Efﬁcient Asymmetric Simmons-Smith Cyclopropanation and Diethylzinc Addition to Aldehydes Promoted by Enantiomeric Aziridine-Phosphines

: During an implementation of current research, a set of optically pure chiral aziridines and aziridine imines bearing a phosphine moiety was prepared with high values of chemical yield. The above chiral heteroorganic derivatives were tested for catalytic utility as chiral ligands in asymmetric Simmons-Smith cyclopropanation and asymmetric diethylzinc addition to various aldehydes. Most of the desired products were formed in high chemical yields, with satisfactory values of enantiomeric excess (sometimes more than 90%) and diastereomeric ratios (in case of cyclopropanation reaction).


Introduction
The asymmetric construction of chiral non-racemic organic compounds is still an extremely important issue for many research teams around the world. Both the chemical yield and optical purity of the desired products of stereocontrolled synthesis depend on the selection of an appropriate promoter for such a reaction. This role can be played by a chiral ligand [1,2], an organocatalyst [3,4], a chiral auxiliary [5], bifunctional catalysts (molecule possessing two distinct functional groups) [6,7] or another cooperative catalytic system [8].
The asymmetric Simmons-Smith reaction is one of the approaches in the synthesis of cyclopropane derivatives [9]. A cyclopropane ring with unusual electronic and steric properties is present in many natural products [10] and drugs [11][12][13][14][15]. Molecules containing this three-membered motif can be constructed in transformations with or without transition metals [16] in the presence of, e.g., complexes of porphyrin [17], proline derivatives [18,19], chiral phase-transfer catalysts [20] or as demonstrated in our laboratory, using chiral aziridinyl ligands containing sulfinyl moiety [21].
In turn, asymmetric diethylzinc addition to carbonyl compounds (especially aromatic aldehydes) is one of the most exploited test reactions in the chemical literature [22,23]; however, it is still a very simple and effective tool for studying the catalytic activity of chiral ligands. Based on our experience, ligands containing an aziridine fragment show very high efficiency in reactions of this type [23][24][25][26][27][28].
Chiral systems containing a phosphine group and an aziridine ring within one molecule are not the subject of many reports in the chemical literature [29]. Enriching the current state of knowledge about such chiral junctions, we recently published a successful application of aziridine phosphines in the asymmetric Friedel-Crafts reaction [30].
Taking into consideration all of the aforementioned circumstances, we decided to synthesize a series of optically pure aziridines and aziridine imines possessing phosphine motif in order to check their catalytic activities in the asymmetric Simmons-Smith cyclopropanation and asymmetric diethylzinc addition to aldehydes. Thus, we wanted to show that chiral aziridine-phosphines are universal catalysts operating in various types of asymmetric transformations.
Catalysts 2021, 11, x FOR PEER REVIEW 2 of 11 current state of knowledge about such chiral junctions, we recently published a successful application of aziridine phosphines in the asymmetric Friedel-Crafts reaction [30].
Taking into consideration all of the aforementioned circumstances, we decided to synthesize a series of optically pure aziridines and aziridine imines possessing phosphine motif in order to check their catalytic activities in the asymmetric Simmons-Smith cyclopropanation and asymmetric diethylzinc addition to aldehydes. Thus, we wanted to show that chiral aziridine-phosphines are universal catalysts operating in various types of asymmetric transformations.
Taking into consideration all of the aforementioned circumstances, we decided to synthesize a series of optically pure aziridines and aziridine imines possessing phosphine motif in order to check their catalytic activities in the asymmetric Simmons-Smith cyclopropanation and asymmetric diethylzinc addition to aldehydes. Thus, we wanted to show that chiral aziridine-phosphines are universal catalysts operating in various types of asymmetric transformations.

Asymmetric Simmons-Smith Cyclopropanation Promoted by Aziridine-Phosphines 1-8 and Imine-Phosphines 9-12
Equipped with all optically pure phosphorus-functionalized aziridines 1-12, we decided to check their utility as chiral ligands catalyzing an asymmetric cyclopropanation reaction of cinnamyl alcohol (13) as a model substrate. The transformations were carried out in DCM with 2 equiv. of diethylzinc and 3 equiv. of diiodomethane in the presence of a ligand (10 mol%) (Scheme 2). All the results are presented in Table 1.  The analysis of the results collected in Table 1 leads to the following conclusions. Ligands 1-4 containing a methylene linker connecting a phenyl ring with an aziridine nitrogen atom were characterized by moderate catalytic efficiency leading to cyclopropyl derivative 14 in chemical yields varying from 63 to 72%, with enantiomeric excess in the range of 53 to 65% and with a moderate diastereomeric ratio of 5:1 ( Table 1, entries 1-4). Much better catalytic activity was shown by aziridine-phosphines 5-8 (without methylene subunit). Their use in the asymmetric cyclopropanation allowed us to obtain the desired chiral product 14 in high yields of around 90%, 80-98% of ee, and with reasonable diastereoselectivity (10:1-15:1) ( Table 1, entries 5-8). In turn, the last group of chiral ligands, namely, imine-phosphines 9-12, exhibited indirect catalytic activity to systems with and without a methylene linker. In these cases, cyclopropane 14 was formed in 79-85% yields, 68-70% of ee, and a 10:1 diastereomeric ratio (Table 1, entries 9-12).
Finally, there is one more interesting aspect to note. The change in the absolute configuration on the carbon atom of the aziridine moiety of the ligand leads to the cyclopropanation product 14 with opposite absolute configuration (Table 1, entries 1, 5 and 10). We observed a similar relationship while conducting research on asymmetric Michael   [21,32]. Conditions: 10 mol% of the ligand, cinnamyl alcohol (0.5 mmol), diethylzinc (1.0 M in hexanes, 1 mmol), diiodomethane (0.6 mmol), DCM (5 mL), 0 • C, 4 h.
The analysis of the results collected in Table 1 leads to the following conclusions. Ligands 1-4 containing a methylene linker connecting a phenyl ring with an aziridine nitrogen atom were characterized by moderate catalytic efficiency leading to cyclopropyl derivative 14 in chemical yields varying from 63 to 72%, with enantiomeric excess in the range of 53 to 65% and with a moderate diastereomeric ratio of 5:1 ( Table 1, entries 1-4). Much better catalytic activity was shown by aziridine-phosphines 5-8 (without methylene subunit). Their use in the asymmetric cyclopropanation allowed us to obtain the desired chiral product 14 in high yields of around 90%, 80-98% of ee, and with reasonable diastereoselectivity (10:1-15:1) ( Table 1, entries 5-8). In turn, the last group of chiral ligands, namely, imine-phosphines 9-12, exhibited indirect catalytic activity to systems with and without a methylene linker. In these cases, cyclopropane 14 was formed in 79-85% yields, 68-70% of ee, and a 10:1 diastereomeric ratio (Table 1, entries 9-12).
Finally, there is one more interesting aspect to note. The change in the absolute configuration on the carbon atom of the aziridine moiety of the ligand leads to the cyclopropanation product 14 with opposite absolute configuration (Table 1, entries 1, 5 and 10). We observed a similar relationship while conducting research on asymmetric Michael [33], Mannich [34] and Friedel-Crafts [30] reactions. Thus, the application of enantiomeric catalysts provides access to both enantiomers of the cyclopropanation product 14.

Asymmetric Simmons-Smith Cyclopropanation Promoted by Aziridine-Phosphine 6
Considering the highest catalytic activity of ligand 6, we decided to study the scope of the asymmetric cyclopropanation in the presence of 6 by the application of another allylic alcohol under the same conditions (Scheme 3). All the results are shown in Table 2.

Asymmetric Simmons-Smith Cyclopropanation Promoted by Aziridine-Phosphine 6
Considering the highest catalytic activity of ligand 6, we decided to study the scope of the asymmetric cyclopropanation in the presence of 6 by the application of another allylic alcohol under the same conditions (Scheme 3). All the results are shown in Table 2.  The data collected in Table 2 clearly indicate a very high catalytic activity of aziridinephosphine 6 in the asymmetric Simmons-Smith cyclopropanation of (E)-allylic alcohols 15-17 using diethylzinc and diiodomethane in the presence of diethylaluminum chloride leading to the appropriate cyclopropyl systems in high chemical yields (up to 90%) with a high degree of enantioselectivity (up to 90% ee) and diastereoselectivity (15:1 of dr). Lower enantio-and diastereoselectivity in the case of the reaction of (Z)-cinnamyl alcohol 18 (Table 2, entry 4) is in accordance with previous studies on the asymmetric cyclopropanation of this system [21].

Asymmetric Diethylzinc Addition to Benzaldehyde Catalyzed by Aziridine-Phosphines 1-8 and Imine-Phosphines 9-12
Based on our experience in the field of asymmetric transformations in the presence of zinc ions catalyzed by aziridine derivatives [35], in the next stage of research, we decided to check the catalytic activity of the chiral systems 1-12 in one of the most basic model asymmetric reactions involving zinc ions, namely, asymmetric diethylzinc addition to benzaldehyde (Scheme 4). The results of these tests are shown in Table 3.  The data collected in Table 2 clearly indicate a very high catalytic activity of aziridinephosphine 6 in the asymmetric Simmons-Smith cyclopropanation of (E)-allylic alcohols 15-17 using diethylzinc and diiodomethane in the presence of diethylaluminum chloride leading to the appropriate cyclopropyl systems in high chemical yields (up to 90%) with a high degree of enantioselectivity (up to 90% ee) and diastereoselectivity (15:1 of dr). Lower enantio-and diastereoselectivity in the case of the reaction of (Z)-cinnamyl alcohol 18 (Table 2, entry 4) is in accordance with previous studies on the asymmetric cyclopropanation of this system [21].

Asymmetric Diethylzinc Addition to Benzaldehyde Catalyzed by Aziridine-Phosphines 1-8 and Imine-Phosphines 9-12
Based on our experience in the field of asymmetric transformations in the presence of zinc ions catalyzed by aziridine derivatives [35], in the next stage of research, we decided to check the catalytic activity of the chiral systems 1-12 in one of the most basic model asymmetric reactions involving zinc ions, namely, asymmetric diethylzinc addition to benzaldehyde (Scheme 4). The results of these tests are shown in Table 3.   The results summarized in Table 3 show that all chiral systems 1-12 are capable of catalyzing an asymmetric addition reaction of diethylzinc to benzaldehyde. The best results in terms of chemical yields and enantioselectivities were achieved using aziridinephosphines 5-8 without a methylene linker (Table 3, entries 5-8) with the most active system 6 leading to the desired chiral alcohol 19a in 95% yield and with 96% ee. Ligands 9-12 (imines) exhibited lower activity (yield and ee around 80%) ( Table 3, entries 9-12). In turn, aziridine-phosphines 1-4 containing a methylene linker showed only moderate efficiency as chiral ligands (Table 3, entries 1-4), which is in line with our previous observations.

Asymmetric Addition of Et 2 Zn to Aldehydes Promoted by Aziridine-Phosphine 6
Equipped with the most effective catalyst 6, we decided to expand the scope of its application using other aldehydes for this purpose (Scheme 5). The results are shown in Table 4. As shown in Table 4, aziridine-phosphine 6 is prone to efficiently catalyzing an asymmetric addition of diethylzinc to aldehydes in most cases. The use of n-butyraldehyde (Table 4, entry 1), 2-and 4-methyl, methoxy-, bromo-and 4-trifluoromethylbenzaldehydes ( sults in terms of chemical yields and enantioselectivities were achieved using aziridine-phosphines 5-8 without a methylene linker (Table 3, entries 5-8) with the most active system 6 leading to the desired chiral alcohol 19a in 95% yield and with 96% ee. Ligands 9-12 (imines) exhibited lower activity (yield and ee around 80%) ( Table 3, entries 9-12). In turn, aziridine-phosphines 1-4 containing a methylene linker showed only moderate efficiency as chiral ligands (Table 3, entries 1-4), which is in line with our previous observations.

Asymmetric Addition of Et2Zn to Aldehydes Promoted by Aziridine-Phosphine 6
Equipped with the most effective catalyst 6, we decided to expand the scope of its application using other aldehydes for this purpose (Scheme 5). The results are shown in Table 4.

Asymmetric Cyclopropanation of Cinnamyl Alcohol and Diethylzinc Addition to Benzaldehyde Catalyzed by Aziridine-Phosphine Oxides
Finally, we decided to check whether the presence of the phosphine group is important for the course of both title asymmetric reactions. To this end, we carried out the cyclopropanation of cinnamyl alcohol and the addition of diethylzinc to benzaldehyde under the same conditions as before using two enantiomerically pure phosphinoyl-aziridines 20 and 21, which were prepared as previously described [33,34] (Scheme 6). The results are summarized in Tables 5 and 6.   9 Vi 87 85 (S) 10 4-O2NC6H4 0 Nd c Nd c 11 C4H3S 70 68 (S) 12 C4H3O 0 Nd c Nd c a Determined by chiral HPLC using Chiralcel OD column. b According to the literature data [37][38][39]. c Not determined. Conditions: 10 mol% of the ligand, aldehyde (1 mmol), diethylzinc (1.0 M in hexanes, 3 mmol), toluene (5 mL), 0 °C, 2 h.

Asymmetric Cyclopropanation of Cinnamyl Alcohol and Diethylzinc Addition to Benzaldehyde Catalyzed by Aziridine-Phosphine Oxides
Finally, we decided to check whether the presence of the phosphine group is important for the course of both title asymmetric reactions. To this end, we carried out the cyclopropanation of cinnamyl alcohol and the addition of diethylzinc to benzaldehyde under the same conditions as before using two enantiomerically pure phosphinoyl-aziridines 20 and 21, which were prepared as previously described [33,34] (Scheme 6). The results are summarized in Tables 5 and 6. Scheme 6. Cyclopropanation of 13 and addition of Et2Zn to benzaldehyde in the presence of phosphinoyl-aziridines.  [21,32]. Conditions: 10 mol% of Scheme 6. Cyclopropanation of 13 and addition of Et 2 Zn to benzaldehyde in the presence of phosphinoyl-aziridines.  The inspection of Tables 5 and 6 clearly indicates that the presence of the phosphine group in the structure of the chiral ligand has a very strong influence on the efficient course of both asymmetric transformations. The application of two chiral ligands bearing phosphinoyl (P=O) moiety instead of phosphine produced cyclopropyl derivative 14 and the chiral alcohol 19a only in moderate chemical yields and with moderate enantiomeric excess and diastereoselectivity.

Materials
Dichloromethane was dried over calcium hydride. Toluene and diethyl ether were distilled from sodium benzophenone ketyl radical. All the NMR spectra were accomplished using a Bruker(Bruker, Billerica, MA, USA) instrument at 600, 150 and 243 MHz, respectively, with CDCl 3 as a solvent and TMS as an internal standard. Data are presented as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m) and broad singlet (br. s). Column chromatography was performed using Merck 60 silica gel. TLC was accomplished on Merck 60 F 254 silica gel plates (Merck Group (Merck KGaA), Darmstadt, Germany). The plates were visualized using UV light (254 nm). The enantiomeric excess (ee) values were determined by HPLC with chiral support (Chiralcel OD-H or OD columns). The corresponding chiral phosphine-aziridines 1-8 were synthesized according to general procedures reported in our group [30].

Synthesis of Imine-Phosphines 9-12-General Procedure
The appropriate 1-(2-aminoalkyl)aziridines were prepared as previously described [31]. A solution of the 1-(2-aminoalkyl)aziridine (1 mmol) and 2-(diphenylphosphino)benzaldehyde (1 mmol) in methanol (10 mL) was refluxed for 16 h. After this time, the solvent was evaporated in vacuo, and the crude product was purified via flash chromatography (silica gel and hexane/ethyl acetate in gradient) to afford the appropriate chiral imine-phosphines as colorless viscous oils. Copies of NMR spectra of compounds 9-12 are included in the Supplementary Materials.

Asymmetric Simmons-Smith Cyclopropanation-General Procedure
The corresponding allylic alcohols (substrates) were prepared using the literature protocols [40,41]. The solution of chiral ligand in anhydrous CH 2 Cl 2 (5 mL) was cooled to 0 • C and alcohol (0.5 mmol), diethylzinc (1.0 M in hexanes, 1 mmol) and CH 2 I 2 (0.6 mmol) were added. The resulting mixture was stirred for 4 h at room temperature. The reaction was quenched by adding a 2 M aqueous solution of NaOH, the phases were separated and the aqueous layer was extracted with dichloromethane (3 × 10 mL). Combined layers were dried with MgSO 4 and evaporated in vacuo. The pure product was obtained by purification via column chromatography on silica gel (hexane:ethyl acetate 2:1). The spectroscopic data