catalysts Article Efficient Asymmetric Simmons-Smith Cyclopropanation and Diethylzinc Addition to Aldehydes Promoted by Enantiomeric Aziridine-Phosphines Aleksandra Buchcic-Szychowska 1, Justyna Adamczyk 1, Lena Marciniak 2, Adam Marek Pieczonka 1 , Anna Zawisza 1, Stanisław Le´sniak 1 and Michał Rachwalski 1,* 1 Department of Organic and Applied Chemistry, University of Lodz, Tamka 12, 91-403 Lodz, Poland; [email protected] (A.B.-S.); [email protected] (J.A.); [email protected] (A.M.P.); [email protected] (A.Z.); [email protected] (S.L.) 2 The Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, University of Lodz, 91-403 Lodz, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-42-635-5767 Abstract: 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 Citation: Buchcic-Szychowska, A.; values of enantiomeric excess (sometimes more than 90%) and diastereomeric ratios (in case of Adamczyk, J.; Marciniak, L.; cyclopropanation reaction). Pieczonka, A.M.; Zawisza, A.; Le´sniak,S.; Rachwalski, M. Efficient Keywords: asymmetric synthesis; aziridines; chiral ligands; cyclopropanation; diethylzinc addition Asymmetric Simmons-Smith Cyclopropanation and Diethylzinc Addition to Aldehydes Promoted by Enantiomeric Aziridine-Phosphines. 1. Introduction Catalysts 2021, 11, 968. https:// The asymmetric construction of chiral non-racemic organic compounds is still an doi.org/10.3390/catal11080968 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 Academic Editor: Filippo Perna selection of an appropriate promoter for such a reaction. This role can be played by a chiral Received: 31 July 2021 ligand [1,2], an organocatalyst [3,4], a chiral auxiliary [5], bifunctional catalysts (molecule Accepted: 12 August 2021 possessing two distinct functional groups) [6,7] or another cooperative catalytic system [8]. Published: 13 August 2021 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 Publisher’s Note: MDPI stays neutral properties is present in many natural products [10] and drugs [11–15]. Molecules containing with regard to jurisdictional claims in this three-membered motif can be constructed in transformations with or without transition published maps and institutional affil- metals [16] in the presence of, e.g., complexes of porphyrin [17], proline derivatives [18,19], iations. 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]; Copyright: © 2021 by the authors. however, it is still a very simple and effective tool for studying the catalytic activity of Licensee MDPI, Basel, Switzerland. chiral ligands. Based on our experience, ligands containing an aziridine fragment show This article is an open access article very high efficiency in reactions of this type [23–28]. distributed under the terms and Chiral systems containing a phosphine group and an aziridine ring within one conditions of the Creative Commons molecule are not the subject of many reports in the chemical literature [29]. Enriching the Attribution (CC BY) license (https:// current state of knowledge about such chiral junctions, we recently published a successful creativecommons.org/licenses/by/ application of aziridine phosphines in the asymmetric Friedel-Crafts reaction [30]. 4.0/). Catalysts 2021, 11, 968. https://doi.org/10.3390/catal11080968 https://www.mdpi.com/journal/catalysts Catalysts 2021,, 11,, xx FORFOR PEERPEER REVIEWREVIEW 2 of 11 Catalysts 2021, 11, 968 2 of 11 current state of knowledge about such chiral junctions,junctions, wewe recentlyrecently 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 TakingTaking into consideration all of the aforementionedaforementioned circumstances, we decided to synthesize a series of optically pure aziridines and aziridine imines possessing phosphine synthesizesynthesize a a series series of of optically optically pure pure aziridines aziridines and and aziridine aziridine imines imines possessing possessing phosphine phosphine motif in order to check their catalytic activities in the asymmetric Simmons–Smith cyclo- motifmotif in in order order to to check check their their catalytic catalytic activities activities in inthe the asymmetric asymmetric Simmons–Smith Simmons-Smith cyclo- cy- propanationclopropanation and and asymmetric asymmetric diethylzinc diethylzinc addition addition to aldehydes. to aldehydes. Thus, Thus, we wanted we wanted to show to thatshow chiral that chiralaziridine-phosphines aziridine-phosphines are universal are universal catalysts catalysts operating operating in in various various types types of asymmetricasymmetric transformations. transformations. 2.2. Results Results and and Discussion Discussion 2.1.2.1. Preparation Preparation of of the the Aziridine-Phosphines Aziridine-Phosphines 11––88 TheThe chiral chiral enantiomeric enantiomeric aziridine-phosphines aziridine-phosphines 1–18– 8(Figure(Figure 1)1 )were were prepared prepared as as previ- pre- ouslyviously described described [30], [30 ],through through triethoxysilan triethoxysilane-mediatede-mediated reduction reduction of of the the corresponding phosphinephosphine oxides oxides [30]. [30]. N N N N PPh PPh PPh PPh2 PPh2 PPh2 PPh2 2 (R)-1 (S)-2 (S)-3 (S)-4 N N N N PPh PPh PPh PPh PPh2 PPh2 PPh2 PPh2 (R)-5 (S)-6 (S)-7 (S)-8 (S)- (S)-7 (S)- Figure 1. TheThe structures structures of chiral aziridine-phosphines 1–8.. 2.2.2.2. Synthesis Synthesis of of Imine-Phosphines Imine-Phosphines 99––1212 ChiralChiral imine-phosphines imine-phosphines 99––1212 (Scheme(Scheme 1)1 )were were obtained obtained starting starting from from appropriate appropriate 1- (2-aminoalkyl)aziridines,1-(2-aminoalkyl)aziridines, which which were were formed asas a a result result of of the the zinc zinc bromide-mediated bromide-mediated self- self-ringring opening opening reaction reaction of NH-aziridines, of NH-aziridines, as previouslyas previously described described [31 [31].]. The The corresponding correspond- ing1-(2-aminoalkyl)aziridines 1-(2-aminoalkyl)aziridines were were then reactedthen reacted with 2-(diphenylphosphino)benzaldehydewith 2-(diphenylphosphino)benzalde- af- hydefording affording 1-(2-iminealkyl)aziridine 1-(2-iminealkyl)aziridine catalysts catalysts functionalized functionalized by a phosphine by a phosphine group in group excellent in excellentyields (Scheme yields1 (Scheme). 1). Scheme 1. SynthesisSynthesis of chiral imine-phosphines 9–12.. Catalysts 20212021,, 1111,, 968x FOR PEER REVIEW 33 of of 11 2.3. Asymmetric Simmons–Smith Simmons-Smith CyclopropanationCyclopropanation PromotedPromoted byby Aziridine-PhosphinesAziridine-Phosphines1 1––88and and Imine-Phosphines 9–12 Equipped with all optically pure ph phosphorus-functionalizedosphorus-functionalized aziridines 11––1212,, we we de- de- cided to check their utility asas chiralchiral ligandsligands catalyzingcatalyzing anan asymmetricasymmetric cyclopropanationcyclopropanation reaction of cinnamyl alcohol (13) as aa modelmodel substrate.substrate. The transformationstransformations werewere carriedcarried out in DCM with 22 equiv.equiv. ofof diethylzincdiethylzinc and and 3 3 equiv. equiv. of of diiodomethane diiodomethane in in the the presence presence of of a aligand ligand (10 (10 mol%) mol%) (Scheme (Scheme2). 2). All All the the results results are are presented presented in in Table Table1. 1. Scheme 2. Asymmetric cyclopropanation cyclopropanation of of alcohol alcohol 1313 inin the the presence presence of of catalysts catalysts 11––1212 leadingleading to to cyclopropane derivative 14. Table 1. Asymmetric Simmons–Smith Simmons-Smith cyclopropanationcyclopropanation ofof cinnamylcinnamyl alcoholalcohol catalyzed by aziridines 1–12. EntryEntry Ligand Ligand Product Product 14 14 Yield (%) ee (%) a Dr b Abs. Conf. c Yield (%) ee (%) a Drb Abs. Conf. c 1 1 70 62 5:1 1R,2R 1 1 70 62 5:1 1R,2R 2 2 72 65 5:1 1S,2S 2 2 72 65 5:1 1S,2S 3 3 3 3 63 6354 54 5:1 5:1 1 1SS,2,2SS 4 4 4 4 65 6558 58 5:1 5:1 1 1SS,2,2SS 5 5 5 5 90 9092 92 12:1 12:1 1 1RR,2,2RR 6 6 6 6 93 9398 98 15:1 15:1 1 1SS,2,2SS 7 7 90 82 10:1 1S,2S 7 8 7 8 90 9182 85 10:1 10:1 1 1SS,2,2SS 8 9 8 9 91 8585 72 10:1 10:1 1 1SS,2,2SS 910 9 10 85 8372 70 10:1 10:1 1 1SR,2,2SR 1011 10 11 83 7970 68 10:1 10:1 1R 1S,2,2RS 12 12 80 70 10:1 1S,2S 11 11 79 68 10:1 1S,2S a Determined by chiral HPLC using Chiralcel OD-H column (for major product). b Determined by 1H NMR of the crude12 mixture.12c According to the80 literature data [21,32].70 Conditions: 10 mol%10:1 of the ligand, cinnamyl1S,2S alcohol (0.5a Determined mmol), diethylzinc by chiral (1.0 HPLC M in hexanes,using Chir 1 mmol),alcel OD-H diiodomethane column (0.6(for mmol), major DCMproduct). (5 mL), b Determined 0 ◦C, 4 h. by 1H NMR of the crude mixture. c According to the literature data [21,32]. Conditions: 10 mol% of the ligand,Theanalysis cinnamyl ofalcohol the results (0.5 mmol), collected diethylz ininc Table (1.01 M leads in hexanes, to the 1 followingmmol), diiodomethane conclusions.