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Synlett 2004(9): 1549-1552  
DOI: 10.1055/s-2004-829538
LETTER
© Georg Thieme Verlag Stuttgart · New York

An Efficient Synthesis of Trihydroxy Quinolizidine Alkaloids Using Ring-Closing Metathesis

Dilip D. Dhavale*a, Santosh M. Jachaka, Navnath P. Karchea, Claudio Trombinib
a Department of Chemistry, Garware Research Centre, University of Pune, Pune 411 007, India
e-Mail: ddd@chem.unipune.ernet.in;
b Dipartimento di Chimica ‘G. Ciamician’, via Selmi-2, 40126-Bologna, Italy
Further Information

Publication History

Received 24 December 2003
Publication Date:
01 July 2004 (online)

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Abstract

The sequential C- and N-allylation of d-glucose-derived nitrone 2 provides the required diene functionality with nitrogen linker that was used in ring-closing metathesis pathway in the synthesis of quinolizidine alkaloids 1a and 1b.

Key words

alkaloids - azasugars - carbohydrates - glycosidase - me­tathesis

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General Procedure for the Ring-Closing Metathesis: To a solution of 5a,b (0.180 g, 0.4 mmol) in dry benzene (15 mL) at 25 °C was added benzylidene-bis-tricyclohexyl-phosphine-dichlororuthenium (0.006 g, 5% mol) and the reaction mixture was refluxed under nitrogen for 18 h. Removal of solvent under vacuum afforded a thick oil that on purification by column chromatography using EtOAc-n-hexane (5:95) afforded corresponding Δ3-piperidine 6a,b.
General Procedure for the Reductive Aminocyclization: A solution of 7a,7b (0.100 g, 0.26 mmol) in TFA-H2O (3:2, 2 mL) was stirred at 25 °C for 2 h. TFA was co-evaporated with benzene to furnish a thick liquid, which was directly used in the next reaction. To a solution of the above product in MeOH (5 mL) was added 10% Pd/C (0.01 g) and the solution was hydrogenated at 80 psi for 16 h. The solution was filtered through celite and the filtrate concentrated to get a sticky solid, which was purified by column chromatography (MeOH-CHCl3 = 5:95) to give 1a,b.

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All new compounds have been characterized by 1H NMR, 13C NMR, and elemental analysis. Selected procedures and data for 3- O -benzyl-1,2- O -isopropylidene-5,6,7,8-tetra-deoxy-5-( N -benzyl- N -hydroxyamino)-α- d - gluco -7-eno-octo-1,4-furanose ( 3a): thick liquid; 80%; Rf = 0.52 (EtOAc-hexane = 3:7); [α]D = -30.0 (c 2.40, CHCl3). IR (neat): 3510-3160 (br), 1639 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.26 (s, 3 H), 1.44 (s, 3 H), 2.49-2.69 (m, 2 H), 3.41 (ddd, J = 8.3, 7.8, 4.8 Hz, 1 H), 3.76 (d, J = 13.6 Hz, 1 H), 3.94 (d, J = 13.6 Hz, 1 H), 4.01 (d, J = 3.0 Hz, 1 H), 4.37 (dd, J = 8.3, 3.0 Hz, 1 H), 4.40-4.45 (br s, exchanges with D2O, 1 H), 4.50 (d, J = 11.7 Hz, 1 H), 4.54 (d, J = 3.9 Hz, 1 H), 4.63 (d, J = 11.7 Hz, 1 H), 4.98 (dd, J = 11.1, 1.6 Hz, 1 H), 5.10 (dd, J = 17.0, 1.6 Hz, 1 H), 5.87 (d, J = 3.9 Hz, 1 H), 5.92-6.10 (m, 1 H), 7.12-7.28 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 26.2, 26.7, 31.4, 60.8, 63.4, 72.0, 79.6, 81.9, 82.5, 104.5, 111.3, 115.6, 127.1, 127.5, 127.6, 128.2, 128.4, 129.1, 137.6, 137.7, 138.3. Anal. Calcd for C25H31NO5: C, 70.57; H, 7.34. Found: C, 70.51; H, 7.30. 3- O -Benzyl-1,2- O -isopropylidene-5,6,7,8-tetra-deoxy-5-( N -benzyl- N -hydroxyamino)-β- l - ido -7-eno-octo-1,4-furanose ( 3b): thick liquid; 13%; Rf = 0.44 (EtOAc-hexane = 3:7); [α]D = -48.0 (c 0.25, CHCl3). IR (neat): 3530-3150 (br), 1639 cm-1. 1H NMR (300 MHz, CDCl3):
δ = 1.27 (s, 3 H), 1.46 (s, 3 H), 1.91-2.09 (m, 1 H), 2.21-2.35 (m, 1 H), 3.38 (ddd, J = 9.5, 8.1, 4.3 Hz, 1 H), 3.84 (d, J = 3.0 Hz, 1 H), 3.92 (d, J = 13.9 Hz, 1 H), 4.09 (d, J = 13.9 Hz, 1 H), 4.39 (d, J = 11.6 Hz, 1 H), 4.44 (dd, J = 9.5, 3.0 Hz, 1 H), 4.57 (d, J = 3.8 Hz, 1 H), 4.61 (d, J = 11.6 Hz, 1 H), 4.84-4.92 (m, 2 H), 4.93-4.96 (br s, exchanges with D2O, 1 H), 5.83-6.05 (m, 1 H), 5.93 (d, J = 3.8 Hz, 1 H), 7.10-7.38 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 26.5, 26.8, 34.3, 49.4, 57.3, 72.0, 81.3, 81.9, 83.5, 104.9, 111.3, 115.0, 126.2, 127.4, 127.5, 127.7, 128.2, 128.4, 137.9, 138.2, 141.5. Anal. Calcd for C25H31NO5: C, 70.57; H, 7.34. Found: C, 70.29; H, 7.59. 3- O -Benzyl-5,6-dideoxy-1,2- O -isopropylidene-5-( N -benzyl- N -propenylamino)-α- d - gluco -7-eno-octo-1,4-furanose ( 5a): thick liquid; 71%; Rf = 0.65 (EtOAc-hex-ane = 2:8); [α]D = -36.4 (c 0.44, CHCl3). IR (neat): 1639, 1605 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.30 (s, 3 H), 1.46 (s, 3 H), 2.48 (br t, J = 7.2 Hz, 2 H), 3.12 (dd, J = 14.1, 6.6 Hz, 1 H), 3.22 (dd, J = 14.1, 6.3 Hz, 1 H), 3.34 (q, J = 7.2 Hz, 1 H), 3.73 (ABq, J = 14.4 Hz, 2 H), 3.95 (d, J = 3.0 Hz, 1 H), 4.22 (dd, J = 7.2, 3.0 Hz, 1 H), 4.48 (d, J = 11.7 Hz,
1 H), 4.53 (d, J = 3.6 Hz, 1 H), 4.63 (d, J = 11.7 Hz, 1 H), 4.87-5.18 (m, 4 H), 5.63-5.80 (m, 1 H), 5.89 (d, J = 3.6 Hz, 1 H), 5.92-6.08 (m, 1 H), 7.16-7.22 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 26.2, 26.8, 32.9, 54.5, 54.7, 57.3, 71.8, 79.9, 81.6, 82.7, 104.7, 111.4, 115.4, 116.6, 126.7, 127.6, 127.7, 128.1, 128.3, 128.5, 137.2, 137.6, 138.3, 140.5. Anal. Calcd for C28H35NO4: C, 74.80; H, 7.85. Found: C, 74.65; H, 7.70. 3- O -Benzyl-5,6-dideoxy-1,2- O -isopropylidene-5-( N -benzyl- N -propenylamino)-β- l - ido -7-eno-octo-1,4-furanose ( 5b): thick liquid; 71%; Rf = 0.53 (EtOAc-hexane = 2:8). [α]D = -38.2 (c 0.33, CHCl3). IR (neat): 1641, 1601 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.41 (s, 3 H), 1.59 (s, 3 H), 1.80-1.93 (m, 1 H), 2.11-2.23 (m, 1 H), 3.30-3.47 (m, 3 H), 3.81 (d, J = 3.0 Hz, 1 H), 3.83 (d, J = 14.1 Hz, 1 H), 3.94 (d, J = 14.1 Hz, 1 H), 4.30 (dd, J = 9.6, 3.0 Hz, 1 H), 4.45 (d, J = 11.7 Hz, 1 H), 4.64 (d, J = 3.9 Hz, 1 H), 4.70 (d, J = 11.7 Hz, 1 H), 4.90-5.24 (m, 4 H), 5.79-5.96 (m, 2 H), 6.02 (d, J = 3.9 Hz, 1 H), 7.20-7.46 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 26.2, 26.8, 34.5, 53.3, 54.9, 56.8, 71.3, 81.1, 81.9, 82.4, 104.8, 111.2, 115.1, 115.9, 126.3, 127.5, 127.8, 127.9, 128.4, 128.9, 137.2, 137.3, 138.3, 141.3. Anal. Calcd for C28H35NO4: C, 74.80; H, 7.85. Found: C, 74.75; H, 7.66. 1,2- O -Isopropylidine-5,6,7,8,9-penta-deoxy-5,9-( N -benzyl-imino)-α- d - gluco -7-eno-nona-1,4-furanose ( 6a): thick liquid; 81%; Rf = 0.50 (EtOAc-hexane = 2:8); [α]D = -21.8 (c 0.55, CHCl3). IR (neat): 1640, 1605 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.34 (s, 3 H), 1.46 (s, 3 H), 2.32-2.48 (m, 2 H), 3.10-3.20 (m, 2 H), 3.51 (dt, J = 9.3, 5.7 Hz, 1 H), 3.70 (d, J = 13.8 Hz, 1 H), 3.85 (d, J = 13.8 Hz, 1 H), 4.11 (d, J = 2.7 Hz, 1 H), 4.35 (dd, J = 9.3, 2.7 Hz, 1 H), 4.62 (d, J = 3.9 Hz, 1 H), 4.75 (ABq, J = 11.7 Hz, 2 H), 5.56-5.64 (m, 1 H), 5.87-5.92 (m, 1 H), 5.95 (d, J = 3.9 Hz, 1 H), 7.20-7.38 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 22.4, 26.2, 26.8, 47.2, 54.1, 55.3, 72.4, 79.6, 81.8, 82.4, 104.5, 111.4, 124.0, 125.3, 126.7, 127.6, 127.7, 128.2, 128.4, 128.5, 137.9, 139.9. Anal. Calcd for C26H31NO4: C, 74.08; H, 7.41. Found: C, 73.99; H, 7.46.
1,2- O -Isopropylidine-5,6,7,8,9-penta-deoxy-5,9-( N -benzyl-imino)-β- l - ido -7-eno-nona-1,4-furanose ( 6b): thick liquid; 78%; Rf = 0.46 (EtOAc-hexane = 2:8); [α]D = -19.4 (c 0.22, CHCl3). IR (neat): 1650, 1603 cm-1.
1H NMR (300 MHz, CDCl3): δ = 1.37 (s, 3 H), 1.52 (s, 3 H), 1.72-1.79 (m, 1 H), 2.29-2.43 (m, 1 H), 3.10-3.28 (m, 2 H), 3.53 (ddd, J = 9.6, 5.8, 3.8 Hz, 1 H), 3.82 (d, J = 3.0 Hz, 1 H), 3.87 (d, J = 13.8 Hz, 1 H), 4.01 (d, J = 13.8 Hz, 1 H), 4.46 (d, J = 11.7 Hz, 1 H), 4.54 (dd, J = 9.6, 3.0 Hz, 1 H), 4.64 (d, J = 3.9 Hz, 1 H), 4.73 (d, J = 11.7 Hz, 1 H), 5.60-5.74 (m, 2 H), 6.05 (d, J = 3.9 Hz, 1 H), 7.19-7.45 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 26.3, 26.7, 26.8, 47.0, 54.4, 58.3, 71.5, 78.4, 81.1, 82.6, 105.1, 111.3, 123.6, 125.7, 126.5, 127.7, 127.9, 128.1, 128.4, 128.8, 137.2, 140.5. Anal. Calcd for C26H31NO4: C, 74.08; H, 7.41. Found: C, 74.15; H, 7.32. (1 R ,2 R ,3 S ,9a R )-octahydro-2 H -quinolizine-1,2,3-triol ( 1a): thick liquid; 85%; Rf = 0.29 (CHCl3-MeOH = 7:3); [α]D = -36.0 (c 0.2, MeOH). IR (neat): 3676-3250 cm-1. 1H NMR (300 MHz, D2O): δ = 1.24-1.53 (m, 2 H), 1.55-1.72 (m, 1 H), 1.79-1.98 (m, 3 H), 2.26 (br d, J = 13.2 Hz, 1 H), 2.60-2.86 (m, 3 H), 3.22-3.36 (m, 2 H), 3.41 (t, J = 9.3 Hz, 1 H), 3.69 (dt, J = 9.3, 4.5 Hz, 1 H). 13C NMR (75 MHz, D2O): δ = 21.6, 23.4, 26.9, 55.3, 56.8, 65.0, 67.0, 72.7, 76.5. Anal. Calcd for C9H17NO3·3H2O: C, 57.73; H, 9.15. Found: C, 57.61; H, 9.01. (1 R ,2 R ,3 S ,9a S )-octahydro-2 H -quinolizine-1,2,3-triol ( 1b): The reaction of 7b (0.13 g, 0.34 mmol) with TFA-H2O (3 mL, 3:2) followed by hydrogenation with 10% Pd/C (0.02 g) as reported for 1a. Column chromatography (MeOH-CHCl3 = 10:90) afforded 1b as a thick liquid (0.058 g, 91%); Rf = 0.25 (CHCl3-MeOH = 7:3); [α]D = -80.0 (c 0.1, MeOH). IR (neat): 3640-3180 cm-1. 1H NMR (300 MHz, D2O): δ = 1.42-1.80 (m, 6 H), 2.79-2.91 (m, 1 H), 3.15-3.38 (m, 4 H), 3.65 (br s, J H = 6 Hz, 1 H), 3.87 (br s, J H = 6 Hz, 2 H). 13C NMR (75 MHz, D2O): δ = 21.7, 22.9, 25.7, 55.7, 61.6, 66.4, 67.2, 70.2 (strong). Anal. Calcd for C9H17NO3·2H2O: C, 57.73; H, 9.15. Found: C, 57.58; H, 8.97.