The ability of supramolecular host-guest complexes to catalyse organic reactions collaboratively with an enzyme is an important goal in the research and discovery of synthetic enzyme mimics. Herein we present a variety of catalytic tandem reactions that employ esterases, lipases or alcohol dehydrogenases and gold(I) or ruthenium(II) complexes encapsulated in a Ga(4)L(6) tetrahedral supramolecular cluster. The host-guest complexes are tolerated well by the enzymes and, in the case of the gold(I) host-guest complex, show improved reactivity relative to the free cationic guest. We propose that supramolecular encapsulation of organometallic complexes prevents their diffusion into the bulk solution, where they can bind amino-acid residues on the proteins and potentially compromise their activity. Our observations underline the advantages of the supramolecular approach and suggest that encapsulation of reactive complexes may provide a general strategy for carrying out classic organic reactions in the presence of biocatalysts.

A polyanionic supramolecular assembly (1) is shown to catalytically cyclize the monoterpene citronellal and two homologues. In contrast to cyclization in acidic aqueous solution, the hydrophobic interior of 1 prevents the capture of reactive intermediates by water. This effect was also observed in the gold-catalyzed cycloisomerization of an enyne. Due to the steric confinement of the catalyst's interior, Prins cyclizations in 1 proceed cleanly both for substrates containing and lacking gem-dimethyl substitution. Encapsulation in 1 consequently imposes a degree of mechanistic control that, similar to enzyme catalysis, is not observed in bulk aqueous solution.

Introduction 4499 2. Diels-Alder Cycloadditions 4499 2.1. Unsaturated Sulfones as Dienophiles 4499 2.1.1. Early Studies 4499 2.1.2. Aromatization of Cycloaddition Products of Acetylenic Sulfones 4501 2.1.3. Iterative Diels-Alder and Ramberg-Backlund Reactions of Chloroalkylsulfonyl Allenes 4502 2.1.4. Diels-Alder Cycloadditions of Bis(sulfonyl)acetylenes and Their Equivalents 4502 2.1.5. Diels-Alder Cycloadditions of Acetylenic Sulfones Containing Heteroatom Substituents 4503 2.1.6. Diels-Alder Reactions of Dienyl Sulfones as Dienophiles 4504 2.1.7. Diels-Alder Reactions of Unsaturated Sulfones with Pyrroles 4505 2.1.8. Diels-Alder Reactions of Unsaturated Sulfones with Furans and Isobenzofurans 4507 2.1.9. Miscellaneous Cycloadditions 4508 2.2. Dienyl Sulfones As the Diene Components in Diels-Alder Reactions 4509 2.2.1. 1-Sulfonyl Derivatives † Dedicated to Professor David N. Harpp, for his inspiring contributions as a teacher, mentor and scholar.

The aza-Morita-Baylis-Hillman reactions of aldimines 2 with several activated conjugated dienes were found to proceed smoothly in DMF in the presence of 3-hydroxyquinuclidine (HQD). Imines 2 reacted with 1-(p-toluenesulfonyl)-1,3-butadiene (3), methyl 2,4-pentadienoate (6), hexa-3,5-dien-2-one (7), and 1-phenylpenta-2,4-dien-1-one (8) to afford adducts 4, 13, 14, and 15, respectively. While products 4, 13, and 15 were formed as E,Z mixtures, adducts 14 were obtained as essentially pure E-isomers. Cyclization of the E-isomers of the products derived from the dienyl sulfone 3 and the dienoate ester 6 occurred via intramolecular conjugate addition under base-catalyzed conditions to afford functionalized piperidines 5 and 16, respectively. The aza-Morita-Baylis-Hillman reaction and subsequent cyclization of the imine 2a with 3 were also carried out as a one-pot reaction, while the reaction mixture was simultaneously irradiated at 300 nm to effect the photoisomerization of the unreactive Z-adduct of the corresponding 4 to the more reactive E-isomer.

Aldimines underwent Morita-Baylis-Hillman reactions with dienes activated by sulfonyl or nitrile groups. The N-allyl or propargyl derivatives of the products were subjected to intramolecular Diels-Alder cycloadditions to produce the corresponding partly saturated 1-arylisoindoline derivatives. The cycloadducts in the nitrile-activated N-propargyl series were aromatized by base-mediated elimination of HCN to afford 1-arylisoindolines, which were in turn oxidized to the corresponding 3-arylisoindolin-1-ones.

Aza-Morita-Baylis-Hillman (aza-MBH) products derived from arylimines and methyl acrylate or acrylonitrile were N-alkylated with (E)-5-bromopenta-1,3-diene, and the resulting trienes were subjected to intramolecular Diels-Alder (IMDA) cyloadditions to afford the corresponding trans- and cis-fused tetrahydroisoindolines as the major and minor products, respectively. Catalysis with boron trichloride improved the IMDA diastereoselectivities of the nitrile derivatives, while yields were improved in both the nitrile and ester series. Treatment of the nitrile-substituted trienes with DABCO in DMF resulted in unexpected transposition of the N-(pentadienyl)sulfonamide group to the beta-position of the acrylonitrile moiety. Subsequent IMDA cycloadditions produced cis-fused positional isomers of the previous tetrahydroisoindolines. When the products of vinylogous aza-MBH reactions in the nitrile series were N-propargylated, the resulting dienynes underwent a similar transposition and IMDA reaction, producing trans and cis diastereomers of the corresponding dihydroisoindolines as the major and minor products, respectively. In all but one case, only the former products were observed in the presence of methylaluminum dichloride, while the corresponding aromatized isoindolines were obtained when the IMDA reactions were carried out in the presence of DDQ. Thus, a variety of aryl-substituted isoindoline products with different levels of unsaturation and complementary substitution patterns and stereochemistry are readily available through these processes.

A concise and efficient synthesis of the antimycotic alkaloid onychine was developed, based on the vinylogous aza-MoritaBaylis-Hillman reaction of N-(benzylidene)benzenesulfonamide with methyl 2,4-pentadienoate, followed by intramolecular conjugate addition, Friedel-Crafts acylation, methyl cuprate addition, and aromatization.The 4-azafluorenones are a group of biologically interesting alkaloids found in trees of the family Annonaceae. 1 Onychine (1, Figure 1) was the first 4-azafluorenone to be discovered and was initially isolated from the trunkwood of the Brazilian tree Onychopetalum amazonicum in 1976. 2 The structure originally assigned to onychine 1 was erroneous; however, it was later corrected on the basis of NMR studies and total synthesis. 3 Interestingly, Taylor and co-workers 4 completed the first synthesis of this compound as an intermediate en route to the related alkaloid eupolauridine (2), before onychine was discovered as a natural product. It was not until 1979 that Koyama et al. 3a realized that the structures of the Taylor intermediate and the natural product were identical. Alkaloids 1 and 2 display antimycotic activity against C. albicans, 5,6 as well as antibacterial activity, 6 prompting the development of several approaches toward their synthesis. Onychine has been prepared by an enamine triazine cycloaddition, 3b a Yb(OTf) 3 -catalyzed [4+2] cycloaddition, 7 a Pummererdipolar cycloaddition cascade, 8 an oxidative thermal rearrangement of 2-indanone oxime O-crotyl ether, 9 zeolite 10 or polyphosphoric acid catalyzed 11 cyclizations of 2-aryl-3-nicotinic acid derivatives, Pd(0)-catalyzed cross coupling of aryl-12 or methylboronic acids 13 with 2-halopyridines, and via an aza-Wittig reaction. 14 Figure 1We recently reported a novel vinylogous variation of the aza-Morita-Baylis-Hillman (aza-MBH) reaction, 15 in which suitably activated dienes 4 reacted with imines 3 in the presence of the nucleophilic catalyst 3-hydroxyquinuclidine (HQD) to afford products 5. 15a,b During these investigations, we observed that when the electronwithdrawing group (EWG) was a sulfonyl or ester moiety, the aza-MBH adduct cyclized via a base-catalyzed intramolecular conjugate addition to afford tetrahydropyridine derivatives 6. Unfortunately, this cyclization occurred exclusively from the E-isomers of 5, as the Zisomers did not have the appropriate geometry to assume the required six-membered transition state for intramolecular conjugate addition. Furthermore, the aza-MBH reactions with these EWG typically gave only moderate to low selectivities, with E/Z ratios ranging from 50:50 to 80:20. In order to overcome this limitation, we employed a convenient in situ photoisomerization of the E/Z mixtures during the cyclization procedure, resulting in the equilibration and ultimate consumption of both geometrical isomers (Scheme 1). We now demonstrate the application of this methodology to the total synthesis of the alkaloid onychine (1). Scheme 1The tetrahydropyridine 7, which we had prepared previously in two separa...

Review: 516 refs.