Abstract
An efficient, short and, a convenient asymmetric total synthesis of filamentous fungi related resorcylic acid lactones 7-epi-zeaenol (2) and zeaenol (1) have been achieved in 7 and 9 linear steps with the high overall yield of 32% and 21% respectively, from the known intermediate 13. Mitsunobu inversion, De Brabander’s protocol for macrolactonisation, Heck cross-coupling, diastereoselective alkyne aldehyde coupling and Ohira–Bestmann alkynylation are the key reactions.
Introduction
Filamentous fungi possess an enormously rich source of biologically active natural products and have immense applications in various fields. Modern synthetic chemistry has enabled the identification, isolation, and manufacturing many of the promising biologically active filamentous fungi related natural products [1, 2, 3]. Included in this natural product family, highly oxygenated natural products zeaenol and 7-epi-zeaenol (Figure 1) are isolated by Oberlies and co-workers [4,5] from a filamentous fungus, MSX 63935, collected from the leaf litter in Nigeria, along with other natural products. These resorcylic acid lactones (RALs) exhibit potent antibacterial activity as well as mitochondrial transmembrane potential activity. Of them, zeaenol (1) and 7-epi-zeaeneol (2) showed cytotoxic activity against human tumor cell lines [6,7] with nearly same IC50 values (IC50 values >50 μM) and inhibition activity towards NF-κB. The first total synthesis of zeaenol along with its analog cochliomycin A was reported by Nanda et al [8] using late stage ring closing metathesis (RCM) strategy. Later, several synthetic procedures [9, 10, 11, 12, 13] for the total synthesis of zeaenol and 7-epi-zeaenol have been developed using diverse methods. In continuation of our efforts on the total synthesis of biologically active lactonic natural products [14, 15, 16, 17, 18, 19, 20, 21], herein we described a first asymmetric total synthesis of zeaenol and 7-epi-zeaenol.
Structures of filamentous fungi derived resorcylic acid lactones (1-6).
Result and discussion
The retrosynthetic analysis of zeaenol and 7-epi-zeaenol is depicted in Scheme 1. The target molecules 1 and 2 could be derived from the common fragment 7 following De Brabander’s lactonization, which could be obtained by the aromatic fragment 8 and aliphatic fragment 9, using Heck cross coupling. The advanced fragment 9 could be traced back from the two individual fragments, aldehyde 10 and alkyne 11. The aldehyde 10 was commenced with D-mannitol.
Retrosynthetic analysis of zeaenol and 7-epi-zeaenol
With the retrosynthetic blueprint in mind, our initial focus was on the synthesis of the alkyne fragment 11 from known aldehyde 12. The known aldehyde 12 [22] was subjected to Ohira–Bestmann‘s protocol [23] with dimethyl(diazo-2-oxopropyl) phosphonate to give the propargyl alcohol 11 in 75% yield.
Reagents and conditions. (a) K2CO3, MeOH, RT, 8 h, 75%.
As planned, with the requisite alkyne fragment 11 and known aromatic fragment 8 [30], the synthesis of natural product 7-epi-zeaenol (2) was accomplished from a known intermediate 13, prepared from commercially available D-mannitol following a known protocol [24]. The dihydroxy functionality in 13 was protected as its benzyl, using benzyl bromide and NaH to afford compound 14 in 81% yield. The TBS group of 14 was deprotected smoothly using camphorsulfonic acid (CSA) in MeOH yielding a primary alcohol, which upon further treatment with Dess–Martin periodinane reagent furnished aldehyde 10 in 83% yield in two steps. Furthermore, the aldehyde 10 was coupled with alkyne 11 in an asymmetric manner following the known protocol [25, 26, 27, 28] using Et2Zn, Ti(OiPr)4 and (R)-BINOL to obtain chromatographically inseparable propargyl alcohol mixture 15. The resulting propargyl alcohol was then reduced with LiAlH4 to trans allyl alcohol 16 (83% yield in two steps), which was then separable by column chromatography (dr:92:08 by HPLC). The secondary allyl alcohol obtained in the LiAlH4 reduction was protected as its MOM-ether using MOM-Cl and DIPEA. The resulting MOM ether was subjected to Heck cross coupling [29] with the known aromatic fragment 8 [30] using Pd(OAc)2 catalyst and K2CO3 in DMF which resulted in the trans olefin 17 as a sole product with 88% yield in two steps. Now, the TBS deprotection of 17 was achieved smoothly with CSA in 89% yield. The macrolactonization of 7 was achieved under De Brabander’s conditions [31] with NaH in 85% yield. Finally, the benzyl and MOM groups were deprotected in one-pot, by treatment of macrolactone 18 using excess TiCl4 to afford the natural product, 7-epi-zeaenol, in 88% yield.
Synthesis of another natural product, zeaenol, commenced with compound 18, beaing treated with TMSCl in methanol to obtain allyl alcohol 19 in 86% yield. The resulting chiral alcohol 19 was then inverted under Mitsunobu conditions [32,33] to afford alcohol 20 in 81% yield.
Reagents and conditions. (a) BnBr, NaH, TBAI, THF 0 °C-rt 8 h, 81%; (b) CSA, MeOH 0 °C -rt, 12h; (c) DMP,CH2Cl2, rt, 3 h, 83% over two steps; (d) 11, Et2Zn, Ti(OiPr)4, (R)-BINOL, THF, rt, 12 h; (e) ) LiAlH4, THF 0 °C rt 12 h, 83% over two steps; (f) MOMCl, DIPEA, DMF, 0 °C-rt 12 h; (g) 8, Pd(OAc)2, Bu4NBr, K2CO3, PPh3, DMF, 80 °C, 5h, 88% over two steps (h) CSA, MeOH, rt, 1 h, 89% ; (i) NaH, THF, rt, 4 h, 85%; (j) TiCl4, DCM, 0 °C-rt, 2 h, 88%.
Reagents and conditions :(a) TMSCl, MeOH, 12 h, 86%; (b) (i) 4-nitrobenzoic acid, Ph3P, DEAD, rt 12 h; (ii) K2CO3, MeOH, 50 °C, 10 h, 81%. over two steps; (c) TiCl4, CH2Cl2, 2 h,0 °C, 83%.
Similarly, upon treatment of alcohol 19 using excess TiCl4, the natural product zeaenol (1) was obtained in 83% yield.
The spectroscopic (1H and 13C NMR) and analytical data were in good agreement with the values reported values reported for the natural products [4,5].
Conclusion
In summary, we have reported a short and an efficient asymmetric total synthesis of filamentous fungi related resorcylic acid lactones 7-epi-zeaenol (2) and zeaenol (1) in 7 and 9 linear steps from an inexpensive known intermediate. The key steps involved in this synthesis are the Mitsunobu inversion, De Brabander’s protocol for macrolactonisation, Heck cross-coupling, asymmetric alkyne aldehyde coupling, and Ohira–Bestmann alkynylation. The current methodology provides a new synthetic route with high yield and can be used further for the synthesis of various natural products of RAL‘s family.
Experimental Section
General remarks and methods: All reactions were performed under inert atmosphere. All glassware apparatus used for reactions were perfectly oven/flame dried. Anhydrous solvents were distilled prior to use: THF from Na and benzophenone; CH2Cl2, DMF from CaH2; MeOH from Mg cake. Other commercial reagents were used without purification. Column chromatography was carried out by using silica gel (60–120 mesh) unless otherwise mentioned. Analytical thin layer chromatography (TLC) was performed on silica gel 60 F254 pre-coated plates (250 μm thickness). Optical rotation values were recorded on Horiba sepa 300 polarimeter given in 10-1 degcm2g−1. HRMS spectra were obtained using a TOF spectrometer. 1H NMR and 13C NMR spectra were recorded using Bruker AVANCE 300 MHz, Varian INOVA 400 MHz, and Bruker AVANCE 500 MHz spectrometers in CDCl3 solution unless otherwise mentioned. The chemical shifts values are in ppm downfield from tetramethylsilane (TMS) and coupling constants (J) were reported in hertz (Hz). The following abbreviations are used to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad.
(S)-tert-Butyldimethyl(pent-4-yn-2-yloxy)silane (11): To a stirred solution of aldehyde 13 (1.0 g, 5.3 mmol) and K2CO3 (2.2 g, 15.9 mmol) in methanol (30 mL), added a solution of dimethyl(diazo-2-oxopropyl) phosphonate (606 mg, 3.15 mmol) in methanol (15 mL) at room temperature and stirred for 8 hr at room temperature. Then the reaction mixture was filtered through celite and extracted with ethyl acetate (3 x 30 mL). The combined organics were washed with brine and dried over anhydrous Na2SO4. The solvent was removed under vacuum and the crude mass was purified by silica gel column chromatography (ethyl acetate/hexane = 1:20) to afford 11 (0.78 g, 75%) as a colorless liquid. [α]D 25 +0.67 (c 2.5, CHCl3).1H NMR (300 MHz, CDCl3)δ 3.96 (m, 1H), 2.36 (ddd, J = 16.6, 5.6, 2.7 Hz, 1H), 2.24 (ddd, J = 16.6, 7.1, 2.7 Hz, 1H), 1.98 (t, J = 2.7 Hz, 1H), 1.23 (d, J = 6.1 Hz, 3H), 0.89 (s, 9H), 0.08,(s, 3H) 0.07 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ 81.9, 69.7, 67.5, 29.4, 25.8, 23.2, 18.1, –4.7, –4.8 ppm; HRMS (ESI): calcd for for C11H22ONaSi [M + Na]+ 221.1333, found: 221.1337.
(((2R,3S)-2,3-Bis(benzyloxy)hex-5-en-1-yl)oxy) (tert-butyl)dimethylsilane (14): To a suspension of NaH (60% in mineral oil, 3.9 g,97.8 mmol) in dry THF (60 mL), added a solution of alcohol 13 (7.5 g, 32.6 mmol) in THF (50 mL) at 0 °C. After 30 min, benzyl bromide (10.0 mL, 81.5 mmol) was added slowly at 0 °C. The resulting mixture was further stirred at room temperature for 8 h and quenched with water at 0 °C and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4 and solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/hexane = 1:20) to give 14 (11.2 g, 81%) as a colorless liquid. [α]D25 –4.3 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.42 – 7.15 (m, 10H), 5.83 (ddt, J = 17.1, 10.0, 7.0 Hz, 1H), 5.16 – 4.95 (m, 2H), 4.73 – 4.55 (m, 2H), 4.53 (s, 2H), 3.75 (qd, J = 10.8, 4.8 Hz, 2H), 3.61 (q, J = 5.5 Hz, 1H), 3.53 (q, J = 4.9 Hz, 1H), 2.38 (t, J = 6.3 Hz, 2H), 0.85 (s, 10H), 0.17 – 0.19 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 138.9, 138.8, 135.5, 128.4, 128.1, 128.0, 127.9, 127.6, 127.6, 117.1, 80.9, 78.6, 72.9, 72.4, 62.9, 35.1, 26.1, 18.4, -5.2, -5.3; HRMS (ESI): calcd. for C26H39O3SiN [M + H]+427.2663 found: 427.2667.
(4S,5R,6R,10S,E)-4,5-Bis(benzyloxy)-10-((tert-butyldimethylsilyl)oxy)undeca-1,7-dien-6-ol (16): Et2Zn (17.6 mL, 17.6 mmol, 1.0 M solution) was added to a solution of alkyne 11 (3.5 g, 17.6 mmol) in toluene (20 mL) then the mixture was stirred under reflux. After 1 h the mixture was cooled to room temperature, thereafter (R)-BINOL (0.44 g, 1.6 mmol), THF (40 mL), and Ti(OiPr)4 (2.6 mL, 8.8 mmol) were added to the solution. After 1 h, aldehyde 10 (2.5 g, 8.0 mmol) was added under an argon atmosphere, and the mixture was stirred for overnight at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with 1.0 M tartaric acid (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed under vacuum, which after purification by flash chromatography on silica gel (5% EtOAc/ hexanes to 20% EtOAc/ hexanes gradient), afforded mixture of propargylic alcohols 15 used in the next step without further characterization. LiAlH4 (1.46 g, 12.0 mmol) was added to a stirred solution of above propargylic alcohol (8.0 mmol) in THF (30 mL) at 0 °C. The resulting solution was then stirred at RT for 12 hr. After completion of the reaction (indicated by TLC), it was cooled to 0 °C and quenched with saturated solution of Na2SO4 (50 mL). The solids were filtered through Celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (5-10% ethyl acetate/ hexane) furnished the desired alcohol 16 (3.4 g, 83%) as a color less liquid; [α]D25 11.3 (c 1.6, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.44 – 7.31 (m, 10H), 6.01 – 5.68 (m, 2H), 5.59 (ddt, J = 15.5, 6.2, 1.3 Hz, 1H), 5.31 – 5.05 (m, 3H), 4.75 (d, J = 11.3 Hz, 1H), 4.70 – 4.62 (m, 2H), 4.57 (d, J = 11.3 Hz, 1H), 4.32 (q, J = 5.6 Hz, 1H), 3.92 – 3.77 (m, 1H), 3.77 – 3.69 (m, 1H), 3.54 (dd, J = 5.8, 4.2 Hz, 1H), 3.00 (d, J = 6.3 Hz, 1H), 2.51 (tdd, J = 7.2, 2.9, 1.4 Hz, 2H), 2.36 – 2.08 (m, 2H), 1.14 (d, J = 6.1 Hz, 3H), 0.92 (d, J = 2.4 Hz, 9H), 0.08 (d, J = 1.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 138.4, 138.0, 134.7, 131.2, 130.1, 128.5, 128.3, 128.2, 128.0, 127.8, 127.7 127.6, 127.5, 126.0, 117.4, 82.1, 79.6, 73.8, 73.7, 71.2, 68.5, 42.8, 34.8, 25.9, 23.4, 18.1, -4.5, -4.6; HRMS (ESI): calcd. for C31H47O4Si [M + H]+ 511.3239 found: 511.3246.
5‐[(1E,4S,5S,6R,7E,10S)‐4,5-bis(benzyloxy)-10-((tert-butyldimethylsilyl)oxy)-6-(methoxymethoxy) undeca-1,7-dien-1-yl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (17): To a stirred solution of compound 16 (0.5 g, 0,95 mmol)) in DMF (10 mL) was added diisopropyl ethylamine (0.31 mL, 1.9 mmol) followed by methoxymethyl chloride (0.11 mL, 1.4 mmol) at 0 oC. The resultant mixture was stirred at room temperature for additional 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with water (2 x 50 mL) and dried over anhydrous Na2SO4 then removed under reduced pressure. The crude mass was purified by silica gel column chromatography (ethyl acetate/hexane = 1:19) to afford the MOM ether which was immediately used for the next reaction without further characterization.
To a stirred solution of aryl triflate 8 (0.507 g, 1.4 mmol), and the above MOM protected compound (0.95 mmol) in DMF (8 mL), Pd(OAc)2 (21 mg, 0.095 mmol), Bu4NBr (120 mg, 0.95 mmol), K2CO3 (262 mg, 1.9 mmol) and PPh3 (12 mg, 0.047 mmol) were added then the mixture was degassed three times with argon under vacuum and the resultant solution was stirred at 80 oC for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through Celite and washed with water (10 mL), then extracted with ethyl acetate (3 x 20 mL). The combined organics were washed with water and dried over Na2SO4. The solvent was removed, and the crude mass was purified by silica gel column chromatography (ethyl acetate/hexane = 1:20) to afford compound 17 (0.66 g, 88%) as a colorless oil. [α]D25 −27.1 (c 1.6, CHCl3);1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 15.7 Hz, 1H), 7.42 – 7.20 (m, 10H), 6.72 (d, J = 2.5 Hz, 1H), 6.35 (d, J = 2.5 Hz, 1H), 6.34 – 6.25 (m, 1H), 5.69 (ddd, J = 15.5, 7.7, 6.1 Hz, 1H), 5.53 (dd, J = 15.9, 8.2 Hz, 1H), 4.87 (d, J = 11.3 Hz, 1H), 4.78 – 4.72 (m, 2H), 4.64 (d, J = 11.4 Hz, 1H), 4.59 – 4.49 (m, 2H), 4.35 (dd, J = 8.2, 3.8 Hz, 1H),3.83 (s, 3H), 3.79 – 3.68 (m, 2H), 3.37 (s, 3H), 2.75 (t, J = 6.9 Hz, 2H), 2.22 (tq, J = 14.0, 7.2 Hz, 2H), 1.72 (s, 6H), 1.28 (s, 6H), 1.12 (d, J = 6.1 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 164.7, 160.2, 158.7, 144.1, 138.8, 138.4, 133.0, 131.6, 130.2, 129.7, 128.5, 128.3, 128.2, 128.1, 128.0, 127.7, 127.5, 127.5, 108.3, 104.9, 103.5, 100.1, 93.4, 81.6, 78.6, 77.5, 74.0, 71.6, 68.3, 55.6, 55.6, 42.9, 33.5, 29.7, 25.9, 25.7, 25.6, 23.3, 18.1, -4.5, -4.7; HRMS (ESI): calcd. for C44H61O9NSi [M + H]+ 761.4080, found: 761.4083.
5‐[(1E,4S,5S,6R,7E,10S)‐4,5-Bis(benzyloxy)-10-hydroxy-6-(methoxymethoxy)undeca-1,7-dien-1-yl)-7-methoxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (7): CSA (30.5 mg, 0.13 mmol) was added to a stirred solution of 17 (0.45 g, 0.1.3 mmol)) in 10 mL methanol and stirred for 1 hr at room temperature. After completion of the reaction (monitored by TLC), the solvent was removed, and the residue was dissolved in a saturated solution of NaHCO3 (20 mL) and then extracted with ethyl acetate (3 x 25 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated the crude mass by silica gel column chromatography (ethyl acetate/hexane = 2:3) and obtained 7 (340 mg, 89%) as a colorless viscous liquid. [α] D25 −17.6 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 15.8 Hz, 1H), 7.41 – 7.22 (m, 10H), 6.70 (d, J = 2.7 Hz, 1H), 6.33 (d, J = 2.5 Hz, 1H), 6.25 (dt, J = 15.1, 7.1 Hz, 1H), 5.62 (dd, J = 6.1, 3.7 Hz, 2H), 4.84 (d, J = 11.4 Hz, 1H), 4.77 – 4.70 (m, 2H), 4.63 (d, J = 11.6 Hz, 1H), 4.58 (q, J = 5.9, 5.5 Hz, 1H), 4.55 – 4.48 (m, 1H), 3.82 (s, 3H), 3.76 (m, 1H), 3.68 (d, J = 5.3 Hz, 2H), 3.36 (s, 3H), 2.72 (q, J = 7.5 Hz, 2H), 2.31 – 2.09 (m, 2H), 1.70 (s, 6H), 1.17 (d, J = 6.4 Hz, 3H).; 13C NMR (75 MHz, CDCl3) δ 164.7, 160.0, 158.7, 144.0, 138.6, 138.3, 131.9, 131.4, 130.3, 130.3, 128.3, 128.3, 128.2, 128.1, 128.0, 127.7, 127.6, 127.5, 108.3, 104.9, 100.4, 100.1, 93.9, 81.4, 78.5, 78.3, 73.9, 71.6, 67.0, 55.6, 42.1, 33.5, 25.7, 25.6, 22.8; HRMS (ESI): calcd. for C38H47O9 [M + H]+647.3215, found: 647.3211.
(3S,5E,7R,8S,9S,11E)-8,9-Bis(benzyloxy)-16-hydroxy-14-methoxy-7-(methoxymethoxy)-3-methyl-3,4,7,8,9,10-hexahydro-1H-benzo[c][1] oxacyclotetradecin-1-one (18): To a suspension of NaH (0.15 g, 3.7 mmol) washed with hexane twice to remove mineral oil and dried in dry THF (10 mL) was added a solution of alcohol 7 (0.3 g, 0.46 mmol) in THF (5 mL) at 0 oC under argon and the suspension was stirred for 5 h at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice pieces at 0 oC and extracted with ethyl acetate (3 x 10 mL). The combined organic layer was dried over anhydrous Na2SO4 and solvent was removed under reduced pressure and purified by silica gel column chromatography (ethyl acetate/hexane = 1:9) to afford 18 (0.27 mg, 85%) as a colorless liquid. [α]D25 −55.8 (c 1.2, CHCl3) 1H NMR (500 MHz, CDCl3) δ 7.31 – 7.17 (m, 10H), 7.09 (d, J = 15.4 Hz, 1H), 6.38 (d, J = 2.5 Hz, 1H), 6.35 (d, J = 2.5 Hz, 1H), 5.89 (s, 1H), 5.79 (dd, J = 15.6, 9.3 Hz, 1H), 5.61 (ddd, J = 15.6, 8.1, 3.5 Hz, 1H), 5.16 – 5.07 (m, 1H), 4.76 (d, J = 33.0 Hz, 2H), 4.62 (t, J = 10.3 Hz, 1H), 4.47 (dd, J = 22.5, 8.9 Hz, 3H), 4.01 (m, 1H), 3.92 (m, 3H), 3.81 (s, 3H), 3.32 (s, 3H), 2.70 (dt, J = 18.5, 9.3 Hz, 1H), 2.65 – 2.53 (m, 3H), 2.44 – 2.27 (m, 1H), 1.42 (d, J = 6.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 171.7, 165.0, 164.0, 143.6, 139.0, 133.3, 132.3, 128.4, 128.2, 127.8, 127.6, 127.6, 127.3, 107.4, 99.8, 92.8, 83.6, 81.3, 78.5, 73.4, 73.2, 71.9, 55.4, 55.3, 38.7, 35.0, 29.7, 20.5; HRMS (ESI): calcd. for C35H41O8 [M + H] +589.2878, found: 589.2881.
7-epi-zeaenol (2): TiCl4 (1.1 mL, 1.1 mmol, 1 M in CH2Cl2) was added to a stirred solution of 18 (35 mg, 0.06 mmol) in CH2Cl2 (5 mL) at 0 °C, and the mixture was stirred for 1 hr for 30 min at 0 oC. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with a saturated solution of NaHCO3 (10 mL), extracted with CH2Cl2 (3 x 25 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford a yellowish liquid, which was purified by silica gel column chromatography (acetone/hexane 1:1) to obtain compound 2 (17.3 mg, 88%) as a white powder. [α]D25 −91 (c 1.5, MeOH); 1H NMR (500 MHz, DMSO-d6) δ 10.57 (s, 1H), 6.62 (d, J = 15.5 Hz, 1H), 6.43 (d, J = 2.28 Hz, 1H), 6.30 (d, J = 2.27 Hz, 1H), 6.1 (m, 1H), 5.66-5.53 (m, 2H), 5.19 (m, 1H), 4.82 (s, 1H), 4.80 (s, 1H), 4.50 (d, J = 4.1 Hz, 1H), 4.05 (m, 1H), 3.75 (s, 3H), 3.60 (m, 1H), 3.35 (m, 1H), 2.48-2.32 (m, 3H), 2.17 (m, 1H), 1.33 (d, J = 5.9 Hz, 3H) ppm; 13C NMR (126 MHz, DMSO) δ 169.0, 161.7, 159.0, 139.6, 133.1, 132.5, 128.6, 127.0, 110.3, 102.7, 99.9, 77.5, 74.7, 72.9, 71.8, 55.2, 38.6, 36.8, 29.6, 20.4. HRMS (ESI): calcd. for C19H24O7Na [M + Na]+387.1415, found: 387.1419.
(3S,5E,7R,8R,9S,11E)-8,9-Bis(benzyloxy)-7,16-dihydroxy-14-methoxy-3-methyl-3,4,7,8,9,10-hexahydro-1H-benzo[c][1]oxacyclotetradecin-1-one (19): TMSCl (0.056 mL, 0.45 mmol) was added to stirred solution of 18 (0.175 mg, 0.297 mmol) in MeOH (5 mL) and allowed to stir for 2 hrs at room temperature. After completion of the reaction as indicated by TLC, the methanol was removed and the residue was dissolved in a saturated solution of NaHCO3 (10 mL) then extracted with ethyl acetate (3 x 15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure and then purified by silica gel column chromatography (ethyl acetate/hexane = 1:3) to give 19 (134 mg, 86%) as a colorless liquid. [α]D25 −76.0 (c 1.1, CHCl3) 1H NMR (500 MHz, C3D6O-d6): 7.48-7.16 (m, 11H), 6.46 (s, 1H), 6.39 (s, 1H), 5.99 (m, 1H), 5.89 (m, 1H), 5.72 (m, 1H), 5.21 (m, 1H), 4.87-4.61 (m, 4H), 4.57 (m, 1H), 4.27 (m, 1H), 3.91-3.82 (m, 4H), 2.79 (m, 1H), 2.64-2.57 (m, 3H), 1.43 (d, J = 5.9 Hz, 3H) ppm; 13C NMR (126 MHz, CDCl3 ) δ 171.6, 165.1, 164.2, 143.6, 138.9, 128.1, 128.0, 127.7, 127.5, 127.2, 106.8, 104.0, 99.7, 83.3, 78.3, 73.2, 55.0, 38.2, 19.5.HRMS (ESI): calcd. for C33H37O7 [M + H]+ 545.2534, found: 545.2541.
(3S,5E,7S,8R,9S,11E)-8,9-Bis(benzyloxy)-7,16-dihydroxy-14-methoxy-3-methyl-3,4,7,8,9,10-hexahydro-1H-benzo[c][1]oxacyclotetradecin-1-one (20): A solution of alcohol 19 (0.12 g, 0.22 mmol), p-nitrobenzoic acid (73 mg,0.44 mmol), and TPP (86 mg, 0.33 mmol) in THF (15 mL) at 0 °C were treated with diisopropyl azodicarboxylate (66.6 g, 0.33 mmol) and the contents were stirred at 0 °C for 1 hr and then at RT for 12 h. After completion of the reaction, the reaction mixture was concentrated, and the resulting crude material was dissolved in ethyl acetate (60 mL), and subsequently washed with the aqueous NaHCO3 (30 mL), water (50 mL), dried over Na2SO4 and concentrated under vacuum. Purification of the residue by silica gel column chromatography (25% EtOAc in hexanes) yielded an ester which is not stable and immediately used in the next step. To a solution of above ester (0.22 mmol) in MeOH (5 mL) was added KOH (24 mg, 0.44 mmol) and the reaction mixture is stirred for 10 hours at RT. After completion of the reaction, as indicated by TLC the solvent was removed under vacuum and the crude material was diluted with water (10 mL), then extracted with ethyl acetate (3 x 20 mL) the combined organic layer was dried over Na2SO4 and concentrated under the vacuum. Purification of the residue by silica gel column chromatography gave compound 20 (96 mg, 81%) as a colorless liquid. [α]D25 −61.3 (c 0.5, CHCl3); 1H NMR (500 MHz, C3D6O-d6): δ 7.50-7.13 (m, 11H), 6.47 (s, 1H), 6.40 (s, 1H), 6.10 (m, 1H), 6.00 (m, 1H), 5.81 (m, 1H), 5.31 (m, 1H), 4.97-4.45 (m, 4H), 4.34 (m, 1H), 3.95 (m, 1H), 3.90 (s, 3H), 3.66 (m, 1H), 2.65-2.47 (m, 4H), 1.44 (d, J = 6.2 Hz, 3H) ; 13C NMR (176 MHz, CDCl3) δ 171.63, 165.3, 164.2, 143.8, 139.7, 139.2, 132.2, 132.0, 131.5, 128.2, 127.8, 127.7, 127.2, 126.7, 106.8, 103.8, 99.6, 83.0, 82.0, 73.3, 72.5, 71.0, 55.0, 37.2, 34.1, 18.8; HRMS (ESI): calcd. for C33H37O7 [M + H]+545.2534, found: 545.2531.
zeaenol (1): TiCl4 (1.1 mL, 1.1 mmol, 1M in CH2Cl2) was added to a stirred solution of 20 (30 mg, 0.05 mmol) in CH2Cl2 (5 mL) at 0 °C and the mixture was stirred for 1.45 hr at 0 oC. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with a saturated solution of NaHCO3 (10 mL), extracted with CH2Cl2 (3 x 20 mL) and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated. The crude mass was that purified by silica gel column chromatography (5% methanol in chloroform) gave zeaenol (1) (16.6 mg, 83%) as a white powder. [α]D25 ‒87 (c 0.9, MeOH); 1H NMR (500 MHz, CDCl3): δ 11.72 (m, 1H), 7.15 (d, J = 15.3 Hz, 1H), 6.47 (d, J = 2.3, 1H), 6.42 (d, J = 2.3 Hz, 1H), 6.08 – 5.95 (m, 1H), 5.90 – 5.80 (m, 1H), 5.74 (dd, J = 15.5, 7.4 Hz, 1H), 5.36 (d, J = 3.6 Hz, 1H), 4.30 (d, J = 7.3 Hz, 1H), 4.01 (t, J = 6.8 Hz, 1H), 3.62 (d, J = 7.7 Hz, 1H), 2.61 – 2.49 (m, 3H), 2.49 – 2.41 (m, 1H), 1.49 (d, J = 6.2 Hz, 3H).); 13C NMR (125 MHz, CDCl3): δ 13C NMR (126 MHz, None) δ 171.2, 165.3, 164.0, 142.9, 133.7, 131.5, 129.2, 128.5, 107.6, 103.9, 100.1, 73.1, 71.96, 71.5, 55.4, 37.8, 36.0, 29.3, 19.7; HRMS (ESI): calcd. for C19H24O7Na [M + Na]+387.1415, found: 387.1421
Acknowledgements
KSR thanks the DST-SERB (Young scientist File: CS-138/2012), New Delhi.
References
[1] Bhadury. P.; Mohammad, B. T.; Wright, P.C. The current status of natural products from marine fungi and their potential as anti-infective agents. J. ind. Microbiol. Biotechnol. 2006, 33 325.10.1007/s10295-005-0070-3Search in Google Scholar
[2] Hoffmeister, D.; Kellerb, N. P. Natural products of filamentous fungi: enzymes, genes, and their regulation. Nat. Prod. Rep., 2007,24, 393-41610.1039/B603084JSearch in Google Scholar
[3] Fabrizio.; Foster, G. D.; Bailey, A. M. Natural products from filamentous fungi and production by heterologous expression. Appl Microbiol Biotechnol. 2017, 101, 493–500.10.1007/s00253-016-8034-2Search in Google Scholar
[4] Ayers, S.; Graf, T. N.; Adcock, A. F.; Kroll, D. J.; Matthew, S.; Carcache deBlanco, E. J.; Shen, Qi.; Swanson, S. M.; Wani, M. C.; Pearce, C. J.; Oberlies. N. H. Resorcylic Acid Lactones with Cytotoxic and NF-κB Inhibitory Activities and Their Structure– Activity Relationships. J. Nat. Prod. 2011, 74, 1126–1131.10.1021/np200062xSearch in Google Scholar
[5] Sugawara, F.; Kim, K. W.; Kobayashi, K.; Yoshida, J. S.; Murfushi, N.; Takahashi N.; Strobel, G. A. Zearalenone derivatives produced by the fungus Drechslera portulacae. Phytochemistry 1992, 31,1987–1990.10.1016/0031-9422(92)80346-GSearch in Google Scholar
[6] Alali, F. Q.; El-Elimat, T.; Li, C.; Qandil, A.; Alkofahi, A.; Tawaha, K.; Burgess, J. P.; Nakanishi, Y.; Kroll, D. J.; Navarro, H. A.; Falkinham, J. O.; Wani M. C.; Oberlies, N. H. New Colchicinoids from a Native Jordanian Meadow Saffron, Colchicum brachyphyllum: Isolation of the First Naturally Occurring Dextrorotatory Colchicinoid J. Nat. Prod. 2005, 68, 173–178.10.1021/np0496587Search in Google Scholar PubMed
[7] Li, C.; Lee, D.; Graf, T. N.; Phifer, S. S.; Nakanishi, Y.; Riswan, S.; Setyowati, F. M.; Saribi, A. M.; Soejarto, D. D.; Farnsworth, N. R.; Falkinham, J. O.; Kroll, D. J.; Kinghorn, A. D.; Wani, M. C.; Oberlies, N. H. Bioactive Constituents of the Stem Bark of Mitrephora glabra. J. Nat. Prod. 2009, 72, 1949–1953.10.1021/np900572gSearch in Google Scholar PubMed PubMed Central
[8] Jana, N.; Nanda, S. Asymmetric Total Syntheses of Cochliomycin A and Zeaenol. EurJ. Org. Chem. 2012, 4313–4320.10.1002/ejoc.201200241Search in Google Scholar
[9] Gao, Y.; Liu, J.; Wang, L.; Xiao, M.; Du, Y. Total Syntheses of Cochliomycin B and Zeaenol. Eur. J. Org. Chem 2014, 2092–2098.10.1002/ejoc.201301613Search in Google Scholar
[10] Mohapatra, D. K.; Reddy, D. S.; Mallampudi, N. A.; Gaddam, J.; Polepalli, S.; Jainb, N.; Yadav, J. S. The protecting-group directed diastereoselective Nozaki–Hiyama–Kishi (NHK) reaction: total synthesis and biological evaluation of zeaenol, 7-epi-zeaenol and its analogues. Org. Biomol. Chem 2014, 12, 9683-9695.10.1039/C4OB01811GSearch in Google Scholar
[11] Pal, P.; Chakraborty, J.; Mali, A.; Nanda, S. Asymmetric total synthesis of paecilomycin F, cochliomycin C, zeaenol, 5-bromozeaenol and 3,5-dibromo-zeaenol by Heck coupling and late stage macrolactonization approach. Tetrahedron 2016, 72, 2336-2348.10.1016/j.tet.2016.03.054Search in Google Scholar
[12] Kumar, R. N.; Meshram, H.M. Convergent and stereoselective synthesis of (−)-zeaenol. Tetrahedron 2015, 71, 5669-5677.10.1016/j.tet.2015.06.035Search in Google Scholar
[13] Bolte, B.; Basutto, J. A.; Bryan, C. S.; Garson, M. J.; Banwell, M. G.; Ward. J. S. Modular Total Syntheses of the Marine-Derived Resorcylic Acid Lactones Cochliomycins A and B Using a Late-Stage Nozaki–Hiyama–Kishi Macrocyclization Reaction. J. Org. Chem. 2015, 80, 460-470.10.1021/jo5024602Search in Google Scholar PubMed
[14] Sabitha, G.; Sudhakar, K.; Sriinvas, Ch.; Yadav, J. S. Stereoselective Synthesis of a Mevinic Acid Analogue. Synthesis 2007, 5, 705-708;10.1055/s-2007-965904Search in Google Scholar
[15] Mohapatra, D. K.; Das, P. P.; Reddy, D. S.; Yadav, J. S. First total syntheses and absolute configuration of rugulactone and 6 (R)-(4′-oxopent-2′-enyl)-5, 6-dihydro-2H-pyran-2-one. Tetrahedron Lett. 2009, 50, 5941-5944.10.1016/j.tetlet.2009.08.028Search in Google Scholar
[16] Reddy, D. S.; Kutateladze, A. G.; Structure Revision of an Acorane Sesquiterpene Cordycepol A. Org. Lett. 2016, 18, 4860-4863.10.1021/acs.orglett.6b02341Search in Google Scholar PubMed
[17] Reddy, D. S.; Kutateladze, A. G.; Computational structure revision of a longipinane derivative meridane. Tetrahedron Lett. 2016, 57, 4727-4729.10.1016/j.tetlet.2016.09.030Search in Google Scholar
[18] Kutateladze, A. G.; Reddy, D. S.; High-Throughput in Silico Structure Validation and Revision of Halogenated Natural Products Is Enabled by Parametric Corrections to DFT-Computed 13C NMR Chemical Shifts and Spin–Spin Coupling Constants. J. Org. Chem. 2017, 82, 3368-3381.10.1021/acs.joc.7b00188Search in Google Scholar PubMed
[19] Mohapatra, D. K.; Reddy, D. S.; Ramaiah, M. J.; Ghosh, S.; Pothula, V.; Lunavath, S.; Thomas, S.; Valli. S. N.; Bhadra, M. P.; Yadav, J. S. Rugulactone derivatives act as inhibitors of NF-κB activation and modulates the transcription of NF-κB dependent genes in MDA-MB-231cells. Bioorg. Med. Chem. Lett Bioorg. Med. Chem. Lett. 2014, 24,1389-1396.10.1016/j.bmcl.2014.01.030Search in Google Scholar PubMed
[20] Mohapatra, D. K.; Reddy, D. S. Reddy, G. S.; Yadav, J. S. Synthesis of the C‐8–C‐24 Fragment of Maltepolide C by Using a Tandem Dihydroxylation/SN2 Cyclization Sequence. Eur. J. Org. Chem.2015, 5266-5274.10.1002/ejoc.201500629Search in Google Scholar
[21] Reddy, D. S.; Mukhina, O. A.; Cronk, W. C.; Kutateladze, A.G. Polyheterocycle-carbohydrate chimeras: photoassisted synthesis of 2,5-epoxybenzoxacines and 2,5-epoxybenzazocine scaffolds and their postphotochemical hydroxylations. Pure Appl. Chem 2017, 89, 259-268.10.1515/pac-2016-0915Search in Google Scholar
[22] David, L.; Rainer, S. Synthesis of the fungus metabolite cladosin C. Org. Biomol. Chem 2017,15, 7672-7677.10.1039/C7OB01795BSearch in Google Scholar PubMed
[23] Müller, S.; Liepold, B.; Roth, G. J.; H. Bestmann, J. An Improved One-pot Procedure for the Synthesis of Alkynes from Aldehydes. Synlett 1996, 521-522.10.1055/s-1996-5474Search in Google Scholar
[24] Mohapatra, D. K.; Reddy, DS.; Mallampudi, N. A.; Yadav, J. S. Stereoselective Total Syntheses of Paecilomycins E and F through a Protecting Group Directed Diastereoselective Intermolecular Nozaki–Hiyama–Kishi (NHK) Reaction Eur. J. Org. Chem.2014, 5023-5032.10.1002/ejoc.201402133Search in Google Scholar
[25] Marshall, J. A.; Bourbeau, M. P. Synthesis of Enantioenriched Propargylic Alcohols Related to Polyketide Natural Products. A Comparison of Methodologies. Org. Lett 2003, 5, 3197–3199.10.1021/ol034918hSearch in Google Scholar PubMed
[26] Anand, N. K.; Carreira, E. M. A Simple, Mild, Catalytic, Enantio-selective Addition of Terminal Acetylenes to Aldehydes. J. Am. Chem. Soc 2001, 123, 9687.10.1021/ja016378uSearch in Google Scholar PubMed
[27] Moore, D.; Pu, L. BINOL-Catalyzed Highly Enantioselective Terminal Alkyne Additions to Aromatic Aldehydes. Org. Lett. 2002, 4, 1855.10.1021/ol025825nSearch in Google Scholar PubMed
[28] Balsells, J.; Davis, T. J.; Carroll, P.; Walsh, P. J. Insight into the Mechanism of the Asymmetric Addition of Alkyl Groups to Aldehydes Catalyzed by Titanium−BINOLate Specie. J. Am. Chem. Soc 2002, 124, 10336.10.1021/ja0171658Search in Google Scholar PubMed
[29] Mikula, H.; Skrinjar, P.; Sohr, B.; Ellmer, D.; Hametner, C.; Frohlich, J. Total synthesis of masked Alternaria mycotoxins—sulfates and glucosides of alternariol (AOH) and alternariol-9-methyl ether (AME). Tetrahedron 2013, 69 10322-10330.10.1016/j.tet.2013.10.008Search in Google Scholar
[30] Srihari, P.; Mahankali, B.; Rajendraprasad, K. Stereoselective total synthesis of paecilomycin E. Tetrahedron Lett. 2012, 53, 56-58.10.1016/j.tetlet.2011.10.137Search in Google Scholar
[31] Bhattacharjee, A.; Sequil, O. R.; De Brabander, J. K. Synthesis of side chain truncated apicularen A. Tetrahedron Lett. 2000, 41, 8069- 8073.10.1016/S0040-4039(00)01403-9Search in Google Scholar
[32] Mitsunobu, O. The Use of Diethyl Azodicarboxylate and Triphenylphosphine in Synthesis and Transformation of Natural Products. Synthesis 1981, 1.10.1016/B978-0-08-023969-9.50025-1Search in Google Scholar
[33] Mitsunobu, O.; Jenkins, I. D., in Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; 8 5379.Search in Google Scholar
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