| 98% |
With boron trichloride; In dichloromethane; at -78 - 20℃; for 3h; |
2,4,5-trimethoxybenzaldehyde (Compound 11) (0.5 g, 2.548 mmol) in CH 2 Cl 2 (20.00 mL) was added dropwise BCl 3 (1.0 M in CH 2 Cl 2; 6.37 mL) at -78 C to the stirred solution.The reaction temperature was raised to room temperature and stirred for three hours.After completion of the reaction, the mixture was cooled to 0 C,A solution of 40% aqueous HCl (1.3 mL) was added dropwise,And extracted with CH2Cl2 (3 x 30 mL).The combined organic solvent layers were washed with brine (2 x 40 mL), purified water (40 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to afford light brown Compound 12 (0.455 g, 98%Was obtained |
| 98% |
With boron trichloride; In dichloromethane; at -78 - 20℃; for 3h; |
2,4,5-trimethoxybenzaldehyde (Compound 11) (0.5 g, 2.548 mmol)In CH 2 Cl 2 (20.00 mL) and BCl 3 (1.0 M in CH 2 Cl 2; 6.37 mL) was added dropwise to the stirred solution at -78 C. The reaction temperature was raised to room temperature and stirred for three hours. After the reaction was completed, it cooled to 0 ,A solution of 40% aqueous HCl (1.3 mL) was added dropwise,And extracted with CH2Cl2 (3 x 30 mL).The combined organic solvent layers were washed with brine (2 x 40 mL)Washed with purified water (40 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give a light brown solid 12 (0.455 g, 98%) |
| 91% |
|
Boron tribromide (5.0 g, 20 mmol) was slowly added to a stirring solution of 2,4,5-trimethoxybenzaldehyde (1) (5.0 g, 25 mmol) in CH2Cl2 in a dry ice/acetone bath. After 1 h, the reaction mixture was warmed to room temperature and stirred for 3 h, then aqueous HCl (10 %; 20 mL) solution was added. The mixture was extracted with CH2Cl2 (3 x 100 mL). The organic layers were washed with NaCl solution (2 x 100 mL) and water (100 mL). The product was dried over Na2SO4 and evaporated to produce 2a (4.3 g, 91 %). M.p.: 103 C, lit. 104 C [32]. |
| 87% |
With boron tribromide; In dichloromethane; at 0 - 20℃; for 16h;Product distribution / selectivity; |
There has been significant interest in the synthesis of frondosin B (6) because of its reported activity as an interleukin-8 (IL-8) receptor antagonist and its novel structure (Inoue, M.; Carson, M. W.; Frontier, AJ. ; Danishefsky, SJ. J. Am. Chem. Soc. 2001, 123, 1878-1889; Hughes, CC; Trauner, D. Angew. Chem. Int. Ed. 2002, 41, 1569-1572; Kerr, DJ.; Willis, A.C; Flynn, B.L. Org. Lett. 2004, 6, 457-460.). The methodologies used by Danishefsky, Flynn, and Trauner to construct the seven membered ring in frondosin B (6) were not readily applicable to the synthesis of liphagal (1). We were intrigued by the possibility that the proposed cation-initiated cyclization reactions involving trapping by a benzofuran as shown in biogenetic Pathway A in Scheme IA or IB might represent an efficient synthetic approach to both racemic and enantiomerically enriched liphagal (1). With this idea in mind, we initiated synthetic efforts towards liphagal (1) in order to confirm the proposed constitution, establish its absolute configuration, provide chemical support for the biogenetic proposal represented in Pathway A, and generate the natural product and analogs in sufficient quantities for further biological evaluation.The synthesis of racemic liphagal (1) started with preparation of the desired cyclization precursor 17 (Scheme 2). Commercially available 2,4,5-trimethoxybenzaldehyde 8 was selectively demethylated at the 2 position with BBr3 and the resulting phenol was brominated at C-3 to give 9. Direct reduction of the aldehyde 9 led to an unstable diol (Kraus, G.A.; Nguyen, T.; Bae, J.; Hostetter, J.; Steadham, E. Tetrahedron 2004, 60, 4223-4225.), so it was necessary to use a protection sequence to get the desired phosphonium salt 11. Protection of the phenol in 9 with TBS, followed by reduction of the aldehyde with sodium borohydride, produced the benzyl alcohol 10. Treatment of the benzyl alcohol 10 with tripehylphosphine/HBr followed by removal of the TBS protecting group with HF/pyridine complex in THF gave the phosphonium salt 11.Synthesis of the isoprenoid fragment started with a Wittig reaction on geranylacetone 12 to give the enol ether 13 (Scheme T). Direct hydrolysis of the enol ether did not proceed cleanly so a two-step hydrolysis, first with PPTS and MeOH to give the dimethoxy acetal, and then with PPTS in a mixture of acetone and H2O was used to generate the aldehyde 14. Oxidation with NaClO2 converted the aldehyde 14 into the corresponding acid 15. EPO <DP n="31"/>Coupling the phenol 11 with the acid 15 using DCC gave the ester 16 (Kraus 2004 supra), which was not isolated. Deprotonation of the phosphonium salt 16 with Et3N in refluxing THF brought about an intramolecular Wittig reaction resulting in the formation of the desired benzofuran 17 (Yuan, Y.; Men, H.; Lee, C. /. Am. Chem. Soc. 2004, 126, 14720).Scheme 2 EPO <DP n="32"/>The key cyclization step was first effected by refluxing 17 in a biphasic system of formic acid and cyclohexane (Scheme 3) (Hercouet A. Le Corre, M. Tetrahedron Lett. 1979, 23, 2145) for 14 days to give a racemic mixture 19 of C-8 epimers as a minor product accompanying a mixture of inseparable partially cyclized alkenes 18, suggesting that the conversion of 17 to 19 proceeded in two steps. In support of this suggestion, it was found that upon treatment with formic acid in refluxing cyclohexane, compound 17 gave within 2 h only a complex mixture of cyclohexenes 18. The alkenes 18 reacted slowly under the same conditions to give after one month the tetracyclic system 19 in 40% isolated yield (50% conversion) as a 1/1 mixture of C-8 epimers 19a (Me-21 alpha) and 19b (Me-21beta). In order to shorten the time required for the polyene cyclization, benzofuran 17 was treated with chlorosulfonic acid at -78 C in nitropropane. Under these conditions, cyclization was complete within 30 minutes yielding 19 in 43% yield as a 2/5 mixture of the C-8 epimers 19a and 19b. We assume that the formation of 19b is kinetically favored under the low temperature chlorosulfonic acid cyclization conditions. Formation of 19b is probably also kinetically favored in the refluxing formic acid in cylohexane cyclization, but under long term exposure to acidic conditions, the C-8 epimers may equilibrate to give a larger proportion of the thermodynamically favored product 19a (vide infra).The aldehyde functionality was introduced by treatment of the isomeric mixture of bromobenzenes 19 with n-butyllithium to give the corresponding phenyllithium mixture that was condensed with DMF followed by hydrolysis. The resulting aldehydes 20a and 20b were separated by normal phase HPLC to give the desired product 20a, which had the trans 6,7 ring junction and the Me-21 alpha configuration as determined by 1 D NOESY analysis. Compound 20b obtained from the HPLC purification crystallized and x-ray diffraction analysis confirmed that it had the Me-21 beta configuration (SupportingInformation). Deprotection of the dimethylcatechol... |
| 87% |
With boron tribromide; In dichloromethane; at 0℃; for 10h;Inert atmosphere; |
To solution of 3,4,5- trimethoxybenzaldehyde (5g, 25.5 mmol) in CH2C12 (125 ml) at 0 C was added BBr3 (6.39 g, 25.5 mmol). The resulting dark mixture was stirred at 0C for 10 hrs after completion of the reaction checked by TLC H20 (100 mL) was then added and the mixture was stirred for 10 min and the aqueous phase was extracted by CH2C12. The organic phase was dried over Na2S0 ) and evaporated under reduced pressure. The resulting residue was purified by silica gel (CH C12) afforded the 2- hydroxy 4,5dimethoxybenzaldehyde Al (4.3g) in 87% yield isolated yellow solid: lH NMR (500 MHz, CDC13) 511.33 (s, 1H), 9.63 (s, 1H), 6.83 (s, 1H), 6.40 (s, 1H), 3.87 (s, 3H), 3.81 (s, 3H) ppm. Mass: ESI [M + Na]+: 225.06; Elemental anal, calcd. for C9H10O4; C: 59.34, H: 5.53, O: 35.13; found C: 59.14, H: 5.13, O: 34.90. |
| 87% |
With boron tribromide; In dichloromethane; at 20℃; for 10h;Inert atmosphere; |
Synthesis of Compound AStep 1Synthesis of 2-hydroxy-4,5-dimethoxybenzaldehyde (A1)To solution of 2,4,5-trimethoxybenzaldehyde (5 g, 25.5 mmol) in CH2Cl2 (125 ml) at 0 C. was added BBr3 (6.39 g, 25.5 mmol). The resulting dark mixture was stirred at 0 C. for 10 hrs after completion of the reaction checked by TLC H2O (100 mL) was then added and the mixture was stirred for 10 min and the aqueous phase was extracted by CH2Cl2. The organic phase was dried over Na2SO4, and evaporated under reduced pressure. The resulting residue was purified by silica gel (CH2Cl2) afforded the 2-hydroxy-4,5-dimethoxybenzaldehyde A1 (4.3 g) in 87 % yield isolated yellow solid: 1H NMR (500 MHz, CDCl3) delta 11.33 (s, 1H), 9.63 (s, 1H), 6.83 (s, 1H), 6.40 (s, 1H), 3.87 (s, 3H), 3.81 (s, 3H) ppm. Mass: ESI [M+Na]+: 225.06; Elemental anal. calcd. for C9H10O4; C, 59.34; H, 5.53; O, 35.13. found C, 59.14; H, 5.13; O, 34.90. |
| 87% |
With boron tribromide; In dichloromethane; at 20℃; for 9h;Inert atmosphere; |
Step 1Synthesis of compound 13 (2-hydroxy-4,5-dimethoxybenzaldehyde)To a solution of 2,4,5-trimethoxybenzaldehyde (5 g, 25.510 mmol) in CH2Cl2 (125 ml) at 0 C., BBr3 (6.39 g, 25.510 mmol) was added. The resulting dark mixture was stirred at rt for 9 h. Water (100 mL) was charged and the mixture was stirred for 10 min, the aqueous phase was extracted by CH2Cl2. Organic phase was dried over Na2SO4, and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using plain dichloromethane as eluent, afforded the 2-hydroxy-4,5-dimethoxybenzaldehyde 13 (4.3 g, 87%) isolated as yellow solid. Mp 105-107 C.; 1H NMR (CDCl3, 400 MHz): delta 11.40 (br. s, 1H), 9.70 (s, 1H), 6.91 (s, 1H), 6.48 (s, 1H), 3.94 (s, 3H), 3.88 (s, 3H) ppm. 13C NMR (CDCl3. 125 MHz): 194.0, 159.3, 157.3, 142.9, 113.3, 112.9, 100.1, 56.4, 56.3. HRMS (ESI) m/z: [M+H]+ calcd for C9H10O4+H+ 183.0657; Found 183.0653. |
| 85% |
|
A solution of 2,4,5-trimethoxybenzaldehyde (26) (3.3 g, 16.78?mmol) [25a], in CH2Cl2 (84?mL) was cooled to 0?C, whereupon BBr3 (freshly distilled from CaH2, 4.59?g, 1.74?mL, 18.45?mmol) was added, and the mixture was warmed to room temperature and stirred for 24?h. H2O (20?mL) was added, and stirring was continued for an additional 10?min. The mixture was extracted with CH2Cl2 (2?x?20?mL), and the combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide 2.60?g (85%) crude 27 as a dark green solid: mp 104-106?C (MeOH). The crude material can be purified by flash chromatography eluting with a gradient of acetone/hexanes (1:3???1:1), but in most cases the material is sufficiently pure for the next step; 1H NMR (400?MHz) delta 11.41 (s, 1?H), 9.71 (s, 1?H), 6.91 (s, 1?H), 6.48 (s, 1?H), 3.94 (s, 3?H), 3.89 (s, 3?H); 13C NMR (100?MHz) delta 194.0, 159.3, 152.2, 142.9, 113.1, 112.8, 100.1, 56.4, 56.3; IR (film) 2838 (C-H), 1625 (C=O), 1506, 1475, 1443, 1369, 1339, 1280, 1251, 1198, 1147, 998?cm-1; LRMS (CI) m/z found, 183.0. |
| 80% |
With boron tribromide; In dichloromethane; at 0 - 20℃; for 1.25h; |
General procedure: BBr3 (3.83 g,15.29 mmol) was added dropwise to a solution of 2,4,6-trimethoxybenzaldehyde (3.00 g, 15.29 mmol) in DCM (20 mL)cooled to 0 C. The ensuing reaction mixture was mechanically stirredat 0 C for approximately 15 min and then at room temperature, theprogress of the reaction was continually monitored by TLC. Uponcompletion, the reaction mixture was again cooled to 0 C andmechanically stirred while HCl (32%, 15 mL) was added slowly tothe reaction mixture. The resulting precipitate was filtered, dried(30 C) and used without further purification. Additionally, thefiltrate was extracted with DCM (5 × 20 mL), the combined organicextracts were dried (MgSO4), filtered and concentrated. The driedprecipitate and concentrated combined organic extracts were pooled toyield compound 2a as a red solid (7.45 g, 89%), which was used without further purification: |
| 78% |
With boron tribromide; In dichloromethane; at 0 - 20℃; for 20h; |
2,4,5-Trimethoxybenzaldehyde (3.92 g, 20.0 mmol) was dissolvedin dry CH2Cl2 (20 mL) before adding dropwise boron tribromide (1.0 N in CH2Cl2, 20 mmol, 20 mL)while cooling at 0 C. The reaction mixture was slowly warmed at room temperature and left undervigorous magnetic stirring for 20 h. Water (250 mL) was carefully added with simultaneous coolingwith an external ice-bath. The suspension was stirred for 1 h and then partitioned with an additionalamount of CH2Cl2 (80 mL). After extraction with CH2Cl2 (3 100 mL), the organic layers werecollected and dried over Na2SO4. The mixture was concentrated to dryness and purified through flashchromatography (gradient eluent: ethyl acetate in n-hexane 10%50%), yielding a yellow solid. Yield:78%. 1H-NMR (DMSO-d6) delta: 3.71 (3H, s, OCH3), 3.80 (3H, s, OCH3), 6.53 (1H, s, H-3), 7.11 (s, 1H, H-6),10.00 (s, 1H, CHO), 10.69 (s, 1H, disappearing with D2O, OH). |
| 77% |
|
Step 1: 3,4-Dimethoxy-6-hydroxy-benzaldehyde In a three-necked flask, disperse 40.8 g of aluminium chloride in 200 ml of dichloromethane with stirring. Cool the solution to 0 C. Pour in dropwise a solution of 20 g (0.101 mol) of 3,4,6-trimethoxybenzaldehyde dissolved in 100 ml of dichloromethane. Allow the temperature to rise again to 19 C. and stir for 45 min. Hydrolyse the reaction mixture with 400 g of water and ice and then add 100 ml of 1N HCl and stir for 30 minutes. Allow to separate and then extract with 200 ml of dichloromethane. The organic phase is washed with 100 ml of 1N HCl, 100 ml of water and 100 ml of saturated aqueous NaCl solution, and then dried over MgSO4, filtered and evaporated to dryness. 16.4 g of title product are obtained. Yield=77% IR (pure): 1625, 1146 cm-1. |
|
With boron tribromide;Product distribution / selectivity; |
Note that the numbering applied to EXAMPLE 4 below is independent of the numbering in the remainder of the document.Below is an example of desformyl liphagal synthesis wherein there is no Br in compound 7 below as there is in compound 9 of Scheme 2 above. |
|
|
To a solution of 2,4,5-trimethoxy benzaldehyde (0.21 g, 1.07 mmol) in CH2Cl2 (5 mL) at 0 C under Ar atmosphere was added BCl3 (1.0M, 3.10 mL, 3.10 mmol) quickly, and the reaction mixture was allowed to attain room temperature slowly. After stirring for 24 h at room temperature, the reaction mixture was cooled to 0 C and very slowly quenched with water (10 mL) and diluted with CH2Cl2 (10 mL). The organic layer was washed with water, brine, dried over Na2SO4 and then concentrated in vacuo to give a white solid which was used in the next step without further purification. |
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