Azaspiro ring

Pd-catalysed allylation of amines proceeds smoothly. Allylamine (132) and di- and triallylamines are produced commercially by the Pd-catalysed reaction of ammonia with allyl alcohol using DPPB as a suitable ligand [69]. Allylic alcohols are rather unreactive substrates for 7r-allylpalladium complex formation under usual conditions. The intramolecular amination of 133 afforded the azaspiro ring 134 and the reaction was applied to the synthesis of perhydrohistrionicotoxin (135) [70]. Smooth Pd-catalyzed allylation of the purine base 136 gives 137, which is utilized for the synthesis of nucleosides [71]. 

In 1995, a report of human illness with diarrhetic shellfish poisoning (DSP)-like symptoms in the Netherlands was eventually found to result from the consumption of poisoned mussels (Mytilus edulis) harvested from Killary Harbour, Ireland (McMahon 1996). Yasumoto, Satake, and co-workers eventually isolated and proposed a stracture for the causative agent of this condition azaspiracid-1 (la. Fig. 16.1). The unique polyether stracture of azaspiracid-1 (la) is characterized by several spiro-cyclic systems, including an azaspiro ring fused to a 2,9-dioxabicyclo[3.3.1]nonane system and a terminal carboxylic acid. In total, there are nine rings and twenty stereogenic centers within the structure proposed by Yasumoto and co-workers in 1998 (Satake 1998). This stracture was based primarily on NMR spectroscopic data and did not include absolute stereochemistry, nor did it specify relative stereochemistry between the ABCDE and FGHI domains. 

There are only few reactions known introducing substituents to the H-bearing nitrogen of oxaziridines. (V-Alkylation of l-oxa-2-azaspiro[2.5]octane (3,3-pentamethylene-oxaziridine 52) with r-butyl chloride to give (53) was carried out for structure proof of (52). This reaction is of no preparative importance, since N-alkylated oxaziridines are easily obtained by ring synthesis. 

Alkaloids Containing an Azaspiro[4.5]decane Ring System Halichlorine... 

For 5-(2-diazo-l,3-dioxobutyl)-l-oxa-5-azaspiro[5,5]undecane (313), intramolecular carbenoid insertion into a (N)C—H bond represents quite an unusual way of constructing a P-laetam ring 285). 

Diastereoselective 1,4- and 1,6-addition reactions of lithium amides to chiral naph-thyloxazolines were used by Shimano and Meyers108-110 for the synthesis of novel amino acids. For example, treatment of (S )-2-(l-naphthyl)-4-t-butyloxazoline with lithi-ated l,4-dioxa-8-azaspiro[4.5]decane and iodomethane provided the diastereomerically pure 1,4-addition product with excellent yield cleavage of the heterocyclic rings then gave the desired /3-amino acid (>99% ee/ds equation 32)108,109. In contrast to this, most acyclic lithium amides reacted with these oxazolines under 1,6-addition the products were transformed smoothly to 5-amino acid derivatives (equation 33)110. 

The total number of atoms in the azaspirocycle is optimally seven or eight, similar to the optimal requirements in the monocyclic guanethidine series. However, an additional factor with the azaspiro-alkanes is that the number of atoms in the heterocyclic ring should be as large as possible consistent with the previous condition. Compound (XXX) has a longer duration of action than guanethidine both in animals [221] and in man [224]. 

The reaction of the silyloxypyrroles 47 possessing a chiral substituent at the nitrogen atom, with cyclobutanone in the presence of a Lewis acid, followed by an acid induced ring expansion of the cyclobutanol intermediate 48, offers an asymmetric route to the l-azaspiro[4.4]nonanes 49 in good diastereoisomeric excess <02SL1629>. In this context it might also be interesting to... 

Initial addition reaction of methyloxirane to 4-methyl-l-oxa-4-azaspiro[4.5]decane 164 is followed by ring expansion under thermal conditions. O-Nucleophilic attack is directed on quaternary carbon of the spiro system rather than on C-4 carbon of the oxazolidine ring, and 8,10-dimethyl-7,13-dioxa-10-azaspiro[5.7]tridecane 165 is a major product of the transformation (Scheme 42 <1995IZV1838>). 

Addition of methoxycarbonylnitrene generated photochemically from methyl azidoformate to methylenecyclopropane gave methyl l-azaspiro[2.2]pentane-l-carboxylate 1, which cannot be isomerized to the cyclobutane derivative like the isosteric oxaspiropentanes. " Treatment with acids such as hydrogen chloride or methanesulfonic acid cleaved the aziridine ring and gave l-(chloromethyl)-l-(methoxycarbonylamino)cyclopropane and l-(mesyloxymethyl)-l-(methoxycarbonylamino)cyclopropane. ... 

A number of alkyl- and arylnitrile oxides have been reacted with methylenecyclopropane to give 4-oxa-5-azaspiro[2.4]hept-5-enes 1 (4,5-dihydrospiro[isoxazole-5-cyclopropane]). The nitrile oxides were usually generated in situ from the appropriate primary nitro compound with phenyl isocyanate and triethylamine. The addition is usually regioselective in such a way that the oxygen atom forms a bond with Cl of the three-membered ring. 

Cyclopropanols can be converted to various cyclopropyloxy derivatives (esters, e.g. acetates, ethers, e.g. methyl and ethyl ethers, and acetals, e.g. tetrahydropyran-2-yloxy derivatives) under the appropriate reaction conditions. In most cases the synthesis of cyclopropyl esters by the reaction between a cyclopropanol and an acid chloride (e.g. formation of 1 ) or acetic anhydride (e.g. formation of 2 ) have been reported. The yields were particularly good (84-95%) when acetic anhydride was used, although a drawback of the reaction can be byproduct formation. When a reactive moiety is attached to the cyclopropane ring in addition to the hydroxy group, other reactions can also occur m-l-(aminomethyl)-2,2-dimethyl-3-(2-methylprop-l-enyl)cyclopropanol (3) reacted with phosgene in benzene to give the corresponding carbamate l,l-dimethyl-2-(2-methylprop-l-enyl)-4-oxa-6-azaspiro[2.4]heptan-5-one (4) in 31% yield. ... 

Aryl-l-azaspiro[2.2]pent-l-enes, on the other hand, underwent cleavage of the cyclopropane and aziridine rings on treatment with C-(4-chlorophenyl)-A-phenylnitrilimine to give 4-aryl-l, 2-diphenyl-2,3,5-triazabicyclo[4.2.0]octa-3,5-dienes in excellent yield. " ... 

Sorensen s synthetic analysis of FR901483 is shown in Scheme 18. The cornerstone of his strategy is the idea that exposure of aminophenol 41 to an appropriate oxidant, such as iodobenzene diacetate, could give rise to 42. This appealing ring-closure would create the azaspiro[4.5]decane substructure of target 1 and would not be complicated by the formation of diastereoisomers. His goal was to effect intramolecular C-N bond... 

In summary, our team developed a new approach to the tricyclic core of FR901483, the key step being the closure of the bridged piperidine ring from an azaspirodecanone using a Pd-catalyzed cross coupling of vinyl bromides with ketone enolates. Additionally, a novel synthetic entry to l-azaspiro[4.5]decan-8-ones based on an iodine promoted cyclization of 1-adlyl-l-aminocyclohexane derivatives is reported. 

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