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

Atsushi Toyao; Osamu Tamura; Hiroko Takagi; Hiroyuki Ishibashi

doi:10.1055/s-2003-36236

LETTER

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

Atsushi Toyao, Osamu Tamura*, Hiroko Takagi, Hiroyuki Ishibashi*
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa, Ishikawa 920-0934, Japan
e-Mail: tamura@mail.p.kanazawa-u.ac.jp;

Abstract

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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

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References

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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.

<A NAME="RU08502ST-10A">10a</A> 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

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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.

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]

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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.

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

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

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.