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

Dilip D. Dhavale; Santosh M. Jachak; Navnath P. Karche; Claudio Trombini

doi:10.1055/s-2004-829538

LETTER

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

Dilip D. Dhavale*^a, Santosh M. Jachak^a, Navnath P. Karche^a, Claudio Trombini^b
^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

Abstract

Alle Artikel dieser Rubrik

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

Volltext

Referenzen

References

For recent reviews, see:

1a Schuster M. Blechert S. Angew. Chem., Int. Ed. Engl. 1997, 36: 2036 ; Angew. Chem. 1997, 109, 2124

1b Fürstner A. Top. Organomet. Chem. 1998, 1: 37

1c Armstrong S. J. Chem. Soc., Perkin Trans. 1 1998, 317

1d Grubbs RH. Chang S. Tetrahedron 1998, 54: 4413

1e Phillips AJ. Abell AD. Aldrichimica Acta 1999, 32: 75

1f Fürstner A. Angew. Chem. Int. Ed. 2000, 39: 3012 ; Angew. Chem. 2000, 112, 3140

1g Larry Y. Chem. Rev. 2000, 100: 2963

For the application of the ring-closing metathesis reaction to the synthesis of aza-sugars, see:

2a Huwe CM. Blechert S. Tetrahedron Lett. 1995, 36: 1621

2b Overkleeft HS. Pandit UK. Tetrahedron Lett. 1996, 37: 547

2c Huwe CM. Blechert S. Synthesis 1997, 61

2d White JD. Hrnciar P. Yokochi AFT. J. Am. Chem. Soc. 1998, 120: 7359

2e Overkleeft HS. Bruggeman P. Pandit UK. Tetrahedron Lett. 1998, 39: 3869

2f Lindstrom UM. Somfai P. Tetrahedron Lett. 1998, 39: 7173

2g Ovaa H. Stragies R. van der Marel GA. van Boom JH. Blechert S. Chem. Commun. 2000, 1501

2h Voigtmann U. Blechert S. Org. Lett. 2000, 2: 3971

2i Subramanian T. Lin C.-C. Tetrahedron Lett. 2001, 42: 4079

2j Klitze CF. Pilli RA. Tetrahedron Lett. 2001, 42: 5605

2k Chandra KL. Chandrasekhar M. Singh VK. J. Org. Chem. 2002, 67: 4630

2l Lindsay KB. Pyne SG. J. Org. Chem. 2002, 67: 7774

2m Buschmann N. Rückert A. Blechert S. J. Org. Chem. 2002, 67: 4325

2n Lee HK. Chun JS. Pak CS. J. Org. Chem. 2003, 68: 2471

2o Verhelst SHL. Martinez BP. Timmer SM. Lodder G. Van der Marel GA. Overkleeft HS. van Boom JH. J. Org. Chem. 2003, 68: 9598

3a Grandnig G. Berger A. Grassberger V. Stuetz A. Tetrahedron Lett. 1991, 32: 4849

3b Rassu G. Casiraghi G. Pinna L. Spanu P. Ulgheri F. Cornia M. Zanardi F. Tetrahedron 1993, 49: 6627

3c Herzegh P. Kovacs I. Szilagyi L. Sztaricskai F. Bericibar A. Riche C. Chiaroni A. Olesker A. Lukacs G. Tetrahedron 1995, 51: 2969

3d Carretero JC. Arrayas RG. De Garcia IS. Tetrahedron Lett. 1997, 38: 8537

3e Iminosugars as Glycosidase Inhibitors Stuetz AE. Wiley-VCH; Weinheim: 1999.

3f Schaller C. Vogel P. Synlett 1999, 1219

4a Michael J. Nat. Prod. Rep. 1999, 16: 675

4b Michael J. Nat. Prod. Rep. 2000, 17: 579

4c Michael J. Nat. Prod. Rep. 2003, 20: 458

5a Dhavale D. Desai V. Sindkhedkar M. Mali R. Castellari C. Trombini C. Tetrahedron: Asymmetry 1997, 1475

5b Dhavale D. Saha N. Desai V. J. Org. Chem. 1997, 62: 7482

5c Dhavale D. Saha N. Desai V. J. Org. Chem. 1999, 64: 1715

5d Dhavale D. Saha N. Desai V. J. Chem. Soc., Chem. Commun. 1999, 1719

5e Saha N. Desai V. Dhavale D. Tetrahedron 2001, 39

5f Patil N. Tilekar J. Dhavale D. J. Org. Chem. 2001, 66: 1065

5g Patil N. Tilekar J. Dhavale D. Tetrahedron Lett. 2001, 42: 747

5h Dhavale D. Patil N. John S. Sabharwal S. Bioorg. Med. Chem. 2002, 10: 2155

5i Dhavale D. Saha N. Desai V. Tilekar J. Arkivoc 2002, 91

5j Patil N. Tilekar J. Jadhav H. Dhavale D. Tetrahedron 2003, 59: 1873

6a Liu P. Rogers R. Kang M. Sankara P. Tetrahedron Lett. 1991, 32: 5853

6b Pearson W. Hembre E. Tetrahedron Lett. 1993, 8221

6c Herczegh P. Kovacs I. Szilagyi L. Sztaricskai F. Tetrahedron 1995, 51: 2969

6d Carretero J. Arrayas R. Gracia I. Tetrahedron Lett. 1997, 38: 8537

6e Pearson W. Hembre E. J. Org. Chem. 1996, 61: 5537

6f Hamana H. Ikota N. Ganem B. J. Org. Chem. 1987, 52: 5492

6g Pandit UK. Overkleeft H. Borer BC. Bieraugel H. Eur. J. Org. Chem. 1999, 959

6h Schaller C. Vogel P. Helv. Chim. Acta 2000, 193

6i Gebarowski P. Sas W. Chem. Commun. 2001, 915

7a

It is known that for a given C5-epimeric pair, derived from the d-gluco-furanose, the J _4,5 in the l-ido isomer (threo-relationship) is consistently larger than that of the corresponding d-gluco isomer (erythro-relationship). In addition, the chemical shift of H-3 in l-ido isomer is upfield as compared to d-gluco isomer. The higher value of J _4,5 observed in the diastereomer 3b (9.5 Hz) as compared to 3a (8.3 Hz) indicated the l-ido configuration for 3b and the d-gluco configuration for 3a. This fact was further supported by comparison of the chemical shift of H-3 in both the isomers. In 3b H-3 appeared upfield at δ = 3.84 ppm as compared to 3a at δ = 4.01 ppm, further supporting the d-gluco- and l-ido configuration at C5 to 3a and 3b, respectively. Thus, the absolute configurations at C-5 in 3a and 3b were assigned as (5R) and (5S), respectively.

7b See: Cornia M. Casiraghi G. Tetrahedron 1989, 45: 2869

8

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.

9

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%; R_f = 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%; R_f = 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%; R_f = 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%; R_f = 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%; R_f = 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%; R_f = 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%; R_f = 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%); R_f = 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.