Yuvraj Garg and
Satyendra Kumar Pandey*
School of Chemistry and Biochemistry, Thapar University, Patiala 147001, India. E-mail: skpandey@thapar.edu; Fax: +91-175-236-4498; Tel: +91-175-239-3832
First published on 3rd March 2016
A novel approach for the synthesis of α-phenyl-β2-amino acid core unit 1 and its application to the total synthesis of (S)-nakinadine B 3, a marine natural product, is described. The synthesis utilizes the optimized combination of diphenylprolinol silyl ether mediated asymmetric Michael addition and a proline catalyzed aminoxylation reactions as key steps.
The absolute configuration of (S)-nakinadine B 3 was determined by Kobayashi and co-workers with the help of 2D NMR spectroscopic studies. The paucity of the material in isolation has hampered further studies of the biochemistry of nakinadine A–F (3–8).1 Therefore, in order to achieve nakinadine alkaloids in larger quantities for further biological evaluation, it is highly desirable to develop a general, convergent and enantiopure synthetic approach which involves stable intermediates. The nakinadine A–F (3–8) have been synthetic targets of considerable interest due to its high cytotoxic activity and with an array of functionalities.3 More recently, Davies and co-workers reported the first asymmetric synthesis of the (S)-nakinadine B 3 in nine steps employing conjugate addition of lithium dibenzylamide to an N-α-phenylacryloyl SuperQuat derivative with in situ diastereoselective enolate protonation as the key step.3b As part of our research on the asymmetric synthesis of bioactive compounds,4 we wish to report herein, a new, general and highly efficient synthetic approach for enantiopure α-phenyl-β2-amino acid core unit 1 and its application to the total synthesis of (S)-nakinadine B 3 employing diphenylprolinol silyl ether mediated asymmetric Michael addition and proline catalyzed aminoxylation reactions as key steps.
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| Scheme 1 Retrosynthetic approach for the asymmetric synthesis of α-phenyl-β2-amino acid core unit 1 and (S)-nakinadine B 3. | ||
As outlined in Scheme 2, the synthesis of (S)-nakinadine B 3 commenced with commercially available nitrostyrene 12, which can be easily synthesized from base catalyzed condensation of benzaldehyde with nitromethane.5 Asymmetric Michael addition of acetaldehyde with nitrostyrene 12 in the presence of catalytic amount of (S)-diphenylprolinol silyl ether6 in a sealed tube afforded the nitroaldehyde adduct,7 which on subsequent reduction with NaBH4 delivered the nitroalcohol derivative 11 in 75% yield with 96% ee {[α]25D −13.8 (c 0.5, CH2Cl2) [Lit.8 [α]25D −13.7 (c 0.5, CH2Cl2)]}. With enantiomerically pure nitroalcohol 11 in hand, we then performed base catalyzed silyl ether protection of free alcohol which afforded the TBS protected derivative 13 in 95% yield. Our next aim was to carry out N-alkylation at terminal nitro group site. To this end, compound (S)-13 was subjected to hydrogenation in the presence of catalytic amount of Pd(OH)2 to afford the terminal amine intermediate. Reductive N-alkylation of the synthesized amine intermediate with 13-(pyridin-3-yl)tridecanal9 14 using Na(CN)BH3 afforded the N-alkylated amine intermediate which on subsequent protection with (Boc)2O in the presence of NaH and catalytic amount of DMAP furnished the Boc protected derivative 15 in 82% yield. The cleavage of silyl ether in compound (S)-15 with TBAF afforded the alcohol derivative 16 quantitatively. Oxidation of alcohol (S)-16 to aldehyde under Swern conditions,10 subsequent treatment of aldehyde with nitrosobenzene in the presence of catalytic amount of L-proline (20 mol%) in DMSO at room temperature furnished α-aminoxylated aldehyde, which on spontaneous reduction with NaBH4 and cleavage of phenylamine moiety with CuSO4·5H2O afforded the diol 17 as a single diastereomer in 61% yield.11 The diol 17 on smooth oxidative cleavage in the presence of NaIO4 (ref. 12) followed by oxidation with oxone13 and finally deprotection of N-Boc with TFA furnished the sponge metabolite (S)-nakinadine B 3 in 81% yield {[α]25D −6.4 (c 1, CHCl3) [Lit.3 [α]20D −6.3 (c 1, CHCl3)]}. The physical and spectroscopic data of (S)-nakinadine B 3 were found in full agreement with those reported in the literature.1,3
To the above crude product were added MeOH (20 mL), NaBH4 (460 mg, 12.1 mmol) and the reaction mixture stirred for 15 min at 0 °C. The reaction was quenched with saturated aqueous NH4Cl solution, extracted with ethyl acetate (3 × 20 mL), dried over anhydrous Na2SO4, concentrated in vacuo and purified by silica gel column chromatography (EtOAc/hexanes 3
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7 v/v) as eluent to afford the nitro alcohol 11 (1.18 g, 75%). {[α]25D −13.8 (c 0.5, CH2Cl2) [Lit.8 −13.7 (c 0.5, CH2Cl2)]}; IR (CH2Cl2) ν: 3378, 2940, 2415, 1549, 1379, 1265, 733 cm−1; 1H NMR (400 MHz, CDCl3) δ: 7.23–7.34 (m, 5H), 4.61–4.65 (m, 2H), 3.66–3.74 (m, 1H), 3.59–3.64 (m, 1H), 3.46–3.52 (m, 1H), 1.87–2.04 (m, 2H), 1.66 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 138.7, 129.0, 127.7, 127.5, 80.6, 59.8, 41.0, 35.5; HRMS (ESI+) m/z calcd for C10H13NO3Na+ ([M + Na]+) 218.0787; found 218.0784.
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9 v/v) as eluent furnished TBS protected derivative 13 (1.5 g, 95%) as pale yellow oil. [α]25D −71.2 (c 1, CH2Cl2); IR (CH2Cl2) ν: 3012, 2945, 2932, 2402, 1552, 1362, 735 cm−1; 1H NMR (400 MHz, CDCl3) δ: 7.20–7.36 (m, 5H), 4.58–4.72 (m, 2H), 3.68–3.74 (m, 1H), 3.56–3.61 (m, 1H), 3.42–3.47 (m, 1H), 1.83–1.97 (m, 2H), 0.89 (s, 9H), 0.009 (s, 6H); 13C NMR (100 MHz, CDCl3) δ: 139.1, 128.8, 127.6, 80.6, 59.9, 41.1, 35.8, 25.8, 18.1, −5.5; HRMS (ESI+) m/z calcd for C16H28NO3Si+ ([M + H]+) 310.1833; found 310.1833.
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1 v/v) as eluent afforded aldehyde derivative 14 (940 mg, 95%) as pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 9.76 (t, J = 1.84 Hz, 1H), 8.42–8.43 (m, 2H), 7.48–7.50 (m, 1H), 7.19–7.22 (m, 1H), 2.60 (t, J = 7.32 Hz, 2H), 2.42 (td, J = 1.80, 7.76 Hz, 2H), 1.59–1.64 (m, 4H), 1.25–1.30 (m, 16H); 13C NMR (100 MHz, CDCl3) δ: 203.0, 149.7, 146.9, 137.9, 135.8, 123.2, 43.8, 32.9, 31.1, 29.5, 29.4, 29.4, 29.3, 29.2, 29.0, 22.0.
Pyridyl aldehyde 14 (665 mg, 2.42 mmol) in ethanol (10 mL) was added to the above synthesized TBS-protected amine intermediate in ethanol (10 mL) followed by addition of anhydrous Na2SO4 (2.1 g, 14.6 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 36 h. After this time, Na(CN)BH3 (305 mg, 4.84 mmol) was added to the reaction mixture at 0 °C and the reaction mixture was stirred at room temperature for additional 12 h. The ethanol from the reaction mixture was evaporated in vacuo. The reaction mixture was then diluted with water and the aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated in vacuo, and used as such for the next step without further purification.
NaH (87 mg, 3.63 mmol) was added to the solution of above coupled amine derivative in 20 mL of dry DMF at 0 °C. After the solution was stirred for 10 min, di-tert-butyl dicarbonate (790 mg, 3.63 mmol) and DMAP (150 mg, 1.2 mmol) were added at the same temperature. The reaction mixture was stirred at room temperature for 12 h. After completion of the reaction as monitored by TLC, the reaction was quenched with water and extracted with diethyl ether (3 × 20 mL). The organic extract was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography (EtOAc/hexane 1
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9 v/v) as eluent furnished the compound 15 (1.27 g, 82%) as yellow oil. [α]25D −45.2 (c 0.8, CH2Cl2); IR (CH2Cl2) ν: 3075, 2982, 2431, 1567, 1383, 775 cm−1; 1H NMR (400 MHz, CDCl3) δ: 8.45–8.47 (m, 2H), 7.51–7.54 (dt, J = 1.84, 7.76 Hz, 1H), 7.29–7.33 (m, 3H), 7.17–7.25 (m, 3H), 3.39–3.64 (m, 3H), 3.02–3.30 (m, 3H), 2.85–2.91 (m, 1H), 2.63 (t, J = 8.28 Hz, 2H), 1.84–1.96 (m, 4H), 1.61–1.68 (m, 2H), 1.44 (s, 9H), 1.19–1.34 (m, 18H), 0.89 (s, 9H), −0.01 (s, 6H); 13C NMR (100 MHz, CDCl3) δ: 149.8, 147.0, 142.6, 137.9, 135.7, 128.3, 128.2, 128.0, 126.4, 123.2, 79.0, 60.9, 60.7, 53.4, 52.7, 47.3, 41.3, 40.7, 35.8, 32.9, 31.1, 29.5, 29.5, 29.3, 29.1, 28.3, 28.1, 27.7, 26.8, 25.8, 18.2, −5.4; HRMS (ESI+) m/z calcd for C39H67N2O3Si+ ([M + H]+) 639.4916; found 639.4921.
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6 v/v) as eluent to give the alcohol derivative 16 (770 mg, 96%) as pale yellow oil. [α]25D −55.8 (c 0.5, CH2Cl2); IR (CH2Cl2) ν: 3362, 2961, 1589, 1269, 732 cm−1; 1H NMR (400 MHz, CDCl3) δ: 8.40–8.42 (m, 2H), 7.48–7.50 (dt, J = 1.40, 7.32 Hz, 1H), 7.27–7.31 (m, 2H), 7.18–7.24 (m, 4H), 3.48–3.72 (m, 3H), 2.86–3.25 (m, 4H), 2.59 (t, J = 7.76 Hz, 2H), 1.81–1.88 (m, 5H), 1.57–1.64 (m, 2H), 1.42 (s, 9H), 1.22–1.30 (m, 18H); 13C NMR (100 MHz, CDCl3) δ: 149.6, 146.8, 138.0, 135.9, 128.4, 127.8, 126.5, 123.2, 79.2, 60.6, 52.8, 47.8, 41.3, 35.7, 32.9, 31.0, 29.6, 29.5, 29.4, 29.4, 29.3, 29.0, 28.3, 28.1, 26.7, 22.6, 14.0; HRMS (ESI+) m/z calcd for C33H53N2O3+ ([M + H]+) 525.4051; found 525.4056.
To a DMSO solution (5 mL) of L-proline (12 mg, 0.104 mmol, 20 mol%) was added above synthesized aldehyde and nitrosobenzene (62 mg, 0.572 mmol) successively at room temperature. After stirring the reaction mixture for 30 min, MeOH (5 mL) and NaBH4 (30 mg, 0.78 mmol) were added and the reaction mixture was stirred for 15 min at 0 °C. The reaction mixture was then quenched with saturated aqueous NH4Cl solution, extracted with ethyl acetate (3 × 10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue thus obtained above was dissolved in MeOH (5 mL) and subjected to treatment with CuSO4·5H2O (33 mg, 0.13 mmol) at 0 °C and stirred at room temperature for 12 h. After completion of reaction as monitored by TLC, it was quenched with saturated aqueous NH4Cl solution. The organic layer was separated and the aqueous phase extracted with EtOAc (3 × 10 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography (EtOAc/hexanes 7
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3 v/v) as eluent to afford the diol 17 (170 mg, 61%). [α]25D −42.2 (c 1.02, CH2Cl2); IR (CH2Cl2) ν: 3369, 2942, 2855, 1467, 1312, 920 cm−1; 1H NMR (400 MHz, CDCl3) δ: 8.43 (m, 2H), 7.48–7.50 (m, 1H), 7.22–7.31 (m, 6H), 4.18–4.24 (m, 1H), 3.87 (bs, 1H), 3.20–3.48 (m, 3H), 2.77–2.98 (m, 3H), 2.59 (t, J = 7.7 Hz, 2H), 1.59–1.61 (m, 4H), 1.48 (s, 9H), 1.25–1.29 (m, 18H); 13C NMR (100 MHz, CDCl3) δ: 157.5, 149.7, 146.9, 138.8, 135.9, 129.0, 128.3, 127.0, 80.5, 70.4, 65.1, 49.0, 47.6, 46.7, 32.9, 31.1, 29.6, 29.5, 29.5, 29.3, 29.2, 29.1, 28.3, 26.8, 14.1; HRMS (ESI+) m/z calcd for C33H53N2O4+ ([M + H]+) 541.4000; found 541.4012.
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1, 2 mL) was added NaIO4 (80 mg, 0.37 mmol). The reaction was stirred at 25 °C for 3 h. After completion of reaction, water (5 mL) and CH2Cl2 (10 mL) were added. The organic layer was separated, and the water layer extracted with CH2Cl2 (3 × 10 mL). The combined organic layer was washed with brine and dried over anhydrous Na2SO4, concentrated in vacuo to give crude aldehyde which was used as such for the next step without further purification.
The above aldehyde was dissolved in DMF followed by addition of oxone (57 mg, 0.185 mmol) and stirred at room temperature for 12 h. The resulting solution was diluted with water, filtered through a Celite pad, washed and extracted with diethyl ether (3 × 10 mL). The organic extract was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed in vacuo to obtain the crude product which was used for the next step without further purification.
To the above acid product in CH2Cl2 (2 mL) was added trifluoroacetic acid (2 mL) and the reaction mixture was stirred at room temperature for 12 h. The reaction was quenched with saturated aqueous NaHCO3 and extracted with dichloromethane (3 × 5 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to near dryness. The crude product was purified by silica gel column chromatography using (CH3OH/CH2Cl2 1
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9 v/v) as eluent to give title compound 3 (63 mg, 81%) as a white solid compound. Mp 120–122 °C; {[α]25D −6.4 (c 1, CHCl3) [Lit.3 −6.3 (c 1, CHCl3)]}; IR (CH2Cl2) ν: 3032, 2925, 2853, 1652, 1562 cm−1; 1H NMR (400 MHz, CDCl3) δ: 8.41–8.42 (m, 2H), 7.47–7.49 (m, 1H), 7.12–7.34 (m, 6H), 3.99 (m, 1H), 3.38–3.48 (m, 1H), 2.78–2.87 (m, 3H), 2.57–2.61 (t, J = 7.56 Hz, 2H), 1.57–1.67 (m, 4H), 1.20–1.29 (m, 18H); 13C NMR (100 MHz, CDCl3) δ: 173.2, 149.8, 147.0, 138.0, 137.8, 135.8, 128.7, 128.1, 127.2, 123.2, 52.3, 51.1, 47.8, 32.9, 31.1, 29.6, 29.6, 29.6, 29.5, 29.5, 29.4, 29.1, 29.1, 26.7, 25.7; HRMS (ESI+) m/z calcd for C27H41N2O2+ ([M + H]+) 425.3163; found 425.3163.
Footnotes |
| † Dedicated to Prof. Bhisma K. Patel in recognition of his seminal contributions to so many aspects of organic chemistry. |
| ‡ Electronic supplementary information (ESI) available: Copies of 1H and 13C NMR spectra of compounds 3, 11 and 13–17. See DOI: 10.1039/c6ra03915d |
| This journal is © The Royal Society of Chemistry 2016 |