A Convenient Preparation of Diastereomerically Pure, Diversely Substituted Piperazine-2,5-diones from N-Protected α-Amino Acids

Abstract

The products of the Ugi reaction of various N-tert-but­oxy­carbonyl-protected α-amino acids, aldehydes, amines and tert-butyl isocyanide, after tert-butoxycarbonyl deprotection, undergo efficient microwave-assisted cyclization in acetic acid to give dia­stereomerically pure, racemic piperazine-2,5-diones. The formation of a single diastereomer is rationalized via an enolization equilibration process in acetic acid at high temperature which enriches the product mixture in the more stable diastereomer. The relative ste­reo­chemistry of the products are confirmed by NOESY experiments and are consistent with molecular mechanics calculations.

Strategic incorporation of potentially reactive functionalities into the structure of any two components of the Ugi multicomponent reaction (U-MCR) provides dipeptoid templates that can undergo further complexity-generating transformations. Such premeditated post-Ugi modification processes have served [¹] as a rich source of diverse heterocyclic compounds that would otherwise be inaccessible, or require tedious synthetic elaboration by alternative preparative strategies.

Previously, we described post-Ugi multicomponent cyclization of Ugi reaction products containing a pyrazole-3-carboxylic acid [²] or an indole-2-carboxylic acid residue, [³] under microwave irradiation in glacial acetic acid. In this procedure, tert-butyl isocyanide (t-BuNC) manifested itself as a convertible isocyanide in the preceding Ugi reaction as the resulting terminal tert-butyl amide was converted, intramolecularly, into an N-acyl azole moiety (Scheme  [¹] ). Clearly, tert-butyl isocyanide serves as an attractive, low-cost alternative to other convertible isocyanides described in the literature. [4] This consideration prompted us to investigate cyclizations of Ugi reaction derived tert-butyl amides with other nitrogen nucleophiles under similar conditions.

An opportunity for such a cyclization exists if, for example, N-tert-butoxycarbonyl-protected α-amino acids are used in combination with tert-butyl isocyanide to construct dipeptoid products via the Ugi multicomponent reaction. Indeed, during the course of our investigations, Hulme reported the microwave-assisted cyclization (following deprotection), in good yields, of Ugi multicomponent reaction products derived from N-tert-butoxycarbonyl-protected α-amino acids and n-butyl isocyanide (n-BuNC). [5] Notably, the products resulting from chiral N-tert-butoxycarbonyl-protected α-amino acids were obtained as 1:1 mixtures of diastereomers (Scheme  [²] ). Herein, we report on the preparation of dia­stereomerically pure piperazine-2,5-diones via a similar microwave-assisted protocol involving intramolecular cyclization onto a tert-butyl amide unit in glacial acetic acid.

A set of 12 dipeptoids, 2a-l, was prepared via the Ugi reaction of various N-tert-butoxycarbonyl-protected amino acids 1, aldehydes and amines with tert-butyl isocyanide. In all cases, the crude products 2 were at least 80% pure according to LC-MS analysis. [6] Without further purification, we next attempted the microwave-assisted cyclization of dipeptoids 2 in glacial acetic acid. Disappointingly, these conditions were insufficiently acidic to enable efficient removal of the tert-butoxycarbonyl group, and significant amounts of the starting materials 2, along with minor unidentified impurities, were recovered after heating in a microwave oven at 180 ˚C for 90 minutes. Prolonged heating (up to three hours) or higher temperatures (200-220 ˚C) resulted in the accumulation of more impurities. Therefore, it was decided to deprotect dipeptoids 2 prior to submitting them to the microwave-assisted cyclization step. To our delight, the respective free-base deprotected products underwent clean cyclization into the target piperazine-2,5-diones 3 (Scheme  [³] ). Surprisingly, in all cases, the crude ^¹H NMR spectra of the products exhibited only one set of signals thereby confirming the formation of only one of the two possible diastereomers during the cyclization. Analytically and diastereomerically pure compounds 3a-l were obtained, either by chromatography or by crystallization, in similar yields over the three steps (Table  [¹] ).

Table 1 Ugi Multicomponent Reaction Templates 2 and Cyclization Products 3 (continued)

Products	Amino acid 1	R³	R4	LC-MS 2, m/z [M + H+]	Yield of 3 (%)
2a/3a				462.5	46a
2b/3b				488.6	42a
2c/3c				538.4	50a
2d/3d				476.7	44a
2e/3e				502.2	50a
2f/3f				544.4	41a
2g/3g				580.3	43a
2h/3h				498.7	45b
2i/3i				560.6	52b
2j/3j				526.3	41b
2k/3k				540.5	45b
2l/3l				540.3	39b
a Yield of isolated product after chromatography. b Yield of isolated product after crystallization.

The observed formation of single diastereomers of compounds 3a-l can be rationalized through enolization of the initially formed diastereomeric mixture in glacial acetic acid, on prolonged heating, and its equilibration via the enol form 4 (and possibly also 5) into a single, more stable diastereomer (Scheme  [4] ). Indeed, when the microwave-assisted cyclization was stopped after 10 minutes, signals corresponding to two diastereomers of 3 were observed in the complex ^¹H NMR spectrum of the reaction mixture (the conversion at this point was <10%). It was noted that the piperazine-2,5-dione products 3a, 3b, 3h and 3j-l, derived from optically pure amino acids, were not optically active. Indeed, we monitored the optical rotation en route to 3h and established that the product was not optically active (Scheme  [5] ). This would appear to be consistent with the proposed enolization and equilibration.

The trans stereochemistry of the products 3a-l was established based on their NOESY spectra (see Figure  [¹] for representative examples). Interestingly, when the energies of the MM2 minimized [8] conformations of cis- and trans-3 were compared, no significant difference was observed in the majority of cases; this is probably due to the piperazine-2,5-dione ring being nearly planar. However, in some cases (products 3a, 3b, 3g and 3i), the calculated energy preference toward the trans isomer was >20 kcal/mol, which is consistent with the proposed equilibration of the diastereomeric mixture into a single trans isomer.

In conclusion, we have developed a convenient protocol for the preparation of diastereomerically pure trans-piperazine-2,5-diones 3 via the Ugi reaction of various N-tert-butoxycarbonyl-protected α-amino acids, aldehydes, amines and tert-butyl isocyanide, deprotection and microwave-assisted cyclization. This method extends the utility of tert-butyl isocyanide as a convertible isocyanide for the design of Ugi reaction products intended for post-Ugi cyclizations, specifically, under microwave irradiation in acetic acid.

All reactions were run in oven-dried glassware under an N₂ atm. Melting points were obtained with a Buchi B-520 melting point apparatus and are uncorrected. Analytical TLC was performed using F₂₅₄ silica gel plates (EM Separations Technology). Compounds were visualized using short-wavelength UV light. Column chromatographic separations were carried out on Merck silica gel (70-230 mesh). ^¹H NMR and ^¹³C NMR spectra were recorded on a Bruker DPX-300 spectrometer in DMSO-d ₆ using TMS as the internal standard. LC-MS analyses were obtained using a PE SCIEX API 150EX mass spectrometer following separation on a Shimadzu LC-10AD liquid chromatography system equipped with a Shimadzu SP d-10A UV-Vis detector (254 nm) and a Sedex 75 ELSD detector. Elemental analyses were recorded at the Research Institute for Chemical Crop Protection (Moscow, Russia) using a Carlo Erba Strumentazione 1106 analyzer. All solvents and reagents were obtained from commercial sources and were used without purification.

Piperazine-2,5-diones 3a-l; Typical Procedure

The syntheses reported herein were performed on 10 mmol scale. Equimolar amounts of an aldehyde and an amine were dissolved in MeOH (20 mL) and the mixture was stirred for 10 min at 60 ˚C. N-Boc-α-amino acid 1 (1 equiv) and t-BuNC (1 equiv) were added and stirring was continued at 60 ˚C for 16 h. The solvent was evaporated and the residue was dissolved in a 3 M soln of HCl in 1,4-dioxane (20 mL). After stirring at r.t. for 10 h, the volatiles were removed in vacuo and the residue was partitioned between CH₂Cl₂ (20 mL) and 10% aq NaHCO₃ soln (20 mL). The organic layer was separated, dried over anhyd Na₂SO₄, filtered and concd. The residue was dissolved in glacial AcOH (5 mL) and the resulting soln was placed in a microwave reactor tube and heated at 180 ˚C for 90 min using a Biotage Initiator™ microwave synthesizer operating at 100 W. Upon cooling, the solvent was removed in vacuo (using GeneVac^® equipment) and the residue again subjected to basic aqueous work-up (vide supra). The crude product was purified by column chromatography on silica gel [10→40% CH₂Cl₂ in hexanes (compounds 3a-g)] or by crystallization [i-PrOH (compounds 3h-l)] to afford analytically pure piperazine-2,5-diones 3.

(±)-(3 R ,8a S )-2-(2-Methoxyethyl)-3-phenylhexahydropyrrolo[1,2- a ]pyrazine-1,4-dione (3a)

Yield: 46%; white solid; mp 119-121 ˚C.

^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.46-7.28 (m, 5 H), 5.18 (s, 1 H), 4.16 (t, J = 7.9 Hz, 1 H), 3.89 (dt, J _d = 14.0 Hz, J _t = 5.2 Hz, 1 H), 3.63-3.36 (m, 3 H), 3.33-3.22 (m, 1 H), 3.19 (s, 3 H), 3.16-3.04 (m, 1 H), 2.19 (m, 1 H), 2.04-1.71 (m, 3 H).

^¹³C NMR (75 MHz, DMSO-d ₆): δ = 167.4, 163.2, 135.5, 128.9, 128.1, 126.0, 69.4, 66.1, 57.9, 57.6, 45.2, 43.9, 29.0, 21.7.

LC-MS: m/z = 289 [M + H⁺].

Anal. Calcd for C₁₆H₂₀N₂O₃: C, 66.65; H, 6.99; N, 9.72. Found: C, 66.73; H, 7.07; N, 9.77.

(±)-(3 R ,8a S )-3-Phenyl-2-(tetrahydrofuran-2-ylmethyl)hexahydropyrrolo[1,2- a ]pyrazine-1,4-dione (3b)

Yield: 42%; white solid; mp 133-135 ˚C.

^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.46-7.28 (m, 5 H), 5.30 (d, J = 11.5 Hz, 1 H), 4.17 (t, J = 8.0 Hz, 1 H), 4.06-3.90 (m, 2 H), 3.81-3.49 (m, 3 H), 3.34-3.22 (m, 1 H), 2.76-2.63 (m, 1 H), 2.34-2.19 (m, 1 H), 2.04-1.69 (m, 6 H), 1.53-1.37 (m, 1 H).

^¹³C NMR (75 MHz, DMSO-d ₆): δ = 167.4, 163.2, 135.3, 128.9, 128.2, 126.0, 77.5, 67.3, 66.3, 57.5, 48.4, 45.2, 29.1, 28.8, 24.7, 21.7.

LC-MS: m/z = 315 [M + H⁺].

Anal. Calcd for C₁₈H₂₂N₂O₃: C, 68.77; H, 7.05; N, 8.91. Found: C, 68.69; H, 6.98; N, 8.83.

(±)-(3 R ,9a S )-2-(4-Methoxybenzyl)-3-phenyltetrahydro-2 H -pyrido[1,2- a ]pyrazine-1,4(3 H ,6 H )-dione (3c)

Yield: 50%; white solid; mp 168 ˚C (dec.).

^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.45-7.20 (m, 5 H), 7.07 and 6.87 (ABq, J = 7.3 Hz, 4 H), 5.07 (d, J = 14.5 Hz, 1 H), 4.78 (s, 1 H), 4.38-4.16 (m, 2 H), 3.75 (s, 3 H), 3.49 (d, J = 14.4 Hz, 1 H), 2.63-2.52 (m, 1 H), 2.45-2.29 (m, 1 H), 1.96-1.81 (m, 1 H), 1.74-1.25 (m, 4 H).

^¹³C NMR (75 MHz, DMSO-d ₆): δ = 165.7, 162.7, 158.7, 137.4, 129.5, 129.2, 128.9, 128.4, 127.7, 127.4, 127.2, 114.0, 62.3, 56.9, 55.0, 45.8, 41.7, 31.5, 23.9, 23.4.

LC-MS: m/z = 365 [M + H⁺].

Anal. Calcd for C₂₂H₂₄N₂O₃: C, 72.51; H, 6.64; N, 7.69. Found: C, 72.60; H, 6.71; N, 7.75.

(±)-(3 R ,9a S )-2-(2-Methoxyethyl)-3-phenyltetrahydro-2 H -pyrido[1,2- a ]pyrazine-1,4(3 H ,6 H )-dione (3d)

Yield: 44%; white solid; mp 139-141 ˚C.

^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.45-7.26 (m, 5 H), 5.11 (s, 1 H), 4.36 (dt, J _d = 13.2 Hz, J _t = 2.0 Hz, 1 H), 4.13 (dd, J = 11.5 Hz, J = 3.3 Hz, 1 H), 3.86 (dt, J _d = 14.0 Hz, J _t = 5.5 Hz, 1 H), 3.52-3.41 (m, 1 H), 3.40-3.30 (m, 1 H), 3.21 (s, 3 H), 2.82-2.70 (m, 1 H), 2.63-2.53 (m, 1 H), 2.41-2.28 (m, 1 H), 1.96-1.83 (m, 1 H), 1.74-1.63 (m, 1 H), 1.53-1.26 (m, 3 H).

^¹³C NMR (75 MHz, DMSO-d ₆): δ = 165.6, 162.9, 138.0, 128.7, 128.3, 127.4, 68.9, 63.8, 58.0, 56.7, 43.1, 41.6, 31.3, 23.9, 23.4.

LC-MS: m/z = 303 [M + H⁺].

Anal. Calcd for C₁₇H₂₂N₂O₃: C, 67.53; H, 7.33; N, 9.26. Found: C, 67.58; H, 7.43; N, 9.32.

(±)-(3 S ,9a R )-3-Phenyl-2-(tetrahydrofuran-2-ylmethyl)tetrahydro-2 H -pyrido[1,2- a ]pyrazine-1,4(3 H ,6 H )-dione (3e)

Yield: 50%; white solid; mp 149-150 ˚C.

^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.46-7.23 (m, 5 H), 5.20 (d, J = 22.1 Hz, 1 H), 4.41-4.29 (m, 1 H), 4.19-4.08 (m, 1 H), 4.06-3.86 (m, 2 H), 3.81-3.55 (m, 2 H), 2.65-2.53 (m, 1 H), 2.43-2.30 (m, 1 H), 2.02-1.25 (m, 10 H).

^¹³C NMR (75 MHz, DMSO-d ₆): δ = 166.4, 163.0, 137.9, 128.8, 128.3, 127.4, 75.5, 67.0, 63.6, 56.9, 47.4, 45.6, 41.5, 31.7, 28.0, 25.3, 23.9.

LC-MS: m/z = 329 [M + H⁺].

Anal. Calcd for C₁₉H₂₄N₂O₃: C, 69.49; H, 7.37; N, 8.53. Found: C, 69.53; H, 7.42; N, 8.62.

(±)-(3 S ,9a R )-3-(4-Isopropylphenyl)-2-(tetrahydrofuran-2-yl­methyl)tetrahydro-2 H -pyrido[1,2- a ]pyrazine-1,4(3 H ,6 H )-dione (3f)

Yield: 41%; white solid; mp 159 ˚C (dec.).

^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.31-7.14 (m, 4 H), 5.16 (d, J = 21.5 Hz, 1 H), 4.41-4.29 (m, 1 H), 4.16-3.85 (m, 3 H), 3.81-3.54 (m, 2 H), 2.94-2.85 (m, 1 H), 2.66-2.53 (m, 1 H), 2.44-2.29 (m, 1 H), 2.05-1.32 (m, 10 H), 1.22 (d, J = 6.9 Hz, 6 H).

^¹³C NMR (75 MHz, DMSO-d ₆): δ = 166.4, 165.5, 163.1, 148.5, 135.2, 127.0, 77.3, 75.6, 67.1, 63.8, 63.3, 56.7, 47.4, 45.5, 41.5, 33.0, 31.6, 28.4, 25.0, 23.7.

LC-MS: m/z = 371 [M + H⁺].

Anal. Calcd for C₂₂H₃₀N₂O₃: C, 71.32; H, 8.16; N, 7.56. Found: C, 71.44; H, 8.26; N, 7.61.

(±)-(3 S ,9a R )-3-(4-Isopropylphenyl)-2-(4-methoxybenzyl)tetra­hydro-2 H -pyrido[1,2- a ]pyrazine-1,4(3 H ,6 H )-dione (3g)

Yield: 43%; white solid; mp 173 ˚C (dec.).

^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.26 and 7.18 (ABq, J = 8.0 Hz, 4 H), 7.08 and 6.87 (ABq, J = 8.3 Hz, 4 H), 5.05 (d, J = 14.8 Hz, 1 H), 4.71 (s, 1 H), 4.36-4.24 (m, 2 H), 3.73 (s, 3 H), 3.40 (d, J = 14.8 Hz, 1 H), 2.89 (sept, J = 6.9 Hz, 1 H), 2.59-2.52 (m, 1 H), 2.36 (d, J = 12.2 Hz, 1 H), 1.87 (d, J = 12.2 Hz, 1 H), 1.70-1.25 (m, 4 H), 1.20 (d, J = 6.9 Hz, 6 H).

^¹³C NMR (75 MHz, DMSO-d ₆): δ = 165.7, 162.8, 158.6, 148.6, 134.8, 129.2, 127.8, 127.3, 126.7, 114.0, 62.0, 56.8, 55.0, 45.8, 41.6, 33.1, 31.5, 23.9, 23.7, 23.4.

LC-MS: m/z = 407 [M + H⁺].

Anal. Calcd for C₂₅H₃₀N₂O₃: C, 73.86; H, 7.44; N, 6.89. Found: C, 73.77; H, 7.50; N, 6.78.

(±)-(3 S ,6 R )-1-(4-Methoxybenzyl)-3-methyl-6-phenylpiperazine-2,5-dione (3h)

Yield: 45%; beige solid; mp 127-129 ˚C.

^¹H NMR (300 MHz, DMSO-d ₆): δ = 8.38 (s, 1 H), 7.47-7.25 (m, 5 H), 7.13 and 6.89 (ABq, J = 8.2 Hz, 4 H), 5.14 (d, J = 14.3 Hz, 1 H), 4.79 (s, 1 H), 4.27-4.15 (m, 1 H), 3.74 (s, 3 H), 3.59 (d, J = 14.4 Hz, 1 H), 1.37 (d, J = 6.6 Hz, 3 H).

^¹³C NMR (75 MHz, DMSO-d ₆): δ = 167.6, 165.7, 158.7, 135.7, 129.3, 128.9, 128.3, 128.1, 126.6, 114.0, 63.4, 55.0, 48.8, 46.6, 17.9.

LC-MS: m/z = 325 [M + H⁺].

Anal. Calcd for C₁₉H₂₀N₂O₃: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.40; H, 6.23; N, 8.57.

(±)-(3 R ,6 S )-1-(4-Methoxybenzyl)-3,6-diphenylpiperazine-2,5-dione (3i)

Yield: 52%; white solid; mp 164 ˚C (dec.).

^¹H NMR (300 MHz, DMSO-d ₆): δ = 8.45 (d, J = 6.2 Hz, 1 H), 7.50-7.10 (m, 10 H), 7.04 (t, J = 6.5 Hz, 2 H), 6.87 (t, J = 9.0 Hz, 2 H), 5.36-5.24 (m, 1 H), 5.11 (t, J = 16.0 Hz, 1 H), 4.92 (s, 1 H), 3.76 (s, 3 H), 3.59 (d, J = 14.7 Hz, 1 H).

^¹³C NMR (75 MHz, DMSO-d ₆): δ = 165.7, 165.4, 164.9, 158.7, 139.0, 137.8, 136.6, 135.4, 129.5, 129.0, 128.3, 128.1, 127.7, 127.2, 126.8, 126.3, 114.0, 63.1, 62.4, 58.0, 55.0, 46.6.

LC-MS: m/z = 387 [M + H⁺].

Anal. Calcd for C₂₄H₂₂N₂O₃: C, 74.59; H, 5.74; N, 7.25. Found: C, 74.68; H, 5.81; N, 7.30.

(±)-(3 R ,6 S )-3-Isopropyl-1-(4-methoxybenzyl)-6-phenylpiperazine-2,5-dione (3j)

Yield: 41%; white solid; mp 140-143 ˚C.

^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.78 (s, 1 H), 7.46-7.25 (m, 5 H), 7.10 and 6.88 (ABq, J = 8.5 Hz, 4 H), 5.16 (d, J = 14.5 Hz, 1 H), 4.77 (s, 1 H), 4.07 (s, 1 H), 3.76 (s, 3 H), 3.52 (d, J = 14.7 Hz, 1 H), 2.48-2.40 (m, 1 H), 1.03 (d, J = 7.1 Hz, 3 H), 0.94 (d, J = 6.9 Hz, 3 H).

^¹³C NMR (75 MHz, DMSO-d ₆): δ = 166.1, 158.7, 136.5, 129.3, 128.9, 128.4, 128.0, 127.0, 114.0, 62.7, 58.4, 55.0, 46.2, 30.9, 18.0, 16.2.

LC-MS: m/z = 353 [M + H⁺].

Anal. Calcd for C₂₁H₂₄N₂O₃: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.64; H, 6.96; N, 7.84.

(±)-(3 R ,6 S )-3-Isobutyl-1-(4-methoxybenzyl)-6-phenylpiperazine-2,5-dione (3k)

Yield: 45%; white solid; mp 139-141 ˚C.

^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.95 (s, 1 H), 7.45-7.24 (m, 5 H), 7.10 and 6.87 (ABq, J = 8.4 Hz, 4 H), 5.13 (d, J = 14.7 Hz, 1 H), 4.79 (s, 1 H), 4.11 (t, J = 5.2 Hz, 1 H), 3.76 (s, 3 H), 3.60 (d, J = 14.7 Hz, 1 H), 1.99-1.79 (m, 2 H), 1.74-1.61 (m, 1 H), 0.89 (d, J = 5.8 Hz, 6 H).

^¹³C NMR (75 MHz, DMSO-d ₆): δ = 167.1, 165.6, 158.7, 136.1, 129.4, 128.9, 128.3, 128.0, 126.9, 114.0, 63.0, 55.0, 51.8, 46.4, 23.6, 22.8, 22.2.

LC-MS: m/z = 367 [M + H⁺].

Anal. Calcd for C₂₂H₂₆N₂O₃: C, 72.11; H, 7.15; N, 7.64. Found: C, 72.10; H, 7.19; N, 7.70.

(±)-(3 R ,6 S )-3- sec -Butyl-1-(4-methoxybenzyl)-6-phenylpiperazine-2,5-dione (3l)

Yield: 39%; white solid; mp 149-152 ˚C.

^¹H NMR (300 MHz, DMSO-d ₆): δ = 8.09 and 8.17 (2 × br s, 1 H), 7.47-7.26 (m, 5 H), 7.10 (dd, J = 8.7 Hz, J = 2.0 Hz, 2 H), 6.89 (d, J = 8.2 Hz, 2 H), 5.17 (d, J = 14.3 Hz, 1 H), 4.72 (d, J = 3.8 Hz, 1 H), 4.18 (d, J = 11.1 Hz, 1 H), 3.74 (s, 3 H), 3.41 (d, J = 14.8 Hz, 1 H), 2.30-2.06 (m, 1 H), 1.50-1.25 (m, 2 H), 1.01-0.76 (m, 6 H).

^¹³C NMR (75 MHz, DMSO-d ₆): δ = 166.3, 166.0, 165.9, 158.7, 136.6, 129.4, 128.9, 128.4, 128.0, 127.0, 114.0, 62.7, 58.0, 56.9, 55.0, 46.2, 37.8, 24.6, 24.0, 14.8, 13.6, 12.0.

LC-MS: m/z = 367 [M + H⁺].

Anal. Calcd for C₂₂H₂₆N₂O₃: C, 72.11; H, 7.15; N, 7.64. Found: C, 72.20; H, 7.24; N, 7.59.

Acknowledgment

This research was supported by the Federal Agency for Science and Innovation (Russian Federation Government Contract 02.740.11.0092). We are grateful to Dr. Pavel Kislitsyn of CDRI for his help in measuring the optical rotations, and Dr. Yan Ivanenkov of CDRI for performing Molecular Mechanics calculations.

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Nikulnikov, M.; Krasavin, M. Poster Abstract 18, 4th International Conference on Multi-Component Reactions and Related Chemistry, Ekaterinburg, 24-28 May, 2009.

The ^¹H NMR spectra (300 MHz, DMSO-d ₆) of the crude products 2 displayed strongly broadened signals when run at ambient temperature, most likely, due to restricted amide bond rotation. On running some of the spectra at increased temperature (314 K), it was possible to confirm that products 2 were obtained as equal mixtures of diastereomers, as would be expected from the non-diastereoselective course of the Ugi reaction.

Sigma-Aldrich chemistry products catalogue: www.sigmaaldrich.com.

Molecular mechanics (MM2) calculations were performed using ChemBio3D Ultra 11.0, CambridgeSoft.

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Nikulnikov, M.; Krasavin, M. Poster Abstract 18, 4th International Conference on Multi-Component Reactions and Related Chemistry, Ekaterinburg, 24-28 May, 2009.

The ^¹H NMR spectra (300 MHz, DMSO-d ₆) of the crude products 2 displayed strongly broadened signals when run at ambient temperature, most likely, due to restricted amide bond rotation. On running some of the spectra at increased temperature (314 K), it was possible to confirm that products 2 were obtained as equal mixtures of diastereomers, as would be expected from the non-diastereoselective course of the Ugi reaction.

Sigma-Aldrich chemistry products catalogue: www.sigmaaldrich.com.

Molecular mechanics (MM2) calculations were performed using ChemBio3D Ultra 11.0, CambridgeSoft.