Issue in Honor of Prof. Binne Zwanenburg ARKIVOC 2004 (ii) 24-50
In 1997 Gaši et al.3 reported the conversion of solanidine (1) to DPA (6) via iminium ion 2 and the enamine intermediates 3 and 4 (Scheme 1). Enamine 4 is oxidized with NaIO4, NaI, and NaHCO3 in a mixture of water and t-BuOH to ketolactam 5, and elimination of the lactam moiety in 5 gives DPA (6) in an overall yield of 28%. Before reinvestigation of the degradation of solanidine (1), it was converted to its acetate prior to oxidation with Hg(OAc)2. Because the Hg(OAc)2 contained some acetic acid7, enamine 4 was directly formed in 90% yield, which made the separate isomerization step superfluous. However, oxidation of enamine 4 according to the procedure of Gaši et al.3 was unsuccessful in our hands and the starting material was recovered almost quantitatively. Many other oxidation reagents were tried (ozone,8 O2/CuCl,9 MnO2,10,11 KMnO4,12 KMnO4/Al2O3,13 CrO3/HOAc,14-16 CrO3/pyridine,17 H2O2,18 MMPP19), but in all cases no oxidation product could be obtained. To rule out a possible involvement of the .5,6 double bond during the oxidation,20 1 was transformed into solanidan-4-en-3-one (7) by treatment of 1 with Al(i-PrO)3 in toluene in the presence of cyclohexanone (Scheme 2). Oxidation of enone (7) with Hg(OAc)2 again showed the exclusive formation of the corresponding .20,22-enamine, which was subjected again to a range of oxidation reactions,3,8,1016,18,19,21 but all failed in our hands.
According to Gaši and co-workers3 the modest yield of the oxidation of enamine 4 was due to its instability. However, Mopac22 PM3 calculations23,24 showed that enamine 4 (.Hf = -76.57 kcal) is more stable than enamine 3 (.Hf = -68.86 kcal).The energy difference is large enough to make isomerization during the oxidation reaction unlikely and the difficulties in the oxidation reaction can not only be imputed to the instability of enamine 4. These calculations also show that enamine 4 is not really an enamine but more an isolated double bond and a separate amino group. The bond order of the C-N bond is 1.03, which indicates that there is nearly a single bond between C22 and N. The .20,22 double bond forces the five membered E-ring to be completely flat, and as a consequence the D-ring is bent in such a way that C18 and the six membered ring shield its top and bottom side, respectively (Figure 1). The methyl group (C21) lies in the plane of the .20,22 double bond making it even more difficult to approach. In our opinion, steric hindrance is the main reason for the low reactivity of this .20,22 double bond.
121724202113231116222725149N126181581037O56194 Figure 1. Enamine 4.
ISSN 1424-6376 Page 27 ©ARKAT USA, Inc
