Metal-free,noncovalent catalysis of diels-alder reactions by neutral hydrogen bond donors in organic solvents and in water

We examined the catalytic activity of substituted thioureas in a series of Diels-Alder reactions and 1,3-dipolar cycloadditions. The kinetic data reveal that the observed accelerations in the relative rates are more dependent on the thiourea substituents than on the reactants or solvent. Although the catalytic effectiveness is the strongest in noncoordinating, nonpolar solvents, such as cyclohexane, it is also present in highly coordinating polar solvents, such as water. In 1,3-dipolar cycloadditions, the thiourea catalysts demonstrate only very moderate selectivity for reactions with inverse electron demand. Our experiments emphasize that both hydrophobic and polar interactions can co-exist, making these catalysts active, even in highly coordinating solvents. This class of catalysts increases the reaction rates and endo-selectivities of Diels-Alder reactions, in a similar manner to weak Lewis acids, without concomitant product inhibition.     

Cage-shaped borate esters with tris(2-oxyphenyl)methane or -silane system frameworks bearing multiple tuning factors: geometric and substituent effects on their Lewis acid properties

Boron complexes that contain new tridentate ligands, tris(o‐oxyaryl)methanes and ‐silanes, were prepared. These complexes had a cage‐shaped structure around a boron center and showed higher Lewis acidity and catalytic activity than open‐shaped boron compounds. The cage‐shaped ligands determined the properties of the borates by altering the geometry and were consistently bound to the metal center by chelation. The synthesized compounds were L?B(OC₆H₄)₃CH, L?B(OC₆H₄)₃SiMe, and its derivatives (L=THF or pyridine as an external ligand). Theoretical calculations suggested that the cage‐shaped borates had a large dihedral angle (C_ipso‐O‐B‐O) compared with open‐shaped borates. The geometric effect due to the dihedral angle means that compared with open‐shaped, the cage‐shaped borates have a greater Lewis acidity. The introduction of electron‐withdrawing groups on the aryl moieties in the cage‐shaped framework increased the Lewis acidity. Substitution of a bridgehead Si for a bridgehead C decreased the Lewis acidity of the boron complexes because the large silicon atom reduces the dihedral angle of C_ipso‐O‐B‐O. The ligand‐exchange rates of the para‐fluoro‐substituted compound B(OC₆H₃F)₃CH and the ortho‐phenyl‐substituted compound B(OC₆H₃Ph)₃CH were less than that of the unsubstituted borate B(OC₆H₄)₃CH. The ligand‐exchange rate of B(OC₆H₄)₃SiMe was much faster than that of B(OC₆H₄)₃CH. A hetero Diels–Alder reaction and Mukaiyama‐type aldol reactions were more effectively catalyzed by cage‐shaped borates than by the open‐shaped borate B(OPh)₃ or by the strong Lewis acid BF₃?OEt₂. The cage‐shaped borates with the bulky substituents at the ortho‐positions selectively catalyzed the reaction with less sterically hindered substrates, while the unsubstituted borate showed no selectivity.     

Unusual coupling reactions of aldehydes and alkynes: a novel preparation of substituted phthalic acid derivatives by automated synthesis

Based upon a highly versatile multicomponent methodology, a new one-pot synthesis of substituted phthalic acid derivatives from alpha,beta-unsaturated aldehydes was developed. The reaction involves the intermediacy of an acetamidodiene species which undergoes Diels-Alder addition to diethyl acetylenedicarboxylate. The resultant acetamidocyclohexadiene is subject to elimination of acetamide under the reaction conditions to give rise to substituted diethyl phthalates in good yields. This domino condensation-cycloaddition-elimination sequence has been applied to a variety of alpha,beta-unsaturated aldehydes. Furthermore, we demonstrated the exploitation of parallelized and automated synthesis technology for the rapid screening of reaction conditions and compositions. Detailed studies revealed the catalytic role of the employed acetamide and the occurrence of a stereoselective 1,4-syn elimination pathway under standard conditions.     

Expeditious asymmetric synthesis of a stereoheptad corresponding to the C(19)-C(27)-ansa chain of rifamycins: formal total synthesis of Rifamycin S

In the presence of sulfur dioxide and an acid promoter, (-)-(1E,3Z)-2-methyl-1-((1S)-1-phenylethoxy)penta-1,3-dien-3-yl isobutyrate reacts with (Z)-3-(trimethylsilyloxy)pent-2-ene giving a silyl sulfinate intermediate that undergoes, in the presence of palladium catalyst, a desilylation and retro-ene elimination of SO(2) with formation of (-)-(1Z,2S,3R,4S)-1-ethylidene-2,4-dimethyl-5-oxo-3-((1S)-1-phenylethoxy)-heptyl isobutyrate as major product. This ethyl ketone undergoes cross-aldol reaction with (2S)-2-methyl-3-[(tert-butyldimethylsilyl)oxy]propanal giving an aldol that is reduced into a stereoheptad corresponding to the C(19)-C(27)-segment of Rifamycins with high diastereoselectivity and enantiomeric excess.     

The Dihydropyrone Diels–Alder Reaction: Development and Application to the Synthesis of Highly Functionalized 1-Oxa-4-decalones

A facile method for the synthesis of highly functionalized 1-oxadecalone derivatives is described via the Diels–Alder reaction of 2,3-dihydro-4-pyrone dienophiles with electron rich dienes. By this process a variety of functional groups and substitution patterns can be incorporated into the oxadecalone framework.     

A new phototransformation of methoxycarbonyl-substituted (E,Z,E)-1,3,5-hexatrienes: easy access to ring-annelated 8-oxabicyclo[3.2.1]octa-2,6-diene derivatives

On attempting photochemically induced electrocyclizations of the previously reported 1,6-bismethoxycarbonyl- or 1,6-bistrimethylsilyl-substituted ring-attached (E,Z,E)-1,3,5-hexatrienes 4 b, 4 c and 5 b, 5 c, equilibrium mixtures of the starting materials and their diastereomers, the corresponding (E,Z,Z)-hexatrienes 4 b, 4 c and 5 b, 5 c were obtained. The desired trans-disubstituted ring-annelated cyclohexadienes 9 b and 10 b were formed by subsequent thermal 6pi-electrocyclization of the (E,Z,Z)-hexatrienes 4 b and 5 b in good yields (77-83 %). Upon treating the bissilyl-substituted hexatrienes (E,Z,E)-5 c or (E,Z,Z)-5 c under the same conditions, 6pi-electrocyclizations did occur, but the primary products immediately isomerized to a large extent, and mixtures of the cyclohexane-annelated cyclohexadienes 10 c-12 c along with the dehydrogenation products 13, 14 c were formed. When the bismethoxycarbonyl-substituted hexatriene (E,Z,E)- 5 b was irradiated for an extended period of time (4.5 h), the gradual formation of the oxabicyclo[3.2.1]octa-2,6-diene 17 b by a formal intramolecular hetero-Diels-Alder reaction was observed and 17 b could be isolated in up to 69 % yield. To explore the scope of this new photochemical reaction, the new ring-attached (E,Z,E)-hexatrienes 4 a, 5 a and 6 b were synthesized by twofold Heck reactions from 1,2-dibromocycloalkenes 1-3 (59-66 %). While irridiation of the cyclopentene-attached 1,3,5-hexatrienes only led to decomposition, the cyclohexene- and cycloheptene-attached hexatrienes gave the hetero-Diels-Alder products or other photoproducts depending on the size of the cycloalkene moiety and the nature of the alkoxycarbonyl substituents at the vinyl termini. The photoreaction products 17 b and 18 b which are bicyclic acetals, underwent cleavage upon treatment with a Lewis acid such as Me(3)SiOTf to give the ring-annelated methoxycarbonyl-substituted troponecarboxylates 21 b and 22 b.     

Total synthesis of 7-ethyl-10-hydroxycamptothecin (SN38) and its application to the development of C18-functionalized camptothecin derivatives

A new chemical synthesis of SN38, the active metabolite of the camptothecin prodrug irinotecan, has been achieved in 12 steps from simple, commercially available starting materials. A mild and efficient FeCl₃‐catalyzed Friedländer condensation was successfully applied to construct the AB ring system. Functionalization of the C ring was accomplished by a vinylogous Mukaiyama reaction of an in situ generated N‐acyliminium intermediate with a silyl enol ether. An intramolecular oxa Diels–Alder reaction efficiently constructed the D and E rings in one step. Successive asymmetric dihydroxylation and I₂‐based hemiacetal oxidation furnished the stereochemistry of SN38 with high enantiopurity. Utilizing the ABC‐ring intermediate and a functionalized silyl enol ether permitted the synthesis of a number of new C18‐functionalized SN38 derivatives. Several of the novel SN38 derivatives that bore a C10 methoxy group were found to exhibit comparable or more potent inhibitory activity against the proliferation of cancer cells relative to SN38.     

Asymmetric binary-acid catalysis with InBr3 in the inverse-electron-demanding hetero-Diels-Alder reaction of mono- and bis-substituted cyclopentadienes: remote fluoro-effect on stereocontrol

Remote F effect: Unprecedented hetero-Diels-Alder reactions of mono- and bis-substituted cyclopentadienes have been realized by an asymmetric binary-acid catalyst that synergistically combines a chiral phosphoric acid 1?h/InBr(3) with good periselectivity, high regioselectivity, and excellent stereoselectivity. Substituent mapping of the chiral phosphoric acid indicates a dramatic remote ortho-fluoro effect on the stereocontrol.