One-pot synthesis of (−)-Ambrox

(−)-Ambrox is recognised as the prototype of all ambergris odorants. Widely used in perfumery, (−)-Ambrox is an important ingredient due to its unique scent and excellent fixative function. An environmentally friendly and practical preparation of (−)-Ambrox is still unavailable at present although a lot of attention has been paid to this hot research topic for many years. A one-pot synthesis of (−)-Ambrox was studied starting from (−)-sclareol through oxidation with hydrogen peroxide in the presence of a quaternary ammonium phosphomolybdate catalyst {[C5H5NC16H33] [H2PMo12O40]}, which gave the product a 20% overall yield.

In route A (− )-Ambrox was synthesised through three steps [23][24][25] , including an oxidative degradation of the (− )-sclareol side chain to give sclareolide, a reduction of sclareolide to ambradiol and a cyclodehydration of ambradiol. It is the most efficient way so far. This system is used in industrial production of (− )-Ambrox in spite of several disadvantages, such as expensive or toxic reagents, elaborate operation, long reaction time and massive pollutant discharge.
In route C (− )-sclareol was transformed into (− )-Ambrox through two steps via β -cleavage of an alkoxy radical intermediate in 11-12% overall yield 27 . The oxidation was carried out using 70% H 2 O 2 as the oxidant in the presence of stoichiometric amounts of Cu(OAc) 2 ·2H 2 O, FeSO 4 ·7H 2 O for 7 d. Obviously this process is not practical due to its low efficacy, possible safety risks and large pollutant discharge.
In our preliminary experiment, (− )-sclareol was oxidized by H 2 O 2 in the presence of Na 2 WO 4 ·2H 2 O (10 mol %) and NaH 2 PO 4 (0.1 equiv) as the catalyst, and TBAB as phase transfer catalyst in 1,4-dioxane at 70 °C for 2 h to give 2% yield of (− )-Ambrox. It was interesting to learn that if a suitable catalyst was selected, (− )-Ambrox could be prepared by one-pot reaction. The oxidant is hydrogen peroxide, which is a green oxidant. It is probably the best terminal oxidant after dioxygen with respect to environmental and economic considerations 28 .
In order to improve the yield of (− )-Ambrox, the reaction mixture was heated to 90 °C after stirring for 2 h at 70 °C. The effect of reaction time at 90 °C on yield was explored and the results are shown in Table 1. The yield of (− )-Ambrox reached the highest value of 3.86% after 60 min (Entry 7, Table 1) and decreased gradually with extended reaction times. Obviously, this was a promising but not ideal yield. It was predicted that various phosphotungstate catalysts might be more effective in view of the real catalytic species produced by the reaction of Na 2 WO 4 ·2H 2 O with NaH 2 PO 4. Phosphotungstate catalyst is one of the Polyoxometalates (POMs). POMs are discrete metal-oxide clusters of W, Mo, V, and Nb that have been attracting increasing interest because of their multi-electronic redox activities, photochemical properties, acidic properties and magnetic properties, resulting in potential applications of POMs as catalysts and functional materials 29 . The Ishii-Venturello system has been used on the epoxidation reaction successfully 30,31 . As Mo and W belong to the same main group, they display similar characteristics. So our main object is to look for effective phosphotungstate and phosphomolybdate catalysts. A series of quaternary ammonium phosphotungstates and phosphomolybdates were prepared 30 and listed in Table 2. All these self-made catalysts were tried as a way of catalysing the oxidation of (− )-sclareol with H 2 O 2 in 1,4-dioxane at 70 °C for 2 h, and then at 90 °C for 1 h. The results are given in Table 3. The catalyst 10 p gave the best yield of 18.20% (entry 20, Table 3), which was almost five times as much as that given by Na 2 WO 4 ·2H 2 O. The product was isolated and purified easily. The quaternary ammonium phosphomolybdates usually displayed better catalytic ability (entries 16-21, Table 3) than quaternary ammonium phosphotungstates (entries 4-15, Table 3). All the quaternary ammonium phosphotungstates belong to Keggin-type phosphotungstates 30 . To explore the catalytic capability of different types of phosphotungstates Dowson-type phosphotungstate HPC (H 6 P 2 W 18 O 62 . H 2 O) was also prepared 32 . The yield given by HPC was 5.47%, which was very close to those values produced by Keggin-type phosphotungstates. The results in Table 3 show that the optimum catalyst for one-pot synthesis for (− )-Ambrox is compound 10   The amount of catalyst 10 p for the reaction was optimised (entries 1-10, Table 4). (− )-Ambrox was produced in the highest yield of 22.79% when 3% equiv. catalyst was used (entry 3, Table 4). The yield decreased from 22.79% to 16.58% when the catalyst loading was lowered from 3% to 1%, whereas the yield didn't increase with the increment of catalyst loading when it exceeded 3%.
The reaction was repeated under the above optimised conditions and (− )-Ambrox was obtained in an average isolated yield of 20%. The determination of its specific rotation was [α ] = − 30° (C = 1, toluene), which was similar to that in other literature 24 .
The plausible one-pot synthesis reaction mechanisms were proposed for the current protocol (Fig. 2). (− )-Sclareol was initially epoxidised to compound 11 ( Figure S5) or converted to compound 12 ( Figure S6) by intramolecular etherification in the presence of the quaternary ammonium phosphomolybdate 10 p. Subsequently, compound 11 or 12 might undergo catalysed substitution with hydrogen peroxide to produce intermediate 13, which fragmented by radical mechanism through radical intermediates 14 and 15 to produce (− )-Ambrox. This one-pot synthesis proceeds through epoxidation 30 , intramolecular etherification 33 , free radical substitution 27 and free radical fragmentation 26 .
A one-pot synthesis of (− )-Ambrox has been accomplished by the use of (− )-sclareol, thus demonstrating the power of catalysis in the synthesis of natural products. This synthesis was made possible by the discovery of a novel route to preparing (− )-Ambrox.

Conclusions
In summary, total syntheses of (− )-Ambrox has been accomplished in 20% total yield by using an inexpensive and simple catalyst and one-pot reactions. This route is not only short and efficient but also has several noteworthy and sustainable features: (1) The total synthesis is performed in only one isolation and chromatographic purification, which reduces the amount of solvent needed and waste formed. (2) The reaction is a highly selective catalytic reaction, involving a quaternary ammonium phosphomolybdates catalyst with 3% catalyst loading and  reduces the generation of waste. (3) The oxidant employed in the present synthesis is hydrogen peroxide and water without any pollution is the only theoretical by-product. Thus, the present one-pot synthesis is not only efficient for the synthesis of (− )-Ambrox, but is also environmentally benign. This work is significant in improving the synthesis of (− )-Ambrox based on (− )-sclareol. We are still doing research in our lab in order to further improve the yield of (− )-Ambrox.

Methods
Synthesis of the catalysts. Synthesis of catalysts was illustrated by the synthesis of catalyst 10 p.
PMA (1.82 g, 1 mmol) and deionized water (10 mL) were combined in a 50 mL three-neck flask. The mixture was stirred for 5 min at 25 °C and further CPC (0.36 g, 1 mmol) in deionized water (10 mL) was added after 5 min, then the mixture was stirred for 3 h at 25 °C. When filtered, the filtrate cake was washed with liquid and dried by vacuum to produce H1 (1.76 g, 82%) as a dark green solid.