Rigid Scaffolds: Synthesis of 2,6-Bridged Piperazines with Functional Groups in all three Bridges.

The activity of pharmacologically active compounds can be increased by presenting a drug in a defined conformation, which fits exactly into the binding pocket of its target. Herein, the piperazine scaffold was conformationally restricted by substituted C2- or C3-bridges across the 2- and 6-position. At first, a three-step, one-pot procedure was developed to obtain reproducibly piperazine-2,6-diones with various substituents at the N-atoms in high yields. Three strategies for bridging of piperazine-2,6-diones were pursued: 1. The bicyclic mixed ketals 8-benzyl-6-ethoxy-3-(4-methoxybenzyl)-6-(trimethylsilyloxy)-3,8-diazabicyclo[3.2.1]octane-2,4-diones were prepared by Dieckmann analogous cyclization of 2-(3,5-dioxopiperazin-2-yl)acetates. 2. Stepwise allylation, hydroboration and oxidation of piperazine-2,6-diones led to 3-(3,5-dioxopiperazin-2-yl)propionaldehydes. Whereas reaction of such an aldehyde with base provided the bicyclic alcohol 9-benzyl-6-hydroxy-3-(4-methoxybenzyl)-3,9-diazabicyclo[3.3.1]nonane-2,4-dione in only 10 % yield, the corresponding sulfinylimines reacted with base to give N-(2,4-dioxo-3,9-diazabicyclo[3.3.1]nonan-6-yl)-2-methylpropane-2-sulfinamides in >66 % yield. 3. Transformation of a piperazine-2,6-dione with 1,4-dibromobut-2-ene and 3-halo-2-halomethylprop-1-enes provided 3,8-diazabicyclo[3.2.1]octane-2,4-dione and 3,9-diazabicyclo[3.3.1]nonane-2,4-dione with a vinyl group at the C2- or a methylene group at the C3-bridge, respectively. Since bridging via sulfinylimines and the one-pot bridging with 3-bromo-2-bromomethylprop-1-ene gave promising yields, these strategies will be exploited for the synthesis of novel receptor ligands bearing various substituents in a defined orientation at the carbon bridge.

Introduction

The piperazine ring is a common structural element in various pharmacologically active compounds1 such as the antidepressant trazodone (1)2 and the histamine H1 receptor antagonist cetirizine (2).3, 4 (Figure 1)

Figure 1

Pharmacologically active compounds containing a piperazine ring.

The piperazine ring can adopt two chair and several twist conformations. Introduction of a bridge into the piperazine scaffold would restrict the conformational flexibility. Presenting a drug in an optimal but fixed conformation would increase its free binding energy due to entropic reasons.5 The natural product atropine (3) represents the most prominent example for an N‐heterocycle bearing an additional two‐carbon bridge. This bridge between 2‐ and 6‐position holds the piperidine ring in a particular chair conformation and forces the O‐acyl moiety to adopt an axial orientation.6 The granatane derivative granisetron is an important 5‐HT3 receptor antagonist used for the treatment of strong emesis caused by chemotherapy and radiotherapy. In the granatane structure, the piperidine ring is bridged by a three‐carbon bridge. As in atropine, this conformational restriction leads to an axial orientation of the acylamino moiety.7, 8 (Figure 2)

Figure 2

Potent drugs with a bridged piperidine ring (3,4) and piperazine ring (5–7) stimulating the design of the 2,6‐bridged piperazines 8.

In general, we are interested in piperidine and piperazine rings with an additional bridge leading to conformational restriction of the ring system. We have reported the bicyclic KOR agonist 5 (K i=73 nM),9 in which the 2‐ and 4‐positions of the piperazine ring are connected by a three‐carbon bridge substituted with an additional amino moiety (pyrrolidine ring). The same three‐carbon bridge connects the 2‐ and 5‐positions of the piperazine ring in the (1S,2R,5R)‐configured KOR agonist 6 (K i=1.0 nM).10 Although the bicyclic systems 5 and 6 contain the same three‐carbon bridge, the piperazine rings adopt different defined conformations due to the different ring positions, which are connected by the bridge (2,4‐bridge in 5, 2,5‐bridge in 6). The 6,8‐diazabicyclo[3.2.2]nonane 7 with an OH moiety at the bridge shows very high affinity towards σ1 receptors (K i=6.5 nM).11 Embedding the σ1 pharmacophoric structural elements (basic amino moiety, two lipophilic residues) into a bicyclic framework resulted in particular high σ1 affinity. Compared to 6, the σ1 ligand 7 contains an enantiomeric scaffold, two benzyl moieties at the N‐atoms and a hydroxy moiety instead of the pyrrolidine ring. (Figure 2)

In order to follow the concept of conformational restriction we became interested in piperazine derivatives bearing a two‐ or three‐carbon bridge across the 2‐ and 6‐positions (see compound 8 in Figure 2). On the one hand, 2,6‐bridged piperazines 8 are regarded as aza‐analogs of the tropane and granatane scaffolds of 3 and 4, on the other hand, they are regarded as regioisomers of 5–7 bearing a 2,6‐bridge instead of a 2,4‐ or 2,5‐bridge across the piperazine ring.

Some methods for the synthesis of 3,8‐diazabicyclo[3.2.1]octane (8a, n=0) and 3,9‐diazabicyclo[3.3.1]nonane derivatives (8b, n=1) have been reported in literature. Compounds with the scaffold 8a were prepared starting from adipic acid. A four‐step reaction sequence provided pyrrolidine‐2,5‐dicarboxylate, which was transformed into the bicyclic imide upon reaction with NH3 and Ac2O. Final reduction of the imide functional group was performed with LiAlH4.12, 13 Corresponding 3,9‐diazabicyclo[3.3.1]nonane derivatives 8b with an extended C3‐bridge were prepared by imide formation from piperidine‐2,6‐dicarboxylate and subsequnt LiAlH4 reduction.14 Another one‐pot synthesis of the bicyclic system 8a started with hexa‐1,5‐diene, which was reacted with trifluoromethanesulfonamide in the oxidation system t‐BuOCl/NaI to introduce two N‐atoms oxidatively at 1,6‐ and 2,5‐position of the diene system in 37 % yield.15

However, there are only few reports dealing with the synthesis of 3,8‐diazabicyclo[3.2.1]octane (8a, n=0) or 3,9‐diazabicyclo[3.3.1]nonane derivatives (8b, n=1) with additional substituents at the two‐ or three‐carbon bridge.16, 17, 18 Herein, we report various strategies to synthesize bicyclic compounds of type 8 with different length of the carbon bridge. The particular feature of type 8 compounds is the additional functional group at the two‐ or three‐carbon bridge allowing introduction of various pharmacophoric elements in a defined 3D orientation.

Results and Discussion

Synthesis

In order to establish the bridge providing the desired bicyclic compounds of type 8 key intermediate piperazine‐2,6‐diones (e. g. 12, 17) should react with various dielectrophiles stepwise or in a one‐pot procedure. Piperazine‐2,6‐diones can be prepared either by alkylation of α‐amino acid esters with bromoacetamide and subsequent cyclization19, 20 or by condensation of iminodiacetic acid derivatives with primary amines or NH3.21, 22, 23, 24 As reported in literature, iminodiacetic acids 13 and 14 (structures see Scheme  2) were reacted with primary amines under microwave irradiation. However, instead of the desired imides only salts could be isolated.

Scheme 2

Preparation of piperazine‐2,6‐dione 17. Reagents and reaction conditions: (a) Boc2O, NaHCO3, THF, H2O, r.t., 72 h, 74 %. (b) i. CDI (1.0 eq), CH3CN, THF, reflux, 60 min; ii. BnNH2, THF, reflux, 60 min; iii. CDI (2.0 eq), CH3CN, THF, reflux, 18 h, 62 %. (c) TFA, CH2Cl2, r.t., 24 h, 99 %. (d) PMB−Cl, DIPEA, CH3CN, reflux, 18 h, 88 %.

Therefore, different strategies were pursued to synthesize key piperazine‐2,6‐diones with two orthogonal protective groups at the N‐atoms. At first, piperazinediones 12a (R=Cbz) and 12b (R=Bz) were prepared in three steps from diethyl iminodiacetate 9. Acylation of the secondary amine 9 with benzyl chloroformate or benzoyl chloride afforded protected diesters 10a and 10b, respectively, which were hydrolyzed by NaOH to give the diacids 11 a and 11b. CDI coupling of the diacids 11a and 11b with p‐methoxybenzylamine led to the imides 12a and 12b in 68 % and 60 % yield, respectively. The imide formation was conducted in three steps. At first, one equivalent CDI was added, which was supposed to form a cyclic anhydride. The anhydride was then opened by addition of p‐methoxybenzylamine to afford an amido acid. Finally, the second acid was activated by another equivalent of CDI to form the imides 12a and 12b. The N‐benzyl derivative 12c was obtained by hydrogenolytic cleavage of the Cbz protective group of 12a followed by alkylation of secondary amine 12d with benzyl bromide. (Scheme 1)

Scheme 1

Preparation of piperazine‐2,6‐diones 12a–d. Reagents and reaction conditions: (a) Cbz‐Cl, NEt3, CH2Cl2, 0 °C, 18 h, 70 %. (b) Bz−Cl, NEt3, CH2Cl2, r.t., 24 h, 90 %. (c) NaOH, EtOH, H2O, r.t., 18 h, 90 % (11a), 90 % (11b). (d) i. CDI (1.0 eq), CH3CN, THF, reflux, 90 min; ii. PMB‐NH2, THF, reflux, 90 min; iii. CDI (2.0 eq), CH3CN, THF, reflux, 60 h, 68 % (12a), 60 % (12b). (e) H2, Pd/C, THF, r.t., 1 h, 95 %. (f) 12d: BnBr, CH3CN, reflux, 18 h, 84 %.

In the second approach leading to piperazine‐2,6‐dione 17 bearing the benzyl and p‐methoxybenzyl protective groups at opposite N‐atoms compared to 12c, iminodiacetic acid (13) was used as starting material. Reaction of the secondary amine 13 with Boc2O afforded 14 in 74 % yield. CDI coupling of diacid 14 with BnNH2 provided the Boc‐protected imide 15. After removal of the Boc‐protective group of 15 with trifluoroacetic acid, the resulting secondary amine 16 was alkylated with p‐methoxybenzyl chloride to afford piperazinedione 17 with two orthogonal protective groups at the N‐atoms. (Scheme 2)

In order to introduce a side chain with two C‐atoms and a functional group for bridging, the piperazinediones 12a–c were deprotonated with LiHMDS or KHMDS and treated with ethyl 2‐bromoacetate. The monoalkylated piperazinediones 18a–c were obtained in 79–84 % yield. Additionally, small amounts of the dialkylated products 19a and 19b (4–6 %) could be isolated from the reaction mixture. (Scheme 3)

Scheme 3

Synthesis of the 3,8‐diazabicyclo[3.2.1]octane framework. Reagents and reaction conditions: (a) LiHMDS or KHMDS, THF, −78 °C, 1 h, then BrCH2CO2Et, THF, −78 °C–r.t., 18 h, 84 % (18a), 79 % (18b), 84 % (18c). (b) KHMDS, THF, −78 °C, 1 h, then BrCH2CO2Et, THF, −78 °C, 3 h, 73 %. (c) LiHMDS, THF, −78 °C, 15 min, then Me3SiCl, THF, −78 °C, 1 h, then r.t., 12 %. (d) LiHMDS, THF, −78 °C, 15 min, then Me3SiCl, THF, −78 °C, 1 h, then r.t., 21 % (21a), 10 % (21b).

The introduction of both substituents at the same position of the piperazinediones 12a and 12b was unexpected. Therefore, the monoalkylated piperazinedione 18b was deprotonated with KHMDS at −78 °C and the resulting enolate was subsequently treated with ethyl bromoacetate. This reaction led exclusively to the dialkylated piperazinedione 19b (73 %) bearing both acetate moieties at the same C‐atom. (Scheme 3) This experiment showed unequivocally that the CH‐group (3‐CH) of N‐acylated piperazinedione 18b reacted preferably with electrophiles compared to the 5‐CH2‐moiety. Other electrophiles such as CH3I also reacted at the 3‐position of 18b. (See Scheme SI1 in Supporting information)

For the synthesis of bicyclic systems, a Dieckmann analogous cyclization making use of trapping the intermediate addition product (anion of an hemiketal) by Me3SiCl proved itself well.25, 26, 27 Therefore the piperazinediones 18a–c with one acetate moiety were treated with LiHMDS at −78 °C and after 15 min Me3SiCl was added to the mixture. Unexpectedly, only the benzylated piperazinedione 18c provided the mixed ethyl silyl ketal 20c in low yield (12 %) and the corresponding mixed ethyl silyl ketals from the Cbz and Bz protected piperazinediones 18a and 18b could not be detected. This failure of the bridging reaction was attributed to the preferred deprotonation in 3‐position of N‐acylated piperazinediones 18a and 18b, which could not lead to the cyclization products. (Scheme 3)

Therefore, the 3,3‐dialkylated piperazinediones 19a and 19b, which could no longer be deprotonated in 3‐position were treated in the same manner with LiHMDS and Me3SiCl. Although the yields were rather low, both compounds led to the mixed ethyl silyl ketals 21a and 21b. This observation supports the hypothesis of first deprotonation in 3‐position of the acylated monoacetates 18a,b as reason for the failure of the bridging reaction. (Scheme 3)

In addition to the preferred deprotonation in 3‐position, the low yields of the ethano bridged piperazinediones 20 and 21 could be due to the short acetate (two C‐atoms) side chain, which could not reach the enolate at the opposite side of the piperazine ring. In order to improve the accessibility of the enolate, a propionate side chain leading to propano bridged piperazinediones was envisaged. Therefore, the conjugate addition of piperazinediones 12a–c at methyl acrylate was investigated. For this purpose, 12a–c were deprotonated with LiHMDS or KHMDS at −78 °C and after 1 h, methyl acrylate was added. However, instead of the expected addition products 25, the tetrahydropyridine derivatives 24 were isolated in 40–90 % yields. Several experiments were performed to avoid this undesired reaction, including variation of the base (LiHMDS, KHMDS, NaHMDS, LDA, KDA), the electrophile (methyl acrylate, ethyl acrylate, ethyl 3‐bromopropionate, ethyl 3‐iodopropionate), the temperature and reaction time. Only, after deprotonation of 12b with KDA or KHMDS and then reaction with ethyl acrylate or ethyl 3‐iodopropionate provided a small amount (15 % and 9 %) of the propionate 25b. (Scheme 4). It is assumed that the larger ethyl ester decreased the reactivity of the intermediate enolate 23 to attack intramolecularely the imide group.

Scheme 4

Reaction of piperazinediones 12a‐c with acrylates. Reagents and reaction conditions: (a) LiHMDS or KHMDS, THF, −78 °C, 1–3 h, then methyl acrylate, −78 °C, 2 h, r.t. 16 h, 90 % (24a), 34 % (24b), 19 % (24c). (b) KDA or KHMDS, THF, −78 °C, 30 min, then ethyl acrylate, −78 °C, 2 h, r.t. 14 h, 15 % (25b). (c) KHMDS, THF, −78 °C, 90 min, then CH3I, −78 °C, 2 h, r.t. 15 h, 33 %.

Formation of the tetrahydropyridines 24 was explained by deprotonation of piperazinediones 12a–c and subsequent addition of the enolates 22 at acrylate resulting in the new enolates 23. Protonation of these enolates 23 can afford the desired propionates 25. However, usually a fast attack of the enolates 23 at one of the imide carbonyl moieties occurred leading to cleavage of the imide and finally to the tetrahydropyridines 24a–c. (Scheme 4)

The structure of the unexpected tetrahydropyridines 24a–c was confirmed unequivocally by 1H and 13C NMR spectroscopy and mass spectrometry. In the 1H NMR spectrum of 24c a singlet at 11.90 ppm typical for an enol proton of a vinylogous acid is observed. Moreover, the imide structure can no longer be identified due to the high field shift of the signals for the CH2 group of the p‐methoxybenzyl moiety. The doublets of doubles for these protons indicate an additional coupling with the NH‐proton of the amide in 24c. Deprotonation of the β‐oxoester 24b and subsequent methylation with CH3I, afforded the methylated β‐oxoester 26b providing an additional proof for the tetrahydropyridine structure of 24a–c.

Since the direct introduction of a propionate side chain was not successful, the stepwise introduction of a C3‐fragment with an electrophilic functional group at the end was envisaged. For this purpose, the piperazinediones 12c and 17 were deprotonated and reacted with allyl bromide to afford racemic allyl substituted piperazinediones 27 and 28, respectively. After hydroboration with 9‐BBN and then oxidation with H2O2, the alcohols 29 and 30 were oxidized with Dess‐Martin Periodinane (DMP) and the resulting aldehydes 31 and 32 were condensed with (S)‐configured Ellman's sulfinamide (S)‐2‐methylpropane‐2‐sulfinamide in the presence of Ti(OC2H5)4 to give the sulfinylimines 33 and 34 in 82 % and 90 % yield, respectively. Due to the high electrophilicity of the sulfinylimines 33 and 34, the bridge could be established by deprotonation with LiHMDS. The resulting enolates were able to attack intramolecularly the electrophilic C‐atom of the sulfinylimine group of 33 and 34 leading to the bicyclic sulfinamides 35 and 36. Both transformations led to high yields of mixtures of diastereomeric bridged piperazinediones 35 (66 %) and 36 (69 %). The main isomer of the mixture of diastereomers could be isolated in 22 % and 27 % yields, respectively. (Scheme 5)

Scheme 5

Synthesis of 3,9‐diazabicyclo[3.2.1]nonanes. Reagents and reaction conditions: (a) LiHMDS, THF, −78 °C, 30 min, then BrCH2CH=CH2, THF, −78 °C, 2 h, r.t., 18 h, 61 % (27), 67 % (28). (b) i. 9‐BBN, r.t. 16 h; ii. H2O2, NaOH, THF, −25 °C, 45 min, r.t., 60 min, 94 % (29), 55 % (30) (c) DMP, CH2Cl2, 3 h, r.t., 87 % (31), 94 % (32). (d) (S)‐2‐methylpropane‐2‐sulfinamide, Ti(OC2H5)4, THF, r.t., 3 h, 82 % (33), 90 % (34). (e) LiHMDS, THF, −78 °C‐r.t., 6 h, 66 % (35), 69 % (36). (f) LiHMDS, THF, −78 °C, 30 min, then r.t. 2.5 h, 10 %.

Since the sulfinylimines 33 and 34 provided the bridged systems 35 and 36 in high yields, the same reaction was tried with the corresponding aldehyde 31. In fact, deprotonation of the aldehyde 31 with LiHMDS led to the endo‐oriented bicyclic alcohol 37. However, the yield of 37 did not exceed 10 % even after careful optimization. (Scheme 5)

As the reaction of the enolates of piperazinediones 12c and 17 with allyl bromide gave high yields of substitution products 27 and 28, a dihalide presenting the allyl halide moiety twice should be reacted with the enolate of 17 to establish the bridge in only one reaction step. The linear dibromide 38 was frequently used in the literature to form systems with a vinyl moiety.28 The branched dihalides 40 were employed to prepare compounds with large rings,29, 30, 31, 32 in particular, 1,5‐diazacyclooctanes and tricyclic fused tetrazole derivatives. 3,7‐Dimethylene‐1,5‐diazacyclooctanes were obtained by reaction of two equivalents of p‐toluenesulfonamide or methanesulfonamide with two equivalents of dichloride 40a.31, 32 Tricyclic fused tetrazole derivatives were achieved in two steps. At first, diazotizative allylation of 2‐aminobenzonitrile derivatives with dibromide 40b was performed and then a tandem reaction comprised of a cycloaddition between the nitrile and (TMS)N3 followed by an intramolecular N‐allylation gave the desired products.29

For this purpose, piperazinedione 17 was deprotonated with 1.2 equivalents of LiHMDS. Subsequently, trans‐1,4‐dibromobut‐2‐ene (38) was added and after 16 h, another 1.2 equivalents of LiHMDS were added. Thus, the 2,6‐bridged piperazinedione 39 was obtained by subsequent SN2 and SN2’ reactions at 1,4‐dibromobut‐2‐ene 38 in 22 % yield. As for the alcohol 37, only the endo‐oriented vinyl derivative 39 was formed. The reaction of piperazinedione 17 with allylic dihalides 40 was performed in the same manner. Among the three allylic dihalides, the highest yield of 52 % was obtained by reacting 17 with 3‐bromo‐2‐(bromomethyl)prop‐1‐ene (40b). This one‐step procedure will allow to prepare large amounts of 41 and exploit the additional double bond in the bridge to introduce further substituents as pharmacophoric elements. (Scheme 6)

Scheme 6

Reaction of piperazinedione 17 with dielectrophiles 38 and 40. Reagents and reaction conditions: (a) i. LiHMDS, THF, −78 °C, 90 min; ii. trans‐1,4‐dibromobut‐2‐ene (38), THF, −78 °C; 90 min, then r.t., 16 h; iii. LiHMDS, THF, −78 °C, 2 h, r.t., 18 h, 22 %. (b) i. LiHMDS, THF, −78 °C, 30 min; ii. 3‐halo‐2‐(halomethyl)prop‐1‐enes 40a‐c, THF, −78 °C; 90 min; iii. LiHMDS, THF, −78 °C, 2 h, r.t., 18 h, 26–52 %.

Conclusions

Different strategies were investigated to obtain 2,6‐bridged piperazine derivatives 8 with various functional groups in the third carbon bridge. For this purpose, at first a method was developed to prepare piperazine‐2,6‐diones 12 and 17 in high and reproducible yields. These piperazine‐2,6‐diones 12 and 17 contain different orthogonal protective groups at the N‐atoms.

The first approach made use of a Dieckmann analogous cyclization of piperazinediones 18 and 19 with an acetate side chain leading to bicyclic ethyl silyl ketals 20 and 21, although in low yields.

Cyclization of sulfinylimines 33 and 34 afforded the 3,9‐diazabicyclo[3.3.1]nonanes 35 and 36 bearing a sulfinamido group in the C3‐bridge in 66 % (35) and 69 % (36) yields. Both compounds were obtained as mixtures of four diastereomers. It has to be noted that the sulfinylimino group is an ideal functional group to initiate this cyclization, since the intramolecular aldol reaction of aldehyde 31 led to the bicyclic alcohol 37 in only 10 % yield.

Two one‐step syntheses of the bicyclic compounds 39 and 41 employed the linear and branched allylic dihalides 38 and 40. The bicyclic system 39 with an additional vinyl group at the C2‐bridge and 41 with a methylene moiety at the C3‐bridge were obtained in 22 % (39) and 52 % (41) yield, respectively. The vinyl and methylene moiety at the carbon bridge will allow the introduction of various substituents and functional groups at the carbon bridge.

Altogether, bridged piperazines with a mixed ketal (20,21), an OH moiety (37) and a vinyl group (39) at the carbon bridge were obtained in low yields, whereas piperazines with a three‐carbon bridge bearing a sulfinamido group (35,36) and a methylene moiety (41) were obtained in high yields. The 3,9‐diazabicyclo[3.3.1]nonanes 35, 36 and 41 will be exploited for synthesis of pharmacologically active compounds.

Experimental Section

Chemistry, General Methods

Oxygen and moisture sensitive reactions were carried out under nitrogen, dried with silica gel with moisture indicator (orange gel, VWR, Darmstadt, Germany) and in dry glassware (Schlenk flask or Schlenk tube). Temperature was controlled with dry ice/acetone (−78 °C/−25 °C), ice/water (0 °C), Cryostat (Julabo TC100E‐F, Seelbach, Germany), magnetic stirrer MR 3001K (Heidolph, Schwalbach, Germany) or RCT CL (IKA, Staufen, Germany), together with temperature controller EKT HeiCon (Heidolph) or VT‐5 (VWR) and PEG or silicone bath. All solvents were of analytical or technical grade quality. Demineralized water was used. CH2Cl2 was distilled from CaH2; THF was distilled from sodium/benzophenone; MeOH was distilled from magnesium methanolate. Thin layer chromatography (tlc): tlc silica gel 60 F254 on aluminum sheets (VWR). Flash chromatography (fc): Silica gel 60, 40–63 μm (VWR); parentheses include: diameter of the column (Ø), length of the stationary phase (l), fraction size (v) and eluent. Automated flash chromatography: Isolera™ Spektra One (Biotage®); parentheses include: cartridge size, flow rate, eluent, fractions size was always 20 mL. Melting point: Melting point system MP50 (Mettler Toledo, Gießen, Germany), open capillary, uncorrected. MS: MicroTOFQII mass spectrometer (Bruker Daltonics, Bremen, Germany); deviations of the found exact masses from the calculated exact masses were 5 ppm or less; the data were analyzed with DataAnalysis® (Bruker Daltonics). NMR: NMR spectra were recorded in deuterated solvents on a AV300 (Bruker), DPX (Bruker), AV400 (Bruker), AS400 mercury plus NMR spectrometer (Varian), a 600 MHz unity plus NMR spectrometer (Varian), Agilent DD2 400 MHz and 600 MHz spectrometers (Agilent, Santa Clara CA, USA); chemical shifts (δ) are reported in parts per million (ppm) against the reference substance tetramethylsilane and calculated using the solvent residual peak of the undeuterated solvent; coupling constants are given with 0.5 Hz resolution; assignment of 1H and 13C NMR signals was supported by 2‐D NMR techniques where necessary.IR: FT/IR IR Affinity®‐1 spectrometer (Shimadzu, Düsseldorf, Germany) using ATR technique. Optical rotation: UniPol L1000 (Schmidt+Haensch); 1.0 dm tube; concentration c in g/100 mL; T=20 °C; wavelength 589 nm (D‐line of Na light); the unit of the specific rotation ([α]D T grad.mL dm−1 g−1) is omitted for clarity.

HPLC

Equipment 1: Pump: L‐7100, degasser: L‐7614, autosampler: L‐7200, UV detector: L‐7400, interface: D‐7000, data transfer: D‐line, data acquisition: HSM‐Software (all from Merck Hitachi, Darmstadt, Germany); Equipment 2: Pump: LPG‐3400SD, degasser: DG‐1210, autosampler: ACC‐3000T, UV‐detector: VWD‐3400RS, interface: DIONEX UltiMate 3000, data acquisition: Chromeleon 7 (equipment and software from Thermo Fisher Scientific, Lauenstadt, Germany); column: LiChrospher® 60 RP‐select B (5 μm), LiChroCART® 250–4 mm cartridge; flow rate: 1.0 mL/min; injection volume: 5.0 μL; detection at λ=210 nm; solvents: A: demineralized water with 0.05 % (V/V) trifluoroacetic acid, B: CH3CN with 0.05 % (V/V) trifluoroacetic acid; gradient elution (% A): 0–4 min: 90 %; 4–29 min: gradient from 90 % to 0 %; 29–31 min: 0 %; 31–31.5 min: gradient from 0 % to 90 %; 31.5–40 min: 90 %. Unless otherwise mentioned, the purity of all test compounds is greater than 95 %.

Synthetic Procedures

Diethyl 2,2‘‐(N‐benzyloxycarbonylimino)diacetate (10a)

Under ice‐cooling, benzyl chloroformate (10.8 mL, 75.68 mmol) was added slowly to a solution of diethyl iminodiacetate 9 (13.0 g, 68.80 mmol) and NEt3 (10.6 mL, 75.68 mmol) in CH2Cl2. The mixture was warmed to rt and stirred for 18 h. Then the solvent was evaporated in vacuum. The residue was purified by fc (cyclohexane:ethyl acetate=3 : 1, Ø=8.0 cm, l=8.0 cm, V=100 mL, Rf 0.17) to yield a colorless oil. Yield 15.6 g (70 %). C16H21NO6 (323.1). 1H NMR (300 MHz, CDCl3): δ (ppm)=1.21 (t, J=7.1 Hz, 3H, OCH2CH 3), 1.27 (t, J=7.1 Hz, 3H, OCH2CH 3), 4.10 (s, 2H, NCH2CO2), 4.14 (q, J=7.1 Hz, 2H, OCH 2CH3), 4.17 (s, 2H, NCH2CO2), 4.20 (q, J=7.1 Hz, 2H, OCH 2CH3), 5.15 (s, 2H, PhCH2O), 7.27–7.39 (m, 5H, Harom.). 13C NMR (300 MHz, CDCl3): δ (ppm)=14.2 (1C, OCH2 CH3), 14.3 (1C, OCH2 CH3), 49.3 (1C, NCH2CO2), 49.5 (1C, NCH2CO2), 61.4 (1C, OCH2CH3), 61.5 (1C, OCH2CH3), 68.0 (1C, OCH2Ph), 127.9 (2C, C‐2phenyl, C‐6phenyl), 128.2 (1C, C‐4phenyl), 128.6 (2C, C‐3phenyl, C‐5phenyl), 136.2 (1C, C‐1phenyl), 156.1 (1C, OCO2N), 169.5 (1C, NCH2 CO2), 169.6 (1C, NCH2 CO2). FT‐IR: ṽ (cm−1)=3062 (w, v, C−H, arom.), 2982 (m, v, C−H, alkyl), 1744 (s, v, C=O, ester), 1708 (s, v, C=O, carbamate), 737, 698 (m, δ, C−H, arom.). MS (APCI): calcd. for C16H21NO6H+ 324.1442, found 324.1377. HPLC: purity 98.4 %, tR=19.44 min.

Diethyl 2,2‘‐(N‐benzoylimino)diacetate (10b)

Diethyl iminodiacetate 9 (1.0 g, 5.29 mmol) was dissolved in CH2Cl2 (30 mL) and NEt3 (535 mg, 5.29 mmol) was added. Then benzoyl chloride (817 mg, 5.81 mmol) was added. The reaction mixture was stirred at rt for 24 h. The solution was washed with H2O (4×), the combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. The remaining residue was purified by fc (Ø=4.5 cm, h=23 cm, V=20 mL, cyclohexane:ethyl acetate=3 : 1, Rf 0.18) to obtain a pale yellow oil. Yield 1.39 g (90 %). C15H19NO5 (293.3). 1H NMR (400 MHz, CDCl3): δ (ppm)=1.26 (t, J=7.1 Hz, 3H, OCH2CH 3), 1.31 (t, J=7.1 Hz, 3H, OCH2CH 3), 4.11 (s, 2H, NCH2CO2), 4.21 (q, J=7.1 Hz, 2H, OCH 2CH3), 4.26 (q, J=7.1 Hz, 2H, OCH 2CH3), 4.32 (s, 2H, NCH2CO2), 7.37–7.47 (m, 5H, Harom.). FT‐IR: ṽ (cm−1)=2983 (w, v, C−H, alkyl), 1739 (s, v, C=O, ester), 1650 (s, v, C=O, amide), 701 (m, δ, C−H, arom.). MS (ESI): 609 [(2×M+Na)+, 100], 587 [(2×M+H)+, 14].

2,2′‐(N‐Benzyloxycarbonylimino)diacetic acid (11a)

The diester 10a (14.68 g, 45.46 mmol) was dissolved in a mixture of 2 M NaOH (200 mL) and EtOH (200 mL). The mixture was stirred for 18 h at rt. Then this mixture was extracted with Et20 (300 mL) once. Conc. HCl was added to the aqueous layer until pH 1 and the aqueous layer was extracted with Et20 (8×). The organic layers were dried (Na2SO4) and the solvent was removed in vacuum. The obtained oil was dried in high vacuum over night to yield a colorless viscous oil. Yield 10.97 g (90 %). C12H13NO6 (267.0). 1H NMR (300 MHz, DMSO): δ (ppm)=3.99 (s, 2H, NCH2CO2), 4.02 (s, 2H, NCH2CO2), 5.08 (s, 2H, PhCH2O), 7.27–7.41 (m, 5H, Hphenyl), 12.75 (s, 2H, CO2H). 13C NMR (300 MHz, DMSO): δ (ppm)=49.2 (1C, NCH2CO2), 49.6 (1C, NCH2CO2), 66.6 (1C, OCH2Ph), 127.2 (2C, C‐2phenyl, C‐6phenyl), 127.8 (1C, C‐4phenyl), 128.4 (2C, C‐3phenyl, C‐5phenyl), 136.7 (1C. C‐1phenyl), 155.6 (1C, OCO2N), 170.9 (1C, NCH2 CO2), 171.0 (1C, NCH2 CO2). FT‐IR: ṽ (cm−1)=3600–2300 (s, v, O−H, acid), 3037 (w, v, C−H, arom.), 2987 (m, v, C−H, alkyl), 1693 (s, v, C=O, acid), 737, 696 (m, δ, C−H, mono‐substituted arom.). A signal for the C=O moiety of the carbamate cannot be detected. MS (APCI): calcd. for C12H13NO6H+ 268.0821, found 268.0847. HPLC: purity 99.1 %, tR=12.21 min.

2,2‘‐(N‐Benzoylimino)diacetic acid (11b)

The diester 10b (839 mg, 2.86 mmol) was dissolved in a mixture of 2 M NaOH (25 mL) and EtOH (25 mL). The mixture was stirred for 6 h at rt. Then this mixture was acidified with 1 M HCl until pH 1. The aqueous layer was extracted with Et2O (6×). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo to obtain a colorless viscous oil. Yield 608 mg (90 %). C15H19NO5 (237.2). 1H NMR (400 MHz, CDCl3): δ (ppm)=3.97 (s, 2H, NCH2CO2), 4.13 (s, 2H, NCH2CO2), 7.29–7.33 (m, 2H, 3‐Hphenyl, 5‐Hphenyl), 7.43–7.50 (m, 3H, 2‐Hphenyl, 4‐Hphenyl, 6‐Hphenyl). FT‐IR: ṽ (cm−1)=3600–2300 (s, v, O−H, acid), 2925 (s, v, C−H, alkyl), 1719, (s, v, C=O, acid), 1596 (s, v, C=O, amide), 700 (m, δ, C−H, arom.). MS (ESI, negative mode): 473 [(2×M−H)−, 100], 236 [(M−H)−, 89].

Benzyl 4‐(4‐methoxybenzyl)‐3,5‐dioxopiperazine‐1‐carboxylate (12a)

A solution of the diacid 11a (11.06 g, 41.40 mmol) in THF (250 mL) was heated to reflux in a three‐neck‐flask (Two necks sealed with rubber septa.). Then a solution of carbonyldiimidazole (6.71 g, 41.40 mmol) in acetonitrile (20 mL) was added slowly over 30 min. The mixture was heated to reflux for 90 min. Subsequently a solution of p‐methoxybenzylamine (5.37 mL, 41.40 mmol) in THF (20 mL) was added slowly over 30 min and the mixture was heated to reflux for 90 min. Subsequently a solution of carbonyldiimidazole (13.42 g, 82.80 mmol) in acetonitrile (50 mL) was added slowly to the reaction mixture over 30 min. The mixture was heated to reflux for 60 h. Then most of the solvent was removed in vacuum. The residue was dissolved in Et2O and 2 M HCl was added. The mixture was extracted with Et2O (2×), then 5 M NaOH was added to the aqueous layer until pH 12. The aqueous layer was extracted with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuum. The residue was purified by fc (cyclohexane:ethyl acetate=7 : 3, Ø=8.0 cm, l=8.0 cm, V=100 mL) to obtain a pale yellow solid. (Rf 0.48, cyclohexane:ethyl acetate=1 : 1): Pale yellow solid, mp. 71 °C. Yield 10.37 g (68 %). C20H20N2O5 (368.1). 1H NMR (300 MHz, CDCl3): δ (ppm)=3.78 (s, 3H, OCH3), 4.39 (s, 4H, 2‐CH2, 6‐CH2), 4.88 (s, 2H, NCH2Ph), 5.15 (s, 2H, PhCH2O), 6.82 (d, J=8.8 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.31–7.41 (m, 5H, Hphenyl), 7.34 (d, J=8.8 Hz, 2H, 2‐HPMB, 6‐HPMB). 13C NMR (300 MHz, CDCl3): δ (ppm)=42.4 (1C, NCH2Ar), 47.3 (2C, C‐2, C‐6), 55.4 (1C, OCH3), 68.5 (1C, OCH2Ph), 114.0 (2C, C‐3PMB, C‐5PMB), 128.4 (1C, C‐1PMB), 128.5 (2C, C‐2phenyl, C‐6phenyl), 128.8 (2C, C‐3phenyl, C‐5phenyl), 128.8 (1C, C‐4phenyl), 131.0 (2C, C‐2PMB, C‐6PMB), 135.5 (1C, C‐1phenyl), 154.0 (1C, OC(=O)N), 159.4 (1C, C‐4PMB), 167.8 (2C, COimide). FT‐IR: ṽ (cm−1)=3067 (w, v, C−H, arom.), 2961 (w, v, C−H, alkyl), 1738 (w, v, C=O, imide), 1676 (s, v, C=O, imide), 820 (w, δ, C−H, para‐substituted arom.), 747, 694 (m, δ, C−H, mono‐substituted arom.). A signal for the C=O of the carbamate group cannot be detected. MS (APCI): calcd. for C20H20N2O5 368.1372, found 368.1362. HPLC: purity 98.9 %, tR=20.22 min.

4‐Benzoyl‐1‐(4‐methoxybenzyl)piperazine‐2,6‐dione (12b)

A solution of the diacid 11b (2.75 g, 11.60 mmol) in THF (150 mL) was heated to reflux in a three‐neck‐flask (Two necks sealed with rubber septa.). Then a solution of carbonyldiimidazole (1.88 g, 11.60 mmol) in acetonitrile (30 mL) was added slowly over 30 min. The mixture was stirred for 60 min. Subsequently a solution of p‐methoxybenzylamine (1.51 mL, 11.60 mmol) in THF (10 mL) was added slowly over 30 min and the mixture was stirred for 60 min. A solution of carbonyldiimidazole (3.76 g, 23.20 mmol) in acetonitrile (50 mL) was added slowly to the reaction mixture over 30 min. The mixture was refluxed for 18 h. Then most of the solvent was removed in vacuum. The remaining residue was dissolved in CH2Cl2 and 1 M HCl was added. The mixture was extracted with CH2Cl2 (3×). The combined CH2Cl2 layers were alkalized with 2 M NaOH and washed with CH2Cl2 (3×). The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuum. The residue was purified by fc (cyclohexane:ethyl acetate=7 : 3, Ø=8.0 cm, l=10.0 cm, V=100 mL) to obtain a pale yellow oil. (Rf 0.35, cyclohexane:ethyl acetate=1 : 1): Pale yellow oil. Yield 2.36 g (60 %). C19H18N2O4 (338.4). 1H NMR (400 MHz, CDCl3): δ (ppm)=3.78 (s, 3H, OCH3), 4.51 (s, broad, 4H, 2×NCH2CO), 4.89 (s, 2H, NCH2Ar), 6.83 (d, J=8.7 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.34 (d, J=8.6 Hz, 2H, 2‐HPMB, 6‐HPMB), 7.37–7.41 (m, 2H, 3‐Hbenzoyl, 5‐Hbenzoyl), 7.41–7.53 (m, 3H, 2‐Hbenzoyl, 4‐Hbenzoyl, 6‐Hbenzoyl). 13C NMR (400 MHz, CDCl3): δ (ppm)=42.6 (1C, NCH2Ar), 48.7 (s, broad, 2C, NCH2CO), 55.4 (1C, OCH3), 114.0 (2C, C‐3PMB, C‐5PMB), 127.6 (2C, C‐2benzoyl, C‐6benzoyl), 128.4 (1C, C‐1PMB), 129.1 (2C, C‐3benzoyl, C‐5benzoyl), 130.9 (1C, C‐4benzoyl), 131.3 (2C, C‐2PMB, C‐6PMB), 133.1 (1C, C‐1benzoyl), 159.4 (1C, C‐4PMB), 167.5 (1C, NCH2 CO), 170.2 (1C, NCH2 CO). FT‐IR: ṽ (cm−1)=3060 (w, v, C−H, arom.), 2927 (m, v, C−H, alkyl), 1737 (m, v, C=O, imide), 1683 (s, v, C=O, imide), 810 (m, δ, C−H, para‐substituted arom.), 721, 701 (m, δ, C−H, mono‐substituted arom.). MS (EI): 338 [M+, 100].

4‐Benzyl‐1‐(4‐methoxybenzyl)piperazine‐2,6‐dione (12c)

N‐Ethyl‐N,N‐diisopropylamine (15.8 mL, 88.1 mmol) and benzyl bromide (1.58 mL, 13.2 mmol) were added to a solution of the secondary amine 12d (2.58 g, 11.01 mmol) in acetonitrile (60 mL). The mixture was heated to reflux and stirred for 18 h. The solvent was removed in vacuum almost completely. The remaining solution was dissolved in CH2Cl2 and saturated NaHCO3 solution and mixture was washed with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuum. The residue was purified by fc (cyclohexane:ethyl acetate=1 : 1, Ø=5.0 cm, l=8.5 cm, V=30 mL) to obtain a pale yellow solid. (Rf 0.63, cyclohexane:ethyl acetate=1 : 1): Yellow solid. Yield 2.99 g (84 %). C19H20N2O3 (324.2). 1H NMR (300 MHz, CDCl3): δ (ppm)=3.39 (s, 4H, NCH2CO), 3.59 (s, 2H, NCH2Ph), 3.78 (s, 3H, OCH3), 4.86 (s, 2H, NCH2Ar), 6.82 (d, J=8.7 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.24 (dd, J=6.1/4.4 Hz, 2H, 2‐Hbenzyl, 6‐Hbenzyl), 7.28–7.39 (m, 3H, 3‐Hbenzyl, 4‐Hbenzyl, 5‐Hbenzyl), 7.34 (d, J=8.7 Hz, 2H, 2‐HPMB, 6‐HPMB). 13C NMR (300 MHz, CDCl3): δ (ppm)=41.9 (1C, NCH2Ar), 55.4 (2C, NCH2CO), 56.5 (1C, OCH3), 60.9 (1C, NCH2Ph), 113.9 (2C, C‐3PMB, C‐5PMB), 128.2 (1C, C‐1PMB), 128.8 (2C, C‐2benzyl, C‐6benzyl), 129.0 (2C, C‐3benzyl, C‐5benzyl), 129.3 (1C, C‐4benzyl), 130.7 (2C, C‐2PMB, C‐6PMB), 135.4 (1C, C‐1benzyl), 159.2 (1C, C‐4PMB), 170.0 (2C, NCH2 CO). FT‐IR: ṽ (cm−1)=3062 (w, v, C−H, arom.), 2958 (m, v, C−H, alkyl), 1736 (s, v, C=O, imide), 1679 (s, v, C=O, imide), 822 (m, δ, C−H, para‐substituted arom.), 742, 700 (m, δ, C−H, mono‐substituted arom.). MS (APCI): calcd. for C19H20N2O3H+ 325.1547, found 325.1582. HPLC: purity 95.1 %, tR=20.19 min.

1‐(4‐Methoxybenzyl)piperazine‐2,6‐dione (12d)

The imide 12a (1.01 g, 2.73 mmol) was dissolved in THF (50 mL) and Pd/C (10 %, 0.11 mg) was added. The mixture was stirred under H2 atmosphere (1 atm) at rt for 1 h. The mixture was filtered through Celite® with THF and the solvent was evaporated in vacuum. The residue was purified by fc (cyclohexane:ethyl acetate=1 : 1→100 % ethyl acetate, Ø=3.0 cm, l=4.5 cm, V=30 mL) to obtain a pale yellow solid. (Rf 0.01, cyclohexane:ethyl acetate=1 : 1). mp: 131–132 °C. Yield 0.61 g (95 %). C12H14N2O3 (234.1). 1H NMR (300 MHz, CDCl3): δ (ppm)=3.70 (s, 4H, NCH2CO), 3.78 (s, 3H, OCH3), 4.88 (s, 2H, NCH2Ar), 6.82 (d, J=8.7 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.35 (d, J=8.7 Hz, 2H, 2‐HPMB, 6‐HPMB). 13C NMR (300 MHz, CDCl3): δ (ppm)=41.5 (1C, NCH2Ar), 50.0 (2C, NCH2CO), 55.4 (1C, OCH3), 113.9 (2C, C‐3PMB, C‐5PMB), 129.2 (1C, C‐1PMB), 130.9 (2C, C‐2PMB, C‐6PMB), 159.2 (1C, C‐4PMB), 171.1 (2C, NCH2 CO). FT‐IR: ṽ (cm−1)=3335 (s, v, N−H, amine), 3075 (w, v, C−H, arom.), 2962 (m, v, C−H, alkyl), 1714 (s, v, C=O, imide), 1665 (s, v, C=O, imide), 832 (m, δ, C−H, para‐substituted arom.). MS (APCI): calcd. for C12H14N2O3H+ 235.1077, found 235.1103. HPLC: purity 99.7 %, tR=11.52 min.

N‐(tert‐Butoxycarbonyl)iminodiacetic acid (14)

A mixture of iminodiacetic acid (11.0 g, 83 mmol, 1 eq) and NaHCO3 (27.8 g, 331 mmol, 4 eq) were dissolved in H2O (100 mL) of water. After bubbling finished, THF (100 mL) was added followed by Boc2O (18.0 g, 83 mmol, 1 eq). The mixture was stirred at ambient temperature for 3 d. THF was removed in vacuo and the aqueous layer was washed with Et2O (2×). The pH of the aqueous layer was then adjusted to pH 1 using 6 M HCl. The aqueous layer was extracted with ethyl acetate (4×). The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuo to provide the product. Colorless solid, mp 127–131 °C, (decomposition), yield 14.2 g (74 %). C9H15NO6 (233.2). 1H NMR (400 MHz, CDCl3): δ (ppm)=1.35 (s, 9H, C(CH 3)3), 3.87 (s, 2H, NCH 2COOH), 3.91 (s, 2H, NCH 2COOH), 12.63 (s, 2H, 2×COOH). 13C NMR (101 MHz, CDCl3): δ (ppm)=27.8 (3C, C(CH3)3), 49.1 (1C, NCH2CO), 49.7 (1C, NCH2CO), 79.5 (1C, C(CH3)3), 154.8 (1C, NCOO), 171.18 (1C, COOH), 171.21 (1C, COOH). IR (neat): ṽ (cm−1)=3113 (O−H), 2978 and 2943 (C‐Haliph), 1724 (C=O, acid), 1651 (C=O, carbamate). MS (APCI): m/z=234.0966 (calcd. 234.0972 for C9H16NO6 [M+H]+).

tert‐Butyl 4‐benzyl‐3,5‐dioxopiperazine‐1‐carboxylate (15)

A solution of the diacid 14 (15.0 g, 64 mmol, 1 eq) in THF (250 mL) was heated to reflux in a three‐necked‐flask. Two necks were sealed with rubber septum. Then, a solution of carbonyldiimidazole (10.0 g, 64 mmol, 1 eq) in CH3CN (60 mL) was added slowly over 30 min. The mixture was stirred for 60 min. Subsequently, a solution of benzylamine (7.03 mL, 64 mmol, 1 eq) in THF (20 mL) was added slowly over 30 min and the mixture was stirred for 60 min. A solution of carbonyldiimidazole (21.0 g, 129 mmol, 2 eq) in CH3CN (100 mL) was added slowly to the reaction mixture over 30 min. The mixture was heated to reflux for 18 h. Then, most of the solvent was removed in vacuo. The remaining residue was dissolved in ethyl acetate and 1 M HCl was added. The mixture was extracted with ethyl acetate (3×). 2 M NaOH was added to the combined ethyl acetate layers and the mixture was extracted with ethyl acetate (3×). The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuo. The residue was purified by fc (cyclohexane: ethyl acetate=91:9→83 : 17, ø=5 cm, l=12 cm, V=100 mL). (Rf 0.66, cyclohexane:ethyl acetate=67 : 33). Colorless solid, mp 147–149 °C, yield 12.1 g (62 %). C16H20N2O4 (304.3). 1H NMR (400 MHz, CDCl3): δ (ppm)=1.45 (s, 9H, C(CH 3)3), 4.32 (s, 4H, NCH 2CO), 4.95 (s, 2H, NCH 2Ph), 7.25–7.32 (m, 3H, 3‐CHbenzyl, 4‐CHbenzyl, 5‐CHbenzyl), 7.35–7.39 (m, 2H, 2‐CHbenzyl, 6‐CHbenzyl). 13C NMR (101 MHz, CDCl3): δ (ppm)=28.3 (3C, C(CH3)3), 42.9 (1C, NCH2Ph), 47.3 (2C, NCH2CO), 82.4 (1C, C(CH3)3), 128.0 (1C, C‐4benzyl), 128.7 (2C, C‐3benzyl, C‐5benzyl), 129.2 (2C, C‐2benzyl, C‐6benzyl), 136.3(1C, C‐1benzyl), 153.2 (1C, NCOO), 168.2 (2C, NCOCH2).IR (neat): ṽ (cm−1)=2982 (C‐Haliph), 1678 (C=O), 856 (C‐Harom). MS (APCI): m/z=305.1408 (calcd. 305.1496 for C16H21N2O4 [M+H]+). Purity (HPLC): 99.8 % (tR=20.9 and 21.1 min).

1‐Benzylpiperazine‐2,6‐dione (16)

A solution of 15 (70 mg, 0.23 mmol, 1 eq) in CH2Cl2 (5 mL) was cooled to 0 °C. CF3COOH (2 mL) was added slowly to the mixture. The mixture was stirred overnight at rt. The solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (20 mL) and the mixture was washed with saturated NaHCO3 solution (20 mL). The aqueous layer was extracted with CH2Cl2 (4×). The organic layers were combined and dried (Na2SO4). The solvent was evaporated in vacuo and the residue was purified by fc (cyclohexane:ethyl acetate:dimethylethylamine=50 : 50:1→25 : 75 : 1, ø=1 cm, l=10 cm, V=7 mL). (Rf 0.24, cyclohexane:ethyl acetate:dimethylethylamine=20 : 80 : 1): Colorless solid, mp 149–151 °C, yield 12.1 g (99 %). C11H12N2O2 (204.2). 1H NMR (600 MHz, DMSO‐d 6): δ (ppm)=3.59 (s, 4H, NCH 2CO), 4.82 (s, 2H, NCH 2Ph), 7.20–7.27 (m, 3H, 2‐CHbenzyl, 4‐CHbenzyl, 6‐CHbenzyl), 7.27–7.33 (m, 2H, 3‐CHbenzyl, 5‐CHbenzyl). 13C NMR (151 MHz, DMSO‐d 6): δ (ppm)=40.8 (1C, NCH2Ph), 49.1 (2C, NCH2CO), 126.9 (1C, C‐4benzyl), 127.4 (2C, C‐2benzyl, C‐6benzyl), 128.2 (2C, C‐3benzyl, C‐5benzyl), 137.2 (1C, C‐1benzyl), 172.1 (2C, C=O). IR (neat): ṽ (cm−1)=3321 (N−H), 2954, 2924 and 2854 (C‐Haliph), 1724 and 1662 (C=O), 840 (C‐Harom). MS (APCI): m/z=205.0973 (calcd. 205.0972 for C11H13N2O2 [M+H]+). Purity (HPLC): 95.9 % (tR=12.2 min).

1‐Benzyl‐4‐(4‐methoxybenzyl)piperazine‐2,6‐dione (17)

N‐Ethyl‐N,N‐diisopropylamine (24.3 mL, 147 mmol, 3 eq) and 4‐methoxybenzyl chloride (7.0 mL, 52 mmol, 1.05 eq) were added to a solution of the secondary amine 16 (10.0 g, 49 mmol, 1 eq) in CH3CN (100 mL). The mixture was heated to reflux for 18 h. The solvent was removed in vacuo almost completely. The remaining residue was dissolved in CH2Cl2 (100 mL) and saturated NaHCO3 solution (100 mL). The mixture was extracted with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuo. The residue was purified by fc (cyclohexane:ethyl acetate=91:9→75 : 25, ø=6 cm, l=18 cm, V=65 mL). (Rf 0.38, cyclohexane:ethyl acetate= 75 : 25). Pale yellow solid, mp. 51–52 °C, yield 14.0 g (88 %). C19H20N2O3 (324.4). 1H NMR (600 MHz, DMSO‐d 6): δ (ppm)=3.46 (s, 4H, NCH 2CO), 3.58 (s, 2H, NCH 2PhOMe), 3.74 (s, 3H, OCH 3), 4.80 (s, 2H, NCH 2Ph), 6.91 (d, J=8.6 Hz, 2H, 3‐CHPMB, 5‐CHPMB), 7.20 (d, J=8.6 Hz, 2H, 2‐CHPMB, 6‐CHPMB), 7.21–7.23 (m, 2H, 2‐CHbenzyl, 6‐CHbenzyl), 7.23–7.26 (m, 1H, 4‐CHbenzyl), 7.28–7.34 (m, 2H, 3‐CHbenzyl, 5‐CHbenzyl). 13C NMR (151 MHz, DMSO‐d 6): δ (ppm)=41.3 (1C, NCH2Ph), 55.0 (1C, CH3O), 55.1 (2C, NCH2CO), 58.3 (1C, NCH2PhOMe), 113.8 (2C, C‐3PMB, C‐5PMB), 127.1 (1C, C‐4benzyl), 127.5 (2C, C‐2benzyl, C‐6benzyl), 127.8 (1C, C‐1PMB), 128.4 (2C, C‐3benzyl, C‐5benzyl), 130.4 (2C, C‐2PMB, C‐6PMB), 136.9 (1C, C‐1benzyl), 158.7 (1C, C‐4PMB), 170.3 (2C, NCH2 CO). IR (neat): ṽ (cm−1)=2955 and 2931 (C‐Haliph), 1735 and 1682 (C=O), 821 (C‐Harom). MS (APCI): m/z=325.1553 (calcd. 325.1547 for C19H21N2O3 [M+H]+). Purity (HPLC): 97.2 % (tR=21.2 min).

Benzyl 2‐(ethoxycarbonylmethyl)‐4‐(4‐methoxybenzyl)‐3,5‐dioxopiperazine‐1‐carboxylate (18a) and diethyl 2,2‘‐[1‐(benzyloxycarbonyl)‐4‐(4‐methoxybenzyl)‐3,5‐dioxopiperazine‐2,2‐diyl]diacetate (19a)

A solution of the imide 12a (1.02 g, 2.76 mmol) in THF (30 mL) was cooled to −78 °C. Then a 1 M solution of lithium hexamethyldisilazide (LiHMDS, 2.76 mL, 2.76 mmol) was added and the mixture was stirred for 1 h. Ethyl 2‐bromoacetate (0.61 mL, 5.51 mmol) was added and the mixture was stirred at −78 °C for 2 h. The mixture was warmed to rt overnight. The solvent was removed in vacuum and the remaining residue was purified by fc (n‐hexane:ethyl acetate=8/2, Ø=4.0 cm, l=8.5 cm, V=30 mL) to obtain two pale yellow oils. 18a (Rf 0.57, cyclohexane:ethyl acetate=1 : 1): Pale yellow oil. Yield 1.06 g (84 %). C24H26N2O7 (454.1). 1H NMR (300 MHz, CDCl3): δ (ppm)=1.18 (t, J=7.2 Hz, 3H, OCH2CH 3), 2.92 (s, broad, 1H, CHCH 2CO2Et), 3.14 (dd, broad, J=17.3/4.8 Hz, 1H, CHCH 2CO2Et), 3.77 (s, 3H, OCH3), 3.99–4.15 (m, 3H, OCH 2CH3, 2‐CH), 4.90 (d, J=13.8 Hz, 1H, NCH2Ph), 4.91 (s, broad, 2H, 6‐CH2), 4.97 (d, J=13.8 Hz, 1H, NCH2Ph), 5.15 (s, 2H, PhCH2O), 6.81 (d, J=8.8 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.29–7.41 (m, 5H, Hphenyl), 7.32 (d, J=8.8 Hz, 2H, 2‐HPMB, 6‐HPMB). FT‐IR: ṽ (cm−1)=3067 (w, v, C−H, arom.), 2962 (m, v, C−H, alkyl), 1726 (s, v, C=O, ester),1712 (s, v, C=O, carbamate), 1681 (s, v, C=O, imide), 815 (m, δ, C−H, para‐substituted arom.), 735, 698 (m, δ, C−H, mono‐substituted arom.). A second signal for the imide‐C=O group cannot be detected. MS (APCI): calcd. for C24H26N2O7H+ 455.1813, found 455.1969. HPLC: purity 82.6 %, tR=21.24 min. 19a (Rf 0.65, cyclohexane:ethyl acetate=1 : 1): Pale yellow oil. Yield 0.06 g (4 %). C28H32N2O9 (540.2). 1H NMR (300 MHz, CDCl3): δ (ppm)=1.09 (t, J=7.1 Hz, 6H, OCH2CH 3), 3.01 (d, J=17.2 Hz, 2H, 2×CH2CO2), 3.76 (s, 3H, OCH3), 3.82–4.10 (m, 6H, OCH 2CH3, 2×CHCO2), 4.45 (s, 2H, 6‐Hdioxopiperazine), 4.97 (s, 2H, NCH2Ph), 5.14 (s, 2H, PhCH2O), 6.79 (d, J=8.8 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.27–7.42 (m, 5H, Hphenyl), 7.32 (d, J=8.8 Hz, 2H, 2‐HPMB, 6‐HPMB). FT‐IR: ṽ (cm−1)=3062 (w, v, C−H, arom.), 2958 (m, v, C−H, alkyl), 1728 (s, v, C=O, ester), 1706 (s, v, C=O, carbamate), 1675 (s, v, C=O, imide), 819 (m, δ, C−H, para‐substituted arom.), 736, 698 (m, δ, C−H, mono‐substituted arom.). A second signal for the imide‐C=O group cannot be detected. MS (ESI, negative mode): m/z (%)=1103 [(2×M+Na)−, 97], 563 [(M+Na)−, 100].

Ethyl 2‐(1‐benzoyl‐4‐(4‐methoxybenzyl)‐3,5‐dioxopiperazin‐2‐yl)acetate (18b) and diethyl 2,2‘‐(1‐benzoyl‐4‐(4‐methoxybenzyl)‐3,5‐dioxopiperazine‐2,2‐diyl)diacetate (19b)

A solution of the imide 12b (257 mg, 0.76 mmol) in THF (15 mL) was cooled to −78 °C and 0.5 M KHMDS‐solution in THF (1.59 mL, 0.76 mmol) was added. After 30 min ethyl 2‐bromoacetate (168 μL, 1.52 mmol) was added. The reaction mixture was stirred for 1.5 h at −78 °C and then warmed to rt. An excess of 1 M HCl solution was added and the mixture was concentrated in vacuum. The residue was dissolved in CH2Cl2 and washed with water (4×). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by fc (cyclohexane:ethyl acetate=8 : 2, Ø=3.0 cm, l=12.0 cm, V=20 mL) to obtain two pale yellow oils 18b and 19b. 18b (Rf 0.42, cyclohexane:ethyl acetate=1 : 1): Pale yellow oil. Yield 254 mg (79 %). C23H24N2O6 (424.5). 1H NMR (400 MHz, CDCl3): δ (ppm)=1.26 (t, J=7.1 Hz, 3H, OCH2CH 3), 3.00 (d, broad, J=16.9 Hz, 1H, CH2CO2Et), 3.20 (d, broad, J=16.3 Hz, 1H, CH2CO2Et), 3.79 (s, 3H, OCH3), 4.12 (q, J=7.1 Hz, 2H, OCH 2CH3), 4.38 (d, J=16.3 Hz, 1H, NCH2CO), 4.61 (s, broad, 1H, NCH2CO), 4.94 (s, 2H, NCH2Ar), 5.48 (s, broad, 1H, NCHCO), 6.83 (d, J=8.7 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.32 (d, J=8.6 Hz, 2H, 2‐HPMB, 6‐HPMB), 7.36 (dd, J=8.0/1.3 Hz, 2H, 3‐Hbenzoyl, 5‐Hbenzoyl), 7.40–7.53 (m, 3H, 2‐Hbenzoyl, 4‐Hbenzoyl, 6‐Hbenzoyl). 13C NMR (400 MHz, CDCl3): δ (ppm)=14.2 (1C, OCH2 CH3), 36.5 (1C, C‐2), 42.9 (1C, NCH2Ar), 51.1 (1C, NCH2CO), 55.4 (1C, OCH3), 60.5 (1C, NCHCO), 61.8 (1C, OCH2CH3), 114.0 (2C, C‐3PMB, C‐5PMB), 127.4 (2C, C‐2benzoyl, C‐6benzoyl), 128.4 (1C, C‐1PMB), 129.0 (2C, C‐3benzoyl, C‐5benzoyl), 130.5 (1C, C‐4benzoyl), 131.1 (2C, C‐2PMB, C‐6PMB), 133.6 (1C, C‐1benzoyl), 159.3 (1C, C‐4PMB), 167.4 (1C, CObenzoyl), 167.4 (1C, NCH2 CO), 170.0 (1C, NCH2 CO), 171.3 (1C, CH2 CO2Et). FT‐IR: ṽ (cm−1)=3062 (w, v, C−H, arom.), 2940 (w, v, C−H, alkyl), 1731 (m, v, C=O, imide), 1683 (s, v, C=O, imide), 1652 (s, v, C=O, amide), 811 (m, δ, C−H, para‐substituted arom.), 722, 702 (m, δ, C−H, mono‐substituted arom.). MS (EI): 424 [M+, 100], 319 [(M–C6H5CO)+, 70], 303 [(M‐H3COC6H4CH2)+, 98]. 19b (Rf 0.52, cyclohexane:ethyl acetate=1 : 1): Pale yellow oil. Yield 22 mg (6 %). C27H30N2O8 (510.5). 1H NMR (400 MHz, CDCl3): δ (ppm)=1.17 (t, J=7.1 Hz, 6H, 2×OCH2CH 3), 3.09 (d, J=17.4 Hz, 2H, 2× CH2CO2Et), 3.76 (s, 3H, OCH3), 4.00 (q, J=7.2 Hz, 4H, 2× OCH 2CH3), 4.16 (d, J=17.4 Hz, 2H, 2× CH2CO2Et), 4.36 (s, 2H, NCH2CO), 4.94 (s, 2H, NCH2Ar), 6.80 (d, J=8.6 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.22–7.25 (m, 2H, 3‐Hbenzoyl, 5‐Hbenzoyl), 7.31 (d, J=8.6 Hz, 2H, 2‐HPMB, 6‐HPMB), 7.37–7.47 (m, 3H, 2‐Hbenzoyl, 4‐Hbenzoyl, 6‐Hbenzoyl). 13C NMR (400 MHz, CDCl3): δ (ppm)=14.2 (2C, OCH2 CH3), 31.1 (1C, CH2CO2Et), 41.1 (1C, CH2CO2Et), 43.8 (1C, NCH2Ar), 51.7 (1C, NCH2CO), 55.3 (1C, OCH3), 60.6 (1C, NCCO), 61.2 (1C, OCH2CH3), 62.5 (1C, OCH2CH3), 113.7 (2C, C‐3PMB, C‐5PMB), 126.2 (2C, C‐2benzoyl, C‐6benzoyl), 128.3 (1C, C‐1PMB), 129.1 (2C, C‐3benzoyl, C‐5benzoyl), 130.3 (1C, C‐4benzoyl), 130.5 (2C, C‐2PMB, C‐6PMB), 136.2 (1C, C‐1benzoyl), 159.1 (1C, C‐4PMB), 166.4 (1C, CObenzoyl), 170.5 (1C, NCH2 CO), 171.6 (1C, NCH2 CO), 172.9 (1C, CH2 CO2). FT‐IR: ṽ (cm−1)=3062 (w, v, C−H, arom.), 2936 (w, v, C−H, alkyl), 1727 (s, v, C=O, imide), 1676 (s, v, C=O, imide), 1651 (s, v, C=O, amide), 818 (m, δ, C−H, para‐substituted arom.), 728, 702 (m, δ, C−H, mono‐substituted arom.). MS (EI): 510 [M+, 100], 465 [(M‐OCH2CH3)+, 16], 405 [(M–C6H5CO)+, 15].

Ethyl 2‐(1‐benzyl‐4‐(4‐methoxybenzyl)‐3,5‐dioxopiperazin‐2‐yl)acetate (18c)

A solution of the imide 12c (21 mg, 0.07 mmol) in THF (5 mL) was cooled to −78 °C. Then a 1 M solution of lithium hexamethyldisilazide (LiHMDS, 0.07 mL, 0.07 mmol) was added and the mixture was stirred for 1 h. Ethyl 2‐bromoacetate (15 μL, 0.13 mmol) was added and the mixture was stirred at −78 °C for 1 h. The mixture was warmed to rt. The solvent was removed in vacuum and the remaining residue was purified by fc (n‐hexane:ethyl acetate=8/2, Ø=1.0 cm, l=4.0 cm, V=5 mL) to obtain a yellow oil. (Rf 0.62, cyclohexane:ethyl acetate=1 : 1): Yellow oil. Method A: Yield 0.32 g (85 %). Method B; Yield 24 mg (89 %). C23H26N2O5 (410.1). 1H NMR (300 MHz, CDCl3): δ (ppm)=1.23 (t, J=7.1 Hz, 3H, OCH2CH 3), 2.87 (dd, J=15.6/7.5 Hz, 1H, CHCH 2CO2Et), 2.96 (dd, J=15.6/5.7 Hz, 1H, CHCH 2CO2Et), 3.40 (d, J=17.6 Hz, 1H, 6‐Hdioxoperazine), 3.62 (d, J=12.9 Hz, 1H, NCH2Ar), 3.67 (d, J=17.6 Hz, 1H, 6‐Hdioxopiperazine), 3.68 (d, J=12.9 Hz, 1H, NCH2Ar), 3.79 (s, 3H, OCH3), 4.04 (t, J=6.8 Hz, 1 H, 2‐Hdioxopiperazine), 4.14 (q, J=7.1 Hz, 2H, OCH 2CH3), 4.84 (d, J=13.8 Hz, 1H, NCH2Ph), 4.90 (d, J=13.8 Hz, 1H, NCH2Ph), 6.83 (d, J=8.8 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.27–7.38 (m, 5H, Hbenzyl) 7.34 (d, J=8.8 Hz, 2H, 2‐HPMB, 6‐HPMB). 13C NMR (300 MHz, CDCl3): δ (ppm)=14.3 (1C, OCH2 CH3), 34.9 (1C, CH2CO2Et), 42.2 (1C, NCH2Ar), 52.4 (1C, NCH2CO), 55.4 (1C, OCH3), 57.7 (1C, NCHCO), 61.1 (1C, OCH2CH3), 61.3 (1C, PhCH2N), 114.0 (2C, C‐3PMB, C‐5PMB), 128.3 (1C, C‐1PMB), 128.8 (1C, C‐4benzyl), 129.2 (2C, C‐2benzyl, C‐6benzyl), 129.7 (2C, C‐3benzyl, C‐5benzyl), 130.7 (2C, C‐2PMB, C‐6PMB), 135.7 (1C, C‐1benzyl), 159.2 (1C, C‐4PMB), 169.6 (1C, NCH2 CO), 170.3 (COester), 171.1 (1C, NCHCO). FT‐IR: ṽ (cm−1)=3062 (w, v, C−H, arom.), 2982 (m, v, C−H, alkyl), 1732 (s, v, C=O, ester), 1679 (s, v, C=O, imide), 819 (m, δ, C−H, para‐substituted arom.), 744, 700 (m, δ, C−H, mono‐substituted arom.). A second signal for the imide‐C=O cannot be detected. MS (APCI): calcd. for C23H26N2O5H+ 411.1914, found 411.1944. HPLC: purity 92.8 %, tR=21.05 min.

(1RS,5SR,6RS)‐8‐Benzyl‐6‐ethoxy‐3‐(4‐methoxybenzyl)‐6‐(trimethylsilyloxy)‐3,8‐diazabicyclo[3.2.1]octane‐2,4‐dione (20c)

A solution of the acetate 18c (145 mg, 0.35 mmol) in THF (15 mL) was cooled to −78 °C and 1.0 M LiHMDS‐solution (531 μL, 0.53 mmol) was added. After 15 min TMS−Cl (157 μL, 1.24 mmol) was added. The reaction mixture was stirred for 1.0 h at −78 °C and then warmed to rt. The solvent was removed in vacuum, the residue dissolved in CH2Cl2 was poured into CH2Cl2/saturated NaHCO3 and extracted four time with CH2Cl2. The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuum. The residue was purified by fc (cyclohexane:ethyl acetate=9 : 1, Ø=2.0 cm, l=8.5 cm, V=20 mL) to obtain a pale yellow oil. (Rf 0.72, cyclohexane:ethyl acetate=1 : 1). Yield 20 mg (12 %). C26H34N2O5Si (482.6). 1H NMR (300 MHz, CDCl3): δ (ppm)=0.02 (s, 9H, Si(CH3)3), 1.16 (t, J=7.1 Hz, 3H, OCH2CH 3), 2.56 (d, J=11.0 Hz, 1H, 7‐CH2), 2.63 (d, J=13.0 Hz, 1H, 7‐CH2), 3.41 (dq, J=9.4/7.0 Hz, 1H, OCH 2CH3), 3.49 (s, 1H, 5‐CH), 3.57 (dq, J=9.4/7.1 Hz, 1H, OCH 2CH3), 3.62 (d, J=12.9 Hz, 1H, NCH2Ph), 3.70 (d, J=13.0 Hz, 1H, NCH2Ph), 3.78 (s, 3H, OCH3), 3.80–3.84 (m, 1H, 1‐CH), 4.79 (d, J=13.6 Hz, 1H, NCH2Ar), 4.85 (d, J=13.7 Hz, 1H, NCH2Ar), 6.84 (d, J=8.8 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.14 (dd, J=7.5/2.0 Hz, 2H, 2‐Hbenzyl, 6‐Hbenzyl), 7.27–7.34 (m, 3H, 3‐Hbenzyl, 4‐Hbenzyl, 5‐Hbenzyl), 7.41 (d, J=8.8 Hz, 2H, 2‐HPMB, 6‐HPMB). FT‐IR: ṽ (cm−1)=3067 (w, v, C−H, arom.), 2925 (m, v, C−H, alkyl), 1736 (m, v, C=O, imide), 1685 (s, v, C=O, imide), 843 (m, δ, C−H, para‐substituted arom.), 739, 697 (m, δ, C−H, mono‐substituted arom.). MS (APCI): calcd. for C26H34N2O5SiH+ 483.2315, found 483.2386. HPLC: purity 83.1 %, tR=23.87 min.

Benzyl (1RS,5RS,7SR)‐6‐ethoxy‐1‐(ethoxycarbonylmethyl)‐3‐(4‐methoxybenzyl)‐2,4‐dioxo‐6‐(trimethylsilyloxy)‐3,8‐diazabicyclo[3.2.1]octane‐8‐carboxylate (21a)

A solution of the diacetate 19a (158 mg, 0.29 mmol) in THF (15 mL) was cooled to −78 °C and 1.0 M LiHMDS‐solution (438 μL, 0.44 mmol) was added. After 15 min TMS−Cl (129 μL, 1.02 mmol) was added. The reaction mixture was stirred for 1.0 h at −78 °C and then warmed to rt. The solvent was removed in vacuum, the remaining residue was purified by fc (cyclohexane:ethyl acetate=8 : 2, Ø=3.0 cm, l=8.0 cm, V=20 mL) to obtain a pale yellow oil. (Rf 0.55, cyclohexane:ethyl acetate=1 : 1). Pale yellow oil. Yield 38 mg (21 %). C31H40N2O9Si (612.7). 1H NMR (400 MHz, CDCl3): δ (ppm)=0.01 (s, 9H, Si(CH3)3), 1.13 (t, J=7.0 Hz, 3H, OCH2CH 3), 1.20 (t, J=7.1 Hz, 3H, CO2CH2CH 3), 2.27 (d, J=13.3 Hz, 1H, 7‐CH2), 2.75 (dd, J=13.9/0.9 Hz, 1H, 7‐CH2), 3.31 (d, J=16.9 Hz, 1H, CH2CO2Et), 3.44 (d, J=16.6 Hz, 1H, CH2CO2Et), 3.43–3‐54 (m, 1H, OCH 2CH3), 3.54–3.63 (m, 1H, OCH 2CH3), 3.74 (s, 3H, OCH3), 4.05–4.16 (m, 2H, CO2CH 2CH3), 4.68 (d, J=13.9 Hz, 1H, NCH2Ar), 4.81 (d, J=13.9 Hz, 1H, NCH2Ar), 4.96 (s, 1H, 5‐CH), 4.96 (d, J=12.2 Hz, 1H, PhCH2O), 5.04 (d, J=12.2 Hz, 1H, PhCH2O), 6.77 (d, J=8.8 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.19–7.25 (m, 2H, 3‐Hphenyl, 5‐Hphenyl), 7.28–7.38 (m, 5H, 2‐Hphenyl, 4‐Hphenyl, 6‐Hphenyl, 2‐HPMB, 6‐HPMB).

Ethyl 2‐[(1RS,5RS,6SR)‐8‐benzoyl‐6‐ethoxy‐3‐(4‐methoxybenzyl)‐2,4‐dioxo‐6‐(trimethylsilyloxy)‐3,8‐diazabicyclo[3.2.1]octan‐1‐yl]acetate (21b)

A solution of the diacetate 19b (42 mg, 0.08 mmol) in THF (10 mL) was cooled to −78 °C and 1.0 M LiHMDS‐solution in THF (123 μL, 0.12 mmol) was added. After 15 min TMS−Cl (36 μL, 0.29 mmol) was added. The reaction mixture was stirred for 1.0 h at −78 °C and then warmed to rt. The solvent was removed in vacuum, the residue was purified by fc (cyclohexane:ethyl acetate=8 : 2, Ø=1.5 cm, l=8.0 cm, V=20 mL) to obtain a pale yellow oil. Yield 5 mg (10 %). C30H38N2O8Si (582.7). 1H NMR (400 MHz, CDCl3): δ (ppm)=0.00 (s, 9H, Si(CH3)3), 1.19 (t, J=7.1 Hz, 3H, COCH2CH 3), 1.20 (t, J=6.9 Hz, 3H, CO2CH2CH 3), 2.32 (d, J=14.0 Hz, 1H, 7‐CH2), 2.87 (d, J=14.1 Hz, 1H, 7‐CH2), 3.28 (dq, J=8.8/6.8 Hz, 1H, OCH 2CH3), 3.50 (d, J=16.4 Hz, 1H, CH2CO2Et), 3.53–3.62 (m, 1H, OCH 2CH3), 3.60 (d, J=16.4 Hz, 1H, CH2CO2Et), 3.78 (s, 3H, OCH3), 4.06–4.17 (m, 2H, CO2CH 2CH3), 4.61 (s, 1H, 5‐CH), 4.73 (d, J=14.0 Hz, 1H, NCH2Ar), 4.90 (d, J=13.9 Hz, 1H, NCH2Ar), 6.83 (d, J=8.6 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.31 (d, J=8.6 Hz, 2H, 2‐HPMB, 6‐HPMB), 7.35–7.51 (m, 5H, Hbenzoyl).

1‐Benzyl 4‐methyl 5‐hydroxy‐2‐[(4‐methoxybenzyl)carbamoyl]‐1,2,3,6‐tetrahydro‐pyridine‐1,4‐dicarboxylate (24a)

A solution of the imide 12a (0.51 g, 1.38 mmol) in THF (20 mL) was cooled to −78 °C. Then a 1 M solution of lithium hexamethyldisilazide (LiHMDS, 1.38 mL, 1.38 mmol) was added and the mixture was stirred for −78 °C for 1 h. Methyl acrylate (0.37 mL, 4.13 mmol) was added and the reaction mixture was stirred at −78 °C for 2 h and then warmed to rt overnight. The reaction was stopped with a few drops of a solution of saturated NaHCO3. The solvent was almost completely evaporated in vacuum and CH2Cl2 and water were added to the residue. The mixture was extracted with CH2Cl2 (4×) and the combined organic layers were dried (Na2SO4). The solvent was removed in vacuum and the residue was purified by fc (cyclohexane:ethyl acetate=7 : 3→1 : 1→100 % ethyl acetate, Ø=3.0 cm, l=8.5 cm, V=30 mL) to obtain a pale yellow solid. (Rf: 0.34, cyclohexane:ethyl acetate=1 : 1). Yield 0.56 g (90 %). C24H26N2O7 (454.5). 1H NMR (300 MHz, CDCl3): δ (ppm)=2.26 (dd, broad, J=15.6/5.9 Hz, 1H, 3‐H), 3.09 (dd, broad, J=27.8/15.9 Hz, 1H, 5‐H), 3.78 (s, 3H, CO2CH3), 3.79 (s, 3H, ArOCH3), 3.85 (d, broad, J=22.0 Hz, 1H, 6‐H), 4.24–4.48 (s, broad, 3H, NHCH2Ar, 2‐H), 4.96 (d, broad, J=22.8 Hz, 1H, 6‐H), 5.14 (d, J=13.0 Hz, 1H, PhCH2O), 5.19 (d, J=13.0 Hz, 1H, PhCH2O), 6.06 (d, broad, J=32.9 Hz, 1H, NH), 6.83 (d, J=8.8 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.12 (d, J=8.8 Hz, 2H, 2‐HPMB, 6‐HPMB), 7.27–7.41 (m, 5H, Hphenyl), 11.96 (s, 1H, OH). 13C NMR (300 MHz, CDCl3): δ (ppm)=22.6 (1C, C‐3), 43.2 (1C, C‐6), 43.4 (1C, NHCH2Ar), 52.0 (1C, CO2 CH3), 52.8 (1C, C‐2), 55.4 (1C, ArOCH3), 68.4 (1C, PhCH2O), 95.1 (1C, C‐4), 110.1 (1C, C‐5), 114.3 (2C, C‐3PMB, C‐5PMB), 128.2 (2C, C‐2phenyl, C‐6phenyl), 128.6 (1C, C‐1PMB), 128.7 (1C, C‐4phenyl), 128.8 (2C, C‐3phenyl, C‐5phenyl), 129.0 (2C, C‐2PMB, C‐6PMB), 135.8 (1C, C‐1phenyl), 159.2 (1C, C‐4PMB), 165.2 (1C, OCON), 169.7 (1C, CO2CH3), 171.7 (1C, CONH). FT‐IR: ṽ (cm−1)=3331 (m, v, O−H), 3067 (w, v, C−H, arom.), 2954 (m, v, C−H, alkyl), 1747 (s, v, C=O, ester), 1704 (s, v, C=O, carbamate), 1665 (s, v, C=O, imide), 808 (m, δ, C−H, para‐substituted arom.), 734, 698 (m, δ, C−H, mono‐substituted arom.). MS (APCI): calcd. for C24H26N2O7H+ 455.1813, found 455.1858.

Methyl 1‐benzoyl‐5‐hydroxy‐2‐[N‐(4‐methoxybenzyl)carbamoyl]‐1,2,3,6‐tetrahydropyridine‐4‐carboxylate (24b)

A solution of the imide 12b (49 mg, 0.15 mmol) in THF (5 mL) was cooled to −78 °C and 0.5 M KHMDS‐solution in THF (290 μL, 0.15 mmol) was added. After 180 min methyl acrylate (39 μL, 0.44 mmol) was added. The reaction mixture was stirred for 2.0 h at −78 °C and then at rt for 16 h. The solvent was removed in vacuum and the residue was purified by fc (cyclohexane:ethyl acetate=7 : 3, Ø=1.5 cm, l=7.5 cm, V=10 mL) to obtain a colorless solid. (Rf 0.21, cyclohexane:ethyl acetate=1 : 1): Colorless solid. Yield 21 mg (34 %). C23H24N2O6 (424.5). The 1H NMR spectrum shows only broad signals. The structure of 24b was identified by subsequent transformation. FT‐IR: ṽ (cm−1)=3316 (m, v, N−H, amide), 3059 (w, v, C−H, arom.), 2953 (m, v, C−H, alkyl), 1733 (s, v, C=O, ester), 1667 (s, v, C=O, amide), 810 (m, δ, C−H, para‐substituted arom.), 730, 702 (m, δ, C−H, mono‐substituted arom.). MS (EI): 424 [M+, 15], 392 [(M‐HOCH3)+, 50], 287 [(M‐H3OC6H4CH2NH2)+, 100].

Methyl 1‐benzyl‐5‐hydroxy‐2‐[(4‐methoxybenzyl)carbamoyl]‐1,2,3,6‐tetrahydro‐pyridine (24c)

A solution of the imide 12c (210 mg, 0.65 mmol) in THF (30 mL) was cooled to −78 °C and 1.0 M LiHMDS‐solution in THF (646 μL, 0.65 mmol) was added. After 180 min methyl acrylate (70 μL, 0.78 mmol) was added. The reaction mixture was stirred for 2.0 h at −78 °C and then at rt for 16 h. The solvent was removed in vacuum and the residue was purified by fc (cyclohexane:ethyl acetate=19 : 1, Ø=2.0 cm, l=9.0 cm, V=10 mL) to obtain a colorless solid. (Rf: 0.38, cyclohexane:ethyl acetate=1 : 1). Yield 50 mg (19 %). C23H26N2O5 (410.5). 1H NMR (300 MHz, CDCl3): δ (ppm)=2.61 (dd, J=16.5/6.0 Hz, 1H, 3‐H), 2.85 (dd, J=16.5/6.3 Hz, 1H, 3‐H), 3.17 (d, J=18.4 Hz, 1H, 6‐H), 3.37 (d, J=18.5 Hz, 1H, 6‐H), 3.48 (t, J=6.1 Hz, 1H, 2‐H), 3.62 (d, J=13.4 Hz, 1H, NCH2Ph), 3.71 (d, J=13.2 Hz, 1H, NCH2Ph), 3.79 (s, 6H, ArOCH3, CO2CH3), 4.36 (dd, J=14.4/5.6 Hz, 1H, NHCH 2Ar), 4.45 (dd, J=14.3/6.3 Hz, 1H, NHCH 2Ar), 6.84 (d, J=8.7 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.07–7.23 (m, 4H, 2‐HPMB, 6‐HPMB, 2‐Hbenzyl, 6‐Hbenzyl) 7.27–7.39 (m, 3H, 3‐Hbenzyl, 4‐Hbenzyl, 5‐Hbenzyl), 11.90 (s, 1H, OH). A signal for the N−H of the amide cannot be detected. 13C NMR (300 MHz, CDCl3): δ (ppm)=19.1 (1C, C‐3), 43.1 (1C, NHCH2Ar), 50.0 (1C, C‐6), 51.8 (1C, CO2 CH3), 55.4 (1C, ArOCH3), 57.0 (1C, C‐2), 60.2 (1C, PhCH2N), 95.2 (1C, C‐4), 114.3 (2C, C‐3PMB, C‐5PMB), 127.1 (2C, C‐2phenyl, C‐6phenyl), 127.8 (1C, C‐1PMB), 128.75 (1C, C‐4phenyl), 128.76 (2C, C‐3phenyl, C‐5phenyl), 129.3 (2C, C‐2PMB, C‐6PMB), 137.5 (1C, C‐1phenyl), 159.2 (1C, C‐4PMB), 167.6 (1C, CO2CH3), 171.1 (1C, C‐5), 172.1 (1C, CONH). FT‐IR: ṽ (cm−1)=3378 (m, v, O−H), 3285 (m, v, N−H, amide), 3062 (w, v, C−H, arom.), 2952 (m, v, C−H, alkyl), 1732 (s, v, C=O, ester), 1666 (s, v, C=O, imide), 817 (m, δ, C−H, para‐substituted arom.), 735, 699 (m, δ, C−H, mono‐substituted arom.). MS (APCI): calcd. for C23H26N2O5H+ 411.1914, found 411.1949.

Ethyl 3‐(1‐benzoyl‐4‐(4‐methoxybenzyl)‐3,5‐dioxopiperazin‐2‐yl)propanoate (25b)

A solution of the imide 12b (155 mg, 0.46 mmol) in THF (10 mL) was cooled to −78 °C and a freshly prepared potassium diisopropylamide solution (KDA, 1 M in THF, 0.46 mL, 0.46 mmol) was added. After 30 min ethyl acrylate (100 μL, 0.92 mmol) was added. The reaction mixture was stirred for 2 h at −78 °C, then warmed to rt and stirred for additional 14 h. Then an excess of 1 M HCl solution was added. The solvent of the mixture was removed in vacuum, the residue was dissolved in CH2Cl2 and washed with water (4×). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by fc (cyclohexane:ethyl acetate=3 : 1, Ø=2.5 cm, l=12.0 cm, V=20 mL) to obtain a pale yellow oil. (Rf 0.40, cyclohexane:ethyl acetate=1 : 1). Yield 30 mg (15 %). C24H26N2O6 (438.5). 1H NMR (400 MHz, CDCl3): δ (ppm)=1.27 (t, J=7.1 Hz, 3H, OCH2CH 3), 2.20 (s, broad, 2H, 3‐CH2), 2.47 (s, broad, 2H, 2‐CH2), 3.79 (s, 3H, OCH3), 4.04–4.15 (m, 2H, OCH 2CH3), 4.25 (s, broad, 1H, NCHCO), 4.86 (d, J=13.7 Hz, 1H, NCH2Ph), 4.91 (d, J=13.8 Hz, 1H, NCH2Ph), 6.83 (d, J=8.8 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.31 (d, J=8.8 Hz, 2H, 2‐HPMB, 6‐HPMB), 7.35 (dd, J=8.1/1.4 Hz, 2H, 3‐Hbenzoyl, 5‐Hbenzoyl), 7.40–7.52 (m, 3H, 2‐Hbenzoyl, 4‐Hbenzoyl, 6‐Hbenzoyl). The signals for the CH2 protons of the piperazine ring appear as very broad signals and are therefore not given. 13C NMR (400 MHz, CDCl3): δ (ppm)=14.3 (1C, OCH2 CH3), 29.9 (1C, C‐1), 32.1 (1C, C‐2), 42.6 (1C, NCH2Ar), 52.8 (1C, NCH2CO), 55.4 (1C, OCH3), 60.6 (1C, NCHCO), 61.1 (1C, OCH2CH3), 114.0 (2C, C‐3PMB, C‐5PMB), 127.4 (2C, C‐2benzoyl, C‐6benzoyl), 128.5 (1C, C‐1PMB), 129.1 (2C, C‐3benzoyl, C‐5benzoyl), 130.6 (1C, C‐4benzoyl), 131.1 (2C, C‐2PMB, C‐6PMB), 133.4 (1C, C‐1benzoyl), 159.4 (1C, C‐4PMB), 166.5 (1C, CObenzoyl), 167.4 (1C, NCH2 CO), 170.6 (1C, NCH2 CO), 177.4 (1C, CH2 CO2). MS (EI): 438 [M+, 20], 333 [(M–C6H5CO)+, 64], 121 [H3COC6H4CH2 +, 100].

Methyl 1‐benzoyl‐2‐(4‐methoxybenzylcarbamoyl)‐4‐methyl‐5‐oxopiperidine‐4‐carboxylate (26b)

A solution of the amide 24b (312 mg, 0.73 mmol) in THF (20 mL) was cooled to −78 °C and 0.5 M KHMDS‐solution in THF (1.47 mL, 0.73 mmol) was added. After 60 min CH3I (181 μL, 2.57 mmol) was added. The reaction mixture was stirred for 2 h at −78 °C and then warmed to rt over 15 h. The solvent was removed in vacuum and the residue was purified by fc (cyclohexane:ethyl acetate=8 : 2, Ø=3.0 cm, l=8.5 cm, V=20 mL) to obtain a colorless oil. (Rf 0.48, cyclohexane:ethyl acetate=3 : 7): Colorless oil. Yield 107 mg (33 %). C24H26N2O6 (438.5). 1H NMR (400 MHz, CDCl3): δ (ppm)=1.42 (s, 3H, CCH3), 2.46 (dd, J=14.7/10.3 Hz, 1H, 3‐CH2), 2.64 (dd, J=14.7/8.6 Hz, 1H, 3‐CH2), 3.75 (s, 3H, CO2CH3), 3.80 (s, 3H, ArOCH3), 4.00 (d, J=19.0 Hz, 1H, 6‐CH2), 4.33 (d, J=18.7 Hz, 1H, 6‐CH2), 4.36 (dd, 14.4/5.9 Hz, 1H, NHCH 2Ar), 4.44 (dd, J=14.6/6.0 Hz, 1H, NHCH 2Ar), 5.24 (t, J=9.4 Hz, 1H, 2‐CH), 6.86 (d, J=8.6 Hz, 2H, 3‐HPMB, 5‐HPMB), 6.99 (s, broad, 1H, NH), 7.19 (d, J=8.5 Hz, 2H, 2‐HPMB, 6‐HPMB), 7.24–7.28 (m, 2H, 3‐Hbenzoyl, 5‐Hbenzoyl), 7.38–7.47 (m, 3H, 2‐Hbenzoyl, 4‐Hbenzoyl, 6‐Hbenzoyl). 13C NMR (400 MHz, CDCl3): δ (ppm)=21.2 (1C, CCH3), 31.2 (1C, C‐3), 43.3 (1C, NCH2Ar), 51.6 (1C, C‐5), 53.1 (1C, CO2 CH3), 53.5 (1C, C‐4), 53.7 (1C, C‐2), 55.5 (1C, ArOCH3), 114.3 (2C, C‐3PMB, C‐5PMB), 127.1 (2C, C‐2benzoyl, C‐6benzoyl), 128.9 (1C, C‐1PMB), 129.0 (2C, C‐3benzoyl, C‐5benzoyl), 130.2 (1C, C‐4benzoyl), 130.8 (2C, C‐2PMB, C‐6PMB), 133.1 (1C, C‐1benzoyl), 159.2 (1C, C‐4PMB), 169.3 (1C, CObenzoyl), 171.5 (1C, CO2CH3), 171.8 (1C, CONH), 202.3 (1C, COketone). FT‐IR: ṽ (cm−1)=3309 (m, v, N−H, amide), 3062 (w, v, C−H, arom.), 2936 (m, v, C−H, alkyl), 1726 (s, v, C=O, ester), 1644 (s, v, C=O, amide), 819 (m, δ, C−H, para‐substituted arom.), 728, 701 (m, δ, C−H, mono‐substituted arom.). MS (EI): 438 [M+, 12], 302 [(M‐H3COC6H4CH2NH)+, 100]. HPLC: purity 82.3 %, tR=18.65 min.

3‐Allyl‐4‐benzyl‐1‐(4‐methoxybenzyl)piperazine‐2,6‐dione (27)

A solution of the imide 12c (1.42 g, 4.38 mmol) in THF (30 mL) was cooled down to −78 °C and a 1 M LiHMDS‐solution in THF (4.38 mL, 5.26 mmol) was added. After 30 min, allyl bromide (0.46 mL, 0.40 mmol) was added. The reaction mixture was stirred at −78 °C for 2 h and then warmed up to rt overnight. The reaction was stopped with an excess of saturated NaHCO3 solution. The solvent was removed in vacuum and the residue was dissolved in CH2Cl2 and washed with saturated NaHCO3 solution (4×). The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuum. The residue was purified by fc (cyclohexane:ethyl acetate=19 : 1, Ø=4.0 cm, l=9.5 cm, V=20 mL) to obtain two pale yellow oils. (Rf 0.58, cyclohexane:ethyl acetate=1 : 1): Pale yellow oil. Yield 0.97 g (61 %). C22H24N2O3 (364.4). 1H NMR (300 MHz, CDCl3): δ (ppm)=2.62 (m, 2H, CHCH 2CH=CH2), 3.38 (d, 17.9 Hz, 1H, 5‐H), 3.54 (t, J=6.9 Hz, 1H, 3‐Hpiperazine‐2,6‐dione), 3.63 (d, J=13.1 Hz, 1H, NCH2Ph), 3.72 (d, J=13.5 Hz, 1H, NCH2Ph), 3.72 (d, J=17.8 Hz, 1H, 5‐H), 3.79 (s, 3H, OCH3), 4.83 (d, J=13.7 Hz, 1H, NCH2Ar), 4.91 (d, J=13.7 Hz, 1H, NCH2Ar), 5.08–5.12 (m, 2H, CHCH2CH=CH 2), 5.70–5.87 (m, 1H, CHCH2CH=CH2), 6.83 (d, J=8.8 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.18–7.25 (m, 2H, 2‐Hbenzyl, 6‐Hbenzyl), 7.27–7.36 (m, 3H, 3‐Hbenzyl, 4‐Hbenzyl, 5‐Hbenzyl), 7.33 (d, J=8.7 Hz, 2H, 2‐HPMB, 6‐HPMB). 13C NMR (400 MHz, CDCl3): δ (ppm)=33.2 (1C, CHCH2CH=CH2), 41.8 (1C, NCH2Ar), 51.7 (1C, NCH2CO), 55.4 (1C, OCH3), 58.2 (1C, NCH2Ph), 63.3 (1C, NCHCO), 113.9 (2C, C‐3PMB, C‐5PMB), 118.1 (1C, CHCH2CH=CH2), 128.1 (1C, C‐1PMB), 128.8 (2C, C‐2benzyl, C‐6benzyl), 129.1 (2C, C‐3benzyl, C‐5benzyl), 129.4 (1C, C‐4benzyl), 130.6 (2C, C‐2PMB, C‐6PMB), 133.5 (1C, CHCH2 CH=CH2), 136.4 (1C, C‐1benzyl), 159.1 (1C, C‐4PMB), 170.1 (1C, NCH2 CO), 172.0 (1C, NCHCO). FT‐IR: ṽ (cm−1)=3064 (w, v, C−H, arom.), 2933 (w, v, C−H, alkyl), 1729 (m, v, C=O, imide), 1677 (s, v, C=O, imide), 821 (m, δ, C−H, para‐substituted arom.), 737, 700 (m, δ, C−H, mono‐substituted arom.). MS (EI): m/z=365 [(M+H)+, 100]. HPLC: purity 98.2 %, tR=22.17 min.

3‐Allyl‐1‐benzyl‐4‐(4‐methoxybenzyl)piperazine‐2,6‐dione (28)

A solution of imide 17 (22.1 g, 68 mmol, 1 eq) in dry THF (500 mL) was cooled down to −78 °C and a 1 M LiHMDS‐solution in THF (72 mL, 72 mmol, 1.05 eq) was added. After 1 h, allyl bromide (7.1 mL, 82 mmol, 1.2 eq) was added. The reaction mixture was stirred at −78 °C for 2 h and then warmed up to rt overnight. The reaction was stopped with an excess of saturated NaHCO3 solution. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2. The CH2Cl2 solution was washed with saturated NaHCO3 solution (4×) and the organic solvent was evaporated in vacuo. The residue was purified by fc (cyclohexane:ethyl acetate=95:5→83 : 17). (Rf 0.62, cyclohexane:ethyl acetate=2 : 1). Pale yellow solid, mp 58–60 °C, yield 16.62 g (67 %). C22H24N2O3 (364.4). 1H NMR (400 MHz, CDCl3): δ (ppm)=2.56–2.75 (m, 2H, CHCH 2CH=CH2), 3.44 (d, J=17.9 Hz, 1H, NCH 2CO), 3.59 (t, J=6.9 Hz, 1H, CHCH2CH=CH2), 3.65 (d, J=12.9 Hz, 1H, NCH 2PhOMe), 3.70 (d, J=12.9 Hz, 1H, NCH 2PhOMe), 3.76 (d, J=17.9 Hz, 1H, NCH 2CO), 3.80 (s, 3H, OCH3), 4.91 (d, J=13.9 Hz, 1H, NCH 2Ph), 4.96 (d, J=13.9 Hz, 1H, NCH 2Ph), 5.09 (d, J=11.5 Hz, 1H, CHCH2CH=CH 2), 5.10 (d, J=15.5 Hz, 1H, CHCH2CH=CH 2), 5.70–5.85 (m, 1H, CHCH2CH=CH2), 6.85 (d, J=8.6 Hz, 2H, 3‐CHPMB, 5‐CHPMB), 7.14 (d, J=8.6 Hz, 2H, 2‐CHPMB, 6‐CHPMB), 7.24–7.28 (m, 1H, 4‐CHbenzyl), 7.28–7.33 (m, 2H, 3‐CHbenzyl, 5‐CHbenzyl), 7.34–7.39 (m, 2H, 2‐CHbenzyl, 6‐CHbenzyl). 13C NMR (101 MHz, CDCl3): δ (ppm)=33.1 (1C, CHCH2CH=CH2), 42.5 (1C, NCH2Ph), 51.3 (1C, NCH 2CO), 55.5 (1C, OCH3), 57.7 (1C, NCH2PhOMe), 62.9 (1C, CHCH2CH=CH2), 114.3 (2C, C‐3PMB, C‐5PMB), 118.4 (1C, CHCH2CH=CH2), 127.2 (1C, C‐1PMB), 127.8 (1C, C‐4benzyl), 128.6 (2C, C‐3benzyl, C‐5benzyl), 129.0 (2C, C‐2benzyl, C‐6benzyl), 130.6 (2C, C‐2PMB, C‐6PMB), 133.1 (1C, CHCH2 CH=CH2), 136.9 (1C, C‐1benzyl), 159.7 (1C, C‐4PMB), 169.4 (1C, NCH2 CO), 171.3 (1C, NCHCO). IR (neat): ṽ (cm−1)=3066 (C‐Harom), 2951 (C‐Haliph), 1732 and 1670 (C=O), 721 (C‐Harom). MS (APCI): m/z=365.1882 (calcd. 365.1860 for C22H25N2O3 [M+H]+). Purity (HPLC): 97.6 % (tR=23.5 min).

4‐Benzyl‐3‐(3‐hydroxypropyl)‐1‐(4‐methoxybenzyl)piperazine‐2,6‐dione (29)

The allyl compound 27 (0.89 g, 2.45 mmol) was dissolved in THF (100 mL). Under N2 atmosphere, 9‐borabicyclo[3.3.1]nonane (0.5 M solution, 9.81 mL, 4.91 mmol) was slowly added. The solution was stirred overnight. On the next morning again 9‐borabicyclo[3.3.1]nonane (0.5 M solution, 3.68 mL, 1.84 mmol) was slowly added to transform 27 completely. 90 min later the solution was cooled to −25 °C and then NaOH (2 M solution, 3.68 mL, 7.36 mmol) was added while vigorously stirring. After 15 min H2O2 (30 % solution, 2.79 mL, 24.5 mmol) was added. The mixture was stirred for further 45 min at −25 °C and subsequently for 60 min at rt. Then it was warmed to 40 °C to destroy the excess of H2O2. When the formation of gas while cooling to rt was finished, the solution was poured into H2O/CH2Cl2 and extracted with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuum. The residue was purified by fc (cyclohexane:ethyl acetate=8:2→1:1, Ø=3.0 cm, l=10.0 cm, V=20 mL) to obtain a colorless oil. (Rf 0.16, cyclohexane:ethyl acetate=1 : 1). Yield 0.88 g (94 %). C22H26N2O4 (382.5). 1H NMR (400 MHz, CDCl3): δ (ppm)=1.72 (q, J=13.1/6.6 Hz, 2H, CH 2CH2CH2OH), 1.91–1.99 (m, 2H, CH2CH 2CH2OH), 3.44 (d, J=18.0 Hz, 1H, NCH2Ph), 3.52 (t, J=7.0 Hz, 1H, 3‐Hpiperazine‐2,6‐dione), 3.53–3.69 (m, 2H, CHOH), 3.69 (s, 2H, NCH2CO2), 3.75 (d, J=18.0 Hz, 1H, NCH2Ph), 3.79 (s, 3H, OCH3), 4.85 (d, J=13.7 Hz, 1H, NCH2Ar), 4.90 (d, J=13.7 Hz, 1H, NCH2Ar), 6.84 (d, J=8.8 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.20 (dd, J=7.7/1.6 Hz, 2H, 2‐Hbenzyl, 6‐Hbenzyl), 7.28–7.36 (m, 3H, 3‐Hbenzyl, 4‐Hbenzyl, 5‐Hbenzyl), 7.33 (d, J=8.7 Hz, 2H, 2‐HPMB, 6‐HPMB). 13C NMR (400 MHz, CDCl3): δ (ppm)=26.0 (1C, CH2CH2CH2OH), 29.4 (1C, CH2 CH2CH2OH), 41.7 (1C, NCH2Ar), 50.9 (1C, NCH2CO), 55.4 (1C, OCH3), 58.7 (1C, NCH2Ph), 62.4 (1C, NCHCO), 63.4 (1C, CH2CH2 CH2OH), 114.0 (2C, C‐3PMB, C‐5PMB), 128.2 (1C, C‐1PMB), 128.9 (2C, C‐2benzyl, C‐6benzyl), 129.3 (2C, C‐3benzyl, C‐5benzyl), 129.3 (1C, C‐4benzyl), 130.6 (2C, C‐2PMB, C‐6PMB), 136.0 (1C, C‐1benzyl), 159.2 (1C, C‐4PMB), 169.7 (1C, NCH2 CO), 172.7 (1C, NCHCO). FT‐IR: ṽ (cm−1)=3454 (m, v, O−H, alcohol), 3062 (w, v, C−H, arom.), 2931 (m, v, C−H, alkyl), 1727 (s, v, C=O, imide), 1674 (s, v, C=O, imide), 822 (m, δ, C−H, para‐substituted arom.), 736, 700 (m, δ, C−H, mono‐substituted arom.). MS (EI): m/z (%)=382 [M+, 40], 91 [PhCH2 +, 100]. HPLC: purity 99.1 %, tR=19.19 min.

1‐Benzyl‐3‐(3‐hydroxypropyl)‐4‐(4‐methoxybenzyl)piperazine‐2,6‐dione (30)

The allyl derivative 28 (9.1 g, 25 mmol, 1 eq) was dissolved in THF (400 mL). Under N2 atmosphere, a 0.5 M solution of 9‐borabicyclo[3,3,1]nonane in THF (0.5 M, 100 mL, 50 mmol) was slowly added. The solution was stirred overnight. After 20 h, again 9‐BBN in THF (0.5 M, 38 mL, 19 mmol) was slowly added to transform 28 completely. 90 min later the solution was cooled to −25 °C and then 2 M NaOH (37 mL, 75 mmol) was added while vigorously stirring. After 15 min H2O2 (30 %, 26 mL, 250 mmol) was added. The mixture was stirred for further 45 min at −25 °C and subsequently for 60 min at rt. Then Na2S2O3 was added to destroy the excess of H2O2. After the mixture was stirred for 30 min, most of the solvent was removed in vacuo. The residue was poured into CH2Cl2/saturated NaHCO3 solution and the mixture was extracted with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuo. The residue was purified by fc (cyclohexane:ethyl acetate=91:9→50 : 50, Ø=5 cm, I=14 cm, V=35 mL). (Rf 0.34, cyclohexane:ethyl acetate=50 : 50): Colorless oil, yield 5.2 g (55 %). 22H26N2O4 (382.5). 1H NMR (400 MHz, DMSO‐d 6): δ (ppm)=1.40–1.60 (m, 2H, CH2CH 2CH2OH), 1.93–1.70 (m, 2H, CH 2CH2CH2OH), 3.37 (q, J=6.1 Hz, 2H, CH2CH2CH 2OH), 3.43 (d, J=18.0 Hz, 1H, NCH 2CO), 3.48 (dd, J=8.9/6.0 Hz, 1H, NCHCO), 3.62 (d, J=13.1 Hz, 1H, NCH 2PhOMe), 3.67 (d, J=13.0 Hz, 1H, NCH 2PhOMe), 3.74 (s, 3H, OCH 3), 3.81 (d, J=17.8 Hz, 1H, NCH 2CO), 4.40 (t, J=5.2 Hz, 1H, CH2CH2CH2OH), 4.80 (d, J=15.1 Hz, 1H, NCH 2Ph), 4.81 (d, J=15.1 Hz, 1H, NCH 2Ph), 6.90 (d, J=8.7 Hz, 2H, 3‐CHPMB, 5‐CHPMB), 7.15 (d, J=8.6 Hz, 2H, 2‐CHPMB, 6‐CHPMB), 7.21–7.26 (m, 3H, 2‐CHbenzyl, 4‐CHbenzyl, 6‐CHbenzyl), 7.32 (t, J=7.2 Hz, 2H, 3‐CHbenzyl, 5‐CHbenzyl). 13C NMR (101 MHz, DMSO‐d 6): δ (ppm)=24.6 (1C, CH2CH2CH2OH), 28.7 (1C, CH2 CH2CH2OH), 41.3 (1C, NCH2Ph), 50.4 (1C, NCH 2CO), 55.0 (1C, OCH3), 56.5 (1C, NCH2PhOMe), 60.01 (1C, CH2CH2 CH2OH), 61.9 (1C, NCHCO), 113.8 (2C, C‐3PMB, C‐5PMB), 127.1 (1C, C‐4benzyl), 127.3 (2C, C‐2benzyl, C‐6benzyl), 128.3 (2C, C‐3benzyl, C‐5benzyl), 128.9 (1C, C‐1PMB), 130.0 (2C, C‐2PMB, C‐6PMB), 137.2 (1C, C‐1benzyl), 158.7 (1C, C‐4PMB), 170.1(1C, NCH2 CO), 172.7 (1C, NCHCO). IR (neat): ṽ (cm−1)=3390 (OH), 2935 (C‐Haliph), 1728 and 1674 (C=O), 817 and 698 (C‐Harom). MS (APCI): m/z=383.1957 (calcd. 365.1965 for C22H27N2O4 [M+H]+). Purity (HPLC): 99.7 % (tR=19.8 min).

3‐[1‐Benzyl‐4‐(4‐methoxybenzyl)‐3,5‐dioxopiperazin‐2‐yl]propanal (31)

The primary alcohol 29 (0.77 g, 2.0 mmol) was dissolved in CH2Cl2 (50 mL) and Dess‐Martin‐Periodinane (1.02 g, 2.4 mmol) was added. The mixture was stirred at rt for 2 h. Then NaOH (2 M solution, 30 mL) was added. When the mixture was clear again the mixture was poured into CH2Cl2/saturated NaHCO3 solution and extracted with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuum. The residue was purified by fc (cyclohexane:ethyl acetate=9:1→8:2, Ø=3.0 cm, l=9.5 cm, V=20 mL) to obtain a colorless oil. (Rf 0.42, cyclohexane:ethyl acetate=1 : 1). Yield 0.66 g (87 %). C22H24N2O4 (380.4). 1H NMR (300 MHz, CDCl3): δ (ppm)=2.02–2.27 (m, 2H, CH 2CH2CHO), 2.55 (t, J=6.8 Hz, 2H, CH2CH 2CHO), 3.38 (d, J=17.6 Hz, 1H, NCH2Ph), 3.41 (dd, J=6.8/2.4 Hz, 1H, 2‐H), 3.64 (s, 2H, 5‐H), 3.71 (d, J=18.0 Hz, 1H, NCH2Ph), 3.79 (s, 3H, OCH3), 4.84 (d, J=13.7 Hz, 1H, NCH2Ar), 4.90 (d, J=13.8 Hz, 1H, NCH2Ar), 6.84 (d, J=8.6 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.17 (d, J=7.7 Hz, 2H, 2‐Hbenzyl, 6‐Hbenzyl), 7.27–7.37 (m, 3H, 3‐Hbenzyl, 4‐Hbenzyl, 5‐Hbenzyll), 7.32 (d, J=8.7 Hz, 2H, 2‐HPMB, 6‐HPMB), 9.77 (s, 1H, CHO). 13C NMR (400 MHz, CDCl3): δ (ppm)=21.6 (1C, CH2CH2CHO), 40.0 (1C, CH2 CH2CHO), 41.7 (1C, NCH2Ar), 50.9 (1C, NCH2CO), 55.3 (1C, OCH3), 58.8 (1C, NCH2Ph), 62.4 (1C, NCHCO), 113.9 (2C, C‐3PMB, C‐5PMB), 128.1 (1C, C‐1PMB), 128.8 (2C, C‐2benzyl, C‐6benzyl), 129.1 (2C, C‐3benzyll, C‐5benzyl), 129.2 (1C, C‐4benzyl), 130.5 (2C, C‐2PMB, C‐6PMB), 136.2 (1C, C‐1benzyl), 159.1 (1C, C‐4PMB), 169.9 (1C, NCH2 CO), 172.1 (1C, NCHCO), 200.7 (1C, CHO). FT‐IR: ṽ (cm−1)=3067 (w, v, C−H, arom.), 2929 (m, v, C−H, alkyl), 1731 (s, v, C=O, aldehyde), 1677 (s, v, C=O, imide), 819 (m, δ, C−H, para‐substituted arom.), 745, 701 (m, δ, C−H, mono‐substituted arom.). MS (APCI): calcd. for C22H24N2O4H+ 381.1809, found 381.1813. HPLC: purity 91.2 %, tR=19.87 min.

3‐[4‐Benzyl‐1‐(4‐methoxybenzyl)‐3,5‐dioxopiperazin‐2‐yl]propanal (32)

The primary alcohol 30 (5.15 g, 13.5 mmol, 1 eq) was dissolved in CH2Cl2 (250 mL) and Dess Martin Periodinane (6.85 g, 16.2 mmol, 1.2 eq) was added. The mixture was stirred at rt for 3 h. Then 2 M NaOH (300 mL) was added. When the mixture became clear again, it was poured into CH2Cl2/saturated NaHCO3 solution and extracted with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuo. The residue was purified by fc (cyclohexane: ethyl acetate=91 : 9→75 : 25, Ø=4 cm, I=10 cm, V=25 mL). (Rf 0.34, cyclohexane:ethyl acetate =2 : 1): Colorless oil, yield 4.8 g (94 %). C22H24N2O4 (380.4). 1H NMR (600 MHz, DMSO‐d 6): δ (ppm)=1.96–2.03 (m, 1H, CHCH 2CH2CHO), 2.15–2.22 (m, 1H, CHCH 2CH2CHO), 2.51 (t, J=6.8 Hz, 2H, CHCH2CH 2CHO), 3.39 (d, J=17.8 Hz, 1H, NCH 2CO), 3.53 (dd, J=9.8, 5.2 Hz, 1H, NCHCO), 3.62 (d, J=13.1 Hz, 1H, NCH 2PhOMe), 3.66 (d, J=13.1 Hz, 1H, NCH 2PhOMe), 3.74 (s, 3H, OCH 3), 3.84 (d, J=17.8 Hz, 1H, NCH 2CO), 4.79 (s, 2H, NCH 2Ph), 6.89 (d, J=8.6 Hz, 2H, 3‐CHPMB, 5‐CHPMB), 7.13 (d, J=8.6 Hz, 2H, 2‐CHPMB, 6‐CHPMB), 7.22 (d, J=6.9 Hz, 2H, 2‐CHbenzyl, 6‐CHbenzyl), 7.25 (t, J=7.4 Hz, 1H, 4‐CHbenzyl), 7.32 (t, J=7.6 Hz, 2H, 3‐CHbenzyl, 5‐CHbenzyl), 9.65–9.63 (t, J=1.4 Hz, 1H, CHCH2CH2CHO). The peak at 2.51 ppm is partly overlapping with the signal for DMSO. 13C NMR (151 MHz, DMSO‐d 6): δ (ppm)=21.2 (1C, CHCH2CH2CHO), 39.5 (1C, CHCH2 CH2CHO), 41.3 (1C, NCH2Ph), 49.9 (1C, NCH 2CO), 55.0 (1C, OCH3), 56.9(1C, NCH2PhOMe), 61.6 (1C, NCHCO), 113.9 (2C, C‐3PMB, C‐5PMB), 127.1 (1C, C‐4benzyl), 127.4 (2C, C‐2benzyl, C‐6benzyl), 128.4 (2C, C‐3benzyl, C‐5benzyl), 128.7 (1C, C‐1PMB), 130.1 (2C, C‐2PMB, C‐6PMB), 137.1 (1C, C‐1benzyl), 158.7 (1C, C‐4PMB), 170.1 (1C, NCH2 CO), 172.2(1C, NCHCO), 202.4 (CH=O). IR (neat): ṽ (cm−1)=2835 (C‐Haliph), 1720 and 1674 (C=O), 821and 698 (C‐Harom). MS (APCI): m/z=383.1768 (calcd. 381.1809 for C22H25N2O4 [M+H]+). Purity (HPLC): 98.3 % (tR=20.7 min).

(S)‐N‐{(E)‐3‐[(S)‐ and (R)‐1‐Benzyl‐4‐(4‐methoxybenzyl)‐3,5‐dioxopiperazin‐2‐yl]propylidene}‐ 2‐methylpropane‐2‐sulfinamide (33)

The aldehyde 31 (0.16 g, 0.42 mmol) was dissolved in THF (10 mL).(S)‐2‐methylpropane‐2‐sulfinamide (0.06 g, 0.49 mmol) and titanium(IV) ethanolate (0.20 mL) were added to this mixture, which was stirred for 3 h at rt. Then the mixture was poured into CH2Cl2/saturated NaHCO3 solution and was extracted with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuum. The residue was purified by fc (cyclohexane:ethyl acetate=8:2→1:1, Ø=3.0 cm, l=9.5 cm, V=20 mL) to obtain a colorless oil of both diastereomers. (Rf 0.36, cyclohexane:ethyl acetate=1 : 1). Yield 0.17 g (82 %). C26H33N3O4S (483.6). 1H NMR (400 MHz, CDCl3): δ (ppm)=1.166 (s, 9×0.5H, C(CH3)3), 1.169 (s, 9×0.5H, C(CH3)3), 2.04–2.30 (m, 2H, CH 2CH2CH=N), 2.50–2.75 (m, 2H, CH2CH 2CH=N), 3.42 (d, J=18.0 Hz, 1H, PhCH2N), 3.50 (dd, J=8.2/6.0 Hz, 0.5H, NCHCO), 3.57 (dd, J=8.2/6.0 Hz, 0.5H, NCHCO), 3.65 (s, 2H, NCH2CO), 3.72 (d, J=17.9 Hz, 0.5 H, PhCH2N), 3.73 (d, J=18.0 Hz, 0.5H, PhCH2N), 3.79 (s, 3H, OCH3), 4.85 (d, J=13.7 Hz, 0.5H, NCH2Ar), 4.86 (d, J=13.8 Hz, 0.5H, NCH2Ar), 4.90 (d, J=13.7 Hz, 1H, NCH2Ar), 6.84 (d, J=8.7 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.15–7.24 (m, 2H, 2‐Hbenzyl, 6‐Hbenzyl), 7.27–7.35 (m, 5H, 3‐Hbenzyl, 4‐Hbenzyl, 5‐Hbenzyl, 2‐HPMB, 6‐HPMB), 8.07 (t, J=3.8 Hz, 0.5H, NH), 8.10 (t, J=3.8 Hz, 0.5H, NH). Ratio of diastereomers 1 : 1. 13C NMR (400 MHz, CDCl3): δ (ppm)=22.5 (0.5 C, CH2CH2CH=N), 22.4 (0.5 C, CH2CH2CH=N), 22.5 (9 C, C(CH3)3), 24.3 (0.5 C, CH2 CH2CH=N), 24.5 (0.5 C, CH2 CH2CH=N), 41.7 (1C, NCH2Ar), 51.1 (0.5 C, NCH2CO), 51.3 (0.5 C, NCH2CO), 55.4 (1C, OCH3), 56.78 (0.5 C, C(CH3)3), 56.82 (0.5 C, C(CH3)3), 58.7 (0.5 C, NCH2Ph), 58.8 (0.5 C, NCH2Ph), 62.4 (0.5 C, NCHCO), 62.6 (0.5 C, NCHCO), 114.0 (2C, C‐3PMB, C‐5PMB), 128.2 (1C, C‐1PMB), 128.9 (2C, C‐2benzyl, C‐6benzyl), 129.1 (2C, C‐3benzyl, C‐5benzyl), 129.3 (1C, C‐4benzyl), 130.5 (2C, C‐2PMB, C‐6PMB), 136.3 (1C, C‐1benzyl), 159.2 (1C, C‐4PMB), 168.1 (1C, C=N), 169.9 (1C, NCH2 CO), 172.2 (2C, NCHCO). FT‐IR: ṽ (cm−1)=3063 (w, v, C−H, arom.), 2928 (m, v, C−H, alkyl), 1724 (m, v, C=O, imide), 1678 (s, v, C=O, imide), 822 (m, δ, C−H, para‐substituted arom.), 745, 702 (m, δ, C−H, mono‐substituted arom.). MS (APCI): calcd. for C26H33N3O4H+ 484.2265, found 484.2347. HPLC: purity 79.2 %, tR=21.66 min.

(S)‐N‐{(E)‐3‐[(S)‐ and (R)‐4‐Benzyl‐1‐(4‐methoxybenzyl)‐3,5‐dioxopiperazin‐2‐yl]propylidene}‐2‐methylpropane‐2‐sulfinamide (34)

The aldehyde 32 (3.13 g, 8.2 mmol, 1.0 eq) was dissolved in THF (200 mL). (S)‐2‐Methylpropane‐2‐sulfinamide (1.00 g, 8.2 mmol, 1.0 eq) and titanium(IV) ethanolate (4 mL) were added to this mixture, which was stirred for 4 h at rt. Then the mixture was poured into CH2Cl2/saturated NaHCO3 solution and was extracted with CH2Cl2 for four times. The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuo. The residue was purified by fc (cyclohexane:ethyl acetate=90 : 10→67 : 33, Ø=4 cm, I=16 cm, V=35 mL). (Rf 0.19, cyclohexane:ethyl acetate=67 : 33). Colorless oil of both diastereomers, yield 3.6 g (90 %). C26H33N3O4S (483.6). 1H NMR (600 MHz, DMSO‐d 6): δ (ppm)=1.07 (s, 9×0.5H, (CH 3)3C),1.08 (s, 9×0.5H, (CH 3)3C), 2.01–2.10 (m, 1H, CHCH 2CH2CH=N), 2.17–2.26 (m, 1H, CHCH 2CH2CH=N), 2.58–2.65 (m, 2H, CHCH2CH 2CH=N), 3.44 (d, J=17.7 Hz, 1H, NCH 2CO), 3.55 (dd, J=9.6/5.3 Hz, 0.5H, NCHCO), 3.60–3.65 (m, 1.5H, NCHCO (0.5H), NCH 2PhOMe (1H)), 3.68 (d, J=13.0 Hz, 0.5H, NCH 2PhOMe), 3.69 (d, J=13.1 Hz, 0.5H, NCH 2PhOMe), 3.735 (s, 3×0.5H, OCH 3), 3.737 (s, 3×0.5H, OCH 3), 3.898 (d, J=17.8 Hz, 0.5H, NCH 2CO), 3.901 (d, J=17.8 Hz, 0.5H, NCH 2CO), 4.80 (s, 2H, NCH 2Ph), 6.88 (d, J=8.7 Hz, 2×0.5H, 3‐CHPMB, 5‐CHPMB), 6.89 (d, J=8.7 Hz, 2×0.5H, 3‐CHPMB, 5‐CHPMB), 7.14 (d, J=8.6 Hz, 2×0.5H, 2‐CHPMB, 6‐CHPMB), 7.15 (d, J=8.5 Hz, 2×0.5H, 2‐CHPMB, 6‐CHPMB), 7.20–7.26 (m, 3H, 2‐CHbenzyl, 4‐CHbenzyl, 6‐CHbenzyl), 7.32 (t, J=7.4 Hz, 2H, 3‐CHbenzyl, 5‐CHbenzyl), 7.96 (t, J=3.9 Hz, 0.5H, CHCH2CH2CH=N), 7.98 (t, J=3.9 Hz, 0.5H, CHCH2CH2CH=N). Ratio of diastereomers 1 : 1. 13C NMR (151 MHz, DMSO‐d 6): δ (ppm)=21.8 (3C, (CH3)3C), 23.7/23.8 (1C, CHCH2CH2CH=N), 31.75/31.76 (1C, CHCH2 CH2CH=N), 41.3 (1C, NCH2Ph), 50.27/50.31 (1C, NCH 2CO), 55.0 (1C, OCH3), 55.9/56.0 (1C, (CH3)3 C), 56.8 /56.9 (1C, NCH2PhOMe), 61.3/61.5 (1C, NCHCO), 113.8/113.9 (2C, C‐3PMB, C‐5PMB), 127.1 (1C, C‐4benzyl), 127.33/127.35 (2C, C‐2benzyl, C‐6benzyl), 128.4 (2C, C‐3benzyl, C‐5benzyl), 128.7 (1C, C‐1PMB), 129.97/130.01 (2C, C‐2PMB, C‐6PMB), 137.1 (1C, C‐1benzyl), 158.7 (1C, C‐4PMB), 169.10 /169.14 (1C, CHCH2CH2 CH=N), 170.05/170.07 (1C, NCH2 CO), 172.28 /172.31 (1C, NCHCO). IR (neat): ṽ (cm−1)=2958 (C‐Haliph), 1728, 1674 and 1620 (C=O), 1342 (S=O), 817and 698 (C‐Harom). MS (APCI): m/z=484.2347 (calcd. 484.2265 for C26H34N3O4S [M+H]+). Purity (HPLC): 83.2 % (tR=22.9 min).

9‐Benzyl‐3‐(4‐methoxybenzyl)‐2,4‐dioxo‐3,9‐diazabicyclo[3.3.1]nonan‐ 6‐yl]‐2‐methylpropane‐2‐sulfinamide (35)

A solution of (S)‐sulfinylimine 33 (ratio of diastereomers 1 : 1, 589 mg, 1.22 mmol) in THF (30 mL) was cooled under N2 atmosphere to −78 °C. Then LiHMDS (1 M solution in THF, 1.82 mL, 1.82 mmol) was added. After 3 h, the mixture was warmed to rt, poured into CH2Cl2/saturated NaHCO3 solution and extracted with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuum. The residue was purified by fc (cyclohexane:ethyl acetate=19:1→1:1→100 % ethyl acetate, Ø=3.0 cm, l=9.5 cm, V=20 mL) to obtain two pale oils of the main diastereomer of 35 and a mixture of the other three diastereomers of 35. Total yield 386 mg (66 %). Main stereoisomer 35 a (Rf 0.32, cyclohexane:ethyl acetate=1 : 1): Pale yellow oil. Yield 127 mg (22 %). C26H33N3O4S (483.6). 1H NMR (300 MHz, CDCl3): δ (ppm)=1.24 (s, 9H, C(CH3)3), 1.39–1.48 (m, 1H, 7‐CH2),1.63–1.68 (m, 1H, 7‐CH2), 1.70–1.78 (m, 1H, 8‐CH2), 1.89–1.99 (m, 1H, 8‐CH2), 3.52–3.54 (m, 1H, 1‐CH), 3.53 (d, J=13.0 Hz, 1H, NCH2Ph), 3.69 (d, J=13.1 Hz, 1H, NCH2Ph), 3.71–3.75 (m, 1H, 6‐CH), 3.79 (s, 3H, OCH3), 3.93 (m, 1H, 5‐CH), 4.44 (d, J=9.1 Hz, 1H, NH), 4.88 (s, 2H, NCH2Ar), 6.83 (d, J=8.8 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.13–7.20 (m, 2H, 2‐Hphenyl, 6‐Hphenyl), 7.27–7.34 (m, 3H, 3‐Hphenyl, 4‐Hphenyl, 5‐Hphenyl), 7.36 (d, J=8.7 Hz, 2H, 2‐HPMB, 6‐HPMB). 13C NMR (400 MHz, CDCl3): δ (ppm)=22.7 (3C, C(CH3)3), 23.0 (1C, C‐8), 25.3 (1C, C‐7), 41.6 (1C, NCH2Ar), 51.9 (1C, C‐6), 55.4 (1C, OCH3), 56.0 (1C, C(CH3)3), 58.3 (1C, C‐1), 59.4 (1C, PhCH2N), 65.9 (1C, C‐5), 114.0 (2C, C‐3PMB, C‐5PMB), 128.2 (1C, C‐1PMB), 128.9 (2C, C‐2benzyl, C‐6benzyl), 129.2 (2C, C‐3benzyl, C‐5benzyl), 129.3 (1C, C‐4benzyl), 130.8 (2C, C‐2PMB, C‐6PMB), 136.2 (1C, C‐1benzyl), 159.2 (1C, C‐4PMB), 170.5 (1C, NCH2 CO), 172.1 (1C, NCHCO). FT‐IR: ṽ (cm−1)=3267 (w, v, N−H, sulfinamide), 2932 (m, v, C−H, alkyl), 1728 (m, v, C=O, imide), 1674 (s, v, C=O, imide), 818 (m, δ, C−H, para‐substituted arom.), 733, 698 (m, δ, C−H, mono‐substituted arom.). MS (APCI): calcd. for C26H33N3O4SH+ 484.2265, found 484.2282. HPLC: purity 97.9 %, tR=21.74 min. specific rotation: [α]20 D=+53.0 (c=0.80; CH2Cl2).

N‐[‐3‐Benzyl‐9‐(4‐methoxybenzyl)‐2,4‐dioxo‐3,9‐diazabicyclo[3.3.1]nonan‐6‐yl]‐2‐methylpropane‐2‐sulfinamide (36)

A solution of the (S)‐sulfinylimine 34 (ratio of diastereomers 1 : 1, 3.37 g, 7.0 mmol, 1 eq) in THF (150 mL) was cooled down to −78 °C under N2 atmosphere. Then LiHMDS (1 M solution in THF, 10.4 mL, 10.4 mmol, 1.5 eq) was added dropwise. After 3 h, the mixture was warmed to rt. Saturated NaHCO3 was added and the mixture was extracted with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by fc (cyclohexane : ethyl acetate=90 : 10→50 : 50, Ø=4 cm, I=15 cm, V=35 mL) to obtain a pale yellow oil of the main diastereomer of 36 and a mixture of the other three diastereomers of 36. Total yield 2.34 g (69 %). Main stereoisomer 36 a (Rf 0.47, cyclohexane:ethyl acetate=50 : 50): pale yellow oil, yield 0.91 g (27 %). C26H33N3O4S (483.6). 1H NMR (400 MHz, DMSO‐d 6): δ (ppm)=1.14 (s, 9H, C(CH 3)3), 1.47 (tt, J=14.0/4.5 Hz, 1H, 7‐CH2), 1.57–1.71 (m, 2H, 7‐CH2, 8‐CH2), 2.07–2.20 (m, 1H, 8‐CH2), 3.50–3.57 (m, 2H, 1‐CH, 6‐CH), 3.62 (s, 2H, NCH 2PhOMe), 3.73 (s, 4H, 5‐CH, OCH 3), 4.85 (s, 2H, NCH 2Ph), 5.12 (d, J=7.6 Hz, 1H, NH), 6.87 (d, J=8.6 Hz, 2H, 3‐CHPMB, 5‐CHPMB), 7.13 (d, J=8.6 Hz, 2H, 2‐CHPMB, 6‐CHPMB), 7.24–7.31 (m, 3H, 2‐CHbenzyl, 4‐CHbenzyl, 6‐CHbenzyl), 7.38–7.32 (m, 2H, 3‐CHbenzyl, 5‐CHbenzyl). 13C NMR (101 MHz, DMSO‐d 6): δ (ppm)=22.0 (1C, C‐8), 22.4 (3C, C(CH3)3), 24.3 (1C, C‐7), 41.6 (1C, NCH2Ph), 49.7 (1C, C‐6), 55.0 (1C, OCH3), 55.3 (1C, C(CH3)3), 57.5 (1C, NCH2PhOMe)„ 58.2 (1C, C‐1), 64.3 (1C, C‐5), 113.8 (2C, C‐3PMB, C‐5PMB), 127.3 (1C, C‐4benzyl), 128.1 (2C, C‐2benzyl, C‐6benzyl), 128.3 (1C, C‐1PMB), 128.4 (2C, C‐3benzyl, C‐5benzyl), 129.8 (2C, C‐2PMB, C‐6PMB), 137.1 (1C, C‐1benzyl), 158.7 (1C, C‐4PMB), 170.7 (1C, C‐4), 171.9 (1C, C‐2). IR (neat): ṽ (cm−1)=3275 (N−H), 2951 (C‐Haliph), 1732 and 1678 (C=O), 1346 and 1330 (S=O), 806 and 698 (C‐Harom). MS (APCI): m/z=484.2275 (calcd. 484.2265 for C26H34N3O4S [M+H]+). Purity (HPLC): 98.3 % (tR=22.8 min). Specific rotation: [α]20 D=+57.1 (c=0.18; CH3CN).

(1RS,5SR,6RS)‐9‐Benzyl‐6‐hydroxy‐3‐(4‐methoxybenzyl)‐3,9‐diazabicyclo[3.3.1]no‐nane‐2,4‐dione (37)

A solution of the aldehyde 31 (100 mg, 0.26 mmol) in THF (10 mL) was cooled under N2 atmosphere to −78 °C. Then LiHMDS (1 M solution in THF, 0.39 mL, 0.39 mmol) was added. After 30 min at −78 °C, the mixture was warmed to rt and stirred at rt for 3 h. The mixture was poured into CH2Cl2/saturated NaHCO3 solution and extracted with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuum. The residue was purified by fc (cyclohexane:ethyl acetate=9 : 1, Ø=2.0 cm, l=9.5 cm, V=20 mL) to obtain a pale yellow oil. (Rf 0.26, cyclohexane:ethyl acetate=1 : 1). Yield 10 mg (10 %). C22H24N2O4 (380.4). 1H NMR (400 MHz, CDCl3): δ (ppm)=1.07–1.22 (m, 1H, 8‐CH2), 1.92–1.99 (m, 2H, 7‐CH2), 2.00–2.08 (m, 1H, 8‐CH2), 3.53 (t, J=2.8 Hz, 1H, 1‐CH), 3.61 (d, J=13.2 Hz, 1H, NCH2Ph), 3.63–3.70 (m, 1H, 5‐CH), 3.67 (d, J=13.0 Hz, 1H, NCH2Ph), 3.79 (s, 3H, OCH3), 4.00 (dt, J=14.2/4.0 Hz, 1H, 6‐CH), 4.93 (d, J=13.7 Hz, 1H, NCH2Ar), 4.97 (d, J=13.7 Hz, 1H, NCH2Ar), 6.85 (d, J=8.8 Hz, 2H, 3‐HPMB, 5‐HPMB), 7.13–7.17 (m, 2H, 2‐Hbenzyl, 6‐Hbenzyl), 7.27–7.35 (m, 3H, 3‐Hbenzyl, 4‐Hbenzyl, 5‐Hbenzyl), 7.38 (d, J=8.7 Hz, 2H, 2‐HPMB, 6‐HPMB). 13C NMR (400 MHz, CDCl3): δ (ppm)=26.9 (1C, C‐8), 27.8 (1C, C‐7), 41.6 (1C, NCH2Ar), 55.4 (1C, OCH3), 59.0 (1C, C‐1), 59.1 (1C, PhCH2N), 64.6 (1C, C‐5), 68.1 (1C, 6‐C), 114.0 (2C, C‐3PMB, C‐5PMB), 128.1 (1C, C‐1PMB), 128.8 (2C, C‐2benzyl, C‐6benzyl), 128.9 (2C, C‐3benzyl, C‐5benzyl), 129.5 (1C, C‐4benzyl), 130.8 (2C, C‐2PMB, C‐6PMB), 136.2 (1C, C‐1benzyl), 159.2 (1C, C‐4PMB), 171.1 (1C, NCH2 CO), 172.5 (1C, NCHCO). FT‐IR: ṽ (cm−1)=3434 (m, v, O−H, alcohol), 3062 (w, v, C−H, arom.), 2932 (m, v, C−H, alkyl), 1726 (m, v, C=O, imide), 1671 (s, v, C=O, imide), 823 (m, δ, C−H, para‐substituted arom.), 730, 698 (m, δ, C−H, mono‐substituted arom.). MS (EI): 380 [M+, 7], 121 [H3COC6H4CH2 +, 88], 91 [C6H5CH2 +, 100].

(1RS,5SR,6SR)‐3‐Benzyl‐8‐(4‐methoxybenzyl)‐6‐vinyl‐3,8‐diazabicyclo[3.2.1]octane‐2,4‐dione (39)

A solution of 17 (120 mg, 0.37 mmol) in dry THF (4 mL) was cooled down to −78 °C and LiHMDS (0.44 mL, 0.44 mmol) was added slowly. After 90 min, trans‐1,4‐dibromobut‐2‐ene (38, 95 mg, 0.44 mmol) was added. The reaction was stirred at −78 °C for 90 min and then warmed up to rt for 16 h. Another portion of LiHMDS (0.44 mL, 0.44 mmol) was added at −78 °C and the mixture was stirred for another 2 h and then warmed up to room temperature overnight. Saturated NaHCO3 solution was added to the reaction mixture, which was then extracted with CH2Cl2 (4×). The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuo. The residue was purified by column chromatography (cyclohexane: ethyl acetate=98:2→94 : 6, Ø=1.5 cm, l=20 cm, V=10 mL). Rf 0.24, cyclohexane:ethyl acetate=80 : 20. Pale yellow oil, yield 30 mg (22 %). C23H24N2O3 (376.5). 1H NMR (600 MHz, CDCl3): δ (ppm)=1.73 (dd, J=13.7/5.5 Hz, 1H, 7‐CH2), 2.64 (ddd, J=13.7/10.6/7.8 Hz, 1H, 7‐CH2), 3.30–3.39 (m, 1H, 6‐CH), 3.63 (d, J=12.7 Hz, 1H, NCH 2PhOMe), 3.66 (d, J=12.1 Hz, 1H, NCH 2PhOMe), 3.79 (s, 3H, OCH3), 3.82 (d, J=6.9 Hz, 1H, 5‐CH), 3.85 (d, J=7.7 Hz, 1H, 1‐CH), 4.91 (s, 2H, NCH 2Ph), 5.02 (dt, J=10.4/1.3 Hz, 1H, CH=CH 2), 5.05 (dt, J=16.9/1.2 Hz, 1H, CH=CH 2), 5.41 (ddd, J=17.1/10.3/7.7 Hz, 1H, CH=CH2), 6.83 (d, J=8.7 Hz, 2H, 3‐CHPMB, 5‐CHPMB), 7.06 (d, J=8.6 Hz, 2H, 2‐CHPMB, 6‐CHPMB), 7.26–7.29 (m, 1H, 4‐CHbenzyl), 7.32 (t, J=7.3 Hz, 2H, 3‐CHbenzyl, 5‐CHbenzyl), 7.44 (d, J=6.9 Hz, 2H, 2‐CHbenzyl, 6‐CHbenzyl). 13C NMR (151 MHz, CDCl3): δ (ppm)=31.9 (1C, C‐7), 41.8 (1C, NCH2Ph), 43.2 (1C, C‐6), 52.8 (1C, NCH2PhOMe), 55.4 (1C, OCH3), 63.7 (1C, C‐1), 68.1 (1C, C‐5), 114.2 (2C, C‐3PMB, C‐5PMB), 118.4 (1C, CH=CH2), 127.6 (1C, C‐1PMB), 128.0 (1C, C‐4benzyl), 128.6 (2C, C‐3benzyl, C‐5benzyl), 129.6 (2C, C‐2benzyl, C‐6benzyl), 130.4 (2C, C‐2PMB, C‐6PMB), 134.3 (1C, CH=CH2), 136.9 (1C, C‐1benzyl), 159.6 (1C, C‐4PMB), 170.4 (1C, C‐4), 172.9 (1C, C‐2). IR (neat): ṽ (cm−1)=2959 (C‐Haliph), 1732 and 1678 (C=O), 822 and 698 (C‐Harom). MS (APCI): m/z=377.1869 (calcd. 377.1860 for C23H25N2O3 [M+H]+). Purity (HPLC): 98.7 % (tR=23.3 min).

3‐Benzyl‐9‐(4‐methoxybenzyl)‐7‐methylene‐3,9‐diazabicyclo[3.3.1]nonane‐2,4‐dione (41)

A solution of 17 (214 mg, 0.66 mmol) in dry THF (5 mL) was cooled down to −78 °C and LiHMDS (0.73 mL, 0.73 mmol) was added slowly. After 30 min, 3‐bromo‐2‐bromomethylprop‐1‐ene (40b, 0.83 μL, 0.73 mmol) was added. The reaction was stirred at −78 °C for 90 min and then LiHMDS (0.73 mL, 0.73 mmol) was added again. The mixture was stirred at −78 °C for another 2 h and then warmed up to room temperature overnight. Saturated NaHCO3 solution was added and THF was removed almost completely in vacuo. The residue was extracted with ethyl acetate (4×). The combined organic layers were dried (Na2SO4) and the solvent was evaporated in vacuo. The residue was purified by column chromatography (cyclohexane: ethyl acetate=20 : 1, Ø=1 cm, l=12 cm, V=8 mL). Rf 0.62, cyclohexane:ethyl acetate=2 : 1. Pale yellow solid, mp 58–60 °C, yield 129 mg (52 %). C23H24N2O3 (376.5). 1H NMR (600 MHz, CDCl3): δ (ppm)=2.48 (dm, J=13.8 Hz, 2H, 6‐CH2, 8‐CH2), 2.69 (dm, J=12.0 Hz, 2H, 6‐CH2, 8‐CH2), 3.65 (s, 2H, NCH 2PhOMe), 3.68–3.71 (m, 2H, 1‐CH, 5‐CH), 3.80 (s, 3H, OCH3), 4.70 (t, J=2.0 Hz, 2H, C=CH2), 4.93 (s, 2H, NCH 2Ph), 6.84 (d, J=8.6 Hz, 2H, 3‐CHPMB, 5‐CHPMB), 7.11 (d, J=8.6 Hz, 2H, 2‐CHPMB, 6‐CHPMB), 7.24 (t, J=7.3 Hz, 1H, 4‐CHbenzyl), 7.29 (t, J=7.3 Hz, 2H, 3‐CHbenzyl, 5‐CHbenzyl), 7.37 (d, J=6.9 Hz, 2H, 2‐CHbenzyl, 6‐CHbenzyl). 13C NMR (151 MHz, CDCl3): δ (ppm)=36.7 (2C, C‐6, C‐8), 42.1 (1C, NCH2Ph), 55.4 (1C, OCH3), 58.3 (1C, NCH2PhOMe), 60.3 (2C, C‐1, C‐5), 114.2 (2C, C‐3PMB, C‐5PMB), 114.6 (1C, C=CH2), 127.7 (2C, C‐1PMB, C‐4benzyl), 128.4 (2C, C‐3benzyl, C‐5benzyl), 129.2 (2C, C‐2benzyl, C‐6benzyl), 130.4 (2C, C‐2PMB, C‐6PMB), 137.1 (1C, C‐1benzyl), 137.7 (1C, C=CH2), 159.6 (1C, C‐4PMB), 172.2 (2C, 2×C=O). IR (neat): ṽ (cm−1)=2959 and 2936 (C‐Haliph), 1670 (C=O), 733 and 694 (C‐Harom). MS (APCI): m/z=377.1852 (calcd. 377.1860 for C23H25N2O3 [M+H]+). Purity (HPLC): 97.9 % (tR=22.4 min).

Supporting Information

Supporting Information contains the methylation of monoalkylated piperazinedione 18b and all 1H and 13C NMR spectra.

Conflict of interest

The authors declare no conflict of interest.

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Supplementary

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