Diels—Alder approach

A number of highly potent DHP-I stable iP-methylcarbapenems having a variety of C-2 substituents have now been described (60,66—69) including SM 7338 [96036-03-2] (42), C yH25N20 S. An acylamiao compound (66) and a iP-methoxy analogue (70) provide other variations. The pyrroHdine substituted iP-methyl-carbapenem SM 7338 (42) is being developed as a broad-spectmm parenteral antibiotic under the name meropenem the synthesis of (42) is by way of the lactone (43) derived by a novel Diels-Alder approach to dihydropyran precursors of (43) (71). 

With this foundation, Boger communicated the use of 1,2,4-triazines as a dependable, azadiene equivalent for Diels-Alder approaches to substituted pyridines. Electron rich olefin 19, prepared from the corresponding ketone, was allowed to... 

There are other Diels-Alder approaches to pyridines but they do not proceed in one step. For example, Weinreb reported the intramolecular Diels-Alder of oximino malonates tethered to a diene. Thermolysis of 102 produced 103 that upon treatment with base afforded pyridine 104. 

Scheme 6. Asymmetric Diels-Alder approach to enantiomerically pure iodolactone 32.

Scheme 8. Catalytic asymmetric Diels-Alder approach to ketone 30.

Vogel P. Combinatorial Diels-Alder Approach to the Synthesis of Anti-Tnmor Anthracyclines and Analogs Curr. Org. Chem. 1998 2 255 280... 

Keywords enantiospecific synthesis, intramolecular Diels-Alder approaches... 

In our efforts toward strychnine, we have integrated an intramolecular Diels-Alder approach to its tetracyclic core with an organometallic D-ring closure. Both of these key reactions were certainly inspired by the previous accomplishments of others as described above. 

The same author used this strategy to synthesize tricydic taxoid skeletons 55, an intramolecular Diels-Alder approach that proceeds in the direction from left to right (ring A to BC) (Scheme 9.14) [56], Once again, microwave irradiation was necessary to perform the required cycloaddition in good yield. 

Similarly, the P-phosphono-a,P-unsaturated carbonyl compounds thus synthesized have been used as dienes in a Diels-Alder approach toward the preparation of analogues of myo-inositol 1,4,5-triphos-phate,45 as well as other carbohydrate-related materials.46-48... 

Scheme 19.17 A tandem Diels-Alder approach to eleutherobin.

Rokach and colleagues79 made use of a Diels-Alder approach to synthesize iso-prostanes. Starting with dienes 67a/67b and enantiomerically pure (>99% ee) dienophile 68, they were able to obtain the desired adducts with high diastereofacial and regioselec-tivities (equation 23). Endo 69 and exo 70 were formed by attack of the diene at the less shielded upper face of the dienophile, whereas exo 71 resulted from attack at the more shielded lower face of 68. 

Scheme 27 Synthesis of the colombiane skeleton via double Diels-Alder approach...

Approaches to oseltamivir phosphate (1) that were independent of ( )-shikimic acid as the raw material were also evaluated. The furan-ethyl acrylate Diels-Alder approach is shown in Scheme 7.8 (Abrecht et al., 2001, 2004). The zinc-catalyzed Diels-Alder reaction between furan and ethyl acrylate was heated at 50°C for 72 h to provide a 9 1 mixture favoring exo-isomer rac-43 over the enJo-isomer. The enJo-isomer was kinetically preferred, but with increased reaction times an equilibrium ratio of 9 1 was achieved favoring the thermodynamically preferred exo-isomer rac-43. The optical resolution of rac-43 was achieved via enantioselective ester hydrolysis using Chirazyme L-2 to give (—)-43 in 97%... 

Scheme 7.8. The Diels-Alder approach to oseltamivir phosphate (1).

Two asymmetric Diels-Alder approaches to analogues like 830 and 831 have been described. In the hrst case, chiral catalysts were employed for an enantiose-lective Diels-Alder reaction, but unfortunately, none of the chiral catalysts showed any enantioselectivity upon analysis of the reaction mixtures. Alternatively, a chiral oxazolone 840 incorporating a menthyl carbonate at C-4 was prepared and used as a dienophile with cyclopentadiene. In this case, the exo/endo ratio was 60 40 but no signihcant endo or exo diastereoselectivity was obtained (Scheme 7.258). ° ... 

Related indolocarbazoles have been synthesized using a Diels-Alder/retro-Diels-Alder approach. The rigid dithiete intermediate 172 produced in the initial cycloadduct reaction undergoes sulfur extrusion and dehydrogenation under the reaction conditions to produce the fully aromatized product (Equation 106) <1999TL3795>. 

A. Dondoni, L. Kniezo, and M. Martinkova, A stereoselective hetero-Diels-Alder approach to carbon-carbon linked disaccharides, J. Chem. Soc. Chem. Commun. p. 1963 (1994). 

Lu, Y.-F. and Fallis, A.G., An intramolecular Diels-Alder approach to tricyclic taxoid skeletons, Tetrahedron... 

Table 3 Tetrahydroquinoline synthesis using an aza-Diels-Alder approach (Equation 133)...

A Diels-Alder approach to varenicline was recently published by Dr. Reddy s Laboratories. Entry to a key bicyclic intermediate is achieved by an iodide-catalyzed Diels-Alder reaction of tetrabromo dimethyl pyrazine (47) with excess norbomadiene. Dihydroxylation of 48, oxidative cleavage, and reductive amination prepares N-p-methoxybenzyl varenicline (50), which is deprotected under transfer hydrogenation conditions to give varenicline (1) in 10% yield for the sequence.47 This approach continues the theme of building the piperidine of 1 through olefin oxidative cleavage and reductive amination, but by doing so late in the sequence however, the approach... 

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