Following the synthetic sequence, the intermediate 5 was submitted to the Wittig reaction using methyltriphenylphosphonium bromide and n-BuLi as the base. However, this met with failure and starting material was recovered. After some attempts, we obtained the olefination product by treating 5 with CH2Br2/Zn/TiCl4 in CH2Cl2, following the Lombardo´s protocol,23 where 7 was obtained in 73% yield (Scheme 2).
f2HO11CH2OHHOHOHe10COOCH3HOHOCOOCH3HOHdcCH2OTsHO9ba 857COOCH3HOO12345678910111615141312
Scheme 2. (a) Zn, TiCl4, CH2Br2, CH2Cl2, rt, 73%; (b) i. THF, HCl 1%, rt; ii. NaBH4, MeOH, rt, 81%; (c) mCPBA, CH2Cl2, rt, 90%; (d) LiAlH4, THF, reflux, 86%; (e) TsCl, Py, rt, 62%; (f) i. NaI, Zn, DMF, 120°C; ii. mCPBA, CH2Cl2, rt, 58% (two steps).
Next, the deprotection of the ketal using 1% HCl in THF furnished an unstable aldehyde which decomposed during purification. Thus, after deprotection, the crude material was treated with NaBH4 in MeOH to furnish the corresponding hydroxy ester 8 in 81% yield. Epoxidation of 8 with mCPBA in CH2Cl2 followed by reduction of the epoxide 9 with LiAlH4, furnished the triol 10 in 77% overall yield. Since it is known that treatment of hydroxy groups at C-8 and C- 12 with 1.0 equivalent of MsCl21 leads to tetrahydrofuran derivatives, triol 10 was treated with 2.0 equivalent of TsCl in pyridine. As expected, monotosylate 11 was obtained in 62% yield. Finally, treatment of 11 with NaI and activated Zn in DMF at 120oC furnished ent-ambrox (2) together with an inseparable mixture of isomeric olefins. The presence of unsaturated compounds was detected by 1H NMR spectral analysis, which showed signals between d 4.0 and 5.2, characteristic of olefinic hydrogens and also by 13C NMR spectra which showed signals of sp2 carbons between d 120 and 140. Analysis by GC/MS showed the presence of at least 4 compounds with masses 2 Daltons less than the expected product. Based on these data, it was
