Bicyclic scaffold

The polymerization of several different protected monomers was executed with the molybdenum initiator. Two types of norbornene templates were generated as mixtures of diastereomers one class possessed a single saccharide substituent attached through either an endo or exo ester group, and the other was equipped with two carbohydrate residues appended to the bicyclic scaffold... 

Banfi L, Basso A, Guanti G, Merlo S, Repetto C, Riva R (2008) A convergent synthesis of enantiopure bicyclic scaffolds through multicomponent Ugi reaction. Tetrahedron 64 1114-1134... 

Bicyclic nitroso acetals were able to be synthesised by employing ethyl vinyl ether (dienophile), styrene (dipolarophile) and the previously discussed resin-bound ni-troalkenes in a one-pot tandem [4+2]/[3+2]. As illustrated in Scheme 7.30, several aromatic and aliphatic substituents could be introduced to the bicyclic scaffold. Reductive cleavage of the cycloadducts with lithium aluminium hydride (LLAIH4) gave rise to the 3a-methyl alcohol substituted nitroso acetals in moderate overall yields. All these examples demonstrate that resin-bound nitroalkenes can be readily synthesised by microwave synthesis and thereafter can be used as starting materials, in a variety of high pressure-promoted cycloadditions. 

The higher rigidity of the bicyclic scaffolds could favor the preferential formation of one of the two diastereoisomeric intermediates 71 and therefore explain the observed selectivity for compounds 73-75. 

The above-described problem demonstrates the first enantioselective synthesis of dysidiolide, a C25 isoprenoid antimitotic agent. The central transformations are the sulfenylation-dehydrosulfenylation sequence to prepare an a,/5-tnone, the biomimetic cationic 1,2-rearrangement to form stereoselectively the bicyclic scaffold, vinyl cuprate displacement of an iodide furnishing the C-l side chain and the photochemical oxidation of furan to generate the j hydroxy-butenolide functionality. 

Significant effort has been focused on bicyclic scaffolds, such as chromanes and indanes, but only recently published research has attempted to establish the role of conformational rigidity in these series, utilizing bicyclic substitutions, or substitution with acyclic derivatives. On the one hand, results from this type of chemistry on an indane scaffold suggested that conformational constraint is not required for Kvl.5 activity [55]. On the other hand, during the study of tetrahydroindolone-derived semicarbazones (see 8i in Table 1), it was observed that replacement of the tetrahydroindolone core with other heteroaromatic cores provided inactive compounds [53]. 

In order to install a benzophenone at the bicyclic scaffold we relied on the previously used oxazole linkage. To this end, the known amino-hydroxybenzophenone 37 (Aichaoui et al. 1990) was coupled to the free acid rac-38, which is available from Kemp s triacid in five synthetic steps. Remarkably, an 0-aeylation instead of the expected /V-acylalion was observed resulting in ester rac-39. As a consequence, oxazole formation was less straightforward but could eventually be achieved under more forceful conditions. The reaction sequence led to the racemic benzophenone rac-40, i.e. to a 1/1 mixture of the enantiomers (+)-40 and (-)-40, which was separated by chiral HPLC (Daicel Chiralpak AD). It is important to mention that a separation of enantiomers at an earlier stage is not sensible. While carboxylic acid 38 can be obtained in enantiomerically pure form, racemisation occurs upon activation, presumably due to a bridged symmetrical intermediate (Kirby et al. 1998) (Scheme 16). 

The broad-spectrum peptidomimetic lAP family inhibitors were also recently developed (107). Designed based on (7, 5)-bicyclic scaffold, these SMAC-mimetics were found to antagonize the protein interactions that involve XIAP, melanoma... 

Dyads 19 and 20 also feature a very rigid bicyclic scaffold between donor and acceptor, and show some unusual properties [98, 105]. The two molecules differ significantly only in the location of the naphthoquinone carbonyl groups relative to the porphyrin macrocycle. Dyad 19, whose quinone carbonyl groups are rela-... 

Alternatively, pyrrolo[3,4-d]pyrimidine-2,5-diones and pyrimido[4,5-d]pyridazine-2,5-diones have been synthesized by using the same pyrimidine resin precursor, which was first treated with a representative set of primary amines or hydrazines, respectively, to substitute the chlorine. Subsequent cyclative cleavage was performed as already described, leading to the corresponding bicyclic scaffolds in high purity but moderate yield. 

Another interesting MW-assisted MCR for construction of the DHP ring as part of a more complex bicyclic scaffold was reported by Quiroga et al. They realized the MW-assisted synthesis of both pyrazolopyridines 7 and pyrido[2,3-d]pyrimidines 8 under solvent-free conditions (Scheme 17.8) [38]. 

In contrast to aldol reactions, the major diastereoisomer formed in the Mannich reaction has syn configuration, because the orientation of the imine is opposite to that of the carbonyl in the transition state (figure C in Scheme 6.5). Carter et al. reported an organocatalysed domino Mannich-aza-Michael reaction for accessing nitrogen-containing [2.2.2]-bicyclic scaffolds promoted by 15e, in a highly enantioselective and diastereoselective manner (eqn. (3) in Scheme 6.5). 

In 2012, Alexakis and co orkers disclosed the first stereoselective annulation reaction between ynals and a-cyano-l,4-diketones which is mediated by a catalytic amount of a triazolium salt precatalyst and a weak carboxylate base. This transformation proceeds smoothly under mild reaction conditions and generates three contiguous stereogenic centers, one of which is a quaternary acetal carbon, and affords privileged bicyclic scaffolds in 61-90% yields with up to 20 1 diastereomeric preference. A mechanistic rationalization for the NHC-catalyzed annulation of a-cyano-l,4-diketones with ynals is proposed as the following. Initially, the free carbene condenses with a molecule of ynal to form the key d,p-unsaturated acylazolium intermediate followed by a direct nucleophilic conjugate addition of 1,4-diketone. Subsequent intramolecular H-migration and an irreversible lactonization furnish the observed bicyclic product and liberate free carbene for the next catalytic cycle (Scheme 7.98). 

Scheme 45 Dienamine-catalyzed synthesis of bicyclic scaffolds according to Christmann et al.

Yang, H., Carter, R. G. (2009). Asymmetric Construction of Nitrogen-Containing [2.2.2] Bicyclic Scaffolds Using Al-(/>-Dodecylphenylsulfonyl)-2-pyrrolidinecarhoxamide. Journal of Organic Chemistry, 74,5151-5156. 

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