Hydroxylation of 1-azabicyclo[4.1.0]hept-3-enes formed by Diels– Alder reactions of benzyl 2 H -azirine-3-carboxylate

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Introduction
In several publications we have described the reactions of 2H-azirines bearing an activating alkoxycarbonyl or aminocarbonyl substituent on the C=N bond with conjugated dienes. 1,2The azirines proved to be highly active dienophiles, and Diels-Alder cycloaddition reactions took place at room temperature without a catalyst.Recently, similar reactions have been reported with 2H-azirines bearing an activating dialkoxyphosphonyl substituent. 3In an attempt to simplify the azirine structure as much as possible the azirine ester 1a, unsubstituted at C-2, was generated from tert-butyl acrylate. 2This azirine is a good dienophile but it is very unstable and cannot be fully characterized.As an alternative the benzyl ester 1b was prepared and it proved to be somewhat more stable and easier to handle.We have previously described the reactions of this azirine with some nitrogen heterocycles 4 and with furans. 5Its reactions with other conjugated dienes have been investigated and are described here.The hydroxylation of the double bonds in the adducts obtained from the dienes, particularly those bearing oxygen substituents, have also been explored with the aim of finding a simple route to glycosidase inhibitors analogous to nojirimycin.

Results and Discussion
The azirine ester 1b is generated by heating a toluene solution of benzyl 2-azidoacrylate under reflux for 5 h. 4 It can be isolated and characterized by NMR spectroscopy but for the purpose of carrying out cycloaddition reactions it is simpler to reduce the volume of the toluene solution under vacuum and to add the diene directly to the solution.In this way Diels-Alder reactions were performed at room temperature with cyclopentadiene, 1,3-cyclohexadiene, 1,4diphenylbutadiene, 1-acetoxybutadiene, and 1,4-diacetoxybutadiene, giving the 1azabicyclo[4.1.0]hept-3-enes2, 3 and 4a-4c which were isolated and characterized.We have described the analogous synthesis of compound 4d from 1,4-bis(tert-butyldimethylsilyl)butadiene earlier. 5

N
All these cycloaddition reactions were remarkably selective and gave only single isomers.The structures of two of these, compounds 4c and 4d, were established by X-ray crystallography (Figures 1 and 2).Selected bond lengths and bond angles are given in Tables 1 and 2. From these and from NMR data it is clear that the azirine approaches the diene in an endo manner with respect to the 3-membered ring. 1,2    a Atom numbering corresponds to that in Figure 2.
The chemistry of the 1-azabicyclo[4.1.0]hept-2-enering system has not previously been investigated and we were attracted by the potential for introducing further functional groups on the double bond.In particular, if those adducts containing oxygen substituents at positions 2 and 5 could be hydroxylated and the benzyloxycarbonyl group reduced, this would provide a very short route into glycosidase inhibitors similar in structure to nojirimycin 5. Several inhibitors of this type that contain an aziridine ring have been described in the literature. 6Some preliminary experiments were first carried out with the cyclohexadiene adduct 3 in order to check that the 3membered ring would survive treatment with oxidising and reducing agents.Reduction with lithium aluminium hydride gave the alcohol 6 which was isolated in 49% yield after chromatography.The cis-hydroxylation of the double bond of the ester 3 was achieved by reaction with a catalytic amount of osmium tetroxide and with N-methylmorpholine N-oxide as co-oxidant; this gave the diol 7 in 42% yield.Having established that the 3-membered ring could survive these conditions, a similar hydroxylation was attempted with the diacetate 4c.However the compound remained unchanged after exposure to the reagents for 7 days, and the use of a stoichiometric amount of osmium tetroxide caused it to decompose.As an alternative we turned to the use of a quaternary ammonium permanganate salt for cis-dihydroxylation. 7 Cetyltrimethylammonium permanganate was made by a slight modification of the literature procedure and was obtained as a violet powder, soluble in dichloromethane.Hydroxylation of the double bond of the diacetate 4c was carried out using this salt in dichloromethane at room temperature and the diol 8 was isolated in yields of up to 50% as a crystalline solid.Its structure was confirmed by an X-ray determination (Figure 3 and Table 3).The same method, when applied to the monoacetate 4b, gave the corresponding diol 9 only in low yield and with the bis(silyl ether) 4d the diol 10 was isolated in, at best, 23% yield.However when this last hydroxylation was carried out under standard osmylation conditions with a catalytic amount of osmium tetroxide, the diol 10 was obtained in 93% yield.It may be that osmylation of the diacetate 4c is inhibited by the two electron deficient oxygen substituents.Finally a small scale reduction of the benzyloxycarbonyl group of the diol 10 was carried out.This gave the triol 11 (31%) as an oil.The final deprotection of the silyl ether functions was not attempted but overall this appears to be a viable route to polyhydroxylated 1azabicyclo[4.1.0]heptanes,albeit in racemic form.Epoxidation of the double bond of the precursor 4d and further functional group manipulation could enable diastereoisomers to be synthesized.

Figure 1 .
Figure 1.ORTEP view of the structure of the aziridine 4c.

a
Atom numbering corresponds to that in Figure1.

Figure 2 .
Figure 2. ORTEP view of the structure of the aziridine 4d.

Table 1 .
Selected bond lengths and bond angles for