Total Synthesis of ()-Isoaltholactone LIU Jun, ZHANG Xing, LIU Yi, BI Jingjing & DU Yuguo Sci China Chem, 2013, 56(7): 928–932

Editorial Board

Honorary Editor General ZHOU GuangZhao (Zhou Guang Zhao) Editor General ZHU ZuoYan Institute of Hydrobiology, CAS, China

Editor-in-Chief WAN Li-Jun Institute of Chemistry, CAS, China

Associate Editors CAO Yong South China University of Technology, China LIN GuoQiang Shanghai Institute of Organic Chemistry, CAS, China CHEN HongYuan Nanjing University, China TIAN ZhongQun Xiamen University, China FENG ShouHua Jilin University, China TIAN He East China University of Science & Technology, China LI YaDong Tsinghua University, China XUE Zi-Ling University of Tennessee, USA

Members

AMATORE Christian LIANG WenPing XIE ZuoWei Ecole Normale Supérieure, France National Natural Science Foundation of China, The Chinese University of Hong Kong, China China AN LiJia XIONG RenGen Changchun Institute of Applied Chemistry, CAS, LIN Jin-Ming South East University, China China Tsinghua University, China XU ChunMing BAO XinHe LIU Jun China University of Petroleum, Beijing, China Dalian Institute of Chemical Physics, CAS, China Pacific Northwest National Laboratory, USA BU XianHe YAM Vivian Wing-Wah LIU ZhiPan The University of Hong Kong, China Nankai University, China Fudan University, China CHAI ZhiFang YANG Bai LIU ZhongFan Jilin University, China Institute of High Energy Physics, CAS, China Peking University, China CHEN GuoPing LU XiaoHua YANG PengYuan National Institute for Materials Science, Japan Nanjing University of Technology, China Fudan University, China CHEN XiaoMing LUO GuangSheng YANG XueMing Sun Yat-Sen University, China Tsinghua University, China Dalian Institute of Chemical Physics, CAS, China CHEN Yi NIE ShuMing YAO ZhuJun Institute of Chemistry, CAS, China Georgia Institute of Technology and Emory Nanjing University, China COMPTON Richard University, USA ZHANG DeQing University of Oxford, UK PU Lin Institute of Chemistry, CAS, China DING KuiLing University of Virginia, USA ZHANG HongJie Shanghai Institute of Organic Chemistry, CAS, QIAO JinLiang Changchun Institute of Applied Chemistry, CAS, China SINOPEC Beijing Research Institute of Chemical China DUAN Xue Industry, China ZHANG JingSong Beijing University of Chemical Technology, China SHAO YuanHua University of California, Riverside, USA GAO ChangYou Peking University, China Zhejiang University, China ZHANG JinZhong SHUAI ZhiGang University of California, Santa Cruz, USA GAO Song Tsinghua University, China Peking University, China ZHANG LiHe SUN LiCheng Peking University, China GUAN ZhiBin Royal Institute of Technology (KTH), Sweden University of California, Irvine, USA ZHANG SuoJiang SUO ZuCai Institute of Process Engineering, CAS, China GUO ZiJian The Ohio State University, USA Nanjing University, China ZHANG Tao TAN WeiHong Dalian Institute of Chemical Physics, CAS, China HAN BuXing Hunan University, China ZHANG YuKui Institute of Chemistry, CAS, China TANG Ben Zhong Dalian Institute of Chemical Physics, CAS, China HE MingYuan The Hong Kong University of Science & Technology, China ZHAO JinCai Research Institute of Petroleum Processing, Institute of Chemistry, CAS, China SINOPEC, China THANG San ZHAO XinSheng HONG MaoChun Commonwealth Scientific & Industrial Research Peking University, China Fujian Institute of Research on the Structure of Organisation (CSIRO), Australia Matter, CAS, China WAN XinHua ZHAO YuFen HU PeiJun Peking University, China Xiamen University, China Queen’s University, UK WANG HaiLin ZHAO YuLiang HUANG PeiQiang Research Center for Eco-Environmental Sciences, National Center for Nanoscience and Technology, Xiamen University, China CAS, China China HUANG Zhen WANG MeiXiang ZHENG NanFeng Georgia State University, USA Tsinghua University, China Xiamen University, China JU HuangXian WANG Shu ZHU Tong Nanjing University, China Institute of Chemistry, CAS, China Peking University, China LE Chris WANG Ye ZHUANG Lin University of Alberta, Canada Xiamen University, China Wuhan University, China LI YongFang XI Zhen ZUO JingLin Institute of Chemistry, CAS, China Nankai University, China Nanjing University, China

Editorial Staffs ZHU XiaoWen (Director) SONG GuanQun XU JunJian ZHANG XueMei

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Contents Vol.56 No.7 July 2013

COVER The essence of heavy oil processing is molecular composition and conversion. The benefit of a refinery is based on the molecules they buy and sell. Refining at molecular level has been a common concept both in academic and industrial communities. However, it is challenging for chemists to under- stand the composition of heavy petroleum and the detailed mechanisms of refining processes. The figure shows a negative-ion electrospray (ESI) Fourier transform ion cyclotron resonance (FT-ICR) mass spectrum of a supercritical fluid extracted fraction of a Canada oil sand bitumen. The expanded mass spectrum resolves 76 peaks at a single nominal mass with a resolving power of 1000000, which exhibits the complexity of the heavy oil. All the peaks can be assigned to a chemically distinct species. The spectrum was conducted by a Bruker SolariX FT-ICR MS with a 12-T superconducting magnet and a dynamically harmonized FT-ICR cell (see the Special Topic about Chemistry of Heavy Petroleum Fractions and Its Impacts on Refining Processes on page 831–882).

Special Topic: Chemistry of Heavy Petroleum Fractions and Its Impacts on Refining Processes Preface XU ChunMing & CHUNG Keng H. Sci China Chem, 2013, 56(7): 831–832

Special Topic·REVIEWS

Prospects for petroleum mass spectrometry and chromatography HSU Chang Samuel & SHI Quan Sci China Chem, 2013, 56(7): 833–839

Special Topic·ARTICLES

Molecule-based modeling of heavy oil HORTON Scott R., HOU Zhen, MORENO Brian M., BENNETT Craig A. & KLEIN Michael T. Sci China Chem, 2013, 56(7): 840–847

Thermal transformation of acid compounds in high TAN crude oil YANG BaiBing, XU ChunMing, ZHAO SuoQi, HSU Chang Samuel, CHUNG Keng H. & SHI Quan Sci China Chem, 2013, 56(7): 848–855

Separation and characterization of petroleum asphaltene fractions by ESI FT-ICR MS and UV-vis spectrometer WANG ShanShan, YANG Chuang, XU ChunMing, ZHAO SuoQi & SHI Quan Sci China Chem, 2013, 56(7): 856–862

Effects of experimental conditions on the molecular composition of maltenes and asphaltenes derived from oilsands bitumen: Characterized by negative-ion ESI FT-ICR MS WANG LiTao, HE Chen, LIU Yang, ZHAO SuoQi , ZHANG YaHe, XU ChunMing, CHUNG Keng H. & SHI Quan Sci China Chem, 2013, 56(7): 863–873

Characterization of heavy petroleum fraction by positive-ion electrospray ionization FT-ICR mass spectrometry and collision induced dissociation: Bond dissociation behavior and aromatic ring architecture of basic nitrogen compounds ZHANG LinZhou, ZHANG YaHe, ZHAO SuoQi, XU ChunMing, CHUNG Keng H. & SHI Quan Sci China Chem, 2013, 56(7): 874–882

SCIENCE CHINA Chemistry

Contents Vol.56 No.7 July 2013

REVIEWS

Recent progress in quantifying substituent effects CAO ChenZhong & WU YaXin Sci China Chem, 2013, 56(7): 883–910

ARTICLES

Carbon black supported ultra-high loading silver nanoparticle catalyst for electro-oxidation and determination of hydrazine TAN Chang, XU XinHua, WANG Feng, LI ZhiLin, LIU JingJun & JI Jing Sci China Chem, 2013, 56(7): 911–916

An above-room-temperature switchable molecular dielectric with a large dielectric change between high and low dielectric states DU Yang, HAO HuiMin, ZHANG QianChong, ZHAO HaiXia, LONG LaSheng, HUANG RongBin & ZHENG LanSun Sci China Chem, 2013, 56(7): 917–922

A highly selective colorimetric sensor for Hg2+ based on a copper (II) complex of thiosemicarbazone in aqueous solutions WEI TaiBao, LI JunJian, BAI CuiBing, LIN Qi, YAO Hong, XIE YongQiang & ZHANG YouMing Sci China Chem, 2013, 56(7): 923–927

Total synthesis of ()-isoaltholactone LIU Jun, ZHANG Xing, LIU Yi, BI JingJing & DU YuGuo Sci China Chem, 2013, 56(7): 928–932

Total synthesis of dansyl and biotin functionalized ganglioside GM3 by chemoenzymatic method SUN Bin & JIANG HeYan Sci China Chem, 2013, 56(7): 933–938

Biocatalytic direct asymmetric aldol reaction using proteinase from Aspergillus melleus YUAN Yi, GUAN Zhi & HE YanHong Sci China Chem, 2013, 56(7): 939–944

Synthesis of naphthalene derivatives through inexpensive BF3·Et2O-catalyzed annulation reaction of arylacetaldehydes with arylalkynes XIANG ShiKai, HU Hao, MA Jing, LI YuanZhuo, WANG BiQin, FENG Chun, ZHAO KeQing, HU Ping & CHEN XiaoZhen Sci China Chem, 2013, 56(7): 945–951

A series of naphthalimide azoles: Design, synthesis and bioactive evaluation as potential antimicrobial agents DAMU Guri L. V., WANG QingPeng, ZHANG HuiZhen, ZHANG YiYi, LV JingSong & ZHOU ChengHe Sci China Chem, 2013, 56(7): 952–969

n-Octyloxyallene homopolymerization and random copolymerization with styrene using catalyst system composed of lanthanide Schiff-base complexes and Al(i-Bu)3 JIAO JunQing, ZHU WeiWei , NI XuFeng & SHEN ZhiQuan Sci China Chem, 2013, 56(7): 970–976

Metal chalcogenide complex-mediated fabrication of Cu2S film as counter electrode in quantum dot sensitized solar cells YU XueChao, ZHU Jun, LIU Feng, WEI JunFeng, HU LinHua & DAI SongYuan Sci China Chem, 2013, 56(7): 977–981

Solvent-induced molecular gel formation at room temperature and the preparation of related gel-emulsions JING Ping, YAN JunLin, CAI XiuQin, LIU Jing, HU BaoLong & FANG Yu Sci China Chem, 2013, 56(7): 982–991

Investigation of interfacial processes in graphite thin film anodes of lithium-ion batteries by both in situ and ex situ infrared spectroscopy LI JunTao, SU Hang, HUANG Ling & SUN ShiGang Sci China Chem, 2013, 56(7): 992–996

Synthesis and photovoltaic properties of a star-shaped molecule based on a triphenylamine core and branched terthiophene end groups GAO Lei, ZHANG Jing, HE Chang, SHEN SuLing, ZHANG Yi, LIU HongTao, SUN QingJiang & LI YongFang Sci China Chem, 2013, 56(7): 997–1003

A DFT study on PtMo resistance to SO2 poisoning XIA MeiRong, LIU Ying, LI Li, XIONG Kun, QI XueQiang, YANG LinJiang, HU BaoShan, XUE Yun & WEI ZiDong Sci China Chem, 2013, 56(7): 1004–1008

Selective DNA detection at Zeptomole level based on coulometric measurement of gold nanoparticle- mediated electron transfer across a self-assembled monolayer WANG Wei, YUAN XiaQing, LIU XuHui, GAO Qiang, QI HongLan & ZHANG ChengXiao Sci China Chem, 2013, 56(7): 1009–1016

SCIENCE CHINA Chemistry

• ARTICLES • July 2013 Vol.56 No.7: 928–932 doi: 10.1007/s11426-012-4823-3

Total synthesis of ()-isoaltholactone

LIU Jun1*, ZHANG Xing1, 2, LIU Yi1, 2, BI JingJing1, 2 & DU YuGuo1, 2*

1State Key Laboratory of Environmental Chemistry and Eco-toxicology; Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China 2School of Chemistry and Chemical Engineering, Graduate University of Chinese Academy of Sciences, Beijing 100049, China

Received November 17, 2012; accepted November 28, 2012; published online December 21, 2012

A short and efficient stereoselective synthesis of a styryllactone ()-isoaltholactone has been achieved in seven steps and 33% overall yield, starting from the readily available carbohydrate D-mannose. The key steps of our synthesis involve intramolecular tetrahydrofuran cyclization and one-pot acetonide deprotection-lactonization.

total synthesis, styryllactone, isoaltholactone, carbohydrate

1 Introduction

Phytochemical studies on Goniothulumus species have led to the isolation and characterization of a large number of styryllactones, a diverse group of secondary metabolites, which were found to possess significant biological activity Figure 1 Structures of ()-altholactone (1) and ()-isoaltholactone (2). including antitumor and antifungal properties, as well as antibiotic potential [1]. Altholactone (1, Figure 1), a drofuran framework bearing four consecutive stereogenic furanopyrone member of the styryllactone family, was first centers. Their unusual structure and promising biological isolated from the bark of an unnamed Polyathia (An- activity have attracted immense interest from the synthetic nonaceae) species in 1977 [2]. This compound, named as community. As a result, several elegant approaches toward goniothalenol, was also isolated from the bark of the An- the total synthesis of (+) and ()-isoaltholactone as well as nonacea plant, Goniothalamus giganteus, and showed anti- its analogues have been reported to date [5]. As part of our tumor activity against a leukemia mouse in vivo [3]. Its dia- ongoing synthetic research into natural products from car- stereomer, isoaltholactone (2), was subsequently isolated bohydrate-based chiral building blocks [6], herein we report from the plants of the Goniothalamus species [4]. The bio- the concise and stereoselective synthesis of ()-isoaltholac- logical evaluation of isoaltholactone revealed that it also tone (2) from D-mannose. displays important biological activities, including antitumor, antifungal and antibacterial properties [4, 5a]. Differing only in the configuration of the stereogenic 2 Experimental centers at C-2 and C-3, isoaltholactone and altholactone consist of a similar 5-oxygenated-5,6-dihydro-2H-pyran- 2.1 General 2-one structural skeleton and a richly substituted tetrahy- Unless noted otherwise, commercially available materials were used without further purification. All solvents were *Corresponding authors (email: [email protected]; [email protected]) dried according to the established procedures ahead of use.

All reagents were purchased from commercial corporations. was concentrated with toluene and poured into saturated aq. Flash chromatography (FC) was performed using silica gel CuSO4 (30 mL), then extracted with dichloromethane (200–300 mesh) according to the standard protocol. All (DCM) (2 × 30 mL). The combined organic phase was reactions under standard conditions were monitored by washed with brine, dried over Na2SO4 and concentrated thin-layer chromatography (TLC) on gel F254 plates. Opti- under vacuum. The crude residue was purified by flash cal rotations were measured using a polarimeter with a column chromatography (hexanes/EtOAc 6:1) to give 25 thermally jacketed 5 cm cell at approximately 25 °C. High- compound 5 as a yellow oil (373 mg, 73%). []D 16.1 (c 1 resolution mass spectrometry data (HRMS) were acquired 2.2, CHCl3); H NMR (400 MHz): δ 1.38 (s, 3H), 1.40 (s, 1 using a Q-TOF analyzer in acetone as solvent. H NMR and 3H), 1.44 (s, 3H), 1.58 (s, 3H), 3.88 (q, J = 4.0 Hz, 1H), 13 C NMR spectra were measured on 400 MHz or 100 MHz 4.17–4.23 (m, 2H), 4.48–4.53 (m, 1H), 4.77 (dd, J = 6.0 Hz, spectrometers (NMR in CDCl3 with TMS as an internal J = 4.0 Hz, 1H), 4.98 (dd, J = 6.0 Hz, J = 0.8 Hz, 1H), 5.20  standard). Chemical shifts ( ) are given in ppm relative to (s, 1H), 7.28–7.37 (m, 5H); 13C NMR (100 MHz)  24.7, residual solvent (usually chloroform;  7.26 for 1H NMR or 25.2, 26.2, 26.9, 67.0, 73.5, 81.1, 81.3, 84.9, 87.5, 109.2, 77.0 for proton decoupled 13C NMR), and coupling con- 112.8, 125.4, 127.4, 128.7, 138.3; HRMS (ESI-TOF) m/z: stants (J) in Hz. Multiplicity is tabulated as s for singlet, d Calcd for C18H24O5: 320.1624; Found 343.1525 ([M + for doublet, t for triplet, q for quadruplet, and m for multi- Na]+). plet and br when the signal is broadened. Synthesis of (R)-1-((3aS,4R,6R,6aR)-2,2-dimethyl-6-phenyltetrahydrofuro[3,4-d] [1,3]dioxol-4-yl)ethane-1,2-diol (6) 2.2 Experimental procedures To a solution of 5 (125 mg, 0.39 mmol) in dry DCM (8 mL) Synthesis of (R)-((R)-2,2-dimethyl-1,3-dioxolan-4-yl) ((4S, was added solid FeCl3·6H2O (11 mg, 0.04 mmol) under an 5R)-5-((S)-hydroxy (phenyl) methyl)-2,2-dimethyl-1,3-dio- N2 atmosphere. After stirring for 1.5–2 h at room tempera- xolan-4-yl) methanol (4) ture, the mixture was filtered through a pad of celite, and To a solution of 2,3:5,6-di-O-isopropylidene-a-D-manno- the pad was washed with DCM (10 mL). The combined furanose [7] (2.08 g, 8 mmol) in dry THF (30 mL) was organic phase was washed with brine, dried over Na2SO4 added phenyl lithium (2 M in dibutyl ether, 26.4 mmol) via and concentrated under vacuum. The crude was purified by flash column chromatography (hexanes/EtOAc 1:3) to give syringe by three portions at 78 °C under N2 protection. 25 After 30 min, the solution was warmed to 40 °C and compound 6 as a yellowish oil (90 mg, 82%). []D +39.0 (c 1 stirred for another 12 h. The reaction was quenched by the 1.0, CHCl3); H NMR (400 MHz): δ 1.39 (s, 3H), 1.60 (s, slow addition of aq. NH4Cl (30 mL, Caution!). The aqueous 3H), 2.30–2.80 (br, 2H), 3.84–3.87 (m, 1H), 3.94–3.97 (m, layer was extracted with ether (3 × 40 mL). The combined 1H), 3.98 (q, J = 4.0 Hz 1H), 4.11–4.15 (m, 1H), 4.85 (dd, J = organic phase was washed with brine, dried over Na2SO4 6.0 Hz, J = 4.0 Hz, 1H), 4.96 (dd, J = 6.0 Hz, J = 0.8 Hz, and concentrated under vacuum. The crude residue was 1H), 5.21 (s, 1H), 7.28–7.38 (m, 5H); 13C NMR (100 MHz) purified by flash column chromatography (hexanes/EtOAc  24.8, 26.2, 64.5, 70.5, 80.4, 81.6, 84.7, 87.3, 113.1, 125.4, 3:2) to give compound 4 as a yellow oil (1.85 g, 68% for 4 127.6, 128.7, 138.2; HRMS (ESI-TOF) m/z: Calcd for 25 1 + and 19% for its diastereomer). []D 22 (c 1.2, CHCl3); H C18H20O5: 280.1311; Found 303.1217 ([M + Na] ). NMR (400 MHz):  1.26 (s, 3H), 1.32 (s, 3H), 1.39 (s, 3H), Synthesis of (Z)-ethyl 3-((3aS,4R,6R,6aR)-2,2-dimethyl- 1.59 (s, 3H), 3.36 (br s, 2H), 3.57 (d, J = 6.4 Hz, 1H), 6-phenyltetrahydrofuro [3,4-d][1,3]dioxol-4-yl)acrylate (7) 3.99–4.09 (m, 3H), 4.36 (d, J = 7.2 Hz, 1H), 4.49 (dd, J = 7.2 Hz, J = 4.0 Hz, 1H), 4.95 (d, J = 4.0 Hz, 1H), 7.29–7.32 To a solution of diol 6 (72 mg, 0.26 mmol) in MeOH (10 (m, 1H), 7.35–7.38 (m, 2H), 7.43–7.44 (m, 2H); 13C NMR mL) was added solid NaIO4 (82 mg, 0.38 mmol) at room (100 MHz) δ 24.6, 25.3, 26.4, 26.7, 67.0, 70.1, 71.9, 75.7, temperature. After stirring for 45 min at room temperature, 76.0, 80.1, 108.5, 109.2, 127.1, 128.2, 128.6, 140.5; HRMS the mixture was filtered through a pad of Celite, and the pad was washed with MeOH (2 mL). To the resulting solution (ESI-TOF) m/z: Calcd for C18H26O6: 338.1729; Found 361.1601 ([M + Na]+). was added (ethoxycarbonylmethylene) triphenylphosphorane (271 mg, 0.78 mmol) at 0 °C. After stirring at 0 °C for Synthesis of (3aS,4R,6R,6aR)-4-((R)-2,2-dimethyl-1,3-dio- 8 h, the reaction mixture was concentrated under vacuum. xolan-4-yl)-2,2-dimethyl-6-phenyl-tetrahydrofuro[3,4-d] The crude residue was purified by flash column chromatog- [1,3]dioxole (5) raphy (hexanes/EtOAc 5:1) to give compound 7 as a color- 25 1 To a solution of diol 4 (540 mg, 1.6 mmol) in dry pyridine less solid (66 mg, 79%). []D 88 (c 0.5, CHCl3) [5h, 5i]; H (12 mL) was added TsCl (671 mg, 3.51 mmol) in two por- NMR (400 MHz):  1.32 (t, J = 7.2 Hz, 3H), 1.35 (s, 3H), tions at 80 °C under N2 protection and the mixture was 1.57 (s, 3H), 4.27 (q, J = 7.2 Hz, 2 H), 4.99 (dd, J = 6.0 Hz, stirred for 60–72 h. The reaction was quenched at room J = 0.4 Hz, 1H), 5.04 (dd, J = 6.0 Hz, J = 4.0 Hz, 1H), 5.27 temperature by the addition of MeOH (10 mL). The solution (s, 1H), 5.40–5.43 (m, 1H), 5.99 (dd, J = 11.6 Hz, J = 1.6 930 Liu J, et al. Sci China Chem July (2013) Vol.56 No.7

Hz, 1H), 6.45 (dd, J = 11.6 Hz, J = 6.8 Hz, 1H), 7.26–7.38 (m, 5H); 13C NMR (100 MHz) δ 14.1, 24.9, 26.3, 60.3, 78.2, 83.0, 85.1, 87.3, 112.7, 120.9, 125.5, 127.5, 128.6, 138.4, 145.5, 165.7; HRMS (ESI-TOF) m/z: Calcd for C18H22O5: 318.1467; Found 341.1377 ([M + Na]+).

Synthesis of ()-isoaltholactone (2) To a solution of ester 7 (36 mg, 0.11 mmol) in THF (1 mL) was added 50% trifluoroacetic acid (TFA) (2 mL) at room temperature. The mixture was stirred for 48 h and concentrated with toluene under vacuum. The crude residue was purified by flash column chromatography (hexanes/EtOAc Scheme 1 Retrosynthetic analysis of ()-isoaltholactone (2). 1:1) to give ()-isoaltholactone (2) (22.5 mg, 88%) as white 25 1 solid, []D 27 (c 0.5, EtOH); H NMR (400 MHz):  3.32 (br s, 1H), 4.27–4.29 (m, 1 H), 4.78 (d, J = 7.2 Hz, 1H), 4.88 The synthesis of stereochemically pure tetrasubstituted (t, J = 5.2 Hz, J = 4.8 Hz, 1H), 5.06 (t, J = 5.6 Hz, 1H), 6.21 tetrahydrofuran subunit 5 was initiated from di-O-isopropy- (d, J = 10.0 Hz, 1H), 6.87 (dd, J = 10.0 Hz, J = 4.4 Hz, 1H), lidene-a-D-mannofuranose (3), as shown in Scheme 2. The 7.27–7.41 (m, 5H); 13C NMR (100 MHz)  67.8, 78.4, 78.6, known di-O-isopropylidene-a-D-mannofuranose (3) was 83.1, 122.5, 125.6, 128.1, 128.5, 138.6, 141.7, 162.0; easily obtained from D-mannose in excellent yield according to a reported procedure [7]. According to a modified HRMS (ESI-TOF) m/z: Calcd for C13H12O4: 232.0736; Found 255.0624 ([M + Na]+). procedure from Mekki [8], excess phenyllithium was added to 3 in dry THF leading to a syn product 4 as a separable mixture of diastereoisomers in 87% yield (dr = 3.7:1 by 3 Results and discussion NMR, syn-4 being the major isomer) [9]. In the initial attempt for the synthesis of the -C- The retrosynthetic strategy for ()-isoaltholactone (2) is furanoside 5, we examined the Mitsunobu cyclization of the depicted in Scheme 1. We envisaged that 2 could be ob- diol 4 [10]. Unfortunately, the Tsunoda modification of the tained from functionalized (Z)-,-unsaturated ethyl ester 7 Mitsunobu reaction revealed no desired product. In the via acidic one-pot acetonide deprotection/lactonization conventional cyclization method utilizing TsCl and pyridine (Scheme 1). The (Z)-,-unsaturated ester 7, which contains [11], the diol 4 was tosylated at 80 °C and furnished all of the four required stereocenters of the natural product, -C-furanoside 5 as a single product in 73% yield. No 1 could be prepared from the key diol 4 by intramolecular -C-furanoside product was detected by careful H NMR tetrahydrofuran cyclization at C5 with inversion of config- analysis of the crude product. The -C-furanoside 5 was uration at C2 followed by cis-Wittig olefination at C6. De- resulted from the initial mesylation of the benzylic hydroxyl tails of the studies thus undertaken are described below. group (C2) of diol 4 and subsequent intramolecular cycliza-

Scheme 2 Total synthesis of ()-isoaltholactone. Liu J, et al. Sci China Chem July (2013) Vol.56 No.7 931 tion involving the C5 hydroxyl group. Alternatively, when active, tetrahydrofurano-2-pyrone from Goniothalamus giganteus MsCl was added to 4 in pyridine, -C-furanoside 5 was also (annonaceae). Tetrahedron Lett, 1985, 26: 955–956 4 Colegate SM, Din LB, Latiff A, Salleh KM, Samsudin MW, Skelton formed in 58% yield with considerable bis-mesylated prod- BW, Tadano K, White AH, Zakaria Z. (+)-Isoaltholactone: A uct even in cold solution. furanopyrone isolated from Goniothalamus species. Phytochemistry, 1990, 29: 1701–1704 FeCl3-mediated selective hydrolysis of the acetonide 5 (a) Ueno Y, Tadano K, Ogawa S, McLaughlin J L, Alkohafi A. Total group in 5 at room temperature for 2–3 h furnished the diol syntheses of (+)-altholactone [(+)-goniothalenol] and three stere- 6 (82%) [12]. Oxidative cleavage of the diol in 6 with NaIO4 ocongeners and their cytotoxicity against several tumor cell lines. in methanol gave the corresponding aldehyde in almost Bull Chem Soc Jpn, 1989, 62: 2328–2337; (b) Harris JM, O’Doherty quantitative yield, and when followed by cis-Wittig olefina- GA. Enantioselective syntheses of isoaltholactone, 3-epi-altholactone, and 5-hydroxygoniothalamin. Org Lett, 2000, 2: 2983–2986; (c) Har- tion with (ethoxycarbonylmethylene) triphenylphosphorane ris JM, O’Doherty GA. An olefination approach to the enantioselec- in dry methanol afforded the (Z)-,-unsaturated ester 7 in tive syntheses of several styryllactones. Tetrahedron, 2001, 57: 5161– 79% yield over two steps (J = 11.6 Hz for the Z-isomer, 5171; (d) Hiratate A, Kiyota H, Oritani TJ. Synthesis of ()-ent- Z:E > 5.5:1) [13]. Finally, one-pot acetonide deprotection/ altholactone, (+)-7a-epi-altholactone, ()-ent-isoaltholactone and ()- 7a-epi-Isoaltholactone from 2, 3-O-cyclohexylidene-D-glyceraldehyde. lactonization was achieved with 50% trifluoroacetic acid in Pesticide Sci, 2001, 26: 361–365; (e) Hiratate A, Kiyota H, Noshita T, THF at room temperature, delivering ()-isoaltholactone (2) Takeuchi R, Oritani T. Synthesis of both enantiomers of altholactone, in 88% yield [5i]. isoaltholactone and 5-hydroxygoniothalamin from tri-O-acetyl-D- The spectroscopic data (1H, 13C NMR, HRMS) and opti- glucal, and their biological activities. Nippon Noyaku Gakkaishi, 25 20 2001, 26: 366–370; (f) Peng X, Li A, Lu J, Wang Q, Pan X, Chan ASC. cal rotation {[]D 27 (c 0.5, EtOH); []D 32.2 (c 0.3, Enantioselective total synthesis of (+)-isoaltholactone. Tetrahedron, 23 EtOH), [5h]; []D 24.5 (c 0.2, EtOH), [5i]} of our syn- 2002, 58: 6799–6804; (g) Yadav JS, Rajaiah G, Raju AK. A concise thetic sample are essentially identical to those in the litera- and stereoselective synthesis of both enantiomers of altholactone and isoaltholactone. Tetrahedron Lett, 2003, 44: 5831–5833; (h) Yadav ture [5]. JS, Raju AK, Rao PR, Rajaiah G. Highly stereoselective synthesis of antitumor agents: Both enantiomers of goniothales diol, altholactone, and isoaltholactone. Tetrahedron: Asym, 2005, 16: 3283–3290; (i) 4 Conclusion Meira P R R, Moro AV, Correia, CRD. Stereoselective Heck-Matsuda arylations of chiral dihydrofurans with arenediazonium tetrafluorobo- rates: An efficient enantioselective total synthesis of ()-isoaltholactone. We have succeeded in the synthesis of the styryllactone Synthesis, 2007: 2279–2286; (j) Unsworth WP, Stevens K, Lamont ()-isoaltholactone from readily available chiral pool D- SG, Robertson J. Stereospecificity in the Au-catalysed cyclisation of mannose in only seven steps and 33% overall yield, includ- monoallylic diols. Synthesis of (+)-isoaltholactone. Chem Commun, 2011, 47: 7659–7661; (k) For formal synthesis: Trost BM, Aponick ing intramolecular tetrahydrofuran cyclization and one-pot A, Stanzl BN. A convergent Pd-catalyzed asymmetric allylic alkyla- deprotection-lactonization as key steps, which represents tion of dl- and meso-divinylethylene carbonate: Enantioselective the shortest route and highest overall yield to isoalt- synthesis of (+)-australine hydrochloride and formal synthesis of iso- holactone so far as we know. This route also allowed us to altholactone. Chem Eur J, 2007, 13: 9547–9560; (l) For analogues synthesis: Moro AV, Santos MRD, Correia CRD. Stereoselective prepare other aromatic analogues of isoaltholactone. synthesis of aza analogues of isoaltholactone and goniothalesdiol–– New applications of the Heck-Matsuda reaction. Eur J Org Chem, 2011, 7259–7270 This work was supported by the MOST of China (2012ZX09502001-001), 6 (a) Liu J, Liu Y, Zhang X, Zhang C, Gao Y, Wang L, Du Y, Total and the National Natural Science Foundation of China (2012CB822101, synthesis of ()-orthodiffenes A and C. J Org Chem, 2012, 77: 9718– 21072217 and 21202193). 9723; (b) Cai C, Liu J, Du Y, Linhardt RJ. Stereoselective total synthesis of ()-Cleistenolide. J Org Chem, 2010, 75: 5754–5756; (c) Du Y, Liu J, Linhardt RJ. Stereoselective synthesis of cytotoxic anhy- 1 For recent reviews on the chemistry and synthesis of styryllactones, drophytosphingosine pachastrissamine (Jaspine B) from D-Xylose. J see: (a) Blazques MA，Bermejo A, Zafra-Polo MC, Cortes D. Styryl- Org Chem, 2006, 71: 1251–1253; (d) Du Y, Chen Q, Linhardt RJ. lactones from Goniothalamus species. Phytochem. Anal, 1999, 10: The first total synthesis of sporiolide A. J Org Chem, 2006, 71: 161–170; (b) Harris JM, Li M, Scott JG, O’Doherty GA. 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Asymmetric synthesis of styryllactones. Curr 1963, 318–319 Org Synth, 2006, 3: 41–75; (f) Marco JA, Carda M, Murga J, Falomir 8 Mekki B, Singh G, Wightman RH, Reactions of 2, 3-O-isopropylidene E. Stereoselective syntheses of naturally occurring 5,6-dihydropyran- derivatives of furanose sugars with organomagnesium and organo- 2-ones. Tetrahedron, 2007, 63: 2929–2958 lithium nucleophiles. Tetrahedron Lett, 1991, 32: 5143–5146. Ac- 2 Loder JW, Nearn BH. Altholactone, a novel tetrahydrofuron[3,2b] cording to Mekki’s procedure, the reaction of phenyl lithium with pyran-5-one from a polyalthia species (Annonaceae) . Heterocycles, compd. 3 in dry THF at 40 °C should give diol 4 as single product 1977, 7: 113–118 (100:0). Unfortunately, we only obtained 2.8:1 mixture of the two 3 El-Zayat AAE, Ferigni NR, McCloud TG, McKenzie AJ, Byrn ST, diastereoisomers with low yield under their condition. Attempts to Cassady JM, Chang C, McLaughlin JL. 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