JOURNAL OF THE CHINESE Article CHEMICAL SOCIETY Synthesis of a Furanosyl-pyranone Derivative Related to the Tri-O-heterocyclic Core of Herbicidins Ching-Yun Hsu,a,* I-Chi Lee,b,c Larry S. Lico,c Biing-Jiun Uangb,* and Shang-Cheng Hungc,d,* aDepartment of Chemical and Materials Engineering, Cheng Shiu University, 840, Chengcing Road, Niaosong District, Kaohsiung City 83347,Taiwan, R.O.C. bDepartment of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu 30043, Taiwan, R.O.C. cGenomics Research Center, Academia Sinica, 128, Section 2, Academia Road, Taipei 11529, Taiwan, R.O.C. dDepartment of Applied Chemistry, National Chiao Tung University, No. 1001, Ta-Hsueh Road, Hsinchu 300, Taiwan, R.O.C. (Received: Jan. 10, 2012; Accepted: Jan. 17, 2012; Published Online: Feb. 6, 2012; DOI: 10.1002/jccs.201100744) A new compound that is structurally related to the undecose ring structure of herbicidins has been pre- pared. The synthesis of this novel furanosyl-pyranone derivative was made possible through the regioselective reductive ring-opening of a 3,5-O-benzylidene-D-xylofuranose and the hetero-Diels–Alder reaction of an aldehyde and a Danishefsky-type diene. The highly functionalized pyranone derivative can be a useful precursor for the synthesis of herbicidins. Keywords: Benzylidene acetal; Cycloaddition; Danishefsky-type diene; Herbicidins; Regioselectivity. INTRODUCTION rice. In the 1970’s, a series of undecose (C11)-based nu- Unique structural features make herbicidins a con- cleoside antibiotics, collectively known as herbicidins (1), spicuous target among synthetic chemists. The core 11-car- were isolated and characterized from the strains of Strepto- bon structure that is b1‘-linked to adenine is an interesting myces saganonensis (Fig. 1).1 These compounds were furanopyranopyran ring system having an internal hemi- shown to exhibit valuable herbicidal and anti-fungal activ- ketal bridging the C3¢and C7¢ positions and a C-glycoside ity while being relatively non-toxic to animals. For exam- linking C5¢ and C6¢. The rigid backbone also forces the ple, herbicidins A (1a)andB(1b) are selectively toxic to C7¢,C8¢,C9¢,andC10¢ substituents to assume the axial po- some dicotyledons and efficiently inhibits Xanthomonas sition. Because the C-glycoside functionality separates the oryzae, the bacteria responsible for leaf blight infections in tri-O-heterocylic structure into two simple sugars, syn- thetic efforts primarily targeted the difficult generation of this crucial sugar link as the key step. To date, however, only Matsuda and co-workers2 have completed the synthe- sis of a herbicidin congener, that is herbicidin B. Other re- search groups only accomplished the partial3 or full assem- bly4 of the undecose backbone. Thus, new avenues that may improve the synthesis of this important series of com- pounds are still much desired. Our synthetic strategy focusing on the formation of the glycosyl core structure of herbicidins (1) is depicted in Scheme I. We envisioned the furanosyl-pyranone 2 as a di- rect precursor to the tricylic ring system and is, thus, the Fig. 1. Structures of herbicidins. target material in the current work. The plan is to access Dedicated to the memory of Professor Yung-Son Hon (1955–2011). * Corresponding author. Tel: +886-2-2787-1279; Fax: +886-2-27878771; E-mail: [email protected], [email protected], [email protected] J. Chin. Chem. Soc. 2012, 59, 421-425 © 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 421 Article Hsu et al. Scheme I Retrosynthetic analysis of herbicidin Scheme II Reductive ring opening of 3,5-O-benzyli- dene acetal this compound through the [4 + 2]-cycloaddition of the Danishefsky-type diene 3 and the aldehyde 4. Here, the stereoselectivity may be controlled by an appropriately se- Scheme III Synthesis of the aldehyde 4 lected Lewis acid catalyst.5 Compound 4, in turn, could be generated by transformations of the commercially abun- dant 1,2-O-isopropylidene-a-D-xylofuranose (5). RESULTS AND DISCUSSION The first encountered challenge is the installation of a benzyl ether at the O3 position of the diol 5.Presumably, this transformation may be directly achieved by regiose- lective reductive ring opening of an installed 3,5-O-ben- zylidene acetal. Nonetheless, although the 1,3-dioxane- type benzylidene acetals in pyranoses (e.g. 4,6-O-benzyli- dene) could be readily opened in either direction by a suit- able set of reagents,6 literature reports on the ring opening of the corresponding acetal in furanosyl sugars only re- sulted in the formation of the primary benzyl ether and a secondary hydroxyl group as the major isomer.7 To test the viability of this synthetic route, compound 5 was converted to the desired acetal 6 according to a known procedure7a (Scheme II). Treatment of 6 with LiAlH4 and AlCl3 only Oxidation of compound 8 with NaHCO3 and NaIO4 in produced the unwanted 3-OH-5-OBn regioisomer 7 in 43% phase transfer conditions led to the aldehyde 98 in an excel- yield without any trace of the target 5-alcohol 8.Fortu- lent yield. The terminal alkene 10, generated from 9 nately, our recently reported BH3×THF/Cu(OTf)2 combina- through a typical Wittig reaction (62%), was sequentially tion6a,b delivered the primary alcohol 8 from acetal 6 to- treated with 9-borabicyclo[3.3.1]nonane (9-BBN) and gether with the diol 5 in 52% and 30% yields, respectively. H2O2/NaOH to form the desired primary alcohol 11 to- The corresponding 3-alcohol 7 was not isolated from the gether with its isomer 12 in 67% and 21% yields, respec- reaction mixture. To our knowledge, this is the first report tively. Compound 11 was, then, subjected to Swern oxida- of a regioselective reductive ring opening at the O5 posi- tion to afford the target aldehyde 4 in 92% yield. tion of a 3,5-O-benzylidene acetal in a furanoside. The formation of the furanosyl-pyranone 2 was facili- With the 5-alcohol 8 in hand, we continued the trans- tated through the hetero-Diels–Alder reaction of the Dan- formations toward the required aldehyde 4 (Scheme III). ishefsky-type diene 3 and the aldehyde dienophile 4 (Table 422 www.jccs.wiley-vch.de © 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim J. Chin. Chem. Soc. 2012, 59, 421-425 JOURNAL OF THE CHINESE Toward the Synthesis of Herbicidins CHEMICAL SOCIETY Table 1. Hetero-Diels–Alder cycloaddition of the Danishefsky- feasibility of this precursor in accessing the herbicidin type diene 3 and the aldehyde 4 congeners. O H O O O OBn O EXPERIMENTAL O R OBn O General remarks O 2a:R=H MeO O 2b:R=OBz All solvents (CH2Cl2,THF,andEt2O) were purified 4 R + and dried from a safe purification system filled with anhy- conditions OTES H O O O drous Al2O3. All other reagents obtained from commercial 3a:R=H sources were used without further purification. Flash col- 3b:R=OBz O R OBn O umn chromatography was carried out on Silica Gel 60 2c:R=H (230-400 mesh, E. Merck). TLC was performed on pre- 2d:R=OBz coated plates of Silica Gel 60 F254 (0.25 mm, E. Merck); de- Product Yield Entry Diene Condition tection was executed by spraying with a solution of (ratio) (%) Ce(NH4)2(NO3)6,(NH4)6Mo7O24,andH2SO4 in water and 1 13 1 3a TiCl4,CH2Cl2,–78°C,1h; 2a/2c 56 subsequent heating on a hotplate. Hand C NMR spectra TFA, rt, 1 h (3/1) were recorded using a 400 MHz spectrometer. Chemical 2 3a ZnCl2,THF,0°Ctort,24h; 2a/2c 88 TFA, rt, 1 h (4/3) shifts are in ppm from Me4Si calibrated using the resonance 3 3b ZnCl2,THF,0°Ctort,24h; 2b/2d 77 of the residual proton and carbon of the deuterated solvent. TFA, rt, 1 h 3-O-Benzyl-1,2-O-isopropylidene-a-D-xylofuranose (8) BH3×THF(1MsolutioninTHF,0.36mL,0.36mmol) was slowly added to the acetal 6 (20.0 mg, 0.0719 mmol) at 1). The reaction requires a Lewis acid catalyst to promote room temperature under nitrogen atmosphere. After stir- the cycloaddition and subsequent treatment with trifluoro- ring for 10 min, freshly dried Cu(OTf)2 (3.91 mg, 10.8 acetic acid (TFA) leads to the elimination the triethylsilyl mmol) was added to the solution, and the mixture was kept 5a (TES) and methoxy groups. In the present case, the endo- stirring for 2 h. The reaction was quenched by sequential adduct is more favored, but the Lewis acid catalyst exerts additions of Et3N and methanol, and the resulting mixture an effect on the stereoselectivity. For example, TiCl4 al- was concentrated under reduced pressure. The residue was lowed for an endo/exo addition (2a/2c) ratio of 3/1 (entry purified by flash column chromatography (ethyl acetate/ 1), whereas ZnCl2 gave a corresponding 4/3 ratio (entry 2). hexanes = 1/2) to afford the 5-alcohol 8 (10.5 mg, 0.0375 29 The yield of the reaction using ZnCl2, however, was much mmol) and the diol 5 (4.1 mg, 0.022 mmol). [a]D –33.4 (c -1 higher (88%). When the benzoate 3b (the E/Z ratio was not 0.3, CHCl3); IR (thin film) n 3396, 1216, 1161, 1074 cm ; 1 determined) was utilized as the diene, compounds 2b and H NMR (400 MHz, CDCl3) d 7.36-7.30 (m, 5H, ArH), 2d were furnished in a combined yield of 77% (entry 3). 5.97 (d, J = 3.8 Hz, 1H, H-1), 4.70 (d, J = 11.9 Hz, 1H, Collectively, pyranone 2 possesses the proper set of func- CH2Ph), 4.62 (d, J = 3.8 Hz, 1H, H-2), 4.55 (d, J =11.9Hz, tional groups that may allow entry to the herbicidin tricylic 1H, CH2Ph), 4.26 (q, J = 4.5 Hz, 1H, H-4), 4.00 (d, J =4.5 core.