Endo-norborneol

Early studies with a purified and reconstituted rabbit P450, CYP2B4 (earlier name P450 LM2) on the hydroxylation of the hydrocarbon, norbomane, found that the reaction proceeded to yield a 3.4 1 mixture of exo-endo norborneols (4). Further, hydroxylation of exo-2,3,5,6-tetradeuteronorbornane was found to proceed with a large deuterium isotope effect (11.5 0.5) and a significant amount of epimerization in forming the endo and exo metabolites (Fig. 4.3). 

The effect of steric hindrance can be nicely demonstrated in the reduction of two bicyclic ketones, norcamphor and camphor. The relatively accessible norcamphor yielded on reduction with complex hydrides predominantly (the less stable) endo norborneol while sterically crowded camphor was reduced by the same reagents predominantly to the less stable exo compound, isobor-neol [837], From the numerous examples shown it can be deduced that the stereoselectivity increases with increasing bulkiness (with some exceptions), and that it is affected by the nucleophilicity of the reagent and by the solvent. 

Catalytic dehydrogenation of volatile alcohols is carried out by passing their vapors over copper at 300 °C [344] or over copper chromite at 275-325 °C for 1.7-4 h, with yields ranging from 20 to 80% [554]. Dehydrogenation in the liquid phase is accomplished by refluxing the alcohol with copper chromite in xylene for 4 h [556] or by heating the alcohol in paraffin oil with Raney nickel and a catalytic amount of potassium hydroxide at 150-180 °C for 6 h. Thus endo-norborneol is transformed into norcamphor in 95% yield [928]. 

Steric effects are evident in the oxidation of sterically hindered alcohols exo-isoborneol is oxidized 2 times faster than endo-homeo], and endo-norborneol is oxidized 2.5 times faster than exo-norborneol (equation 248) [1145]. 

The mechanism of this reaction and the structure of the intermediate carbocation were once the subject of intense controversy. When the double bond of norbornene is protonated, a carbocation is produced (Eq. 10.25). The question of whether this cation is 54a and is in rapid equilibrium with the isomeric cation 54b, or whether 54a and 54b are simply two contributing resonance structures to the resonance hybrid 55, has been the focus of the debate. Note that the contributing structures 54a and 54b dijfer in the location of an cr-bond, not in the location of Tr-bonds as is more commonly encountered in resonance structures. The delocalized structure 55 is thus referred to as a nonclassical carbocation, and most chemists now accept this formulation as the more likely representation of this intermediate. It is evident from empirical results that the sterically more accessible side of the carbocation is the one away from or exo to the bridging carbon atom as shown. Nucleophilic attack of water solely from this side leads to cxo-norborneol (53) rather than endo-norborneol (56). 

Silylation of Alcohols. Primary, secondary, and tertiary alcohols are silylated by reaction with TBDMS triflate in excellent yields. For instance, treatment of f-butanol with 1.5 equiv of TBDMS triflate and 2 equiv of 2,6-Lutidine in CH2CI2 at 25 °C for 10 min gives a 90% yield of (f-butoxy)-r-butyldimethylsilane. The following alcohols are similarly silylated in excellent yields (70-90%) 2-phenyl-2-propanol, endo-norborneol, ds-2,2,4,4-tetramethylcyclobutane-l,3-diol, and 9-O-methylmaytansinol (converted to the 3-TBDMS derivative) (eq I). ... 

Analysis of the crystal structure of the p-nitrobenzoate and 2,4-dinitrobenzoate daiva-tives of enrfo-3-(trimethylsilyl)-endo-2-norborneol 47, in which the Si—C and C—O bonds are in the synperiplanar geometry, showed that there was no significant lengthening of the C—O bond in these cases . By comparison, the cyclohexyl ester 48, in which the Si—C and C—O bonds are in the antiperiplanar conformation, did show a significant lengthening of the C—O bond compared to model compounds ". ... 

NMR spectra (15.4 MHz) of selectively deuterated exo- (A) and endo- (B) 2-benzamido-4,5 d2 norborneol in chloroform. Data taken from Ref. 1. 

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