(N-Acylamino)Alkylphosphonium Salts with Dimethyl Phosphite

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Article The Synthesis of α-Aminophosphonates via Enantioselective Organocatalytic Reaction of 1-(N-Acylamino)alkylphosphonium Salts with Dimethyl Phosphite

Alicja Wal˛ecka-Kurczyk 1,2, Krzysztof Walczak 1 , Anna Ku´znik 1,2, Sebastian Stecko 3 and Agnieszka Pa´zdzierniok-Holewa 1,2,*

1 Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland; [email protected] (A.W.-K.); [email protected] (K.W.); [email protected] (A.K.) 2 Biotechnology Center of Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland 3 Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-032-237-2218; Fax: +48-032-237-2094

Academic Editor: Erika Bálint Received: 2 December 2019; Accepted: 16 January 2020; Published: 18 January 2020

Abstract: α-Aminophosphonic acids are phosphorus analogues of α-amino acids. Compounds of this type find numerous applications in medicine and crop protection due to their unique biological activities. A crucial factor in these activities is the configuration of the stereoisomers. Only a few methods of stereoselective transformation of α-amino acids into their phosphorus analogues are known so far and all of them are based on asymmetric induction, thus involving the use of a chiral substrate. In contrast, we have focused our efforts on the development of an effective method for this type of transformation using a racemic mixture of starting N-protected α-amino acids and a chiral catalyst. Herein, a simple and efficient stereoselective organocatalytic α-amidoalkylation of dimethyl phosphite by 1-(N-acylamino)alkyltriphenylphosphonium salts to enantiomerically enriched α-aminophosphonates is reported. Using 5 mol% of chiral quinine- or hydroquinine-derived quaternary ammonium salts provides final products in very good yields up to 98% and with up to 92% ee. The starting phosphonium salts were easily obtained from α-amino acid derivatives by decarboxylative methoxylation and subsequent substitution with triphenylphosphonium tetrafluoroborate. The appropriate self-disproportionation of enantiomers (SDE) test for selected α-aminophosphonate derivatives via achiral flash chromatography was performed to confirm the reliability of the enantioselectivity results that were obtained.

Keywords: α-aminophosphonic acids; α-aminophosphonates; phosphonium salts; stereoselectivity; α-amidoalkylation; Cinchona alkaloids

1. Introduction α-Aminophosphonic acids are one of the most recognizable classes of organophosphorus compounds. Structurally, they are analogues of α-amino acids in which the planar carboxylic group is replaced with a tetrahedral phosphonic acid group (Figure1a). Almost 60 years of research has shown that many naturally occurring and synthetic α-aminophosphonic acids, as well as their derivatives, exhibit multidirectional, signiﬁcant biological activities [1,2]. Compounds of this class are increasingly used in the synthesis of various types of peptidomimetics, clearly showing greater activity than the genuine peptides. Among the structurally diverse α-aminophosphonic acids and

Molecules 2020, 25, 405; doi:10.3390/molecules25020405 www.mdpi.com/journal/molecules Molecules 2020, 25, 405 2 of 14 Molecules 2020, 25, x 2 of 14 their derivatives, enzyme inhibitors, antibacterial an andd antifungal agents, anticancer agents, as well as herbicides and plant growth regulators can be found (Figure1 1b)b) [ 1[1–7].–7].

Figure 1. ((aa)) Structure Structure of of α-amino-amino acid acid and α-aminophosphonic acid. acid; ( (bb)) Selected examples of biologically active ph phosphonicosphonic analogues of α-amino acids and their derivatives.

Due to the possibility of wide applications of α-aminophosphonic acids acids and their derivatives, various methods for their synthesis have been developeddeveloped over thethe pastpast severalseveral decadesdecades [[5,8–11].5,8–11]. It seemsseems natural natural that thatα-amino α-amino acids acids should should be the be most the frequentlymost frequently used substrates used substrates for the synthesis for the synthesisof α-aminophosphonic of α-aminophosphonic acids. However, acids. However, to the best to the of our best knowledge, of our knowledge, only a few only methods a few methods for the fortransformation the transformation of α-amino of α-amino acids into acids their into phosphonic their phosphonic analogues analogues have been have reported been reported so far [12 so– 24far]. [12–24].Furthermore, Furthermore, only five only of them five canof them be classified can be classified as stereoselective as stereoselective processes. processes. For example, For example, Seebach Seebachand Renaud and [Renaud12] have [12] described have described a diastereoselective a diastereoselective transformation transformation of a trans of-4-hydroxy- a trans-4-hydroxy-L-prolineL- prolinederivative derivative into its into phosphonic its phosphonic analogue analogue (Scheme (Scheme1a). The 1a). proposed The proposed three-step three-step path path involved involved the theoxidative oxidative decarboxylation decarboxylation of a proline of a proline derivative derivative leading leading to 2-methoxyproline, to 2-methoxyproline, which by which the Ti-catalyzed by the Ti- catalyzedaddition ofaddition P(OMe) 3 offollowed P(OMe) by3 acidicfollowed hydrolysis by acidic produced hydrolysis the generation produced of the aminophosphonic generation of aminophosphonicacids with high dr acids 96:4 via with a carbenium high dr 96:4 ion via (Scheme a carbenium1a). Seebach ion (Scheme et al. [ 141a).] haveSeebach also et used al. [14] the samehave alsoconcept used in athe diastereoselective same concept synthesis in a ofdias acyclictereoselectiveN-protected synthesis phosphonodiesters, of acyclic startingN-protected from phosphonodiesters,l-threonine (Scheme starting1b). However, from L-threonine in this case, (Scheme the Michaelis-Arbuzov-type 1b). However, in this reaction case, the exhibited Michaelis- no Arbuzov-typesignificant stereoselectivity, reaction exhibited leading no significant to an essentially stereoselectivity, equimolar leading mixture to ofan products essentially (Scheme equimolar1b). mixtureIn 2002, Larchevof productsêque (Scheme and Pousset 1b). [ 17In] 2002, reported Larche anothervêque method and Pousset for the preparation[17] reported of anotherN-Boc-protected method forα-aminophosphonic the preparation of acidN-Boc-protected esters with high α-aminophosphonic diastereoselectivity acid (Scheme esters wi1c).th high The diastereoselectivity crucial step in this (Schemestrategy was1c). The the regioselectivecrucial step in catalytic this strategy hydrogenation was the regioselective of N-Boc protected catalytic cis hydrogenation aziridines derived of N from-Boc protectedsyn α-hydroxy cis aziridinesβ-aminophosphonates. derived from syn In 2008, α-hydroxy Kapoor β et-aminophosphonates. al. [19] described the reactionIn 2008, ofKapoor ethyl esterset al. [19]of (S )-phenylglycinedescribed the reaction or (S)-phenylalanine of ethyl esters with of aryl (S aldehydes)-phenylglycine and dimethyl or (S)-phenylalanine phosphite in the with presence aryl aldehydesof antimony and trichloride dimethyl adsorbedphosphite onin the alumina presence as a of catalyst antimony (Scheme trichloride1d). The adsorbed authors on obtained alumina theas a catalystexpected (Scheme mixtures 1d). of Theα-aminophosphonates authors obtained the in expected good yields mixtures and a of diastereomeric α-aminophosphonates ratio equal in togood 9:1 yieldsor 3:2. and In 2013,a diastereomeric Boto et al. [ 24ratio] developed equal to 9:1 a sequentialor 3:2. In 2013, radical Boto scission-oxidation et al. [24] developed/phosphorylation a sequential radicalprotocol scission-oxidation/phosp for the synthesis of 2-phosphonoprolinehorylation protocol derivatives for the (Scheme synthesis1e). Itof was 2-phosphonoproline demonstrated that derivativesthe diastereoselectivity (Scheme 1e). of It thiswas reaction demonstrated was highly that the dependent diastereoselectivity on the nitrogen of this substituent reaction was type highly at the dependentC-4 position. on Forthe example,nitrogen substituent azanucleotide type analogues at the C-4 were position. obtained For example, with very azanucleotide good overall yieldsanalogues and werediastereomeric obtained with cis/trans very ratios good in overall the range yields from and 98:2 diastereomeric to 15:85. cis/trans ratios in the range from 98:2 to 15:85.

Molecules 2020, 25, 405 3 of 14 Molecules 2020, 25, x 3 of 14

α Scheme 1. The stereoselective stereoselective transformation of N-protected α-amino acids and their derivatives into their phosphorus analogues—known syntheticsynthetic routesroutes. ( a–e). In 2012, we described an eﬃcient protocol for the synthesis of 1-(N-acylamino)alkylphosphonium In 2012, we described an efficient protocol for the synthesis of 1-(N- salts 2 from N-acyl-α-amino acids 1 (Scheme2b) [ 25], which may serve as attractive precursors acylamino)alkylphosphonium salts 2 from N-acyl-α-amino acids 1 (Scheme 2b) [25], which may serve of 1-(N-acylamino)alkylphosphonic and phosphinic acid esters via the Michaelis-Arbuzov-type as attractive precursors of 1-(N-acylamino)alkylphosphonic and phosphinic acid esters via the reaction [26,27]. In an extension of these studies, in 2016, Mazurkiewicz et al. [28] targeted pure Michaelis-Arbuzov-type reaction [26,27]. In an extension of these studies, in 2016, Mazurkiewicz et enantiomers of α-aminoalkylphosphonic acids and α-aminophosphonates by the enzymatic kinetic al. [28] targeted pure enantiomers of α-aminoalkylphosphonic acids and α-aminophosphonates by resolution of their racemic mixtures (Scheme2a) in the presence of Penicillin G acylase to provide the enzymatic kinetic resolution of their racemic mixtures (Scheme 2a) in the presence of Penicillin G the corresponding enantiomers with high ee (enantiomeric excess) values. Of course, the maximum acylase to provide the corresponding enantiomers with high ee (enantiomeric excess) values. Of 50% yield of such an approach was its main limitation. So far, there are no reports on purely course, the maximum 50% yield of such an approach was its main limitation. So far, there are no enantioselective methods for the preparation of enantiomerically enriched phosphonic acid esters reports on purely enantioselective methods for the preparation of enantiomerically enriched directly from phosphonium salts in a carbon–phosphorus bond-forming reaction in the presence of an phosphonic acid esters directly from phosphonium salts in a carbon–phosphorus bond-forming enantiodiﬀerentiating agent. reaction in the presence of an enantiodifferentiating agent. Here, we present our recent results on the enantioselective catalytic α-amidoalkylation of dimethyl phosphite with 1-(N-acylamino)alkylphosphonium salts 2 in the presence of a chiral catalyst. Taking into account that the starting 1-(N-acylamino)alkylphosphonium tetrafluoroborates

Molecules 2020, 25, x 4 of 14

2 are readily available from N-acyl-α-amino acids 1, the presented approach can be considered a new Moleculesstrategy2020 for, 25 , 405the transformation of N-acyl-α-amino acids 1 into non-racemic 41-( ofN 14- acylamino)alkylphosphonic acid esters 3 (Scheme 2b).

SchemeScheme 2.2. TheThe transformationtransformation ofof NN-protected-protected αα-amino-amino acidsacids intointo αα-aminophosphonate-aminophosphonate derivativesderivatives viavia 1-(1-(NN-acylamino)alkylphosphonium-acylamino)alkylphosphonium salts: salts: (a)a) The The method method based on enzymatic kinetic resolution ofof racemicracemic mixturesmixtures ofof αα-aminoalkylphosphonic-aminoalkylphosphonic acidsacids andandα α-aminophosphonates;-aminophosphonates. (bb)) A newnew approachapproach basedbased onon enantioselective catalyticcatalytic αα-amidoalkylation-amidoalkylation ofof dimethyldimethyl phosphitephosphite withwith phosphoniumphosphonium salts.salts. α 2. ResultHere, s weand present Discussion our recent results on the enantioselective catalytic -amidoalkylation of dimethyl phosphite with 1-(N-acylamino)alkylphosphonium salts 2 in the presence of a chiral catalyst. Taking into accountAt the outset that the of startingour studies, 1-(N-acylamino)alkylphosphonium systematic exploration of different tetrafluoroborates reaction conditions2 are readily was availableconducted from in orderN-acyl- to optimizeα-amino acidsthe yield1, the and presented enantioselectivity. approach canThis be initial considered screening a new was strategy performed for theusing transformation two phosphonium of N-acyl- salts,α -amino2a and 2b acids, obtained1 into non-racemic from N-benzyloxycarbonyl 1-(N-acylamino)alkylphosphonic alanine (Cbz-Ala-OH) acid estersand N3-benzyloxycarbonyl(Scheme2b). phenylalanine (Cbz-Phe-OH), respectively (Scheme 3, Table 1). Four chiral quaternary ammonium salts 4–7, derived from hydroquinine or quinine, were selected as stereo- 2.differentiating Result s and agents. Discussion We decided to use this type of chiral catalysts in our reaction for several reasons. First, these Cinchona alkaloid derivatives can be obtained by simple and low-cost methods At the outset of our studies, systematic exploration of different reaction conditions was from commercially available substrates [29,30]. Moreover, this class of organocatalysts has emerged conducted in order to optimize the yield and enantioselectivity. This initial screening was as a useful chiral base, as well as chiral phase transfer (PT) catalysts for the reaction of stable or in performed using two phosphonium salts, 2a and 2b, obtained from N-benzyloxycarbonyl alanine situ generated N-acylimines with various nucleophiles, for example carbon nucleophiles [30–34] and (Cbz-Ala-OH) and N-benzyloxycarbonyl phenylalanine (Cbz-Phe-OH), respectively (Scheme3, Table1). phosphorus nucleophiles, such as dialkyl phosphites [30,34–39]. Therefore, we expected the use of Four chiral quaternary ammonium salts 4–7, derived from hydroquinine or quinine, were selected as chiral catalysts 4–7 for the stereoselective α-amidoalkylation of dimethyl phosphite with stereo-differentiating agents. We decided to use this type of chiral catalysts in our reaction for several phosphonium salts 2 to provide satisfactory results (Scheme 3). reasons. First, these Cinchona alkaloid derivatives can be obtained by simple and low-cost methods Initially, salt 2a was reacted with dimethyl phosphite in toluene, using 2-fluoro substituted N- from commercially available substrates [29,30]. Moreover, this class of organocatalysts has emerged benzylhydroquininium bromide 4 as the catalyst (5 mol%) and excess K2CO3 at −70°C (Table 1, entry as a useful chiral base, as well as chiral phase transfer (PT) catalysts for the reaction of stable or in 1). After three days, the expected dimethyl N-protected α-aminoethylphosphonate 3a was obtained situ generated N-acylimines with various nucleophiles, for example carbon nucleophiles [30–34] and with a moderate yield and enantioselectivity. The same reaction carried out in the presence of 3 equiv. phosphorus nucleophiles, such as dialkyl phosphites [30,34–39]. Therefore, we expected the use of of KOH as a base allowed us to increase the yield of 3a to 84% and enhanced the enantiomeric excess chiral catalysts 4–7 for the stereoselective α-amidoalkylation of dimethyl phosphite with phosphonium to 84% (Table 1, entry 2). In order to improve the solubility of phosphonium salt 2a in the reaction salts 2 to provide satisfactory results (Scheme3). mixture, a further experiment with the addition of a small amount of CH2Cl2 was performed. Initially, salt 2a was reacted with dimethyl phosphite in toluene, using 2-fluoro substituted Unfortunately, we obtained the expected product 3a in a lower yield and enantioselectivity (cf. Table N-benzylhydroquininium bromide 4 as the catalyst (5 mol%) and excess K2CO3 at 70◦C (Table1, entry 1, entries 2 and 3). − 1). After three days, the expected dimethyl N-protected α-aminoethylphosphonate 3a was obtained Next, screening of catalysts for the reaction of phosphonium salt 2a with dimethyl phosphite with a moderate yield and enantioselectivity. The same reaction carried out in the presence of 3 equiv. was performed (Scheme 3, Table 1, entry 5 to 7). The reactions were carried out under standard of KOH as a base allowed us to increase the yield of 3a to 84% and enhanced the enantiomeric excess to conditions using 3 equiv. of KOH, 5 mol% of catalysts 5 to 7 (all bearing an ortho substituent at the 84% (Table1, entry 2). In order to improve the solubility of phosphonium salt 2a in the reaction mixture, benzylic quinuclidinic moiety) in toluene at −70°C (Table 1, entries 5 to 7). Among the examined a further experiment with the addition of a small amount of CH2Cl2 was performed. Unfortunately, we catalysts, 4-F-substituted catalyst 4, derived from hydroquinine, and 2-methoxy substituted catalyst obtained the expected product 3a in a lower yield and enantioselectivity (cf. Table1, entries 2 and 3). 5, derived from quinine, gave the best results (see Table 1, entries 2 and 5). Taking into account the Next, screening of catalysts for the reaction of phosphonium salt 2a with dimethyl phosphite strong amidoalkylating properties of phosphonium salts 2 [40,41], we decided to perform the next was performed (Scheme3, Table1, entry 5 to 7). The reactions were carried out under standard conditions using 3 equiv. of KOH, 5 mol% of catalysts 5 to 7 (all bearing an ortho substituent at the benzylic quinuclidinic moiety) in toluene at 70 C (Table1, entries 5 to 7). Among the examined − ◦ Molecules 2020, 25, x 5 of 14 experiment with the amount of KOH decreased by half. However, this decrease in the base loading caused a drop in yield and enantioselectivity (Table 1, entry 4). Next, phosphonium salt 2b with a larger substituent at the α-position was subjected to the model reaction as a starting material (Scheme 3, Table 1, entries 8–15). The influence of the catalyst type and the amount of KOH on the reaction efficiency was investigated. As highlighted in Table 1, the reaction of phosphonium salt 2b with dimethyl phosphite in toluene conducted for 3 days at −70°C in the presence of chiral catalyst 5 and KOH (3 equiv.) gave the most satisfactory results. The expected α- aminophosphonate 3b was obtained with a high yield and good enantioselectivity (Table 1, entry 13, 84%Molecules yield,2020 73%, 25, 405ee). Additionally, in order to examine the possibility of racemization of the product5 of 14 under these reaction conditions, subsequent experiments were performed during a shorter time of 1 orcatalysts, 2 days. 4-F-substitutedBased on the results catalyst obtained,4, derived we excluded from hydroquinine, the probability and of 2-methoxy such side substituted processes (Table catalyst 1, entries5, derived 14 to from 15). quinine, gave the best results (see Table1, entries 2 and 5). Taking into account the strongThus, amidoalkylating we decided that properties the best ofreacti phosphoniumon conditions salts for2 the [40 ,stereoselective41], we decided α-amidoalkylation to perform the next of dimethylexperiment phosphite with the by amount phosphoniu of KOHm salts decreased were three by half. equivalents However, of this KOH decrease and three in the days base in loadingtoluene atcaused the temperature a drop in yield of − and70°C, enantioselectivity in the presence of (Table chiral1, PT entry catalyst 4). 4 or 5.

Scheme 3. ReactionReaction of of phosphonium phosphonium salts salts 2a-b2a-b with dimethyl phosphite in in the presence of chiral catalysts 4-7. Table 1. Screening of the reaction conditions for PT-catalyzed stereoselective α-amidoalkylation Table 1. Screening of the reaction conditions for PT-catalyzed stereoselective α-amidoalkylation reaction 1. reaction.1. Catalyst Base Time Entry Salt R Yield 2 [%]2 ee 3 [%] 3 Entry Salt R Catalyst (5(5 mol%) mol%) Base(equiv.) (equiv.) [days] Time [days] Yield [%] ee [%] 1 2a Me 4 K2CO3 (3) 3 62 49 1 2a Me 4 K2CO3 (3) 3 62 49 2 2a2 Me 2a Me 4 4 KOH KOH (3) (3) 3 3 84 84 84 84 34 32a4 Me2a Me 4 4 KOHKOH (3) (3) 3 3 71 71 59 59 4 2a4 Me2a Me 4 4 KOHKOH (1.5) (1.5) 3 3 64 64 78 78 5 2a5 Me 2a Me 5 5 KOH KOH (3) (3) 3 3 84 84 83 83 6 2a Me 6 KOH (3) 3 75 81 6 2a Me 6 KOH (3) 3 75 81 7 2a Me 7 KOH (3) 3 82 72 7 2a Me 7 KOH (3) 3 82 72 8 2b PhCH2 4 KOH (3) 3 87 65 8 2b9 PhCH2b 2 PhCH2 4 4 KOHKOH (3) (3) 1 3 78 87 68 65 5 9 2b10 PhCH2b 2 PhCH2 4 4 KOHKOH (1.5) (3) 3 1 47 78 78 68 11 2b PhCH 4 KOH (2) 1 70 73 10 2b PhCH2 2 4 KOH (1.5) 3 475 78 12 2b PhCH2 4 KOH (1.5) 1 63 70 11 2b PhCH2 4 KOH (2) 1 70 73 13 2b PhCH2 5 KOH (3) 3 84 73 12 2b PhCH2 4 KOH (1.5) 1 63 70 14 2b PhCH2 5 KOH (3) 2 79 70 13 2b15 PhCH2b 2 PhCH2 5 5 KOH KOH (3) (3) 13 71 84 74 73 141 Reaction2b conditions:PhCH2 Phosphonium5 salt 2 (0.2 mmol),KOH dimethyl (3) phosphite (0.6 2 mmol, 3 equiv.), 79 catalyst 4– 707 2 3 15(0.01 mmol,2b 5 mol%),PhCH toluene2 (2 mL),5 70 ◦C. IsolatedKOH yield. (3)The enantiomeric 1 excess (ee) was 71 determined by 74 − 4 HPLC using a column with a chiral stationary phase. The reaction was carried out in a mixture of toluene/CH2Cl2 1 9:1Reaction (2 mL) 5 Theconditions: reaction mixturePhosphonium additionally salt contained 2 (0.2 mmol), benzyl Ndimethyl-(1-hydroxy-2-phenylethyl)carbamate. phosphite (0.6 mmol, 3 equiv.), catalyst 4–7 (0.01 mmol, 5 mol%), toluene (2 mL), −70 °C. 2 Isolated yield. 3 The enantiomeric excess (ee) was determined by HPLC using a column with a chiral stationary phase. 4 The reaction was Next, phosphonium salt 2b with a larger substituent at the α-position was subjected to the model reaction as a starting material (Scheme3, Table1, entries 8–15). The inﬂuence of the catalyst type and the amount of KOH on the reaction eﬃciency was investigated. As highlighted in Table1, the reaction of phosphonium salt 2b with dimethyl phosphite in toluene conducted for 3 days at 70 C in the − ◦ presence of chiral catalyst 5 and KOH (3 equiv.) gave the most satisfactory results. The expected α-aminophosphonate 3b was obtained with a high yield and good enantioselectivity (Table1, entry 13, 84% yield, 73% ee). Additionally, in order to examine the possibility of racemization of the product under these reaction conditions, subsequent experiments were performed during a shorter time of 1 or 2 days. Based on the results obtained, we excluded the probability of such side processes (Table1, entries 14 to 15). Molecules 2020, 25, 405 6 of 14

Molecules 2020, 25, x 6 of 14 Molecules 2020,Molecules 25, x 2020, 25, x 6 of 14 6 of 14 Thus, weMolecules decided 2020, that25, x the best reaction conditions for the stereoselective α-amidoalkylation of 6 of 14 Molecules 2020,, 25,, xx 6 of 14 Molecules 2020, 25, x 5 6 of 14 dimethyl phosphitecarried by out phosphonium in a mixture saltsof toluene/CH were three2Cl2 equivalents9:1 (2 mL) 5 The of KOHreaction and mixture three additionally days in toluene contained at Moleculescarried 2020 ,out 25, xin a mixture of toluene/CH2 2 2Cl2 9:15 (2 mL) 5 The reaction mixture additionally contained6 of 14 carried out incarried a mixture out in of a toluene/CHmixture of toluene/CHCl 9:1 (2 mL)2Cl2 9:1 The (2 mL)reaction 5 The mixture reaction additionallymixture additionally contained contained Moleculescarried 2020 ,out 25, xin a mixture of toluene/CH2Cl2 9:1 (2 mL) 5 The reaction mixture additionally contained6 of 14 the temperaturecarriedbenzyl of 70 Nout◦C,-(1-hydroxy-2-phenylethyl)carbamate. in in a the mixture presence of toluene/CH of chiral22Cl PT22 9:19:1 catalyst (2(2 mL)mL) 45 TheorThe5 reaction.reaction mixturemixture additionallyadditionally containedcontained benzyl N-(1-hydroxy-2-phenylethyl)carbamate.benzylcarried Nout-(1-hydroxy-2-phenylethyl)carbamate. in a mixture of toluene/CH 2Cl2 9:1 (2 mL) 5 The reaction mixture additionally contained benzylcarried− Nout-(1-hydroxy-2-phenylethyl)carbamate. in a mixture of toluene/CH2Cl2 9:1 (2 mL) The reaction mixture additionally contained With the optimizedbenzylcarried Nout-(1-hydroxy-2-phenylethyl)carbamate.conditions in a mixture inof hand,toluene/CH the2 scopeCl2 9:1 of(2 mL) the 5 stereoselective The reaction mixtureα-amidoalkylation additionally contained of benzyl N-(1-hydroxy-2-phenylethyl)carbamate. 5 carriedWithbenzyl the Nout-(1-hydroxy-2-phenylethyl)carbamate. optimized in a mixture conditions of toluene/CH in hand,2Cl2 9:1 the (2 mL)scope The of reactionthe stereoselective mixture additionally α-amidoalkylation contained of dimethylWith phosphite the optimizedWithbenzyl with the N-(1-hydroxy-2-phenylethyl)carbamate. variousoptimizedconditions phosphonium conditions in hand, thein salts hand, scope2a –the kof , catalyzedscopethe stereoselective of the by chiralstereoselective ammonium α-amidoalkylation α-amidoalkylation salts 4 or of5 of dimethylWithbenzyl phosphitethe N-(1-hydroxy-2-phenylethyl)carbamate. optimized with conditionsvarious phosphonium in hand, the salts scope 2a –ofk, thecatalyzed stereoselective by chiral αammonium-amidoalkylation-amidoalkylation salts 4 orofof dimethyl phosphitedimethylWith withphosphite the optimizedvarious with phosphonium variousconditions phosphonium in salts hand, 2a the–k salts, scopecatalyzed 2a– ofk, thecatalyzed by stereoselective chiral by ammonium chiral αammonium-amidoalkylation salts 4 orsalts 4 orof was investigateddimethyl5 wasWith (Schemeinvestigated phosphite the optimized4, Table (Scheme with2). variousconditions 4, Table phosphonium 2).in hand, the salts scope 2a– ofk,, catalyzedthecatalyzed stereoselective byby chiralchiral αammoniumammonium-amidoalkylation saltssalts 4 ororof 5 was investigateddimethyl5 wasWith investigated (Scheme phosphite the optimized 4, (Scheme Tablewith conditionsvarious 2). 4, Table phosphonium 2).in hand, the salts scope 2a– ofk, thecatalyzed stereoselective by chiral αammonium-amidoalkylation salts 4 orof 5dimethyl waswas investigatedinvestigated phosphite (Scheme(Scheme with various 4,4, TableTable phosphonium 2).2). salts 2a–k, catalyzed by chiral ammonium salts 4 or dimethyl5 was investigated phosphite (Scheme with various 4, Table phosphonium 2). salts 2a–k, catalyzed by chiral ammonium salts 4 or 5 was investigated (Scheme 4, Table 2). 5 was investigated (Scheme 4, Table 2).

Scheme 4. Enantioselective organocatalytic α-amidoalkylation of dimethyl phosphite with Scheme 4. Enantioselective organocatalytic α-amidoalkylation of dimethyl phosphite with Scheme 4. SchemephosphoniumEnantioselective 4. Enantioselective salts 2. organocatalytic organocatalyticα-amidoalkylation α-amidoalkylation of dimethyl of dimethyl phosphite phosphite with with Scheme 4. SchemephosphoniumEnantioselective 4. EnantioselectiveEnantioselective salts 2organocatalytic. organocatalyticorganocatalytic α-amidoalkylation α-amidoalkylation-amidoalkylation of dimethyl ofof dimethyldimethyl phosphite phosphitephosphite with withwith phosphoniumphosphoniumScheme salts 2 . 4. Enantioselective salts 2. organocatalytic α-amidoalkylation of dimethyl phosphite with phosphoniumphosphoniumScheme salts 2 . 4. Enantioselective salts 2.. organocatalytic α-amidoalkylation of dimethyl phosphite with SchemephosphoniumTable 2. 4.Substrate Enantioselective salts 2scope. of theorganocatalytic stereoselective α -amidoalkylationreaction of phosphonium of dimethyl salts 2phosphite with dimethyl with Table2. SubstrateTablephosphonium scope 2. Substrate of thesalts stereoselective 2scope. of the reaction stereoselect of phosphoniumive reaction saltsof phosphonium2 with dimethyl salts phosphite 2 with 1dimethyl. phosphoniumTable 2. Substrate1. salts 2scope. of the stereoselective reaction of phosphonium salts 2 with dimethyl Tablephosphite. 2. Substrate1. scope of the stereoselective reaction of phosphonium salts 2 with dimethyl Table 2. Substratephosphite.Table 2.scope Substrate1. of the scope stereoselect of the stereoselective reactionive ofreaction phosphonium of phosphonium salts 2 withsalts dimethyl2 with dimethyl Tablephosphite. 2. Substrate1. scope of the stereoselective reaction of phosphonium salts 2 with dimethyl 1. phosphite.1.1. 2 3 phosphite. phosphite.TableEntry 2. Substrate1. Product scope of 3 the stereoselect Catalystive reactionYield of[%] phosphonium ee [%] salts2 2 with dimethyl3 EntryTable 2. Substrate1. Productscope of 3the stereoselective reaction Catalyst of phosphoniumYield salts2 [%] 2 with eedimethyl3 [%] phosphite.1. 2 3 Entryphosphite. Product 3 Catalyst Yield2 [%] ee3 [%] Entry 1. Product 3 4 Catalyst84 Yield 84 2 [%] ee3 [%] Entry Entryphosphite.1 Product 3 Product 3 3a Catalyst Catalyst 4 Yield2 [%]Yield 842 [%][%] ee 3 [%] ee ee384 [%][%] Entry1 Product 3 3a 5 Catalyst4 84 Yield 83 842 [%] ee384 [%] Entry1 Product 3 3a Catalyst45 Yield842 [%] ee84383 [%] Entry1 Product 3 3a 4 Catalyst54 84 Yield842 [%] 84 ee38384 [%] 1 1 3a 3a 54 84 8384 1 3a 5 45 84 84 83 8483 212 3b3b3a 4 54 84 73 84 7383 12 3b3a 45 84 7383 2 3b 54 84 8373 2 3b 4 84 73 2 2 3b 3b 4 4 84 8493 73 7372 2 3b 4 4 93 72 9384 7273 23 3 3c 3b3c 4 8493 7372 3 3c 5 45 73 61 9373 7261 3 3c 4 54 93 7393 72 6172 3 3c 54 7393 6172 3 3 3c 3c 54 7393 6172 3 3c 5 5 73 73 61 61 34 4 3d3d3c 4 45 82 56 8273 5661 4 3d 54 7382 6156 4 3d 4 82 56 4 3d 4 82 56 4 54 3d 3d3e 4 4 82 8882 56 23564 4 45 3d3e 4 4 8288 23564 55 3e3e 4 4 88 23 88 234 5 3e 4 88 234 5 3e 4 8882 4 23804 5 5 3e 3e 4 4 88 8288 23 23804 4 82 804 56 3e3f 4 4 82 80 8288 2380 66 3f 3f 54 6082 7980 6 3f 54 54 6082 79 6082 80 7980 6 3f 54 6082 7980 6 6 3f 3f 5 60 79 67 3g3f 5 54 60 6085 79 7980 7 3g 54 6085 7980 77 3g3g 4 4 85 80 85 80 7 3g 4 85 80 7 3g 4 85 80 7 87 3g 3h3g 4 4 85 8085 80 9280 78 3g3h 4 8580 8092 8 3h 4 80 92 8 8 3h3h 4 4 80 92 80 92 8 3h 4 8079 9265 8 98 3h 3h3i 4 4 80 7980 92 6592 89 3h3i 45 798069 659255 9 3i 54 6979 5565 9 3i 4 54 79 65 6979 5565 99 3i 3i 4 54 79 6979 65 5565 9 3i 45 9869 5355 9 109 3i 3i3j 5 45 69 55 9869 5355 10 3j 5 45 69 986988 55 535554 10 3j 54 8898 5453 10 3j 4 54 98 53 8898 5453 1010 3j 3j 4 54 98 8898 53 5453 10 3j 54 8869 5442 10 1011 3j 3k3j 45 6988 4254 11 3k 55 45 8888 54 698884 54 425453 11 3k 54 8469 5342 11 3k 54 8469 5342 1 The11 reaction was carried ou t with phosphonium3k 44 salt 2 (0.254 69 mmol) and69 dimethyl 42 8469 phosphite42 (0.65342 mmol, 1 The11 reaction was carried ou t with phosphonium3k salt 2 (0.25 mmol) and dimethyl84 phosphite (0.653 mmol, 1 The11 reaction was carried ou t with3k phosphonium salt 2 (0.2 mmol) and dimethyl phosphite (0.6 mmol, 11 1 The11 reaction was carried3k ou t with phosphonium3k salt 2 (0.25 mmol) and dimethyl84 phosphite (0.6 53mmol, 31 The equiv.) reaction in the was presence carried ouof tt catalyst withwith phosphoniumphosphonium 4 or 5 (0.01 salt saltmmol, 2 (0.2(0.25 5 mmol)mmol)mol%) andandand dimethyldimethyl KOH 84(0.6 phosphitephosphite mmol, 3 (0.6 (0.6equiv.) 53 mmol,mmol, in 31 The equiv.) reaction in the was presence carried ouof tcatalyst with phosphonium 4 or 5 (0.015 saltmmol, 2 (0.2 5 mmol)mol%) andand84 dimethyl KOH (0.6 phosphite mmol,53 3 (0.6equiv.) mmol, in 3The equiv.) reaction in the was presence carried ouof2 tcatalyst with phosphonium 4 or 53 5(0.01 saltmmol, 2 (0.2 5 84mmol)mol%) andand dimethyl KOH 53 (0.6 phosphite mmol, 3 (0.6equiv.) mmol, in 3toluene1 The equiv.) reaction (2 in mL), the was atpresence carried −70°C. ouof2 Isolated tcatalyst with phosphonium yield. 4 or 53 The(0.01 enantiomeric saltmmol, 2 (0.2 5 mmol)mol%) excess andand ( dimethyl ee)KOH was (0.6 determined phosphite mmol, 3 (0.6 equiv.)by mmol,HPLC in 1toluene3 equiv.) (2 in mL), the atpresence −70°C. of2 Isolated catalyst yield. 4 or 53 The(0.01 enantiomeric mmol, 5 mol%) excess and (ee) KOH was (0.6 determined mmol, 3 equiv.)by HPLC in 1 3toluene equiv.) (2 in mL), the atpresence −70°C. of2 Isolated catalyst yield. 4 or 53 The(0.01 enantiomeric mmol, 5 mol%) excess and ( ee)KOH was (0.6 determined mmol, 3 equiv.)by HPLC in 1 toluene3The equiv.) reaction (2 in mL), the was atpresence carried −70°C. ou2of Isolated t catalystwith phosphonium yield. 4 or 53 The(0.01 enantiomeric saltmmol,4 2 (0.2 5 mmol)mol%) excess andand ( dimethylee) KOH was (0.6 determined phosphite mmol, 3 (0.6 equiv.)by mmol,HPLC in TheThe reaction tolueneusing was was carried carrieda (2column mL), out ou withatt with −70°C. phosphonium phosphoniuma chiral2 Isolated stationary salt yield. 2salt(0.2 32 Themmol)(0.2phase. enantiomericmmol) and4 Determined dimethyl and dimethyl excess phosphite after ( ee)phosphite Boc was (0.6 deprotection mmol,determined (0.6 3 mmol, equiv.) byand HPLC Cbz usingtoluene3 equiv.) a (2 columnin mL), the atpresence with −70°C. a ofchiral2 Isolated catalyst stationary yield. 4 or 53 The(0.01phase. enantiomeric mmol, 4 Determined 5 mol%) excess andafter (ee) KOH Boc was (0.6deprotection determined mmol, 3 equiv.)byand HPLC Cbz in 3using equiv.) a columnin the presence with a ofchiral2 catalyst stationary 4 or 53 (0.01phase. mmol, 4 Determined 5 mol%) andafter KOH Boc (0.6deprotection mmol, 3 equiv.)and Cbz in in the presenceusingtoluene of catalyst a (2column mL),4 or 5at (0.01with −70°C. mmol, a chiral2 Isolated 5 mol%) stationary yield. and KOH 3 Thephase. (0.6 enantiomeric mmol,4 Determined 3 equiv.) excess inafter toluene(ee) Boc was (2deprotection mL),determined at 70 ◦ C.byand HPLC Cbz 23 equiv.) in usingthederivatisation.toluene3 presence a (2column mL), of at catalystwith −70°C. a chiral4 Isolatedor 5 stationary(0.01 yield. mmol, Thephase. 5 enantiomericmol%) 4 Determined and KOH excess after (0.6 (ee) Bocmmol, was deprotection determined 3 equiv.)− inbyand HPLC Cbz Isolated yield.derivatisation.usingThe a enantiomericcolumn with excess a 2chiral (ee) was stationary determined 3 phase. by HPLC 4 Determined using a column after with Boc a chiraldeprotection stationary and Cbz toluenederivatisation.using a (2column mL),2 at with −70°C. a chiral Isolated 3 stationary yield. Thephase. enantiomeric Determined excess after (ee) Boc was deprotection determined byand HPLC Cbz phase.toluene4 Determined(2 mL),derivatisation.using at after−a 70°C.column Boc deprotectionIsolated with a yield.chiral and Cbz Thestationary derivatisation. enantiomeric phase. 4excess Determined (ee) was after determined Boc deprotection by HPLC and Cbz Similarlyderivatisation. as for the above mentioned reaction4 of N-Cbz-protected salt 2b with dimethyl usingderivatisation.Similarly a column as for with the aabove chiral mentionedstationary4 phase. reaction Determined of N-Cbz-protected after Boc deprotection salt 2b with and dimethylCbz using a columnSimilarlyderivatisation. with asa chiral for the stationary above mentionedphase. Determined reaction ofafter N-Cbz-protected Boc deprotection salt and 2b Cbzwith dimethyl phosphite,Similarlyderivatisation. the sameas for reaction the above of N -Boc-protectedmentioned reaction phosphonium of N-Cbz-protected-Cbz-protected salt 2c resulted saltsalt in 2b a verywithwith good dimethyldimethyl yield derivatisation.phosphite,Similarly the sameas for reaction the above of N -Boc-protectedmentioned reaction phosphonium of N-Cbz-protected salt 2c resulted salt in 2b a verywith good dimethyl yield phosphite, Similarly the sameas for reaction the above of N -Boc-protected-Boc-protectedmentioned reaction phosphoniumphosphonium of N-Cbz-protected saltsalt 2c resultedresulted salt inin 2b aa veryverywith goodgood dimethyl yieldyield phosphite, Similarly the sameas for reaction the above of N -Boc-protectedmentioned reaction phosphonium of N-Cbz-protected salt 2c resulted salt in 2b a verywith good dimethyl yield Similarly phosphite, as for thethe sameabove reaction mentioned of N-Boc-protected reaction of phosphoniumN-Cbz-protected salt 2csalt resulted 2b with in a dimethylvery good yield phosphite, the same reaction of N-Boc-protected phosphonium salt 2c resulted in a very good yield phosphite, the same reaction of N-Boc-protected phosphonium salt 2c resulted in a very good yield

Molecules 2020, 25, 405 7 of 14

Similarly as for the above mentioned reaction of N-Cbz-protected salt 2b with dimethyl phosphite, the same reaction of N-Boc-protected phosphonium salt 2c resulted in a very good yield of 93% and 72% ee (compare Table2, entries 2 to 3). In the case of more sterically hindered salts, such as 2d and 2i–k, the reaction with dimethyl phosphite furnished generally good yields in the range of 69%–98% and moderate 42%–65% ee (see Table2, entries 4, 9 to 11). Interestingly, in the case of N-Boc-protected valine-derivative 2e, a significant decrease in enantioselectivity (to 23% ee) was observed (Table2, entry 5), indicating that the steric hindrance at the β-position of the amino acid moiety could affect the transition state responsible for enantiodifferentiation. In comparison, the removal of the unfavorable steric interaction, as in the case of leucine-derived salt 2f, led to a respectable stereoselectivity level to provide product 3f in good yields and with ee values of 80% (with cat. 4) and 79% (with cat. 5), respectively (see Table2, entry 6). To our delight, under these conditions, phosphonium salts derived from unnatural amino acids, such as norvaline 2g and norleucine 2h, gave the expected products 3g,h with very good yields and useful enantioselectivities (see Table2, entry 7, 85% yield, 80% ee and entry 8, 80% yield, 92% ee). It is well known that ee values can be improved via recrystallization, which leads to the self-disproportionation of enantiomers (SDE) phenomenon [42]. Additionally, it has been demonstrated that some compounds, e.g., enantiomerically enriched α and β-amino acid derivatives [43,44] and especially β-amino-α,α-difluorophosphonic acid derivatives [45] exhibit pronounced SDE during achiral column chromatography. The occurrence of the SDE phenomenon may cause mistakes in the reporting of the ee value of catalytic asymmetric reactions. Thus, we conducted the SDE test via achiral flash chromatography in order to confirm that the values of enantiomeric excess that were obtained were reliable. After performing the appropriate test, we found that no SDE phenomenon was present in our case (for details, see Supplementary Materials). The comparison of the optical rotation of two selected dimethyl aminophosphonate derivatives 3a and 3f with literature values allowed us to determine the absolute configuration of the products to be R (see paragraph in Materials and Methods). It has been found that phosphonic acid derivatives possessing the (R)-configuration, corresponding to the stereochemistry of proteinogenic L-α-amino acids, exhibit higher biological activities than their S analogues [2]. For example, the R enantiomer of the phosphonic acid analogue of leucine is a significantly more potent inhibitor of leucine aminopeptidase than its S enantiomer [46]. In conclusion, we developed a simple and effective enantioselective route for the α-amidoalkylation of dimethyl phosphite with 1-(N-acylamino)alkyltriphenylphosphonium tetrafluoroborates in the presence of inexpensive and easily available chiral Cinchona alkaloid derivatives under PTC conditions. The methodology provided constitutes a convenient approach for the synthesis of enantiomerically enriched, especially sterically unhindered dimethyl N-protected α-aminophosphonates, with useful ee values above 80%. Taking into account that the starting phosphonium salts are readily available from the corresponding α-amino acids, the presented procedure can be considered a new strategy for the enantioselective construction of non-racemic α-aminophosphonates from N-acyl-α-amino acids and sets the basis for further developments.

3. Materials and Methods

3.1. General Information Infrared spectra (IR) were recorded on a Nicolet 6700 FT-IR spectrophotometer, Thermo Scientiﬁc, USA (ATR method). 1H-NMR spectra were acquired on Varian 400 at 400 MHz. Data were given as follows: chemical shift in ppm with tetramethylsilane (TMS) as the internal standard, multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; br = broad; m = multiplet), coupling constant (Hz), and integration. 13C-NMR spectra were measured on Varian 400 at 100 MHz. Chemical shifts were reported in ppm from the solvent resonance employed as the internal standard (CDCl3 at 77.0 ppm). 31P NMR spectra were measured on a Varian 400 spectrometer at 162 MHz without the resonance shift Molecules 2020, 25, 405 8 of 14

standard, with respect to H3PO4 as zero ppm. Melting points were determined in capillaries in a Stuart Scientiﬁc SMP3 melting point apparatus and were uncorrected. The high-resolution mass spectra (HRMS) were obtained by electrospray ionization (ESI) using a Waters Corporation Xevo G2 QTOF instrument. Sonication was carried out using Elmasonic 10H laboratory ultrasonic bath (37 kHz, 30 W). α-Amidoalkylation reactions of dimethyl phospite were performed at 70 C using Julabo − ◦ ultra-low refrigerated-circulator F81-ME. For TLC analysis, Merck TLC silica gel 60 F254 plates were used. The plates were visualized by UV light (254 nm) and/or dipped in a solution of cerium sulfate and tetrahydrate of ammonium heptamolybdate in H2SO4aq and heated. Kieselgel 60 (Merck, 0.040–0.063 mm) was used for column chromatography. The enantiomeric excess (ee) of the products was determinated by HPLC using Hitachi, LaChrom Elite, HPLC Chromatograph, Tokyo, Japan (Diode Array L-2450 detector) or Knauer HPLC Chromatograph, Berlin, Germany (UV WellChrom K-2501 detector, RI WellChrom K-2301 detector) using Daicel Chiralpak IA, AD-H, OD-H column. T Optical rotations were measured on a JASCO V-650 polarimeter and reported as follows: [α]D (c in g/100 mL solvent). Materials. All solvents and common reagents were obtained from commercial suppliers. Dimethyl phosphite was purchased from Alfa Aesar. 3-(1-Piperidino)propyl-functionalized silica gel (SiO2-Pip) was purchased from Sigma-Aldrich. Racemic samples rac 3a–k were obtained using tetrabutylammonium bromide as the catalyst. The chiral catalysts 4 [36], 5 [32], 6 [31], and 7 [33] were obtained following literature procedures.

3.2. Substrate Synthesis The starting phosphonium salts 2a–k were synthesized by a previously described two-step protocol [25], which consists of electrochemical decarboxylative α-methoxylation of N-acyl-α-amino acids (Step 1) and transformation of the resulting N-(1-methoxyalkyl)carbamates to 1-(N-acylamino)alkyltriphenylphosphonium tetraﬂuoroborates 2 (Step 2). The analytical data and spectra of compounds 2a–f,j,k were identical to those previously described [25,41]. For previously unknown phosphonium salts 2g–i, analytical and spectroscopic data are reported below.

General Procedure for the Synthesis of 1-(N-acylamino)alkyltriphenylphosphonium Tetraﬂuoroborates 2

3 Step 1: Methanol (30 cm ), N-acyl-α-amino acid (3.0 mmol), and SiO2-Pip (200 mg, 0.22 mmol) were added to an undivided cylindrical glass electrolyzer (85 cm3) with a thermostatic jacket, equipped with a magnetic stirrer, a cylindrical Pt mesh anode (47 cm2), and a similar cathode (44 cm2), all arranged concentrically to one another at a distance of 2.5 0.5 mm. The electrolysis was conducted while 2 ± stirring at a current density of 0.3 A/dm at 10◦C until 3.5–3.75 F/mol charge had passed [3.5 F/mol for N-Cbz-valine and 3.75 F/mol for other N-protected α-amino acids]. When the process of electrolysis was finished, SiO2-Pip was filtered out and methanol was evaporated under reduced pressure to afford the corresponding N-(1-methoxyalkyl)carbamates. Crude N-(1-methoxyalkyl)carbamates were used in the next step without purification. Step 2: A mixture of the corresponding N-(1-methoxyalkyl)carbamates and Ph3P HBF4 (0.98 equiv.) 3 · in CH2Cl2 (2 cm ) was stirred at 25◦C for 30 min and then the solvent was removed under reduced pressure. The crude 1-(N-acylamino)alkyltriphenylphosphonium salts 2g–i were used in the reaction with dimethyl phosphite without further purification. Recrystallization from the mixture of CH2Cl2/Et2O failed. 1-(N-Benzyloxycarbonylamino)butyltriphenylphosphonium tetrafluoroborate (2g). White solid; 96% yield 1 (1.60 g); mp 110◦C to 111◦C. H-NMR (400 MHz, CDCl3): δ 7.88–7.60 (m, 15H), 7.35–7.20 (m, 5H), 6.97 (br d, J = 9.2 Hz, 1H), 5.54–5.46 (m, 1H), 4.99 (d, J = 12.4 Hz, 1H), 4.89 (d, J = 12.4 Hz, 1H), 2.33–2.21 13 (m, 1H), 1.75–1.56 (m, 2H), 1.56–1.43 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H). C-NMR (100 MHz, CDCl3): δ 156.6 (d, J = 3.0 Hz), 135.9, 135.1 (d, J = 2.9 Hz), 134.1 (d, J = 9.3 Hz), 130.3 (d, J = 12.1 Hz), 128.4, 127.9, 127.8, 116.9 (d, J = 80.7 Hz), 67.3, 50.6 (d, J = 53.1 Hz), 32.9 (d, J = 5.4 Hz), 19.7 (d, J = 13.0 Hz), Molecules 2020, 25, 405 9 of 14

31 13.1 (d, J = 0.7 Hz). P NMR (162 MHz, CDCl3): δ 25.5. IR (ATR): 3321, 2964, 1716, 1521, 1438, 1234, 1 + 1051 cm− . HMRS (ESI) m/z: calcd for C30H31NO2P [M ] 468.2092, found 468.2092. 1-(N-Benzyloxycarbonylamino)pentyltriphenylphosphonium tetraﬂuoroborate (2h). White solid; 92% yield 1 (1.57 g); mp 114◦C. H-NMR (400 MHz, CDCl3): δ 7.78–7.59 (m, 15H), 7.32–7.27 (m, 3H), 7.24–7.20 (m, 2H), 6.95 (br d, J = 9.2 Hz, 1H), 5.51–5.43 (m, 1H), 4.99 (d, J = 12.4 Hz, 1H), 4.89 (d, J = 12.4 Hz, 1H), 2.29–2.17 (m, 1H), 1.72–1.58 (m, 2H), 1.49–1.23 (m, 3H), 0.82 (t, J = 7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3): δ 156.6 (d, J = 3.0 Hz), 136.0, 135.1 (d, J = 3.0 Hz), 134.1 (d, J = 9.2 Hz), 130.4 (d, J = 12.3 Hz), 128.4, 127.9, 127.8, 116.9 (d, J = 80.7 Hz), 67.3, 50.9 (d, J = 52.6 Hz), 30.8 (d, J = 5.5 Hz), 28.5 (d, 31 J = 12.5 Hz), 21.7 (d, J = 1.0 Hz), 13.7. P NMR (162 MHz, CDCl3): δ 25.5. IR (ATR): 3320, 2960, 1716, + 1519, 1438, 1236, 1051. HMRS (ESI) m/z: calcd for C31H33NO2P [M ] 482.2249, found 482.2254. 1-(N-Benzyloxycarbonylamino)cyclohexylmethyltriphenylphosphonium tetraﬂuoroborate (2i). White solid; 1 90% yield (1.61 g); mp 119 ◦C to 120 ◦C. H-NMR (400 MHz, CDCl3): δ 7.80–7.67 (m, 9H), 7.65–7.56 (m, 6H), 7.31–7.25 (m, 3H), 7.17–7.12 (m, 2H), 7.00 (br d, J = 8.8 Hz, 1H), 5.34 (q, J = 8.9 Hz, 1H), 4.84 (d, J = 12.4 Hz, 1H), 4.75 (d, J = 12.4 Hz, 1H), 2.39–2.26 (m, 1H), 1.80–1.30 (m, 6H), 1.22–1.06 (m, 3H), 13 0.89–0.75 (m, 1H). C-NMR (100 MHz, CDCl3): δ 156.3 (d, J = 1.8 Hz), 135.7, 134.6 (d, J = 3.0 Hz), 134.5 (d, J = 9.2 Hz), 130.0 (d, J = 12.2 Hz), 128.4, 127.9, 127.8, 118.4 (d, J = 79.5 Hz), 67.1, 55.4 (d, J = 45.9 Hz) 38.8 (d, J = 5.8 Hz), 32.3 (d, J = 2.9 Hz), 29.6 (d, J = 7.9 Hz), 25.6 (d, J = 11.2 Hz), 25.6. 31P 1 NMR (162 MHz, CDCl3): δ 27.4. IR (ATR): 3339, 2932, 1713, 1519, 1438, 1233, 1051 cm− . HMRS (ESI) + m/z: calcd for C33H35NO2P [M ] 508.2400, found 508.2410.

3.3. General Procedure for the PT-Catalyzed Reaction of 1-(N-acylamino)alkyltriphenylphosphonium Salts 2 with Dimethyl Phosphite 1-(N-Acylamino)alkyltriphenylphosphonium salt 2 (0.2 mmol), catalyst 4 or 5 (0.01 mmol), and toluene (2 mL) were placed in a test tube. The mixture was sonicated in an ultrasonic bath for 10 min and dimethyl phosphite (55 µL, 66 mg, 0.6 mmol) was added. After cooling the resulting mixture to 70 C, solid KOH (34 mg, 0.6 mmol) was added. After vigorously stirring at the same − ◦ temperature ( 70 C) for 3 days, the reaction mixture was treated with saturated NH Cl (4 to 5 mL). − ◦ 4 The mixture was allowed to warm to room temperature and then extracted three times with CH2Cl2. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using mixtures of hexane/EtOAc/acetone (5:3:2) as the eluent. (R)-Benzyl N-[1-(dimethoxyphosphoryl)ethyl]carbamate (3a)[36]. Colorless oil; 84% yield (48.4 mg). The enantiomeric excess (84% ee for catalyst 4) was determined by HPLC using Chiralpak AD-H column (n-hexane/isopropanol = 90/10, flow rate 0.75 mL/min, λ = 210 nm) t (major) = 17.0 min, t (minor) = 20.8 min. [α]24 = 15 (CHCl , c = 0.5). 1H-NMR (400 MHz, CDCl ): δ 7.38–7.31 (m, 5H), D − 3 3 5.23 (br d, J = 9.6 Hz, 1H), 5.12 (s, 2H), 4.25–4.14 (m, 1H), 3.76 (d, J = 10.8 Hz, 3H), 3.73 (d, J = 10.8 Hz, 13 3H), 1.39 (dd, J1 = 16.6 Hz, J2 = 7.4 Hz, 3H). C-NMR (100 MHz, CDCl3): δ 155.6 (d, J = 6.0 Hz), 136.2, 128.4, 128.1, 128.0, 67.1, 53.2 (d, J = 7.0 Hz) 53.0 (d, J = 6.0 Hz), 42.8 (d, J = 158.0 Hz), 15.8. 31P NMR 1 (162 MHz, CDCl3): δ 27.9. IR (ATR): 3239, 2955, 1714. 1537, 1225, 1022 cm− . The absolute configuration of compound 3a was determined to be R by comparison of its optical rotation with a literature value: 24 Measured optical rotation (84% ee): [α]D = 15 (CHCl3, c = 0.5) 20 − Literature data: [α]D = -17.5 (CHCl3, c = 1.0) for the (R)-isomer [47]. (R)-Benzyl N-[1-(dimethoxyphosphoryl)-2-phenylethyl]carbamate (3b)[48] Colorless oil; 84% yield (60.9 mg). The enantiomeric excess (73% ee for the catalyst 4) was determined by HPLC using Chiralpak AD-H column (n-hexane/isopropanol = 85:15, flow rate 0.8 mL/min, λ = 210 nm) t (major) = 20.6 min, t (minor) = 28.7 min. [α]24 = 28 (CHCl , c = 0.5). 1H-NMR (400 MHz, CDCl ): δ 7.34–7.20 (m, 10H), 5.05 (br d, D − 3 3 J = 10.0 Hz, 1H), 5.00 (s, 2H), 4.48–4.37 (m, 1H), 3.74 (d, J = 10.4 Hz, 3H), 3.70 (d, J = 10.8 Hz, 3H), 3.22 Molecules 2020, 25, 405 10 of 14

13 (ddd, J1 = 14.0 Hz, J2 = 8.8 Hz, J3 = 4.7 Hz, 1H), 2.87 (dt, J1 = 20.2 Hz, J2 = 10.0 Hz, 1H). C-NMR (100 MHz, CDCl3): δ 155.7 (d, J = 5.4 Hz), 136.4, 136.2, 129.2, 128.4, 128.4, 128.0, 127.8, 126.8, 67.0, 53.2 31 (d, J = 7.1 Hz), 53.0 (d, J = 6.6 Hz), 48.2 (d, J = 155.9 Hz) 35.8 (d, J = 3.6 Hz). P NMR (162 MHz, CDCl3): 1 δ 26.4. IR (ATR): 3223, 2954, 1708, 1542, 1255, 1222, 1028 cm− . (R)-tert-Butyl N-[1-(dimethoxyphosphoryl)-2-phenylethyl]carbamate (3c)[36]. White solid; 93% yield (61.1 mg); mp 77 ◦C to 79 ◦C. The enantiomeric excess (72% ee for the catalyst 4) was determined by HPLC using Chiralpak AD-H column (n-hexane/isopropanol = 85:15, flow rate 0.5 mL/min, λ = 210 nm) t (major) = 26.4 min, t (minor) = 19.1 min. [α]25 = 21 (CHCl , c = 0.5). Compound 3c exists as D − 3 a 85:15 mixture of rotamers at 25 ◦C in CDCl3. The spectra for the major rotamer are as follows: 1 H-NMR (400 MHz, CDCl3): δ 7.31–7.20 (m, 5H), 4.70 (br d, J = 10.0 Hz, 1H), 4.44–4.33 (m, 1H), 3.75 (d, J = 10.4 Hz, 6H), 3.21 (ddd, J1 = 13.6 Hz, J2 = 8.8 Hz, J3 = 4.8 Hz, 1H), 2.84 (dd, J1 = 14.4 Hz, J2 = 10.2 Hz, 13 1H), 1.32 (s, 9H). C-NMR (100 MHz, CDCl3): δ 154.9 (d, J = 7.0 Hz), 136.5 (d, J = 13.1 Hz), 129.2, 128.3, 126.7, 80.0, 53.2 (d, J = 7.1 Hz), 52.9 (d, J = 6.7 Hz), 47.5 (d, J = 155.6 Hz) 36.0 (d, J = 3.8 Hz), 28.1.31P 1 NMR (162 MHz, CDCl3): δ 32.1. IR (ATR): 3255, 2981, 1706, 1525, 1237, 1155, 1043 cm− . (R)-Benzyl N-[1-(dimethoxyphosphoryl)-2-methylpropyl]carbamate (3d)[49]. Colorless oil; 85% yield (53.7 mg). The enantiomeric excess (56% ee for the catalyst 4) was determined by HPLC using Chiralpak AD-H column (n-hexane/isopropanol = 90:10, flow rate 0.75 mL/min, λ = 210 nm) t (major) = 14.5 min, t (minor) = 23.0 min. [α]24 = 5 (CHCl , c = 0.5). 1H-NMR (400 MHz, CDCl ): δ 7.37–7.31 (m, D − 3 3 5H), 5.16 (d, J = 12.0 Hz, 1H), 5.11 (d, J = 12.4 Hz, 1H), 5.08 (br d, J = 9.6 Hz, 1H), 4.05 (ddd, J1 = 18.6 Hz, J2 = 10.4 Hz, J3 = 4.2 Hz, 1H), 3.75 (d, J = 10.8 Hz, 3H), 3.71 (d, J = 10.8 Hz, 3H), 2.25–2.15 (m, 1H), 13 1.03 (d, J = 6.8 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H). C-NMR (100 MHz, CDCl3): δ 156.3 (d, J = 6.4 Hz), 136.2, 128.5, 128.2, 128.0, 67.2, 52.9 (d, J = 6.3 Hz), 52.8 (d, J = 7.2 Hz), 52.2 (d, J = 151.8 Hz), 28.9 (d, 31 J = 4.4 Hz), 20.3 (d, J = 12.6 Hz), 17.7 (d, J = 4.1 Hz). P NMR (162 MHz, CDCl3): δ 26.7. IR (ATR) 3239, 1 2958, 1710, 1533, 1289, 1228, 1024 cm− . (R)-tert-Butyl N-[1-(dimethoxyphosphoryl)-2-methylpropyl]carbamate (3e)[50]. White solid; 88% yield (49.4 mg); mp 83◦C to 84◦C. The enantiomeric excess (23% ee for the catalyst 4) of the product 3e was determined by HPLC, after transformation into its Cbz derivative 3e’ through Boc deprotection followed by CbzCl derivatization as described by Ricci et al. [36], using Chiralpak IA column (n-hexane/isopropanol = 90:10, flow rate 0.75 mL/min, λ = 210 nm) t (major) = 13.3 min, 1 t (minor) = 19.8 min. H-NMR (400 MHz, CDCl3): δ 4.76 (br d, J = 9.6 Hz, 1H), 3.99 (ddd, J1 = 18.4 Hz, J2 = 10.8 Hz, J3 = 4.4 Hz, 1H), 3.76 (d, J = 10.8 Hz, 6H), 2.22–2.10 (m, 1H), 1.45 (s, 9H), 1.01 (dd, 13 J1 = 6.8 Hz, J2 = 1.2 Hz, 3H), 0.99 (d, J = 7.2 Hz, 3H). C-NMR (100 MHz, CDCl3): δ 155.6 (d, J = 6.3 Hz), 80.0, 52.9 (d, J =7.2 Hz), 52.7 (d, J = 6.7 Hz), 51.5 (d, J = 151.4 Hz), 28.9 (d, J = 4.8 Hz), 28.2, 31 20.3 (d, J = 12.6 Hz), 17.8 (d, J = 4.2 Hz). P NMR (162 MHz, CDCl3): δ 27.2. IR (ATR): 3267, 2972, 1 1701, 1530, 1293, 1233, 1163, 1035 cm− . (R)-Benzyl N-[1-(dimethoxyphosphoryl)-3-methylbutyl]carbamate (3f)[36]. Colorless oil; 82% yield (54.1 mg). The enantiomeric excess (80% ee for the catalyst 4) was determined by HPLC using Chiralpak IA column (n-hexane/isopropanol = 85/15, flow rate 0.75 mL/min, λ = 254 nm) t (major) = 10.1 min, t (minor) = 13.4 min. [α]25 = 32 (CHCl , c = 1.0). 1H-NMR (400 MHz, CDCl ): δ 7.37–7.28 (m, 5H), D − 3 3 5.16 (d, J = 12.4 Hz, 1H), 5.08 (d, J = 12.4 Hz, 2H), 4.25–4.14 (m, 1H), 3.75 (d, J = 10.4 Hz, 3H), 3.70 (d, J = 10.4 Hz, 3H), 1.79–1.68 (m, 1H), 1.58 (q, J = 7.2 Hz, 2H), 0.94 (d, J = 2.4 Hz, 3H), 0.92 (d, J = 2.0 Hz, 13 3H). C-NMR (100 MHz, CDCl3): δ 155.9 (d, J = 4.6 Hz), 136.3, 128.4, 128.1, 127.9, 67.0, 53.1 (d, J = 7.1 Hz), 52.9 (d, J = 6.5 Hz), 45.5 (d, J = 155.6 Hz), 38.3 (d, J = 2.4 Hz), 24.3 (d, J = 13.2 Hz), 23.2, 21.0. 31 1 P NMR (162 MHz, CDCl3): δ 29.0. IR (ATR): 3274, 2955, 1686, 1541, 1267, 1233, 1027 cm− . The absolute configuration of compound 3f was determined to be R by comparison of its optical rotation with a literature value: Measured optical rotation (80% ee): [α]25 = 32 (CHCl , c = 1.0) D − 3 Literature data: [α]20 = 36.4 (CHCl , c = 1.0) for the (R)-isomer [51]. D − 3 Molecules 2020, 25, 405 11 of 14

(R)-Benzyl N-[1-(dimethoxyphosphoryl)butyl]carbamate (3g). Colorless oil; 85% yield (53.4 mg). The enantiomeric excess (80% ee for the catalyst 4) was determined by HPLC using Chiralpak AD-H column (n-hexane/isopropanol = 90/10, flow rate 0.75 mL/min, λ = 210 nm) t (major) = 18.1 min, t (minor) = 24.9 min. [α]25 = 25 (CHCl , c = 0.5). 1H-NMR (400 MHz, CDCl ): δ 7.38–7.30 (m, 5H), D − 3 3 5.15 (d, J = 12.4 Hz, 1H), 5.10 (d, J = 12.4 Hz, 1H), 4.93 (br d, J = 10.4 Hz, 1H), 4.17–4.07 (m, 1H), 3.76 (d, J = 10.8 Hz, 3H), 3.72 (d, J = 10.4 Hz, 3H), 1.87–1.80 (m, 1H), 1.63–1.33 (m, 3H), 0.93 (t, J = 7.2 Hz, 3H). 13 C-NMR (100 MHz, CDCl3): δ 156.0 (d, J = 5.5 Hz), 136.2, 128.5, 128.2, 128.0, 67.2, 53.1 (d, J = 7.2 Hz), 53.0 (d, J = 6.5 Hz), 46.9 (d, J = 155.0 Hz), 31.8 (d, J = 2.4 Hz), 19.0 (d, J = 12.7 Hz), 13.5. 31P NMR 1 (162 MHz, CDCl3): δ 27.5. IR (ATR): 3239, 2957, 1714, 1537, 1226, 1025cm− . HMRS (ESI) m/z: calcd for + C14H22NO5NaP [M+Na] 338.1133, found 338.1135. (R)-Benzyl N-[1-(dimethoxyphosphoryl)pentyl]carbamate (3h)[52]. Colorless oil; 80% yield (53.0 mg). The enantiomeric excess (92% ee for the catalyst 4) was determined by HPLC using Chiralpak AD-H column (n-hexane/isopropanol = 90/10, flow rate 0.75 mL/min, λ = 210 nm) t (major) = 15.7 min, t (minor) = 23.2 min. [α]24 = 23 (CHCl , c = 0.5).1H-NMR (400 MHz, CDCl ): δ 7.36–7.29 (m, 5H), 5.15 D − 3 3 (d, J = 12.0 Hz, 1H), 5.11 (d, J = 12.4 Hz, 1H), 5.02 (br d, J = 10.4 Hz, 1H), 4.15–4.05 (m, 1H), 3.75 (d, J = 10.8 Hz, 3H), 3.72 (d, J = 10.4 Hz, 3H), 1.87–1.80 (m, 1H), 1.62–1.26 (m, 5H), 0.89 (t, J = 7.0 Hz, 3H). 13 C-NMR (100 MHz, CDCl3): δ 156.0 (d, J = 5.7 Hz), 136.2, 128.5, 128.1, 128.0, 67.1, 53.1 (d, J = 7.2 Hz), 52.9 (d, J = 6.5 Hz), 47.2 (d, J = 155.0 Hz), 29.5 (d, J = 2.7 Hz), 27.8 (d, J = 12.4 Hz), 22.1, 13.8. 31P NMR 1 (162 MHz, CDCl3): δ 27.4. IR (ATR): 3242, 2955, 1715, 1537, 1223, 1026 cm− . (R)-Benzyl N-[cyclohexyl(dimethoxyphosphoryl)methyl]carbamate (3i)[36]. White solid; 71% yield (50.6 mg); mp 61.5◦C to 62.5◦C. The enantiomeric excess (65% ee for the catalyst 4) was determined by HPLC using Chiralpak IA column (n-hexane/isopropanol = 85:15, flow rate 0.75 mL/min, λ = 205 nm) t (major) = 15.6 min, t (minor) = 20.9 min. [α]24 = 3 (CHCl , c = 0.5). 1H-NMR (400 MHz, CDCl ): δ 7.37–7.30 D − 3 3 (m, 5H), 5.16 (d, J = 12.4 Hz, 1H), 5.10 (d, J = 12.0 Hz, 1H), 5.02 (br d, J = 10.4 Hz, 1H), 4.04 (ddd, J1 = 18.7 Hz, J2 = 10.8 Hz, J3 = 4.3 Hz, 1H), 3.75 (d, J = 10.4 Hz, 3H), 3.70 (d, J = 10.8 Hz, 3H), 1.89–1.63 13 (m, 6H), 1.33–1.00 (m, 5H). C-NMR (100 MHz, CDCl3): δ 156.2 (d, J = 6.4 Hz), 136.2, 128.5, 128.2, 128.0, 67.2, 52.9 (d, J = 6.5 Hz), 52.8 (d, J = 7.2 Hz), 52.0 (d, J = 151.3 Hz), 38.6 (d, J = 4.2 Hz), 30.5 (d, 31 J = 11.4 Hz), 28.0 (d, J = 4.3 Hz), 26.1 (d, J = 1.7 Hz), 25.9 (d, J = 10.9 Hz). P NMR (162 MHz, CDCl3): 1 δ 26.7. IR (ATR): 3243, 2927, 1715, 1545, 1219, 1030 cm− . (R)-Benzyl N-[2-(tert-butoxy)-1-(dimethoxyphosphoryl)ethyl]carbamate (3j). White solid; 98% yield (70.6 mg); mp 67◦C to 69◦C. The enantiomeric excess (53% ee for the catalyst 4) was determined by HPLC using Chiralpak AD-H column (n-hexane/isopropanol = 90:10 flow rate 0.75 mL/min, λ = 210 nm) t (major) = 25 1 18.8 min, t (minor) = 22.3 min. [α]D = 3 (CHCl3, c = 0.5). H-NMR (400 MHz, CDCl3): δ 7.37–7.30 (m, 5H), 5.30 (br d, J = 9.6 Hz, 1H), 5.13 (s, 2H), 4.33–4.21 (m, 1H), 3.79–3.74 (m, 1H), 3.76 (d, J = 10.8 Hz, 13 6H), 3.58 (ddd, J1 = 28.0 Hz, J2 = 9.4 Hz, J3 = 3.8 Hz, 1H), 1.18 (s, 9H). C-NMR (100 MHz, CDCl3): 155.8 (d, J = 6.4 Hz), 136.2, 128.5, 128.2, 128.1, 73.7, 67.2, 60.6, 53.3 (d, J = 5.9 Hz), 52.7 (d, J = 6.4 Hz), 31 48.3 (d, J = 155.5 Hz), 27.3. P NMR (162 MHz, CDCl3): δ 26.1. IR (ATR): 3229, 2971, 1706, 1551, 1277, 1 + 1223, 1183, 1033 cm− . HMRS (ESI) m/z: calcd for C16H26NO6NaP [M+Na] 382.1395, found 382.1398. (R)-tert-Butyl N-[2-(benzyloxy)-1-(dimethoxyphosphoryl)ethyl]carbamate (3k). Colorless oil; 84% yield (60.2 mg). The enantiomeric excess (53% ee for the catalyst 5) was determined by HPLC using Chiralpak OD-H column (n-hexane/isopropanol = 97:3, flow rate 0.5 mL/min, λ = 212 nm) t (major) = 54.1 min, t 25 1 (minor) = 62.0 min. [α]D = 2 (CHCl3, c = 1.0). H-NMR (400 MHz, CDCl3): δ 7.35–7.27 (m, 5H), 5.06 (br d, J = 9.2 Hz, 1H), 4.56 (s, 2H), 4.36–4.24 (m, 1H), 3.85–3.79 (m, 1H), 3.75 (d, J = 10.4 Hz, 3H), 3.75 (d, 13 J = 10.4 Hz, 3H), 3.70 (ddd, J1 = 24.0 Hz, J2 = 9.8 Hz, J3 = 3.8 Hz 1H), 1.45 (s, 9H). C-NMR (100 MHz, CDCl3): 155.1 (d, J = 7.4 Hz), 137.6, 128.4, 127.8, 127.7, 80.2, 73.3, 68.8 (d, J = 2.3 Hz), 53.3 (d, J = 6.3 Hz), 31 52.8 (d, J = 6.3 Hz), 47.4 (d, J = 155.0 Hz), 28.3. P NMR (162 MHz, CDCl3): δ 25.7. IR (ATR): 3263, 1 + 2956, 1708, 1497, 1365, 1242, 1165, 1026 cm− . HMRS (ESI) m/z: calcd for C16H26NO6NaP [M+Na] 382.1395, found 382.1390. Molecules 2020, 25, 405 12 of 14

Supplementary Materials: The following are available online. Supporting information includes 1H-, 13C-, 31P-NMR, HRMS spectra of all new compounds 2, 3, and HPLC data for compounds 3 and results of the SDE test. Author Contributions: Conceptualization, A.P.-H.; Methodology, A.P.-H. and A.W.-K.; Formal analysis, A.P.-H., A.W.-K., A.K., and S.S.; Investigation, A.P.-H., A.W.-K., A.K., and S.S.; Supervision, A.P.-H. and K.W. Writing—original draft preparation, A.P.-H.; Writing—review and editing, A.P.-H., A.W.-K., and A.K. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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Sample Availability: Samples of the compounds 2, 3 are available from the authors.

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