two short C-H⋯O contacts occur within the ligand and two weak inter-molecular C-H⋯F bonds may help to establish the packing.