TPAP oxidations

Fig. 1.13 Possible cycle for a TPAP oxidation step in the synthesis of (+)-batzeUadine A [101]...

Gaseous oxygen can be employed, instead of NMO, as secondary oxidant in TPAP oxidations. This environment-friendly secondary oxidant, although not used routinely in synthetic organic laboratories, is very attractive for the industrial point of view and is the subject of active research, both in combination with TPAP68 and with several forms of supported perruthenate.69... 

An important corollary of these observations is that sudden exotherms can happen during TPAP oxidations, particularly on a multigram scale. 

Due to the neutral and very mild conditions used in TPAP oxidations, virtually all protecting groups remain unaffected, including the very oxidant-sensitive PMB ethers77 and p-methoxybenzylidene acetals 78 and the very acid-sensitive TMS ethers.76... 

Functional groups able to withstand TPAP oxidations include esters, ethers, amides, epoxides, alkynes, urethanes and even alkenes.61b It is quite remarkable that alkenes are resistant to TPAP because they are known to react with aqueous perruthenate ions.79... 

TPAP oxidizes lactols to lactones.85 Treatment of 1,4- and 1,5-diols with TPAP, in which one of the alcohols is a primary one, leads to an intermediate hydroxyaldehyde that normally is transformed into a lactone86 via an intermediate lactol. No transformation into lactone occurs when the formation of the intermediate lactol is not permited by geometric constraints.87... 

TPAP oxidizes sulfides94 to sulfones. There is one published example in which an alcohol is oxidized in the presence of an unreacting ketene dithioacetal.81b... 

Sometimes, aldehydes obtained by TPAP oxidations suffer in situ intramolecular transformations in substrates with a great predisposition to do so. Examples found in the literature include retro-Claisen rearrangements,108 dipolar additions on enals,106a and attack of malonates109 and indole rings11 on aldehydes. 

To avoid the C4a-C5 epoxide issue, a new route to the keto enal "73-a" was pursued [Scheme 15]. Triol 71 could be attained via LAH reduction of epoxy diol 49, and acylation of 71 would lead to the acetate 72 whose stereochemistry was assigned by X-ray analysis. The subsequent TPAP oxidation of 72 followed by deacylation and PCC oxidation led to the keto-enal "73-a" in 73% overall yield. 

To avoid this unexpected ntro-aldol-aldol predicament, the desired pentacyclc 75 was prepared via yet another route. As shown in Scheme 17, the triol 71 was oxidixed using I.cy s TPAP oxidation without protecting... 

Finally 50 is reduced to the corresponding allylic alcohol (1,2-reduction see above) followed by a further TPAP oxidation to get the corresponding r,/funsaturated aldehyde 12. 

The oxidation to the enone was realized with catalytic amounts of tetra-n-propylammonium perruthenate (TPAP)21 (46), which is a mild oxidant for conversion of multifunctionalized alcohols to aldehydes or ketones. Catalytic TPAP oxidations are carried out in the presence of stoichiometric or excess A-methylmorpholine-A-oxide (NMO)22 (47) as cooxidant. Other common reagents for oxidation of alcohols are e.g. DMS0/C202C1223, Dess-Martin periodinane24, PCC25, PDC26 or the Jones reagent27. 

Fig. 17.15. Mechanism of the TPAP oxidation of an atcohot to an aldehyde (TPAP stands for tetrapropylammonium per-ruthenate). The effective oxidant is a Ru(VII) oxide, other than in Figure 17.12 where a Ru(VIII) oxide is employed. Here, the stoichiometrically used oxidizing agent is N-methylmorpholin-/V-oxide ("NMO"), whereas in Figure 17.12 NaI04 is used.

The effective oxidant in the TPAP oxidation of alcohols is the perruthenate ion, a Ru(VII) compound. This compound is employed only in catalytic amounts hut is continuously replenished (see below). The mechanism of the alcohol — aldehyde oxidation with TPAP presum-... 

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