Enantioselective Total Synthesis of (–)‐Subglutinols A and B: Potential Immunosuppressive Agents Isolated from a Microorganism

Abstract

Potential immunosuppressive diterpenoid pyrones (–)‐subglutinols A and B were efficiently synthesized in an enantioselective manner starting from a known trans‐decalone derivative. The synthetic method involved the following key steps: (i) [2,3]‐Wittig rearrangement of a stannyl methyl ether to access the requisite decalin segment; (ii) coupling of the decalin segment with a γ‐pyrone moiety to set up the desired carbon framework; (iii) construction of a characteristic tetrahydrofuran ring in one‐pot fashion through an internal SN2‐type cyclization, and (iv) conversion of a γ‐pyrone moiety into an α‐pyrone ring to yield the target (–)‐subglutinols A and B.

Synthesis and Biological Evaluation of Subglutinol Analogs for Immunomodulatory Agents

“…Flash column chromatography was performed using silica gel (particle size 230−400 mesh, 60 Å). All 1 H NMR and 13 C NMR spectra were recorded with a Varian 400 (400 MHz) and a Bruker 500 (500 MHz) spectrometer in CDCl 3 using the signal of residual CHCl 3 as an internal standard. All NMR δ values are given in ppm, and all J values are in hertz (Hz).…”

“…The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes/EtOAc, 2/1) to afford 11 as a white solid (14 mg, 90%): 1 H NMR (400 MHz, MeOD-d 4 ) δ 5.60−5.89 (m, 1H), 5.20−5.05 (m, 2H), 4.48 (t, J = 2.3 Hz, 1H), 4.20 (t, J = 2.0 Hz, 1H), 3.54−3.46 (m, 1H), 2.72 (dd, J = 13.0, 11.8 Hz, 1H), 2.54 (dd, J = 13.1, 4.4 Hz, 1H), 2.43 (td, J = 13.3, 5.3 Hz, 1H), 2.33 (dd, J = 14.2, 7.4 Hz, 1H), 2.20 (s, 3H), 2.12 (dd, J = 11.7, 4.5 Hz, 1H), 2.09−2.00 (m, 2H), 1.93 (s, 3H), 1.83−1.61 (m, 4H), 1.42− 1.21 (m, 3H), 0.96 (s, 3H), 0.81 (s, 3H); 13 4-Hydroxy-5,6-dimethyl-3-(((1R,4aR,8aS)-8a-methyl-2-methylenedecahydronaphthalen-1-yl)methyl)-2H-pyran-2-one (Analog 19). To a solution of 18 (5 mg, 0.02 mmol) in THF/MeOH (2/1, 1.5 mL) was added 2 N NaOH (0.5 mL) at 25 °C.…”

“…The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes/EtOAc, 3/1) to afford 19 as a white solid (4 mg, 84%): 1 H NMR (400 MHz, CDCl 3 ) δ 5.73 (s, 1H), 4.69 (s, 1H), 4.49 (s, 1H), 2.81 (dd, J = 14.7, 3.7 Hz, 1H), 2.52 (dd, J = 14.5, 10.2 Hz, 1H), 2.40 (td, J = 13.6, 5.5 Hz, 1H), 2.20 (s, 3H), 2.16 (d, J = 4.6 Hz, 1H), 1.98 (dd, J = 10.5, 3.8 Hz, 1H), 1.91 (s, 3H), 1.76−1.69 (m, 2H), 1.63−1.54 (m, 2H), 1.49 (dt, J = 13.1, 3.7 Hz, 1H), 1.45−1.34 (m, 2H), 1.34−1.10 (m, 4H), 0.84 (s, 3H); 13…”

“…The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes/EtOAc, 2/1) to afford 27 as a colorless oil (4 mg, 13% for two steps): 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J = 9.1 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.37 (dd, J = 8.2, 7.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.64 (s, 1H), 5.66 (q, J = 9.0 Hz, 1H), 5.50 (dt, J = 8.5, 1.5 Hz, 1H), 4.21 (s, 3H), 3.62 (dd, J = 15.4, 9.3 Hz, 1H), 3.16 (dd, J = 15.3, 8.3 Hz, 1H), 2.19 (s, 3H), 1.83 (d, J = 1.4 Hz, 3H), 1.80 (d, J = 1.4 Hz, 3H), 1.77 (s, 3H); 13 33 (6 mg, 0.02 mmol) in THF/MeOH (2/1, 1.5 mL) was added 2 N NaOH (0.5 mL) at 25 °C. The resulting mixture was refluxed for 24 h, cooled to 25 °C, neutralized with saturated aqueous NH 4 Cl, and diluted with EtOAc.…”

Divergent Synthesis of Pyrone Diterpenes via Radical Cross Coupling

“…Prior approaches to this family ( Figure 1 A) have demonstrated the feasibility of accessing selected α-pyrone diterpenes in 21–27 steps via 5-methyl Wieland–Miescher ketone (prepared in 2 steps). 4 The main drawback of such approaches stems from a reliance on polar 2-electron disconnections that complicate stereoselective C–C bond formation and necessitate excessive functional group manipulations, protecting group interchanges, and unnecessary redox fluctuations. 5 Such a design makes it challenging to utilize one divergent route to access multiple family members.…”