Approach to the Core Structure of the Polycyclic Alkaloid Palhinine A

Abstract

A synthesis of the tricyclic partly substituted core structure of palhinine A was achieved. To reach the bicyclo[2.2.2]octane motif a domino Michael reaction was employed as a key step. After Arndt–Eistert homologation and intramolecular aldol reaction the isotwistane core could be obtained after simple functional-group manipulations.

Key words

palhinine A - domino Michael reaction - X-ray crystal structure - Arndt–Eistert homologation - intramolecular aldol re­action

• References and Notes

• 1 Zhao F.-W, Sun Q.-Y, Yang F.-M, Hu G.-W, Luo J.-F, Tang G.-H, Wang Y.-H, Long C.-L. Org. Lett. 2010; 12: 3922
• 2 Zhao C, Zheng H, Jing P, Fang B, Xie X, She X. Org. Lett. 2012; 14: 2293
• 3 Zhang G.-B, Wang F.-X, Du J.-Y, Qu H, Ma X.-Y, Wei M.-X, Wang C.-T, Li Q, Fan C.-A. Org. Lett. 2012; 14: 3696

For representative bimolecular domino Michael reactions, see:
• 4a Lee RA. Tetrahedron Lett. 1973; 14: 3333
• 4b White KB, Reusch W. Tetrahedron 1978; 34: 2439
• 4c Roberts MR, Schlessinger RH. J. Am. Chem. Soc. 1981; 103: 724
• 4d Gibbons EG. J. Am. Chem. Soc. 1982; 104: 1767
• 4e Nagaoka H, Kobayashi K, Matsui T, Yamada Y. Tetrahedron Lett. 1987; 28: 2021
• 4f Spitzner D, Engler A. Org. Synth. 1987; 66: 37 ; Org. Synth., Coll. Vol. VIII 1993, 219
• 4g Iwashima M, Nagaoka H, Kobayashi K, Yamada Y. Tetrahedron Lett. 1992; 33: 81
• 4h Hagiwara H, Yamada Y, Sakai H, Suzuki T, Ando M. Tetrahedron 1998; 54: 10999
• 4i Hagiwara H, Sakai H, Kirita M, Hoshi T, Suzuki T, Ando M. Tetrahedron 2000; 56: 1445
• 4j Spitzner D, Oesterreich K. Eur. J. Org. Chem. 2001; 1883
• 4k Giardini A, Lesma G, Passarella D, Perez M, Silvani A. Synlett 2001; 132
• 4l Hagiwara H, Endou S, Fukushima M, Hoshi T, Suzuki T. Org. Lett. 2004; 6: 1115
• 4m Hua Z, Yu W, Su M, Jin Z. Org. Lett. 2005; 7: 1939
• 4n Srikrishna A, Ravi G, Satyanarayana G. Tetrahedron Lett. 2007; 48: 73
• 4o Fukushima M, Morii A, Hoshi T, Suzuki T, Hagiwara H. Tetrahedron 2007; 63: 7154
• 4p Srikrishna A, Ravi G. Tetrahedron 2008; 64: 2565
• 4q Komanduri V, Pedraza F, Krische MJ. Adv. Synth. Catal. 2008; 350: 1569
• 4r Li W, Xiao Y, Zhang J. Adv. Synth. Catal. 2009; 351: 3083
• 4s Yang J, Huang H, Jin Z, Wu W, Ye J. Synthesis 2011; 1984

For representative intramolecular domino Michael reactions, see:
• 5a Ihara M, Toyota M, Fukumoto K, Kametani T. Tetrahedron Lett. 1984; 25: 2167
• 5b Ihara M, Ishida Y, Abe M, Toyota M, Fukumoto K, Kametani T. J. Chem. Soc., Perkin Trans. 1 1988; 1155
• 5c Ihara M, Makita K, Fujiwara Y, Tokunaga Y, Fukumoto K. J. Org. Chem. 1996; 61: 6416
• 5d Takasu K, Mizutani S, Noguchi M, Makita K, Ihara M. J. Org. Chem. 2000; 65: 4112
• 5e Kuwahara S, Hamade S, Leal WS, Ishikawa J, Kodama O. Tetrahedron 2000; 56: 8111
• 5f Kanoh N, Sakanishi K, Iimori E, Nishimura Ki, Iwabuchi Y. Org. Lett. 2011; 13: 2864
• 6 For a review, see: Ihara M, Fukumoto K. Angew. Chem., Int. Ed. Engl. 1993; 32: 1010 ; Angew. Chem. 1993, 105, 1059
• 7 Arndt F, Eistert B. Ber. Dtsch. Chem. Ges. 1935; 68: 200

For some reviews, see:
• 8a Kirmse W. Eur. J. Org. Chem. 2002; 2193
• 8b Zhang Z, Wang J. Tetrahedron 2008; 64: 6577
• 9 Cahiez G, Alexakis A, Normant JF. Tetrahedron Lett. 1978; 19: 3013
• 10a Hara R, Furukawa T, Kashima H, Kusama H, Horiguchi Y, Kuwajima I. J. Am. Chem. Soc. 1999; 121: 3072
• 10b Yamada S, Suemune H. Chem. Pharm. Bull. 2000; 48: 1171
• 10c Gulías M, Rodríguez JR, Castedo L, Mascareñas JL. Org. Lett. 2003; 5: 1975

Addition reactions with Grignard reagents derived from ω-halohydrins:
• 11a Conia J.-M, Rouessac F. Tetrahedron 1961; 16: 45
• 11b Tietze LF, Schirok H, Wöhrmann M. Chem. Eur. J. 2000; 6: 510
• 11c Findley TJ. K, Sucunza D, Miller LC, Davies DT, Procter DJ. Chem. Eur. J. 2008; 14: 6862

Addition reactions with other Grignard reagents:
• 12a Becker D, Harel Z, Nagler M, Gillon A. J. Org. Chem. 1982; 47: 3297
• 12b Schinzer D. Angew. Chem., Int. Ed. Engl. 1984; 23: 308 ; Angew. Chem. 1984, 96, 292
• 13 Mascaretti OA, Furlán RL. E. Aldrichimica Acta 1997; 30: 55
• 14 Sheldrick GM. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008; 64: 112
• 15a Dess DB, Martin JC. J. Org. Chem. 1983; 48: 4155
• 15b Meyer SD, Schreiber SL. J. Org. Chem. 1994; 59: 7549
• 15c Boeckman RK. Jr, Shao P, Mullins JJ. Org. Synth. 2000; 77: 141 ; Org. Synth., Coll. Vol. X; 2004, 696
• 16 Acetate 17 To a solution of tosylhydrazone 16 (182 mg, 270 μmol) in abs. MeOH (3 mL) were added anhyd ZnCl₂ (44 mg, 703 μmol, 2.6 equiv) and NaCNBH₃ (59 mg, 433 μmol, 1.6 equiv) at r.t. The reaction was then stirred at reflux temperature for 3.5 h. Then additional NaCNBH₃ (59 mg, 433 μmol, 1.6 equiv) was added and reflux was continued for 2 h. Thereafter, the mixture was cooled to r.t. and treated with aq NaOH (10 mL, 1 M) and sat. NaCl solution (10 mL). The milky mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were dried over Na₂SO₄, filtered, concentrated in vacuo, and purified by flash chromatography (1.5 × 15 cm, PE–EtOAc, 10:1 to 0:1) to give 94 mg (192 μmol, 71%) of acetate 17 as a colorless oil; R_f = 0.63 (cyclohexane–EtOAc = 2:1). ¹H NMR (400 MHz, CDCl₃): δ = 1.05 (s, 9 H, H _t-Bu), 1.16–1.31 (m, 2 H, 2′-H, 10-H), 1.35–1.64 (m, 9 H, 1-H, 1′-H, 2′-H, 5-H, 8-H, 9-H), 1.73–1.95 (m, 9 H, 2-H, 3-H, 5-H, 6-H, 10-H, CH₃CO₂), 3.56–3.69 (m, 2 H, 3′-H), 4.89–4.96 (m, 1 H, 4-H), 7.34–7.45 (m, 6 H, H_Ar), 7.65–7.70 (m, 4 H, H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 19.2 [C(CH₃)₃], 21.3 (CH₃CO₂), 24.0 (C-8), 24.0 (C-1), 26.9 [C(CH₃)₃], 27.3 (C-1′),28.6 (C-9), 33.2 (C-2′), 34.4 (C-5), 37.1 (C-10), 38.5 (C-6), 40.7 (C-7), 41.1 (C-2), 44.9 (C-3), 64.8 (C-3′), 85.3 (C-4), 127.6 (C_Ar), 129.5 (C_Ar), 134.1 (C_Ar), 134.1 (C_Ar), 135.5 (C_Ar), 170.9 (CH₃ CO₂). HRMS: calcd for C₃₁H₄₂O₃Si [M + Na]⁺: 513.279543; found: 513.279442.
• 17 Taber DF, Wang Y, Stachel SJ. Tetrahedron Lett. 1993; 34: 6209
• 18 Ketone 5 To a solution of alcohol 18 (58 mg, 129 μmol) in abs. CH₂Cl₂ (1.3 mL) were added NaHCO₃ (43 mg, 517 μmol, 4 equiv) and DMP (71 mg, 168 μmol, 1.3 equiv) at r.t. After 1 h at r.t. DMP (71 mg, 168 μmol, 1.3 equiv) was added. After additional 30 min at r.t. sat. aq NaHCO₃ solution (2 mL) and sat. aq Na₂S₂O₃ solution (2 mL) were added, and the mixture was stirred for 30 min. H₂O (5 mL) was added, and the mixture was extracted with Et₂O (3 × 15 mL). The combined organic layers were washed with sat. NaCl solution (10 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (1.5 × 15 cm, PE–EtOAc = 8:1) to give 51 mg (114 μmol, 88%) of tricyclic ketone 5 as a colorless oil; R_f = 0.45 (cyclohexane–EtOAc, 5:1). ¹H NMR (400 MHz, CDCl₃): δ = 1.04 (s, 9 H, H _t-Bu), 1.08–1.28 (m, 2 H, 1′-H), 1.36–1.72 (m, 9 H, 1-H, 2-H, 2′-H, 8-H, 9-H, 10-H), 1.79–2.05 (m, 4 H, 2-H, 3-H, 5-H, 10-H), 2.13–2.21 (m, 1 H, 6-H), 2.42 (dd, J = 7.2, 18.8 Hz, 1 H, 5-H), 3.53–3.66 (m, 2 H, 3′-H), 7.33–7.46 (m, 6 H, H_Ar), 7.60–7.68 (m, 4 H, H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 19.1 [C(CH₃)₃], 24.0 (C-8), 24.3 (C-1), 26.8 [C(CH₃)₃], 27.1 (C-2′), 28.0 (C-9), 30.5 (C-2), 33.7 (C-1′), 35.0 (C-6), 36.5 (C-10), 38.6 (C-7), 45.4 (C-5), 51.5 (C-3), 64.1 (C-3′), 127.6 (C_Ar), 129.5 (C_Ar), 133.9 (C_Ar), 135.5 (C_Ar), 222.4 (C-4). HRMS: m/z calcd for C₂₉H₃₈O₂Si [M + Na]⁺: 469.253328; found: 469.253565.