Heterocycles functionalizations

Large, rigid molecules with functional heterocyclic units (effectors) located on a carbocyclic framework and taking part in 1,3-dipolar cycloaddition and heterodiene reactions 98SL566. 

Synthesis, reactions, and metal-chelating properties of functionalized heterocycles possessing N-hydroxyamide moiety 97YGK524. 

Synthesis of the densely functionalized heterocyclic system of antitumor antibiotics azinomycins AandB, azirino [l,2-<2]pyrrolidine derivatives 98SL1031. 

The potential of such reaction sequences for the generation of molecular diversity was also demonstrated by the synthesis of a library of heterocycles. Epoxide ring-opening with hydrazine and subsequent condensation with (3-diketones or other bifunctional electrophiles gave rise to a variety of functionalized heterocyclic structures in high purity [34]. A selection based on the substrate derived from cyclohexene oxide is shown in Scheme 12.12. 

An advantage of the metal-catalyzed conversion of styrenyl ethers to chromenes is that control of relative stereochemistry on the carbocyclic substrate before catalytic synthesis of chromenes can lead to the formation of various functionalized heterocycles that are diastereomerically pure (Table 1). 

The examples illustrated in the almost 100 schemes in this chapter demonstrate how versatile donor-substituted allenes can be in synthetic processes. The major applications concern addition reactions and cycloadditions to the allenic double bonds, which furnish products with valuable functional groups. Of particular interest are metalations - usually at C-l of the allene unit - followed by reactions with electrophiles that deliver compounds which can often be used for cyclization reactions. A variety of highly substituted and functionalized heterocycles arises from these flexible methods, which cannot be obtained by other reactions. Many of these transformations proceed with good regioselectivity and excellent stereoselection. 

With the fully functionalized heterocyclic core completed, synthetic attention next focused on introduction of the 3,5-dihydroxyheptanoic acid side-chain. This required initial conversion of the ethyl ester of 35 to the corresponding aldehyde through a two-step reduction/oxidation sequence. In that event, a low-temperature DIBAL reduction of 35 provided primary alcohol 36, which was then oxidized to aldehyde 37 with TRAP. Subsequent installation of the carbon backbone of the side-chain was accomplished using a Wittig olefination reaction with stabilized phosphonium ylide 38 resulting in exclusive formation of the desired -olefin 39. The synthesis of phosphonium ylide 38 will be examined in Scheme 12.5 (Konoike and Araki, 1994). 

The reaction of triphenylphosphine and dimethyl acetylenedicarboxylate (DMAD) in the presence of either 2-, 3-, or 4-aminophenol and 2-amino-3-hydroxypyridine gives a vinylphosphonium salt which undergoes Michael addition to give a range of highly functionalized heterocyclic systems <2002T6895>. 

Functionalized heterocycles such as 308 can be prepared in a one-pot synthesis, in which the key step is the addition-elimination of a functionalized copper-zinc reagent 309 to the unprotected 3-iodoenone 310, producing the annelated heterocycle 308 in 41% (Scheme 87) . ... 

C-Ethenylpyrroles 140 proved to be rewarding starting materials for the synthesis of diverse functionalized heterocyclic assemblies with pyrrole moieties pyrrolyl-pyrazoles (99RJ01214, OOSULl, 01RJO1736),... 

Cheng, Q. Oritani, T. Horiguchi, T. Yamada, T. Mong, Y. Synthesis and biological evaluation of novel 9-functional heterocyclic coupled 7-deoxy-9-dihydropaclitaxel analogues. Bioorg. Med. Chem. Lett., 2000, 10 517-521. 

In addition to isocyanide-based MCRs, a wealth of highly functionalized heterocycles can be obtained from 1,3-dicarbonyl, cyanomalonate and malononitrile based MCRs [19]. These easily accessible starting materials participate in a variety of multi-component reactions and have found numerous applications in drug discovery. 

Some noteworthy intramolecular nucleophilic ring openings have been reported in the recent literature, which can be used to prepare functionalized heterocycles of synthetic interest. For example, the highly oxygenated epoxide 100 undergoes rearrangement induced by boron trifluoride etherate, whereby anchimeric assistance from the pendant phenylthio substituent leads to an intermediate episulfonium ion 101 which subsequently suffers 5-e o-tet cyclization to form the tetrahydrofiiran derivative 102 <03TL5547>. 

Highly functionalized heterocycles can be easily generated using RCM reactions. The Hanson group has demonstrated that a family of highly functionalized sulfur and phosphorous compounds can be prepared in good yield using the ruthenium catalysts (Eq. 6.10) [31]. 

Xia, Q., Ganem, B. Metal-Promoted Variants of the Passerini Reaction Leading to Functionalized Heterocycles. Org. Lett. 2002, 4, 1631-1634. 

Benmansour, H., Chambers, R. D., Sandford, G., et al (2001) Multi-functional heterocycles from bromofluoro pyridine derivatives. J. Fluorine Chem., 112, 349-355. 

These selected synthetic applications of the ring-closing allylation reaction illustrate the opportunities for obtaining with high stereoselectivity functionalized heterocycles and carbocycles, common units found in natural products. Other applications of intramolecular allylation reactions have been reported [95-101, 103]. 

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