An enantioselective approach to 2-alkyl substituted tetrahydroquinolines: total synthesis of (+)-angustureine

Abstract

A simple and highly efficient synthetic approach to enantiopure 2-alkyl substituted tetrahydroquinoline 1 skeleton from aldehydes as starting materials and its application to the total synthesis of (+)-angustureine 2 is described. Key transformations include proline catalyzed aminoxylation, Corey–Fuchs protocol, Sonogashira coupling and intramolecular Mitsunobu reactions.

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Introduction

Quinoline and tetrahydroquinoline alkaloids are found abundantly in nature and most of them exhibit interesting biological activity.¹ Enantiomerically pure 2-alkyl substituted tetrahydroquinoline alkaloids 1 from which angustureine 2, galipeine 3, cuspareine 4, and galipinine 5 were first extracted from the bark of the Galipea officinalis Hancock shrub tree found in the mountains of Venezuela (Fig. 1).²

Fig. 1 Some naturally occurring 2-alkyl substituted tetrahydroquinoline alkaloids.

These alkaloids exhibits anti-malarial, anti-tuberculous, cytotoxic, and antiplasmodial activities.³ Galipea species have also been used in folk medicine for the treatment of dysentery, dyspepsia, chronic diarrhea, spinal motor nerve problems and fevers.⁴ Enantiomerically pure 2-alkyl substituted tetrahydro-quinoline alkaloids have synthetic target of considerable interest due to their wide range of important biological activities and with an array of functionalities. Various methods for the synthesis of (+)-angustureine 2 and others 3–5 have been documented in the literature.⁵ Very recently, M. Yus and co-workers reported the synthesis of the (+)-angustureine 2 using diastereoselective addition of an allylic indium intermediate to chiral O-bromophenyl N-tert-butylsulfinyl aldimines.^5v Herein, we wish to report a new, general and highly efficient synthetic approach for enantiopure 2-alkyl substituted tetrahydroquinolines 1 and its application to the total synthesis of (+)-angustureine 2 employing proline catalyzed asymmetric aminoxylation, Corey–Fuchs protocol, palladium catalyzed Sonogashira coupling, and Mitsunobu reaction as key steps.

Results and discussion

Our retrosynthetic approach for the synthesis of 2-alkyl substituted tetrahydroquinolines 1 including (+)-angustureine 2 is outlined in Scheme 1. We envisioned that the aryl nitro-alkyne derivative 6 from which 2-alkyl substituted tetrahydro-quinolines 1 and (+)-angustureine 2 could be synthesized via hydrogenation, Mitsunobu intramolecular ring closer in S_N2 fashion followed by alkylation. The aryl nitro-alkyne derivative 6 could be obtained from the monoprotected alkyne derivative 7 through palladium catalyzed Sonogashira coupling reaction with suitable aromatic nitro-halides. The alkyne derivative 7 in turn could be obtained by means of Corey–Fuchs protocol from the aldehyde synthesized from oxidation of monoprotected alcohol 8. Enantiomerically pure monoprotected alcohol 8 could be obtained from the commercially available aldehydes 9 via proline catalyzed aminoxylation followed by standard organic transformation. The (S)- and (R)-configuration of the 2-alkyl substituted tetrahydroquinolines 1 and (+)-angustureine 2 could be manipulated by simply changing the D-proline and L-proline, respectively, during organocatalytic step.

Scheme 1 Retrosynthetic approach to 2-alkyl substituted tetrahydroquinolines 1 and (+)-angustureine 2.

The synthesis of (+)-angustureine 2 started from the commercially available n-heptanal 10, which on treatment with nitrosobenzene in the presence of catalytic amount of L-proline (10 mol%) in DMSO at room temperature afforded α-aminoxylated aldehyde which on subsequent reduction with NaBH₄/CH₃OH followed by benzylamine cleavage with CuSO₄·5H₂O afforded the required diol 11 in 71% yield over three steps with >99% ee.⁶ {[α]²⁵_D −14.4 (c 1, CH₃OH)}. The physical and spectroscopic data were in full agreement with those reported in literature (Scheme 2).

Scheme 2 Reagents and conditions: (a) (i) nitrosobenzene, L-proline, DMSO, rt, 12 h, (ii) NaBH₄, CH₃OH, 0 °C, 15 min, (iii) CuSO₄·5H₂O, CH₃OH, 0 °C to rt, 12 h, 71% (one pot, three steps) (b) PhCH(OMe)₂, C₆H₆, PPTS, reflux, 1 h, 89% (c) DIBAL-H, CH₂Cl₂, −40 °C to rt, 2 h, 93% (d) (i) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, –78 °C to −60 °C, 2 h, (ii) CBr₄, PPh₃, CH₂Cl₂, 0 °C, 30 min, (iii) n-BuLi, THF, −78 °C to rt, 3 h, 86% (over three steps) (e) 1-iodo-2-nitrobenzene, 2 mol% Pd(PPh₃)₂Cl₂, 1 mol% CuI, Et₃N, DMF, reflux, 3 h, 95% (f) H₂, Pd/C (10%), EtOAc, rt, 24 h, 96% (g) (i) PPh₃, DEAD, CH₂Cl₂, rt, 12 h, (ii) HCHO, Na(CN)BH₃, AcOH, CH₃CN, rt, 10 h, 88% (over two steps).

With enantiomerically pure diol 11 in hand, we then subjected it to protection with benzaldehyde dimethyl acetal in presence of catalytic amount of PPTS, which furnished 1,2-benzylidene acetal 12 in 89% yield.⁷ Regioselective reductive opening of 1,2-benzylidene acetal 12 with DIBAL-H afforded monobenzyl protected alcohol 13 in 93% yield. Oxidation of alcohol 13 under Swern conditions⁸ and subsequent treatment with CBr₄/TPP followed by treatment with n-BuLi under Corey–Fuchs protocol⁹ afforded the terminal alkyne 14 in 86% yield. The terminal alkyne 14 under Sonogashira coupling conditions¹⁰ with commercially available 1-iodo-2-nitro benzene in the presence of Et₃N as a base afforded the 2-nitrobenzene-alkyne derivative 15 in excellent yield (95%). Concomitant reduction of the triple bond, nitro group to amine and deprotection of benzyl group of 2-nitrobenzene-alkyne derivative 15 was achieved in one pot via hydrogenation under 1 atm. pressure in presence of catalytic amount of Pd/C (10%) which furnished the key intermediate amino alcohol 16 in 96% yield. Cyclization of amino alcohol 16 under Mitsunobu conditions¹¹ (DEAD, PPh₃, CH₂Cl₂, rt) afforded the tetrahydroquinoline (norangustureine), and subsequent methylation using reductive amination with formaldehyde in presence of Na(CN)BH₃ afforded the target compound (+)-angustureine 2 in 88% yield {[α]²⁵_D +7.6 (c 0.4, CHCl₃) [Lit.^5t +7.5 (c 0.4, CHCl₃)}. The physical and spectroscopic data were in full agreement with those documented in literature.

Conclusions

In conclusion, a simple, flexible and highly efficient synthetic approach for 2-alkyl substituted tetrahydroquinolines 1 and its application to the total synthesis of (+)-angustureine 2 has been developed. The overall yield for alkaloid (+)-angustureine 2 was 41% in ten steps. The merits of this synthesis are high enantioselectivity with high yielding reaction steps. The synthetic strategy described has significant potential for stereochemical variation and further extension to 2-alkyl substituted tetrahydroquinolines derived natural products with interesting pharmacological activities.

Experimental

The solvents and chemicals were purchased from Merck and Sigma Aldrich chemical company. Progress of the reactions was monitored by TLC using precoated aluminium plates of Merck kieselgel 60 F254. 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. IR spectra were recorded on Agilent resolution Pro 600 FT-IR spectrometer, fitted with a beam-condensing ATR accessory. HRMS were recorded using Electron Spray Ionization. Optical rotations were measured on Automatic polarimeter AA-65. Column chromatography was performed on silica gel (60–120 and 100–200 mesh) using a mixture of hexane and ethyl acetate. All reactions were carried out under argon or nitrogen in oven-dried glassware using standard glass syringes, cannulas and septa. Solvents and reagents were purified and dried by standard methods prior to use.

(R)-Heptane-1,2-diol, 11

To a DMSO solution (60 mL) of L-proline (168 mg, 1.46 mmol) was added n-heptanal 10 (5.0 g, 43.86 mmol) and nitrosobenzene (1.56 g, 14.6 mmol) successively at room temperature. After stirring the reaction mixture for 12 h, MeOH (20 mL) and NaBH₄ (835 mg, 22 mmol) were added and the reaction mixture was stirred for 15 min at 0 °C. The reaction was quenched with aqueous saturated 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 (15 mL) and subjected to treatment with CuSO₄·5H₂O (913 mg, 3.65 mmol) at 0 °C and warm to room temperature over 12 h. After completion of reaction as monitored by TLC, it was quenched with aqueous saturated NH₄Cl solution. The organic layer was separated and the aqueous phase extracted with EtOAc (3 × 20 mL). The combined organic phase was dried over anhydrous Na₂SO₄, concentrated in vacuo, and purified by silica gel column chromatography (EtOAc/hexanes 1 : 1 v/v) to afford the desired diol 11 (1.35 g, 71%). {[α]²⁵_D −14.4 (c 1, CH₃OH) [Lit.¹² −14.1 (c 1, CH₃OH)]}; IR (CH₂Cl₂) ν: 3359, 2941, 2853, 1462, 1312, 1062, 927 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ: 3.6 (m, 2H), 3.4 (m, 1H), 2.67 (bs, 2H), 1.29–1.43 (m, 8H), 0.9 (t, 3H, J = 6.4 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ: 72.3, 66.8, 33.1, 31.8, 25.2, 22.5, 14.0; HRMS (ESI) m/z calcd for C₇H₁₆O₂Na [M + Na⁺] 155.1043; found 155.1041.

(4R)-4-Pentyl-2-phenyl-1,3-dioxolane, 12

To a benzene solution (50 mL) of diol 11 (1.35 g, 10.4 mmol) was added benzaldehyde dimethylacetal (1.58 g, 10.4 mmol) and catalytic amount of PPTS (260 mg, 1.04 mmol). The mixture was then heated to reflux with a Dean–Stark apparatus. After 1 h, triethylamine (1 mL) was added to the mixture, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc/hexanes 1 : 99 v/v) to afford the 1,2-benzylidene acetal 12 (2.0 g, 89%). [α]²⁵_D −11.5 (c 1, CHCl₃); IR (CH₂Cl₂) ν: 1478, 1366, 1260, 1120, 1015 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ: 7.35–7.48 (m, 5H), 5.92 (s, 1H), 4.2 (m, 2H), 3.59–3.67 (m, 1H), 1.31–1.75 (m, 8H), 0.9 (t, 3H, J = 6.9 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ: 138.4, 129.0, 128.3, 126.4, 103.0, 70.8, 33.3, 31.8, 25.4, 22.5, 14.0; HRMS (ESI) m/z calcd for C₁₄H₂₁O₂ [M + 1] 221.1536; found 221.1537.

(R)-2-(Benzyloxy)heptan-1-ol, 13

To a solution of 1,2-benzylidene acetal 12 (2.0 g, 9.2 mmol) in dry CH₂Cl₂ (30 mL) at −40 °C was added dropwise DIBAL-H (6.3 mL, 11.1 mmol, 1.75 M in toluene) through a syringe. The reaction mixture was allowed to warm at room temperature over a period of 2 h, then re-cooled to 0 °C and treated with saturated aqueous solution of potassium sodium tartrate. The solid material was filtered through a pad of Celite and concentrated in vacuo. Silica gel column chromatography of the crude product using EtOAc/hexane (3 : 7 v/v) as eluent furnished monobenzyl protected alcohol 13 (1.9 g, 93%) as a pale yellow oil. [α]²⁵_D −44.7 (c 1, CHCl₃); IR (CH₂Cl₂) ν: 2957, 2902, 2820, 1609, 1505, 772 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ: 7.33–7.36 (m, 5H), 4.56 (s, 2H), 3.8 (m, 1H), 3.5 (m, 1H), 3.3 (m, 1H), 2.4 (s, 1H), 1.28–1.43 (m, 8H), 0.9 (t, 3H, J = 6.4 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ: 137.9, 128.4, 127.8, 127.7, 74.6, 73.3, 70.4, 33.0, 31.8, 25.2, 22.5, 14.0. HRMS (ESI) m/z calcd for C₁₄H₂₂O₂Na [M + Na⁺] 245.1512; found 245.1510.

(R)-((Oct-1-yn-3-yl-oxy)methyl)benzene, 14

To a solution of oxalyl chloride (1.63 g, 1.1 mL, 12.84 mmol) in dry CH₂Cl₂ (30 mL) at −78 °C was added dropwise DMSO (2.07 g, 1.9 mL, 26.53 mmol) in CH₂Cl₂ (10 mL) over 15 min. The reaction mixture was stirred for 30 min and a solution of monobenzyl protected alcohol 13 (1.9 g, 8.56 mmol) in CH₂Cl₂ (20 mL) was added dropwise over 15 min. The reaction mixture was stirred for 30 min at −60 °C and then Et₃N (3.80 g, 5.20 mL, 37.7 mmol) was added dropwise and stirred for 1 h. The reaction mixture was poured into saturated solution of NaHCO₃ (50 mL) and the organic layer separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL) and the combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo to give the crude aldehyde, which was used as such for the next step without further purification.

To a solution of CBr₄ (5.68 g, 17.12 mmol) in dry CH₂Cl₂ (30 mL) at 0 °C was added PPh₃ (8.97 g, 34.24 mmol) and stirred for 15 min at 0 °C. To this reaction mixture, a solution of crude aldehyde obtained above in dry CH₂Cl₂ (20 mL) was added dropwise and stirred for 15 min at 0 °C. The reaction mixture was quenched with water and aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo to give the crude dibromoolefin, which was used as such for the next step without further purification. To a solution of above crude dibromoolefin in dry THF (30 mL) at −78 °C was added n-BuLi (6.85 mL, 17.12 mmol, 2.5 M in hexane). The reaction mixture was stirred for 1 h at −78 °C and 2 h at 0 °C. The reaction mixture was quenched with saturated aqueous solution of NH₄Cl and extracted with ethyl acetate (3 × 20 mL). The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. Silica gel column chromatography of the crude product using EtOAc/hexane (1 : 19 v/v) as eluent furnished the corresponding terminal alkynes 14 (1.59 g, 86% over three steps) as a pale yellow oil. [α]²⁵_D +34.2 (c 1, CHCl₃); IR (CH₂Cl₂) ν: 3302, 2952, 2851, 2125, 1610, 1512, 1102 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ: 7.26–7.36 (m, 5H), 4.8 (m, 1H), 4.5 (m, 1H), 4.0 (m, 1H), 2.46 (d, 1H, J = 1.84 Hz), 1.28–1.78 (m, 8H), 0.9 (t, 3H, J = 6.88 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ: 137.9, 128.4, 128.0, 127.7, 83.0, 73.7, 70.5, 68.5, 35.6, 31.4, 24.9, 22.5, 14.0; HRMS (ESI) m/z calcd for C₁₅H₂₁O [M + 1] 217.1587; found 217.1587.

(R)-1-(3-(Benzyloxy)oct-1-enyl)-2-nitrobenzene, 15

A mixture of 1-iodo-2-nitrobenzene (1.67 g, 6.7 mmol), Pd(PPh₃)₂Cl₂ (94 mg, 0.134 mmol, 2 mol%), CuI (13 mg, 0.067 mmol, 1 mol%), Et₃N (60 mL) and 14 (1.45 g, 6.7 mmol) in 20 mL DMF was purged with nitrogen for 10 min. The resulting mixture was then stirred at 100 C for 3 h. It was then concentrated, diluted with water, extracted with ether, dried over sodium sulfate and concentrated in vacuo. Silica gel column chromatography of the crude product using EtOAc/hexane (1 : 19 v/v) as eluent gave the coupled product 15 (2.15 g, 95%) as a yellow oil. [α]²⁵_D −121.3 (c 1, CHCl₃); IR (CH₂Cl₂) ν: 3275, 1540, 1341, 2205, 870 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ: 8.0 (m, 1H), 7.6 (m, 2H), 7.26–7.42 (m, 6H), 4.9 (d, 1H, J = 11.5 Hz), 4.6 (d, 1H, J = 11.9 Hz), 4.3 (t, 1H, J = 6.8 Hz), 1.84–1.88 (m, 2H), 1.5 (m, 2H), 1.3 (m, 4H), 0.9 (t, 3H, J = 6.8 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ: 149.8, 137.9, 134.9, 132.8, 128.7, 128.4, 128.2, 127.7, 124.6, 118.3, 97.0, 81.1, 70.8, 69.1, 35.5, 31.5, 25.0, 22.5, 14.0; HRMS (ESI) m/z calcd for C₂₁H₂₄NO₃ [M + 1] 338.1779; found 338.1780.

(R)-1-(2-Aminophenyl)octan-3-ol, 16

To a solution of 15 (1.0 g, 2.96 mmol) in EtOAc (12 mL) was added catalytic amount of HCl followed by addition of 10% Pd/C (150 mg, 5 mol%). The reaction mixture was subjected to hydrogenation under 1 atmosphere pressure for 24 h. After this time, a solution of saturated Na₂CO₃ was added to the reaction mixture, filtered through a pad of Celite and washed with additional EtOAc (30 mL) and organic layer separated. The resulting organic layer was dried over Na₂SO₄ and concentrated in vacuo. Silica gel column chromatography purification (EtOAc/hexanes 1 : 1 v/v) of the crude product furnished amino alcohol 16 (630 mg, 96%) as a yellow oil. [α]²⁵_D −94.5 (c 1, CHCl₃); IR (CH₂Cl₂) ν: 3472, 3302, 937, 632 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ: 7.0 (m, 2H), 6.7 (m, 2H), 3.5 (m, 1H), 3.2 (bs, 2H), 2.6 (m, 2H), 2.1 (bs, 1H), 1.7 (m, 2H), 1.25–1.28 (m, 8H), 0.87 (t, 3H, J = 6.88 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ: 144.0, 129.6, 127.0, 119.2, 116.1, 70.9, 37.7, 37.0, 31.9, 27.0, 25.4, 22.6, 14.0; HRMS (ESI) m/z calcd for C₁₄H₂₃NONa [M + Na⁺] 244.1710; found 244.1711.

(+)-Angustureine, 2

To a solution of amino alcohol 16 (400 mg, 1.8 mmol) in dry CH₂Cl₂ (6.0 mL) was slowly added triphenylphosphine (520 mg, 1.98 mmol) in portion wise at room temperature. To the resulting solution, diethylazodicarboxylate (345 mg, 1.98 mmol) in CH₂Cl₂ (5.0 mL) was added dropwise and stirred at room temperature for 12 h. After this time, the solution was quenched with water, diluted with CH₂Cl₂ and organic layer separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL) and the combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated in vacuo to afford the crude tetrahydroquinolone (norangustureine), which was used as such for next step without further purification.

To an acetonitrile solution (6 mL) of above crude tetrahydroquinolone (norangustureine) was added formaldehyde (37% w/w in H₂O, 1.5 mL, 18 mmol), sodium cyanoborohydride (1.13 g, 18 mmol) and acetic acid (1 mL, 18 mmol) and stirred for 10 h at room temperature. TLC monitoring showed complete conversion {hexane/ethyl acetate 19 : 1 v/v, R_f = 0.60}. The mixture was diluted with diethyl ether and the aqueous layer was extracted with diethyl ether (3 × 10 mL). The combined organic layer was washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Silica gel column chromatography of the crude product using EtOAc/hexane (1 : 99 v/v) as eluent furnished the target compound (+)-angustureine 2 (345 mg, 88% over two steps) as pale yellow oil. {[α]²⁵_D +7.6 (c 0.4, CHCl₃) [Lit.^5t +7.5 (c 0.4, CHCl₃); IR (CH₂Cl₂) ν: 2930, 2860, 950, 750 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz) δ: 7.1 (t, 1H, J = 7.2 Hz), 6.9 (d, 1H, J = 7.2 Hz), 6.57 (t, 1H, J = 7.2 Hz), 6.52 (d, 1H, J = 7.2 Hz), 3.2 (m, 1H), 2.92 (s, 3H), 2.66 (m, 1H), 2.62 (m, 1H), 1.8 (m, 2H), 1.56 (m, 1H), 1.25–1.3 (m, 7H), 0.9 (t, 3H, J = 6.84 Hz); ¹³C NMR (CDCl₃, 100 MHz) δ: 145.3, 128.6, 127.0, 121.8, 115.1, 110.3, 58.9, 37.9, 32.0, 31.1, 25.7, 24.3, 23.5, 22.7, 14.0; HRMS (ESI) m/z calcd for C₁₅H₂₄N [M + 1] 218.1902; found 218.1902.

Acknowledgements

Y.G. and S.G. thank UGC and CSIR, respectively, New Delhi for research fellowships. S.K.P. is thankful to University Grant Commission, New Delhi, for generous funding of the project [Grant no. F.20-40(12)/2013(BSR)]. We are grateful to Prof. Prakash Gopalan for his support and encouragement.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra of compounds 2 and 11–16. See DOI: 10.1039/c5ra05987a

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