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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;
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Publication History

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

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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.

Key words

intramolecular aza-[3+3] annulation - lasubine I - ­lasubine II - quinolizidines - piperidinium trifluoroacetate salt - ­Barton’s decarboxylation

    References and Notes

  • For reviews, see:
  • 1a Harrity JPA. Provoost O. Org. Biomol. Chem.  2005,  3:  1349 
    Google Scholar
  • 1b Hsung RP. Kurdyumov AV. Sydorenko N. Eur. J. Org. Chem.  2005,  23 
    Google Scholar
  • 1c Coverdale HA. Hsung RP. Chemtracts  2003,  16:  238 
    Google Scholar
  • For recent studies in aza-annulations, see:
  • 2a Hayashi Y. Gotoh H. Masui R. Ishikawa H. Angew. Chem. Int. Ed.  2008,  47:  4012 
    Google Scholar
  • 2b Trost BM. Dong G. Org. Lett.  2007,  9:  2357 
    Google Scholar
  • 2c Schmidt A. Gütlein J.-P. Mkrrchyan S. Görls H. Langer P. Synlett  2007,  1305 
    Google Scholar
  • 2d Pattenden LC. Wybrow RAJ. Smith SA. Harrity JPA. Org. Lett.  2006,  8:  3089 
    Google Scholar
  • 2e Shintani R. Hayashi T. J. Am. Chem. Soc.  2006,  128:  6330 
    Google Scholar
  • 2f Halliday JI. Chebib M. Turner P. McLeod MD. Org. Lett.  2006,  8:  3399 
    Google Scholar
  • 2g Katsuyama I. Funabiki K. Matsui M. Muramatsu H. Shibata K. Heterocycles  2006,  68:  2087 
    Google Scholar
  • 2h Bose DS. Kumar RK. Heterocycles  2006,  68:  549 
    Google Scholar
  • 2i Goodenough KM. Raubo P. Harrity JPA. Org. Lett.  2005,  7:  2993 
    Google Scholar
  • 2j Goodenough KM. Moran WJ. Raubo P. Harrity JPA. J. Org. Chem.  2005,  70:  207 
    Google Scholar
  • 2k Agami C. Dechoux L. Hebbe S. Ménard C. Tetrahedron  2004,  60:  5433 
    Google Scholar
  • 2l Ji S.-J. Jiang Z.-Q. Lu J. Loh T.-P. Synlett  2004,  831 
    Google Scholar
  • 2m Hedley SJ. Moran WJ. Price DA. Harrity JPA. J. Org. Chem.  2003,  68:  4286 
    Google Scholar
  • 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 
    CrossrefPubMedGoogle Scholar
  • Also see:
  • 4a Ghosh SK. Buchanan GS. Long QA. Wei Y. Al-Rashid ZF. Sklenicka HM. Hsung RP. Tetrahedron  2008,  63:  883 
    Google Scholar
  • 4b Sydorenko N. Hsung RP. Vera EL. Org. Lett.  2006,  8:  2611 
    Google Scholar
  • 4c Sydorenko N. Hsung RP. Darwish OS. Hahn JM. Liu J. J. Org. Chem.  2004,  69:  6732 
    Google Scholar
  • 4d McLaughlin MJ. Hsung RP. Cole KC. Hahn JM. Wang J. Org. Lett.  2002,  4:  2017 
    Google Scholar
  • 4e Sklenicka HM. Hsung RP. Wei L.-L. McLaughlin MJ. Gerasyuto AI. Degen SJ. Mulder JA. Org. Lett.  2000,  2:  1161 
    Google Scholar
  • 4f Hsung RP. Wei L.-L. Sklenicka HM. Douglas CJ. McLaughlin MJ. Mulder JA. Yao LJ. Org. Lett.  1999,  1:  509 
    Google Scholar
  • 5 For structural types 2a and 2b, see: Wei L.-L. Sklenicka HM. Gerasyuto AI. Hsung RP. Angew. Chem. Int. Ed.  2001,  40:  1516 
    CrossrefPubMedGoogle Scholar
  • For structural type 2c, see:
  • 6a Luo S. Zificsak CZ. Hsung RP. Org. Lett.  2003,  5:  4709 
    Google Scholar
  • 6b Sydorenko N. Zificsak CA. Gerasyuto AI. Hsung RP. Org. Biomol. Chem.  2005,  3:  2140 
    Google Scholar
  • For structural type 2d, see:
  • 7a Swidorski JJ. Wang J. Hsung RP. Org. Lett.  2006,  8:  777 
    Google Scholar
  • 7b Wang J. Swidorski JJ. Sydorenko N. Hsung RP. Coverdale HA. Kuyava JM. Liu J. Heterocycles  2006,  70:  423 
    Google Scholar
  • For structural type 2e, see:
  • 8a Gerasyuto AI. Hsung RP. Org. Lett.  2006,  8:  4899 
    Google Scholar
  • 8b Gerasyuto AI. Hsung RP. J. Org. Chem.  2007,  72:  2476 
    Google Scholar
  • 9 For an asymmetric intramolecular aza-[3+3] annulation, see: Gerasyuto AI. Hsung RP. Sydorenko N. Slafer BW. J. Org. Chem.  2005,  70:  4248 
    CrossrefPubMedGoogle Scholar
  • For isolations of (±)-lasubine I and II, see:
  • 10a Fuji K. Yamada K. Fujita E. Murata H. Chem. Pharm. Bull.  1978,  26:  2515 
    Google Scholar
  • 10b For a leading review in quinolizidine alkaloids, see: Michael JP. Nat. Prod. Rep.  2008,  25:  139; and references cited therein 
    Google Scholar
  • For syntheses of (±)-lasubine I and II, see:
  • 11a Iida H. Tanaka M. Kibayashi C. J. Chem. Soc., Chem. Commun.  1983,  20:  1143 
    Google Scholar
  • 11b Iida H. Tanaka M. Kibayashi C. J. Org. Chem.  1984,  49:  1909 
    Google Scholar
  • 11c Ent H. De Koning H. Speckamp WN. Heterocycles  1988,  27:  237 
    Google Scholar
  • 11d Bardot V. Gardette D. Gelas-Mialhe Y. Gramain J.-C. Remuson R. Heterocycles  1998,  48:  507 
    Google Scholar
  • 11e Narasaka K. Yamazaki S. Ukaji Y. Chem. Lett.  1985,  1177 
    Google Scholar
  • 11f Hoffmann RW. Endesfelder A. Liebigs Ann. Chem.  1986,  1823 
    Google Scholar
  • 11g Brown JD. Foley MA. Comins DL. J. Am. Chem. Soc.  1988,  110:  7445 
    Google Scholar
  • 11h Pilli RA. Dias LC. Maldaner AO. Tetrahedron Lett.  1993,  34:  2729 
    Google Scholar
  • 11i Pilli RA. Dias LC. Maldaner AO. J. Org. Chem.  1995,  60:  717 
    Google Scholar
  • 11j Ukaji Y. Ima M. Yamada T. Inomata K. Heterocycles  2000,  52:  563 
    Google Scholar
  • For syntheses of (-)-lasubine I, see:
  • 12a Chalard P. Remuson R. Gelas-Mialhe Y. Gramain J.-C. Tetrahedron: Asymmetry  1998,  9:  4361 
    Google Scholar
  • 12b Kundig PE. Ratni H. Org. Lett.  1999,  1:  1997 
    Google Scholar
  • 12c Davis FA. Roa A. Carroll PJ. Org. Lett.  2003,  5:  3855 
    Google Scholar
  • 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 
    Google Scholar
  • 12e Liu S. Fan Y. Peng X. Wang W. Hua W. Akber H. Liao L. Tetrahedron Lett.  2006,  47:  7681 
    Google Scholar
  • 13 For syntheses of (+)-lasubine I, see: Mancheno OG. Arrayas RG. Adrio J. Carretero JC. J. Org. Chem.  2007,  72:  10294 
    CrossrefGoogle Scholar
  • For syntheses of (-)-lasubine II, see:
  • 14a Comins DL. LaMunyon DH. J. Org. Chem.  1992,  57:  5809 
    Google Scholar
  • 14b Chalard P. Remuson R. Gelas-Mialhe Y. Gramain J.-C. Tetrahedron: Asymmetry  1998,  9:  4361 
    Google Scholar
  • 14c Davis FA. Chao B. Org. Lett.  2000,  2:  2623 
    Google Scholar
  • 14d Ma D. Zhu W. Org. Lett.  2001,  3:  3927 
    Google Scholar
  • 14e Hamilton MD. Back TG. Org. Lett.  2002,  4:  1779 
    Google Scholar
  • 14f Gracias V. Zeng Y. Desai P. Aubé J. Org. Lett.  2003,  5:  4999 
    Google Scholar
  • 14g Blechert S. Zaja M. Tetrahedron  2004,  60:  9629 
    Google Scholar
  • 14h Back TG. Hamilton MD. Lim VJJ. Parvez M. J. Org. Chem.  2005,  70:  967 
    Google Scholar
  • 14i Liu S. Hua W. Haji A. Liao L. Wang W. Zhongguo Yaoke Daxue Xuebao  2007,  38:  193 
    Google Scholar
  • 14j Kim G. Lim J. Tetrahedron Lett.  2008,  49:  88 
    Google Scholar
  • For syntheses of (+)-lasubine II, see:
  • 15a Yu RT. Rovis T. J. Am. Chem. Soc.  2006,  128:  12370 
    Google Scholar
  • 15b Mancheno OG. Arrayas RG. Adrio J. Carretero JC. J. Org. Chem.  2007,  72:  10294 
    Google Scholar
  • 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 
    CrossrefGoogle Scholar
  • 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
    CrossrefGoogle Scholar
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-¹. 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-¹. 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-¹. MS (APCI): m/e (relative intensity) = 276 (100) [M + H]+; m/e calcd for C17H26NO2: 276.1958; found: 276.1958.