3-Azabicyclo octane synthesis

Keywords isoquinuclidine, 2-azabicyclo[2.2.2]octane, synthesis, pharmacophore, pharmacology, iboga... 

Monochloramine is also used in organic synthesis for preparation of amines, substituted hydrazines, etc. For example, reaction of NH2CI with 3-azabicyclo [3.3.0]octane [5661-03-0] yields A/-amino-3-azabicyclo[3.3.0]octane [54528-00-6] a pharmaceutical intermediate (38). 

The pyrrolizidines and indolizidines are a group of alkaloids that are characterized by the presence of the basic azabicyclo[3.3.0]octane and azabicyclo[4.3.0]nonane frameworks, respectively. These alkaloids exhibit remarkably diverse types of biological activity and have been reported to act as antitumor, hypotensive, anti-inflammatory, carcinogenic, or hepatoxic agents. Various pyrrolizidines and indolizidines have been prepared by 1,3-dipolar cycloaddition.115 Synthesis of these is described in the section 8.2 discussing cycloaddition. 

Thomson, C.G., Carlson, E., Chicchi, G.G., Kulagowski, J.J., Kurtz, M.M., Swain, C.J., Tsao, K.C. and Wheeldon, A. (2006) Synthesis and structure-activity relationships of 8-azabicyclo[3.2.1]octane benzylamine NKj antagonists. Bioorganic el Medicinal Chemistry Letters, 16,811-814. 

As an example of non-enzymatic catalyst using oxazaborolidines [10], Corey and his associates have described an efficient synthesis of (-i-)-l(S),5(R),8(S)-8-phenyl-2-azabicyclo[3.3.0]octan-8-ol (2.) and its enantiomer. The B-methyloxazaborolidine derivatives (3) of these amino alcohols are excellent catalysts -or chemzymes- for the enantioselective reduction of a variety of achiral ketones to chiral secondary alcohols [11]. 

In connection with the enantioselective alkylation of Pro or 4-hydroxy-proline, the azabicyclo[3.3.0]octane system 81 was obtained after reaction with pivaldehyde (81HCA2704 85HCA155). In a more complex transformation A-protected L-Pro was transformed into the same bicyclic system (Scheme 49) (81JA1851 84JA4192). The product was prepared as a model substance in the total synthesis of pumiliotoxin. A related compound 82 was prepared from 5-(hydroxymethyl)-2-pyrrolidinone (prepared from L-pyroglutamic acid) by an acid-catalyzed condensation with benzaldehyde (86JOC3140). 

Akritopoulou-Zanze I, Whitehead A, Waters JE, Henry RE, Djuric SW (2007) Synthesis of novel and uniquely shaped 3-azabicyclo[4.2.0]octan-4-one derivatives by sequential Ugi/[2 -I- 2] ene-enone photocycloadditions. Org Lett 9 1299-1302... 

An efficient asymmetric synthesis of the 3-substituted /3-sultams 163 has been reported. The key step of the synthesis is the Lewis acid-catalyzed aza-Michael addition of the enantiopure hydrazines (A)-l-amino-2-methoxy-methylpyrrolidine (SAMP) or CR,l ,l )-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]octane (RAMBO) to the alke-nylsulfonyl sulfonates 176. /3-Hydrazino sulfonates were obtained in good yield and excellent enantioselectivity. Cleavage of the sulfonates followed by chlorination resulted in the corresponding sulfonyl chlorides 177. The (A)-3-substituted /3-sultams 163 have been obtained in moderate to good yields and high enantioselectivity over two steps, an acidic N-deprotection followed by in situ cyclization promoted by triethylamine (Scheme 55) <2002TL5109, 2003S1856>. 

Hajdu P, Schmidt D, Bomm M, Keller A (1984) Determination of (2-[N-[(S)-l-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid) (HOE 498) and its hydrolysis product in serum and urine. Arznm Forsch/Drug Res 34 1431-1435 Schmidt D, Keller A (1985) Sensitive determination of the ACE-Inhibitor HOE 498 and its metabolites in human urine by capillary GC. Fresenius Z Anal Chem 320 731 Walle T, Ehrsson H, Bogentoft C, Dolby J (1972) Synthesis and structure of an enaminic bis(trifluoroacetyl) derivatives of desipramine. Acta Pharm Suecica 9 509-512... 

Isomeric l-aryl-6-azabicyclo[3.2.1]octanes (24) that possess a five-membered heterocyclic ring and that may be thought of as bridged analogs of profadol<16) have been described and evaluated for analgesic responses.(17 20) Synthesis was from a previously reported arylcyclohexanone ketal (25) according to Scheme 5.6. 

Mori M, Saitoh F, Uesaka N, Okamura K, Date T (1994) Synthesis and X-Ray Crystal Structures of Tricyclic Ketones Containing trans-Fused Azabicyclo[3.3.0]octane Units. J Org Chem 59 4993... 

Schwarz, S., Kampchen, T, Tilotta, M.C., Gundisch, D, and Seitz, G. 2003. Synthesis and nicotinic binding studies on enan-tiopure pinnamine variants with an 8-azabicyclo[3.2.1]octane moiety. Pharmazie 58, 295-299. 

In order to maximize yields and regioselectivity in the Friedlander synthesis of quinolines, the bicyclic pyrrolidine base l,3,3-trimethyl-6-azabicyclo[3.2.1]octane (TABO) was utilized to good effect. TTie reaction was carried out with unactivated methyl ketones <03JOC467>. The ratios of the two products were 86% 2-substituted and 14% 2,3-disubstituted. 

The intramolecular carbenoid insertion into the N — H bond of j8-lactams is frequently used for constructing the l-azabicyclo[4.2.0]octane ring system. Thus, in the synthesis of (-)-homothienamycin, the crucial ring closure was effected by refluxing compound 160 in a benzene solution containing Rh2(OAc)4 (80TL1193). Such an approach was used to advantage in... 

Wilken, J., Thorey, C., Groger, H., Haase, D., Saak, W., Pohl, S., Muzart, J., Martens, J. Utilization of industrial waste materials. Part 11. Synthesis of new, chiral P-sec-amino alcohols. Diastereodivergent addition of Grignard reagents to a-amino aldehydes based on the (all-R)-2-azabicyclo[3.3.0]octane system. Liebigs Ann. Chem. 1997, 2133-2146. 

Francisco, C. G., Herrera, A. J., Suarez, E. Intramolecular Hydrogen Abstraction Reaction Promoted by N-Radicals in Carbohydrates. Synthesis of Chiral 7-Oxa-2-azabicyclo[2.2.1]heptane and 8-Oxa-6-azabicyclo[3.2.1]octane Ring Systems. J. Org. Chem. 2003, 68, 1012-1017. 

The four-step synthesis begins with the hydrogenation of PABA using Rh/AliOs to furnish a 92% yield of 77 as an 80 20 cisitrans mixture. Subsequent heating at 250°C in Dowtherm A to effect epimerization-cyclization afforded the bicyclic lactam (78) in 84% yield. Red-Al reduction furnished 2-azabicyclo[2.2.2]octane which was subsequently protected as the tosylate salt (79) in 85% yield. Employment of more concentrated Dowtherm mixtures and a decreased amount of Red-Al increased the yield for the cyclization step to 89% and the tosylate salt to 91% (overall yield 70%) [85]. Earlier, Werner [86] demonstrated that using the carboxylate methyl ester instead of the carboxylic acid allows the cyclization to occur at lower temperatures (190°C). 

The direct synthesis of the morphinan skeleton (107) from (105) involves the intramolecular ring opening by the enolate anion of the in situ generated aziridine cation (106) (Scheme 41) <88J0C2144>. Compound (108) was found to rearrange thermally to the thermodynamically favored azabicyclo-[3.3.1]octane (110) via the aziridinium ion (109) (Scheme 42) <93CC758>. 

Hakimelahi, G.H., and Janahpour, A.A., Synthesis of ethyl cw-2-[(diethoxyphosphoryl)methyl]-7-oxo-3-phenyl-6-phthalimido-l-azabicyclo[3.2.0]hept-3-ene-2-carboxylate and methyl cB-2-bromo-3-methyl-8-oxo-7-phthalimido-4-oxa-l-azabicyclo[4.2.0]octane-2-carboxylate, Helv. Chim. Acta. 72, 1501, 1989. 

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