Asymmetric Total Synthesis of (2E)-Macrolactin 3

Dedicated to Dr. Mukund K. Gurjar on the occasion of his 70^th birthday

Abstract

Asymmetric total synthesis of (2E)-macrolactin 3 has been accomplished in a highly convergent manner utilizing our earlier developed tandem isomerization followed by C–O and C–C bond-forming reaction, Sharpless asymmetric dihydroxylation, and a late-stage intramolecular Heck coupling reaction. Comparison of the NMR spectra of the coupled product and thorough analysis of the 2D NMR data of the final compound led to the conclusion that the Z-double bond at C2 was isomerized during the coupling reaction.

Key words

macrolactin - natural products - asymmetric synthesis - isomerization/C–O/C–C - Heck coupling

Publication History

Received: 01 September 2022

Accepted after revision: 07 October 2022

Accepted Manuscript online:
07 October 2022

Article published online:
15 November 2022

• References and Notes

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• 24 Typical Experimental Details for the Synthesis of (S,2Z,4E)-7-(Methoxymethoxy)nona-2,4,8-trienoic Acid (7) To a stirred solution of ester 25 (300 mg, 1.32 mmol) in 1:1 THF/MeOH (6 mL) was added LiOH·H₂O (557 mg, 13.2 mmol) at 0 °C. The reaction mixture was allowed to stir for 12 h at room temperature. After complete consumption of the starting material (monitored by TLC), the mixture was acidified with 1.0 N HCl and diluted with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with saturated aqueous NaHCO₃ (15 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/hexane = 2:3) to afford the acid compound 7 (251 mg, 89%) as a colorless liquid. [α]_D ²⁵ –3.1 (c 1.2, CHCl₃). IR (CHCl₃): ν_max = 3292, 2924, 2853, 1689, 1638, 1441, 1229, 1151, 1024, 964, 918, 826, 665 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.42 (m, 1 H), 6.66 (t, J = 11.5 Hz, 1 H), 6.13 (m, 1 H), 5.71 (ddd, J = 17.5, 10.3, 7.5 Hz, 1 H), 5.62 (d, J = 11.4 Hz, 1 H), 5.28–5.21 (m, 2 H), 4.71 (d, J = 6.8 Hz, 1 H), 4.56 (d, J = 6.8 Hz, 1 H), 4.13 (dd, J = 13.3, 6.8 Hz, 1 H), 3.37 (s, 3 H), 2.62–2.42 (m, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 171.6, 147.0, 141.6, 137.4, 129.1, 117.8, 115.5, 93.8, 76.4, 55.5, 39.0 ppm. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₁H₁₆O₄Na: 235.0946; found: 235.0954.
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• 29 Typical Experimental Details for the Synthesis of (1S,2E,7R,10Z,12E,15S,16E,18Z,21S,23R,24R)-15,23,24-Trihydroxy-7-methyl-8,25-dioxa-bicyclo[19.3.1]pentacosa-2,10,12,16,18-pentaen-9-one (2E-4) To a stirred solution of cyclic compound 29 (5.0 mg, 0.009 mmol) in MeOH (2 mL) was added 4.0 N HCl (0.3 mL) at 0 °C. The reaction mixture was allowed to stir for 24 h at room temperature. After complete consumption of the starting material (monitored by TLC), it was quenched with saturated aqueous NaHCO₃ (2 mL) solution. MeOH solvent was removed under reduced pressure, and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/hexane = 1:1) to afford macrolactin 3 (2E-4, 3.04 mg, 73%) as an amorphous solid. [α]_D ²⁵ –93.6 (c 0.09, CH₃OH). IR (CHCl₃): ν_max = 3264, 3172, 3014, 2982, 1643, 1604, 1546, 1517, 1447, 1364, 1226, 1143, 1042, 1037, 812, 721 cm^–1. ¹H NMR (500 MHz, CD₃OD): δ = 7.19 (dd, J = 15.3, 10.9 Hz, 1 H), 6.44 (dd, J = 15.2, 10.3 Hz, 1 H), 6.21 (dd, J = 15.1, 10.9 Hz, 1 H), 6.03 (ddd, J = 15.1, 8.3, 6.8 Hz, 1 H), 6.07 (t, J = 10.3 Hz, 1 H), 5.77 (d, J = 15.3 Hz, 1 H), 5.73 (m, 1 H), 5.58 (dd, J = 15.2, 6.9 Hz, 1 H), 5.55 (m, 1 H), 5.50 (dt, J = 10.3, 7.2 Hz, 1 H), 4.95 (m, 1 H), 4.35 (br, 1 H), 4.28 (m, 1 H), 3.81 (ddd, J = 11.4, 4.9, 3.0 Hz, 1 H), 3.69 (t, J = 3.0 Hz, 1 H), 3.50 (m, 1 H), 2.57 (m, 1 H), 2.51 (m, 1 H), 2.39 (m, 1 H), 2.17 (m, 1 H), 2.06 (m, 2 H), 1.72 (m, 2 H), 1.62 (m, 2 H), 1.42 (m, 2 H), 1.24 (d, J = 6.3 Hz, 3 H) ppm. ¹³C{¹H} (150 MHz, CD₃OD): δ = 168.9, 146.7, 141.5, 137.3, 136.0, 132.7, 131.2, 128.3, 127.5, 127.4, 121.3, 81.0, 73.5, 72.6, 72.3, 72.0, 67.4, 41.7, 37.3, 35.8, 35.7, 33.8, 26.7, 21.2 ppm. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₄H₃₄O₆Na: 441.2253; found: 441.2248.