Key words asymmetric hydroxylation - organocatalysis - reductive cleavage
(–)-Bestatin (Ubenimex) is a dipeptide containing an α-hydroxy-β-amino amide subunit that was first isolated from Streptomyces olivoreticulithe by Umezawa et al. in 1976.[1 ]
[2 ] It is an aminopeptidase inhibitor that exhibits immunostimulatory activity as well as cytotoxic activity.[3,4 ] It is used clinically for the treatment of cancer, HIV, hypertension, and shows potential as an anti-inflammatory agent.[5–8 ] Structure modification studies of bestatin and similar molecules such as phebestin, a tripeptide, indicate that biological activities of these molecules are significantly influenced by the (2S )-syn -stereochemistry of the hydroxyl group.[9 ]
[10 ]
Various stereoselective methods for the synthesis of bestatin, phebestin[11 ]
[12 ]
[13 ]
[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ]
[26 ]
[27 ] and epibestatin[28,29 ] are available and most of them utilized d -phenylalanine as a chiral starting material. Reported herein is an alternative and short method for the synthesis of bestatin, epibestatin, phebestin and (3S ,4R )-4-amino-3-hydroxy-5-phenylpentanoic acid using proline-catalysed asymmetric α-hydroxylation of an aldehyde derived from d -phenylalanine. The structures of these compounds are shown in Figure [1 ].
Figure 1
Proline-catalysed α-hydroxylation of an aldehyde using nitrosobenzene followed by reduction of the N–O bond is an attractive method to introduce a hydroxyl group stereoselectively.[30 ]
[31 ]
[32 ] The aldehyde functional group can be further reduced to an alcohol or converted into an alkene through Wittig reaction in order to avoid racemization at the α-position. As the part of our studies towards the synthesis of various bioactive and naturally occurring molecules,[32–41 ] we recently reported the synthesis of d -threo -sphinganine, l -erythro -sphinganine and (–)-spisulosine from an aldehyde derived from aspartic acid.[42 ]
In the retrosynthetic analysis, it was anticipated that both bestatin and epibestatin could be synthesized from acid 9 using peptide coupling followed by deprotection of the Boc and MOM groups. Diol 5 could be obtained from aldehyde 4 using an α-hydroxylation reaction. Compound 9a could be converted into phebestin. Olefin 15 could be obtained from aldehyde 4 using an α-hydroxylation reaction followed by Wittig reaction and would yield compound 3 as shown in Scheme [1 ].
Scheme 1 Retrosynthetic analysis of compounds 1 , 2 and 3 from 4
Aldehyde 4 (for preparation see the literature[43 ]) was subjected to diastereoselective hydroxylation using nitrosobenzene, and d -proline as catalyst and subsequently reduced to the corresponding primary alcohol by NaBH4 in one pot. The crude product was further subjected to N–O bond cleavage using Cu(OAc)2 to give diol 5a in 66% yield overall. It was observed by 1 H NMR spectroscopy that the hydroxylation reaction proceeded with 90:10 diastereoselectivity. The primary and secondary hydroxyl groups of compound 5a were protected as their TBDPS and MOM derivatives, respectively, to obtain the fully protected compound 7a in 64% overall yield. TBAF was then used to remove the silyl protecting group in compound 7a to furnish the primary alcohol 8a in 89% yield, which was then treated with PDC in DMF to produce the corresponding carboxylic acid 9a in 76% yield (Scheme [2 ]).
Scheme 2 Synthesis of bestatin (1a )
The fully protected α-hydroxy-β-amino acid 9a is the precursor for the synthesis of both bestatin and phebestin. To obtained bestatin, compound 9a was coupled with the benzyl ester of l -leucine in the presence of EDC·HCl, HOBt and DIPEA to give the corresponding fully protected dipeptide 10a in 82% yield. Compound 10a was further subjected to Pd-catalysed hydrogenolysis followed by acidolysis of the Boc and MOM groups to furnish target molecule 1a from 10a in 86% yield (Scheme [2 ]).
Epibestatin 1b was obtained in an overall yield of 22% from aldehyde 4 using exactly the same sequence of reactions but using l -proline in the asymmetric α-hydroxylation reaction (Scheme [3 ]) leading to a diastereomer ratio of 87:13 as judged by 1 H NMR spectroscopy. Epibestatin is available in very limited quantities commercially and to date only a few synthetic strategies have been reported.[28 ]
[29 ]
Scheme 3 Synthesis of epibestatin (1b )
To synthesize phebestin, compound 9a was coupled with dipeptide 12 , which was obtained from coupling the methyl ester of l -phenylalanine with NH-Boc protected l -valine, to give the fully protected tripeptide 13 in 70% yield. Hydrolysis of the methyl ester using LiOH followed by acidolysis of the Boc and MOM groups furnished the target molecule 2 in 89% yield over two steps (Scheme [4 ]).
Scheme 4 Synthesis of phebestin (2 )
β-Hydroxy-γ-amino acids have been designed for biologically active peptide mimics and for HIV protease inhibitors. Stictamide A, tasiamide B and hapolosin are biologically important compounds that contain 4-amino-3-hydroxy-5-phenylpentanoic acid as a structural fragment. The activities of such compounds depend on the stereochemistries of both the amino- and hydroxyl groups.[44 ]
[45 ] A variety of stereoselective methods for the synthesis of these acids and their analogues is available.[46–50 ] (3S ,4R )-4-Amino-3-hydroxy-5-phenylpentanoic acid (3 ) was also synthesized from the same starting material 4 in eight steps and in an overall yield of 15% (Scheme [5 ]).
Thus, aldehyde 4 was subjected to l -proline-catalysed asymmetric α-hydroxylation and subsequent Wittig reaction in one pot. The crude product was further treated with Cu(OAc)2 leading to cleavage of the N–O bond to form olefin 15 in 70% overall yield (Scheme [5 ]).
Scheme 5 Synthesis of 3 from aldehyde 4
Both the hydroxyl and amino groups in compound 15 were protected as an oxazolidine using 2,2-dimethoxypropane (DMP) and a catalytic amount of p -TsOH to 16 in 85% yield. LiBH4 was used to reduce compound 16 to primary alcohol 17 in 80% yield, and this was then oxidized to aldehyde 18 using 2-iodoxybenzoic acid (IBX) in 88% yield. The aldehyde 18 was subjected to l -proline-catalysed asymmetric α-hydroxylation reaction followed by reduction and N–O bond cleavage using NaBH4 and Cu(OAc)2 , respectively, to furnish diol 19 in 65% overall yield. NaIO4 was used to cleave the diol to produce aldehyde 20 , which was further oxidised to an acid 21 using PDC in 57% yield after two steps. Acidolysis of the Boc group and oxazolidine ring in compound 21 furnished 3 in 98% yield (Scheme [5 ]).
In conclusion, we have demonstrated a convenient and efficient route for the synthesis of bestatin, epibestatin, phebestin and (3S ,4R )-4-amino-3-hydroxy-5-phenylpentanoic acid using proline-catalysed α-hydroxylation of an aldehyde derived from d -phenylalanine with high diastereoselectivities and in good overall yields. The method described here offers a general method to synthesize several similar molecules using an organocatalytic route.
See the Supporting Information for general information.
Asymmetric α-Hydroxylation of Aldehydes; General Procedure
Asymmetric α-Hydroxylation of Aldehydes; General Procedure
To a stirred solution of aldehyde 4 (1.00 g, 3.80 mmol) and nitrosobenzene (0.44 g, 4.18 mmol) in anhydrous DMSO (10 mL), d - or l -proline (0.13 g, 1.14 mmol, 30 mol%) was added at 15 °C. The mixture was stirred for 3 h at the same temperature, then cooled to 0 °C and NaBH4 (0.28 g, 7.60 mmol) in EtOH (15 mL) was added and the mixture was stirred vigorously for 30 min at 0 °C. On complete disappearance of starting material, the reaction was quenched with saturated aqueous NH4 Cl (30 mL) and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over Na2 SO4 , filtered, and concentrated. The crude aminohydroxylated product was taken as such to the next step leading to the cleavage of O–N bond.
Cu(OAc)2 (0.17 g, 0.96 mmol) was added to a stirred solution of the above product in EtOH (15 mL) and the mixture was stirred vigorously for 6 h at room temperature. On complete disappearance of starting material, the reaction was quenched with saturated aqueous NH4 Cl (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine (30 mL), dried over Na2 SO4 , filtered, concentrated, and purified by column chromatography.
The same procedure was used for the preparation of compound 19 .
tert -Butyl ((2R ,3S )-3,4-Dihydroxy-1-phenylbutan-2-yl)carbamate (5a)
tert -Butyl ((2R ,3S )-3,4-Dihydroxy-1-phenylbutan-2-yl)carbamate (5a)
Column chromatography (petroleum ether/EtOAc, 60:40).
Yield: 0.70 g (66%); clear oil; [α]D
27 +18.97 (c 1.22, CHCl3 ).
IR (thin film): 3382, 3063, 3028, 2924, 2854, 1682, 1604 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.28–7.17 (m, 5 H), 4.98 (d, J = 8.0 Hz, 1 H), 4.65 (d, J = 8.0 Hz, 1 H), 3.91–3.89 (m, 1 H), 3.63–3.38 (m, 4 H), 3.18 (br s, 1 H), 2.88 (d, J = 8.0 Hz, 2 H), 1.37 (s, 9 H).
13 C NMR (CDCl3 , 125 MHz): δ = 156.9, 138.0, 129.5, 129.3, 128.6, 126.5, 80.5, 80.1, 73.2, 71.6, 64.0, 59.6, 52.6, 38.2, 31.3, 29.8, 28.4.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C15 H23 NNaO4 : 304.1525; found: 304.1523.
tert -Butyl ((2R ,3R )-3,4-Dihydroxy-1-phenylbutan-2-yl)carbamate (5b)
tert -Butyl ((2R ,3R )-3,4-Dihydroxy-1-phenylbutan-2-yl)carbamate (5b)
Column chromatography (petroleum ether/EtOAc, 60:40).
Yield: 0.69 g (64%); clear oil; [α]D
27 –8.59 (c 0.74, CHCl3 ).
IR (thin film): 3360, 2978, 2928, 1686, 1524 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 7.31–7.22 (m, 5 H), 4.82 (d, J = 5.0 Hz, 1 H), 4.56 (d, J = 5.0 Hz, 1 H), 3.86–3.81 (m, 1 H), 3.68–3.36 (m, 4 H), 3.11–3.08 (m, 1 H), 2.92–2.88 (m, 2 H), 1.38 (s, 9 H).
13 C NMR (CDCl3 , 125 MHz): δ = 157.2, 137.4, 129.5, 128.8, 126.8, 80.6, 73.2, 63.0, 52.4, 36.6, 31.7, 29.8, 28.3.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C15 H23 NNaO4 : 304.1525; found: 304.1528.
tert -Butyl (4R ,5S )-4-Benzyl-5-((R )-2,3-dihydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate (19)
tert -Butyl (4R ,5S )-4-Benzyl-5-((R )-2,3-dihydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate (19)
Column chromatography (petroleum ether/EtOAc, 50:50).
Yield: 0.68 g (65%); clear oil; [α]D
27 +11.94 (c 0.92, CHCl3 ).
IR (thin film): 3418, 3063, 3029, 2924, 2855, 1694, 1682, 1604 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 7.27–7.18 (m, 5 H), 4.29–4.10 (m, 2 H), 3.66 (br s, 1 H), 3.46–3.23 (m, 2 H), 2.97–2.82 (m, 2 H), 1.82–1.67 (m, 3 H), 1.57–1.53 (m, 6 H), 1.44, 1.34 (s, 9 H).
13 C NMR (CDCl3 , 125 MHz): δ = 151.9, 151.6, 138.7, 129.4, 129.3, 128.6, 128.4, 126.4, 126.2, 93.6, 92.9, 80.4, 80.0, 76.1, 71.2, 71.1, 66.3, 61.1, 60.9, 36.7, 36.0, 32.9, 29.8, 28.4, 28.1, 27.5, 26.8, 25.2, 24.0.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C20 H31 NNaO5 : 388.2100; found: 388.2100.
Silyl Protection; General Procedure
Silyl Protection; General Procedure
Compound 5 (1.00 g, 3.55 mmol) was dissolved in anhydrous DCM (20 mL) and the solution cooled to 0 °C. TBDPSCl (1.07 mL, 3.91 mmol), DMAP (0.08 g, 0.71 mmol) and triethylamine (0.74 mL, 5.32 mmol) were added and the reaction mixture was stirred at r.t. for 8 h. On complete disappearance of starting material, the reaction was quenched with saturated aqueous citric acid (20 mL), the crude product was extracted with DCM (2 × 30 mL) and the combined organic phases containing crude product were dried over Na2 SO4 , filtered, concentrated under vacuum, and purified by column chromatography.
tert -butyl ((2R ,3S )-4-((tert -Butyldiphenylsilyl)oxy)-3-hydroxy-1-phenylbutan-2-yl)carbamate (6a)
tert -butyl ((2R ,3S )-4-((tert -Butyldiphenylsilyl)oxy)-3-hydroxy-1-phenylbutan-2-yl)carbamate (6a)
Column chromatography (petroleum ether/EtOAc, 80:20).
Yield: 1.51 g (82%); clear oil; [α]D
27 +17.28 (c 0.96, CHCl3 ).
IR (thin film): 3434, 3070, 3027, 2927, 2856, 1689 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.62–7.57 (m, 4 H), 7.42–7.21 (m, 11 H), 4.93 (br s, 1 H), 3.76–3.69 (m, 2 H), 3.61–3.60 (m, 2 H), 2.96–2.85 (m, 2 H), 2.67 (br s, 1 H), 1.35 (s, 9 H), 1.04 (s, 9 H).
13 C NMR (CDCl3 , 100 MHz): δ = 155.9, 138.4, 135.6, 133.1, 130.0, 129.5, 128.5, 127.9, 126.4, 79.4, 71.1, 65.7, 52.7, 38.6, 29.8, 28.4, 27.0, 19.3.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C31 H41 NNaO4 Si: 542.2703; found: 542.2700.
tert -Butyl ((2R ,3R )-4-((tert -Butyldiphenylsilyl)oxy)-3-hydroxy-1-phenylbutan-2-yl)carbamate (6b)
tert -Butyl ((2R ,3R )-4-((tert -Butyldiphenylsilyl)oxy)-3-hydroxy-1-phenylbutan-2-yl)carbamate (6b)
Column chromatography (petroleum ether/EtOAc, 80:20).
Yield: 1.55 g (84%); clear oil; [α]D
27 +2.26 (c 1.45, CHCl3 ).
IR (thin film): 3417, 2930, 2857, 1692, 1497 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 7.70–7.68 (m, 3 H), 7.46–7.39 (m, 6 H), 7.29–7.17 (m, 6 H), 4.98 (br s, 1 H), 3.99 (br s, 1 H), 3.76–3.62 (m, 3 H), 3.08 (br s, 1 H), 2.96–2.85 (m, 2 H), 1.36 (s, 9 H), 1.11 (s, 9 H).
13 C NMR (CDCl3 , 125 MHz): δ = 156.0, 138.0, 135.7, 132.9, 132.8, 130.0, 129.5, 128.5, 128.0, 127.9, 126.4, 79.4, 72.6, 65.4, 54.3, 36.6, 29.8, 28.4, 27.0, 19.3.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C31 H41 NNaO4 Si: 542.2703; found: 542.2705.
MOM Protection; General Procedure
MOM Protection; General Procedure
MOM chloride (0.58 mL, 7.68 mmol) followed by Hunig’s base, DIPEA (1.68 mL, 9.62 mmol) were added to a stirred solution of compound 6 (1.00 g, 1.92 mmol) in DCM (25 mL) at 0 °C, and the mixture was stirred vigorously at r.t. for 6 h. On complete disappearance of starting material, the reaction was quenched with water (20 mL), and the mixture was extracted with DCM (2 × 30 mL) and the combined organic phases were washed with 2% HCl (2 × 20 mL), dried over Na2 SO4 , filtered, concentrated and purified through column chromatography.
tert -Butyl ((2R ,3S )-4-((tert -Butyldiphenylsilyl)oxy)-3-(methoxymethoxy)-1-phenylbutan-2-yl)carbamate (7a)
tert -Butyl ((2R ,3S )-4-((tert -Butyldiphenylsilyl)oxy)-3-(methoxymethoxy)-1-phenylbutan-2-yl)carbamate (7a)
Column chromatography (petroleum ether/EtOAc, 85:15).
Yield: 0.84 g (78%); clear oil; [α]D
27 +1.65 (c 0.48, CHCl3 ).
IR (thin film): 2928, 2856, 1715, 1494 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.53–7.47 (m, 4 H), 7.35–7.15 (m, 11 H), 4.93 (d, J = 8.0 Hz, 1 H), 4.58–4.43 (m, 2 H), 4.09–4.04 (m, 1 H), 3.56–3.51 (m, 3 H), 3.28 (s, 3 H), 2.88–2.71 (m, 2 H), 1.33 (s, 9 H), 0.91 (s, 9 H).
13 C NMR (CDCl3 , 100 MHz): δ = 155.5, 135.6, 133.2, 129.7, 129.6, 128.5, 127.8, 126.3, 97.1, 79.1, 63.6, 55.9, 52.4, 38.7, 28.5, 26.8, 19.2.
HRMS (ESI–TOF): m /z [M + H]+ calcd for C33 H46 NO5 Si: 564.3145; found: 564.3141.
tert -Butyl ((2R ,3R )-4-((tert -Butyldiphenylsilyl)oxy)-3-(methoxymethoxy)-1-phenylbutan-2-yl)carbamate (7b)
tert -Butyl ((2R ,3R )-4-((tert -Butyldiphenylsilyl)oxy)-3-(methoxymethoxy)-1-phenylbutan-2-yl)carbamate (7b)
Column chromatography (petroleum ether/EtOAc, 85:15).
Yield: 0.86 g (80%); clear oil; [α]D
27 +11.05 (c 2.63, CHCl3 ).
IR (thin film): 3070, 3027, 2930, 2891, 2857, 1713, 1603, 1589 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.70–7.68 (m, 4 H), 7.45–7.38 (m, 6 H), 7.25–7.16 (m, 5 H), 5.38 (d, J = 12.0 Hz, 1 H), 4.65 (br s, 2 H), 4.17 (d, J = 8.0 Hz, 1 H), 3.84–3.80 (m, 1 H), 3.71–3.61 (m, 2 H), 3.32 (s, 3 H), 2.82 (d, J = 8.0 Hz, 2 H), 1.35 (s, 9 H), 1.08 (s, 9 H).
13 C NMR (CDCl3 , 125 MHz): δ = 155.6, 138.4, 135.7, 135.7, 133.0, 129.9, 129.9, 129.2, 128.3, 127.8, 127.8, 126.2, 96.6, 93.6, 78.7, 64.4, 63.5, 55.7, 52.9, 38.6, 36.9, 28.4, 26.9, 19.2.
HRMS (ESI–TOF): m /z [M + H]+ calcd for C33 H46 NO5 Si: 564.3145; found: 564.3149.
Silyl Deprotection; General Procedure
Silyl Deprotection; General Procedure
TBAF (1 M in THF, 1.94 mL, 1.94 mmol) was added to a stirred solution of compound 7 (1.00 g, 1.77 mmol) in anhydrous THF (15 mL) at 0 °C and the solution was stirred at r.t. for 2 h. On complete disappearance of starting material, the reaction was quenched with saturated aqueous NH4 Cl (30 mL) and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic phases were dried over Na2 SO4 , filtered, concentrated under vacuum, and purified by column chromatography.
tert -Butyl ((2R ,3S )-4-Hydroxy-3-(methoxymethoxy)-1-phenylbutan-2-yl)carbamate (8a)
tert -Butyl ((2R ,3S )-4-Hydroxy-3-(methoxymethoxy)-1-phenylbutan-2-yl)carbamate (8a)
Column chromatography (petroleum ether/EtOAc, 70:30).
Yield: 0.51 g (89%); clear oil; [α]D
27 +42.55 (c 0.79, CHCl3 ).
IR (thin film): 3444, 3063, 3028, 2927, 2854, 1693, 1604 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 7.23–7.12 (m, 5 H), 4.71 (d, J = 10.0 Hz, 1 H), 4.67–4.53 (m, 2 H), 4.05 (dd, J = 15.0, 10.0 Hz, 1 H), 3.61 (dd, J = 10.0, 5.0 Hz, 1 H), 3.46–3.44 (m, 1 H), 3.41–3.37 (m, 1 H), 3.34 (s, 3 H), 2.84–2.74 (m, 2 H), 1.33 (s, 9 H).
13 C NMR (CDCl3 , 125 MHz): δ = 156.6, 137.9, 129.1, 128.6, 126.6, 97.7, 80.7, 80.0, 62.6, 55.9, 52.1, 38.3, 29.8, 28.4.
HRMS (ESI– TOF): m /z [M + Na]+ calcd for C17 H27 NNaO5 : 348.1787; found: 348.1788.
tert -Butyl ((2R ,3R )-4-Hydroxy-3-(methoxymethoxy)-1-phenylbutan-2-yl)carbamate (8b)
tert -Butyl ((2R ,3R )-4-Hydroxy-3-(methoxymethoxy)-1-phenylbutan-2-yl)carbamate (8b)
Column chromatography (petroleum ether/EtOAc, 70:30).
Yield: 0.52 g (90%); clear oil; [α]D
27 +0.47 (c 1.02, CHCl3 ).
IR (thin film): 3471, 3368, 3021, 2964, 2929, 1692, 1523 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 7.28–7.18 (m, 5 H), 4.80–4.70 (m, 3 H), 4.04 (br s, 1 H), 3.70–3.66 (m, 2 H), 3.50 (br s, 1 H), 3.45 (s, 3 H), 3.03–3.00 (m, 1 H), 2.75–2.70 (m, 1 H), 1.89 (br s, 1 H), 1.32 (s, 9 H).
13 C NMR (CDCl3 , 125 MHz): δ = 156.0, 137.9, 129.3, 128.5, 126.5, 97.0, 82.4, 79.7, 62.3, 56.0, 52.0, 36.7, 29.7, 28.3.
HRMS (ESI–TOF): m /z [M + H]+ calcd for C17 H28 NO5 : 326.1967; found: 326.1968.
Oxidation of Primary Alcohols; General Procedure
Oxidation of Primary Alcohols; General Procedure
Pyridinium dichromate (11.56 g, 30.75 mmol) was added to the stirred solution of alcohol 8 (1.00 g, 3.07 mmol) in DMF (30 mL) and stirring was continued at r.t. for 8 h. On complete disappearance of the starting material, the reaction was quenched with water (300 mL) and extracted with Et2 O (2 × 50 mL). The combined organic phases were washed with saturated aqueous NaHCO3 (2 × 30 mL) and the aqueous extracts containing the carboxylate salts were combined and acidified with saturated aqueous KHSO4 (2 × 50 mL) and this was extracted with Et2 O (2 × 50 mL). The ether layers were combined, dried over Na2 SO4 , filtered, concentrated, and purified by column chromatography.
(2S ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoic Acid (9a)
(2S ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoic Acid (9a)
Column chromatography (DCM/MeOH, 95:5).
Yield: 0.79 g (76%); clear oil; [α]D
27 +9.18 (c 0.29, CHCl3 ).
IR (thin film): 3334, 2924, 2853, 1715, 1497 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 8.03 (s, 1 H), 7.30–7.19 (m, 5 H), 5.09 (d, J = 8.0 Hz, 1 H), 4.77–4.70 (m, 2 H), 4.37 (d, J = 4.0 Hz, 1 H), 4.17 (s, 1 H), 3.46 (s, 3 H), 2.90–2.88 (m, 2 H), 1.34 (s, 9 H).
13 C NMR (CDCl3 , 125 MHz): δ = 173.1, 163.2, 155.6, 137.5, 129.4, 128.7, 126.7, 96.8, 80.1, 75.1, 56.7, 54.0, 38.5, 29.8, 28.3.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C17 H25 NNaO6 : 362.1580; found: 362.1558.
(2R ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoic Acid (9b)
(2R ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoic Acid (9b)
Column chromatography (DCM/MeOH, 95:5).
Yield: 0.80 g (78%); clear oil; [α]D
27 +48.55 (c 0.41, CHCl3 ).
IR (thin film): 3395, 2924, 2853, 1692, 1603, 1497 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.30–7.19 (m, 5 H), 5.07 (d, J = 8.0 Hz, 1 H), 4.76–4.69 (m, 2 H), 4.37 (d, J = 8.0 Hz, 1 H), 4.16 (br s, 1 H), 3.45 (s, 3 H), 2.88 (d, J = 8.0 Hz, 2 H), 1.33 (s, 9 H).
13 C NMR (CDCl3 , 100 MHz): δ = 173.4, 163.4, 155.3, 137.5, 129.3, 128.3, 126.4, 96.6, 79.6, 56.2, 53.3, 36.9, 36.0, 31.8, 29.7, 28.2, 28.0.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C17 H25 NNaO6 : 362.1580; found: 362.1584.
Peptide Coupling of 9
Compound 9 (0.19 g, 0.55 mmol) was dissolved in anhydrous DCM (10 mL) and the solution was cooled in an ice bath followed by addition of EDC·HCl (0.21 g, 1.12 mmol) and HOBt (0.15 g, 1.12 mmol) and then stirred for 20 min. H-Leu-OBn (0.17 g, 0.55 mmol) was added to the reaction mixture followed by DIPEA (0.20 mL, 1.23 mmol) and the mixture was stirred at r.t. for 6 h. On complete disappearance of starting material, the organic layer was washed with aqueous citric acid (3 × 15 mL) and 2 M aqueous NaHCO3 (3 × 15 mL). The organic layers were combined, dried over Na2 SO4 , filtered, concentrated, and purified by column chromatography.
Benzyl ((2S ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoyl)-l -leucinate (10a)
Benzyl ((2S ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoyl)-l -leucinate (10a)
Column chromatography (petroleum ether/EtOAc, 70:30).
Yield: 0.24 g (82%); white solid; [α]D
27 +32.23 (c 0.69, CHCl3 ); mp 99–101 °C.
IR (thin film): 3333, 3277, 3063, 3030, 2961, 2929, 2873, 1748, 1688, 1650, 1547, 1524 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.31–7.09 (m, 10 H), 6.96 (d, J = 8.7 Hz, 1 H), 5.19 (d, J = 9.9 Hz, 1 H), 5.11–5.04 (m, 2 H), 4.69–4.62 (m, 3 H), 4.17 (br s, 1 H), 4.06 (m, 1 H), 3.35 (s, 3 H), 2.82 (dd, J = 13.7, 5.4 Hz, 1 H), 2.59–2.54 (m, 1 H), 1.62–1.50 (m, 3 H), 1.23 (s, 9 H), 0.86 (d, J = 4.3 Hz, 6 H).
13 C NMR (CDCl3 , 125 MHz): δ = 172.5, 170.5, 155.0, 137.8, 135.3, 129.4, 128.7, 128.6, 128.4, 128.4, 126.5, 115.5, 96.9, 79.2, 78.1, 67.2, 56.7, 53.3, 50.4, 41.5, 37.5, 29.8, 28.3, 24.9, 22.9, 21.8.
HRMS (ESI–TOF): m /z [M + H]+ calcd for C30 H43 N2 O7 : 543.3070; found: 543.3079.
Benzyl ((2R ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoyl)-l -leucinate (10b)
Benzyl ((2R ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoyl)-l -leucinate (10b)
Column chromatography (petroleum ether/EtOAc, 70:30).
Yield: 0.24 g (82%); white solid; [α]D
27 +14.68 (c 0.68, CHCl3 ); mp 98–99 °C.
IR (thin film): 3348, 3306, 3030, 2957, 2929, 1738, 1693, 1654, 1524 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 7.33–7.17 (m, 10 H), 6.87 (d, J = 5.0 Hz, 1 H), 5.22–5.13 (m, 3 H), 4.71–4.61 (m, 3 H), 4.34–4.23 (m, 2 H), 3.37 (s, 3 H), 2.93–2.55 (m, 2 H), 1.73–1.56 (m, 3 H), 1.34 (s, 9 H), 0.93 (d, J = 5.0 Hz, 6 H).
13 C NMR (CDCl3 , 125 MHz): δ = 172.6, 169.9, 155.6, 138.0, 135.4, 129.5, 128.7, 128.5, 128.4, 126.4, 96.9, 79.3, 78.8, 67.3, 56.4, 54.1, 50.7, 40.8, 36.8, 29.8, 28.4, 25.1, 22.9, 21.8.
HRMS (ESI–TOF): m /z [M + H]+ calcd for C30 H43 N2 O7 : 543.3070; found: 543.3079.
Procedure for Hydrogenolysis of 10
Procedure for Hydrogenolysis of 10
To a stirred solution of 10 (0.13 g, 0.24 mmol) in anhydrous MeOH (10 mL), Pd/C (10 mol%) was added and the mixture was stirred vigorously for 3 h at r.t. under H2 . On complete disappearance of starting material, the reaction mixture was filtered through a Celite® pad, solvent was removed under vacuum and the residue was purified by column chromatography.
((2S ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoyl)-l -leucine (11a)
((2S ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoyl)-l -leucine (11a)
Column chromatography (CH2 Cl2 /MeOH, 95:5).
Yield: 0.10 g (92%); clear oil; [α]D
27 +21.11 (c 0.36, CHCl3 ).
IR (thin film): 3333, 2925, 2854, 1714, 1529, 1454 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 7.73 (d, J = 10.0 Hz, 1 H), 7.30–7.22 (m, 5 H), 6.84 (d, J = 5.0 Hz, 1 H), 4.88–4.75 (m, 2 H), 4.56 (d, J = 5.2 Hz, 1 H), 4.14–4.08 (m, 2 H), 3.47 (s, 3 H), 2.98–2.86 (m, 2 H), 1.73–1.54 (m, 3 H), 1.29 (s, 9 H), 0.92–0.89 (m, 6 H).
13 C NMR (CDCl3 , 125 MHz): δ = 176.4, 169.6, 157.5, 137.8, 129.6, 128.8, 126.8, 97.1, 81.8, 78.0, 57.1, 56.1, 50.5, 43.3, 39.7, 29.8, 28.1, 25.0, 22.8, 22.4.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C23 H36 N2 NaO7 : 475.2420; found: 475.2452.
((2R ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoyl)-l -leucine (11b)
((2R ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoyl)-l -leucine (11b)
Column chromatography (DCM/MeOH, 95:5).
Yield: 0.10 g (92%); clear oil; [α]D
27 +25.37 (c 0.66, CHCl3 ).
IR (thin film): 3300, 2954, 2740, 1730, 1520 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.25–7.10 (m, 5 H), 5.24 (br s, 1 H), 4.63 (m, 2 H), 4.31–4.14 (m, 2 H), 3.35 (s, 3 H), 2.94–2.73 (m, 2 H), 1.79–1.53 (m, 3 H), 1.24 (s, 9 H), 0.93–0.83 (m, 6 H).
13 C NMR (CDCl3 , 100 MHz): δ = 175.7, 175.4, 170.6, 169.6, 157.3, 155.8, 138.3, 137.9, 129.6, 129.4, 128.4, 126.4, 96.6, 96.4, 81.1, 79.5, 79.0, 78.4, 56.4, 55.8, 54.2, 50.7, 50.4, 41.2, 37.4, 36.7, 32.0, 29.8, 28.3, 28.0, 25.1, 23.1, 22.8, 21.7, 14.2.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C23 H36 N2 NaO7 : 475.2420; found: 475.2452.
Acidolysis Reaction; General Procedure
Acidolysis Reaction; General Procedure
HCl (6 M in EtOAc, 0.50 mL) was added to 11 (0.083 g, 0.18 mmol), 14 (0.092 g, 0.15 mmol) or 21 (0.050 g, 0.14 mmol) at 0 °C and the mixture was stirred at r.t. for 4 h. On complete disappearance of starting material, solvent was removed under vacuum and the white residual solid was triturated 3 to 4 times with cold EtOAc (5 mL).
((2S ,3R )-3-Amino-2-hydroxy-4-phenylbutanoyl)-l -leucine (1a)
((2S ,3R )-3-Amino-2-hydroxy-4-phenylbutanoyl)-l -leucine (1a)
Yield: 0.058 g (94%); white solid; [α]D
27 –15.83 (c 0.24, CH3 OH); mp 212–215 °C {lit.[19 ] [α]D
20 –15.2 (c 0.83, 1 M HCl); mp 210–214 °C}.
IR (thin film): 3737, 2953, 1725, 1660, 1555, 1518, 1492 cm–1 .
1 H NMR (D2 O, 500 MHz): δ = 7.48–7.36 (m, 5 H), 4.41 (dd, J = 10.0, 5.1 Hz, 1 H), 4.33 (d, J = 5.0 Hz, 1 H), 3.89–3.85 (m, 1 H), 3.19 (dd, J = 15.0, 5.0 Hz, 1 H), 2.97 (dd, J = 15.0, 10.0 Hz, 1 H), 1.79–1.67 (m, 3 H), 0.97 (d, J = 5.0 Hz, 3 H), 0.94 (d, J = 5.0 Hz, 3 H).
13 C NMR (D2 O, 125 MHz): δ = 176.3, 172.7, 134.9, 129.4, 129.2, 127.7, 69.5, 54.9, 51.6, 39.1, 34.8, 24.5, 22.0, 20.7.
HRMS (ESI–TOF): m /z [M + H]+ calcd for C16 H25 N2 O4 : 309.1814; found: 309.1811.
((2R ,3R )-3-Amino-2-hydroxy-4-phenylbutanoyl)-l -leucine (1b)
((2R ,3R )-3-Amino-2-hydroxy-4-phenylbutanoyl)-l -leucine (1b)
Yield: 0.060 g (97%); white solid; [α]D
27 +5.82 (c 0.38, H2 O); mp 226–228 °C {lit.[28 ] [α]D
20 +5.90 (c 0.38 H2 O); mp 228–230 °C}.
IR (thin film): 3394, 2926, 1739, 1651, 1454 cm–1 .
1 H NMR (CD3 OD, 500 MHz): δ = 7.26–7.18 (m, 5 H), 4.38 (br s, 2 H), 4.08 (d, J = 5.0 Hz, 2 H), 3.72 (d, J = 10.0 Hz, 1 H), 3.02–3.00 (m, 1 H), 2.83–2.79 (m, 1 H), 1.65–1.61 (m, 3 H), 0.90 (d, J = 5.0 Hz, 3 H), 0.86 (d, J = 5.0 Hz, 3 H).
13 C NMR (CD3 OD, 125 MHz): δ = 173.6, 173.2, 137.0, 130.4, 130.0, 128.4, 72.0, 62.5, 56.9, 52.0, 41.0, 34.3, 25.9, 23.2, 21.7, 14.4.
HRMS (ESI–TOF): m /z [M + H]+ calcd for C16 H25 N2 O4 : 309.1814; found: 309.1812.
((2S ,3R )-3-Amino-2-hydroxy-4-phenylbutanoyl)-l -valyl-l -phenylalanine (2)
((2S ,3R )-3-Amino-2-hydroxy-4-phenylbutanoyl)-l -valyl-l -phenylalanine (2)
Yield: 0.068 g (95%); white solid; [α]D
27 –12.20 (c 1.02, H2 O); mp 187–189 °C {lit.[19 ] [α]D
20 –11.9 (c 1.00, HOAc); 188–191 °C}.
IR (thin film): 2924, 2853, 1732, 1647, 1456 cm–1 .
1 H NMR (DMSO-d
6 , 500 MHz): δ = 8.41 (d, J = 10.0 Hz, 1 H), 8.06 (br s, 1 H), 7.81 (d, J = 10.0 Hz, 1 H), 7.34–7.11 (m, 10 H), 6.83 (br s, 1 H), 4.43–4.39 (m, 1 H), 4.19–4.16 (m, 1 H), 4.02 (s, 1 H), 3.55 (s, 1 H), 3.06–2.90 (m, 4 H), 2.02–1.98 (m, 1 H), 0.84–0.82 (m, 6 H).
13 C NMR (DMSO-d
6 , 125 MHz): δ = 172.6, 170.5, 137.5, 136.4, 129.5, 129.1, 128.6, 128.1, 126.9, 126.4, 68.2, 57.2, 54.2, 53.5, 36.5, 34.6, 30.7, 29.0, 19.0, 18.0.
HRMS (ESI–TOF): m /z [M + H]+ calcd for C24 H32 N3 O5 : 442.2342; found: 442.2343.
(3S ,4R )-4-Amino-3-hydroxy-5-phenylpentanoic Acid (3)
(3S ,4R )-4-Amino-3-hydroxy-5-phenylpentanoic Acid (3)
Yield: 0.032 g (98%); clear oil; [α]D
27 –1.50 (c 0.13, MeOH).
IR (thin film): 3405, 2925, 2854, 1737, 1458 cm–1 .
1 H NMR (D2 O, 500 MHz): δ = 7.44–7.33 (m, 5 H), 4.18–4.14 (m, 1 H), 3.62–3.58 (m, 1 H), 3.15 (dd, J = 15.0, 5.0 Hz, 1 H), 2.89 (dd, J = 15.0, 10.0 Hz, 1 H), 2.82–2.78 (m, 1 H), 2.64 (dd, J = 15.0, 10.0 Hz, 1 H).
13 C NMR (D2 O, 125 MHz): δ = 174.8, 135.1, 129.4, 129.2, 127.7, 66.8, 56.6, 38.7, 35.3.
HRMS (ESI–TOF): m /z [M + H]+ calcd for C11 H16 NO3 : 210.1130; found: 210.1129.
Synthesis of Dipeptide Boc-Val-Phe-OMe
Synthesis of Dipeptide Boc-Val-Phe-OMe
Boc-Val-OH (0.20 g, 0.92 mmol) was dissolved in anhydrous DCM (10 mL) and the solution was cooled in an ice bath followed by addition of EDC·HCl (0.35 g, 1.84 mmol) and HOBt (0.24 g, 1.84 mmol) and the mixture was stirred for 20 min. HCl·H2 N-Phe-OMe (0.19 g, 0.92 mmol) was added to the reaction mixture followed by DIPEA (0.35 mL, 2.03 mmol) and the mixture was stirred at r.t. for 6 h. On complete disappearance of starting material, the organic layer was washed with aqueous citric acid (3 × 15 mL) and 2 M aqueous NaHCO3 (3 × 15 mL). The organic layers were combined, dried over Na2 SO4 , filtered, concentrated under vacuum, and purified by column chromatography.
Methyl (tert -Butoxycarbonyl)-l -valyl-l -phenylalaninate (12)
Methyl (tert -Butoxycarbonyl)-l -valyl-l -phenylalaninate (12)
Column chromatography (petroleum ether/EtOAc, 70:30).
Yield: 0.31 g (90%); white solid; [α]D
27 +30.38 (c 0.88, CHCl3 ); mp 101–103 °C.
IR (thin film): 3361, 3287, 3094, 2958, 2929, 2871, 1746, 1691, 1656, 1567, 1514 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 7.28–7.20 (m, 3 H), 7.09 (d, J = 7.3 Hz, 2 H), 6.40 (br s, 1 H), 5.05 (br s, 1 H), 4.85 (dd, J = 15.0, 5.0 Hz, 1 H), 3.90 (m, 1 H), 3.68 (d, J = 1.4 Hz, 3 H), 3.10–3.07 (m, 2 H), 2.08–2.04 (m, 1 H), 1.43 (s, 9 H), 0.90 (d, J = 5.0 Hz, 3 H), 0.84 (d, J = 5.0 Hz, 3 H).
13 C NMR (CDCl3 , 125 MHz): δ = 171.8, 171.3, 155.8, 135.8, 129.3, 128.7, 127.2, 79.9, 59.9, 53.23, 52.3, 38.0, 30.9, 28.4, 19.2, 17.7.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C20 H30 N2 NaO5 : 401.2052; found: 401.2052.
Synthesis of Tripeptide 13
Synthesis of Tripeptide 13
TFA (1.00 mL) was added to a stirred solution of Boc-Val-Phe-OMe (0.22 g, 0.58 mmol) in anhydrous DCM (4 mL) at 0 °C and the mixture was stirred for 30 min. After completion of the reaction as observed in TLC, the solvent was removed under vacuum with addition of DCM (5 mL, 3 to 4 times). The residue (0.20 g, 0.58 mmol) was dissolved in anhydrous DCM (10 mL) in an ice bath, followed by addition of EDC·HCl (0.22 g, 1.18 mmol) and HOBt (0.15 g, 1.18 mmol) and stirred for 20 min. Boc deprotected dipeptide 12 (0.22 g, 0.58 mmol) was added to the reaction mixture followed by DIPEA (0.20 mL, 1.30 mmol). The reaction mixture was stirred at r.t. for a further 6 h. On complete disappearance of starting material, the organic layer was washed with aqueous citric acid (3 × 15 mL) and 2 M aqueous NaHCO3 (3 × 15 mL). The organic layers were combined, dried over Na2 SO4 , filtered, concentrated, and purified by column chromatography.
Methyl ((2S ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoyl)-l -valyl-l -phenylalaninate (13)
Methyl ((2S ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoyl)-l -valyl-l -phenylalaninate (13)
Column chromatography (petroleum ether/EtOAc, 70:30).
Yield: 0.24 g (70%); white solid; [α]D
27 +18.26 (c 0.56, CHCl3 ); mp 135–137 °C.
IR (thin film): 3295, 3064, 3029, 2923, 2854, 1747, 1692, 1650, 1531, 1455 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 7.22–7.13 (m, 9 H), 7.05–7.01 (m, 3 H), 6.28 (d, J = 5.1 Hz, 1 H), 5.10 (d, J = 9.9 Hz, 1 H), 4.76 (dd, J = 10.0, 5.0 Hz, 1 H), 4.64–4.60 (m, 2 H), 4.21 (dd, J = 10.0, 5.0 Hz, 2 H), 4.00 (d, J = 2.0 Hz, 1 H), 3.65 (s, 3 H), 3.34 (s, 3 H), 3.06 (dd, J = 10.0, 5.0 Hz, 1 H), 2.97 (dd, J = 10.0, 5.0 Hz, 1 H), 2.82 (dd, J = 10.0, 5.0 Hz, 1 H), 2.63 (dd, J = 13.6, 10.0 Hz, 1 H), 2.06–2.04 (m, 1 H), 1.24 (s, 9 H), 0.86 (d, J = 6.6 Hz, 3 H), 0.81 (d, J = 6.5 Hz, 3 H).
13 C NMR (CDCl3 , 125 MHz): δ = 171.7, 170.5, 154.9, 137.8, 135.7, 129.4, 129.3, 128.7, 128.5, 127.3, 126.5, 97.4, 79.3, 78.8, 58.0, 56.8, 53.5, 53.3, 52.4, 38.1, 37.9, 31.1, 29.8, 28.4, 19.3, 17.8.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C32 H46 N3 O8 : 600.3285; found: 600.3282.
Procedure for Hydrolysis of 13
Procedure for Hydrolysis of 13
LiOH (0.030 g, 0.48 mmol) was added to a stirred solution of 13 (0.24 g, 0.40 mmol) in MeOH/H2 O (4:1, 10 mL) at 0 °C and the reaction mixture was stirred for 1 h at the same temperature. After the disappearance of starting material as observed in TLC, the reaction was quenched with saturated aqueous KHSO4 (10 mL) and the free acid was extracted with EtOAc (2 × 40 mL). The organic layers were combined, dried over Na2 SO4 , filtered, concentrated under vacuum, and purified by column chromatography.
((2S ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoyl)-l -valyl-l -phenylalanine (14)
((2S ,3R )-3-((tert -Butoxycarbonyl)amino)-2-(methoxymethoxy)-4-phenylbutanoyl)-l -valyl-l -phenylalanine (14)
Column chromatography (DCM/MeOH, 95:5).
Yield: 0.22 g (94%); white solid; [α]D
27 +15.69 (c 0.86, CHCl3 ); mp 109–110 °C.
IR (thin film): 3312, 3064, 3029, 2962, 2925, 2854, 1716, 1650, 1524 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 7.47 (br s, 1 H), 7.27–7.13 (m, 10 H), 6.07 (br s, 1 H), 5.07 (d, J = 5.0 Hz, 1 H), 4.81 (br s, 1 H), 4.61–4.59 (m, 2 H), 4.34–4.07 (m, 3 H), 3.39 (s, 3 H), 2.90–2.71 (m, 3 H), 2.04 (br s, 1 H), 1.76–1.61 (m, 1 H), 1.25 (s, 9 H), 0.89–0.84 (m, 6 H).
13 C NMR (CDCl3 , 125 MHz): δ = 175.7, 174.2, 173.7, 171.0, 170.7, 156.6, 155.1, 137.9, 137.6, 136.1, 129.6, 128.6, 127.1, 126.7, 115.5, 97.3, 96.9, 81.1, 79.6, 78.5, 58.4, 58.2, 56.9, 55.7, 53.7, 53.3, 39.7, 38.5, 37.8, 31.8, 31.1, 29.8, 28.3, 27.9, 20.8, 19.4, 18.3.
HRMS (ESI–TOF): m /z [M + H]+ calcd for C31 H44 N3 O8 : 586.3128; found: 586.3121.
Asymmetric α-Hydroxylation of Aldehyde 4
Asymmetric α-Hydroxylation of Aldehyde 4
l -Proline (0.13 g, 1.14 mmol, 30 mol%) and nitrosobenzene (0.44 g, 4.18 mmol) were added to a stirred solution of 4 (1.00 g, 3.80 mmol) in anhydrous DMSO (10 mL) at 15 °C and the mixture was stirred for 3 h at the same temperature. After 3 h the reaction was cooled to 0 °C and phosphorane Ph3 P=CHCO2 Et (2.65 g, 7.60 mmol) in DCM (10 mL) was added and the reaction mixture was stirred for a further 2 h at 0 °C. On complete disappearance of starting material, the reaction was quenched with saturated aqueous NH4 Cl (30 mL) and the mixture was extracted with DCM (2 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over Na2 SO4 , filtered, and concentrated under vacuum. The crude aminohydroxylated product was taken as such to the next step, leading to the cleavage of O–N bond.
Cu(OAc)2 (0.17 g, 0.96 mmol) was added to a stirred solution of the above product (1.43 g, 3.24 mmol) in EtOH (10 mL) and the mixture stirred at r.t. for 6 h. On complete disappearance of starting material, the reaction was quenched with saturated aqueous NH4 Cl (20 mL) and the mixture was extracted with DCM (2 × 20 mL). The combined organic phases were washed with brine (30 mL), dried over Na2 SO4 , filtered, concentrated under vacuum, and purified by column chromatography.
Ethyl (4S ,5R ,E )-5-((tert -Butoxycarbonyl)amino)-4-hydroxy-6-phenylhex-2-enoate (15)
Ethyl (4S ,5R ,E )-5-((tert -Butoxycarbonyl)amino)-4-hydroxy-6-phenylhex-2-enoate (15)
Column chromatography (petroleum ether/EtOAc, 80:20).
Yield: 0.80 g (70%); clear oil; [α]D
27 –3.91 (c 0.23, CHCl3 ).
IR (thin film): 3355, 2926, 1729, 1683, 1524 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 7.31–7.17 (m, 5 H), 6.98 (dd, J = 15.0, 5.0 Hz, 1 H), 6.15 (d, J = 15.0, 5.0 Hz, 1 H), 4.62 (d, J = 10.0 Hz, 1 H), 4.43 (br s, 1 H), 4.21 (q, J = 5.0 Hz, 2 H), 4.02 (s, 1 H), 3.81 (s, 1 H), 2.84–2.77 (m, 2 H), 1.36 (s, 9 H), 1.29 (t, J = 5.0 Hz, 3 H).
13 C NMR (CDCl3 , 125 MHz): δ = 166.4, 157.0, 146.0, 137.4, 129.2, 128.8, 126.9, 122.8, 80.5, 73.6, 60.6, 57.0, 36.2, 29.8, 28.3, 14.3.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C19 H27 NNaO5 : 372.1787; found: 372.1772.
Procedure for Oxazolidine Protection of 15
Procedure for Oxazolidine Protection of 15
A catalytic amount of p -TsOH (0.09 g, 0.57 mmol) and dimethoxypropane (1.11 mL, 8.59 mmol) were added to a stirred solution of 15 (1.00 g, 2.86 mmol) in anhydrous DCM (20 mL) and the mixture was stirred at r.t. for 2 h. On complete disappearance of starting material, the reaction was quenched with saturated aqueous NaHCO3 (20 mL) and the crude product was extracted with DCM (2 × 30 mL). The combined organic phases were dried over Na2 SO4 , filtered, concentrated under vacuum, and purified by column chromatography.
tert -Butyl (4R ,5S )-4-Benzyl-5-((E )-3-ethoxy-3-oxoprop-1-en-1-yl)-2,2-dimethyloxazolidine-3-carboxylate (16)
tert -Butyl (4R ,5S )-4-Benzyl-5-((E )-3-ethoxy-3-oxoprop-1-en-1-yl)-2,2-dimethyloxazolidine-3-carboxylate (16)
Column chromatography (petroleum ether/EtOAc, 85:15).
Yield: 0.95 g (85%); clear oil; [α]D
27 –13.77 (c 0.80, CHCl3 ).
IR (thin film): 2978, 2930, 1723, 1701, 1604 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.29–7.10 (m, 5 H), 6.61–6.54 (m, 1 H), 6.16–6.12 (m, 1 H), 4.69 (br s, 1 H), 4.47–4.24 (m, 1 H), 4.19–4.10 (m, 2 H), 3.22 (dd J = 12.0, 4.0 Hz, 1 H), 2.91–2.79 (m, 1 H), 2.71–2.66 (m, 1 H), 1.56 (s, 3 H), 1.52 (s, 3 H), 1.46 (s, 3 H), 1.37 (s, 3 H), 1.28–1.22 (m, 6 H).
13 C NMR (CDCl3 , 125 MHz): δ = 165.8, 151.9, 151.5, 141.7, 141.6, 138.2, 137.1, 130.0, 129.9, 128.4, 128.2, 126.3, 126.2, 122.6, 93.7, 93.0, 80.4, 80.1, 75.7, 75.4, 63.2, 61.7, 61.3, 60.6, 60.5, 37.4, 36.6, 28.6, 28.5, 28.0, 27.4, 27.0, 25.2, 24.0, 14.3, 14.2.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C22 H31 NNaO5 : 412.2100; found: 412.2105.
LiBH4 Reduction of 16
LiBH4 (0.17 g, 7.70 mmol) was added to a stirred solution of 16 (1.00 g, 2.57 mmol) in anhydrous THF (20 mL) at 0 °C and the mixture was stirred at r.t. for 8 h. On complete disappearance of starting material, the reaction was quenched with saturated aqueous NaHCO3 (20 mL). The crude product was extracted with EtOAc (2 × 30 mL) and the combined organic phases were dried over Na2 SO4 , filtered, concentrated under vacuum, and purified by column chromatography.
tert -Butyl (4R ,5S )-4-Benzyl-5-(3-hydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate (17)
tert -Butyl (4R ,5S )-4-Benzyl-5-(3-hydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate (17)
Column chromatography (petroleum ether/EtOAc, 70:30).
Yield: 0.72 g (80%); clear oil; [α]D
27 +21.04 (c 0.51, CHCl3 ).
IR (thin film): 3445, 3062, 3027, 2928, 2856, 1696, 1604 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 7.29–7.14 (m, 5 H), 4.26–4.11 (m, 1 H), 4.05–3.86 (m, 1 H), 3.52–3.50 (m, 2 H), 3.22–3.18 (dd, J = 12.0, 4.0 Hz, 1 H), 2.92–2.81 (m, 2 H), 1.66–1.49 (m, 9 H), 1.43 (s, 4 H), 1.32 (s, 4 H), 1.24 (s, 2 H).
13 C NMR (CDCl3 , 100 MHz): δ = 152.0, 151.7, 139.1, 139.1, 129.5, 129.3, 128.5, 128.3, 126.2, 126.1, 93.0, 92.4, 80.1, 79.7, 62.4, 60.9, 60.8, 36.5, 35.9, 29.9, 29.8, 28.5, 28.4, 28.1, 27.5, 26.2, 25.0, 23.8.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C20 H31 NNaO4 : 372.2151; found: 372.2151.
Oxidation of Primary Alcohols
Oxidation of Primary Alcohols
IBX (0.69 g, 2.47 mmol) was added to a solution of 17 (0.72 g, 2.06 mmol) in DMSO (10 mL) at r.t. and the mixture was stirred for 3 h. On complete disappearance of starting material, the reaction was quenched with saturated aqueous NaHCO3 (50 mL) and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic phases washed with brine (30 mL) and dried over Na2 SO4 , filtered, concentrated under reduced pressure, and purified by column chromatography.
tert -Butyl (4R ,5S )-4-Benzyl-2,2-dimethyl-5-(3-oxopropyl)oxazolidine-3-carboxylate (18)
tert -Butyl (4R ,5S )-4-Benzyl-2,2-dimethyl-5-(3-oxopropyl)oxazolidine-3-carboxylate (18)
Column chromatography (petroleum ether/EtOAc, 80:20).
Yield: 0.63 g (88%); clear oil; [α]D
27 +15.25 (c 0.72, CHCl3 ).
IR (thin film): 2927, 2854, 2719, 1727, 1696, 1604 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 9.60, 9.57 (s, 1 H), 7.30–7.15 (m, 5 H), 4.25–4.11 (m, 1 H), 3.99–3.96 (m, 1 H), 2.96–2.79 (m, 2 H), 2.44–2.29 (m, 1 H), 2.23–2.08 (m, 1 H), 1.95–1.79 (m, 1 H), 1.69–1.63 (m, 3 H), 1.54–1.50 (m, 4 H), 1.46–1.44 (m, 5 H), 1.35 (s, 4 H).
13 C NMR (CDCl3 , 100 MHz): δ = 201.3, 152.0, 151.6, 138.9, 129.4, 129.3, 128.6, 128.4, 126.3, 126.2, 92.9, 92.4, 80.1, 79.8, 76.4, 76.2, 60.8, 60.6, 40.7, 36.5, 35.9, 29.8, 28.5, 28.4, 28.1, 27.4, 25.0, 23.8, 22.1.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C20 H29 NNaO4 : 370.1994; found: 370.1992.
Synthesis of 20 from Diol 19
Synthesis of 20 from Diol 19
NaIO4 (0.56 g, 2.62 mmol) was added to a stirred solution of diol 19 (0.48 g, 1.31 mmol) in DCM/MeOH (1:1, 10 mL) and the mixture was stirred at r.t. for 4 h. On complete disappearance of starting material, the reaction mixture was filtered and washed with brine (20 mL). The crude product was extracted with EtOAc (2 × 30 mL) and dried over Na2 SO4 , filtered, concentrated under reduced pressure, and purified by column chromatography.
tert -Butyl (4R ,5S )-4-Benzyl-2,2-dimethyl-5-(2-oxoethyl)oxazolidine-3-carboxylate (20)
tert -Butyl (4R ,5S )-4-Benzyl-2,2-dimethyl-5-(2-oxoethyl)oxazolidine-3-carboxylate (20)
Column chromatography (petroleum ether/EtOAc, 80:20).
Yield: 0.38 g (85%); clear oil; [α]D
27 –2.82 (c 0.49, CHCl3 ).
IR (thin film): 3439, 2975, 2931, 1728, 1697, 1495, 1455 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 9.55 (s, 1 H), 7.30–7.19 (m, 5 H), 4.53–4.40 (m, 1 H), 3.84 (br s, 1 H), 3.32 (d, J = 5.0 Hz, 1 H), 2.76–2.71 (m, 1 H), 2.52–2.46 (m, 1 H), 2.21–2.17 (m, 1 H), 1.39 (s, 15 H).
13 C NMR (CDCl3 , 100 MHz): δ = 200.0, 152.2, 151.7, 138.2, 137.3, 129.7, 129.4, 128.7, 126.9, 95.1, 94.4, 80.4, 74.3, 73.5, 63.3, 48.7, 48.2, 43.7, 39.8, 37.7, 29.8, 28.6, 26.9.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C19 H27 NNaO4 : 356.1838; found: 356.1841.
Synthesis of 21 from 20
Pyridinium dichromate (0.45 g, 1.20 mmol) was added to a stirred solution of 20 (0.10 g, 0.30 mmol) in DMF (10 mL) and stirring was continued at r.t. for 8 h. On complete disappearance of the starting material, the reaction was quenched with water (100 mL), the crude product was extracted with Et2 O (2 × 40 mL) and the combined organic phases were further extracted with saturated aqueous NaHCO3 (2 × 30 mL). The aqueous extracts containing the carboxylate salt were combined and acidified with saturated aqueous KHSO4 (2 × 40 mL) and extracted with Et2 O (2 × 50 mL). The combined organic phases were dried over Na2 SO4 , filtered, concentrated under reduced pressure, and purified by column chromatography.
2-((4R ,5S )-4-Benzyl-3-(tert -butoxycarbonyl)-2,2-dimethyloxazolidin-5-yl)acetic Acid (21)
2-((4R ,5S )-4-Benzyl-3-(tert -butoxycarbonyl)-2,2-dimethyloxazolidin-5-yl)acetic Acid (21)
Column chromatography (DCM/MeOH, 95:05).
YIeld: 0.07 g (67%); clear oil; [α]D
27 –5.77 (c 0.48, CHCl3 ).
IR (thin film): 3478, 2976, 2927, 2854, 1698, 1495, 1455 cm–1 .
1 H NMR (CDCl3 , 500 MHz): δ = 7.29–7.25 (m, 2 H), 7.21–7.20 (m, 3 H), 4.46–4.34 (m, 1 H), 3.89–3.83 (m, 1 H), 3.26 (br s, 1 H), 2.88–2.66 (m, 1 H), 2.49–2.44 (m, 1 H), 2.23–2.19 (m, 1 H), 1.37 (s, 15 H).
13 C NMR (CDCl3 , 100 MHz): δ = 175.6, 152.3, 138.2, 137.5, 129.4, 128.7, 126.8, 95.1, 94.5, 80.5, 75.7, 75.0, 72.8, 63.4, 59.9, 40.0, 38.0, 28.7, 28.5, 27.3.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C19 H27 NNaO5 : 372.1787; found: 372.1789.
Synthesis of Aldehyde 4
To a stirred solution of methoxymethyltriphenyl-phosphonium chloride (2.05 g, 6.02 mmol) and t -BuOK (0.58 g, 5.21 mmol) in anhydrous THF (10 mL), HN-Boc-d -phenyl-alaninal (1.00 g, 4.01 mmol) in anhydrous THF (10 mL) was added slowly at –10 °C and the mixture was stirred vigorously for 2 h at the same temperature. On complete disappearance of starting material, the reaction was quenched with saturated aqueous NH4 Cl (30 mL) and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic phases were dried over Na2 SO4 , filtered, concentrated under vacuum, and purified by column chromatography using 90:10 petroleum ether/EtOAc as eluent.
HCl (2 M, 5 mL) was added to the above compound (1.02 g, 3.68 mmol) in THF (5 mL) at 0 °C and the mixture was stirred vigorously at 0 °C for 1 h. On complete disappearance of starting material, the reaction was quenched with saturated aqueous NaHCO3 (10 mL), and the mixture was extracted with EtOAc (2 × 20 mL) and the combined organic phases containing crude product were dried over Na2 SO4 , filtered, concentrated, and purified by column chromatography.
tert -Butyl (R )-(4-Oxo-1-phenylbutan-2-yl)carbamate (4)
tert -Butyl (R )-(4-Oxo-1-phenylbutan-2-yl)carbamate (4)
Column chromatography (petroleum ether/EtOAc, 80:20).
Yield: 0.85 g (81%); clear oil; [α]D
27 +12.04 (c 0.51, CHCl3 ).
IR (thin film): 2928, 2856, 2718, 1727, 1696, 1604 cm–1 .
1 H NMR (CDCl3 , 400 MHz): δ = 9.69 (s, 1 H), 7.31–7.14 (m, 5 H), 4.76 (br s, 1 H), 4.25 (br s, 1 H), 2.95–2.61 (m, 2 H), 2.58–2.48 (m, 2 H), 1.39 (s, 9 H).
13 C NMR (CDCl3 , 100 MHz): δ = 201.1, 155.2, 137.5, 129.4, 128.7, 126.9, 79.7, 47.7, 47.5, 40.8, 31.3, 29.8, 28.4.
HRMS (ESI–TOF): m /z [M + Na]+ calcd for C15 H21 NNaO3 : 286.1419; found: 286.1421.
