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Article

Novel Furanoid α-Substitued α-Amino Acid as a Potent Turn Mimic in Peptide Synthesis

Institute of Chemical Sciences, Department of Organic Chemistry, P. J. Šafárik University, Moyzesova 11, SK-040 01 Košice, Slovak Republic
*
Author to whom correspondence should be addressed.
Molecules 2006, 11(7), 564-573; https://doi.org/10.3390/11070564
Submission received: 23 June 2006 / Revised: 20 July 2006 / Accepted: 21 July 2006 / Published: 26 July 2006

Abstract

:
A stereoselective approach has been developed to the new sugar amino acid and potential potent turn mimic 5-O-(tert-butyldimethylsilyl)-3-deoxy-1,2-O-isopropylidene-3-methoxycarbonylamino-α-d-xylofuranose 3-C-carboxylic acid (12), via the [3,3]-sigmatropic rearrangement of allylic thiocyanates (Z)-6 and (E)-7, prepared from d-xylose. The synthesis of a new dipeptide 13 is also described.

Introduction

Sugar amino acids (SAAs) can be found in nature largely as a molecules that combine the structural features of simple amino acids with those of simple carbohydrates [1]. The resulting hybrid is a highly substitued polyfunctionalized synthon which can be used for the preparation of modified analogues of biologically active peptides and/or oligosaccharides. Sugar amino acids represent an important class of conformationally constrained templates that have been used extensively in recent years in many peptidomimetic studies [1, 2] and have emerged as attractive building blocks for the incorporation of a sugar moiety into short peptide sequences using standard peptide coupling techniques, thus opening the door to novel peptidomimetics. They are also known as β-turn mimics and introduction of conformationally restricted nonpeptide isosteres into the peptide backbone to achieve desirable secondary structures is a great interest of many synthetic chemists [3].

Results and Discussion

We report herein a synthetic approach to 5-O-(tert-butyldimethylsilyl)-3-deoxy-1,2-O-isopropylidene-3-methoxycarbonylamino-α-d-xylofuranose 3-C-carboxylic acid (12) as a building block for peptide scaffold and conformationally restrained peptidomimetics. The Wittig reaction of known 5-O-TBDMS-1,2-O-isopropylidene-α-d-erytro-pentofuranos-3-ulose (1) [4] with ethoxycarbonylmethyl-enetriphenylphosphorane in dry dichloromethane gave, after chromatographic separation, pure (Z)-α,β-unsaturated ester 2 and its (E)-isomer 3 (9.6:1, 90.5%) (Scheme 1). The Z and E configurations of the exocyclic double bond in 2 and 3 were determined by 1H-NMR spectral analysis, including NOE data. The irradiation of the H-4 proton in 2 led to a 3.4 % enhancement of the intensity of H-6, while the irradiation of the H-6 proton resulted in a 3.9 % enhancement of the intensity of the H-4 signal, along with a small 1.3 % enhancement of the H-2 proton. On the other hand, when the H-2 proton in 3 was irradiated, a strong (5.0 %) NOE enhancement of the H-6 signal was observed, while the irradiation of the H-6 proton resulted in a 4.2 % enhancement of the intensity of the H-2 signal. Finally, the irradiation of the H-4 proton in 3 resulted in a 1.2 % enhancement of the intensity of the H-6 proton signal. Reduction of esters with LiAlH4 in dry diethyl ether afforded the allylic alcohols (Z)-4 and (E)-5 in 96 and 72% yields, respectively, after silica-gel chromatography. The thiocyanates (Z)-6 and (E)-7 were prepared by SN2 substitution of the O-mesyl group in the corresponding mesylates, derived from allylic alcohols (Z)-4 and (E)-5, by the thiocyanate group (KSCN/CH3CN) (Scheme 1).
Scheme 1.
Scheme 1.
Molecules 11 00564 g002
The thermal rearrangements of thiocyanates (Z)-6 and (E)-7 was carried out in heptane under a N2 atmosphere at 90 oC for 16 h and gave isothiocyanate 8 as the sole reaction product in 82 and 70% yields, respectively, after silica-gel chromatography. The epimeric isothiocyanate 8a was not detected in the reaction mixtures. The stereochemistry of the new quarternary carbon center (C-3) introduced in 8 was determined as (S) by 1H-NMR spectral analysis, including NOE data. Thus, when the H-4 proton was irradiated, a strong (8.2%) enhancement of the intensity of the H-6 signal was noted and the irradiation of the H-6 proton resulted in a 5.4 % enhancement of the intensity of the H-4 signal, indicating a cis relationship between the vinyl group and the H-4 proton on the furanoside ring (Figure 1).
Figure 1.
Figure 1.
Molecules 11 00564 g001
In our subsequent strategy, the isolated isothiocyanate 8 was converted into the desired α-substitued α-amino acid 12. In the first step, the isothiocyanate group was transformed into the thiourethane 9 in 95% yield after silica-gel chromatography by its reaction with CH3ONa in dry methanol at room temperature for 4 h. The thus prepared thiocarbamate 9 was converted into the corresponding oxygen derivative 10 by the action of mesitylnitrile oxide in acetonitrile (23 h, 93%) (Scheme 2).
Scheme 2.
Scheme 2.
Molecules 11 00564 g003
The oxidation of carbamate 10 was accomplished with a catalytic amount of ruthenium (III) chloride and NaIO4 in 2:2:3 CCl4/CH3CN/H2O to give aldehyde 11 in 70% yield. This aldehyde was then oxidized to the protected amino acid 12 in 74% yield (after flash chromatography) by treatment with sodium chlorite/2-methyl-2-butene (Scheme 2).
Among the methods available for the linkage of amino acids and peptides coupling with carbodiimides is one of the most frequently used. Our coupling reaction with DCC [5] and glycine methyl ester hydrochloride was performed in dry dichloromethane in the presence of Et3N at 0 oC for 1 h and then for 18 h at room temperature to afford dipeptide 13 in 78% yield after silica-gel chromatography (Scheme 2).

Conclusions

In summary, a stereocontrolled synthesis of the nonproteinogenic α-substitued α-amino acid 12 employing thiocyanates (Z)-6 and (E)-7 as the educts has been reported. The coupling reaction between this sugar amino acid 12 and glycine methyl ester provided dipeptide 13 as a potent peptidomimetic.

Experimental

General

The melting points were determined on the Kofler block and are uncorrected. Optical rotations were measured in chloroform with a P3002 Krűss polarimeter and reported as follows: [α]D25 (c in g per 100 mL). NMR spectra were recorded at room temperature on a Varian Mercury Plus 400 FT NMR spectrometer (1H at 400.13 MHz and 13C at 100.6 MHz). Chemical shifts are referenced either to tetramethylsilane used as internal standard for 1H or to the solvent signal (13C-NMR, δ CDCl3=77.0). 13C-NMR multiplicities were determined by using a DEPT pulse sequence. Reactions were routinely monitored by TLC (Merck 60 F254) and the products were visualized by UV light absorption at 254 nm or by spraying with Mo-reagent or KMnO4-reagent. All reactions were performed under an atmosphere of nitrogen. Solvents were purified by standard procedures and distilled before use. Column chromatography was carried out on the glass columns using Kieselgel (0.035-0.070 mm) silica gel. 5-O-(tert-Butyldimethylsilyl)-1,2-O-isopropylidene-α-D-erythro-pentofuranosyl-3-ulose (1) was prepared according to a published procedure [4].

5-O-(tert-Butyldimethylsilyl)-3-C-(Z)-carboethoxymethylene-3-deoxy-1,2-O-isopropylidene-α-d-xylo-furanose (2) and its (E)-isomer (3)

(Carboethoxymethylene)triphenylphosphorane (7.84 g, 22.4 mmol) was added to a solution of ketone 1 [4] (6.18 g, 20.4 mmol) in dry CH2Cl2 (80 mL). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (hexane-ethyl acetate, 13:1) to afford (E)-3 (0.65 g, 8.5%) and (Z)-2 (6.21 g, 82%) as colorless oils. Compound 3: [α]D25 = +233.9 (c 0.20); 1H-NMR: δ -0.01 (3H, s, CH3), 0.02 (3H, s, CH3), 0.86 (9H, s, 3 x CH3), 1.30 (3H, t, J =7.2 Hz, CH3), 1.40 (3H, bs, CH3), 1.43 (3H, bs, CH3), 3.78 (1H, dd, J5,5=10.4 Hz, J5,4=2.2 Hz, H5), 3.93 (1H, dd, J5,5=10.4 Hz, J5,4=1.6 Hz, H5), 4.19 (2H, q, J =7.2 Hz, CH2O), 5.03 (1H, ddd, J2,1=4.7 Hz, J2,4=1.8 Hz, J6,2=1.8 Hz, H2), 5.57-5.59 (1H, m, H4), 5.95 (1H, d, J2,1=4.7 Hz, H1), 6.13 (1H, dd, J6,4=1.8 Hz, J6,2=1.8 Hz, H6); 13C-NMR: δ -5.7, -5.5, 14.2, 18.2, 25.9 (3 x C), 27.7, 27.8, 60.5, 65.8, 82.4, 82.6, 104.5, 113.2, 116.2, 160.8, 165.5; Anal. Calcd for C18H32O6Si (372.54): C 58.03, H 8.66; found C 57.91, H 8.78. Compound 2: [α]D25 = +131.3 (c 0.20); 1H-NMR: δ 0.05 (3H, s, CH3), 0.06 (3H, s, CH3), 0.88 (9H, s, 3 x CH3), 1.30 (3H, t, J =7.1 Hz, CH3), 1.43 (3H, bs, CH3), 1.48 (3H, bs, CH3), 3.74 (1H, dd, J5,5=10.7 Hz, J5,4=3.5 Hz, H5), 3.79 (1H, dd, J5,5=10.7 Hz, J5,4=4.3 Hz, H5), 4.25 (2H, q, J =7.1 Hz, CH2O), 4.84-4.87 (1H, m, H4), 5.64-5.66 (1H, m, H2), 5.91 (1H, d, J1,2=4.1 Hz, H1), 6.01 (1H, dd, J6,2=1.7 Hz, J6,4=1.7 Hz H6); 13C-NMR: δ -5.6, -5.5, 14.1, 18.1, 25.7(3 x C), 27.2, 27.5, 60.5, 65.3, 78.8, 81.0, 105.4, 112.7, 116.5, 156.8, 164.9; Anal. Calcd for C18H32O6Si (372.54): C 58.03, H 8.66; found C 58.15, H 8.55.

5-O-(tert-Butyldimethylsilyl)-3-deoxy-3-C-(E)-(2-hydroxyethylidene)-1,2-O-isopropylidene-α-d-xylo-furanose (5)

LiAlH4 (0.045 g, 1.18 mmol) was added at 0 °C to a solution of (E)-3 (0.44 g, 1.18 mmol) in dry Et2O (7.2 mL). The reaction mixture was stirred at 0 °C for 15 min and then for 1.5 h at room temperature. The reaction was quenched by careful addition of water (0.3 mL) and the precipitate was removed by filtration. The filtrate was dried (Na2SO4) and concentrated under reduced pressure. Chromatography of the residue (hexane-ethyl acetate, 3:1) afforded 0.28 g (72 %) of allylic alcohol 5 as a white solid; m.p. 42 – 43 °C; [α]D25 = +79.6 (c 0.20); 1H-NMR: δ -0.01 (3H, s, CH3), 0.06 (3H, s, CH3), 0.88 (9H, s, 3 x CH3), 1.41 (3H, bs, CH3), 1.45 (3H, bs, CH3), 2.18-2.30 (1H, m, OH), 3.68 (1H, dd, J5,5=10.8 Hz, J5,4=4.0 Hz, H5), 3.72 (1H, dd, J5,5=10.8 Hz, J5,4=2.9 Hz, H5), 4.16-4.18 (2H, m, H7), 4.95-4.97 (1H, m, H2), 5.05-5.09 (1H, m, H4), 5.84 (1H, d, J2,1=4.4 Hz, H1), 5.99-6.04 (1H, m, H6); 13C-NMR: δ -5.6, -5.4, 18.3, 25.8 (3 x C), 27.6, 27.9, 60.1, 66.1, 80.2, 82.4, 104.5, 112.8, 126.6, 140.8; Anal. Calcd for C16H30O5Si (330.50): C 58.15, H 9.15; found C 58.25, H 9.05.

5-O-(tert-Butyldimethylsilyl)-3-deoxy-3-C-(Z)-(2-hydroxymethylidene)-1,2-O-isopropylidene-α-d-xylo-furanose (4)

To a solution of (Z)-2 (6.03 g, 16.2 mmol) in dry Et2O (100 mL) was added LiAlH4 (0.61 g, 16.2 mmol) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C and then for 1 hour at room temperature. The reaction was quenched with water (4.2 mL) and the precipitate was removed by filtration. The filtrate was dried (Na2SO4) and concentrated under reduced pressure. Chromatography of the residue (hexane-ethyl acetate, 3:1) gave 5.14 g (96 %) of allylic alcohol 4 as a colorless oil; [α]D25= +136.3 (c 0.79); 1H-NMR: δ 0.04 (3H, s, CH3), 0.05 (3H, s, CH3), 0.88 (9H, s, 3 x CH3), 1.40 (3H, bs, CH3), 1.47 (3H, bs, CH3), 2.29-2.35 (1H, m, OH), 3.61 (1H, dd, J5,5=10.6 Hz, J5,4=3.4 Hz, H5), 3.74 (1H, dd, J5,5=10.6 Hz, J5,4=3.6 Hz, H5), 4.29 (1H, m, H7), 4.37 (1H, m, H7) 4.76-4.80 (1H, m, H4), 5.18-5.21 (1H, m, H2), 5.84 (1H, dddd, J7,6=6.3 Hz, J7,6=6.2 Hz, J6,2=1.9 Hz, J6,4=1.9 Hz, H6), 5.92 (1H, d, J2,1=4.5 Hz, H1); 13C-NMR: δ -5.5, -5.4, 18.2, 25.8 (3 x C), 27.5, 27.6, 60.3, 66.4, 79.1, 81.9, 105.5, 112.4, 125.9, 141.5; Anal. Calcd for C16H30O5Si (330.50): C 58.15, H 9.15; found C 58.03, H 9.25.

5-O-(tert-Butyldimethylsilyl)-3-deoxy-1,2-O-isopropylidene-3-C-(E)-(2-thiocyanatoethylidene)-α-d-xylofuranose (7)

To a solution of (E)-5 (0.23 g, 0.70 mmol) in dry CH2Cl2 (1.7 mL) were added Et3N (0.15 mL, 1.04 mmol) and CH3SO2Cl (0.07 mL, 0.83 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and then at room temperature for 45 min. The solvent was evaporated under reduced pressure. The residue was diluted with diethyl ether (3 mL) and the solid was removed by filtration. Evaporation of the solvent under reduced pressure afforded crude mesylate which was used directly in the next reaction without any further purification. To a solution of crude mesylate (0.27 g, 0.66 mmol) in CH3CN (3 mL), KSCN (0.08 g, 0.82 mmol) was added. After stirring for 3 h at room temperature under a nitrogen atmosphere, the solvent was evaporated. The residue was diluted with diethyl ether (3 mL) and the solid was removed by filtration. The evaporation of the solvent under reduced pressure and chromatography of the residue (hexane-ethyl acetate, 7:1) afforded 0.18 g (70% from 5) of pure thiocyanate 7 as a colorless oil; [α]D25 = +164.3 (c 0.21); 1H-NMR: δ 0.05 (3H, s, CH3), 0.06 (3H, s, CH3), 0.88 (9H, s, 3 x CH3), 1.42 (3H, bs, CH3), 1.47 (3H, bs, CH3), 3.61-3.67 (2H, m, H7, H5), 3.74 (1H, dd, J5,5=10.6 Hz, J5,4=3.8 Hz, H5), 3.80 (1H, dd, J7,7= 13.0 Hz, J7,6= 8.8 Hz, H7), 4.98-5.03 (2H, m, H2, H4), 5.89 (1H, d, J2,1=4.4 Hz, H1), 5.95 (1H, dddd, J7,6= 8.8 Hz, J7,6=7.6 Hz, J6,4=1.8 Hz, J6,2=1.8 Hz, H6); 13C-NMR: δ -5.5, -5.4, 18.2, 25.8 (3 x C), 27.7, 27.9, 32.5, 66.3, 80.3, 81.9, 105.0, 111.4, 113.2, 119.4, 147.0; Anal. Calcd for C17H29NO4SSi (371.57): C 54.95, H 7.87, N 3.77, S 8.63; found C 54.83, H 7.77, N 3.85, S 8.50.

5-O-(tert-Butyldimethylsilyl)-3-deoxy-1,2-O-isopropylidene-3-C-(Z)-(2-thiocyanatoethylidene)-α-d-xylofuranose (6)

Et3N (3.18 mL, 22.9 mmol) and CH3SO2Cl (1.42 mL, 18.3 mmol) were added at 0 °C to a solution of (Z)-4 (5.05 g, 15.3 mmol) in dry CH2Cl2 (36 mL). The reaction mixture was stirred for 15 min at 0 °C and then for 45 min at room temperature. The solvent was evaporated under reduced pressure. The residue was diluted with diethyl ether (60 mL) and the solid was removed by filtration. Evaporation of the solvent under reduced pressure afforded crude mesylate which was used directly in the next reaction without further purification. To a solution of crude mesylate (5.99 g, 14.7 mmol) in CH3CN (55 mL), KSCN (1.78 g, 18.3 mmol) was added. After stirring for 5 h at room temperature the solvent was evaporated. The residue was diluted with diethyl ether (60 mL) and the solid was removed by fitration. The evaporation of the solvent at reduced pressure and chromatography of the residue (hexane-ethyl acetate, 7:1) gave 4.13 g (73% from 4) of pure thiocyanate 6 as a white solid; m.p. 58 – 60 °C; [α]D25 = +159.3 (c 0.34); 1H NMR: δ 0.06 (3H, s, CH3), 0.07 (3H, s, CH3), 0.89 (9H, s, 3 x CH3), 1.41 (3H, bs, CH3), 1.46 (3H, bs, CH3), 3.66 (1H, dd, J5,5=10.5 Hz, J5,4=3.2 Hz, H5), 3.74 (1H, dd, J5,5=10.5 Hz, J5,4=4.1 Hz, H5), 3.75 (1H, ddd, J7,7=13.1 Hz, J7,6=7.5 Hz, J7,2=1.2 Hz, H7), 3.95 (1H, dd, J7,7= 13.1 Hz, J7,6= 8.5 Hz, H7), 4.79-4.82 (1H, m, H4), 5.13-5.15 (1H, m, H2), 5.79-5.85 (1H, m, H6), 5.92 (1H, d, J2,1= 4.5 Hz, H1); 13C-NMR: δ -5.5, -5.4, 18.2, 25.9 (3 x C), 27.6, 27.9, 32.3, 66.3, 78.9, 81.7, 105.6, 111.7, 113.0, 119.0, 146.8; Anal. Calcd for C17H29NO4SSi (371.57): C 54.95, H 7.87, N 3.77, S 8.63; found C 54.86, H 7.95, N 3.85, S 8.55.

5-O-(tert-Butyldimethylsilyl)-3-deoxy-1,2-O-isopropylidene-3-isothiocyanato-3-C-vinyl-α-d-xylo-furanose (8)

A solution of (E)-7 (0.10 g, 0.27 mmol) in dry heptane (1 mL) was heated at 90 °C for 16 h. The solvent was evaporated under reduced pressure and chromatography of the residue on silica gel (hexane-ethyl acetate, 13:1) afforded 0.07 g (70%) of isothiocyanate 8. Alternatively, a solution of (Z)-6 (1.0 g, 2.69 mmol) in dry heptane (5.8 mL) was heated at 90 °C for 16 h under a nitrogen atmosphere. The solvent was evaporated under reduced pressure and the chromatography of the residue (hexane-ethyl acetate, 13:1) gave 0.82 g (82%) of isothiocyanate 8 as a colorless oil; [α]D25 = +49.8 (c 0.22); 1H-NMR: δ 0.06 (3H, s, CH3), 0.07 (3H, s, CH3), 0.88 (9H, s, 3 x CH3), 1.33 (3H, bs, CH3), 1.56 (3H, bs, CH3), 3.78 (1H, dd, J5,5=11.1 Hz, J5,4=5.5 Hz, H5), 3.86 (1H, dd, J5,5=11.1 Hz, J5,4=5.8 Hz, H5), 4.19 (1H, dd, J5,4=5.8 Hz, J5,4=5.5 Hz, H4), 4.50 (1H, d, J2,1=3.5 Hz, H2), 5.39 (1H, d, J7cis,6=10.6 Hz, H7cis), 5.56 (1H, d, J7trans,6=17.0 Hz, H7trans), 5.93 (1H, dd, J7trans,6=17.0 Hz, J7cis,6=10.6 Hz, H6), 5.96 (1H, d, J2,1=3.5 Hz, H1); 13C-NMR: δ -5.5, -5.4, 18.3, 25.8 (3 x C), 26.5, 26.7, 61.1, 74.9, 82.7, 87.9, 104.3, 113.1, 118.0, 130.7, 138.2; Anal. Calcd for C17H29NO4SSi (371.57): C 54.95, H 7.87, N 3.77, S 8.63; found C 54.82, H 7.98, N 3.68, S 8.71.

5-O-(tert-Butyldimethylsilyl)-3-deoxy-1,2-O-isopropylidene-3-methoxythiocarbonylamino-3-C-vinyl-α-d-xylofuranose (9)

To a solution of isothiocyanate 8 (0.58 g, 1.56 mmol) in dry methanol (15.5 mL) was added sodium methoxide (0.093 g, 1.72 mmol). The reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure and the residue was partitioned between CH2Cl2 (20 mL) and water (5 mL). The organic layer was dried (Na2SO4) and the solvent evaporated under reduced pressure. Chromatography of the residue (hexane–ethyl acetate, 11:1) afforded 0.60 g (95%) of compound 9 as a colorless oil; [α]D25 = +62.1 (c 0.49); 1H-NMR: δ 0.17 (3H, s, CH3), 0.18 (3H, s, CH3), 0.97 (9H, s, 3 x CH3), 1.35 (3H, bs, CH3), 1.52 (3H, bs, CH3), 3.71 (1H, dd, J5,4=3.0 Hz, J5,4=0.8 Hz, H4), 3.97-4.04 (2H, m, H5), 4.01 (3H, s, CH3O), 4.81 (1H, d, J2,1=3.7 Hz, H2), 5.29 (1H, dd, J7trans,6=17.5 Hz, J7trans,7cis=0.8 Hz, H7trans), 5.33 (1H, dd, J7cis,6=10.9 Hz, J7trans,7cis=0.8 Hz, H7cis), 5.92 (1H, d, J2,1=3.7 Hz, H1), 6.01 (1H, dd, J7trans,6=17.5 Hz, J7cis,6=10.9 Hz, H6), 9.37 (1H, bs, NH); 13C-NMR: δ -5.6, -5.3, 18.5, 26.0 (3 x C), 26.4, 26.7, 57.9, 59.1, 71.6, 78.6., 83.7, 104.5, 112.2, 117.0, 131.9, 191.3; Anal. Calcd for C18H33NO5SSi (403.62): C 53.57, H 8.24, N 3.47, S 7.94; found C 53.80, H 8.38, N 3.66, S 7.70.

5-O-(tert-Butyldimethylsilyl)-3-deoxy-1,2-O-isopropylidene-3-methoxycarbonylamino-3-C-vinyl-α-d-xylofuranose (10)

To a solution of 9 (0.56 g, 1.39 mmol) in CH3CN (13.5 mL) was added mesitylnitrile oxide (0.25 g, 1.53 mmol). The reaction mixture was stirred at room temperature for 23 h, acetonitrile was evaporated under reduce pressure. Chromatography of residue (hexane-ethyl acetate, 9:1) gave 0.50 g (93%) of 10 as a white crystals; m.p. 103 − 106 oC; [α]D25= +69.5 (c 0.28); 1H-NMR: δ 0.11 (3H, s, CH3), 0.12 (3H, s, CH3), 0.92 (9H, s, 3 x CH3), 1.33 (3H, bs, CH3), 1.52 (3H, bs, CH3), 3.62 (3H, s, CH3O), 3.79 (1H, m, H4), 3.94 (1H, d, J5,5=12.4 Hz, H5), 4.06 (1H, dd, J5,5=12.4 Hz, J5,4=3.0 Hz, H5), 5.07 (1H, d, J2,1=3.5 Hz, H2), 5.32 (1H, d, J7trans,6=17.5 Hz, H7trans), 5.37 (1H, d, J7cis,6=10.8 Hz, H7cis), 5.88 (1H, d, J2,1=3.5 Hz, H1), 6.08 (1H, dd, J7trans,6=17.5 Hz, J7cis,6=10.8 Hz, H6), 7.57 (1H, bs, NH); 13C-NMR: δ -5.7, -5.5, 18.2, 25.7 (3 x C), 26.3, 26.8, 51.8, 59.4, 68.6, 78.7., 83.4, 104.5, 112.1, 116.6, 132.6, 155.8; Anal. Calcd for C18H33NO6Si (387.55): C 55.79, H 8.58, N 3.61; found C 55.58, H 8.27, N 3.42.

5-O-(tert-Butyldimethylsilyl)-3-deoxy-1,2-O-isopropylidene-3-methoxycarbonylamino-α-d-xylo-furanose 3-C-carbaldehyde (11)

To a solution of 10 (0.30 g, 0.77 mmol) in 2:2:3 CCl4/CH3CN/H2O (8.5 mL) were added sodium periodate (0.68 g, 3.16 mmol) and ruthenium trichloride hydrate (4.2 mg, 2.5 mol %). The reaction mixture was stirred at room temperature for 20 h, then extracted with CH2Cl2 (3 x 20 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (hexane–ethyl acetate, 7:1) to afford 0.21 g (70%) of compound 11 as a colorless oil; [α]D25 = +69.3 (c 0.29); 1H-NMR: δ 0.09 (3H, s, CH3), 0.10 (3H, s, CH3), 0.90 (9H, s, 3 x CH3), 1.35 (3H, bs, CH3), 1.56 (3H, bs, CH3), 3.67 (3H, s, CH3O), 3.92 (1H, dd, J5,5=12.1 Hz, J5,4=1.8 Hz, H5), 4.01 (1H, dd, J5,5=12.1 Hz, J5,4=4.2 Hz, H5), 4.27 (1H, dd, J5,4=4.2 Hz, J5,4=1.8 Hz, H4) 5.12 (1H, d, J2,1=3.6 Hz, H2), 5.99 (1H, d, J2,1=3.6 Hz, H1), 7.31 (1H, bs, NH), 9.91 (1H, s, CHO); 13C-NMR: δ -5.7, -5.6, 18.1, 25.7 (3 x C), 26.3, 26.7, 52.4, 60.3, 71.8, 76.2, 84.4, 105.3, 113.3, 156.5, 197.4; Anal. Calcd for C17H31NO7Si (389.53): C 52.42, H 8.02, N 3.60; found C 52.27, H 8.27, N 3.42.

5-O-(tert-Butyldimethylsilyl)-3-deoxy-1,2-O-isopropylidene-3-methoxycarbonylamino-α-d-xylo-furanose 3-C-carboxylic acid (12)

A solution of NaClO2 (0.23 g, 2.54 mmol) and NaH2PO4 (0.285 g, 1.83 mmol) in water (1.55 mL) was added dropwise to the solution of aldehyde 11 (0.107 g, 0.275 mmol) in 4:4:1 acetonitrile/tert-butyl alcohol/2-methyl-2-butene (6.2 mL) at 0 oC over 5 min and then stirred at the same temperature for 25 min. The reaction mixture was poured into brine (8 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (1:2 hexane–ethyl acetate) to give 0.082 g (74%) of carboxylic acid 12 as a colorless oil; [α]D25 = +45.4 (c 0.57); 1H-NMR: δ 0.11 (3H, s, CH3), 0.12 (3H, s, CH3), 0.91 (9H, s, 3 x CH3), 1.35 (3H, bs, CH3), 1.53 (3H, bs, CH3), 3.76 (3H, s, CH3O), 4.22 (2H, m, H5), 4.42 (1H, m, H4), 5.04 (1H, d, J2,1=3.9 Hz, H2), 5.95 (1H, d, J2,1=3.9 Hz, H1), 8.30 (1H, bs, NH); 13C-NMR: δ -5.7, -5.6, 18.2, 25.6 (3 x C), 26.3, 26.5, 53.4, 61.0, 70.6, 76.8, 82.1, 104.3, 113.2, 159.5, 167.6; Anal. Calcd for C17H31NO8Si (405.52): C 50.35, H 7.71, N 3.45; found C 50.17, H 7.53, N 3.20.

5-O-[(tert-Butyldimethylsilyl)-3-deoxy-1,2-O-isopropylidene-3-methoxycarbonylamino-α-d-xylo-furanosyl-3-C-carbonyl]glycine methyl ester (13)

To a solution of glycine methyl ester hydrochloride (11 mg, 0.0886 mmol) in dry dichloromethane (0.5 mL) was added Et3N (0.041 mL, 0.30 mmol). The suspension was cooled to 0 oC. Then, a solution of aminoacid 12 (24 mg, 0.059 mmol) in dry CH2Cl2 (0.3 mL) and DCC (24.4 mg, 0.12 mmol) were added. The reaction mixture was stirred at 0 oC for 1 h and then at room temperature for 18 h. Dichloromethane (3 mL) was added and solution was washed with ice water (0.5 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (2:1 hexane–ethyl acetate) to afford 22 mg (78%) of dipeptide 13 as a colorless oil; [α]D25 = +35.1 (c 0.14); 1H-NMR: δ 0.11 (3H, s, CH3), 0.12 (3H, s, CH3), 0.91 (9H, s, 3 x CH3), 1.37 (3H, bs, CH3), 1.58 (3H, bs, CH3), 3.67 (3H, s, CH3O), 3.75 (3H, s, CH3O), 4.01 (1H, dd, J=18.4 Hz, JCH2,NH= 4.7 Hz, CH2NH), 4.13 (1H, dd, J5,5=12.4 Hz, J5,4=2.8 Hz, H5), 4.18 (1H, m, H5), 4.19 (1H, dd, J=18.4 Hz, JCH2,NH= 5.7 Hz, CH2NH), 4.25 (1H, m, H4), 5.15 (1H, d, J2,1=3.6 Hz, H2), 5.92 (1H, d, J2,1=3.6 Hz, H1), 7.93 (1H, bs, NH), 8.28 (1H, dd, JCH2,NH= 5.7 Hz, JCH2,NH= 4.7 Hz, NH); 13C-NMR: δ -5.7, -5.6, 18.2, 25.7 (3 x C), 26.5, 26.8, 41.5, 52.2, 52.3, 61.0, 69.7, 78.2, 82.6, 104.9, 113.1, 157.2, 168.3, 170.1; Anal. Calcd for C20H36N2O9Si (476.60): C 50.40, H 7.61, N 5.88; found C 50.22, H 7.49, N 5.61.

Acknowledgements

This work was supported by the Grant Agency (No.1/2472/05) of the Ministry of Education, Slovak Republic. NMR experiments were supported by Establishment of the “top-class” laboratory for Nuclear Magnetic Resonance (No. 200280203/2003) of the Ministry of Education, Slovak Rebublic.

References and Notes

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  • Sample Availability: Samples of the compounds (Z)-6, 8, 10 are available from the authors.

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MDPI and ACS Style

Martinková, M.; Gonda, J.; Raschmanová, J. Novel Furanoid α-Substitued α-Amino Acid as a Potent Turn Mimic in Peptide Synthesis. Molecules 2006, 11, 564-573. https://doi.org/10.3390/11070564

AMA Style

Martinková M, Gonda J, Raschmanová J. Novel Furanoid α-Substitued α-Amino Acid as a Potent Turn Mimic in Peptide Synthesis. Molecules. 2006; 11(7):564-573. https://doi.org/10.3390/11070564

Chicago/Turabian Style

Martinková, Miroslava, Jozef Gonda, and Jana Raschmanová. 2006. "Novel Furanoid α-Substitued α-Amino Acid as a Potent Turn Mimic in Peptide Synthesis" Molecules 11, no. 7: 564-573. https://doi.org/10.3390/11070564

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