Bicyclic compounds natural products synthesis

Homoconjugate additions of secondary amines to cyclopropyl ketones catalysed by acid have been reported as well as formation of certain 5,6-dihydro-4H-l,2-oxazines with hydroxylamine hydrochloride. Demuth and Mikhail have recently demonstrated that cyclopropanes of the tricyclo[3.3.0.0 ] octan-3-one type can be selectively converted to functionalized bicyclic compounds with different kinds of electrophilic/nucleophilic reagents (equation 41) the products have extensively been exploited for natural product synthesis ". ... 

In a natural product synthesis aza bicyclic compound 11 was hydrogenated over Raney nickel in excellent yield. As expected, hydrogenation occurs from the less hindered side to give 12 as the sole product39. 

The chemo- and regioselectivity problems can be solved by the [2+2+2] cycloaddition of diynes with monoynes, although the accessible products are limited to bicyclic compounds. The [2+2+2] cycloaddition of diynes with monoynes has been applied to the synthesis of biologically active molecules and functional materials. The first application in the natural product synthesis was the dl-estrone synthesis using CpCo(CO)j as a catalyst. The [2+2+2] cycloaddition followed by the benzocyclobutane to ort/jo-quinodimethane rearrangement and intramolecular Diels-Alder reaction afforded a dZ-estrone precursor (Scheme 21.8) [11]. 

Another recent and outstanding achievement of Canesi s group is their version of a synthesis of rac-isostrychnine in only nine steps starting from the readily available phenol 166, which was first converted into the phenohc amide 167 (Fig. 42) [106]. This compound was subjected to a DIB-mediated methoxylative phenol dearomatization to afford the para-quinol ether 168, the amide function of which was then engaged in an intramolecular aza-Michael addition (Mito its cyclohexa-2,5-dienone moiety to forge the fused bicyclic system 169 en route to isostrychnine, which was obtained after six additional steps (Fig. 42) [106]. Canesi s group also reported several elegant applications of the phenol dearomatization-induced processes of their own invention in natural product synthesis, such as in... 

The 2-azadiene system of the pyrazinone scaffold undergoes inter- and intramolecular cycloaddition reactions with a variety of (functionalized) alkenes forming bicyclic adducts, leading to the stereoselective generation of a variety of natural product analogues as well as peptidomimetics [58]. These bicyclic compounds could serve as key intermediates in the synthesis... 

Both natural and non-natural compounds with a 2ff,5ff-pyrano[4,3-fc]pyran-5-one skeleton are of interest in medicinal chemistry. Several natural products, such as the pyripyropenes, incorporate this bicyclic ring system. The group of Beifuss has described an efficient microwave-promoted domino synthesis of the 2ff,5H-pyr-ano[4,3-fo]pyran-5-one skeleton by condensation of a,/3-unsaturated aldehydes with 4-hydroxy-6-methyl-2]-f-pyran-2-one (Scheme 6.244) [428]. It is assumed that in the presence of an amino acid catalyst a Knoevenagel condensation occurs first, which is then followed by a 6jr-electron electrocyclization to the pyran ring. While the conventional thermal protocol required a reaction time of up to 25 h (refluxing ethyl... 

Schreiber and his coworkers have published extensively over the past decade on the use of this photocycloaddition for the synthesis of complex molecules730 81. Schreiber was the first to recognize that the bicyclic adducts formed in these reactions could be unmasked under acidic conditions to afford threo aldol products of 1,4-dicarbonyl compounds (175 to 176) (Scheme 40). The c -bicyclic system also offers excellent stereocontrol in the addition of various electrophilic reagents (E—X) to the enol ether of these photoadducts on its convex face (175 to 177). This strategy has been exploited in the synthesis of a variety of architecturally novel natural products. 

Feringa and co-workers described the tandem addition-aldol cyclization protocol leading to the formation of 6,6-, 6,7-, and 6,8-annulated bicyclic systems (Scheme 68).39 Using Cu(n)-29 as catalyst and functionalized organozinc reagents as nucleophiles, the conjugate addition reaction followed by aldol cyclization can offer highly enantioselec-tive annulation products (up to 98% ee). This method can be used in the synthesis of carbocyclic compounds, such as steroids, terpenes, and other natural products. 

The synthesis of bicyclic molecules containing guanidinium subunits, such as 156 (Scheme 22), are of considerable interest due to the wide range of biological activities presented by this family of natural products (see Section 11.11.9). In one of the first biomimetic studies toward ptylomycalin A, a series of polycyclic compounds have been prepared through an intermediate l-imino-hexahydropyrrolo[l,2-f]pyrimidin-3(4//)-one such as 155. Succinaldehyde... 

The alkylation of cyclopentanoid enolate groups, which are part of polycyclic systems, is a common step in natural product syntheses, particularly in the synthesis of terpenoids and steroids. A high degree of stereoselectivity is usually encountered in such reactions, for example, in the preparation of the bicyclic compounds 17-2054 59. Steric, rather than electronic, control elements determine the diastereoselectivity. 

The chiral bicyclic enones, levoglucosenone, isolevoglucosenone, and new functionalized L-arabinose enone possess excellent reactivity and functionality. Their properties mid application as convenient precursors in the synthesis of many attractive templates or intermediates of complex natural products are reviewed. These compounds are attracting increasing interest due to their structural rigidity and ability for stereoselective functionalization without protection, deprotection sequences necessary in many synthetic organic methodologies. 

The Weinreb group has used an intramolecular imino Diels-Alder cycloaddition as the key step in a total synthesis of the fungal neurotoxin slaframine (74) (equation 25). Thus, thermolysis of acetate (71) produced an intermediate A -acyl imine (72) which underwent [4 + 2] cycloaddition to afford bicyclic lactam (73) as a 1.8 1 mixture of epimers. Both compounds were converted to the natural product in a few steps. 

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