**5. Modified Rosales Martínez's Synthesis of Ambrox (1)**

The retrosynthetic route of (D2)-ambrox (**2**) by the Cp2TiCl-catalyzed radical tandem cyclization of a farnesol derivative is based on the research carried out by our research group [42] (Scheme 3). This approach comprises three retrosynthetic operations: (a) The incorporation of deuterium was achieved by reduction of nitrile **7** with LiAlD4, a process that would give as intermediate (D2)-homoalbicanol. Subsequently, this deuterated intermediate can be converted into (D2)-ambrox (**2**) by acid-mediated cyclization. (b) The second retrosynthetic operation is the homologation of albicanol (**8**) with NaCN to form the nitrile derivative **7**. (c) Finally, albicanol (**8**) can be enantioselectively prepared by the Cp2TiCl-catalyzed radical cyclization of enantiomerically pure epoxyfarnesyl acetate (**9**). The required epoxide **9** can be obtained from commercially available (*E*,*E*)-farnesol following the procedure reported by Spinella and coworkers [50], followed by the deoxygenation of the hydroxyl group at C3 using the Barton–McCombie deoxygenation protocol.

**Scheme 3.** Retrosynthesis of enantiomeric (D2)-ambrox (**2**). (a) Reduction of nitrile **7** with LiAlD4, and subsequently acid-mediated cyclization; (b) Homologation of albicanol (**8**); (c) Cp2TiCl-catalyzed radical cyclization of epoxyfarnesyl acetate (**9**).

The key step of this retrosynthetic route is a highly diastereoselective Cp2TiCl-catalyzed radical tandem cyclization of epoxide **9**.

In summary, this article intends to be a proposal for the use of deuteration as a powerful tool to decrease the volatility of deuterated derivative compounds compared to their non-deuterated analogues. This new application could be used to obtain deuterated ambrox in order to reduce its volatility and improve the long-term scent and the shelf life of perfumes. For this purpose, different retrosynthetic approaches have been proposed. We believe that this new way of preparing ambrox with a low exchange of hydrogen by deuterium may be highly attractive for the perfume industry and analytical chemistry since the deuterated ambrox derivatives can also be used as internal standards for the determination of low concentrations of ambrox (**1**) in water after biodegradability test [31].

**Author Contributions:** A.R.M.: design and coordination of the project, writing—original draft, writing—review and editing. I.R.-G.: review and editing. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by the University of Seville, through the Vicerrectorado de Investigación (Projects 2020/00001014 and 2021/00000422: Ayudas a Consolidación de Grupos de la Junta de Andalucía and Project Politec-Biomat: Red de Biomateriales en la Universidad de Sevilla) and also by the University of Almería and Junta de Andalucía (Conserjería de Transformación Económica, Industria, Conocimiento y Universidades) and Fondo Europeo de Desarrollo Regional (FEDER) for the Project UALFEDER 2020-FQM-B1989.

**Acknowledgments:** Antonio Rosales Martínez acknowledges the University of the Sevilla for his position, and for a grant for the requalification of university teaching staff at the CIQSO, University of Huelva.

**Conflicts of Interest:** The authors declare no conflict of interest.
