*3.2. General Procedure for the Enantioselective Synthesis of Nitroalkanes (***4***)*

To a stirred solution of nitroalkenes (**3**) in toluene (0.3 mmol 0.3M), catalyst A (10 mol%) and Hanztsch ester (1.2 eq, 0.36 mmol) were added. The reaction mixture was heated at 60 ◦C for 24 h. Then, the mixture was allowed to warm to room temperature and the solvent was eliminated under reduced pressure, and the crude product was purified using column chromatography and an appropriate mixture of eluents.

#### **4. Conclusions**

Although the preparation of tetrasubstituted nitroacrylates proved to be very challenging, in this work a reproducible strategy for the synthesis of tetrasubstituted nitroalkenes was successfully developed using a two-step procedure; the HWE olefination of the ketone followed by the reaction of nitration affords the desired tetrasubstituted nitroalkenes (**3**).

The enantioselective reduction of these synthetized tetrasubstituted nitroalkenes (**3**) to access the functionalized nitroalkanes (**4**) was also performed, using a Hantzsch ester as the reductive agent and a thiourea based chiral catalyst, to afford the products with good to moderate yields, in a 1:1 mixture of *syn/anti* isomers, and up to 67% e.e. Although the level of enantioselectivity could not be considered satisfactory yet, it should be noted that the enantioselective organocatalytic reduction of tetrasubsituted alkenes was almost completely unknown. Even if the poor reactivity of the substrates represents a major problem, the present work demonstrates that the asymmetric catalytic reduction of functionalized nitroacrylates may offer a viable strategy for the synthesis of chiral amino ester derivatives.

The absolute configuration of the major enantiomer obtained in the enantioselective reduction was established by converting the nitroalkane **4a** into a known product. DFT calculations, performed in order to rationalize the stereochemical outcome of the reaction did not lead to satisfactory results. Further studies, considering other alternative coordination

modes between the catalyst and the substrate, will be necessary in order to understand the origins of the stereocontrol of the reaction.

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules28073156/s1.

**Author Contributions:** Conceptualization, M.B.; methodology, M.S., P.C.G. and S.R.; validation, M.S., P.C.G. and S.R.; formal analysis, F.V.; investigation, P.C.G.; data curation, S.R., F.V. and P.C.G.; writing—original draft preparation, M.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** M.B. and P.C.G. thank ITN-EID project Marie Sklodowska-Curie Actions Innovative Training Network—TECHNOTRAIN H2020-MSCA-ITN-2018 Grant Agreement 812944. www.technotrain-ITN.eu. M.B. and M.S. thank Taros Chemicals.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Data available on request from the authors.

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

**Sample Availability:** Not applicable.
