Synthesis of densely functionalized

Gomez, A.M., L6pez, J.C., Fraser-Reid, B. (1994) Serial Radical Cyclization ofPyranose-Derived Dienes in the StereocontroUed Synthesis of Densely Functionalized Cyclohexanes. A Route to Woodward s Reserpine Precursor. Journal of Organic Chemistry, 59, 4048M 050. 

Marco, LL., and Chinchon, P.M., Michael reactions of P-keto phosphonates with aryhnethylenema-lononitriles. The first synthesis of densely functionalized 5-diethylphosphinyl-2-amino /7-pyrans, Heterocycles, 51, 1137, 1999. 

Guerra, F.M., Mish, M.R., and Carreira, E.M., Versatile, diastereoselective additions of sUyl ketene acetals, allyl tributylstannane, and Me3SiCN to N-acyl pyrazolines asymmetric synthesis of densely functionalized pyrazolidines, Org. Lett. 2 (26), 4265, 2000. 

Within the following sections on general methodology, examples of oxindoles with relatively simple substitution patterns have been selected for making reasonable comparisons between different strategies for bond construction. Applications of methods toward the synthesis of densely functionalized oxindoles within sensitive chemical environments appear within the section on natural product total synthesis. 

Scheme 2.15 Enantioselective Michael addition of aldehydes with functionalized nitroalkenes and an application to the total synthesis of densely functionalized homoprolines and natural product (-)-botryodipIodin.

S. Samai, G. Chandra Nandi, S. Chowdhury, M. S. Singh, Tetrahedron 2011, 67, 5935-5941. L-Proline catalyzed synthesis of densely functionalized pyrido[2,3-d]pyrimidines via three-component one-pot domino Knoevenagel aza-Diels-Alder reaction. 

Khan AT, Khan MM, Bannuru KKR (2010) Iodine catalyzed one-pot five-component reactions for direct synthesis of densely functionalized piperidines. Tetrahedron 66 7762-7772... 

Brahmachari, G., and Das, S. (2012). Bismuth nitrate-catalyzed multicomponent reaction for efficient and one-pot synthesis of densely functionalized piperidine scaffolds at room temperature. Tetrahedron Lett., 53, 1479-1484. 

An elegant approach to the diastereoselective synthesis of densely functionalized 1,2,5,6-tetrahydropyridines 31 based on the a,Y-difunctionalization of 1,3-dicarbonyl compounds was pioneered in 2007 by Clarke [23], and then followed up by other groups [24-26], It generates five new eovalent bonds and proceeds via a domino pseudo five-component reaction from anilines, aromatic aldehydes (2 equiv. of each). 

Synthesis of Densely Loaded APTMS-Functionalized SBA-15 (6)-Control Sample. Excess 3-aminopropyltrimethoxysilane (0.5 g, 2.79 mmol APTMS) was added to 1 g of SBA-15 in anhydrous toluene. The mixture was allowed to stir for 24 h at room temperature under argon. The resulting sohd was filtered, washed with toluene, dried under vacuum at room temperature overnight, and then stored in a drybox. TGA showed 1.15 mmol/g Si02 of APTMS was immobilized on the SBA-15. 

A microwave-driven Sonogashira coupling step is involved in the total synthesis of azaphilones, a structurally diverse family of natural products containing a highly oxygenated bicyclic core and a quaternary center. Porco and his colleagues have described the alkynylation of densely functionalized bromobenzaldehydes with... 

Zhang et al. reported the use of densely functionalized molecules through Suzuki cross-coupling reactions [65]. This synthesis involves the reductive amination of mucaholic acids to form the unexpected lactone (e.g., 82). Compound 82 can then be reacted with phenylboronic acid (83) to form the 2,3-diaryl-a, /J-unsaluralcd-y-lactone 84 as outlined in Scheme 19 in a 78% yield. A similar procedure is outlined in the work of Beilina et al. [66]. 

Servin P, Rebout C, Laurent R, Peruzzini M, Caminade A-M, Majoral J-P. Reduced number of steps for the synthesis of dense and highly functionalized dendrimers. Tetrahedron Lett... 

A bioxantracene (-)-ES-242-4 (46) was isolated from the culture broth of Verticillium sp. in 1992 as one of eight antagonists for the 7V-methy 1-D-aspartate (NMDA) receptor (7<5). These novel natural products are reported to inhibit the PH]thienyl cyclohexylpiperidine binding to rat crude synaptic membranes, and therefore, are of potential therapeutic interest for die treatment of neurodegenerative diseases. (-)-ES-242-4 (46) is structurally remarkable having an axially chiral binaphthalene core that is adorned with two pyrans of the same absolute chirality. Our interest in the construction of densely functionalized naphthopyran ring systems, via tandem Michael-Dieckmann reactions, promoted us to attempt the first stereocontrolled total synthesis of (-)-ES-242-4 (46) (19). 

Diels-Alder reactions of alkynyl(phenyl)iodonium triflates (i.e. containing electron-withdrawing groups in the alkynyl moiety) and [bis(phenyliodonium)] ethyne ditrifiate have been employed for the synthesis of cyclic vinyliodonium salts (equations 143 and 144)17,41. The availability of such compounds offers considerable potential for the elaboration of densely functionalized cyclic molecules. 

To expedite the synthesis of densely packed dendrons, Percec and co-workers110 have utilized the triply branched monomer 37, methyl 3,4,5-trihydroxy-benzoate.84-85 111-113 The materials were synthesized by coupling the phenolic groups of the monomer to 3 equiv of a benzylic chloride, followed by transformation of the focal ester functionality to a chloromethyl group, via LiAlFF reduction and SOCT chlorination. This procedure could be repeated up to the fourth generation. 

Total synthesis of amphidinolides X (23) and Y (24) have been accomplished by Professor Fiirstner s group using a powerful iron-catalyzed process (Scheme 8), while amphidinolide Y (24) has been synthesized by Professor Dai s group using the formation of trisubstituted ( )-double bond through ring-closing metathesis of densely functionalized alkenes (Scheme 9). ... 

A range of densely functionalized five- and six-membered nitrones were formed in this way, and the method is proposed as suitable for the synthesis of the alkaloid laccarin. Under the influence of nucleophilic fluoride sources, including TBAT, a carbamoyl silane undergoes addition to ketones and aldehydes to give a-silyloxyamide products. TBAT can be used in combination with Mc3SiN3 to effect glycosyl azide formation, and finally it can be used to effect self-condensation of some unsaturated carbonyl compounds, a process in which fluoride presumably acts as a base. ... 

Practically, the design of new MBFTs requires the use or the synthesis of substrates displaying several complementary reactive sites, which can be exploited successively in the transformation. Some families of densely functionalized small molecules are particularly well adapted to serve as substrates for these reactions. We can cite, for... 

Huang A, Wang N, Caro J. Seeding-free synthesis of dense zeolite FAU membranes on 3-aminopropyltriethoxysiolane-functionalized alumina supports. J Membr Sci 2012 389 272. 

Inspired by the success of intramolecular addition and tautomerization of aldehydes with a pendant alkyne through cooperative catalysis of a secondary amine and an An complex, in 2008, Yang et al. reported a cascade reaction with the combination of a copper complex and an achiral secondary amine catalyst for the synthesis of attractive carbocycles [48]. This chemistry merged a pyrrolidine-promoted Michael addition via iminium ion intermediates and a Cu-catalyzed cycloisomerization protocol (Scheme 9.54). Various ketones and alkyne-tethered active methylene compounds could be converted into densely functionalized cyclopentene derivatives. Although the asymmetric version was not given, the chemistry described here was amenable for the implementation of asymmetric synthesis of such functionalized molecules by a combination of chiral amines and suitable Au complexes. 

Lithiation of (7 )-ethyl / -tolyl sulfoxide 41 and condensation with the imine 33 afforded the P-sulfinyl amines 42,43 in almost equimolar ratio (50). These compounds are key intermediates for the preparation of both enantiomers of a-Tfm-butyrine 44 (Scheme 9), as well as of densely functionalized a-Tfm-allo-threoninate 45 and threoninate 46. In the synthesis of compounds 45,46 the lithium derivative of sulfoxide... 

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