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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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Publikationsverlauf

Received 18 September 2008
Publikationsdatum:
15. Januar 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

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.