Bicyclo 2.2.2 octane

Intramolecular cycloadditions are among the most efficient methods for the synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine skeleton encompasses two key retro-cycloaddition key elements. (1) a bridging pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a [2.2.2] bicyclo-octane accessible via a [4+2] Diels-Alder carbocyclic cycloaddition (Chart 1.4). While intramolecular [4+2] Diels—Alder cycloadditions to form [2.2.2] bicycle-octane systems have extensive precedence [3+2], azomethine dipolar cycloadditions to form highly fused aza systems are rare [31-33]. The staging of these two operations in sequence is critical to a unified synthetic plan. As the proposed [3+2] dipolar cycloaddition is expected to be the more challenging of the two transformations, it should be conducted in an early phase in the forward synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C-C bond disconnections for this transformation. 

Two possible intramolecular disconnections are available for the [2.2.2] bicyclo-octane ring system (path A and path B, Scheme 1.4). The choice between the initial [4+2] disconnections A and B at first appears inconsequential leading to idealized intermediates of comparable complexity (54 and 57). However, when the [4+2] and [3+2] disconnections are considered in sequence, the difference becomes clear. For path A, retrosynthetic [3+2] disconnection of intermediate 54 leads to the conceptual precursor 56, which embodies a considerable simplification. In contrast, path B reveals a retrosynthetic [3+2] disconnection of intermediate 57 to provide the precursor 59, a considerably less simplified medium-ring bridged macrocycle. Thus, unification of the [3+2]/[4+2] dual cycloaddition strategy, using the staging... 

The rearrangement of isopent-3-enyl epoxy esters with Cp2ZrCl2/AgC104 yields ABO esters (2,7,8-trioxabicyclo[3.2.1]octane Asymmetric Bicyclo-Octane esters), which are base-stable protecting groups for carboxylic acids [57,79,80] (Scheme 8.40). 

The fused cyclobutenes prefer a path which leads to disallowed cis, cis cyclic diene. Thus bicyclo-octane(IV) opens at 230°-260°C to give cis, cis 1,3 cyclooctadiene and not cis-trans diene. 

As in the case of the bicyclo-octane the isomerizations must occur by a disrotatory process. It is clear that, owing to the rigid nature of these bicyclobutenes, considerable stretching of the bridgehead bond is necessary before appreciable twisting of the cyclobutene ring can... 

While most tertiary amine catalysts are effective approximately in proportion to their base strength, an exception is triethylene diamine, 4-diaza[2.2.2]bicyclo-octane). As shown by Farkas et al. [142,143] this catalyst is much more powerful than would be predicted from its base strength, being five times stronger as a catalyst than iV,JV -dimethyl-piperazine, which has slightly greater basicity. It was first suggested that the explanation may be the complete lack of steric hindrance in the structure. 

Under the same conditions, the bicyclo[3.2.1]-2-octene (5) yields 52% of bioyolo[3.3.0]-2-octene 6, besides 4% of the corresponding bicyclo-octane (17). Obviously, 6 is thermodynamically favored under these circumstances, and the passage of 5 to 7 is very slow (20). 

The squalestatins, e.g. 6.28, also known as the zaragozic adds, have attracted considerable interest as inhibitors of squalene synthase and hence of cholesterol biosynthesis and lipid deposition in the circulatory system. They are also inhibitors of farnesyl protein transferase and thus they may have other potentially useful biological applications. They are formed by Phoma spedes and also by Setosphaeria khartoumensis. The squalestatins are characterized by a dioxabicyclo-octane core bearing three carboxyl groups and two polyketide chains, one of which is attached as an ester. The biosynthetic incorporation of succinic acid into part of the bicyclo-octane, together with its oxygenation pattern, indicate that it may be derived via oxaloacetic acid. Both the polyketide chains have several pendant methyl groups attached to them, which arise from methionine, whilst benzoic add ads as a starter unit for one of the chains. These complex structures are thus the summation of several biosynthetic pathways. 

A hetero-Diels-Alder reaction between the imine (115) and the cyclohexadiene (116) produces the aza-bicyclo-octane (117), which after Baeyer-Villiger ring expansion followed by reduction, gave the triol (1l8), an advanced intermediate with all three chiral centres in their correct relative stereochemistry, for the synthe-... 

Bicycloheptane and Bicyclo-octane Derivatives.—Relative positional reactivities in nitration of benzonorbornene, benzonorbornadiene, (727), and the endo-isomer of (727) have been determined for the ipso-, a-, and /S-positions. The lower a-reactivity of (727) as compared to its endo-isomer is explained by the buttressed fused ortho effect , arising in (727) because steric hindrance between bridge and cyclopropane methylene hydrogens is sufficient to cause bridge bending, thus moving the sy -H... 

Bases accelerate all the isocyanate reactions and in general their catalytic effect increases with increasing strength of the base. Table 4.7 compares the action of several amine catalysts at near ambient temperature. The significant increase in urethane reaction rate is apparent but particularly so in the case of triethylene diamine (l,4-diazo-[2,2,2]-bicyclo-octane), commonly known as DABCO. The reason for this is probably the complete lack of steric hindrance, given its cage-like structure. 

The Pd-catalyzed cascade Heck reaction of 5-methylenecycloheptene precursor 108 was utilized to construct the scopadulan ring system and chiral centers at C9 and C12 of the bicyclo-octane 109 and 110 for the first total synthesis of scopadulcic acid B, which is a powerful inhibitors of H+, K+ -adenosine triphosphatase and have potential for the treatment of peptic ulcers, gastritis, and esophagitis. (Scheme 55) (103,104). 

We attempted to solve this kinetically insoluble problem by using solvent effect. For this purpose various tertiary amines have been reacted with cyclic anhydrides in aprotic media [38,48]. (amines dimethylformamide, N,N -dimethylaniline, triethyl-amine, 1,4-diaza-[2,2,2] bicyclo-octane and pyridine anthydrides tetrachloroph-thalic, 3,6-dichlorophthalic, 3-nitrophthalic, 4-nitrophthalic, 3,5-dinitrophthalic, phthalic and 1,8-naphthalic). 

Kinetic data obtained in the pyrolyses of endo- and exo-5-methylbicyclo[2,2,2]oct-2-ene suggests that biradical mechanisms are involved. The conformations of bicyclo[2,2,2]octane derivatives have been examined by the classic extended Hiickel theory the existence of privileged conformations is discussed. It has been found that aminobicyclo [2,2,2] octanols are quaternized faster than are the corresponding amino-bornanols, probably because the relative flexibility of the bicyclo-octanes allows for easier accommodation of the cation. The effects of H-bonding, steric and electronic features on the pX values of these amino-alcohols is discussed. 

Bkycloheptane and Bicyclo-octane Derivatives.—Room temperature addition of diphenyldiazomethane to 7-t-butoxynorbornadiene yielded all of the possible 1,3-dipolar cycloaddition products (exo rule not obeyed). Pyrolysis of these adducts effects entry to the 3,3-diphenyltricyclo[3,2,l,0 ]octane system e.g. (852) is thus obtained. Procedures for the preparation of tricyclo[3,2,l,0 ]oct-6-ene-3-carboxylic acids, e.g. (853), essentially isomer-free have been described. Reductive dechlorination of (854), the Diels-Alder product of addition of 3,3-dimethylcyclo-propene to tetrachlorocyclopentadienone dimethyl acetal, followed by acetal hydrolysis and cheletropic loss of CO has been used to prepare 7,7-dimethylcyclohepta-triene. °... 

Hajos, Z. Parrish, D. R. (1974) Synthesis and conversion of 2-methyl-2-(3-oxobutyl)-l,3-cyclopentanedione to the isomeric racemic ketols of the [3.2.1] bicyclo octane and of the perhydroindan series, / Org. Chem., 39,1612-15. 

Fig. 17. CD spectra in TFE of polyamides and model diamide derived from (+)-frfl s-l,2-bicyclo-octane dicarboxylic acid.

The intra-intermolecular polymerization of c/5-l,3-divinylcyclopentane and cyclohexane has been effected by a Ziegler catalyst prepared from titanium tetrachloride and triisobutylaluminum (38). A 38 % conversion to the bicyclo-octane polymer was obtained in 72 hours (11-42). Under similar conditions,... 

AAS = atomic absorption spectroscopy ATOF-MS = aerosol time-of-flight mass spectrometry 2,6-ndc = 2,6-naphthalenedicarboxylate bdc = 1,4-benzenedicar-boxylate bpdc = 1,3,5-benzenetricarboxylate bpydc = 2,2 -bipyridine-5,5 -dicarboxylate btb = 4,4, 4"-benzene-1,3,5-triylbenzoate btc = 1,3,5-benzenetricarboxylate 3D = three-dimensional dabco = l,4-diaza[2.2.2]bicyclo-octane EDX = energy-dispersive X-ray spectroscopy EXAFS = extended X-ray fine structure Fc = ferrocenyl ICP-AES = inductively coupled plasma atomic emission spectroscopy MOF = metal-organic framework PSD = postsynthetic deprotection PSM = Postsynthetic modification PXRD = Powder X-ray diffraction 1,4-ndc = 1,4-naphthalenedicarboxylate SALE = solvent-assisted linker exchange SBU = secondary building unit ... 

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