Enantioselective total synthesis of (S)-nakinadine B

Abstract

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.

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Introduction

During recent years, marine sponges have been recognized as a rich source of bioactive natural products with fascinating chemical structures. The nakinadine A–F (3–8) alkaloids were recently isolated from an Okinawan marine sponge Amphimedon sp. (SS-1059) (Fig. 1).¹ Metabolites from the Okinawan marine sponge family illicit a myriad of biological activities that includes antimicrobial, cardiotonic, cytotoxic and antitumor activities.² The nakinadine alkaloids possess an α-phenyl-β-amino acid moiety with a long chain N-alkyl substituent capped by a terminal 3-pyridyl moiety. The nakinadine B 3 and C 4 possess an α-phenyl-β²-amino acid core unit 1 which is different from the nakinadines A 5 and D–F (6–8) having an α-phenyl-β^2,3-amino acid core unit 2. The nakinadine A–C (3–5) alkaloids have been shown to possess significant cytotoxicity against a variety of tumour cell lines including L1210 murine leukaemia and KB human epidermoid carcinoma cells.¹

Fig. 1 Structures of nakinadine A–F alkaloids.

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.

Results and discussion

Our synthetic approach for the synthesis of α-phenyl-β²-amino acid core unit 1 and (S)-nakinadine B 3 was envisioned via the retrosynthetic route as shown in Scheme 1. The diol 9 was visualized as a synthetic intermediate from which α-phenyl-β²-amino acid core unit 1 could be synthesized by oxidative cleavage followed by oxidation of the intermediate aldehyde. The diol 9 in turn could be synthesized from alcohol derivative 10 through proline catalyzed α-aminoxylation of aldehyde derived from 10 followed by standard organic transformations. The alcohol 10 could be obtained from nitroalcohol derivative 11 by employing hydrogenation to get amine intermediate followed by reductive N-alkylation. The key intermediate nitroalcohol 11 could be easily prepared from commercially available nitrostyrene 12 via diphenylprolinol silyl ether mediated asymmetric Michael addition with acetaldehyde. The (S)- and (R)-configuration of α-phenyl-β²-amino acid core unit 1 could be manipulated by simply changing the (S)- and (R)-configuration of the catalyst diphenylprolinol silyl ether during asymmetric Michael addition step.

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]²⁵_D −13.8 (c 0.5, CH₂Cl₂) [Lit.⁸ [α]²⁵_D −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]²⁵_D −6.4 (c 1, CHCl₃) [Lit.³ [α]²⁰_D −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

Scheme 2 Reagents and conditions: (a) (i) acetaldehyde, (S)-diphenylprolinol silyl ether, 1,4-dioxane, 4 °C to rt, 18 h, (ii) NaBH₄, CH₃OH, 0 °C, 15 min, 75% (over two steps) (b) TBSCl, imidazole, dry CH₂Cl₂, 0 °C to rt, 6 h, 95% (c) (i) H₂, Pd(OH)₂/C (20%), CH₃OH, rt, 6 h, (ii) Ar(CH₂)₁₂CHO 14, Na(CN)BH₃, Na₂SO₄, C₂H₅OH, 0 °C to rt, 48 h, (iii) (Boc)₂O, NaH, DMAP, dry DMF, 0 °C to rt, 12 h, 82% (over three steps) (d) TBAF, THF, rt, 6 h, 96% (e) (i) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, −78 °C, 3 h, (ii) nitrosobenzene, L-proline, DMSO, rt, 30 min, (iii) NaBH₄, CH₃OH, 0 °C, 15 min, (iv) CuSO₄·5H₂O, CH₃OH, 0 °C to rt, 12 h, 61% (over four steps) (f) (i) NaIO₄, dioxane : water 3 : 1 v/v, rt, 3 h, (ii) oxone, DMF, rt, 12 h, (iii) TFA, CH₂Cl₂, rt, 12 h, 81% (over three steps).

Conclusions

In conclusion, we have described an expeditious 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 employing diphenylprolinol silyl ether mediated asymmetric Michael addition and proline catalyzed aminoxylation reactions as key steps. The overall yield for (S)-nakinadine B 3 was 28% after six column chromatography steps. Moreover, the synthetic strategy described has significant potential for stereochemical variation of substituents at the 2-aryl and N-alkyl sites to synthesize other analogues of nakinadine alkaloids. Currently, the work is in progress, and the results will be disclosed in due course.

Experimental

All reactions were carried out under argon or nitrogen in oven-dried glassware using standard glass syringes and septa. The solvents and chemicals were purchased from Merck and Sigma Aldrich chemical company. Solvents and reagents were purified and dried by standard methods prior to use. Progress of the reactions was monitored by TLC using precoated aluminium plates of Merck kieselgel 60 F254. Column chromatography was performed on silica gel (60–120 and 100–200 mesh) using a mixture of n-hexane/ethyl acetate and dichloromethane/MeOH. Optical rotations were measured on automatic polarimeter AA-65. ¹H and ¹³C NMR spectra were recorded in CDCl₃ (unless otherwise mentioned) on JEOL ECS operating at 400 and 100 MHz, respectively. Chemical shifts are reported in δ (ppm), referenced to TMS. HRMS were recorded on Agilent 6530 Accurate-Mass Q-TOF using Electron Spray Ionization. IR spectra were recorded on Agilent resolution Pro 600 FT-IR spectrometer, fitted with a beam-condensing ATR accessory.

(S)-4-Nitro-3-phenylbutan-1-ol, 11

To a 1,4-dioxane (2.0 mL) solution of (S)-diphenyltrimethylsiloxymethyl pyrrolidine (265 mg, 0.81 mmol, 10 mol%) and nitrostyrene 12 (1.2 g, 8.05 mmol) was added acetaldehyde (4.5 mL, 80.5 mmol) in a sealed tube at 4 °C. The reaction mixture was stirred at room temperature for 18 h and then quenched with 1 N HCl (10 mL). The aqueous phase was extracted with EtOAc (3 × 20 mL) washed with brine, dried over anhydrous Na₂SO₄, concentrated in vacuo, and used as such for the next step without further purification.

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 : 7 v/v) as eluent to afford the nitro alcohol 11 (1.18 g, 75%). {[α]²⁵_D −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.

(S)-tert-Butyldimethyl(4-nitro-3-phenylbutoxy)silane, 13

To a solution of nitro alcohol 11 (1.0 g, 5.13 mmol) in CH₂Cl₂ (20 mL) was added imidazole (525 mg, 7.7 mmol) followed by tert-butyldimethylsilyl chloride (940 mg, 6.2 mmol) at 0 °C. The reaction was then stirred under N₂ for 6 h at room temperature, after which it was quenched by adding saturated aqueous NH₄Cl (20 mL) solution. The aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL), organic layer separated, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Purification by silica gel column chromatography (EtOAc/hexane 1 : 9 v/v) as eluent furnished TBS protected derivative 13 (1.5 g, 95%) as pale yellow oil. [α]²⁵_D −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.

13-(Pyridin-3-yl)tridecanal, 14

To a solution of oxalyl chloride (685 mg, 460 μL, 5.4 mmol) in dry CH₂Cl₂ (10 mL) at −78 °C was added dropwise DMSO (870 mg, 790 μL, 11.2 mmol) in CH₂Cl₂ (10 mL) over 15 min. The reaction mixture was stirred for 30 min and a solution of 13-(pyridin-3-yl)tridecan-1-ol⁹ (1.0 g, 3.6 mmol) in CH₂Cl₂ (10 mL) was added dropwise over 15 min. The reaction mixture was stirred for 30 min at same temperature, then added Et₃N (1.6 g, 2.2 mL, 15.84 mmol) in CH₂Cl₂ (10 mL) dropwise and stirred for 3 h. The reaction mixture was diluted with water (20 mL), organic layer separated, extracted with CH₂Cl₂ (3 × 20 mL) washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Purification by silica gel column chromatography (EtOAc/hexane 1 : 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.

(S)-tert-Butyl-4-(tert-butyldimethylsilyloxy)-2-phenylbutyl(13-(pyridin-3-yl)tridecyl)carbamate, 15

To a solution of compound 13 (750 mg, 2.42 mmol) in MeOH (12 mL) was added catalytic amount of 20% Pd(OH)₂/C. The reaction mixture was then subjected to hydrogenation under 1 atmospheric pressure for 6 h. After this time, the reaction mixture was filtered through a pad of Celite and washed with additional MeOH (30 mL). The resulting organic layer was concentrated in vacuo, which was used as such for the next step without further purification.

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 : 9 v/v) as eluent furnished the compound 15 (1.27 g, 82%) as yellow oil. [α]²⁵_D −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.

(S)-tert-Butyl-4-hydroxy-2-phenylbutyl(13-(pyridin-3-yl)tridecyl)carbamate, 16

To a solution of compound 15 (1.0 g, 1.56 mmol) in THF (10 mL) was added TBAF solution (3.12 mL, 1.0 M in THF, 3.12 mmol) dropwise via syringe. The reaction mixture was stirred for 6 h at room temperature, after which the reaction mixture was quenched with saturated aqueous NH₄Cl solution (15 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic fractions were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane 4 : 6 v/v) as eluent to give the alcohol derivative 16 (770 mg, 96%) as pale yellow oil. [α]²⁵_D −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.

tert-Butyl(2S,3R)-3,4-dihydroxy-2-phenylbutyl(13-(pyridin-3-yl)tridecyl)carbamate, 17

To a solution of oxalyl chloride (100 mg, 68 μL, 0.78 mmol) in dry CH₂Cl₂ (5 mL) at −78 °C was added dropwise DMSO (125 mg, 115 μL, 1.6 mmol) in CH₂Cl₂ (5 mL) over 15 min. The reaction mixture was stirred for 30 min and a solution of alcohol 16 (270 mg, 0.52 mmol) in CH₂Cl₂ (5 mL) was added dropwise over 15 min. The reaction mixture was stirred for 30 min, then Et₃N (230 mg, 320 μL, 2.3 mmol) in CH₂Cl₂ (5 mL) was added dropwise and stirred for 3 h. The reaction mixture was diluted with water and the organic layer separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL) and the combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo to give the crude aldehyde, which was used in the next step without further purification.

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 : 3 v/v) as eluent to afford the diol 17 (170 mg, 61%). [α]²⁵_D −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.

(S)-Nakinadine B, 3

To a solution of diol 17 (100 mg, 0.185 mmol) in dioxane–water (3 : 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 : 9 v/v) as eluent to give title compound 3 (63 mg, 81%) as a white solid compound. Mp 120–122 °C; {[α]²⁵_D −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.

Acknowledgements

Y. G. thanks UGC, New Delhi for a senior research fellowship. S. K. P. is thankful to Department of Science and Technology, New Delhi, for generous funding of the project (Grant No. SB/FT/CS-178/2011). We are grateful to Prof. Prakash Gopalan for his support and encouragement.

Notes and references

1. (a) T. Kubota, T. Nishi, E. Fukushi, J. Kawabata, J. Fromont and J. Kobayashi, Tetrahedron Lett., 2007, 48, 4983; (b) T. Nishi, T. Kubota, J. Fromont, T. Sasaki and J. Kobayashi, Tetrahedron, 2008, 64, 3127.
2. (a) D. M. Roll, P. J. Scheuer, G. K. Matsumot and J. Clardy, J. Am. Chem. Soc., 1983, 105, 6177; (b) H. Nakamura, J. Kobayashi, M. Kobayashi, Y. Ohizumi and Y. Hirata, Chem. Lett., 1985, 14, 713; (c) F. J. Schmitz and S. J. Bloor, J. Org. Chem., 1988, 53, 3922; (d) I. Shin and M. J. Krische, Org. Lett., 2015, 17, 4786; (e) D. B. Abdjul, H. Yamazaki, S. Kanno, O. Takahashi, R. Kirikoshi, K. Ukai and M. Namikoshi, J. Nat. Prod., 2015, 78, 1428; (f) J. Uenishi, T. Iwamoto and J. Tanaka, Org. Lett., 2009, 11, 3262; (g) Y. Takahashi, T. Kubota, J. Fromont and J. Kobayashi, Org. Lett., 2009, 11, 21.
3. For synthesis of nakinadine-A 5, see: (a) S. G. Davies, A. M. Fletcher, P. M. Roberts, R. S. Shah, A. L. Thompson and J. E. Thomson, Org. Lett., 2014, 16, 1354; for synthesis of nakinadine-B 3, see: (b) S. G. Davies, J. A. Lee, P. M. Roberts, R. S. Shah and J. E. Thomson, Chem. Commun., 2012, 48, 9236; for synthesis of nakinadine-C 4, see: (c) S. G. Davies, P. M. Roberts, R. S. Shah and J. E. Thomson, Tetrahedron Lett., 2013, 54, 6423; for synthesis of nakinadine-D–F 6–8, see: (d) S. G. Davies, A. M. Fletcher, R. S. Shah, P. M. Roberts and J. E. Thomson, J. Org. Chem., 2015, 80, 4017.
4. (a) Y. Garg and S. K. Pandey, J. Org. Chem., 2015, 80, 4201; (b) Y. Garg, S. Gahalawat and S. K. Pandey, RSC Adv., 2015, 5, 38846; (c) S. Gahalawat and S. K. Pandey, RSC Adv., 2015, 5, 41013; (d) S. Gahalawat, Y. Garg and S. K. Pandey, Asian J. Org. Chem., 2015, 4, 1025.
5. D. E. Worrall, Org. Synth., 1929, 9, 66.
6. (S)-Diphenylprolinol silyl ether was prepared from (S)-diphenylprolinol and TMSCl using a known procedure; see: Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem., Int. Ed., 2005, 44, 4212.
7. (a) P. Garcia-Garcia, A. Ladepeche, R. Halder and B. List, Angew. Chem., Int. Ed., 2008, 47, 4719; (b) Y. Hayashi, T. Itoh, M. Ohkubo and H. Ishikawa, Angew. Chem., Int. Ed., 2008, 47, 4722; (c) Y. Qiao, J. He, B. Ni and A. D. Headley, Adv. Synth. Catal., 2012, 354, 2849.
8. C. Palomo, A. Landa, A. Mielgo, M. Oiarbide, A. Puente and S. Vera, Angew. Chem., Int. Ed., 2007, 46, 8431.
9. 13-(Pyridin-3-yl)tridecanal 14 was prepared from dodecane-1,12-diol and 3-picoline using a known procedure followed by Swern oxidation; see: B. J. Shorey, V. Lee and J. E. Baldwin, Tetrahedron, 2007, 63, 5587.
10. (a) T. T. Tidwell, Synthesis, 1990, 10, 857; (b) T. T. Tidwell, Org. React., 1990, 39, 297.
11. The diastereoselectivity of compound 17 was determined by ¹H-NMR and ¹³C-NMR spectroscopy. For aminoxylation reactions see: (a) Y. Hayashi, J. Yamaguchi, T. Sumiya, K. Hibino and M. Shoji, J. Org. Chem., 2004, 69, 5966; (b) A. Cordova, H. Sunden, A. Bogevig, M. Johansson and F. Himo, Chem.–Eur. J., 2004, 10, 3673; (c) L. Yang, R. Liu, B. Wang, L. Weng and H. Zheng, Tetrahedron Lett., 2009, 50, 2628.
12. W. Yu, Y. Mei, Y. Kang, Z. Hua and Z. Jin, Org. Lett., 2004, 6, 3217.
13. R. T. Benjamin, S. Meenakshi, G. O. Hollist and B. Borhan, Org. Lett., 2003, 5, 1031.

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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

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