Oxabicycles

Ring opening of oxabicyclic compounds as a strategy in organic synthesis 97MI37. 

Stereocontrolled synthesis of oxabicyclic (3-lactam antibiotics via [2- -2] cycloaddition of isocyanates to sugar vinyl ethers 96CC2689. 

An early example of the use of a subcatalytic amoimt of sparteine for the activation of an organolithium nucleophile was reported by Lautens et al. in the carbometallation of a meso-unsaturated oxabicycle 25, with ring opening leading to the substituted cycloheptene derivative 26 (Scheme 4) [4]. Both yield and enantiomeric excess remained virtually unchanged when the ratio n-BuLi sparteine was lowered to 1 0.15. However, when a 3 mol% amount of the ligand 1 was used, a 20% decrease in enantioselectivity was observed. 

Hydroaluiriination of Functional Croups 61 Tab. 2-3 Reductive ring opening of unsymmetric oxabicyclic substrates ... 

Hydroalumination of Functional Croups 65 Tab. 2-5 Enantioselective reductive ring opening of oxabicyclic subrates... 

Among recently described new Pd-catalysed enantioselective reactions, the ring opening of meso oxabicyclic alkenes with dialkyl zinc reagents in the presence of chiral P/P and P/N ligands reported by Tautens el al. constitutes a synthetically outstanding C-C bond-forming desymmetrization reaction. 

Waymouth and coworkers used chiral zirconocene complexes such as 56 with Et3Al as the stoichiometric reductant to enantioselectively desymmeter-ize oxabicyclic compounds (Scheme 9) [29]. A reductive coupling mechanism to give 57 followed by (i-alkoxidc ring opening and transmetallation is consistent with the experimental results. Neither direct insertion of the alkene into the M - C bond nor nucleophilic attack mechanisms can be ruled out, however [12]. 

Rhodium catalysts have also been used with increasing frequency for the allylic etherification of aliphatic alcohols. The chiral 7r-allylrhodium complexes generated from asymmetric ring-opening (ARO) reactions have been shown to react with both aromatic and aliphatic alcohols (Equation (46)).185-188 Mechanistic studies have shown that the reaction proceeds by an oxidative addition of Rh(i) into the oxabicyclic alkene system with retention of configuration, as directed by coordination of the oxygen atom, and subsequent SN2 addition of the oxygen nucleophile. 

While transition metal-catalyzed hydroboration is a well-established reaction, the same cannot be said for the transition metal-catalyzed hydroalumination. The synthetic utility of this reaction is only just beginning to emerge. Lautens has led the way in the use of hydroaluminations as the key step in the total synthesis of complex natural products. The synthesis of the anti-depressant sertraline130 involved the formation of the tetrahydronaphthalene core, and this is best achieved using the nickel-catalyzed hydroalumination of oxabicyclic alkenes (Table 16). 

Lautens also used this nickel-catalyzed hydroalumination methodology in the total synthesis of ionomycin 145. The starting compound was a [3.2.1]oxabicyclic alkene 143.144 Their rigid bicyclic structures can be used to introduce functional groups in a highly stereoselective manner. The synthesis of the key intermediate 144 involves the slow addition of DIBAL to the oxabicyclic alkene and the Ni(COD)2/(6T)-BINAP in toluene to afford 144 in 95% yield and 93-95% ee. (Scheme 18). 

Figure 3.44. Scope of Rh/47-catalyzed asymmetric ring-opening of oxabicyclic alkenes with organoboronic acids.

Enantioselective alkylative ring opening of these oxabicyclic alkenes has also been studied. Lautens and coworkers discovered that palladium complexes efficiently catalyze the addition of organozinc reagents to these activated alkenes with concomitant ring opening. In the presence of (Tol-BINAP)PdCl2, diethylzinc adds to oxabenzonor-... 

Desymmetrizations by C—H insertion using diazo decomposition strategies is well established. Chiu and coworkers have recently applied this strategy to the oxabicyclic system 195. A ferf-leucine-derived Rh(II) catalyst provided the best results [Eq. (10.58a)]. Wardrop and coworkers have applied a similar strategy en route to sordidin unfortunately, both yield and ee proved to be suboptimal [Eq. (10.58b)] ... 

THF solution containing aqueous cesium carbonate. The reaction of [2.2.1]oxabicycle 37b with phenylboronic acid 2m gave the ring-opened alcohol 38bm, with 95% enantiomeric excess. 

The proposed catalytic cycle is outlined in Scheme 9.9 [14]. Dimeric complex 23 is cleaved to give the monomeric complex 24 by solvation, substrate binding, or reaction with the nucleophile. Reversible exo-coordination of the substrate is followed by oxidative insertion with retention into a bridgehead C-O bond to give the 7r-aUyl or u-rho-dium aUcoxide complexes 26 or 27. It is likely that the formation of these rhodium] 111) aUcoxide complexes is irreversible due to the release of the ring strain present in the oxabicyclic aUcene substrate. The oxidative cleavage of the C-O bond is proposed to be the enantiodiscriminating step in the catalytic cycle. 

Based on this model, the regiochemical outcome of both oxabicycHc alkenes and vinyl epoxides can be explained by the relative stability of the two cr-intermediates. With oxabicyclic alkenes intermediate 41 is generated directly and then goes on to give product, whereas with the vinyl epoxides a more highly strained intermediate 40 is first produced which must first isomerize to 41 prior to product formation. The regiochemical outcome with each substrate may therefore arise from the commonahty of a cr-in-termediate 41 to both reaction pathways (Scheme 9.13). 

Scheme 9.12 (a) exo-coordination of the oxabicyclic alkene (b) oxidative insertion... 

In conclusion, this is the most practical and least expensive method available for the synthesis of [3.2.1]oxabicyclic compounds. 

Over the past several years, Mascarenas and co-workers (150-153) utilized the oxidopyrylium ion with variously hetero-substituted olefin tethers. Mascarenas has used this methodology in tandem with a Diels-Alder reaction to prepare tricyclic cycloheptanoid substrates. Further, Mascarenas and co-workers (154—156) achieved the synthesis of optically active oxabicyclic[3.2.1]octane derivatives through the addition of a homochiral p-tolylsulfinyl group substituted at the olefin tether. The Mascarenas group has also used this methodology to prepare the THF portion of ( )-nemorensic acid via oxidative cleavage of the substituted a-hydroxyketone moiety (157) (Scheme 4.78). 

In the same year, Nakamura and coworkers published an iron-catalyzed ring opening reaction of oxabicyclic alkenes by Grignard reagents (Scheme 51). This reaction is highly regio- and stereoselective. 

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