Synlett 2009(2): 237-240  
DOI: 10.1055/s-0028-1087661
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A General Approach to the Quinolizidine Alkaloids via an Intramolecular Aza-[3+3] Annulation: Synthesis of (±)-2-Deoxylasubine II

Yu Zhang, Aleksey I. Gerasyuto, Quincy A. Long, Richard P. Hsung*
Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin, 777 Highland Avenue, Rennebohm Hall, Madison, WI 53705, USA
Fax: +1(608)2625345; e-Mail: rhsung@wisc.edu;
Further Information

Publication History

Received 18 September 2008
Publication Date:
15 January 2009 (online)

Abstract

The first success in constructing a member of quinolizidine family of alkaloids employing an intramolecular aza-[3+3] annulation strategy is described here. The key feature is the usage of vinylogous urethane tethered to a vinyl iminium intermediate with trifluoroacetate serving as the counteranion. The proof-of-concept is illustrated with the synthesis of 2-deoxylasubine II.

    References and Notes

  • For reviews, see:
  • 1a Harrity JPA. Provoost O. Org. Biomol. Chem.  2005,  3:  1349 
  • 1b Hsung RP. Kurdyumov AV. Sydorenko N. Eur. J. Org. Chem.  2005,  23 
  • 1c Coverdale HA. Hsung RP. Chemtracts  2003,  16:  238 
  • For recent studies in aza-annulations, see:
  • 2a Hayashi Y. Gotoh H. Masui R. Ishikawa H. Angew. Chem. Int. Ed.  2008,  47:  4012 
  • 2b Trost BM. Dong G. Org. Lett.  2007,  9:  2357 
  • 2c Schmidt A. Gütlein J.-P. Mkrrchyan S. Görls H. Langer P. Synlett  2007,  1305 
  • 2d Pattenden LC. Wybrow RAJ. Smith SA. Harrity JPA. Org. Lett.  2006,  8:  3089 
  • 2e Shintani R. Hayashi T. J. Am. Chem. Soc.  2006,  128:  6330 
  • 2f Halliday JI. Chebib M. Turner P. McLeod MD. Org. Lett.  2006,  8:  3399 
  • 2g Katsuyama I. Funabiki K. Matsui M. Muramatsu H. Shibata K. Heterocycles  2006,  68:  2087 
  • 2h Bose DS. Kumar RK. Heterocycles  2006,  68:  549 
  • 2i Goodenough KM. Raubo P. Harrity JPA. Org. Lett.  2005,  7:  2993 
  • 2j Goodenough KM. Moran WJ. Raubo P. Harrity JPA. J. Org. Chem.  2005,  70:  207 
  • 2k Agami C. Dechoux L. Hebbe S. Ménard C. Tetrahedron  2004,  60:  5433 
  • 2l Ji S.-J. Jiang Z.-Q. Lu J. Loh T.-P. Synlett  2004,  831 
  • 2m Hedley SJ. Moran WJ. Price DA. Harrity JPA. J. Org. Chem.  2003,  68:  4286 
  • 3 For a leading reference on developing our aza-annulations, see: Sklenicka HM. Hsung RP. McLaughlin MJ. Wei L.-L. Gerasyuto AI. Brennessel WW. J. Am. Chem. Soc.  2002,  124:  10435 
  • Also see:
  • 4a Ghosh SK. Buchanan GS. Long QA. Wei Y. Al-Rashid ZF. Sklenicka HM. Hsung RP. Tetrahedron  2008,  63:  883 
  • 4b Sydorenko N. Hsung RP. Vera EL. Org. Lett.  2006,  8:  2611 
  • 4c Sydorenko N. Hsung RP. Darwish OS. Hahn JM. Liu J. J. Org. Chem.  2004,  69:  6732 
  • 4d McLaughlin MJ. Hsung RP. Cole KC. Hahn JM. Wang J. Org. Lett.  2002,  4:  2017 
  • 4e Sklenicka HM. Hsung RP. Wei L.-L. McLaughlin MJ. Gerasyuto AI. Degen SJ. Mulder JA. Org. Lett.  2000,  2:  1161 
  • 4f Hsung RP. Wei L.-L. Sklenicka HM. Douglas CJ. McLaughlin MJ. Mulder JA. Yao LJ. Org. Lett.  1999,  1:  509 
  • 5 For structural types 2a and 2b, see: Wei L.-L. Sklenicka HM. Gerasyuto AI. Hsung RP. Angew. Chem. Int. Ed.  2001,  40:  1516 
  • For structural type 2c, see:
  • 6a Luo S. Zificsak CZ. Hsung RP. Org. Lett.  2003,  5:  4709 
  • 6b Sydorenko N. Zificsak CA. Gerasyuto AI. Hsung RP. Org. Biomol. Chem.  2005,  3:  2140 
  • For structural type 2d, see:
  • 7a Swidorski JJ. Wang J. Hsung RP. Org. Lett.  2006,  8:  777 
  • 7b Wang J. Swidorski JJ. Sydorenko N. Hsung RP. Coverdale HA. Kuyava JM. Liu J. Heterocycles  2006,  70:  423 
  • For structural type 2e, see:
  • 8a Gerasyuto AI. Hsung RP. Org. Lett.  2006,  8:  4899 
  • 8b Gerasyuto AI. Hsung RP. J. Org. Chem.  2007,  72:  2476 
  • 9 For an asymmetric intramolecular aza-[3+3] annulation, see: Gerasyuto AI. Hsung RP. Sydorenko N. Slafer BW. J. Org. Chem.  2005,  70:  4248 
  • For isolations of (±)-lasubine I and II, see:
  • 10a Fuji K. Yamada K. Fujita E. Murata H. Chem. Pharm. Bull.  1978,  26:  2515 
  • 10b For a leading review in quinolizidine alkaloids, see: Michael JP. Nat. Prod. Rep.  2008,  25:  139; and references cited therein 
  • For syntheses of (±)-lasubine I and II, see:
  • 11a Iida H. Tanaka M. Kibayashi C. J. Chem. Soc., Chem. Commun.  1983,  20:  1143 
  • 11b Iida H. Tanaka M. Kibayashi C. J. Org. Chem.  1984,  49:  1909 
  • 11c Ent H. De Koning H. Speckamp WN. Heterocycles  1988,  27:  237 
  • 11d Bardot V. Gardette D. Gelas-Mialhe Y. Gramain J.-C. Remuson R. Heterocycles  1998,  48:  507 
  • 11e Narasaka K. Yamazaki S. Ukaji Y. Chem. Lett.  1985,  1177 
  • 11f Hoffmann RW. Endesfelder A. Liebigs Ann. Chem.  1986,  1823 
  • 11g Brown JD. Foley MA. Comins DL. J. Am. Chem. Soc.  1988,  110:  7445 
  • 11h Pilli RA. Dias LC. Maldaner AO. Tetrahedron Lett.  1993,  34:  2729 
  • 11i Pilli RA. Dias LC. Maldaner AO. J. Org. Chem.  1995,  60:  717 
  • 11j Ukaji Y. Ima M. Yamada T. Inomata K. Heterocycles  2000,  52:  563 
  • For syntheses of (-)-lasubine I, see:
  • 12a Chalard P. Remuson R. Gelas-Mialhe Y. Gramain J.-C. Tetrahedron: Asymmetry  1998,  9:  4361 
  • 12b Kundig PE. Ratni H. Org. Lett.  1999,  1:  1997 
  • 12c Davis FA. Roa A. Carroll PJ. Org. Lett.  2003,  5:  3855 
  • 12d Kundig PE. Cannas R. Fabritius C.-H. Grossheimann G. Kondratenko M. Laxmisha M. Pache S. Ratni H. Robvieux F. Romanens P. Tchertchian S. Pure Appl. Chem.  2004,  76:  689 
  • 12e Liu S. Fan Y. Peng X. Wang W. Hua W. Akber H. Liao L. Tetrahedron Lett.  2006,  47:  7681 
  • 13 For syntheses of (+)-lasubine I, see: Mancheno OG. Arrayas RG. Adrio J. Carretero JC. J. Org. Chem.  2007,  72:  10294 
  • For syntheses of (-)-lasubine II, see:
  • 14a Comins DL. LaMunyon DH. J. Org. Chem.  1992,  57:  5809 
  • 14b Chalard P. Remuson R. Gelas-Mialhe Y. Gramain J.-C. Tetrahedron: Asymmetry  1998,  9:  4361 
  • 14c Davis FA. Chao B. Org. Lett.  2000,  2:  2623 
  • 14d Ma D. Zhu W. Org. Lett.  2001,  3:  3927 
  • 14e Hamilton MD. Back TG. Org. Lett.  2002,  4:  1779 
  • 14f Gracias V. Zeng Y. Desai P. Aubé J. Org. Lett.  2003,  5:  4999 
  • 14g Blechert S. Zaja M. Tetrahedron  2004,  60:  9629 
  • 14h Back TG. Hamilton MD. Lim VJJ. Parvez M. J. Org. Chem.  2005,  70:  967 
  • 14i Liu S. Hua W. Haji A. Liao L. Wang W. Zhongguo Yaoke Daxue Xuebao  2007,  38:  193 
  • 14j Kim G. Lim J. Tetrahedron Lett.  2008,  49:  88 
  • For syntheses of (+)-lasubine II, see:
  • 15a Yu RT. Rovis T. J. Am. Chem. Soc.  2006,  128:  12370 
  • 15b Mancheno OG. Arrayas RG. Adrio J. Carretero JC. J. Org. Chem.  2007,  72:  10294 
  • 16 For a synthesis of 10, see: O’Malley SJ. Tan KL. Watzke A. Bergman RG. Ellman JA. J. Am. Chem. Soc.  2005,  127:  13496 
  • 18 See: Parikh JR. von Doering WE. J. Am. Chem. Soc.  1967,  89:  5505 ; this is the only oxidation in which the Z-geometry of the vinylogous urethane does not scramble
17

Selected Experimental Procedures and Characterizations Aza-[3+3] Annulation
To a stirring heterogeneous suspension of enal 13 (2.81 g, 8.09 mmol) and grounded Na2SO4 (flame-dried, 9.00 g) in freshly distilled anhyd EtOAc (180 mL) was added piperidinium trifluoroacetate salt (796.0 mg, 4.00 mmol) at 0 ˚C. The resulting suspension was allowed to warm up to r.t. slowly. After 16 h, NMR showed complete consumption of the aldehyde. To this reaction mixture was added Pd/C (869.0 mg, 0.81 mmol), and the flask was filled with H2 gas by five evacuate-back-fill cycles. After which, the mixture was stirred under H2 at r.t. for 6 h. The mixture was then filtered through CeliteTM to remove the solid, and the solution was concentrated in vacuo to give a reddish oil. The crude product was purified by silica gel flash column chromatography buffered with Et3N (isocratic eluent: EtOAc-hexanes, 1:2) to give the desired annulation product 16 (1.65 g, 4.98 mmol) in 62% yield as yellow solid.
Compound 16: R f  = 0.32 (EtOAc-hexanes, 1:2); mp 114-117 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 1.21-1.25 (m, 1 H), 1.36-1.42 (m, 3 H), 1.66-1.75 (m, 2 H), 1.78 (d, 1 H, J = 6.4 Hz), 1.95 (dd, 1 H, J = 6.5, 13.1 Hz), 2.37-2.54 (m, 3 H), 3.11-3.14 (m, 2 H), 3.36 (s, 3 H), 3.83 (s, 3 H), 3.86 (s, 3 H), 6.63 (s, 1 H), 6.67 (d, 1 H, J = 8.2 Hz), 6.82 (d, 1 H, J = 8.2 Hz). ¹³C NMR (100 MHz, CDCl3): δ = 21.4, 24.5, 26.5, 29.0, 32.7, 49.5, 50.3, 55.6, 55.8, 57.0, 95.9, 109.7, 110.6, 120.8, 130.9, 148.2, 148.6, 156.1, 168.9. IR (neat): 2940 (s), 1643 (s), 1562 (s), 1511 (s), 1122 (s) cm. MS (APCI): m/e (relative intensity) = 332 (100) [M + H]+; m/e calcd for C19H25NO4Na: 354.1676; found: 354.1679.
Hydrogenation
To a flame-dried 100 mL round-bottom flask was added PtO2 (102.0 mg, 0.45 mmol) and MeOH (10 mL). The flask was filled with H2 by three evacuate-back-fill cycles and the resulting suspension was stirred at r.t. for 20 min, and the original brown powder of PtO2 turned into black sponge. To this heterogeneous mixture was added via syringe a solution of the freshly purified annulation product 16 (296.0 mg, 0.89 mmol) in MeOH (30 mL). The resulting mixture was stirred at r.t. for 16 h and TLC showed complete conversion of the starting material. The solution was filtered through CeliteTM and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography buffered with Et3N (isocratic eluent: EtOAc-hexanes, 1:4) to give ester 17 (258.0 mg, 0.77 mmol) in 87% yield as colorless oil.
Compound 17: R f  = 0.26 (EtOAc-hexanes, 1:4). ¹H NMR (400 MHz, CDCl3): δ = 1.23 (tq, 1 H, J = 4.3, 12.5 Hz), 1.35-1.44 (m, 3 H), 1.46-1.58 (m, 3 H), 1.61-1.70 (m, 2 H), 1.87 (1 H, tt, J = 4.5, 13.0 Hz), 1.87-1.91 (m, 1 H), 2.11 (1 H, dq, J = 3.6, 13.0 Hz), 2.70 (t, 1 H, J = 4.5 Hz), 2.78-2.81 (m, 1 H), 3.09 (d, 1 H, J = 4.4 Hz), 3.30 (s, 3 H), 3.80 (s, 3 H), 3.81 (s, 3 H), 6.71-6.76 (m, 2 H), 6.86 (s, 1 H). ¹³C NMR (125 MHz, CDCl3): δ = 24.9, 26.0, 26.7, 28.7, 33.6, 47.3, 50.7, 53.9, 55.7, 55.8, 63.3, 69.9, 110.3, 110.5, 119.7, 134.9, 147.7, 148.6, 173.6. IR (neat): 2929 (s), 1735 (s), 1591 (s), 1259 (s), 1152 (s) cm. MS (APCI): m/e (relative intensity) = 334 (100) [M + H]+; m/e calcd for C19H27NO4Na: 356.1832; found: 356.1848.
Demethylation of Ester 17
To a solution of ester 17 (112 mg, 0.336 mmol) in freshly distilled EtOAc (7 mL) was added LiI (270 mg, 2.02 mmol). The resulting solution was deoxygenated via purging with Argon gas for 15 min, and then the reaction vessel was sealed under Argon, wrapped with aluminum foil, and heated in a 105 ˚C oil bath. After heating for 36 h, the solution was cooled down to r.t. and filtered. The light brown solid filter cake was washed with EtOAc (3 mL) and Et2O (2 mL), and dried in vacuo to give a brown solid. The solid salt was then dissolved in H2O (10 mL), and acidified via dropwise addition of 1.0 N aq HCl solution until the pH value of the aqueous solution reached 3-4. The aqueous solution was then saturated with solid NaCl, and extracted with CHCl3 (6 × 8 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give product acid 18 (91.0 mg, 0.29 mmol) in 85% yield as a light brown solid. Acid 18 was used immediately for decarboxylation.
Barton’s Decarboxylation
To a solution of acid 18 (130.0 mg, 0.41 mmol) in anhyd CH2Cl2 (10 mL) was added one drop of DMF. The solution was stirred at 0 ˚C for 2 min before oxalyl chloride (104.0 mg, 0.82 mmol) was added via syringe. The resulting solution was allowed to warm up to r.t. over 30 min, and was stirred at r.t. for an additional 1 h. After which, a high vacuum (0.665-1.33 mbar) was slowly applied to remove solvent and volatile materials. The residual material was then further dried under high vacuum for 30 min, before it was dissolved in anhyd CH2Cl2 (8 mL) and transferred via syringe to a chilled solution of 2-mercaptopyridine-1-oxide sodium salt (122.0 mg, 0.82 mmol) and DMAP (10 mg, 0.08 mmol) in anhyd CH2Cl2 (8 mL). The resulting suspension was stirred at 0 ˚C with the flask shielded from light using Al foil. It was then slowly warmed up to r.t. and stirred at r.t. for 1.5 h.
After which, t-BuSH (587.0 mg, 6.50 mmol) was added via syringe all at once and the yellowish suspension was then irradiated with a 300 W tungsten lamp for 3 h with the solution cooled by a water bath. Solvent and excess of
t-BuSH was then removed in vacuo, and 5% aq NaHCO3 (30 mL) solution was added. The aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic layers were washed with sat. aq NaCl (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography buffered with Et3N (isocratic eluent: EtOAc-hexanes, 1:4) to give product (±)-2-deoxylasubine II (19, 44.0 mg, 0.16 mmol) in 39% yield as colorless oil, which solidified upon standing.
Compound 19: R f  = 0.29 (EtOAc-hexanes, 1:4); mp 68-70 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 1.25 (tt, 1 H, J = 4.3, 11.5 Hz), 1.33-1.47 (m, 5 H), 1.54-1.61 (m, 4 H), 1.63-1.75 (m, 3 H), 1.87-1.92 (t, 1 H, J = 10.5 Hz), 2.66 (d, 1 H, J = 9.3 Hz), 2.82 (dd, 1 H, J = 2.9, 10.9 Hz), 3.85 (s, 3 H), 3.88 (s, 3 H), 6.76-6.89 (m, 3 H). ¹³C NMR (125 MHz, CDCl3): δ = 24.8, 24.9, 26.2, 33.7, 33.8, 36.5, 53.5, 55.7, 55.9, 63.4, 70.2, 110.3, 110.7, 119.5, 138.2, 147.6, 148.9. IR (neat): 2926 (s), 1502 (s), 1147 (s) cm. MS (APCI): m/e (relative intensity) = 276 (100) [M + H]+; m/e calcd for C17H26NO2: 276.1958; found: 276.1958.