HETEROCYCLES

Note | Regular issue | Vol. 78, No. 10, 2009, pp. 2589-2594
Received, 23rd May, 2009, Accepted, 29th June, 2009, Published online, 30th June, 2009.
DOI: 10.3987/COM-09-11764

■ A Short Synthesis of Indolizidine (+)-209B from (3R,6S,8AS)-(-)-6-Methyl-3-phenyl-hexahydrooxazolo[3,2-a]pyridin-5-one

Dino Gnecco, Ana M. Lumbreras, Joel Luis Terán,* Alberto Galindo, Jorge R. Juárez, María L. Orea, Alejandro Castro, Raúl G. Enríquez, and William F. Reynolds

Síntesis Orgánica, Benemérita Universidad Autónoma de Puebla, Complejo de Ciencias, Edif 103H, Ciudad Universitaria 72300, Mexico

Abstract

The synthetic potential of enantiopure (3R,6S,8aS)-(-)-6-methyl-3- phenylhexahydrooxazolo[3,2-a]pyridin-5-one 2 is illustrated by a short synthesis of the 5,8-disubstituted indolizidine alkaloid (+)-209B.

(3R,8aS)-(-)-3-Phenylhexahydrooxazolo[3,2-a]pyridin-5-one 1 has generated considerable interest, because this compound has demonstrated to be useful intermediate in the synthesis of natural products and functionalized piperidines.1,2 Amat et al.3 reported the synthesis of this compound in 73% yield through a cyclocondensation reaction of (R)-(-)-2-amino-2-phenylethanol with ethyl 5-oxopentanoate. After, by alkylation of compound 1 they prepared compounds 2 and 3 (Scheme 1).

In this sense, we have recently reported a new strategy to prepare the enantiopure compounds 1, 2 and 3 in good overall yields using as starting material the corresponding (1'R)-(-)-1-(2'-hydroxy-1'- phenylethyl)pyridin-2(1H)-ones.4,5 Now, as part of our ongoing studies toward the synthesis of 5,8-disubstituted indolizidines, we describe a successive stereo- and enantiocontrolled introduction of substituents onto enantiopure compound 2 to prepare the intermediate (R)-(-)-2-((2'R,3'S,6'S)-2'-(2- (1,3-dioxolan-2-yl)ethyl)-3'-methyl-6'-pentyl-piperidin-1'-yl)-2-phenylethanol 7, which is precursor of the 5,8-disubstituted indolizidine (+)-209B (Scheme 2).

Treatment of a solution of compound 2 in anhydrous THF at -20 °C with an excess of pentylmagnesium bromide afforded a mixture of two diastereoisomers in 80% yield in a 95:5 ratio (determined by 1H-NMR). This mixture was purified by column chromatography over silica gel to give the (1'R,3S,6S)-(-)-1-(2'-hydroxy-1'-phenylethyl)-3-methyl-6-pentylpiperidin-2-one 4 in 70% isolated yield. The absolute configuration at the new stereocentre C-6 was assigned as (S), in agreement with that reported by Terán et al.4 After, a solution of 4 in anhydrous dichloromethane at 10 °C was treated with POBr3 and refluxed for 1h. The crude product was purified by flash chromatography over silica gel affording the unstable oxazoliminium bromide 5 in 90% yield (sensitive to aerial degradation). Immediately, a solution of 5 in dichloromethane at -78 °C was treated with 1.1 equivalent of Red-Al® and stirred for 20 min to give a mixture of two isomers in 85% yield in a 90:10 ratio.6 1H-NMR was valuable for the structural analysis of this mixture and the major isomer was characterized by a H-8a proton which, appeared as a doublet at 3.40 ppm, JH-8a-JH-8 = 8.4 Hz.7 This result was enough to define the trans relationship H8a-H8 and the configuration of C-8a as (R). Flash chromatography over silica gel of this mixture afforded the compound (3R,5S,8S,8aR)-(-)-8-methyl-5-pentyl-3-phenylhexahydrooxazolo[3,2-a]pyridine 6 in 70% isolated yield (Scheme 3).

After, a solution of 6 in anhydrous THF at -10 °C was treated with an excess of [2-(1,3-dioxolan-2-yl)- ethyl]magnesium bromide to give a mixture of two isomers in 80% yield in a ratio 90:10. Grignard reagents took place with retention of the configuration at the C-8a stereocentre, generating the corresponding 2,3-trans isomer 7. Consequently, the equatorial methyl substituent at C-8 does not change the stereochemical result previously observed in the α-amidoalkylation reactions reported.1 This mixture was separated by flash chromatography over silica gel to provide the isomer 7 in 65% isolated yield. Finally, hydrogenolysis of compound 7 furnished the indolizidine (+)-209B8 in 90% yield [α]D +93 (c 1.0, MeOH). NMR spectral data of this alkaloid are in good agreement with those previously reported by Holmes et al. for the synthetic indolizidine (-)-209B. This Dendrobatid alkaloid has been identified as a trace component and its optical rotation is not available at present due to insufficient material.9,10 (Scheme 4).

To our knowledge, this is the first time that the synthesis of the unnatural indolizidine (+)-209B is reported using as starting material the (3R,6S,8aS)-(-)-6-methyl-3-phenylhexahydrooxazolo[3,2-a]- pyridin-5-one 2. In addition the present strategy offers a practical stereocontrolled synthesis of 2,3,6-trisubstituted piperidines and trans-5,8-disubstituted indolizidines. The synthesis of trans-1,4-disubstituted quinolizidines is in progress and the results will be forthcoming.

EXPERIMENTAL
General
1H-NMR spectra were recorded at 400 MHz, and 13C-NMR spectra at 100 MHz (tetramethylsilane as internal reference). IR spectra were obtained with a Nicolet FT-IR Magna 750 spectrometer. Optical rotations were determined at room temperature with a Perkin-Elmer 341 polarimeter, using a 1dm cell with a total volume of 1 mL and are referenced to the D-line of sodium. Mass spectra were recorded with a JEOL JEM-AX505HA instrument at a voltage of 70 eV.

(1'R,3S,6S)-(-)-1-(2'-Hydroxy-1'-phenylethyl)-3-methyl-6-pentylpiperidin-2-one 4.
To a solution of 2 (0.29 g, 1.32 mmol) in anhydrous THF (15 mL) under nitrogen atmosphere and at -20 °C was added pentylmagnesium bromide (3 eq.) and the reaction mixture was stirred at room temperature for 6 h. Finally, this mixture was treated with a saturated aqueous solution of NH4Cl (4.0 mL), extracted with EtOAc (3x10 mL), dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, CH2Cl2: MeOH = 95:5) affording 4 in 70% yield.
Compound 4. Pale yellow oil, [α]D -8 (c 1, CH2Cl2). IR (KBr) 3386, 2978, 1615 cm-1. 1H-NMR (400 MHz, CDCl3, J Hz) δ 0.80 (t, 3H, J = 7.4), 0.96 (d, 3H, J = 7.2), 1.26- 1.80 (m, 12H), 2.40 (m, 1H), 3.20 (m, 1H), 4.18 (AB, 1H, H-2’, J = 4.0, 11.5), 4.24 (AB, 1H, H-2’, J = 7.5, 11.5), 4.50 (br, OH), 5.02 (dd, 1H, H-1,’ J = 4.0, 7.5), 7.20-7.30 (m, 5H). 13C-NMR (100 MHz, CDCl3) δ 11.1, 22.2 (2C), 24.4 (2C), 26.3 (2C), 29.8, 36.5 43.0, 57.9, 66.0, 126-130, 138.0, 174.2. HRMS Calcd for C19H29NO2 : 303.2198; found: 303.2178.


(3R,5S,8S,8aR)-(-)-8-Methyl-5-pentyl-3-phenyl-hexahydro-2H-oxazolo[3,2-a]pyridine 6.
To a stirred solution of 4 (0.200 g, 0.661 mmol) in anhydrous CH2Cl2 (5 mL) at 10 °C under nitrogen atmosphere was added dropwise a solution of POBr3 (0.234 g, 0.820 mmol) in CH2Cl2 (5 mL) and, then the reaction mixture was refluxed for 1 h. The crude product was purified by flash chromatography (SiO2, CH2Cl2: MeOH = 95:5) affording the unstable oxazoliminium bromide 5 in 90% yield. Immediately, a solution of this compound in anhydrous CH2Cl2 (15 mL) under nitrogen atmosphere was treated with Red-Al® (1.01 mmol, 65% in toluene) at -78 °C and stirred for 20 min. Then, the reaction mixture was quenched with saturated aqueous of NH4Cl (2 mL), extracted with CH2Cl2 (3x10 mL), dried with Na2SO4 and concentrated under reduced pressure to give a mixture of two isomers in 85% yield in a 90:10 ratio. Compound 6 was isolated as oil in 70% yield after chromatography over silica gel using a gradient of CH2Cl2: petroleum ether = 80:20.
Compound 6. Pale yellow oil, [α]D -76 (c 1, CH2Cl2). IR (KBr), 2978, 1160 cm-1. 1H-NMR (400 MHz, CDCl3, J Hz) δ 0.89 (t, 3H, J = 7.2), 1.10 (d, 3H, J = 7.5), 1.28-1.60 (m, 12H), 1.89 (m, 1H), 2,28 (m, 1H), 3.40 (d, 1H, J = 8.4), 3.60 (t, 1H, J = 7.5), 3.70 (t, 1H, J = 7.5), 4.20 (t, 1H, J = 7.5, 11.5), 7.18-7.30 (m, 5H). 13C-NMR (100 MHz, CDCl3) δ 12.1, 14.2, 22.2, 24.3 (2C), 30.6 (2C), 34.4, 37.0, 62.0, 64.1, 73.8, 100.6, 126-128, 144.1. HRMS (FAB): Calcd for C19H29NO: 287.4397; found: 287.4370.

(R)-(-)-2-((2'R,3'S,6'S)-2'-(2-(1,3-Dioxolan-2-yl)ethyl)-3'-methyl-6'-pentylpiperidin-1'-yl)-2-phenylethanol 7.
To a stirred solution of 6 (0.150g, 0.523 mmol) in anhydrous THF (10 mL) under nitrogen atmosphere at 0 °C was dropwise added [2-(1,3-dioxolan-2-yl)ethyl]magnesium bromide in THF (1.5 mmol), and then the reaction mixture was stirred at rt for 8 h. After, the reaction mixture was quenched with saturated aqueous NH4Cl (2 mL), extracted with CH2Cl2 (3x10 mL), dried with Na2SO4 and concentrated under reduced pressure to give a mixture of two isomers in 80% yield in a ratio 90:10. The major product 7 was isolated as oil in 65% yield after chromatography over silica gel using a gradient of CH2Cl2-MeOH.
Compound 7. Pale yellow oil, [α]D -55 (c 1, CH2Cl2). IR (KBr), 3450, 2967 cm-1. 1H-NMR (400 MHz, CDCl3, J Hz) δ 0.89 (t, 3H, J = 7.0), 1.10 (d, 3H, J = 7.2), 1.28-1.40 (m, 11H), 1.50-1.75 (m, 5H), 2.22-2.24 (m, 2H), 3.85-4.10 (m, 7H), 4.82 (t, 3H, J = 4.0, 11.5), 7.25-7.35 (m, 5H). 13C-NMR (CDCl3) δ 14.13, 19.50, 22.34, 22.83 (2C), 25.68, 29.12, 30.85, 31.37, 32.28 (2C), 53.50, 59.93, 63.43, 64.96, 65.10 (2C), 104.60, 127.63-129.84, 140.90. HRMS (FAB): Calcd for C24H39NO3: 389.2930; found: 389.2910.

(5S,8S,8aR)-(+)-8-Methyl-5-pentyloctahydroindolizine (+)-209B.
To a stirred solution of 6 (80 mg, 2.06 mmol) in EtOH-HCl (g) (7 mL) was added 10% Pd/C (20 mg), and the resulting suspension was hydrogenated under hydrogen atmosphere for 18 h. The crude product was purified by flash chromatography on basic alumina (petroleum ether/CH2Cl2 90:10) to afford (+)-209B in 90% yield.
Indolizidine (+)-209B. Colorless oil, [α]D +93 (c 1, MeOH). Indolizidine (-)-209B lit.,11 [α]D -91.3 (c 0.58, MeOH); lit.,12 [α]D -94.3 (c 1.85, MeOH). IR (KBr), 2929, 2862 cm-1. 1H-NMR (400 MHz, CDCl3, J Hz) δ 0.76 (3H, t, J = 7.2), 0.84 (3H, d, J = 7.2), 1.10-1.90 (m, 20H), 3.40 (m, 1H). 13C-NMR (CDC13, 100 MHz) δ 14.2, 18.90, 20.54, 22.74, 25.64, 29.12, 31.30, 32.40, 33.60, 34.66, 36.62, 51.80, 63.70, 70.42. HRMS (FAB): Calcd for C14H27N: 209.2143; found: 209.2150.

ACKNOWLEDGEMENTS
D. Gnecco, J. L. Terán and J. R. Juárez gratefully acknowledge support from CONACyT (México) project 46930. A. Lumbreras thanks to CONACyT for a scholarship doctoral (171984).

References

1. D. Gnecco, A. Galindo, J. L. Terán, and L. F. Roa, Tetrahedron: Asymmetry, 2004, 15, 3393. CrossRef
2. C. Escolano, M. Amat, and J. Bosch, Chem. Eur. J., 2006, 12, 8198. CrossRef
3. M. Amat, N. Llor, J. Hidalgo, and J. Bosch, Tetrahedron: Asymmetry, 1997, 13, 2237; CrossRef M. Amat, C. Escolano, N. Llor, O. Lozano, A. Gómez, R. Griera, and J. Bosch, Arkivok, 2005, IX, 115.
4. J. L. Terán, D. Gnecco, A. Galindo, J. Juárez, S. Bernés, and R. G. Enríquez, Tetrahedron: Asymmetry, 2001, 12, 357. CrossRef
5. A. M. Lumbreras, D. Gnecco, J. L. Terán, J. Juárez, M. L. Orea, and R. G. Enríquez, J. Mex. Chem. Soc., 2007, 51, 103.
6. A. Castro, J. Ramírez, J. Juárez, J. L. Terán, M. L. Orea, A. Galindo, and D. Gnecco, Heterocycles, 2007, 71, 2699. CrossRef
7. M. Amat, M. Pérez, A.T. Minaglia, B. Peretto, and J. Bosch, Tetrahedron, 2007, 63, 5839. CrossRef
8. For a recent synthesis of (-)-209B see: N. Toyooka, H. Tsuneki, S. Kobayashi, Z. Dejun, M. Kawasaki, I. Kimura, T. Sasaoka, and H. Nemoto, Current Chemical Biology, 2007, 1, 97.
9. A. L. Smith, S. F. Williams, A. B. Holmes, L. R. Hughes, Z. Lidert, and C. Swithenbank, J. Am. Chem. Soc., 1988, 110, 8696. CrossRef
10. A. B. Holmes, A. L. Smith, S. F. Williams, L. R. Hughes, Z. Lidert, C. Swithenbank, J. Org. Chem., 1991, 56, 1393. CrossRef
11. T. Kobayahi, T. Sakakura, and M. Tanaka, Tetrahedron Lett., 1987, 28, 2721. CrossRef
12. T. Shishido and C. Kibayashi, J. Org. Chem., 1992, 57, 2876 CrossRef