Bicyclic acid precursor

A short asymmetric synthesis of the 2-ketocarbacepham (27) involving as the initial step for the preparation of the starting piperidone, a hetero Diels-Alder reaction of the benzylimine derived from the enantiomer of Gamer s aldehyde with Danishesky s diene, has been described <02JOC598>. The key cyclization step to form the bicyclic P-lactam system was achieved from a P-amino acid precursor using the Mukaiyama reagent, 2-chloro-A-methylpyridinium iodide. 

The reaction of monooxo C-H acids such as acetone/ ethyl methyl ketone,or cyclo-pentanone with monocyclic A, 0-acetals or bicyclic A, 0-acetals or aminals gave the expected substitution products 1. Aqueous buffer solutions of pH 5.5 were reported to be sufficient for activation of bicyclic aminal precursors. Monocyclic aminal or hemiaminal starting materials were less reactive. Remarkably, methyl cyanoacetate could not be aminocyclopropylated. The sterical course of the reaction of bicyclic derivatives was not determined. 

Bridged bicyclic systems can be constructed with equal lacility using acetal terminators under hydrolytic conditions. Husson and cowoikers construction of the lady bug alkaloid adaline is exemplary. Aminonitrile (21) served as the iminium ion precursor. Refluxing a solution of (21) in methanol containing 10% hydrochloric acid for 48 h afforded Ae bicyclic adaline precursor (22) in 90% yield. 

Then, the amino acid precursor 105 is selected by the adenylation domain A and attached to the peptidyl carrier protein PCP of the SalB didomain. PCP-bound 105 is subsequently oxidized by the cytochrome P450 hydroxylase SalD. Fusion of the PKS-and the NRPS-derived precursors by the C-terminal condensation domain of SalA, leads to a PCP-bound linear intermediate, which after bicyclization and concurrent release from the synthetase yields the fully assembled salinosporamide molecules by an unknown process. The observed structural diversity of the salinosporamide family is essentially due to the relaxed substrate specificity of the AT domains of SalA. Although selection of an acetate starter unit by ATL leads to the typical methyl substituent at C-3 of the salinosporamides, an alternative priming with propionate would produce the C-3-ethyl derivative salinosporamide 194. The promiscuity of ATj in turn facilitates the formation of the observed variability in the substitution pattern at C-2. For the assembly of 86, ATj incorporates the halogenated PKS extender unit chloroethylmalonyl-CoA, which is unique to the salinosporamide family. 

Carboxylative TMM q cloaddition has also been realized with 3-methoxytropone and precursor (56) to produce an epimeric mixture of acids (122), which was employed in a synthetic study of the bicyclic diterpene sanadaol (123). The use of bi-dentate ligand tpdp (12) and high pressure did not improve the reaction. However, the addition of MesSnOAc as a co-catalyst did produce a better yield of (122) (Scheme 2.33) [16]. 

Asymmetric 1,3-dipolar cycloaddition of cyclic nitrones to crotonic acid derivatives bearing chiral auxiliaries in the presence of zinc iodide gives bicyclic isoxazolidines with high stereoselectivity (Eq. 8.51). The products are good precursors of (3-amino acids such as (+)sedridine.73 Many papers concerning 1,3-dipolar cycloaddition of nitrones to chiral alkenes have been reported, and they are well documented (see Ref. 63). 

The grem-dibromocyclopropanes 152 bearing a hydroxyalkyl group, prepared by the addition of dibromocarbene to allylic or homoallylic alcohols, undergo an intramolecular reductive carbonylation to the bicyclic lactones 153. bicyclic lactone derived from prenyl alcohol is an important precursor for the synthesis of ris-chrysanthemic acid. (Scheme 54)... 

C-Alkylation has also been observed in intramolecular reactions where the O-alkylation is not favoured.76 This property has been recently exploited in a stereocontrolled intramolecular cyclization of nitronate of nitro sugar 101 (Scheme 32), that provided the novel bicyclic nitrolactone 102, a synthetic precursor of tripeptide 103, that includes the first reported polyhydroxylated cyclopentane (3-amino acid.77... 

The double bond of butenolides reacts under Diels-Alder conditions and the resulting chiral bicycles have served as precursors of prostacycline analogs and chrysanthemic acids (250,251). The butenolide 248 was obtained by the procedure described by Ireland et al. (237). A bicyclo[4.3.0] ring system (254) was prepared by Diels-Alder reaction of 248 with butadiene in the presence of aluminum trichloride. Reduction of 254 (LiBH4) yielded the... 

Ionic hydrogenation of the same bicyclic diene 382 by Et3SiH in the presence of CF3COOH at room temperature or at 80 °C via ions 387 and 388 is accompanied by transannular cyclizations (equation 139)192. The behavior of diene 382 under Ritter reaction conditions (MeCN, H2SO4) reveals new possibilities to control the transannular cyclizations (equation 140)193. Depending on the sulfuric acid concentration, the reaction temperature and the presence of a nucleophilic solvent, these transformations can be directed to the formation of either the bicyclic amides 389 and 390 having the precursor structure or the tricyclic products 391193. 

The direct A -nitration of the amino groups of the hexahydrotriazine (23) is only possible due to the inherent low basicity of the methylenediamine functionality. The methylenediamine unit is present in many cyclic and bicyclic polyamines and these are potential precursors to energetic polynitramines. Unfortunately, this route to polynitramines is rarely possible because such polyamines are usually intrinsically unstable and will readily equilibrate to a lower energy, less strained system. For the same reason, polyamines containing the methylenediamine functionality are difficult to prepare and isolate, often rapidly decomposing in both aqueous and acidic solution. A far more common route involves the preparation of iV-protected versions of the polyamine followed by nitrolysis (Section 5.6). Even so, examples of heterocyclic methylenediamine iV-nitration exist. 

Padwa and co-workers (60,106,107) have been highly active in using carbonyl ylides for the synthesis of a number of bioactive alkaloids (Scheme 4.51). In an approach to the aspidosperma alkaloids, a push-pull carbonyl ylide was used to generate a bicyclic ylide containing a tethered indole moiety. This strategy ultimately allowed for the synthesis of the dehydrovindorosin skeleton (108). Starting from a quaternary substimted piperidone (200), elaboration of the 3-carboxylic acid provided p-ketoester amide 201. Addition of the indole tethered side chain provided a very rapid and efficient method to generate the cycloaddition precursor 203. 

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