A Versatile Chiral Pyrrolidine Aldehyde Building-Block for Synthesis and Formal Synthesis of ent-Nakadomarin A

Abstract

A stable, simple to synthesise and versatile chiral aldehyde building-block has been developed, its reactivity in Wittig, Horner-Wadsworth-Emmons and Grignard reactions investigated, and its use is demonstrated in a highly efficient synthesis of an intermediate in Dixon’s synthesis of nakadomarin A.

Key words

aldehyde - building-block - nakadomarin - manzamine

References and Notes

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• 11 Jakubec P. Cockfield DM. Dixon DJ. J. Am. Chem. Soc.  2009,  131:  16632 
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• 13 Compound 18 has also been reported previously in racemic form, see: Martin SF. Chen H.-J. Courtney AK. Liao Y. Patzel M. Ramser MN. Wagman AS. Tetrahedron  1996,  52:  7521.  Data for compound 20: R _f = 0.3 (EtOAc); [α]_D ^²² +86.6 (c 1.0, CHCl₃); IR (thin film): 1683 (lactam), 1485 (olefin) cm^-¹; ^¹H NMR (300 MHz, CDCl₃): δ = 5.80 (dt, J = 10.6, 8.5 Hz, 1 H), 5.41 (dd, J = 10.6, 6 Hz, 1 H), 4.26 (dt, J = 6.5, 6 Hz, 1 H), 3.42 (t, J = 5.4 Hz, 2 H), 2.50-2.05 (m, 6 H), 1.91-1.70 (m, 2 H), 1.68-1.49 (m, 2 H); ^¹³C NMR (75 MHz, CDCl₃): δ = 174.4, 131.9, 130.4, 56.8, 41.0, 30.9, 27.0, 26.4, 25.9, 25.2; MS (CI): m/z (%) = 166 (100) [M + 1]⁺, 152 (23); HRMS: m/z [M + H]⁺ calcd for C₁₀H₁₆NO: 166.1232; found: 166.1232. Anal. Calcd for C₁₀H₁₅NO: C, 72.69; H, 9.15; N, 8.48. Found: C, 72.82; H, 9.28; N, 8.51

14

Procedure for the synthesis of chiral aldehyde 2b: A solution of pyroglutamic acid methyl ester (3; 25.7 g, 0.180 mol) in anhydrous CH₂Cl₂ (500 mL) was cooled to 0 ˚C under an atmosphere of argon. The reaction solution was treated with DMAP (2.19 g, 0.018 mol), Et₃N (27.0 mL, 0.198 mol) and (Boc)₂O (41.2 g, 0.189 mol). The solution was allowed to warm to r.t. and stirred for 16 h. HCl (1 M, 300 mL) was added, and the organic layer was separated, washed with sat. NaHCO₃ (300 mL), dried over Na₂SO₄, and evaporated in vacuo. Recrystallisation from hexanes-EtOAc gave N-tert-butyloxycarbonylpyroglutamic acid methyl ester (4; 38.74 g, 89%) as colourless needles. Mp 58-65 ˚C; [α]_D ^²0 -30 (c 2.06, CHCl₃); IR (nujol): 1763, 1703 cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 4.61 (dd, J = 9.4, 3 Hz, 1 H), 3.75-3.74 (m, 3 H), 2.65-2.55 (m, 1 H), 2.50-2.42 (m, 1 H), 2.34-2.23 (m, 1 H), 2.04-1.96 (m, 1 H), 1.45-1.41 (m, 9 H); ^¹³C NMR (100 MHz, CDCl₃): δ = 173.5, 172.1, 149.3, 83.8, 59.0, 52.8, 31.4, 28.1, 21.7; MS: m/z (%) = 261 (98) [M + NH₄]⁺, 144 (100); Anal. Calcd for C₁₁H₁₇NO₅ [M + NH₄]⁺: 261.1445. Found: 261.1443. A solution of N-tert-butyloxycarbonylpyroglutamic acid methyl ester (4; 34.12 g, 0.14 mol) in anhydrous THF (350 mL) was cooled to -78 ˚C under an atmosphere of argon. DIBAL-H (1 M in toluene, 150 mL) was added over a period of 1 h. The resulting solution was stirred at -78 ˚C for a further 2 h, before being quenched by the addition of anhydrous MeOH (30 mL). After warming to 0 ˚C, a 1 M aqueous solution of Rochelle’s salt (600 mL) and EtOAc (300 mL) were added and the biphasic solution was stirred vigorously for 2 h. The organic layer was separated, dried over Na₂SO₄ and evaporated to give 1-(tert-butyloxycarbonyl)-5-(hydroxy)pyrrolidine-2-carboxylic acid methyl ester (5; 33.17 g, 98%) as a 2:1 mixture of diastereomers, as a colourless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 5.63-5.39 (m, 1 H), 4.60-4.17 (m, 1 H), 3.75-3.66 (m, 3 H), 2.64-1.83 (m, 4 H), 1.45-1.36 (m, 9 H); ^¹³C NMR (100 MHz, CDCl₃): δ = 82.52-81.20, 70.71, 59.5, 52.5, 33.4, 28.5, 28.1, 27.3; MS: m/z (%) = 263 (5) [M + NH₄]⁺, 245 (40), 128 (100); Anal. Calcd for C₁₁H₁₉NO₅ [M + NH₄]⁺: 263.1601. Found: 263.1604. A solution of 1-(tert-butyloxycarbonyl)-5-(hydroxy)pyrrolidine-2-carboxylic acid methyl ester (5; 33.12 g, 0.135 mol) in EtOH (600 mL) was treated with PTSA˙H₂O (1.85 g, 9.73 mmol), and the solution was allowed to stand for 18 h. The solvent was then removed under reduced pressure and the resulting residue was partitioned between EtOAc (300 mL) and sat. aq NaHCO₃ (300 mL). The organic layer was separated, dried over Na₂SO₄ and evaporated in vacuo to give 1-(tert-butyloxycarbonyl)-5-(ethoxy)pyrrolidine-2-carboxylic acid methyl ester (6; 35.90 g, 96%) as a 2:1 mixture of diastereo-mers, as a colourless oil. Bp 92˚C (0.15 Torr); IR: 1755, 1703 cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 5.38-5.20 (m, 1 H), 4.37-4.22 (m, 1 H), 3.72 (s, 3 H), 3.66-3.49 (m, 2 H), 2.48-1.76 (m, 4 H), 1.41 (s, 9 H), 1.08 (t, J = 3.6 Hz, 3 H); ^¹³C NMR (100 MHz, CDCl₃): δ = 87.3, 64.0, 59.0, 52.07, 51.92, 32.5, 30.6, 27.5, 15.3; MS: m/z (%) = 273 (6) [M + H]⁺, 228 (100); Anal. Calcd for C₁₃H₂₄NO₅ [M + H]⁺: 274.1664. Found: 274.1654. A solution of 1-(tert-butyloxy-carbonyl)-5-(ethoxy)pyrrolidine-2-carboxylic acid methyl ester (6; 16.3 g, 59.7 mmol) in anhydrous toluene (100 mL) was cooled to -78 ˚C under an atmosphere of argon. DIBAL-H (1 M in toluene, 71.6 mL) was added over a period of 30 min by cannula (dribbling down the inside of the flask). The resulting solution was stirred at -78 ˚C for a further 6 h before being quenched by the addition of anhydrous MeOH (10 mL). After warming to 0 ˚C, a 1 M aqueous solution of Rochelle’s salt (300 mL) and EtOAc (100 mL) were added, and the biphasic solution was stirred vigorously for 2 h. The organic layer was separated, dried over Na₂SO₄, and evaporated in vacuo to give aldehyde 2b (12.95 g, 89%) as a colourless oil after distillation (bp 96-98 ˚C, 0.2 Torr); IR: 1739, 1698 cm^-¹; ^¹H NMR (300 MHz, CDCl₃): δ = 9.55-9.36 (m, 1 H, 5-H), 5.39-5.18 (m, 1 H), 4.35-4.00 (m, 1 H), 3.72-3.48 (m, 2 H), 2.48-2.00 (m, 2 H), 1.98-1.63 (m, 2 H), 1.47-1.38 (m, 9 H), 1.09 (t, J = 7 Hz, 3 H); ^¹³C (100 MHz, CDCl₃): δ = 200.43, 200.31, 166.70, 88.0, 81.5, 81.2, 65.5, 64.4, 32.0, 28.4, 25.0, 15.5; MS:
m/z (%) = 244 (10) [M + H]⁺, 198 (62); Anal. Calcd for C₁₂H₂₂NO₄ [M + H]⁺: 244.1549. Found: 244.1552.