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

Publikationsverlauf

Eingereicht: 01. September 2022

Angenommen nach Revision: 07. Oktober 2022

Accepted Manuscript online:
07. Oktober 2022

Artikel online veröffentlicht:
15. November 2022

• References and Notes

• 1 Edmond MB, Ober JF, Weinbaum DL, Pfaller MA, Hwang T, Sanford MD, Wenzel RP. Clin. Infect. Dis. 1995; 20: 1126
• 2 Katz ML, Mueller LV, Polyakov M, Weinstock SF. Nat. Biotechnol. 2006; 24: 1529
• 3 Kong DX, Jiang YY, Zhang HY. Drug Discov. Today 2010; 15: 884
• 4 Molinski TF, Dalisay DS, Lievens SL, Saludes JP. Nat. Rev. Drug Discov. 2009; 8: 69
• 5 Bhatnagar I, Kim SK. Mar. Drugs 2010; 8: 2673
• 6a Liu Y. J. Mar. Sci.: Res. Dev. 2012; 2: e106
• 6b Newman DJ, Cragg GM. J. Nat. Prod. 2020; 83: 770
• 7 Gustafson K, Roman M, Fenical W. J. Am. Chem. Soc. 1989; 111: 7519
• 8 Mondol MA. M, Shin HJ, Islam MT. Mar. Drugs 2013; 11: 2846 ; and references therein
• 9 Mondol MA. M. Tareq F. S, Kin JH, Lee M, Lee H.-S, Lee Y.-J, Lee JS, Shin HJ. J. Nat. Prod. 2011; 74: 2582
• 10a Krishna PR, Rajesh N, Ramakrishna KV. S. Tetrahedron Lett. 2014; 55: 3381
• 10b Thodupunuri P, Hanumaiah M, Bommagani S, Sharma GV. M. J. Carbohydr. Chem. 2017; 36: 100
• 10c Reddy AM, Sabitha G. SynOpen 2017; 1: 166
• 11a Mallampudi NA, Srinivas B, Reddy JG, Mohapatra DK. Org. Lett. 2019; 21: 5952
• 11b Srinivas B, Reddy DS, Mallampudi NA, Mohapatra DK. Org. Lett. 2018; 20: 6910
• 11c Pradhan TR, Mohapatra DK. Org. Biomol. Chem. 2018; 16: 8810
• 11d Reddy GS, Padhi B, Bharath Y, Mohapatra DK. Org. Lett. 2017; 19: 6506
• 11e Mohapatra DK, Bhimireddy E, Krishnarao PS, Das PP, Yadav JS. Org. Lett. 2011; 13: 744
• 12 Mohapatra DK, Das PP, Pattanayak MR, Yadav JS. Chem. Eur. J. 2010; 16: 2072
• 13a Tokunaga M, Larrow JF, Kakiuchi F, Jacobsen EN. Science 1997; 227: 936
• 13b Schaue SE, Brandes BD, Larrow JF, Tokunaga M, Hansen KB, Gould AE, Furrow ME, Jacobsen EN. J. Am. Chem. Soc. 2002; 124: 1307
• 13c Nielson LP. C, Stevenson CP, Blackmond DG, Jacobsen EN. J. Am. Chem. Soc. 2004; 126: 1360
• 14 Yu W, Mei Y, Hua Z, Jin Z. Org. Lett. 2004; 6: 3217
• 15a Corey EJ, Gras JL, Ulrich P. Tetrahedron Lett. 1976; 17: 809
• 15b Bhatt MV, Kulkarni SU. Synthesis 1983; 249
• 15c Reddy DS, Gaddam J, Devunuri N, Mohapatra DK. Tetrahedron Lett. 2015; 56: 4299
• 15d Seetharamsingh B, Ganesh R, Reddy DS. J. Nat. Prod. 2017; 80: 560
• 16a Yu XM, Han H, Blagg BS. J. J. Org. Chem. 2005; 70: 5599
• 16b Lim W, Kim J, Rhee YH. J. Am. Chem. Soc. 2014; 136: 13618
• 16c Crimmins MT, Zuccarello JL, Pamela AC, Parrish JD. Org. Lett. 2006; 8: 159
• 17a Kolb HC, VanNieuwenhze MS, Sharpless KB. Chem. Rev. 1994; 94: 2483
• 17b Noe MC, Letavic MA, Snow SL, McCombie SW. Org. React. 2005; 66: 109
• 18a Sinha SC, Sinha A, Yazbak A, Keinan E. J. Org. Chem. 1996; 61: 7640
• 18b Boyer FD, Hanna I, Nolan SP. J. Org. Chem. 2001; 66: 4094
• 19 Typical Experimental Details for the Synthesis of (3aR,4S,6S,7aR)-6-[2-(4-Methoxy benzyloxy)ethyl]-2,2-dimethyl-4-vinyltetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran (9) To a stirred solution of iodo compound 20 (520 mg, 1.09 mmol) in THF (5 mL) was added potassium tert-butoxide (122 mg, 1.09 mmol) at 0 °C. The reaction mixture was allowed to stir for 30 min at room temperature. After complete conversion of the starting material (monitored by TLC), it was quenched with water (5 mL) 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 dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/hexane = 1:9) to afford olefin compound 9 (327 mg, 86%) as a colorless liquid. [α]_D ²⁵ –15.2 (c 0.6, CHCl₃). IR (CHCl₃): ν_max = 3012, 2841, 1832, 1642, 1524, 1507, 1348, 1245, 1179, 1035, 854, 716 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.25 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 5.88 (ddd, J = 17.4, 10.7, 5.1 Hz, 1 H), 5.34 (dt, J = 17.4, 1.6 Hz, 2 H), 4.43 (q, J = 14.8, 3.3 Hz, 2 H), 4.32–4.25 (m, 2 H), 3.97 (t, J = 5.9 Hz, 1 H), 3.88 (m, 1 H), 3.80 (s, 3 H), 3.62–3.51 (m, 2 H), 2.02–1.91 (m, 2 H), 1.77 (m, 1 H), 1.69 (m, 1 H), 1.51 (s, 3 H), 1.35 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 159.1, 136.0, 130.5, 129.2, 117.0, 113.7, 108.5, 75.1, 72.6, 72.2, 71.4, 66.6, 66.3, 55.2, 35.2, 33.2, 27.9, 25.7 ppm. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₀H₂₈O₅Na: 371.1834; found: 371.1837
• 20 Alcaraz L, Mioskowski C, Le Gall T, Shin D.-S, Falck JR. Tetrahedron Lett. 1994; 35: 5449
• 21 Horita K, Yoshioka T, Tanaka YO, Yonemitsu O. Tetrahedron 1986; 42: 3021
• 22a Dess DB, Martin JC. J. Org. Chem. 1983; 48: 4155
• 22b Dess DB, Martin JC. J. Am. Chem. Soc. 1991; 113: 7277
• 23a Still WC, Gennari C. Tetrahedron Lett. 1983; 24: 4405
• 23b Janickia I, Kiełbasiński P. Adv. Synth. Catal. 2020; 362: 2552
• 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.
• 25a Garber SB, Kingsbury JS, Gray BL, Hoveyda AH. J. Am. Chem. Soc. 2000; 122: 8168
• 25b Chatterjee AK, Sanders DP, Grubbs RH. Org. Lett. 2002; 4: 1939
• 25c Chatterjee AK, Choi TL, Sanders DP, Grubbs RH. J. Am. Chem. Soc. 2003; 125: 11360
• 26a Nagasawa T, Kuwahara S. Org. Lett. 2013; 15: 3002
• 26b Stork G, Zhao K. Tetrahedron Lett. 1989; 30: 2173
• 27a Shiina I, Kubota M, Oshiumi H, Hashizume M. J. Org. Chem. 2004; 69: 1822
• 27b Schmidt B, Kunz O, Petersen MH. J. Org. Chem. 2012; 77: 10897
• 28a Li P, Li J, Arikan F, Ahlbrecht W, Dieckmann M, Menche D. J. Am. Chem. Soc. 2009; 131: 11678
• 28b Menche D, Hassfeld J, Li J, Rudolph S. J. Am. Chem. Soc. 2007; 129: 6100
• 28c Menche D, Hassfeld J, Li J, Mayer K, Rudolph S. J. Org. Chem. 2009; 74: 7220
• 28d Li P, Li J, Arikan F, Ahlbrecht W, Dieckmann M, Menche D. J. Org. Chem. 2010; 75: 2429
• 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.