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Stereoselective synthesis of (+)-valienamine starting from the naturally abundant (−)-shikimic acid
Tetrahedron: Asymmetry xxx (2015) xxx–xxx
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Stereoselective synthesis of (+)-valienamine starting from the naturally abundant ( )-shikimic acid Wei Ding, Jiang-Ping Yu, Xiao-Xin Shi ⇑, Liang-Deng Nie, Na Quan, Feng-Lei Li Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, 130 Mei-Long Road, Shanghai 200237, PR China
a r t i c l e
i n f o
Article history: Received 11 May 2015 Accepted 20 July 2015 Available online xxxx
a b s t r a c t A stereoselective synthesis of the pharmaceutically useful pseudo-aminosugar (+)-valienamine 1 is described. Epoxide 2 was first prepared via four steps in 79.7% overall yield starting from the naturally abundant ( )-shikimic acid. Epoxide 2 was then converted into the vicinal dihydroxyl compound 3 in 96% yield via a highly regio- and stereoselective water-mediated epoxide opening. Compound 3 was transformed into compound 4 in 86% yield over two steps via ester-reduction and benzylation of the three hydroxyl groups. Compound 4 was converted into azido compound 5 in 90% yield via an SN2-type nucleophilic substitution of the OMs leaving group with sodium azide. Ruthenium-catalyzed stereoselective dihydroxylation of compound 5 afforded dihydroxyl compound 6 in 91% yield. Compound 6 was transformed into compound 7 in 92% yield via selective mono-acetylation of the less-hindered hydroxyl group. Dehydration of tertiary alcohol 7 via an acid-mediated elimination furnished olefinic compound 8 in 85% yield. Finally, compound 8 was converted into the title compound 1 in 91% yield over two steps via deprotection and Lindlar-catalyst-promoted highly selective hydrogenation of the azido group (N3) in the presence of a double bond. (+)-Valienamine 1 was thus synthesized starting from the naturally abundant ( )-shikimic acid via 13 steps in 38.3% total yield. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction (+)-Valienamine 1 (Fig. 1), a pseudo-aminosugar, was first isolated from the culture broth of validamycin A (see Fig. 1) with Pseudomonas denitrificans in 1972.1 It was also isolated from the culture broth of validamycin A with Flavobacterium saccharophilum in 1980.2 Valienamine 1 is an essential core unit in many types of pseudo-oligosaccharides, such as validamycins,3 validoxylamines,4 acarbose (see Fig. 1),5 amylostatins,6 adiposins,7 acarviosines,8 and trestatins,9 all of which exhibit much stronger glucosidase inhibitory activities than valienamine itself. Acarbose, a valienaminebased pseudo-oligosaccharide, is currently used as an orally administrated medicine in clinics for controlling diabetes mellitus.10 Due to the pharmaceutical importance of (+)-valienamine 1 and the valienamine-based pseudo-oligosaccharides, they have attracted much interest from synthetic chemists since the first isolation in 1972. Several elegant stereoselective syntheses of (+)valienamine 1 have been reported,11–18 and these syntheses have started from natural materials such as cyclitol quebrachitol,11 12 13 14 D-glucose, D- or L-tartaric acid, D-arabinose, myo-inositol,15 ⇑ Corresponding author.
amino acid16 and ( )-quinic acid,17 or from some simple industrial chemicals.18 ( )-Shikimic acid (see Fig. 1) can be readily obtained in large quantities by extraction from Chinese star anise or other natural plants,19 and has recently been used as a starting material for the syntheses of oseltamivir phosphate,20 (+)-valiolamine,21 and some other chiral building blocks.22 Due to the wide availability of ( )-shikimic acid, and the structural resemblance between ( )-shikimic acid and (+)-valienamine 1, ( )-shikimic acid could be used as an appropriate starting material for the synthesis of (+)-valienamine 1. Herein, we report a stereoselective synthesis of (+)-valienamine 1 starting from the naturally abundant ( )-shikimic acid. 2. Results and discussion The synthetic route for the stereoselective synthesis of (+)-valienamine 1 starting from ( )-shikimic acid is shown in Scheme 1. Firstly, ( )-shikimic acid was converted into epoxy compound 2 via four steps in 79.7% overall yield according to a previously reported procedure.21 Epoxide 2 was then treated with hot water at 80 °C by Qu’s method23 to furnish ethyl 3-epi-5-Omethanesulfonyl shikimate 3 in 96% yield. In the water-mediated
E-mail address: [email protected] (X.-X. Shi). http://dx.doi.org/10.1016/j.tetasy.2015.07.013 0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ding, W.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.013
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W. Ding et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
and exposed to 4.0 equiv of benzoyl chloride, 5.0 equiv of triethylamine, and a catalytic amount of DMAP at 0 °C to room temperature in ethyl acetate; compound 4 was thus obtained in 86% yield over two steps. Compound 4 was then treated with 4.0 equiv of sodium azide at 90 °C in the presence of 2.0 equiv of triethylammonium hydrochloride in a mixed solvent of dimethyl sulfoxide and water (DMSO/H2O = 5:1) to afford azido compound 5 in 90% yield via an SN2-type nucleophilic substitution; meanwhile the (R)-configuration of C-5 was inverted to the (S)-configuration via a Walden-type inversion. Next, when compound 5 was treated with 1.5 equiv of sodium periodate (NaIO4), 1.0 equiv of sulfuric acid, and 0.002 equiv of ruthenium trichloride at 0–5 °C in a mixed solvent of ethyl acetate, acetonitrile, and water (EtOAc/CH3CN/H2O = 3:3:1), dihydroxyl compound 6 was obtained in 91% yield via Rh-catalyzed stereoselective dihydroxylation.24 The bulkiness of the benzoate (OBz) group at C-3 rendered the ruthenium catalyst to approach the double bond from the opposite side of the OBz group during the stereoselective dihydroxylation, thus the two stereogenic centers at the C-4 and C-5 positions of compound 6 have an (S,S)-absolute configuration. Stereoselectivity of the dihydroxylation was very high; almost none of the other diastereomers was detected by careful TLC monitoring. Furthermore, it was observed that the addition of sulfuric acid (H2SO4) could significantly reduce the loading of the ruthenium catalyst, otherwise 0.05 equiv of ruthenium trichloride should be used for the reaction in the absence of sulfuric acid. The mechanism for the role of the acid has been extensively discussed by Plietker et al.25 Compound 6 was treated with 1.2 equiv of acetic anhydride, 2.0 equiv of triethylamine, and a catalytic amount of N,N-dimethylaminopyridine (DMAP) at 0 °C in ethyl acetate to afford compound 7 in 92% yield via selective acetylation of the secondary hydroxyl group at the C-4 position. It is noteworthy that the tertiary hydroxyl group at the C-5 position was hard to acetylate even when using 3.0 equiv of acetic anhydride probably due to the bulkiness of the neighborhood of the C-5 position.
OH HO
HO
COOH
OH HO
HO
OH
NH2 (+)-valienamine 1
(−)-shikimic acid
OH
OH OH
HO
O
O HO
OH OH
HO
N H
OH
OH
OH validamycin A
valienamine unit
OH
OH O
HO
HO
O
O HO
OH OH O
OH
N H OH
O HO
OH
OH
OH
acarbose
Figure 1. Structures of some related compounds.
ring-opening of epoxide 2, water preferentially attacked the much more reactive allylic (C-3) position on the opposite side of the epoxide, and thus highly regio- and stereoselective epoxideopening of compound 2 occurred. Subsequently, when compound 3 was treated with 2.5 equiv of diisobutylaluminum hydride (DIBAL-H) at 10 °C in CH2Cl2, the ester group of compound 3 was selectively reduced, leaving the methanesulfonyl group (Ms) intact. The intermediate compound I-A (as shown in square parenthesis in Scheme 1) was used as such
HO
CO2 H
1
3
Ref.21
CO2 Et
HO
CO2 Et
a
O
HO
OH
b
5
HO
4 steps
96%
79.7%
OH
OMs
OMs
2
3
I-A
2
c
BzO OBz
HO
OMs
(-)-shikimic acid
BzO
HO
3
1
OBz
d
BzO
e
4 2
4
86% (2 steps)
BzO
N3
4
5
6
OAc OBz
BzO
3 4 2
85%
OBz
OH OH
h
1
BzO
92%
OH HO
5
i 91% (2 steps)
HO
N3
N3
N3
7
8
I-B
f
OBz
BzO
N3
g
5
1
OMs
OAc OH
BzO
91%
BzO
90%
BzO
OH OH
3
HO
OH
HO NH2 (+)-valienamine 1
Scheme 1. Stereoselective synthesis of (+)-valienamine 1 starting from ( )-shikimic acid. Reagents and conditions: (a) stirring at 80 °C for 2.5 h in pure water. (b) 2.5 equiv of diisobutylaluminum hydride (DIBAL-H) at 10 °C for 1 h in CH2Cl2. (c) 4.0 equiv of BzCl, 5.0 equiv of Et3N, 0.2 equiv of 4-N,N-dimethylaminopyridine (DMAP), 0 °C–rt for 6 h in EtOAc. (d) 4.0 equiv of NaN3, 2.0 equiv of Et3N–HCl, 90 °C for 4 h in aqueous dimethyl sulfoxide (DMSO/H2O = 5:1). (e) 1.5 equiv of NaIO4, 1.0 equiv of H2SO4, 0.002 equiv of RuCl3, 0–5 °C for 8 h in a mixed solvent of EtOAc/CH3CN/H2O (3:3:1). (f) 1.2 equiv of Ac2O, 2.0 equiv of Et3N, 0.1 equiv of DMAP, 0 °C for 4 h in EtOAc. (g) 5.0 equiv of SOCl2, 3.0 equiv of pyridine (Py), 41 °C for 4 h in CH2Cl2. (h) Stirring at rt for 24 h in a mixed solvent of CH3OH/NH3–H2O (4:1). (i) Lindlar-catalyst, H2, rt for 3 h in CH3OH.
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W. Ding et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
We next attempted the elimination of the tertiary hydroxyl group of compound 7 under various acidic conditions. The tested acids included sulfuric acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid. However, the elimination with all of these acids failed to give the desired product 8 in an acceptable yield. Fortunately, when compound 7 was treated with 5.0 equiv of thionyl chloride (SOCl2) and 3.0 equiv of pyridine at reflux (41 °C) in CH2Cl2,26 the elimination occurred smoothly to afford compound 8 in 85% yield. The three benzoyl groups and one acetyl group of compound 8 could be removed via ammonolysis27 in a single step. When a solution of compound 8 in a mixed solvent of methanol and concentrated aqueous ammonia (CH3OH/NH3H2O, 4:1) was stirred at room temperature for approximately 24 h, the three benzoyl groups and one acetyl group of compound 8 were cleanly removed to give an intermediate compound I-B as shown in the square parenthesis in Scheme 1. It was found that compound I-B gradually decomposed during the purification; hence the crude intermediate compound I-B was immediately exposed to H2 atmosphere in methanol at room temperature for 3 h in the presence of Lindlarcatalyst. Finally, the target compound (+)-valienamine 1 was obtained in 91% yield over two steps from compound 8 via a highly selective hydrogenation of the azido group (N3) in the presence of the double bond.28 3. Conclusion In conclusion, we have successfully developed a stereoselective synthesis of (+)-valienamine 1, using the naturally abundant and commercially available ( )-shikimic acid as the starting material. Target compound (+)-valienamine 1 was synthesized via 13 steps in 38.3% overall yield. Two reactions in the stereoselective synthesis are noteworthy. The first one is the ruthenium-catalyzed highly stereoselective dihydroxylation of compound 5; the presence of sulfuric acid is crucial for low catalyst-loading for this stereoselective dihydroxylation. The second one is the acid-mediated highly regioselective elimination of tertiary alcohol 7; the combination of thionyl chloride and pyridine is crucial for obtaining a good yield of the elimination of compound 7. In addition, the clean water-mediated ring-opening of epoxide 2 is also noteworthy from a green chemistry point of view. 4. Experimental 4.1. General 1 H and 13C NMR spectra were acquired on a Bruker AM-400 instrument. Chemical shifts were given on the delta scale as parts per million (ppm) with tetramethylsilane (TMS) as the internal standard. IR spectra were recorded on a Nicolet Magna IR-550 spectrometer. MS spectra were recorded on a Shimadzu GC–MS 2010 (EI) or a Mariner Mass Spectrum (ESI) equipment. Optical rotations of chiral compounds were measured on WZZ-1S polarimeter at room temperature. Melting points were determined on a Mel-TEMP II melting point apparatus. Column chromatography was performed on silica gel. All chemicals were analytically pure, and were used as received from the chemical suppliers. Epoxide 2 was obtained in 79.7% yield from ( )-shikimic acid according to the literature.21
4.2. (3S,4R,5R)-Ethyl 5-O-(methanesulfonyl)shikimate 3 A suspension of compound 2 (5.000 g, 19.06 mmol) in H2O (50 mL) in a flask with a condenser was vigorously stirred at 80 °C for 2.5 h. After the reaction was complete (checked by TLC,
3
eluent: EtOAc/hexane = 1:2), sodium chloride (10.00 g, 171.1 mmol) was added, and the mixture was then gradually cooled down to room temperature. The aqueous mixture was extracted twice with EtOAc (2 80 mL), and the organic extracts were combined and dried over anhydrous MgSO4. Evaporation of the solvent under vacuum gave the crude product as an off-white solid, which was triturated in a mixed solvent of ethyl acetate and hexane (1:4). Suction on a Buchner funnel afforded pure compound 3 (5.129 g, 18.30 mmol, 96%) as white crystals, mp 125–126 °C. [a]20 34.1 (c 1.00, CH3OH). 1H NMR (DMSO-d6, 400 MHz) D = d = 1.22 (t, J = 7.1 Hz, 3H, CH3 in COOEt), 2.36–2.46 (m, 1H, H-6), 2.83 (dd, J1 = 17.1 Hz, J2 = 5.8 Hz, 1H, H-6), 3.18 (s, 3H, CH3 in Ms), 3.50 (dd, J1 = 9.9 Hz, J2 = 7.6 Hz, 1H, H-4), 4.12–4.22 (m, 3H, CH2 in COOEt, and H-3), 4.54–4.64 (m, 1H, H-5), 5.52 (br s, 1H, OH), 5.67 (br s, 1H, OH), 6.56–6.61 (m, 1H, H-2). 13C NMR (DMSO-d6, 100 MHz) d = 165.08 (COOEt), 140.61 (C-2), 125.53 (C1), 79.54 (C-3), 73.12 (C-5), 70.86 (CH2 in COOEt), 60.52 (C-4), 37.71 (CH3 in Ms), 30.84 (C-6), 14.00 (CH3 in COOEt). HRMS (ESI): calcd for C10H17O7S [M+H]+: 281.0695; found: 281.0695. IR (KBr film): m = 3435 (O–H), 3242 (O–H), 1697 (C@O), 1350, 1294, 1266, 1174, 1096, 954, 841, 793, 744, 522 cm 1. 4.3. (3S,4R,5R)-1-Benzoyloxymethyl-3,4-dibenzoyloxy-5methanesulfonyloxycyclohex-1-ene 4 A solution of compound 3 (2.000 g, 7.135 mmol) in dichloromethane (40 mL) was cooled to 10 °C by a salt-ice bath, and a solution of DIBAL-H (1.0 M in hexane, 18.0 mL, 18.0 mmol) was slowly added using a syringe. When the addition was complete, the mixture was stirred at 10 °C for 1 h. Next, H2O (972.0 mg, 54.00 mmol) was added to quench the reaction, and the mixture was vigorously stirred at 10 °C for 15 min. Removal of the solvent by vacuum distillation gave a crude solid residue. Anhydrous methanol (40 mL) was added, the turbid mixture was vigorously stirred at room temperature for 30 min and then filtered by suction. The filter cake was washed with anhydrous methanol (2 20 mL) and the filtrate was concentrated under vacuum to give a pale-yellow oily residue. After the residue was dried under vacuum for several hours, it was dissolved in EtOAc (40 mL), and the resulting solution was cooled to 0 °C by an ice bath. Next, Et3N (3.610 g, 35.68 mmol), BzCl (4.012 g, 28.54 mmol), and a catalytic amount of DMAP (174.0 mg, 1.424 mmol) were added in turn. After the addition, the mixture was warmed to room temperature and stirred for 6 h. The reaction was quenched by adding a dilute hydrochloric acid aqueous solution (2 M, 20 mL). After the mixture was vigorously stirred for 5 min, two phases were separated, and the aqueous phase was extracted again with ethyl acetate (20 mL). The organic extracts were combined and washed with a dilute potassium carbonate aqueous solution (2 M, 20 mL) and brine (10 mL) in turn. The organic solution was then dried over anhydrous MgSO4. Evaporation of the solvent under vacuum gave a crude product as an off-white solid, which was triturated in a mixed solvent of ethyl acetate and hexane (1:8), and then filtered by suction to give pure compound 4 (3.536 g, 6.422 mmol, 90%) as 1 white crystals, mp 155–156 °C. [a]20 D = +85.1 (c 0.80, CHCl3). H NMR (CDCl3, 400 MHz) d = 2.82 (dd, J1 = 17.6 Hz, J2 = 9.3 Hz, 1H, H-6), 2.91 (s, 3H, CH3 in Ms), 2.98 (dd, J1 = 17.6 Hz, J2 = 6.2 Hz, 1H, H-6), 4.82 (ab peak, J = 13.6 Hz, 1H, CHHOBz), 4.87 (ab peak, J = 13.6 Hz, 1H, CHHOBz), 5.17–5.28 (m, 1H, H-5), 5.88 (dd, J1 = 10.1 Hz, J2 = 7.5 Hz, 1H, H-4), 5.94 (d, 1H, J = 2.2 Hz, H-2), 5.99 (dd, J1 = 2.2 Hz, J2 = 7.5 Hz, 1H, H-3), 7.38–7.52 (m, 6H, aromatic protons in Bz), 7.52–7.67 (m, 3H, aromatic protons in Bz), 7.98– 8.12 (m, 6H, aromatic protons in Bz). 13C NMR (CDCl3, 100 MHz) d = 165.96 (PhCOO), 165.87 (PhCOO), 165.43 (PhCOO), 133.58 (ArC), 133.52 (Ar-C), 133.41 (Ar-C), 133.37 (C-2), 129.84 (2C, Ar-C), 129.83 (2C, Ar-C), 129.74 (2C, Ar-C), 129.49 (Ar-C), 129.24 (Ar-C),
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129.01 (Ar-C), 128.59 (2C, Ar-C), 128.54 (2C, Ar-C), 128.47 (2C, ArC), 122.59 (C-1), 75.28 (C-5), 72.11 (C-3), 71.90 (CH2OBz), 66.10 (C4), 38.56 (CH3 in Ms), 32.79 (C-6). HRMS (ESI) calcd for C29H27O9S [M+H]+: 551.1376; found: 551.1378. IR (KBr film) m = 1731 (C@O), 1716 (C@O), 1354, 1275, 1253, 1174, 1108, 1070, 949, 709 cm 1. 4.4. (3S,4S,5S)-5-Azido-1-benzoyloxymethyl-3,4-dibenzoyloxycyclohex-1-ene 5 Compound 4 (2.000 g, 3.633 mmol) was dissolved in a mixed solvent of DMSO (15 mL) and H2O (3 mL), after which Et3NHCl (1.000 g, 7.265 mmol) and sodium azide (944.6 mg, 14.53 mmol) were added. The mixture was then heated and stirred at 90 °C for approximately 4 h. When TLC (eluent: EtOAc/hexane, 1:4) showed that the reaction was complete, ethyl acetate (60 mL) and H2O (60 mL) were added and the mixture was vigorously stirred for 15 min. The phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The organic extracts were combined, washed with brine (20 mL), and dried over anhydrous MgSO4. The organic solution was concentrated under vacuum to give a crude product, which was purified by flash chromatography (EtOAc/hexane, 1:6) to afford compound 5 (1.627 g, 3.270 mmol, 90%) as a colorless oil, [a]20 D = +76.6 (c 1.30, CHCl3). 1H NMR (CDCl3, 400 MHz) d = 2.61 (dd, J1 = 18.0 Hz, J2 = 5.2 Hz, 1H, H-6), 2.78 (dd, J1 = 18.0 Hz, J2 = 4.3 Hz, 1H, H-6), 4.29–4.39 (m, 1H, H-5), 4.85 (ab peak, J = 13.8 Hz, 1H, CHHOBz), 4.89 (ab peak, J = 13.8 Hz, 1H, CHHOBz), 5.69 (dd, J1 = 6.4 Hz, J2 = 2.4 Hz, 1H, H-4), 5.98–6.10 (m, 2H, H-3 and H-2), 7.39–7.53 (m, 6H, aromatic protons in Bz), 7.54–7.67 (m, 3H, aromatic protons in Bz), 8.02–8.15 (m, 6H, aromatic protons in Bz). 13C NMR (CDCl3, 100 MHz) d = 166.07 (PhCOO), 165.70 (PhCOO), 165.65 (PhCOO), 134.76 (C-1), 133.60 (Ar-C), 133.35 (2C, Ar-C), 129.97 (2C, Ar-C), 129.82 (2C, Ar-C), 129.73 (2C, Ar-C), 129.65 (Ar-C), 129.52 (Ar-C), 129.08 (Ar-C), 128.56 (2C, Ar-C), 128.55 (2C, Ar-C), 128.47 (2C, Ar-C), 121.86 (C-2), 72.63 (C-3), 69.49 (CH2OBz), 66.59 (C-4), 57.63 (C-5), 29.86 (C-6). HRMS (ESI): calcd for C28H23N3O6Na [M+Na]+: 520.1485; found: 520.1487. IR (neat): m = 2937, 2109 (N3), 1722 (C@O), 1451, 1267, 109, 1070, 1027, 710 cm 1. 4.5. (1S,2S,3S,4S,5S)-1-Azido-5-benzoyloxymethyl-2,3-dibenzoyloxy-4,5-dihydroxycyclohexane 6 An aqueous solution of H2SO4 (2.0 mL, 1 M, 2.000 mmol) and the powdered NaIO4 (644.9 mg, 3.015 mmol) were added into a 50-mL round-bottomed flask equipped with a magnetic stirrer bar. The mixture was stirred at room temperature for 10 min, and then a dilute aqueous solution of RuCl3 (400 lL, 0.01 M, 0.004 mmol) was added. The resulting solution was stirred at room temperature until the color turned bright yellow, after which the temperature was cooled down to 0 °C by an ice-bath. A solution of compound 5 (1.000 g, 2.010 mmol) in a mixed solvent of ethyl acetate (7 mL) and CH3CN (7 mL) was added at 0 °C. The mixture was then vigorously stirred at 0–5 °C for approximately 8 h. When TLC (eluent: EtOAc/hexane, 1:3) showed the reaction was complete, a saturated aqueous Na2S2O3 solution (15 mL) and a saturated aqueous NaHCO3 solution (15 mL) were added and the mixture was vigorously stirred for 15 min. The mixture was then transferred into a separatory funnel and extracted three times with ethyl acetate (3 20 mL). The combined organic extracts were then dried over anhydrous MgSO4 and filtered. Concentration of the filtrate under vacuum gave a crude product which was purified by flash chromatography (EtOAc/hexane, 1:4) to afford compound 6 (972.2 mg, 1.829 mmol, 91%) as white crystals, mp 77–78 °C. [a]20 7.65 (c 1.00, CHCl3). 1H NMR (CDCl3, 400 MHz) d = 2.14 D = (dd, J1 = 15.8 Hz, J2 = 3.5 Hz, 1H, H-6), 2.34 (dd, J1 = 15.8 Hz, J2 = 3.0 Hz, 1H, H-6), 2.93 (br s, 2H, two OH), 3.89 (d, J = 9.9 Hz,
1H, H-4), 4.30 (ab peak, J = 11.2 Hz, 1H, CHHOBz), 4.42–4.46 (m, 1H, H-1), 4.47 (ab peak, J = 11.2 Hz, 1H, CHHOBz), 5.52 (dd, J1 = 10.3 Hz, J2 = 3.5 Hz, 1H, H-2), 6.01 (dd, J1 = 10.3 Hz, J2 = 9.9 Hz, 1H, H-3), 7.32–7.43 (m, 4H, aromatic protons in Bz), 7.47–7.56 (m, 4H, aromatic protons in Bz), 7.63 (t, J = 7.4 Hz, 1H, aromatic proton in Bz), 7.95–8.03 (m, 4H, aromatic protons in Bz), 8.08 (d, J = 7.2 Hz, 2H, aromatic protons in Bz). 13C NMR (CDCl3, 100 MHz) d = 166.76 (PhCOO), 166.17 (PhCOO), 165.79 (PhCOO), 133.76 (Ar-C), 133.50 (Ar-C), 133.29 (Ar-C), 129.99 (2C, Ar-C), 129.82 (2C, Ar-C), 129.77 (2C, Ar-C), 129.46 (Ar-C), 129.31 (Ar-C), 128.61 (2C, Ar-C), 128.57 (2C, Ar-C), 128.50 (Ar-C), 128.35 (2C, Ar-C), 74.01 (C-3), 73.63 (C-2), 72.94 (CH2OBz), 71.77 (C-4), 66.57 (C-5), 59.06 (C-1), 33.01 (C-6). HRMS (ESI): calcd for C28H25N3O8Na [M+Na]+: 554.1539; found: 554.1537. IR (KBr film): m = 3482 (O-H), 2933, 2113 (N3), 1724 (C@O), 1451, 1271, 1113, 1070, 1027, 711 cm 1. 4.6. (1S,2S,3R,4S,5S)-4-Acetoxy-1-azido-5-benzoyloxymethyl2,3-dibenzoyloxy-5-hydroxycyclohexane 7 Compound 6 (1.000 g, 1.881 mmol) was dissolved in ethyl acetate (15 mL), after which triethylamine (380.7 mg, 3.762 mmol) and DMAP (23.0 mg, 0.188 mmol) were added. The resulting solution was cooled down to 0 °C by an ice bath. Acetic anhydride (230.4 mg, 2.257 mmol) was then added dropwise. After the addition was finished, the reaction mixture was further stirred at 0 °C for 4 h. The reaction was quenched by adding a dilute hydrochloric aqueous solution (1 M, 15 mL). After the mixture was vigorously stirred for 5 min, the two phases were separated, and the aqueous phase was extracted again with ethyl acetate (20 mL). The organic extracts were combined and washed with a dilute potassium carbonate aqueous solution (1 M, 10 mL) and brine (10 mL) in turn. The organic solution was dried over anhydrous MgSO4, and then was filtered. Evaporation of the solvent under vacuum gave an off-white solid residue, which was triturated in a mixed solvent of ethyl acetate and hexane (1:9) to give pure compound 7 (992.8 mg, 1.731 mmol, 92%) as white crystals, mp 164–165 °C. 1 [a]20 D = +21.2 (c 1.00, CHCl3). H NMR (CDCl3, 400 MHz) d = 1.95 (s, 3H, CH3 in Ac), 2.20 (dd, J1 = 15.5 Hz, J2 = 2.8 Hz, 1H, H-6), 2.31 (dd, J1 = 15.5 Hz, J2 = 2.0 Hz, 1H, H-6), 3.70 (br s, 1H, OH), 4.21 (ab peak, J = 11.4 Hz, 1H, CHHOBz), 4.28 (ab peak, J = 11.4 Hz, 1H, CHHOBz), 4.46–4.52 (m, 1H, H-1), 5.47–5.55 (m, 2H, H-2 and H4), 6.23 (dd, J1 = 10.3 Hz, J2 = 10.2 Hz, 1H, H-3), 7.30–7.43 (m, 4H, aromatic protons in Bz), 7.45–7.56 (m, 4H, aromatic protons in Bz), 7.61 (t, J = 7.1 Hz, 1H, aromatic proton in Bz), 7.92 (d, J = 8.0 Hz, 2H, aromatic protons in Bz), 8.01 (d, J = 8.0 Hz, 2H, aromatic protons in Bz), 8.09 (d, J = 8.0 Hz, 2H, aromatic protons in Bz). 13C NMR (CDCl3, 100 MHz) d = 169.90 (MeCOO), 165.91 (PhCOO), 165.65 (PhCOO), 165.63 (PhCOO), 133.80 (Ar-C), 133.48 (Ar-C), 133.39 (Ar-C), 130.07 (2C, Ar-C), 129.79 (2C, Ar-C), 129.72 (2C, Ar-C), 129.40 (Ar-C), 128.96 (Ar-C), 128.64 (2C, Ar-C), 128.57 (2C, Ar-C), 128.50 (2C, Ar-C), 128.22 (Ar-C), 74.13 (C-3), 73.67 (C4), 71.95 (C-2), 68.93 (CH2OBz), 65.89 (C-5), 58.73 (C-1), 33.73 (C-6), 20.55 (CH3 in Ac). HRMS (ESI): calcd for C30H27N3O9Na [M +Na]+: 596.1645; found: 596.1641. IR (KBr film): m = 3390 (O-H), 2121 (N3), 1749 (C@O), 1724 (C@O), 1265, 1220, 1114, 1069, 707 cm 1. 4.7. (1S,2S,3S,4R)-4-Acetoxy-1-azido-5-benzoyloxymethyl-2,3dibenzoyloxy-cyclohex-5-ene 8 Compound 7 (1.000 g, 1.744 mmol) was dissolved in CH2Cl2 (15 mL), then the resulting solution was cooled down to 0 °C by an ice bath. Next, SOCl2 (1.038 g, 8.725 mmol) and pyridine (413.9 mg, 5.232 mmol) were added in turn. After the addition was complete, the ice bath was removed, and the mixture was
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W. Ding et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
heated and stirred at reflux (41 °C) for approximately 4 h. When TLC (eluent: EtOAc/hexane, 1:4) showed the reaction was complete, the reaction was quenched by adding a dilute hydrochloric aqueous solution (1 M, 10 mL). After the mixture was vigorously stirred for 5 min, two phases were separated, and the aqueous phase was extracted twice with dichloromethane (2 25 mL). The organic extracts were combined and washed with a dilute potassium carbonate aqueous solution (1 M, 10 mL) and brine (10 mL) in turn. The organic solution was dried over anhydrous MgSO4, and then filtered. The filtrate was concentrated under vacuum to give a crude product, which was purified by flash chromatography (EtOAc/hexane, 1:6) to afford pure compound 8 (823.8 mg, 1.483 mmol, 85%) as white crystals, mp 80–81 °C. 1 [a]20 D = +71.8 (c 1.00, CHCl3). H NMR (CDCl3, 400 MHz) d = 1.99 (s, 3H, CH3 in Ac), 4.63 (dd, J1 = 4.9 Hz, J2 = 4.4 Hz, 1H, H-1), 4.86 (ab peak, J = 13.5 Hz, 1H, CHHOBz), 4.94 (ab peak, J = 13.5 Hz, 1H, CHHOBz), 5.59 (dd, J1 = 10.3 Hz, J2 = 4.4 Hz, 1H, H-2), 5.96 (dd, J1 = 10.3 Hz, J2 = 7.5 Hz, 1H, H-3), 6.05 (d, J = 7.5 Hz, 1H, H-4), 6.16 (d, J = 4.9 Hz, 1H, H-6), 7.31–7.42 (m, 4H, aromatic protons in Bz), 7.43–7.55 (m, 4H, aromatic protons in Bz), 7.59 (t, J = 7.3 Hz, 1H, aromatic proton in Bz), 7.93 (d, J = 8.1 Hz, 2H, aromatic protons in Bz), 7.99 (d, J = 8.1 Hz, 2H, aromatic protons in Bz), 8.06 (d, J = 8.1 Hz, 2H, aromatic protons in Bz). 13C NMR (CDCl3, 100 MHz) d = 169.90 (MeCOO), 165.88 (PhCOO), 165.63 (PhCOO), 165.59 (PhCOO), 136.60 (C-5), 133.64 (Ar-C), 133.42 (Ar-C), 133.38 (Ar-C), 130.00 (2C, Ar-C), 129.77 (3C, Ar-C), 129.42 (Ar-C), 129.03 (Ar-C), 128.56 (2C, Ar-C), 128.52 (Ar-C), 128.49 (2C, Ar-C), 128.45 (2C, Ar-C), 123.79 (C-6), 70.44 (C-4), 70.07 (CH2OBz), 69.83 (C-3), 63.30 (C-2), 57.13 (C-1), 20.57 (CH3 in Ac). HRMS (ESI): calcd for C30H25N3O8Na [M+Na]+: 578.1539; found: 578.1534. IR (KBr film): m = 2105 (N3), 1739 (C@O), 1723 (C@O), 1270, 1217, 1098, 1026, 706 cm 1. 4.8. (1S,2S,3S,4R)-1-Amino-5-hydroxymethyl-2,3,4-trihydroxycyclohex-5-ene [(+)-valienamine] 1 Compound 8 (300.0 mg, 0.540 mmol) was dissolved in a mixed solvent of methanol (4 mL) and ammonia hydrate (25% w/w, 1 mL), and the mixture was stirred at room temperature for approximately 24 h. The solution was then concentrated under vacuum to give an oily residue, which was dissolved in pure water (2 mL). The aqueous solution was washed twice with diethyl ether (2 10 mL), and the ether phase was decanted each time. The aqueous solution was concentrated under vacuum to remove the water to give an oily residue. The residue was dissolved in methanol (2 mL), and the solution was put into a flask, after which active carbon (50 mg) was added. The suspension mixture was stirred at 30 °C for 1 h. The mixture was then filtered through a thin layer of Celite to remove the active carbon. The wet cake was washed twice with methanol (2 5 mL), and the filtrate was concentrated to dryness. After the residue was dissolved in methanol (2 mL), the solution was transferred to a flask, which was equipped with a magnetic stirrer bar, and an inlet and an outlet of H2. Lindlar-catalyst (30% w/w, 35.0 mg) was then added. After the flask was purged with H2 several times, the black suspension was stirred at room temperature for 3 h under an atmosphere of H2. The mixture was then filtered through a thin layer of Celite to remove the Lindlar-catalyst. The solvent was removed by vacuum distillation to afford compound 1 (86.1 mg, 0.491 mmol, 91%) as a pale-yellow 14 syrup. [a]20 [a]D = +90 (c 0.43, H2O)}. D = +88.9 (c 0.35, H2O) {lit. 1 H NMR (D2O, 400 MHz): d = 3.41–3.47 (m, 1H, H-1), 3.54–3.61 (m, 2H, H-2 and H-3), 3.96 (d, J = 4.8 Hz, 1H, H-4), 4.00 (d, J = 13.8 Hz, 1H, CHHOH), 4.11 (d, J1 = 13.8 Hz, 1H, CHHOH), 5.69 (d, J = 5.1 Hz, 1H, H-6). 13C NMR (D2O, 100 MHz): d = 139.75 (C5), 123.84 (C-6), 72.06 (C-4), 71.84 (CH2OH), 69.92 (C-3), 61.34 (C-2), 48.98 (C-1). HRMS (ESI): calcd for C7H14NO4 [M+H]+:
5
176.0923; found: 176.0929. IR (neat) 3373 (O-H), 2881, 1582, 1385, 1315, 1105, 1010, 867 cm 1. Acknowledgment We are grateful to the National Natural Science Foundation of China (No. 20972048) for the financial support of this work. References 1. Kameda, Y.; Horii, S. J. Chem. Soc., Chem. Commun. 1972, 746–747. 2. Kameda, Y.; Asano, N.; Teranishi, M.; Matsui, K. J. Antibiot. 1980, 33, 1573–1574. 3. (a) Mahmud, T. Nat. Prod. Rep. 2003, 20, 137–166; (b) Chen, X.; Fan, Y.; Zheng, Y.; Shen, Y. Chem. Rev. 2003, 103, 1955–1977; (c) Asano, N.; Kameda, Y.; Matsui, K.; Horii, S.; Fukase, H. J. Antibiot. 1990, 43, 1039–1041; (d) Kameda, Y.; Asano, N.; Matsui, K.; Horii, S.; Fukase, H. J. Antibiot. 1988, 41, 1488–1492; (e) Kameda, Y.; Asano, N.; Yamaguchi, T.; Matsui, K.; Horii, S.; Fukase, H. J. Antibiot. 1986, 39, 1491–1494; (f) Horii, S.; Kameda, Y.; Kawahara, K. J. Antibiot. 1972, 25, 48–53; (g) Iwasa, T.; Kameda, Y.; Asai, M.; Horii, S.; Mizuno, K. J. Antibiot. 1971, 24, 119–123. 4. 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Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of (+)-valienamine starting from the naturally abundant ( )-shikimic acid Wei Ding, Jiang-Ping Yu, Xiao-Xin Shi ⇑, Liang-Deng Nie, Na Quan, Feng-Lei Li Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, 130 Mei-Long Road, Shanghai 200237, PR China
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Article history: Received 11 May 2015 Accepted 20 July 2015 Available online xxxx
a b s t r a c t A stereoselective synthesis of the pharmaceutically useful pseudo-aminosugar (+)-valienamine 1 is described. Epoxide 2 was first prepared via four steps in 79.7% overall yield starting from the naturally abundant ( )-shikimic acid. Epoxide 2 was then converted into the vicinal dihydroxyl compound 3 in 96% yield via a highly regio- and stereoselective water-mediated epoxide opening. Compound 3 was transformed into compound 4 in 86% yield over two steps via ester-reduction and benzylation of the three hydroxyl groups. Compound 4 was converted into azido compound 5 in 90% yield via an SN2-type nucleophilic substitution of the OMs leaving group with sodium azide. Ruthenium-catalyzed stereoselective dihydroxylation of compound 5 afforded dihydroxyl compound 6 in 91% yield. Compound 6 was transformed into compound 7 in 92% yield via selective mono-acetylation of the less-hindered hydroxyl group. Dehydration of tertiary alcohol 7 via an acid-mediated elimination furnished olefinic compound 8 in 85% yield. Finally, compound 8 was converted into the title compound 1 in 91% yield over two steps via deprotection and Lindlar-catalyst-promoted highly selective hydrogenation of the azido group (N3) in the presence of a double bond. (+)-Valienamine 1 was thus synthesized starting from the naturally abundant ( )-shikimic acid via 13 steps in 38.3% total yield. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction (+)-Valienamine 1 (Fig. 1), a pseudo-aminosugar, was first isolated from the culture broth of validamycin A (see Fig. 1) with Pseudomonas denitrificans in 1972.1 It was also isolated from the culture broth of validamycin A with Flavobacterium saccharophilum in 1980.2 Valienamine 1 is an essential core unit in many types of pseudo-oligosaccharides, such as validamycins,3 validoxylamines,4 acarbose (see Fig. 1),5 amylostatins,6 adiposins,7 acarviosines,8 and trestatins,9 all of which exhibit much stronger glucosidase inhibitory activities than valienamine itself. Acarbose, a valienaminebased pseudo-oligosaccharide, is currently used as an orally administrated medicine in clinics for controlling diabetes mellitus.10 Due to the pharmaceutical importance of (+)-valienamine 1 and the valienamine-based pseudo-oligosaccharides, they have attracted much interest from synthetic chemists since the first isolation in 1972. Several elegant stereoselective syntheses of (+)valienamine 1 have been reported,11–18 and these syntheses have started from natural materials such as cyclitol quebrachitol,11 12 13 14 D-glucose, D- or L-tartaric acid, D-arabinose, myo-inositol,15 ⇑ Corresponding author.
amino acid16 and ( )-quinic acid,17 or from some simple industrial chemicals.18 ( )-Shikimic acid (see Fig. 1) can be readily obtained in large quantities by extraction from Chinese star anise or other natural plants,19 and has recently been used as a starting material for the syntheses of oseltamivir phosphate,20 (+)-valiolamine,21 and some other chiral building blocks.22 Due to the wide availability of ( )-shikimic acid, and the structural resemblance between ( )-shikimic acid and (+)-valienamine 1, ( )-shikimic acid could be used as an appropriate starting material for the synthesis of (+)-valienamine 1. Herein, we report a stereoselective synthesis of (+)-valienamine 1 starting from the naturally abundant ( )-shikimic acid. 2. Results and discussion The synthetic route for the stereoselective synthesis of (+)-valienamine 1 starting from ( )-shikimic acid is shown in Scheme 1. Firstly, ( )-shikimic acid was converted into epoxy compound 2 via four steps in 79.7% overall yield according to a previously reported procedure.21 Epoxide 2 was then treated with hot water at 80 °C by Qu’s method23 to furnish ethyl 3-epi-5-Omethanesulfonyl shikimate 3 in 96% yield. In the water-mediated
E-mail address: [email protected] (X.-X. Shi). http://dx.doi.org/10.1016/j.tetasy.2015.07.013 0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ding, W.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.013
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W. Ding et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
and exposed to 4.0 equiv of benzoyl chloride, 5.0 equiv of triethylamine, and a catalytic amount of DMAP at 0 °C to room temperature in ethyl acetate; compound 4 was thus obtained in 86% yield over two steps. Compound 4 was then treated with 4.0 equiv of sodium azide at 90 °C in the presence of 2.0 equiv of triethylammonium hydrochloride in a mixed solvent of dimethyl sulfoxide and water (DMSO/H2O = 5:1) to afford azido compound 5 in 90% yield via an SN2-type nucleophilic substitution; meanwhile the (R)-configuration of C-5 was inverted to the (S)-configuration via a Walden-type inversion. Next, when compound 5 was treated with 1.5 equiv of sodium periodate (NaIO4), 1.0 equiv of sulfuric acid, and 0.002 equiv of ruthenium trichloride at 0–5 °C in a mixed solvent of ethyl acetate, acetonitrile, and water (EtOAc/CH3CN/H2O = 3:3:1), dihydroxyl compound 6 was obtained in 91% yield via Rh-catalyzed stereoselective dihydroxylation.24 The bulkiness of the benzoate (OBz) group at C-3 rendered the ruthenium catalyst to approach the double bond from the opposite side of the OBz group during the stereoselective dihydroxylation, thus the two stereogenic centers at the C-4 and C-5 positions of compound 6 have an (S,S)-absolute configuration. Stereoselectivity of the dihydroxylation was very high; almost none of the other diastereomers was detected by careful TLC monitoring. Furthermore, it was observed that the addition of sulfuric acid (H2SO4) could significantly reduce the loading of the ruthenium catalyst, otherwise 0.05 equiv of ruthenium trichloride should be used for the reaction in the absence of sulfuric acid. The mechanism for the role of the acid has been extensively discussed by Plietker et al.25 Compound 6 was treated with 1.2 equiv of acetic anhydride, 2.0 equiv of triethylamine, and a catalytic amount of N,N-dimethylaminopyridine (DMAP) at 0 °C in ethyl acetate to afford compound 7 in 92% yield via selective acetylation of the secondary hydroxyl group at the C-4 position. It is noteworthy that the tertiary hydroxyl group at the C-5 position was hard to acetylate even when using 3.0 equiv of acetic anhydride probably due to the bulkiness of the neighborhood of the C-5 position.
OH HO
HO
COOH
OH HO
HO
OH
NH2 (+)-valienamine 1
(−)-shikimic acid
OH
OH OH
HO
O
O HO
OH OH
HO
N H
OH
OH
OH validamycin A
valienamine unit
OH
OH O
HO
HO
O
O HO
OH OH O
OH
N H OH
O HO
OH
OH
OH
acarbose
Figure 1. Structures of some related compounds.
ring-opening of epoxide 2, water preferentially attacked the much more reactive allylic (C-3) position on the opposite side of the epoxide, and thus highly regio- and stereoselective epoxideopening of compound 2 occurred. Subsequently, when compound 3 was treated with 2.5 equiv of diisobutylaluminum hydride (DIBAL-H) at 10 °C in CH2Cl2, the ester group of compound 3 was selectively reduced, leaving the methanesulfonyl group (Ms) intact. The intermediate compound I-A (as shown in square parenthesis in Scheme 1) was used as such
HO
CO2 H
1
3
Ref.21
CO2 Et
HO
CO2 Et
a
O
HO
OH
b
5
HO
4 steps
96%
79.7%
OH
OMs
OMs
2
3
I-A
2
c
BzO OBz
HO
OMs
(-)-shikimic acid
BzO
HO
3
1
OBz
d
BzO
e
4 2
4
86% (2 steps)
BzO
N3
4
5
6
OAc OBz
BzO
3 4 2
85%
OBz
OH OH
h
1
BzO
92%
OH HO
5
i 91% (2 steps)
HO
N3
N3
N3
7
8
I-B
f
OBz
BzO
N3
g
5
1
OMs
OAc OH
BzO
91%
BzO
90%
BzO
OH OH
3
HO
OH
HO NH2 (+)-valienamine 1
Scheme 1. Stereoselective synthesis of (+)-valienamine 1 starting from ( )-shikimic acid. Reagents and conditions: (a) stirring at 80 °C for 2.5 h in pure water. (b) 2.5 equiv of diisobutylaluminum hydride (DIBAL-H) at 10 °C for 1 h in CH2Cl2. (c) 4.0 equiv of BzCl, 5.0 equiv of Et3N, 0.2 equiv of 4-N,N-dimethylaminopyridine (DMAP), 0 °C–rt for 6 h in EtOAc. (d) 4.0 equiv of NaN3, 2.0 equiv of Et3N–HCl, 90 °C for 4 h in aqueous dimethyl sulfoxide (DMSO/H2O = 5:1). (e) 1.5 equiv of NaIO4, 1.0 equiv of H2SO4, 0.002 equiv of RuCl3, 0–5 °C for 8 h in a mixed solvent of EtOAc/CH3CN/H2O (3:3:1). (f) 1.2 equiv of Ac2O, 2.0 equiv of Et3N, 0.1 equiv of DMAP, 0 °C for 4 h in EtOAc. (g) 5.0 equiv of SOCl2, 3.0 equiv of pyridine (Py), 41 °C for 4 h in CH2Cl2. (h) Stirring at rt for 24 h in a mixed solvent of CH3OH/NH3–H2O (4:1). (i) Lindlar-catalyst, H2, rt for 3 h in CH3OH.
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We next attempted the elimination of the tertiary hydroxyl group of compound 7 under various acidic conditions. The tested acids included sulfuric acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid. However, the elimination with all of these acids failed to give the desired product 8 in an acceptable yield. Fortunately, when compound 7 was treated with 5.0 equiv of thionyl chloride (SOCl2) and 3.0 equiv of pyridine at reflux (41 °C) in CH2Cl2,26 the elimination occurred smoothly to afford compound 8 in 85% yield. The three benzoyl groups and one acetyl group of compound 8 could be removed via ammonolysis27 in a single step. When a solution of compound 8 in a mixed solvent of methanol and concentrated aqueous ammonia (CH3OH/NH3H2O, 4:1) was stirred at room temperature for approximately 24 h, the three benzoyl groups and one acetyl group of compound 8 were cleanly removed to give an intermediate compound I-B as shown in the square parenthesis in Scheme 1. It was found that compound I-B gradually decomposed during the purification; hence the crude intermediate compound I-B was immediately exposed to H2 atmosphere in methanol at room temperature for 3 h in the presence of Lindlarcatalyst. Finally, the target compound (+)-valienamine 1 was obtained in 91% yield over two steps from compound 8 via a highly selective hydrogenation of the azido group (N3) in the presence of the double bond.28 3. Conclusion In conclusion, we have successfully developed a stereoselective synthesis of (+)-valienamine 1, using the naturally abundant and commercially available ( )-shikimic acid as the starting material. Target compound (+)-valienamine 1 was synthesized via 13 steps in 38.3% overall yield. Two reactions in the stereoselective synthesis are noteworthy. The first one is the ruthenium-catalyzed highly stereoselective dihydroxylation of compound 5; the presence of sulfuric acid is crucial for low catalyst-loading for this stereoselective dihydroxylation. The second one is the acid-mediated highly regioselective elimination of tertiary alcohol 7; the combination of thionyl chloride and pyridine is crucial for obtaining a good yield of the elimination of compound 7. In addition, the clean water-mediated ring-opening of epoxide 2 is also noteworthy from a green chemistry point of view. 4. Experimental 4.1. General 1 H and 13C NMR spectra were acquired on a Bruker AM-400 instrument. Chemical shifts were given on the delta scale as parts per million (ppm) with tetramethylsilane (TMS) as the internal standard. IR spectra were recorded on a Nicolet Magna IR-550 spectrometer. MS spectra were recorded on a Shimadzu GC–MS 2010 (EI) or a Mariner Mass Spectrum (ESI) equipment. Optical rotations of chiral compounds were measured on WZZ-1S polarimeter at room temperature. Melting points were determined on a Mel-TEMP II melting point apparatus. Column chromatography was performed on silica gel. All chemicals were analytically pure, and were used as received from the chemical suppliers. Epoxide 2 was obtained in 79.7% yield from ( )-shikimic acid according to the literature.21
4.2. (3S,4R,5R)-Ethyl 5-O-(methanesulfonyl)shikimate 3 A suspension of compound 2 (5.000 g, 19.06 mmol) in H2O (50 mL) in a flask with a condenser was vigorously stirred at 80 °C for 2.5 h. After the reaction was complete (checked by TLC,
3
eluent: EtOAc/hexane = 1:2), sodium chloride (10.00 g, 171.1 mmol) was added, and the mixture was then gradually cooled down to room temperature. The aqueous mixture was extracted twice with EtOAc (2 80 mL), and the organic extracts were combined and dried over anhydrous MgSO4. Evaporation of the solvent under vacuum gave the crude product as an off-white solid, which was triturated in a mixed solvent of ethyl acetate and hexane (1:4). Suction on a Buchner funnel afforded pure compound 3 (5.129 g, 18.30 mmol, 96%) as white crystals, mp 125–126 °C. [a]20 34.1 (c 1.00, CH3OH). 1H NMR (DMSO-d6, 400 MHz) D = d = 1.22 (t, J = 7.1 Hz, 3H, CH3 in COOEt), 2.36–2.46 (m, 1H, H-6), 2.83 (dd, J1 = 17.1 Hz, J2 = 5.8 Hz, 1H, H-6), 3.18 (s, 3H, CH3 in Ms), 3.50 (dd, J1 = 9.9 Hz, J2 = 7.6 Hz, 1H, H-4), 4.12–4.22 (m, 3H, CH2 in COOEt, and H-3), 4.54–4.64 (m, 1H, H-5), 5.52 (br s, 1H, OH), 5.67 (br s, 1H, OH), 6.56–6.61 (m, 1H, H-2). 13C NMR (DMSO-d6, 100 MHz) d = 165.08 (COOEt), 140.61 (C-2), 125.53 (C1), 79.54 (C-3), 73.12 (C-5), 70.86 (CH2 in COOEt), 60.52 (C-4), 37.71 (CH3 in Ms), 30.84 (C-6), 14.00 (CH3 in COOEt). HRMS (ESI): calcd for C10H17O7S [M+H]+: 281.0695; found: 281.0695. IR (KBr film): m = 3435 (O–H), 3242 (O–H), 1697 (C@O), 1350, 1294, 1266, 1174, 1096, 954, 841, 793, 744, 522 cm 1. 4.3. (3S,4R,5R)-1-Benzoyloxymethyl-3,4-dibenzoyloxy-5methanesulfonyloxycyclohex-1-ene 4 A solution of compound 3 (2.000 g, 7.135 mmol) in dichloromethane (40 mL) was cooled to 10 °C by a salt-ice bath, and a solution of DIBAL-H (1.0 M in hexane, 18.0 mL, 18.0 mmol) was slowly added using a syringe. When the addition was complete, the mixture was stirred at 10 °C for 1 h. Next, H2O (972.0 mg, 54.00 mmol) was added to quench the reaction, and the mixture was vigorously stirred at 10 °C for 15 min. Removal of the solvent by vacuum distillation gave a crude solid residue. Anhydrous methanol (40 mL) was added, the turbid mixture was vigorously stirred at room temperature for 30 min and then filtered by suction. The filter cake was washed with anhydrous methanol (2 20 mL) and the filtrate was concentrated under vacuum to give a pale-yellow oily residue. After the residue was dried under vacuum for several hours, it was dissolved in EtOAc (40 mL), and the resulting solution was cooled to 0 °C by an ice bath. Next, Et3N (3.610 g, 35.68 mmol), BzCl (4.012 g, 28.54 mmol), and a catalytic amount of DMAP (174.0 mg, 1.424 mmol) were added in turn. After the addition, the mixture was warmed to room temperature and stirred for 6 h. The reaction was quenched by adding a dilute hydrochloric acid aqueous solution (2 M, 20 mL). After the mixture was vigorously stirred for 5 min, two phases were separated, and the aqueous phase was extracted again with ethyl acetate (20 mL). The organic extracts were combined and washed with a dilute potassium carbonate aqueous solution (2 M, 20 mL) and brine (10 mL) in turn. The organic solution was then dried over anhydrous MgSO4. Evaporation of the solvent under vacuum gave a crude product as an off-white solid, which was triturated in a mixed solvent of ethyl acetate and hexane (1:8), and then filtered by suction to give pure compound 4 (3.536 g, 6.422 mmol, 90%) as 1 white crystals, mp 155–156 °C. [a]20 D = +85.1 (c 0.80, CHCl3). H NMR (CDCl3, 400 MHz) d = 2.82 (dd, J1 = 17.6 Hz, J2 = 9.3 Hz, 1H, H-6), 2.91 (s, 3H, CH3 in Ms), 2.98 (dd, J1 = 17.6 Hz, J2 = 6.2 Hz, 1H, H-6), 4.82 (ab peak, J = 13.6 Hz, 1H, CHHOBz), 4.87 (ab peak, J = 13.6 Hz, 1H, CHHOBz), 5.17–5.28 (m, 1H, H-5), 5.88 (dd, J1 = 10.1 Hz, J2 = 7.5 Hz, 1H, H-4), 5.94 (d, 1H, J = 2.2 Hz, H-2), 5.99 (dd, J1 = 2.2 Hz, J2 = 7.5 Hz, 1H, H-3), 7.38–7.52 (m, 6H, aromatic protons in Bz), 7.52–7.67 (m, 3H, aromatic protons in Bz), 7.98– 8.12 (m, 6H, aromatic protons in Bz). 13C NMR (CDCl3, 100 MHz) d = 165.96 (PhCOO), 165.87 (PhCOO), 165.43 (PhCOO), 133.58 (ArC), 133.52 (Ar-C), 133.41 (Ar-C), 133.37 (C-2), 129.84 (2C, Ar-C), 129.83 (2C, Ar-C), 129.74 (2C, Ar-C), 129.49 (Ar-C), 129.24 (Ar-C),
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129.01 (Ar-C), 128.59 (2C, Ar-C), 128.54 (2C, Ar-C), 128.47 (2C, ArC), 122.59 (C-1), 75.28 (C-5), 72.11 (C-3), 71.90 (CH2OBz), 66.10 (C4), 38.56 (CH3 in Ms), 32.79 (C-6). HRMS (ESI) calcd for C29H27O9S [M+H]+: 551.1376; found: 551.1378. IR (KBr film) m = 1731 (C@O), 1716 (C@O), 1354, 1275, 1253, 1174, 1108, 1070, 949, 709 cm 1. 4.4. (3S,4S,5S)-5-Azido-1-benzoyloxymethyl-3,4-dibenzoyloxycyclohex-1-ene 5 Compound 4 (2.000 g, 3.633 mmol) was dissolved in a mixed solvent of DMSO (15 mL) and H2O (3 mL), after which Et3NHCl (1.000 g, 7.265 mmol) and sodium azide (944.6 mg, 14.53 mmol) were added. The mixture was then heated and stirred at 90 °C for approximately 4 h. When TLC (eluent: EtOAc/hexane, 1:4) showed that the reaction was complete, ethyl acetate (60 mL) and H2O (60 mL) were added and the mixture was vigorously stirred for 15 min. The phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The organic extracts were combined, washed with brine (20 mL), and dried over anhydrous MgSO4. The organic solution was concentrated under vacuum to give a crude product, which was purified by flash chromatography (EtOAc/hexane, 1:6) to afford compound 5 (1.627 g, 3.270 mmol, 90%) as a colorless oil, [a]20 D = +76.6 (c 1.30, CHCl3). 1H NMR (CDCl3, 400 MHz) d = 2.61 (dd, J1 = 18.0 Hz, J2 = 5.2 Hz, 1H, H-6), 2.78 (dd, J1 = 18.0 Hz, J2 = 4.3 Hz, 1H, H-6), 4.29–4.39 (m, 1H, H-5), 4.85 (ab peak, J = 13.8 Hz, 1H, CHHOBz), 4.89 (ab peak, J = 13.8 Hz, 1H, CHHOBz), 5.69 (dd, J1 = 6.4 Hz, J2 = 2.4 Hz, 1H, H-4), 5.98–6.10 (m, 2H, H-3 and H-2), 7.39–7.53 (m, 6H, aromatic protons in Bz), 7.54–7.67 (m, 3H, aromatic protons in Bz), 8.02–8.15 (m, 6H, aromatic protons in Bz). 13C NMR (CDCl3, 100 MHz) d = 166.07 (PhCOO), 165.70 (PhCOO), 165.65 (PhCOO), 134.76 (C-1), 133.60 (Ar-C), 133.35 (2C, Ar-C), 129.97 (2C, Ar-C), 129.82 (2C, Ar-C), 129.73 (2C, Ar-C), 129.65 (Ar-C), 129.52 (Ar-C), 129.08 (Ar-C), 128.56 (2C, Ar-C), 128.55 (2C, Ar-C), 128.47 (2C, Ar-C), 121.86 (C-2), 72.63 (C-3), 69.49 (CH2OBz), 66.59 (C-4), 57.63 (C-5), 29.86 (C-6). HRMS (ESI): calcd for C28H23N3O6Na [M+Na]+: 520.1485; found: 520.1487. IR (neat): m = 2937, 2109 (N3), 1722 (C@O), 1451, 1267, 109, 1070, 1027, 710 cm 1. 4.5. (1S,2S,3S,4S,5S)-1-Azido-5-benzoyloxymethyl-2,3-dibenzoyloxy-4,5-dihydroxycyclohexane 6 An aqueous solution of H2SO4 (2.0 mL, 1 M, 2.000 mmol) and the powdered NaIO4 (644.9 mg, 3.015 mmol) were added into a 50-mL round-bottomed flask equipped with a magnetic stirrer bar. The mixture was stirred at room temperature for 10 min, and then a dilute aqueous solution of RuCl3 (400 lL, 0.01 M, 0.004 mmol) was added. The resulting solution was stirred at room temperature until the color turned bright yellow, after which the temperature was cooled down to 0 °C by an ice-bath. A solution of compound 5 (1.000 g, 2.010 mmol) in a mixed solvent of ethyl acetate (7 mL) and CH3CN (7 mL) was added at 0 °C. The mixture was then vigorously stirred at 0–5 °C for approximately 8 h. When TLC (eluent: EtOAc/hexane, 1:3) showed the reaction was complete, a saturated aqueous Na2S2O3 solution (15 mL) and a saturated aqueous NaHCO3 solution (15 mL) were added and the mixture was vigorously stirred for 15 min. The mixture was then transferred into a separatory funnel and extracted three times with ethyl acetate (3 20 mL). The combined organic extracts were then dried over anhydrous MgSO4 and filtered. Concentration of the filtrate under vacuum gave a crude product which was purified by flash chromatography (EtOAc/hexane, 1:4) to afford compound 6 (972.2 mg, 1.829 mmol, 91%) as white crystals, mp 77–78 °C. [a]20 7.65 (c 1.00, CHCl3). 1H NMR (CDCl3, 400 MHz) d = 2.14 D = (dd, J1 = 15.8 Hz, J2 = 3.5 Hz, 1H, H-6), 2.34 (dd, J1 = 15.8 Hz, J2 = 3.0 Hz, 1H, H-6), 2.93 (br s, 2H, two OH), 3.89 (d, J = 9.9 Hz,
1H, H-4), 4.30 (ab peak, J = 11.2 Hz, 1H, CHHOBz), 4.42–4.46 (m, 1H, H-1), 4.47 (ab peak, J = 11.2 Hz, 1H, CHHOBz), 5.52 (dd, J1 = 10.3 Hz, J2 = 3.5 Hz, 1H, H-2), 6.01 (dd, J1 = 10.3 Hz, J2 = 9.9 Hz, 1H, H-3), 7.32–7.43 (m, 4H, aromatic protons in Bz), 7.47–7.56 (m, 4H, aromatic protons in Bz), 7.63 (t, J = 7.4 Hz, 1H, aromatic proton in Bz), 7.95–8.03 (m, 4H, aromatic protons in Bz), 8.08 (d, J = 7.2 Hz, 2H, aromatic protons in Bz). 13C NMR (CDCl3, 100 MHz) d = 166.76 (PhCOO), 166.17 (PhCOO), 165.79 (PhCOO), 133.76 (Ar-C), 133.50 (Ar-C), 133.29 (Ar-C), 129.99 (2C, Ar-C), 129.82 (2C, Ar-C), 129.77 (2C, Ar-C), 129.46 (Ar-C), 129.31 (Ar-C), 128.61 (2C, Ar-C), 128.57 (2C, Ar-C), 128.50 (Ar-C), 128.35 (2C, Ar-C), 74.01 (C-3), 73.63 (C-2), 72.94 (CH2OBz), 71.77 (C-4), 66.57 (C-5), 59.06 (C-1), 33.01 (C-6). HRMS (ESI): calcd for C28H25N3O8Na [M+Na]+: 554.1539; found: 554.1537. IR (KBr film): m = 3482 (O-H), 2933, 2113 (N3), 1724 (C@O), 1451, 1271, 1113, 1070, 1027, 711 cm 1. 4.6. (1S,2S,3R,4S,5S)-4-Acetoxy-1-azido-5-benzoyloxymethyl2,3-dibenzoyloxy-5-hydroxycyclohexane 7 Compound 6 (1.000 g, 1.881 mmol) was dissolved in ethyl acetate (15 mL), after which triethylamine (380.7 mg, 3.762 mmol) and DMAP (23.0 mg, 0.188 mmol) were added. The resulting solution was cooled down to 0 °C by an ice bath. Acetic anhydride (230.4 mg, 2.257 mmol) was then added dropwise. After the addition was finished, the reaction mixture was further stirred at 0 °C for 4 h. The reaction was quenched by adding a dilute hydrochloric aqueous solution (1 M, 15 mL). After the mixture was vigorously stirred for 5 min, the two phases were separated, and the aqueous phase was extracted again with ethyl acetate (20 mL). The organic extracts were combined and washed with a dilute potassium carbonate aqueous solution (1 M, 10 mL) and brine (10 mL) in turn. The organic solution was dried over anhydrous MgSO4, and then was filtered. Evaporation of the solvent under vacuum gave an off-white solid residue, which was triturated in a mixed solvent of ethyl acetate and hexane (1:9) to give pure compound 7 (992.8 mg, 1.731 mmol, 92%) as white crystals, mp 164–165 °C. 1 [a]20 D = +21.2 (c 1.00, CHCl3). H NMR (CDCl3, 400 MHz) d = 1.95 (s, 3H, CH3 in Ac), 2.20 (dd, J1 = 15.5 Hz, J2 = 2.8 Hz, 1H, H-6), 2.31 (dd, J1 = 15.5 Hz, J2 = 2.0 Hz, 1H, H-6), 3.70 (br s, 1H, OH), 4.21 (ab peak, J = 11.4 Hz, 1H, CHHOBz), 4.28 (ab peak, J = 11.4 Hz, 1H, CHHOBz), 4.46–4.52 (m, 1H, H-1), 5.47–5.55 (m, 2H, H-2 and H4), 6.23 (dd, J1 = 10.3 Hz, J2 = 10.2 Hz, 1H, H-3), 7.30–7.43 (m, 4H, aromatic protons in Bz), 7.45–7.56 (m, 4H, aromatic protons in Bz), 7.61 (t, J = 7.1 Hz, 1H, aromatic proton in Bz), 7.92 (d, J = 8.0 Hz, 2H, aromatic protons in Bz), 8.01 (d, J = 8.0 Hz, 2H, aromatic protons in Bz), 8.09 (d, J = 8.0 Hz, 2H, aromatic protons in Bz). 13C NMR (CDCl3, 100 MHz) d = 169.90 (MeCOO), 165.91 (PhCOO), 165.65 (PhCOO), 165.63 (PhCOO), 133.80 (Ar-C), 133.48 (Ar-C), 133.39 (Ar-C), 130.07 (2C, Ar-C), 129.79 (2C, Ar-C), 129.72 (2C, Ar-C), 129.40 (Ar-C), 128.96 (Ar-C), 128.64 (2C, Ar-C), 128.57 (2C, Ar-C), 128.50 (2C, Ar-C), 128.22 (Ar-C), 74.13 (C-3), 73.67 (C4), 71.95 (C-2), 68.93 (CH2OBz), 65.89 (C-5), 58.73 (C-1), 33.73 (C-6), 20.55 (CH3 in Ac). HRMS (ESI): calcd for C30H27N3O9Na [M +Na]+: 596.1645; found: 596.1641. IR (KBr film): m = 3390 (O-H), 2121 (N3), 1749 (C@O), 1724 (C@O), 1265, 1220, 1114, 1069, 707 cm 1. 4.7. (1S,2S,3S,4R)-4-Acetoxy-1-azido-5-benzoyloxymethyl-2,3dibenzoyloxy-cyclohex-5-ene 8 Compound 7 (1.000 g, 1.744 mmol) was dissolved in CH2Cl2 (15 mL), then the resulting solution was cooled down to 0 °C by an ice bath. Next, SOCl2 (1.038 g, 8.725 mmol) and pyridine (413.9 mg, 5.232 mmol) were added in turn. After the addition was complete, the ice bath was removed, and the mixture was
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W. Ding et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
heated and stirred at reflux (41 °C) for approximately 4 h. When TLC (eluent: EtOAc/hexane, 1:4) showed the reaction was complete, the reaction was quenched by adding a dilute hydrochloric aqueous solution (1 M, 10 mL). After the mixture was vigorously stirred for 5 min, two phases were separated, and the aqueous phase was extracted twice with dichloromethane (2 25 mL). The organic extracts were combined and washed with a dilute potassium carbonate aqueous solution (1 M, 10 mL) and brine (10 mL) in turn. The organic solution was dried over anhydrous MgSO4, and then filtered. The filtrate was concentrated under vacuum to give a crude product, which was purified by flash chromatography (EtOAc/hexane, 1:6) to afford pure compound 8 (823.8 mg, 1.483 mmol, 85%) as white crystals, mp 80–81 °C. 1 [a]20 D = +71.8 (c 1.00, CHCl3). H NMR (CDCl3, 400 MHz) d = 1.99 (s, 3H, CH3 in Ac), 4.63 (dd, J1 = 4.9 Hz, J2 = 4.4 Hz, 1H, H-1), 4.86 (ab peak, J = 13.5 Hz, 1H, CHHOBz), 4.94 (ab peak, J = 13.5 Hz, 1H, CHHOBz), 5.59 (dd, J1 = 10.3 Hz, J2 = 4.4 Hz, 1H, H-2), 5.96 (dd, J1 = 10.3 Hz, J2 = 7.5 Hz, 1H, H-3), 6.05 (d, J = 7.5 Hz, 1H, H-4), 6.16 (d, J = 4.9 Hz, 1H, H-6), 7.31–7.42 (m, 4H, aromatic protons in Bz), 7.43–7.55 (m, 4H, aromatic protons in Bz), 7.59 (t, J = 7.3 Hz, 1H, aromatic proton in Bz), 7.93 (d, J = 8.1 Hz, 2H, aromatic protons in Bz), 7.99 (d, J = 8.1 Hz, 2H, aromatic protons in Bz), 8.06 (d, J = 8.1 Hz, 2H, aromatic protons in Bz). 13C NMR (CDCl3, 100 MHz) d = 169.90 (MeCOO), 165.88 (PhCOO), 165.63 (PhCOO), 165.59 (PhCOO), 136.60 (C-5), 133.64 (Ar-C), 133.42 (Ar-C), 133.38 (Ar-C), 130.00 (2C, Ar-C), 129.77 (3C, Ar-C), 129.42 (Ar-C), 129.03 (Ar-C), 128.56 (2C, Ar-C), 128.52 (Ar-C), 128.49 (2C, Ar-C), 128.45 (2C, Ar-C), 123.79 (C-6), 70.44 (C-4), 70.07 (CH2OBz), 69.83 (C-3), 63.30 (C-2), 57.13 (C-1), 20.57 (CH3 in Ac). HRMS (ESI): calcd for C30H25N3O8Na [M+Na]+: 578.1539; found: 578.1534. IR (KBr film): m = 2105 (N3), 1739 (C@O), 1723 (C@O), 1270, 1217, 1098, 1026, 706 cm 1. 4.8. (1S,2S,3S,4R)-1-Amino-5-hydroxymethyl-2,3,4-trihydroxycyclohex-5-ene [(+)-valienamine] 1 Compound 8 (300.0 mg, 0.540 mmol) was dissolved in a mixed solvent of methanol (4 mL) and ammonia hydrate (25% w/w, 1 mL), and the mixture was stirred at room temperature for approximately 24 h. The solution was then concentrated under vacuum to give an oily residue, which was dissolved in pure water (2 mL). The aqueous solution was washed twice with diethyl ether (2 10 mL), and the ether phase was decanted each time. The aqueous solution was concentrated under vacuum to remove the water to give an oily residue. The residue was dissolved in methanol (2 mL), and the solution was put into a flask, after which active carbon (50 mg) was added. The suspension mixture was stirred at 30 °C for 1 h. The mixture was then filtered through a thin layer of Celite to remove the active carbon. The wet cake was washed twice with methanol (2 5 mL), and the filtrate was concentrated to dryness. After the residue was dissolved in methanol (2 mL), the solution was transferred to a flask, which was equipped with a magnetic stirrer bar, and an inlet and an outlet of H2. Lindlar-catalyst (30% w/w, 35.0 mg) was then added. After the flask was purged with H2 several times, the black suspension was stirred at room temperature for 3 h under an atmosphere of H2. The mixture was then filtered through a thin layer of Celite to remove the Lindlar-catalyst. The solvent was removed by vacuum distillation to afford compound 1 (86.1 mg, 0.491 mmol, 91%) as a pale-yellow 14 syrup. [a]20 [a]D = +90 (c 0.43, H2O)}. D = +88.9 (c 0.35, H2O) {lit. 1 H NMR (D2O, 400 MHz): d = 3.41–3.47 (m, 1H, H-1), 3.54–3.61 (m, 2H, H-2 and H-3), 3.96 (d, J = 4.8 Hz, 1H, H-4), 4.00 (d, J = 13.8 Hz, 1H, CHHOH), 4.11 (d, J1 = 13.8 Hz, 1H, CHHOH), 5.69 (d, J = 5.1 Hz, 1H, H-6). 13C NMR (D2O, 100 MHz): d = 139.75 (C5), 123.84 (C-6), 72.06 (C-4), 71.84 (CH2OH), 69.92 (C-3), 61.34 (C-2), 48.98 (C-1). HRMS (ESI): calcd for C7H14NO4 [M+H]+:
5
176.0923; found: 176.0929. IR (neat) 3373 (O-H), 2881, 1582, 1385, 1315, 1105, 1010, 867 cm 1. Acknowledgment We are grateful to the National Natural Science Foundation of China (No. 20972048) for the financial support of this work. References 1. Kameda, Y.; Horii, S. J. Chem. Soc., Chem. Commun. 1972, 746–747. 2. Kameda, Y.; Asano, N.; Teranishi, M.; Matsui, K. J. Antibiot. 1980, 33, 1573–1574. 3. (a) Mahmud, T. Nat. Prod. Rep. 2003, 20, 137–166; (b) Chen, X.; Fan, Y.; Zheng, Y.; Shen, Y. Chem. Rev. 2003, 103, 1955–1977; (c) Asano, N.; Kameda, Y.; Matsui, K.; Horii, S.; Fukase, H. J. Antibiot. 1990, 43, 1039–1041; (d) Kameda, Y.; Asano, N.; Matsui, K.; Horii, S.; Fukase, H. J. Antibiot. 1988, 41, 1488–1492; (e) Kameda, Y.; Asano, N.; Yamaguchi, T.; Matsui, K.; Horii, S.; Fukase, H. J. Antibiot. 1986, 39, 1491–1494; (f) Horii, S.; Kameda, Y.; Kawahara, K. J. Antibiot. 1972, 25, 48–53; (g) Iwasa, T.; Kameda, Y.; Asai, M.; Horii, S.; Mizuno, K. J. Antibiot. 1971, 24, 119–123. 4. 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