Hydroxylated Piperidines

To return to a more historical development the mercuric acetate oxidation of substituted piperidines (77) should be discussed next. This study established that the normal order of hydrogen removal from the aW-carbon is tertiary —C—H > secondary —C—H > primary —C—H, an observation mentioned earlier in this section. The effect of substitution variations in the piperidine series can be summarized as follow s l-mcthyl-2,6-dialkyl and 1-methyl-2,2,6-trialkyl piperidines, as model systems, are oxidized to the corresponding enamines the 1,2-dialkyl and l-methyl-2,5-dialkyl piperidines are oxidized preferentially at the tertiary a-carbon the 1-methyl-2,3-dialkyl piperidines gave not only the enamines formed by oxidation at the tertiary a-carbon but also hydroxylated enamines as found for 1-methyl-decahydroquinoline (48) (62) l-methyl-2,2,6,6-tctraalkyl piperidines and piperidine are resistant to oxidation by aqueous mercuric acetate and... 

The phenothiazine duoperone (5) combines structural elements found in phenothiazine and buty-rophenone antipsychotic agents. Alkylation of substituted piperidine 1 with 3-chloropropanol affords the intermediate 2 treatment of this with thionyl chloride converts the terminal hydroxyl to chloride. Alkylation of the phenothiazine 4 with halide 3 affords the antipsychotic agent duoperone (5) [1]. 

Here the alcoholic hydroxyl is first protonated and then eliminated as water. The allylcarbenium ion (2) is initially stabilized by elimination of the proton at C-14. Then the ether link is opened after protonation of the ring oxygen with the formation of carbenium ion (3), whereby the neighboring C-C bond of the piperidine ring is cleaved with aromatization of the C ring. The carbenium ion (4) formed is stabilized by elimination of a proton and ring closure to apomorphine (5). 

Chakraborty and Scott have reported the detection of N-OH groups in the photo-oxidation of methylcyclohexane containing a bis-piperidine or a nitroxide, based on their observation of an IR absorption at 2765 cm-1(13). However we have found the )>N-0H absorption to occur at 3 60 cm 1 (ll) in 1-hydroxyl-2,2,6,6-tetramethylpiperidines which throws some doubt on their IR detection of >N0H. 

The selective monohydroxylation of heterocyclic compounds such as piperidine derivatives1741 and the 7-lactam (19)[751 have been studied. It is also been shown that hydroxylation of phenylcyclohexane can be effected using cytochrome P450 and the regioselectivity of hydroxylation can be altered by site-directed mutagenesis of the enzyme1761. 

Another example, in which the piperidine cycle is generated de novo, exploits a hetero Diels-Alder cycloaddition of 1 -/r-tolylsulfinyl-1,3-penta-diene 91 with benzylnitrosoformate, that generates an oxazine 92 with complete regioselectivity and 7i-facial diastereoselectivity.69 Osmilation of the double bond inserts stereoselectively two hydroxyl groups on the oxazine skeleton, protection and catalytic hydrogenation finally afforded the enantiomerically pure imino sugars 94 (Fig. 38). 

A thioglycoside was immobilized by the following sequence of reactions. Treatment of the dibutyltin acetal of diol 36 with succinic anhydride afforded 37 in an excellent yield of 85%. Attachment of Fmoc protected glycine to TentaGel hydroxyl resin (38, 0.37 mmol/g resin) under standard conditions followed by removal of the Fmoc group by treatment with piperidine gave polymer 27. Compound 37 was immobilized by amide bond formation with 27 in the presence of... 

TABLE 2. Second-order reaction rate coefficients, a> at 15, 25 and 40 °C, and activation parameters for the reactions 10-4 M of l-chloro-2,4-dinitrobenzene with piperidine in hydroxylic solvents4813... 

Sphingomonas sp. HXN-200 was also able to accept a six-member ring substrate. Hydroxylation of A/-benzyl- and A/-/ert-butoxycarbonyl-2-piperidinone gave the corresponding (/J)-4-hydroxy-piperidin-2-ones in 31% and 68% ee, respectively (Figure 15.4). This provides a simple synthesis of such types of useful synthons. 

To facilitate its application in organic synthesis, we developed a lyophilized cell powder of Sphingomonas sp. HXN-200 as a biohydroxylation catalyst. Hydro-xylation of A-benzyl-piperidine with such catalyst powder showed 85% of the activity of a similar hydroxylation with frozen/thawed cells, shown in Figure 15.6. The fact that rehydrated lyophilized cells are able to carry out such a reduced nicotinamide adenine dinucleotide (NADH)-dependent hydroxylation indicates that these cells are capable of retaining and regenerating NADH at rates equal to or exceeding the rate of hydroxylation. To our knowledge, this is the first example of the use of lyophilized cells for a cofactor-dependent hydroxylation. 

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