6-Azaspiro decane

Studies in the synthesis of the immunosuppressant FR901483 tricyclic skeleton showed that by palladium- and radical-mediated cyclizations of azaspiro-decanes the formation of azatricyclic derivatives was possible. Depending on the reaction conditions, 7,10 -methanopyrrolo[l,2- ]azocine 292 could be obtained from iV-(2-bromoprop-2-enyl)-l-azaspiro[4.5]decane 291 (Scheme 121) <2007ARKIVOG320>. When the reaction was performed in the presence of Bu3SnH, pyrrolo[2,3-r ]indoles were obtained instead. 

The reaction of propane-1,3-diamine with phthalic anhydride gives the pyrimidoisoindolone (415), some of whose reactions were investigated Syntheses of the l,8-diazaspiro[4,5]decane (416) and l-oxa-8-azaspiro-decane (417) systems have been reported. ... 

CN 8-[4-[4-(2-pyrimidinyl)-1 -piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione monohydrochloride... 

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

CARBOETHOXY-2,3-DIMETHYL-1-OXA-8-AZASPIRO[4-5]DECANE, a procedure that exemplifies a new stereocontrolled method for constructing substituted tetrahydrofurans. 

A. Preparation of (2R,3S)- ana (2S,3S)-1,4-dioxa-2,3-dimethyl-2-(1-methyl-ethenyl)-8-carbcethoxy-8-azaspiro[4.5]decane. An oven-dried, 500-mL, three-necked, round-bottomed flask is fitted with a mechanical stirrer, 100-mL addition funnel, and rubber septum, and then is charged with 100 mL of dry tetrahydrofuran (Note 1) and... 

Stereochemical control of intramolecular 1,3-dipolar cycloadditions by route b (Scheme 2.211) was realized in the asymmetric synthesis of l-azaspiro[4.5] decanes by using the chiral (2R)-bomane-10,2-sultam (X ) auxiliary in the dipo-larophilic fragment (Scheme 2.220) (718). 

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. 

Buspirone Buspirone, 8-[4-[4-(2-pyrimidyl)-l-piperazinyl]butyl]-8-azaspiro [4,5] decan-7,9-dione (5.2.6), is synthesized by the reaction of l-(2-pyrimidyl)-4-(4-aminobutyl)piperazine (5.2.4) with 8-oxaspiro[4,5]decan-7,9-dione (5.2.5). In turn, 1-(2-pyrimidyl)-4-(4-aminobutyl)piperazine (5.2.4) is synthesized by the reaction of l-(2-pyrimidyl)piperazine with 4-chlorobutyronitrile, giving 4-(2-pyrimidyl)-l-(3-cyanopropyl)piperazine (5.2.3), which is hydrogenated with Raney nickel into buspirone (5.2.4) [51-55]. 

By enantiotopos-differentiating deprotonation the lithiated complex is formed in a reagent-controlled reaction with excellent selectivity. The lithiated center of the complex is assumed to have the S configuration, as follows from the carboxylation, to give an (7 )-lactic acid derivative based on the reasonable assumption of metalloretentive electrophilic attack. Trapping with chlorotrimethylstannane gave the corresponding chiral (.S -SjS-dimethyl-l-trimethylstannyl-alkyl-l-oxa-4-azaspiro[4.5]decane-4-carboxylates. Enantioselectivity of the overall transformation is excellent. 

The conversion of heptyl 3,3-dimethyl-l-oxa-4-azaspiro[4.5]decane-4-carboxylate into (S)-2-octanol demonstrates the easy availability of chiral secondary alcohols by this method42. 

Halichlorine (1) (Fig. 11.1) is an alkaloid which was isolated from the marine sponge H. okadai Kadota (Kuramoto et ah, 1996). This compound was revealed to be a novel alkaloid containing an azaspiro[4.5]decane skeleton clarified by detailed spectroscopic analyses. The absolute stereostructure was confirmed by many synthetic studies (Arimoto et ah, 1998 Clive et ah, 2005 Liu et ah, 2009 Trauner et ah, 1999). Halichlorine was shown to inhibit the induction of vascular cell adhesion molecule-1 (VCAM-1) in cultured human umbilical vein endothelial cells. Drugs that block the inflammatory stimuli-induced expression of VCAM-1 may be useful for treating atherosclerosis, coronary artery diseases, angina, and noncardiovascular inflammatory diseases (Kock et ah, 1995). We introduce here the recent aspects of the biological and physiological activities of halichlorine. 

Further comparative studies77-79 have been carried out with N<3-dimethyl-aminopropyl)-8,8-dimethyl-2-azaspiro[4.5]decane 101a) and N-(3-dimethylamino-propyl)-9,9-dimethyl-3-azaspiro[5.5]undecane 102a) and their sila-analogues 101b and 102b, respectively. 

Chou T, Kuramoto M, Otani Y, Shikano M, Yazawa K, Uemura D (1996) Pinnaic Acid and Tauropinnaic Acid Two Novel Fatty Acids Composing a 6-Azaspiro[4.5]decane Unit from the Okinawan Bivalve Pinna muricata. Tetrahedron Lett 37 3871... 

There is the 3 methods for preparing of 8-azaspiro(4.5)decane-7,9-dione, 8-(4-(4-(2-pyrimidinyl)-l-piperazinyl)butyl) monohydrochloride (U.S. Patent 3,717,634). One of them is follows a mixture of 0.1 mole of the substituted glutaric anhydride, 0.1 mole of l-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (U.S. Pat. 3,398151), and 300 ml of pyridine was refluxed until imide formation was completed. The degree of reaction was readily followed by taking an aliquot portion of the reaction mixture, removing the solvent, and obtaining the infrared absorption spectrum of the residue. When reaction is complete, the spectrum exhibited typical infrared imide bands at 1701 and 1710 cm-1 whereas if incomplete, the infrared spectrum contains amide and carboxyl absorption bands at 1680, 1760 and 3300 cm 1. 

The azospiroalkenedione 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione was purified as free base by stripping off the pyridine solvent and crystallizing the residue from a suitable solvent or by vacuum distillation thereof hydrochloric salt of it was prepared by treating of an ethanol solution of free base with equimolar amount of HCI. 

Tetranitro-l, 3,7,9-tetra azaspiro(4.5)decane (TNSD) (JEXMEE)... 

Wu Y-H, Rayburn JW, Allen LE, Ferguson HC, Kissel JW. Psychosedative agents. 2. 8-(4-substituted 1-piperaziny-lalkyl)-8-azaspiro[4.5]decane-7,9-diones. /. Med. Chem., 1972, 15, 477-479. 

Patel, R. N., Linda, C., Nanduri, V., Jianqing, L., Kotnis, A., Parker, W., Liu, M., and Mueller, R. 2005. Enantioselective microbial reduction of 6-oxo-8-[4-[4-(2-pyrim-idinyl)-l-piperazinyl] butyl]-8-azaspiro[4.5]decane-7,9-dione. Tetrahedron Asymm., 16(16), 2778-2783. 

Benzyl-l-oxa-4-azaspiro[4.5]decane (149, R = CH2Ph) gave 1,4-diben-zylpiperazine (150, R = CH2Ph) and cyclohexanone (polyphosphoric acid, 200°C, 10 h 40%) 413 l,4-bis(2-hydroxyethyl)- (150, R = CH2CH2OH) and 1,4-diphenylpiperazine (150, R = Ph) were made similarly and in comparable yields.413... 

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