A Concise Synthesis of (-)-Codonopsinine and an Approach to Synthesis of (+)-Hyacinthacines A₁ and A₂ from a Polyhydroxylated Cyclic Nitrone

Abstract

Synthesis of (-)-codonopsinine (2) was accomplished in seven steps that involved an addition of five-membered cyclic nitrone 1, readily obtained from l-xylose, with the Grignard reagent. Nitrone 1 also underwent intermolecular cycloaddition with several α,β-unsaturated esters 12 to afford cycloadducts 13, one of which, 13c, was elaborated to the key intermediate 17 for (+)-hyacintha­cines A₁ (3a) and A₂ (3b).

Key words

cyclic nitrone - nucleophilic addition - cycloaddition - total synthesis - natural products

References

• 1a Watson AA. Fleet GWJ. Asano N. Molyneux RJ. Nash RJ. Phytochemistry  2001,  56:  265 
• 1b Asano N. Nash RJ. Molyneux RJ. Fleet GWJ. Tetrahedron: Asymmetry  2000,  11:  1645 
• 2a Shibano M. Tsukamoto D. Kusano G. Heterocycles  2002,  57:  1539 
• 2b Nash RJ. Fellows LE. Dring JV. Fleet GWJ. Girdhar A. Ramsden NG. Peach JM. Hegarty MP. Scofield AM. Phytochemistry  1990,  29:  111 
• 2c Harris CM. Harris TM. Molyneux RJ. Tropea JE. Elbein AD. Tetrahedron Lett.  1989,  30:  5685 
• 2d Nash RJ. Fellows LE. Plant AC. Fleet GWJ. Derome AE. Baird PD. Hegarty MP. Scofield AM. Tetrahedron  1988,  44:  5959 
• For recent reviews of syntheses of pyrrolidine and pyrrolizidine alkaloids, see:
• 3a Liddell JR. Nat. Prod. Rep.  1999,  16:  499 
• 3b Michael JP. Nat. Prod. Rep.  1997,  14:  619 
• 3c Robins DJ. Nat. Prod. Rep.  1995,  12:  413 
• 3d For leading references, see: Hulme AN. Rosser EM. Org. Lett.  2002,  4:  265 
• 3e See also: Cordero FM. Pisaneschi F. Gensini M. Goti A. Brandi A. Eur. J. Org. Chem.  2002,  1941 
• 3f See also: Severino EA. Correia CRD. Org. Lett.  2000,  2:  3039 
• 3g See also: Cordero FM. Gensini M. Goti A. Brandi A. Org. Lett.  2000,  2:  2475 
• 3h See also: Yoda H. Asai F. Takabe K. Synlett  2000,  1001 
• 3i See also: Yoda H. Katoh H. Takabe K. Tetrahedron Lett.  2000,  41:  7661 
• 3j See also: Ahn J.-B. Yun C.-S. Kim KH. Ha D.-C. J. Org. Chem.  2000,  65:  9249 
• 3k See also: Pearson WH. Hines JV. J. Org. Chem.  2000,  65:  5785 
• 3l See also: Denmark SE. Herbert B. J. Org. Chem.  2000,  65:  2887 
• 3m See also: Denmark SE. Hurd AR. Org. Lett.  1999,  1:  1311 
• 4a Behr J.-B. Erard A. Guillerm G. Eur. J. Org. Chem.  2002,  1256 
• 4b Izquierdo I. Plaza MT. Robles R. Franco F. Tetrahedron: Asymmetry  2001,  12:  2481 
• 4c Person WH. Guo L. Tetrahedron Lett.  2001,  42:  8267 
• 4d Pearson WH. Hembre EJ. Tetrahedron Lett.  2001,  42:  8273 
• 4e Gallos JK. Sarli VC. Koftis TV. Coutouli-Argyropoulou E. Tetrahedron Lett.  2000,  41:  4819 
• 5a Matkhalikova SF. Malikov VM. Yunusov SYu. Khim. Prir. Soedin.  1969,  5:  607 ; Chem. Abstr. 1970, 73, 25712d
• 5b Khanov MT. Sultanov MB. Egorova TA. Farmakol. Alkaloidov Serdech. Glikoyidov.  1971,  210 ; Chem. Abstr. 1972, 77, 135091r
• 5c For recent syntheses of codonopsinine and codonopsine, see: Yoda H. Nakajima T. Takabe K. Tetrahedron Lett.  1996,  37:  5531 
• 5d See also: Wang C.-LJ. Calabrese JC. J. Org. Chem.  1991,  56:  4341 
• 5e See further: Iida H. Yamazaki N. Kibayashi C. J. Org. Chem.  1987,  52:  1956 ; see also ref. 3f
• 6a Asano N. Kuroi H. Ikeda K. Kizu H. Kameda Y. Kato A. Adachi I. Watson AA. Nash RJ. Fleet GWJ. Tetrahedron: Asymmetry  2000,  11:  1 
• 6b For the first synthesis of (-)-3b, see: Rambaud L. Compain P. Martin OR. Tetrahedron: Asymmetry  2001,  12:  1807 
• 7 Tamura O. Toyao A. Ishibashi H. Synlett  2002,  1344 
• 8a Lim MH. Kim HO. Moon HR. Chun MW. Jeong LS. Org. Lett.  2002,  4:  529 
• 8b Jeong LS. Moon HR. Choi YJ. Chun MW. Kim HO. J. Org. Chem.  1998,  63:  4821 
• 10a The exclusive formation of compound 8 can be explained by nucleophilic addition of the Grignard reagent from the less-hindered side and/or formation of a rigid chelated complex between 1 and MgX₂, see: Portolés R. Murga J. Falomir E. Carda M. Uriel S. Marco JA. Synlett  2002,  711 
• 10b For a review of nucleophilic addition to nitrones, see: Lombardo M. Trombini C. Synthesis  2000,  759 
• For recent reviews of cycloaddition of nitrones, see:
• 13a Broggini G. Zecchi G. Synthesis  1999,  905 
• 13b Gothelf KV. Jørgensen KA. Chem. Rev.  1998,  98:  863 
• 15 Barton DHR. Dorchak J. Jaszberenyi JC. Tetrahedron  1992,  48:  7435 

9

Analytical Data of Compound 1: [α]_D ²⁸ -13.0 (c 0.50, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 3.33 (3 H, s), 3.74 (1 H, dd, J = 2.9, 10.3 Hz), 3.99 (1 H, m), 4.35 (1 H, dd, J = 4.9, 10.3 Hz), 4.36 (1 H, br dd, J = 2.5, 3.9 Hz), 4.51 (1 H, d, J = 12.2 Hz), 4.58 (1 H, d, J = 11.7 Hz), 4.61 (1 H, d, J = 12.2 Hz), 4.63 (1 H, d, J = 11.7 Hz), 4.66 (1 H, d, J = 7.3 Hz), 4.68 (1 H, d, J = 7.3 Hz), 4.70 (1 H, br t, J = 2.5 Hz), 6.96 (1 H, br s), 7.25-7.35 (10 H, m). ¹³C NMR (125 MHz, CDCl₃): δ = 55.7, 65.9, 72.0, 73.5, 77.3, 80.8, 81.8, 96.4, 127.6, 127.7, 127.8, 128.1, 128.3, 128.5, 133.4, 137.2, 137.7.

11

Analytical Data of Compound 8: ¹H NMR (500 MHz, CDCl₃): δ = 3.11 (3 H, s), 3.64 (1 H, m), 3.72 (1 H, dd, J = 7.3, 9.3 Hz), 3.77 (3 H, s), 3.83 (1 H, dd, J = 4.2, 9.3 Hz), 4.05 (1 H, dd, J = 2.9, 3.4 Hz), 4.12 (1 H, d, J = 7.3 Hz), 4.25 (1 H, dd, J = 3.4, 7.3 Hz), 4.42 (1 H, d, J = 6.4 Hz), 4.51-4.63 (5 H, m), 5.28 (1 H, br s), 6.86 (2 H, d, J = 8.3 Hz), 7.25-7.50 (12 H, m). ¹³C NMR (125 MHz, CDCl₃): δ = 55.2, 55.3, 67.0, 68.8, 71.7, 73.4, 73.5, 83.9, 84.6, 95.6, 113.8, 127.6, 127.7, 127.9, 128.3, 128.4, 129.7, 130.8, 138.2, 138.3, 159.3.

12

Analytical Data of Compound (-)-2: Mp 173-174 °C (MeOH), [α]_D ²⁸ -13.2 (c 0.3, MeOH) [lit. [5a] mp 169-170 °C, [α]_D ²⁰ -8.8 (c 0.1, MeOH), lit. [5c] [α]_D ²⁰ -11.8 (c 0.69, MeOH)]. ¹H NMR (500 MHz, pyridine-d ₅ ): δ = 1.32 (3 H, d, J = 6.8 Hz), 2.21 (3 H, s), 3.66 (3 H, s), 3.68 (1 H, qd, J = 3.9, 6.8 Hz), 4.02 (1 H, br d, J = 6.4 Hz), 4.37 (1 H, br t, J = 3.9 Hz), 4.61 (1 H, br dd, J = 3.9, 6.4 Hz), 6.96 (2 H, J = 8.3 Hz), 7.60 (2 H, d, J = 8.3 Hz). Two protons of hydroxyl groups were not observed in this spectrum. The ¹H NMR spectral data of our synthetic (-)-2 are identical with those previously reported. [3f] [5e]

14

Analytical Data of Compound 13c: ¹H NMR (500 MHz, CDCl₃): δ = 1.47 (9 H, s), 2.55 (2 H, br t, J = 7.3 Hz), 3.33 (1 H, m), 3.34 (3 H, s), 3.61 (1 H, dd, J = 6.4, 10.3 Hz), 3.71 (1 H, dd, J = 4.4, 10.3 Hz), 3.74 (1 H, dt, J = 3.9, 7.3 Hz), 4.01 (1 H, dd, J = 3.9, 5.9 Hz), 4.07 (1 H, br t, J = 3.9 Hz), 4.53 (1 H, t, J = 7.3 Hz), 4.55 (1 H, d, J = 12.2 Hz), 4.58 (2 H, br s), 4.60 (1 H, d, J = 12.2 Hz), 4.61 (1 H, d, J = 6.8 Hz), 4.63 (1 H, d, J = 6.8 Hz), 7.25-7.31 (10 H, m). ¹³C NMR (125 MHz, CDCl₃): δ = 28.0, 37.8, 55.6, 68.3, 69.8, 70.1, 72.3, 73.4, 75.5, 82.0, 84.3, 85.1, 96.0, 127.5, 127.7, 127.8, 128.2, 128.3, 138.0, 138.3, 169.5.

16

The stereochemistry of compound 15 was established by its NOE difference spectrum shown below.

17

Amide 16 was also obtained from 13c′ via three similar steps.

18

Analytical Data of Compound (-)-17: [α]_D ³¹ -64.1 (c 0.16, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.81-1.89 (1 H, m), 2.33-2.39 (2 H, m), 2.62 (1 H, br ddd, J = 8.8, 10.7, 16.6 Hz), 3.20 (1 H, br s), 3.64 (1 H, br dd, J = 2.9, 9.8 Hz), 3.70 (1 H, br dd, J = 3.9, 9.8 Hz), 3.81-3.84 (2 H, m), 4.05 (1 H, br t, J = 2.9 Hz), 4.17 (1 H, br q, J = 2.9 Hz), 4.49 (1 H, br d, J = 11.7 Hz), 4.51 (1 H, br d, J = 11.2 Hz), 4.57 (1 H, br d, J = 11.2 Hz), 4.59 (1 H, br d, J = 11.7 Hz), 7.26-7.36 (10 H, m). ¹³C NMR (125 MHz, CDCl₃): δ = 26.3, 33.2, 59.4, 67.5, 71.0, 71.9, 73.8, 81.4, 89.2, 127.7, 127.8, 127.9, 128.1, 128.5, 128.6, 137.6, 138.1, 176.6.