Cyclobutyl-Containing Rigid Analogues of Threonine: Synthesis and

Oct 11, 2017 - Hitherto unknown cis- and trans-1-amino-3-hydroxy-3-methylcyclobutanecarboxylic acids were synthesized in multigram scale. The obtained...
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Cyclobutyl-Containing Rigid Analogues of Threonine: Synthesis and Physical Chemical Properties Illia O. Feskov,†,‡ Anton V. Chernykh,‡,§ Ivan S. Kondratov,*,†,‡ Mariya Klyachina,‡ Constantin G. Daniliuc,⊥ and Günter Haufe*,⊥,∥ †

Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Str. 1, Kyiv 02660, Ukraine ‡ Enamine Ltd, Chervonotkatska Str. 78, Kyiv 02094, Ukraine § Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Str. 5, Kyiv 02660, Ukraine ⊥ Organisch-Chemisches Institut, Universität Münster, Corrensstraße 40, 48149 Münster, Germany ∥ Cells-in-Motion Cluster of Excellence, Universität Münster, Waldeyerstraße 15, 48149 Münster, Germany S Supporting Information *

ABSTRACT: Hitherto unknown cis- and trans-1-amino-3-hydroxy-3methylcyclobutanecarboxylic acids were synthesized in multigram scale. The obtained compounds can be considered as achiral conformationally restricted analogues of threonine with fixed spatial orientation of functional groups. pKa values are noticeably different for both amino acids. According to the X-ray data the cyclobutane rings in both compounds are almost planar (the corresponding torsion angles are below 7°).

other fluorine containing α-aminocyclobutane carboxylic acids 4,6 5,7 and 68 were used as labels for 19F NMR solid state structural studies of membrane peptides. Also many other cyclobutane containing amino acids (e.g., compounds 7,9 8,10 9,11 and others12−14) were intended as restricted analogues of the corresponding natural amino acids with the cyclobutane ring as a rigid replacement of a carbon−carbon single bond. Continuing our previous investigations on new 3-substituted cyclobutyl amines15 and amino acids,16 we present here multigram syntheses of other hitherto unknown α-aminocyclobutane carboxylic acids, 1-amino-3-hydroxy-3-methylcyclobutanecarboxylic acids cis- and trans-1017 which can be considered as conformationally restricted analogues of threonine, where the rigid cyclobutane ring is a bioisostere of the C−C single bond (Figure 2). Compounds cis- and trans-10 are achiral due to the plane of symmetry while threonine contains two stereogenic centers.

ubstituted α-aminocyclobutane carboxylic acid is a remarkable conformationally restricted pharmacophore and numerous compounds bearing this motif found various applications as biologically active substances and analogues of natural amino acids in design of peptidomimetics (Figure 1).

S

Figure 1. Examples of suitable 1-aminocyclobutane carboxylic acids.

Thus, 1-aminocyclobutane carboxylic acid 1 and trans-1aminocyclobutane-1,3-dicarboxylic acid (trans-ACBD) (2) are well-known as ligands of the NMDA receptor.1,2 Several fluorine-18 labeled cyclobutane amino acids are attractive PETimaging agents.3 Among them [18F]-Fluciclovine (3) (trans-1amino-3-[18F]fluorocyclobutane-carboxylic acid) was recently approved for PET-diagnostics of prostate cancer.4,5 Several © 2017 American Chemical Society

Figure 2. L-Threonine and rigid analogues cis- and trans-10. Received: September 7, 2017 Published: October 11, 2017 12863

DOI: 10.1021/acs.joc.7b02259 J. Org. Chem. 2017, 82, 12863−12868

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The Journal of Organic Chemistry

the hitherto unknown 1-amino-3-methylcyclobutane carboxylic acid 19, the “dehydroxy” analog of compound cis/trans-10 (Scheme 3).

The synthesis started from commercially available ketoester 11 (Scheme 1), which was methylated with AlMe3 using a Scheme 1. Synthesis of Compound cis-10

Scheme 3. Synthesis of Amino Acid 19

previously validated procedure.16 The following monohydrolysis proceeded stereoselectively: only the cis-monoester 1317 was isolated in diastereomerically pure form. Such a remarkable stereoselectivity is probably caused by assistance of the neighboring OH group. Earlier we carried out similar hydrolysis of diisopropyl 3-fluoro-3-methylcyclobutane-1,1-dicarboxylate, which proceeded without stereoselectivity.16 Subsequently, the Curtius rearrangement of compound 13 was accompanied by intramolecular cyclization to carbamate 14. Its structure was confirmed by X-ray analysis (see Figure S1 in SI).18 The final step, alkaline hydrolysis of carbamate 14, led to amino acid hydrochloride cis-10 after treatment with HCl. This approach was applied to synthesize 15 g of compound cis-10 in 53% overall yield (4 steps, based on compound 11). In order to synthesize the diastereomeric compound trans10, compound 13 was first transformed to lactone 15 by reaction with 1,1′-carbonyldiimidazole (CDI) and then reacted with 1-phenylethyl amine giving amide 16 (Scheme 2).

Dialkylation of diethyl malonate with commercially available 1-bromo-3-chloro-2-methylpropane gave the diester 20, which was hydrolyzed to monoester 21. This reaction was not stereoselective and afforded a mixture of cis- and trans-isomers of 21 (∼1:1 ratio). The mixture of diastereomers was submitted to Curtius rearrangement followed by ester hydrolysis and Bocdeprotection leading to 9.1 g of amino acids 19 (1:1 mixture of cis- and trans-diastereomers, 41% overall yield over 4 steps, based 1-bromo-3-chloro-2-methylpropane). Our attempts to separate isomers of 19 or intermediates 21 or 22 by chromatography or fractional crystallization failed. Therefore, pKa values were measured for the obtained 1:1 mixture of cisand trans-diastereomers which are assumed to have similar values as previously studied 3-alkyl/aryl substituted cyclobutyl amines15 and α-amino acids.16 Along with compounds cis- and trans-10 and 19 we measured the pKa values for natural L-threonine in the same assay since there are different pKa values for this compound in the literature depending on the methods and conditions used. Obtained pKa values are presented in Figure 3 which also contains the pKa values of earlier measured fluorinated cyclobutane amino acids cis- and trans-22.16 Most remarkable is the significant difference in the acidity of carboxylic groups for compounds cis- and trans-10 (ΔpKa = 1). This is probably the result of a hydrogen bond between the carboxylic and the 3hydroxyl groups where the latter is a H-bond acceptor. Such a

Scheme 2. Synthesis of Compound trans-10

Subsequent hydrolysis and Curtius rearrangement led to hydantoin 18 which was hydrolyzed under basic conditions and treated with HCl to afford compound trans-10 (as hydrochloride). This approach was applied to synthesize 3.4 g of hydrochloride trans-10 in 11% overall yield (7 steps, based on compound 11). With regard to future application in synthesis of small peptides, it was interesting to study acid−base properties of the prepared γ-hydroxy-α-amino acids. The spatially close OHgroup might significantly influence the basicity of the amino group in cis-10 and the acidity of the carboxylic group of trans10. Therefore, we compared their pKa values with those of Lthreonine. Also in order to evaluate its impact, we synthesized

Figure 3. Measured pKa data of compounds cis-/trans-10, 19, and Lthreonine together with earlier described compounds cis/trans-22.16 12864

DOI: 10.1021/acs.joc.7b02259 J. Org. Chem. 2017, 82, 12863−12868

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The Journal of Organic Chemistry difference was not observed for fluorinated amino acids cis- and trans-22, which have equal acidity16 (similar to acidity of compound 19). The data also demonstrate a slightly higher basicity of trans-10 in comparison to cis-10 that is opposite to difference in basicity of fluorinated analogues cis-/trans-22. Moreover, it should be noted that the pKa values of compound cis-10 are the same as those of L-threonine, while the values for compounds trans-10 are significantly different. Interestingly, the X-ray structure of compounds cis- and trans-10 (Figure 4) do not show any intramolecular

respectively) while the corresponding angle in cyclobutane was found to be 26°. Similar “flat” cyclobutane ring was also observed previously in the crystal structure of amino acid cis-22 (8.4(4)°).16 The distances between C1 and C3 atoms of the cyclobutane rings are 2.19 Å for trans-10 and 2.21 Å (in the protonated carboxylic unit) and 2.19 Å (in the zwitterion unit) for cis-10, respectively. These distances are ∼1.5 times longer as the C−C distances in L-threonine (1.532 Å in zwitterion structure19 or 1.544 Å in the L-threonine hydrochloride20). In conclusion we developed an efficient synthetic approach to new hydroxyl amino acids cis- and trans-10. The developed synthetic protocol can be applied for selective multigram synthesis of the amino acids. Measured pKa values for compounds cis- and trans-10 demonstrate a noticeable difference in acid−base properties for diastereoisomers presumably as a result of intramolecular interaction between OH-group and neighboring NH2- or CO2H groups in solution. Such interactions were not observed in the crystal structures of compounds cis- and trans-10, which exhibit a remarkably flat conformation of cyclobtuane rings in both compounds. Obtained compounds cis- or trans-10 can be considered as achiral conformationally restricted analogues of threonine with fixed spatial orientation of functional groups and a longer distance between the α-carbon and the OH bearing carbon atom in comparison to threonine. Both new amino acids are of interest for further investigations, e.g. incorporation into peptides instead of natural L-threonine.

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EXPERIMENTAL SECTION

General Experimental Methods. Melting points are uncorrected. NMR spectra were recorded at 300, 400, 500, and 600 MHz (1H), at 25 °C. TMS (for 1H and 13C NMR) was used as internal standard. Mass spectra (ESI-MS) were measured on a MicroTof apparatus. The progress of reactions was monitored by TLC-plates (silica gel 60 F254, Merck). Column chromatography was carried out on silica gel 60 (Merck, particle size 0.040−0.063 mm). Elemental analyses are correct within the limits of ±0.3% for C, H, and N. Compound 12 was prepared by a previously validated procedure.16 (1r,3r)-3-Hydroxy-1-(isopropoxycarbonyl)-3-methylcyclobutane-1-carboxylic Acid (13). Tetramethylammonium hydroxide (25% solution in water, 118.6 g, 0.325 mol) was slowly added to a stirred solution of compound 12 (80.0 g, 0.31 mol) in 800 mL i-PrOH at room temperature. The reaction mixture was stirred overnight, then concentrated under reduced pressure, diluted with 10% aq. NaHSO4 (500 mL) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with water and dried with Na2SO4, filtered, and concentrated under reduced pressure giving pure compound 13 which was used for the next step without purification. Yield: 66 g (98%). Colorless solid, m.p. = 91−93 °C. 1H NMR (400 MHz, CDCl3): δ 6.47 (br s, 2H), 5.07 (sept, J = 6.2 Hz, 1H), 2.57−2.76 (m, 4H), 1.35 (s, 3H), 1.25 (d, J = 6.2 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 176.1, 171.1, 69.6, 69.2, 44.8, 44.3, 27.3, 21.3. HRMS (ESITOF) m/z: [M − H]− calcd for C10H15O5− 215.0925; found 215.0934. Anal. calcd for: C10H16O5 (216.23): C, 55.55; H, 7.46; found: C, 55.40; H, 7.59. Isopropyl (1s,5s)-1-Methyl-3-oxo-2-oxa-4-azabicyclo[3.1.1]heptane-5-carboxylate (14). A mixture of compound 13 (25 g, 116 mmol), triethylamine (17.5 g, 173 mmol), and t-BuOH (85.55 g, 1.16 mol) were dissolved in toluene (200 mL). Then DPPA (35 g, 127 mmol) was added portionwise. The reaction mixture was slowly heated and stirred overnight under reflux. After cooling to room temperature, the reaction mixture was poured to saturated aq. NaHCO3 (200 mL) and extracted with EtOAc (2 × 300 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure to afford pure product 14 which was used for the next step without further purification.

Figure 4. Crystal structure for compounds cis-10 (a) and trans-10 (b). Thermal ellipsoids are shown at 30% probability.18

interactions between OH group and NH2- or CO2H-groups. In the packing diagram of cis-10 (Figure 4a as well as Figure S3 and Table S1 in SI) an intermolecular hydrogen bond (O3AH3A···O3B: 1.70(3) Å and 171.0(2)°) between a carboxyl OH and the carboxylate group of the next molecule, which exists as a zwitter ion, was observed. Moreover, intermolecular hydrogen bonds NH···O involving the ammonium groups and the neighboring hydroxyl oxygen atom OH (N1B−H21B···O1A: 1.94(2) Å and 164.2(2)°; N1B−H21A···O1B: 2.18(2) Å and 144.9(2)°) or carboxylate oxygen atoms of the zwitter ion group (N1A-H11C···O2B: 1.85(2) Å and 158.5(2)°; N1B− H21C···O3B: 2.06(2) Å and 177.4(2)°) were found in the packing diagram of cis-10. The chlorine anion interacts through hydrogen bonds with both hydroxyl groups and both ammonium groups. Similar, the packing diagram of trans-10 (Figure 4b as well as Figure S5 and Table S2 in SI) presents the formation of numerous hydrogen bonds involving the ammonium group, chlorine anion, hydroxyl, and carboxyl groups and a water molecule. These interactions build a complex three dimensional network. Furthermore, the cyclobutane rings in both compounds are comparatively flat: torsion angles C1−C2−C3-C4 are 5.0(1)° for cis-10; 1.4(1)° and 7.0(1)° for trans-10 (in the molecules with protonated carboxylic group and zwitter-ion structure, 12865

DOI: 10.1021/acs.joc.7b02259 J. Org. Chem. 2017, 82, 12863−12868

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The Journal of Organic Chemistry Yield: 21.5 g (87%). Light yellow solid, m.p.=135−136 °C. 1H NMR (500 MHz, CDCl3): δ 6.41 (s, 1H), 5.08 (sept, J = 6.2 Hz, 1H), 2.40−2.56 (m, 2H), 1.86−2.03 (m, 2H), 1.54 (s, 3H), 1.27 (d, J = 6.2 Hz, 6H). 13C NMR (126 MHz, CDCl3): δ 167.5, 152.4, 82.9, 70.4, 57.0, 43.1, 22.8, 21.6. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C 10 H 15 NNaO 4 + 236.0893; found 236.0882. Anal. calcd for: C10H15NO4 (213.23): C, 56.33; H, 7.09; N, 6.57; found C, 56.48; H, 6.98; N, 6.71. (1s,3s)-1-Amino-3-hydroxy-3-methylcyclobutane-1-carboxylic Acid Hydrochloride (cis-10). Compound 14 (20 g, 93.9 mmol) was added to a stirred solution of NaOH (22.5 g, 0.56 mol) in water (120 mL). The mixture was refluxed for 72 h, then cooled to room temperature, washed with EtOAc (2 × 200 mL). The aqueous phase was acidified with 12 N HCl aq. solution to pH 1−2 and then concentrated under reduced pressure. The resulting residue was treated with hot i-PrOH (200 mL) and the precipitate of NaCl formed was filtered off. The filtrate was concentrated to afford compound cis10 which was recrystallized from acetonitrile. Yield: 15.33 g (90%). Colorless solid, m.p.=195 °C (decomp.). 1H NMR (400 MHz, D2O): δ 2.77 (d, J = 14.6 Hz, 2H), 2.32 (d, J = 14.6 Hz, 2H), 1.33 (s, 3H). 13 C NMR (101 MHz, D2O) δ: 173.4, 68.0, 51.2, 43.9, 26.4. HRMS (ESI-TOF) m/z: [M−H]− calcd for C6H10NO3− 144.0666; found 144.0675. Isopropyl (1r,4s)-1-Methyl-3-oxo-2-oxabicyclo[2.1.1]hexane-4-carboxylate (15). A solution of compound 13 (31 g, 143.5 mmol) in DCM (310 mL) was added dropwise to a stirred solution of carbonyldiimidazole (23.25 g, 143.5 mmol) in DCM (500 mL). When gas evolution ended the resulting mixture was stirred additional 8 h. The reaction mixture was poured in saturated aq. NaHCO3 (300 mL), the layers was separated and aqueous phase was washed with DCM (2 × 250 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure giving crude product 15 which was purified by flash chromatography (EtOAc:hexane = 1:5, Rf = 0.23). Yield: 16.5 g, (58%). Colorless solid, m.p.=41−42 °C. 1H NMR (500 MHz, CDCl3): δ 5.02−5.12 (m, 1H), 2.60−2.71 (m, 2H), 2.44−2.55 (m, 2H), 1.56 (s, 3H), 1.25 (d, J = 6.3 Hz, 6H). 13C NMR (126 MHz, CDCl3): δ 173.2, 165.7, 84.3, 69.2, 54.2, 53.3, 21.5, 17.1. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C10H14NaO4+ 221.0784; found 221.0789. Anal. calcd for: C10H14O4 (198.21): C, 60.59; H, 7.12; found: C, 60.45; H, 7.26. Isopropyl (1r,3r)-3-Hydroxy-3-methyl-1-[(1-phenylethyl)carbamoyl]cyclobutane-1-carboxylate (16). Phenethylamine (10.1 g, 83.35 mmol) and lactone 15 (16,5 g, 83.35 mmol) were dissolved in 170 mL of DMF and heated at 85 °C for 3 days. Then the reaction mixture was cooled to room temperature, diluted with water (ca. 500 mL) and extracted with EtOAc (600 mL). The organic layers were combined and subsequently washed with water (2 × 300 mL), 10% aq. NaHSO4 (300 mL), and brine (300 mL) then dried with Na2SO4, filtered, and concentrated under reduced pressure giving crude product 16 which was purified by column chromatography (EtOAc/hexane = 2:1, Rf = 0.43). Colorless solid, m.p. = 76−78 °C. Yield: 25.8 g (97%). 1H NMR (400 MHz, CDCl3): δ 7.50 (br s, 1H), 7.11−7.41 (m, 5H), 5.00−5.15 (m, 2H), 3.56−4.25 (br s, 1H), 2.38− 2.82 (m, 4H), 1.48 (d, J = 6.9 Hz, 3H), 1.33 (s, 3H), 1.26 (d, J = 6.4, 3H), 1.24 (d, J = 6.4, 3H). 13C NMR (126 MHz, CDCl3): δ 173.7, 171.4, 142.9, 128.7, 127.4, 125.9, 69.6, 69.1, 49.4, 45.3, 45.2, 45.2, 27.8, 22.0, 21.5. HRMS (ESI-TOF) m/z: [M+Na] + calcd for C 18 H 25 NNaO 4 + 342.1676; found 342.1688. Anal. calcd for: C18H25NO4 (319.40): C, 67.69; H, 7.89; N, 4.39; found: C, 67.48; H, 7.94; N, 4.56. (1r,3r)-3-Hydroxy-3-methyl-1-[(1-phenylethyl)carbamoyl]cyclobutane-1-carboxylic Acid (17). A solution of NaOH (9.58 g, 239.5 mmol) in water (100 mL) was added to a stirred solution of compound 16 (25.5 g, 79.8 mmol). The reaction mixture was stirred overnight at room temperature and then concentrated to 1/3 volume under reduced pressure. The resulting residue was washed with EtOAc (250 mL). The aqueous layer was acidified by 10% aq. NaHSO4 until pH 1−2 and extracted with EtOAc (2 × 200 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated under reduced pressure giving crude compound 17 which was purified

by crystallization from CHCl3. Yield: 13.8 g (62%). Colorless solid, m.p.=106−108 °C. 1H NMR (500 MHz, CDCl3): δ 8.44 (br s, 1H), 7.22−7.40 (m, 5H), 5.05−5.18 (m, 1H), 2.91 (t, J = 13.6 Hz, 2H), 2.45−2.57 (m, 2H), 1.53 (d, J = 6.8 Hz, 3H), 1.46 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 176.2, 174.8, 142.5, 128.8, 127.6, 125.9, 70.9, 49.8, 45.2, 42.9, 28.3, 22.1. HRMS (ESI-TOF) m/z: [M−H]− calcd for C15H18NO4− 276.1241; found 276.1233. Anal. calcd for: C15H19NO4 (277.32): C, 64.97; H, 6.91; N, 5.05; found: C, 65.06; H, 6.87; N, 4.88. (2r,4r)-2-Hydroxy-2-methyl-7-(1-phenylethyl)-5,7-diazaspiro[3.4]octane-6,8-dione (18). Compound 17 (13.6 g, 49 mmol), triethylamine (10.25 mL, 73.5 mmol), DPPA (16.17 g, 58.8 mmol), and t-BuOH (36.25g, 490 mmol) were dissolved in toluene (120 mL). The reaction mixture was slowly heated to 100 °C (oil bath) and stirred overnight at reflux. The reaction mixture was cooled, poured into EtOAc (250 mL), and washed with 10% aqueous K2CO3 (200 mL) and water (200 mL). The organic phase was dried with Na2SO4, filtered, and concentrated under reduced pressure. Resulting solid was dissolved in minimal volume of DCM (20 mL) and then filtered through a thin pad of silica gel (150 g, 45 mm diameter). The silica gel was washed with DCM:MeOH (10:1) (3 × 100 mL). The resulting solutions were combined and concentrated under reduced pressure giving pure compound 18 which was used for the next step without purification. Yield 12.6 g (93%). Light yellow solid, m.p.=135−137 °C. 1 H NMR (500 MHz, CDCl3): δ 7.44 (d, J = 7.2 Hz, 2H), 7.24−7.38 (m, 3H), 6.82 (s, 1H), 5.33 (q, J = 7.1 Hz, 1H), 4.61 (br s, 1H), 2.48− 2.61 (m, 2H), 2.40 (d, J = 12.9 Hz, 2H), 1.85 (d, J = 7.3 Hz, 3H), 1.40 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 178.5, 156.5, 139.7, 128.4, 127.8, 127.1, 67.1, 55.4, 50.5, 47.2, 27.5, 17.1. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C15H18N2NaO3+ 297.1210; found 297.1222. Anal. calcd for: C15H18N2O3 (274.32): C, 65.68; H, 6.61; N, 10.21; found: C, 65.75; H, 6.49; N, 10.33. (1r,3r)-1-Amino-3-hydroxy-3-methylcyclobutanecarboxylic Acid Hydrochloride (trans-10). Compound 18 (12.6 g, 45.9 mmol) was added to a stirred solution of NaOH (14.69 g, 367.2 mmol) in water (120 mL). The mixture was heated and refluxed for 72 h, then cooled to room temperature, washed with MTBE (2 × 200 mL). The aqueous phase was acidified with 12 N HCl aq. solution to pH 1−2 and then concentrated under reduced pressure. The resulting residue was treated with hot i-PrOH (200 mL) and the precipitate of NaCl formed was filtered off. The filtrate was concentrated to afford compound trans-10, which was crystallized from acetonitrile. Yield: 3.43 g (51%). Yellow solid, m.p. = 210 (decomp.). 1H NMR (500 MHz, D2O): δ 2.66 (d, J = 13.4 Hz, 2H), 2.46 (d, J = 13.5 Hz, 2H), 1.31 (s, 3H). 13C NMR (126 MHz, D2O): δ 174.1, 67.7, 51.4, 44.0, 27.8. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C6H10NO3− 144.0666; found 144.0673. Diethyl 3-Methylcyclobutane-1,1-dicarboxylate (20). Diethyl malonate (61.65 g, 385 mmol) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil, 14.00 g, 350 mmol) in DMF (600 mL) keeping temperature below 30 °C. After additional 20 min, 1-bromo-3-chloro-2-methylpropane was added and the resulting solution was heated to 70 °C and stirred overnight at this temperature. After cooling, the reaction mixture was poured into 1.2 L of water and extracted with Ethyl Acetate (2 × 500 mL). Organic layers were combined, washed with water (2 × 500 mL), dried with Na2SO4 and concentrated under reduced pressure giving crude compound 20 which was purified by column chromatography (EtOAc:hexane, 1:5, Rf = 0.55). Yield 22.5 g (60%). Colorless oil. 1 H NMR (500 MHz, CDCl3): δ 4.27−4.10 (m, 4H), 2.70−2.56 (m, 2H), 2.51−2.38 (m, 1H, CH), 2.19−2.07 (m, 2H), 1.30−1.18 (m, 6H), 1.05 (d, J = 6.5 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 172.1, 171.8, 61.3, 61.1, 49.4, 36.2, 24.6, 21.5, 14.0. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C11H18NaO4+ 237.1097; found 237.1083. Anal. calcd for: C11H18O4 (214.26): C, 61.66; H, 8.47; found: C, 61.49; H, 8.33. 1-(Ethoxycarbonyl)-3-methylcyclobutane-1-carboxylic Acid (21). NaOH (3.93 g, 98 mmol) was dissolved in water (150 mL) and then added to stirred solution of compound 20 (21.5 g, 100 mmol) in EtOH (150 mL). Resulting mixture was stirred overnight at room temperature, then concentrated under reduced pressure, diluted with 12866

DOI: 10.1021/acs.joc.7b02259 J. Org. Chem. 2017, 82, 12863−12868

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The Journal of Organic Chemistry water (200 mL), and washed with EtOAc (100 mL). The aqueous layer was acidified with 1 M HCl to pH 1−2 and extracted with EtOAc (3 × 100 mL). Organic layers were combined and dried with Na2SO4, and concentrated under reduced pressure giving pure compound 21 (as ∼1:1 mixture of cis- and trans-isomers) which was used for the next step without additional purification. Yield 16.42 g (88%). Colorless solid, m.p. = 33−35 °C. Signals of both diastereomers are partially overlapping in NMR spectra. 1H NMR (500 MHz, CDCl3): δ 11.44 (s, 1H), 4.30−4.18 (m, 2H, CH2O), 2.79−2.63 (m, 2H, 2Ha of 2CH2), 2.60−2.43 (m, 1H, CH), 2.29−2.15 (m, 2H, 2Hb of 2CH2), 1.33−1.25 (m, 3H, CH3), 1.15−1.04 (m, 3H, CH3). 13C NMR (126 MHz, CDCl3): δ 178.1, 177.6, 171.9, 171.6, 61.8, 61.7, 49.3, 49.3, 36.4, 24.7, 24.6, 21.6, 14.0. HRMS (ESI-TOF) m/z: [M−H]− calcd for C9H13O4− 185.0819; found 185.0830. Anal. calcd for: C9H14O4 (186.21): C, 58.05; H, 7.58; found: C, 58.19; H, 7.42. 1-Amino-3-methylcyclobutane-1-carboxylic Acid Hydrochloride (19). Compound 21 (14.00 g, 75.23 mmol), triethylamine (15.7 mL, 112.8 mmol), DPPA (22.75 g, 82.73 mmol), and t-BuOH (105 mL, 1.13 mol) were dissolved in toluene (250 mL). The resulting mixture was slowly heated to 100 °C (oil bath) and stirred overnight at reflux. The reaction mixture was cooled, poured into EtOAc (450 mL), and washed with 10% aqueous K2CO3 (200 mL) and water (200 mL). The organic phase was dried with Na2SO4 and concentrated under reduced pressure giving crude ethyl 1-[(tert-butoxycarbonyl)amino]-3methylcyclobutanecarboxylate. This material was used for the next step without purification. The obtained crude material was dissolved in THF (120 mL) and solution of LiOH·H2O (9.5 g, 225.6 mmol) in water (360 mL) was added. The reaction mixture was stirred overnight, concentrated under reduced pressure to ∼150 mL volume and washed with EtOAc (250 mL). The aqueous layer was acidified with 1 M HCl to pH 1−2 and extracted by CHCl3 (3 × 100 mL). Organic layers were combined and dried with Na2SO4 and concentrated under reduced pressure giving pure 1-[(tertbutoxycarbonyl)amino]-3-methylcyclobutanecarboxylic acid which was used for the next step without purification. 4 M HCl solution in dioxane was added dropwise to a solution of the obtained 1-[(tertbutoxycarbonyl)amino]-3-methylcyclobutanecarboxylic acid (13.3 g, 58.00 mmol) in MeOH (100 mL). The reaction mixture was stirred overnight and concentrated under reduced pressure giving pure compound 19 (as ∼1:1 mixture of cis- and trans-isomers). Yield = 9.14 g (78% based on compound 22). Colorless solid, m.p. = 226 °C (decomp.). Signals of both diastereomers are present in NMR spectra. 1 H NMR (400 MHz, D2O): δ 2.69−2.48 (m, 2H), 2.37−2.27 (m, 2H), 2.00−1.85 (m, 1H), 1.05−1.00 (m, 3H). 13C NMR (101 MHz, D2O): δ 174.5, 174.4 55.5, 53.5, 37.3, 36.0, 22.9, 22.7, 21.1, 20.1. HRMS (ESI-TOF) m/z: [M−H]− calcd for C6H10NO2− 128.0717; found 128.0705. Anal. calcd for: C6H12ClNO2 (165.62): C, 43.51; H, 7.30; N, 8.46. Found: C, 43.38; H, 7.33; N, 8.61. X-ray Diffractions. Data sets for compound 14 were collected with an APEX II CCD Bruker diffractometer. Data sets for compound trans-10 were collected with a D8 Venture Dual Source 100 CMOS diffractometer. Programs used: data collection, APEX3 V2016.1−0 (Bruker AXS Inc., 2016); cell refinement, SAINT V8.37A (Bruker AXS Inc., 2015); data reduction, SAINT V8.37A (Bruker AXS Inc., 2015); absorption correction, SADABS V2014/7 (Bruker AXS Inc., 2014); structure solution SHELXT-2015 (Sheldrick, 2015); structure refinement SHELXL-2015 (Sheldrick, 2015); and graphics XP (Bruker AXS Inc., 1998).21−23 For compound cis-10 data sets were collected with a Nonius Kappa CCD diffractometer. Programs used: data collection, COLLECT;24 data reduction Denzo-SMN;25 absorption correction, Denzo;26 structure solution SHELXS-97;27 structure refinement SHELXL-97.22a Thermals ellipsoids are shown with 30% probability. R-values are given for observed reflections, and wR2 values are given for all reflections. X-ray Crystal Structure Analysis of Compound 14. A colorless plate-like specimen of C10H15NO4, approximate dimensions 0.100 mm × 0.250 mm × 0.300 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured. A total of 1262 frames were collected. The total exposure time was 17.93 h. The frames were integrated with the Bruker SAINT software package using

a wide-frame algorithm. The integration of the data using a triclinic unit cell yielded a total of 3638 reflections to a maximum θ angle of 65.07° (0.85 Å resolution), of which 1774 were independent (average redundancy 2.051, completeness = 94.6%, Rint = 3.07%, Rsig = 3.52%) and 1593 (89.80%) were greater than 2σ(F2). The final cell constants of a = 5.5617(2) Å, b = 9.7074(4) Å, c = 10.4167(3) Å, α = 88.569(2)°, β = 85.582(2)°, γ = 77.614(2)°, V = 547.65(3) Å3 are based upon the refinement of the XYZ-centroids of 2445 reflections above 20 σ(I) with 8.514° < 2θ < 133.2°. Data were corrected for absorption effects using the multiscan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.816. The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.7870 and 0.9210. The final anisotropic full-matrix least-squares refinement on F2 with 143 variables converged at R1 = 4.01%, for the observed data and wR2 = 10.31% for all data. The goodness-of-fit was 1.091. The largest peak in the final difference electron density synthesis was 0.239 e−/Å3 and the largest hole was −0.277 e−/Å3 with an RMS deviation of 0.052 e−/Å3. On the basis of the final model, the calculated density was 1.293 g/cm3 and F(000), 228 e−. X-ray Crystal Structure Analysis of Compound cis-10. Formula C6H12NO3Cl × C6H11NO3, M = 326.77, colorless crystal, 0.26 × 0.20 × 0.12 mm, a = 9.5142(2), b = 9.6019(3), c = 10.1754(2) Å, α = 63.556(1), β = 71.826(2), γ = 68.914(1)°, V = 763.7(1) Å3, ρcalc = 1.421 gcm−3, μ = 0.279 mm−1, empirical absorption correction (0.931 ≤ T ≤ 0.967), Z = 2, triclinic, space group P1̅ (No. 2), λ = 0.71073 Å, T = 173(2) K, ω and φ scans, 6298 reflections collected (±h, ± k, ± l), 2564 independent (Rint = 0.029) and 2478 observed reflections [I > 2σ(I)], 222 refined parameters, R = 0.031, wR2 = 0.079, max. (min.) residual electron density 0.28 (−0.18) e·Å−3, the position of the hydrogen atoms at N1A and N1B were refined freely; others hydrogen atoms were calculated and refined as riding atoms. X-ray Crystal Structure Analysis of trans-10. A colorless prismlike specimen of C6H14ClNO4, approximate dimensions 0.098 mm × 0.164 mm × 0.226 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured. The total exposure time was 19.96 h. The frames were integrated with the Bruker SAINT software package using a wide-frame algorithm. The integration of the data using an orthorhombic unit cell yielded a total of 14261 reflections to a maximum θ angle of 72.22° (0.81 Å resolution), of which 1836 were independent (average redundancy 7.767, completeness = 99.6%, Rint = 2.96%, Rsig = 1.97%) and 1797 (97.88%) were greater than 2σ(F2). The final cell constants of a = 10.2719(3) Å, b = 10.6899(3) Å, c = 16.9891(5) Å, V = 1865.50(9) Å3 are based upon the refinement of the XYZ-centroids of 9906 reflections above 20 σ(I) with 10.41° < 2θ < 144.4°. Data were corrected for absorption effects using the multiscan method (SADABS). The ratio of minimum to maximum apparent transmission was 0.898. The calculated minimum and maximum transmission coefficients (based on crystal size) are 0.5050 and 0.7250. The final anisotropic full-matrix least-squares refinement on F2 with 138 variables converged at R1 = 3.24%, for the observed data and wR2 = 7.99% for all data. The goodness-of-fit was 1.103. The largest peak in the final difference electron density synthesis was 0.369 e−/Å3 and the largest hole was −0.291 e−/Å3 with an RMS deviation of 0.052 e−/Å3. On the basis of the final model, the calculated density was 1.422 g/cm3 and F(000), 848 e−. Measurement of pKa Values. The measurements were done in accordance with the technical protocols for pKa measurement provided by Pion, Inc. and Sirius Analytical, Inc. Acquisition and analysis of the data were performed using SmartLogger II 1.0.14 software (Beckman Coulter). The recording pH-meter (Beckman Coulter pHi510) was calibrated before the measurements using calibration standards with pH 1.68 and 10.01. Data analysis was done using GraphPad Prism 5.01, and Excel 2010 software. pKa values of compounds cis-/trans-10, 19, and L-threonine were determined by pH-metric method based on potentiometric acid−base titration at 25 °C. The compounds were dissolved in acidified solution of NaCl (150 mM, pH 1.9) and slowly titrated with 75 mM sodium hydroxide solution, while recording pH of the solution as a function of NaOH volume used during the titration (construction of the titration curve). 12867

DOI: 10.1021/acs.joc.7b02259 J. Org. Chem. 2017, 82, 12863−12868

Note

The Journal of Organic Chemistry Titration of acidified NaCl solution in absence of any compounds is used for blank plotting. The titration assembly was based on Graseby MS16A Hourly Rate Syringe Driver (Smiths Medical) and a system of tubing and syringes. Buffering capacity was calculated for each point of titration curve as the ratio of the NaOH flow (constant) to the pH rise velocity. The pKa value was determined from resulting plot of buffering capacity versus pH as the maximum of buffering capacity.

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(11) Chernykh, A. V.; Radchenko, D. S.; Grygorenko, O. O.; Volochnyuk, D. M.; Shishkina, S. V.; Shishkin, O.; Komarov, I. V. RSC Adv. 2014, 4, 10894. (12) Radchenko, D. S.; Mykhailiuk, P. K.; Bezdudny, A. V.; Komarov, I. V. Synlett 2009, 2009, 1827. (13) Radchenko, D. S.; Grygorenko, O. O.; Komarov, I. V. Tetrahedron: Asymmetry 2008, 19, 2924. (14) Radchenko, D. S.; Michurin, O. M.; Grygorenko, O. O.; Scheinpflug, K.; Dathe, M.; Komarov, I. V. Tetrahedron 2013, 69, 505. (15) Chernykh, A. V.; Radchenko, D. S.; Chernykh, A. V.; Kondratov, I. S.; Tolmachova, N. A.; Datsenko, O. P.; Kurkunov, M. A.; Zozulya, S.; Kheylik, Yu. P.; Bartels, K.; Daniliuc, C. G.; Haufe, G. Eur. J. Org. Chem. 2015, 6466. (16) Chernykh, A. V.; Feskov, I. O.; Chernykh, A. V.; Kondratov, I. S.; Tolmachova, N. A.; Radchenko, D. S.; Daniliuc, C. G.; Haufe, G. Eur. J. Org. Chem. 2016, 4782. (17) For compounds 10 the cis/trans assignment refers to the orientation of hydroxyl- and amino groups and for compound 13 for the orientation of the hydroxyl- and carboxyl groups. (18) CCDC 1565861 (compound 14), CCDC 1565862 (compound cis-10), and CCDC 1565863 (compound trans-10) contains the supplementary crystallographic data for this article. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif (19) X-ray analysis of L-threonine zwitterion structure (LTHREO02) is described in: Ramanadham, M.; Sikka, S. K.; Chidambaram, R. Pramana 1973, 1, 247. (20) X-ray analysis of L -threonine hydrochloride structure (MOVLOZ) is described in Chapman, R. P.; Bryce, R. P. Phys. Chem. Chem. Phys. 2007, 9, 6219. (21) APEX3 (2016), SAINT (2015), and SADABS (2015), Bruker AXS Inc: Madison, Wisconsin, USA. (22) SHELX software (a) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112. (b) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Adv. 2015, 71, 3. (23) XP − Interactive molecular graphics, Version 5.1; Bruker AXS Inc.: Madison, Wisconsin, USA, 1998. (24) Hooft, R. W. W. COLLECT software; Bruker AXS: Delft, The Netherlands, 2008. (25) Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307. (26) Otwinowski, Z.; Borek, D.; Majewski, W.; Minor, W. Acta Crystallogr., Sect. A: Found. Crystallogr. 2003, 59, 228. (27) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr. 1990, 46, 467.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02259. X-ray crystallography data for compounds 14, cis-10, and trans-10 (CIF) Copies of the 1H and 13C NMR spectra for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]; Tel.: +38-044-537-3218; Fax: +38-044-537-32-53. *E-mail: [email protected]; Tel.: +49-251-83-33281; Fax: +49-251-83-39772. ORCID

Günter Haufe: 0000-0001-8437-9035 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work has been supported by the Deutsche Forschungsgemeinschaft (Ha 2145/9-2; AOBJ: 560896). We also thank Enamine Ltd. (Kiev) for technical and financial support and especially Drs. S. Zozulya and R. Morev (Bienta, Enamine Biology Services) for measuring the pKa values.

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REFERENCES

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DOI: 10.1021/acs.joc.7b02259 J. Org. Chem. 2017, 82, 12863−12868