**3. Modified Yamamoto's Synthesis of Ambrox (1)**

This retrosynthetic proposal of (D2)-ambrox (**2**) by the cyclization of polyprenoids induced by chiral Brönsted acid is based on research previously developed by Yamamoto and coworkers [48] (Scheme 1). There are two key steps: (A) chiral Brönsted-acid-induced enantioselective cyclization of (D2)-(*E*,*E*)-homofarnesyl trialkyl silylether (**3**, P = SiEt3) to produce a chiral decalinic intermediate which, after diastereoselective cyclization, could form (D2)-ambrox (**2**). (B) The homologation of commercially available (*E*,*E*)-farnesyl chloride (**4**) to generate **3**. This transformation can be accomplished by the preparation of the barium derivative of **4**; in situ treatment of this organometallic species—(*E*,*E*) homofarnesylbarium(II) chloride—with excess of CO2 to yield (*E*,*E*)-homofarnesylic acid; reduction of this acid with LiAlD4; and final silylation of the primary alcohol formed to produce the desired deuterated compound **3**.

**Scheme 1.** Retrosynthesis of (-)-(D2)-ambrox (**2**) through cyclization of a polyprenoid derivative. (a) Chiral cyclization of (D2)-(*E*,*E*)-homofarnesyl trialkyl silylether (**3**, P = SiEt3); (b) Homologation of (*E*,*E*)-farnesyl chloride (**4**).

This non-enzymatic enantioselective polyene cyclization of deuterated compound **3** is an attractive alternative to other multistep synthesis which use chiral natural products as starting materials. The cyclization of compound **3** should be enantioselective because it has been reported that a chiral Brönsted acid can induce the enantioselective cyclization of polyprenoids [48].

#### **4. Modified Schaub's Synthesis of Ambrox (1)**

The retrosynthetic scheme for this approach is depicted in Scheme 2. The synthesis of (D2)-ambrox (**2**) is based on a manganese-pincer-complex-catalyzed deuteration of (+) sclareolide (**6**) with D2 gas to yield (D2)-ambradiol (**5**), a procedure inspired on recent research carried out by Schaub and coworkers [49] (Scheme 2b). Subsequently, (D2)-ambrox (**2**) could be obtained by an acid-catalyzed cyclization of (D2)-ambradiol (**5**) (Scheme 2a).

**Scheme 2.** Retrosynthesis of (-)-(D2)-ambrox (**2**) through manganese-pincer-complex-catalyzed deuteration of (+)-sclareolide (**6**). (a) Acid-catalyzed cyclization of (D2)-ambradiol (**5**); (b) Deuteration of (+)-sclareolide (**6**) with D2 gas.

This retrosynthetic route represents a methodology in tune with the principles of green chemistry since the desired (D2)-ambradiol (**5**) could be obtained using substoichiometric amounts of catalyst, and an almost quantitative yield is expected.
