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Synthesis of key macrolactone structure of resin glycosides using a Keck macrolactonization method ab
ab
ab
Hong Huang , Chun-Song Yang , Li-Nan Zeng
& Ling-Li Zhang
ab
a
Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu 610041, China b
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Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China Published online: 08 Jan 2015.
To cite this article: Hong Huang, Chun-Song Yang, Li-Nan Zeng & Ling-Li Zhang (2015): Synthesis of key macrolactone structure of resin glycosides using a Keck macrolactonization method, Journal of Asian Natural Products Research, DOI: 10.1080/10286020.2014.998653 To link to this article: http://dx.doi.org/10.1080/10286020.2014.998653
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Journal of Asian Natural Products Research, 2015 http://dx.doi.org/10.1080/10286020.2014.998653
Synthesis of key macrolactone structure of resin glycosides using a Keck macrolactonization method Hong Huanga,b, Chun-Song Yanga,b, Li-Nan Zenga,b and Ling-Li Zhanga,b*
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a
Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu 610041, China; bKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China (Received 27 October 2014; final version received 10 December 2014) We present in this paper the efficient synthesis of three macrocyclic lactone units which are core structures of natural resin glycosides by the use of a Keck macrolactonization approach. Keywords: resin glycoside; Keck macrolactonization; macrolactone; synthesis
1.
Introduction
Resin glycosides are a type of amphiphilic glycolipids with a characteristic macrolactone backbone [1,2]. They are often isolated from the morning glory family (Convolvulaceae) plants most of which are widely used in folk medicine for treating various diseases. The hydrophobic aglycons found in resin glycosides are chiral hydroxyaliphatic acids mainly including jalapinolic acid (11(S)-hydroxyhexadecanoic acid) and convolvulinolic acid (11(S)hydroxytetradecanoic acid). However, the hydrophilic oligosaccharide portions are typically composed of four to six monosaccharides such as D -glucose, D -fucose, L -rhamnose, and D -quinovose. These sugar moieties are often substituted with fatty acids. Moreover, it is reported that resin glycosides possess a wide range of bioactivities such as cytotoxic activity against human cancer cell lines [3], antibacterial activity [4], and ionophoretic activity [5], as well as plant growthcontrolling effects [3,6]. Analysis of the structure – activity relationships showed that the macrocycle is an essential structural feature for all the bioactivities
of these plant glycolipids. Cleavage of the lactone bond leads to lose of activity [1]. To further study the structure –activity relationship and search for potential medicinal molecule, we set out to synthesize resin glycosides and their structural analogs. In this study, we report the highly efficient synthesis of the core macrolactone structures of resin glycosides by use of a Keck macrolactonization method.
2.
Results and discussion
Constructing the unique macrocyclic lactone core in resin glycosides has been considered a major synthetic challenge. In this aspect, two methods have been adopted so far [7]. One is a macrolactonization method. For instance, the Corey – Nicolaou macrolactonization protocol was used, respectively, by Schmidt [8], Yu [9], and Yang [10] for the total synthesis of calonyctin A1, tricolorin A, and batatoside L. Besides, the Yamaguchi approach was applied by the groups of Heathcock [11,12] and Sakairi [13], respectively, in the synthesis of tricolorin A and other resin glycosides. But this strategy suffers from
*Corresponding author. Email: [email protected]; [email protected] q 2015 Taylor & Francis
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H. Huang et al.
either long reaction times (5 –7 days) [8 – 10] or modest cyclization yields (60 – 71%) [11 – 13]. The other protocol is an olefin ring-closing metathesis (RCM) method, by which the Fu¨rstner group [14] and later a team from the Eisai Research Institute [15] assembled the macrolidic systems and realized the synthesis of a set of complex resin glycosides. But in this approach, the need to selectively reduce the formed disubstituted CvC double bond in the tether without affecting the unsaturated ester substituents on the carbohydrate chain required careful planning. Recently, Yang and co-workers [16] reported a highly convergent synthesis of the proposed structure of batatin VI, an architecturally novel ester-type resin glycoside dimer. In their elegant work, a Keck macrolactonization method was introduced to the production of the crucial 18membered macrolactone core and the ringclosing process was greatly improved. This strategy facilitates the final total synthesis of the target octasaccharide glycolipid. Here, we sought to apply the Keck macrolactonization approach to the synthesis of three macrolactone backbones of resin glycosides. Our first synthetic target is the protected macrolactone 1 (Scheme 1) which represents the core structure of tetrasaccharide resin glycosides batatosides J– N. These natural products were isolated by Kong and co-workers from the tuber of Ipomoea batatas (L.) Lam. PMBO PMBO PMBO
(Convolvulaceae) [17], a plant with the common name of sweet potato. Among these glycolipids, batatoside L possesses significant cytotoxicity against laryngeal carcinoma cells. As mentioned above, the Yang group previously employed a Corey – Nicolaou macrolactonization method to create such 18-membered macrolactone 1 and eventually succeeded in the total synthesis of batatoside L [10]. Thus, the known ring-closing precursor seco-acid 2 [10] was first prepared according to the literature procedures. Then, 2 was subjected to cyclization under Keck macrolactonization conditions (Scheme 1). In the event, treatment of 2 with a combination of N,N0 -dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP), and pyridinium 4toluenesulfonate (PPTS) in highly dilute 1,2-dichloroethane (DCE) solution (3.5 £ 1023 M) under reflux for 3 h gave the desired cyclized product 1 in a good 91% yield. Compared with the previous method reported by Yang et al. [10], a more reliable approach to get access to the macrocyclic framework of batatoside L via a Keck macrolactonization protocol has been established. This protocol offers a significant advantage over the previous method in terms of shorter reaction time, simpler operation, and higher yield. In order to further demonstrate the viability of the Keck macrolactonization reaction in the construction of macrolactone structure of resin glycoside, a 19membered macrocycle 3 was prepared
C5H11 O
DCC (10 equiv) DMAP (100 equiv) PPTS (10 equiv)
O
O
PMBO PMBO PMBO
C5H11 O O
TBDPSO
O
DCE, reflux, 3 h 91%
PMBO OH
TBDPSO PMBO
HO 2
O O
1 O
Scheme 1. Synthesis of macrolactone 1.
O
O
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Journal of Asian Natural Products Research utilizing the developed Keck macrolatonization approach as key cyclization strategy. This compound represents the common macrocyclic subunit of the pescaprein-type resin glycosides [18] and dimeric glycolipids batatins I and II [19]. As shown in Scheme 2, the synthesis began with the known allyl 3-O-PMB-a-L -rhamnopyranoside (4) [20]. Treatment of 4 with chloroacetyl chloride (ClCH2COCl) via a Ag2O-mediated regioselective monoacylation methodology [21] and followed by 4O-silylation with t-butyldimethylsilyl chloride (TBSCl) afforded L -rhamnose derivative 5 in 65% yield over two steps. Then, the anomeric hydroxyl group of 5 was unmasked by a PdCl2-catalyzed deallylation of the allyl ether. Activation of the resulting crude hemiacetal was completed by treatment with trichloroacetonitrile (CCl3CN) and 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) [22] to give the desired trichloroacetimidate 6 in 62% yield over two steps. Utilizing the Schmidt glycosylation conditions [23], donor 6 was easily coupled to the known 7 [9] in CH2Cl2 at 2 78 → 08C promoted by a catalytic amount of trimethylsilyl trifluoromethanesulfonate (TMSOTf), furnishing disaccharide lipid 8 in 97% yield. Conversion of 8 to 9 was realized via selective removal of the 20 -O-chloroacetyl group by mild saponification with K2CO3 in MeOH/CH2Cl2 (1:10) [24] and re-protection of the 20 position with a methyloxymethyl (MOM) group, thereby giving 9 in 65% over two steps. Subsequent removal of p-methoxybenzyl (PMB) of 9 with 2,3-dichloro-5,6dicyano-p-benzoquinone (DDQ) in CH2Cl2 afforded alcohol 10 in 80% yield. This compound was readily saponified with KOH in a THF/H2O (9:1) cosolvent at 558C for 6 h to liberate the aglycon carboxyl group, leading to hydroxy acid 11 in 90% yield. With this ring-closing precursor in hand, the key cyclization procedure was run according to the conditions described above to give 82% yield of the target disaccharide macrocycle 3.
3
The usefulness of this efficient synthetic technique is also proved by construction of a protected trisaccharide glycolipid 12 with a larger 21-membered macrolide ring (Scheme 3). Compound 12 represents the backbone of natural tricolorin f which was isolated by Bah and Pereda-Miranda from Mexican herb Ipomoea tricolor [25]. Previously, in the total synthesis of tricolorin f, 12 was assembled in a moderate 60% yield by Heathcock and co-workers via cyclization of 13 under a Yamaguchi macrolactonization protocol [12]. Here, hydroxyl acid 13 was subjected to the aforementioned Keck macrolactonization conditions (DCC, DMAP, PPTS, DCE, reflux, 5 h). As a result, the desired cyclized product 12 was obtained in an improved 75% yield. We noticed a good relationship between the yield of the Keck macrolactonization reaction and the size of each macrocycle. Namely, the yield of 1 with a 18-membered ring is higher than that of 3 with a 19-membered ring, while the yield of the latter is higher than that of 12 having a 21-membered ring (91% vs 82% vs 75%, Schemes 1, 2, and 3, respectively). In conclusion, three macrolactones which represent the core structures of natural resin glycosides have been efficiently constructed based on the use of a Keck macrolactonization approach. These compounds can be utilized as advanced intermediates in the final total synthesis of the corresponding resin glycosides. Further application of the Keck macrolactonization approach to the synthesis and structural modification of resin glycosides is currently underway. 3. 3.1
Experimental General experimental procedures
Optical rotations were measured with a PE-314 automatic polarimeter (PerkinElmer, Waltham, MA, USA) at 20 ^ 18C for solutions in a 1.0-dm cell. The HRESI-MS were measured by a Micromass
OH
O
O
O
O
C5H11
Scheme 2. Synthesis of macrolactone 3.
9 R = MOM
8 R = COCH2Cl
O
OR
O
O
2) TBSCl imidazole, DMAP CH2Cl2 65% over 2 steps
H3CO
TBSO PMBO
4
O
1) K2CO3, MeOH/CH2Cl2 2) MOMCl, DIPEA, CH2Cl2 65% over 2 steps
HO PMBO
1) ClCH2COCl OAll Ag2O, KI, n-Bu4NI CH2Cl2
5
OCOCH2Cl
OAll
80%
TBSO R1O
O O
O
C5H11
11 R1 = R2 = H
6
O CCl3
DCE, reflux, 3 h 82%
O
OH
O
7
O
O
O
O
O O
3
OMOM
O
O
O
C5H11
C5H11
TMSOTf, CH2Cl2 –78 to 0 °C, 2 h 97%
H3CO
TBSO
OCOCH2Cl
O
DCC, DMAP PPTS
TBSO PMBO
10 R1 = H, R2 = CH3
O
OMOM
O
O
R2O
O
2) CCl3CN, DBU, rt 62% over 2 steps
1) PdCl2, NaOAc AcOH-H2O, 30 °C
KOH, THF/H2O 55°C, 6 h 90%
DDQ, CH2Cl2 30 °C, 20 h
TBSO PMBO
O
NH
O O
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Journal of Asian Natural Products Research O BnO BnO BnO BnO BnO
O O
O
O
DCC, DMAP PPTS DCE, reflux, 5 h 75%
O
O
O
C5H11
O
OH
BnO BnO BnO BnO BnO
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O
O O O
C5H11 O
O
O
O
HO 13
5
O
12
O
Scheme 3. Synthesis of macrolactone 12.
Q-TOF mass spectrometer (Waters Corporation, Milford, MA, USA). 1H and 13C NMR spectra were recorded on a Varian Inova-400/54 spectrometer (Varian, Palo Alto, CA, USA) in CDCl3 with tetramethylsilane (TMS) as the internal reference. Chemical shifts (d) are expressed in parts per million downfield from the internal TMS absorption. Standard splitting patterns are abbreviated: s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). J values are given in Hertz. All nonaqueous reactions were performed under a nitrogen atmosphere and monitored by thin-layer chromatography (TLC) using silica gel GF254 plates from Merck (Darmstadt, Germany) with detection by charring with 10% (v/v) H2SO4 in EtOH or by UV detection. Column chromatography (CC) was carried out on silica gel (200 – 300 mesh, Qingdao Haiyang Chemical Group Co., Qingdao, China) or Sephadex LH-20 (GE Healthcare, Uppsala, Sweden). Solvents used in the reactions were distilled from appropriate drying agents prior to use. 3.2 Synthesis of allyl 2-O-chloroacetyl3-O-p-methoxybenzyl-4-O-tertbutyldimethylsilyl-a-L rhamnopyranoside (5) A mixture of 4 (1.1 g, 3.39 mmol), Ag2O (1.83 g, 7.89 mmol), and Bu4NI (127 mg, 0.35 mmol) in CH2Cl2 (34.0 ml) was stirred for 20 min at room temperature.
Then, to the mixture were added KI (227 mg, 1.37 mmol) and ClCH2COCl (310 ml, 3.70 mmol). After being stirred at room temperature for 12 h, the reaction mixture was filtered. The filtrate was concentrated to dryness, and the resulting residue was purified by CC (8:1, petroleum ether –EtOAc) to afford the corresponding regioselective acylation product as a colorless syrup. To a solution of the obtained syrup (103.8 mg, 0.26 mmol) in CH2Cl2 (1.21 ml) were added imidazole (114 mg, 1.48 mmol), DMAP (8.8 mg, 0.08 mmol), and TBSCl (0.25 ml, 1.16 mmol). The reaction mixture was stirred overnight at room temperature. Then, it was filtered and the filtrate was concentrated to dryness. The resulting residue was purified by CC (11:1, petroleum ether–EtOAc) to afford compound 5 as a colorless syrup (1.13 g, 65% over two steps). Rf 0.55 (5:1, petroleum ether – EtOAc). [a ]20 D 2 57.9 (c ¼ 1.8, CHCl3); 1 H NMR (400 MHz, CDCl3): d 7.21, 6.85 (each 2H, J ¼ 8.4 Hz), 5.85 – 5.95 (m, 1H), 5.36 (s, 1H), 5.31 (ddd, 1H, J ¼ 1.2, 2.4, 16.0 Hz), 5.24 (d, 1H, J ¼ 10.8 Hz), 4.75 (s, 1H), 4.58 (d, 1H, J ¼ 10.8 Hz), 4.36 (d, 1H, J ¼ 10.8 Hz), 4.14– 4.18 (m, 1H), 4.12 (2H, s), 3.94 –3.99 (m, 1H), 3.80 (s, 3H), 3.68 –3.69 (m, 1H), 3.65– 3.67 (m, 1H), 3.57 (t, 1H, J ¼ 8.8 Hz), 1.29 (t, 3H, J ¼ 7.2 Hz), 0.87 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (100 Hz, CDCl3): d 2 4.7, 2 3.7, 18.2, 18.4, 55.2, 67.4, 68.1, 68.6, 69.2, 70.8, 73.0, 77.5, 96.9, 113.5,
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117.6, 129.5, 130.1, 133.6, 158.9, 170.4; HRESIMS: m/z 537.3155 [M þ Na]þ (calcd for C25H39ClNaO7Si, 537.3147).
2 4.6; HRESIMS: m/z 640.1944 [M þ Na]þ (calcd for C24H35Cl4NNaO7Si, 640.1931).
3.3 Synthesis of 2-O-chloroacetyl-3-Op-methoxybenzyl-4-O-tertbutyldimethylsilyl-a-L -rhamnopyranosyl trichloroacetimidate (6)
3.4 Synthesis of 1-(methoxycarbonyl) pentadec-10(S)-yl 2-O-chloroacetyl-3-Op-methoxybenzyl-4-O-tertbutyldimethylsilyl-a-L rhamnopyranosyl-(1→2)-3,4-Oisopropylidene-b-D -fucopyranoside (8)
A mixture of 5 (514 mg, 1.00 mmol), PdCl2 (356 mg, 2.01 mmol), and NaOAc (674 mg, 8.22 mmol) in AcOH – H2O (9:1, v/v, 6.4 ml) was stirred overnight at 308C. Then, the insoluble material was filtered off. The filtrate was concentrated in vacuo to give a residue which was extracted with EtOAc (20 ml £ 2). The combined organic extracts were washed with water (10 ml £ 2), saturated aqueous NaHCO3 (15 ml £ 2), and brine (15 ml), dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by CC (6:1, petroleum ether– EtOAc) to afford the desired lactol as a colorless syrup which was directly used for the next step without further purification. To a solution of the obtained lactol (460 mg, 0.97 mmol) in CH2Cl2 (9.56 ml) were added CCl3CN (750 ml, 7.05 mmol) and catalytic DBU at 08C. The mixture was stirred for 5 h during which time it was gradually warmed to ambient temperature, and then concentrated to give a residue which was purified by CC (8:1, petroleum ether – EtOAc) to afford compound 6 as a colorless syrup (382 mg, 62% over two steps). Rf 0.60 (3:1, petroleum ether – EtOAc). [a ]20 D 2 48.0 (c ¼ 2.3, CHCl3); 1H NMR (400 MHz, CDCl3): d 8.64 (s, 1H), 7.23 (d, 2H, J ¼ 8.4 Hz), 6.85 (d, 2H, J ¼ 8.4 Hz), 6.14 (d, 1H, J ¼ 1.2 Hz), 5.43 (t, 1H, J ¼ 2.4 Hz), 4.59 (d, 1H, J ¼ 11.2 Hz), 4.43 (d, 1H, J ¼ 10.8 Hz), 4.12(2H, s), 3.80 –3.84 (m, 1H), 3.79 (s, 3H), 3.62– 3.71 (m, 2H), 1.31 (d, 3H, J ¼ 6.4 Hz), 0.88 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); 13C NMR (100 Hz, CDCl3): d 170.0, 160.1, 159.1, 129.8, 129.5, 113.6, 95.3, 76.6, 72.4, 72.3, 71.2, 67.4, 67.2, 55.2, 25.9, 18.3, 2 3.7,
A mixture of donor 6 (210 mg, 0.34 mmol), ˚ acceptor 7 (90 mg, 0.19 mmol), and 4 A molecular sieves (350 mg) in CH2Cl2 (3.0 ml) was stirred for 10 min at room temperature and then cooled to 2 788C. To the slurry was added a solution of TMSOTf (12.4 ml, 0.068 mmol) in CH2Cl2 (0.5 ml). The reaction mixture was stirred at 2 788C for 1 h. Then, the reaction was allowed to warm to 08C over 1 h, quenched with triethylamine and filtered. The combined filtrates were concentrated in vacuo to give a residue, which was purified by CC (8:1, petroleum ether – EtOAc) to afford 8 as a colorless syrup (306 mg, 97%). Rf 0.55 (4:1, petroleum ether – EtOAc); 0 1 ½a20 D 2 15.8 (c ¼ 1.1, CHCl3); H NMR (400 MHz, CDCl3): d 7.19 (d, 2H, J ¼ 8.8 Hz), 6.84 (d, 2H, J ¼ 8.0 Hz), 5.44 (s, 1H), 5.20 (s, 1H), 4.60 (d, 1H, J ¼ 10.8 Hz), 4.26 (d, 1H, J ¼ 8.0 Hz), 4.24 (d, 1H, J ¼ 10.8 Hz), 4.11 (2H, s), 4.10 –4.17 (m, 2H), 3.97 (dd, 1H, J ¼ 1.6, 5.2 Hz), 3.79– 3.82 (m, 1H), 3.79 (s, 3H), 3.70 (t, 1H, J ¼ 8.0 Hz), 3.65 (s, 3H), 3.58 – 3.63 (m, 2H), 3.52 (t, 1H, J ¼ 8.8 Hz), 2.29 (t, 2H, J ¼ 7.2 Hz), 1.49 –1.60 (m, 6H), 1.53 (s, 3H), 1.39 (d, 3H, J ¼ 6.4 Hz), 1.32 (s, 3H), 1.24– 1.36 (m, 18H), 1.22 (d, 3H, J ¼ 6.4 Hz), 0.91 (t, 3H, J ¼ 6.8 Hz), 0.85 (s, 9H), 0.00 (s, 3H), 2 0.08 (s, 3H); 13C NMR (100 Hz, CDCl3): d 174.3, 170.3, 158.9, 130.3, 129.4, 113.4, 109.9, 99.5, 96.1, 80.1, 78.5, 78.1, 76.7, 74.4, 73.0, 70.9, 68.7, 68.6, 68.4, 67.1, 55.2, 51.4, 34.6, 34.1, 33.4, 32.0, 30.0, 29.8, 29.7, 29.6, 29.3, 29.2, 28.1, 26.4, 25.9, 25.1, 24.9, 24.5, 22.6, 18.2, 16.6,
Journal of Asian Natural Products Research
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14.1, 2 3.7, 2 4.4; HRESIMS: m/z 951.6119 [M þ Na]þ (calcd for C48H81ClNaO13Si, 951.6129). 3.5 Synthesis of 1-(methoxycarbonyl) pentadec-10(S)-yl 2-O-methyloxymethyl3-O-p-methoxybenzyl-4-O-tertbutyldimethylsilyl-a-L rhamnopyranosyl-(1→2)-3,4-Oisopropylidene-b-D -fucopyranoside (9) A mixture of 8 (928 mg, 1.00 mmol) and K2CO3 (276 mg, 2.0 mmol) in MeOH – CH2Cl2 (1:10, v/v, 6.0 ml) was stirred 5 h at 308C. Then, the insoluble material was filtered off. The filtrate was concentrated in vacuo to give a residue which was extracted with EtOAc (20 ml £ 2). The combined organic extracts were washed with water (10 ml £ 2), saturated aqueous NaHCO3 (15 ml £ 2), and brine (15 ml), dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by CC (4:1, petroleum ether – EtOAc) to afford the desired alcohol as a colorless syrup. To a solution of the obtained alcohol (827 mg, 0.97 mmol) in dry CH2Cl2 (24 ml) were added DIPEA (1.21 ml, 6.79 mmol) and MOMCl (0.29 ml, 2.91 mmol). The solution was stirred at room temperature for 22 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (1 ml). The aqueous phase was extracted with CH2Cl2 (3 £ 10 ml). The combined organic phases were dried over anhydrous Na2SO4 and concentrated. The crude residue was purified by CC (7:1, petroleum ether – EtOAc) to afford MOM ether 9 as a colorless syrup (583 mg, 65% over two steps). Rf 0.65 (4:1, petroleum ether – EtOAc); [a ]20 D 2 40.1 (c ¼ 1.1, CHCl3); 1 H NMR (400 MHz, CDCl3): d 7.19 (d, 2H, J ¼ 8.8 Hz), 6.84 (d, 2H, J ¼ 8.0 Hz), 5.44 (s, 1H), 5.20 (s, 1H), 4.60 (d, 1H, J ¼ 10.8 Hz), 4.59 (d, J ¼ 6.8 Hz, 1H), 4.51 (d, J ¼ 6.8 Hz, 1H), 4.26 (d, 1H, J ¼ 8.0 Hz), 4.24 (d, 1H, J ¼ 10.8 Hz), 4.11 (2H, s), 4.10 –4.17 (m, 2H), 3.97 (dd,
7
1H, J ¼ 1.6, 5.2 Hz), 3.79– 3.82 (m, 1H), 3.79 (s, 3H), 3.70 (t, 1H, J ¼ 8.0 Hz), 3.65 (s, 3H), 3.58 –3.63 (m, 2H), 3.34 (s, 3H), 3.52 (t, 1H, J ¼ 8.8 Hz), 2.29 (t, 2H, J ¼ 7.2 Hz), 1.49 –1.60 (m, 6H), 1.53 (s, 3H), 1.39 (d, 3H, J ¼ 6.4 Hz), 1.32 (s, 3H), 1.24 – 1.36 (m, 18H), 1.22 (d, 3H, J ¼ 6.4 Hz), 0.91 (t, 3H, J ¼ 6.8 Hz), 0.85 (s, 9H), 0.00 (s, 3H), 2 0.08 (s, 3H); 13 C NMR (100 Hz, CDCl3): d 170.3, 158.9, 130.3, 129.4, 113.4, 109.9, 99.5, 97.9, 96.1, 80.1, 78.5, 78.1, 76.7, 74.4, 73.0, 70.9, 68.7, 68.6, 68.4, 67.1, 56.7, 55.2, 51.4, 34.6, 34.1, 33.4, 32.0, 30.0, 29.8, 29.7, 29.6, 29.3, 29.2, 28.1, 26.4, 25.9, 25.1, 24.9, 24.5, 18.2, 16.6, 14.1, 2 3.6, 2 4.8; HRESIMS: m/z 919.6670 [M þ Na]þ (calcd for C48H84NaO13Si, 919.6675). 3.6 Synthesis of 1-(methoxycarbonyl) pentadec-10(S)-yl 2-O-methyloxymethyl4-O-tert-butyldimethylsilyl-a-L rhamnopyranosyl-(1→2)-3,4-Oisopropylidene-b-D -fucopyranoside (10) To a solution of 9 (500 mg, 0.56 mmol) in CH2Cl2 – H2O (17:1, v/v, 6.0 ml) was added DDQ (191 mg, 0.84 mmol) at 08C. The mixture was stirred for 8 h at 308C, then the reaction was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 (10 ml £ 3). The combined organic extracts were washed with water (15 ml £ 3) and brine (15 ml), dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by CC (6:1, petroleum ether –EtOAc) to afford 10 as a white solid (348 mg, 80%). Rf 0.45 (5:1, petroleum ether – EtOAc); ½a20 D 2 25.5 (c ¼ 1.1, CHCl3); 1H NMR (400 MHz, CDCl3): d 5.44 (s, 1H), 5.20 (s, 1H), 4.59 (d, J ¼ 6.8 Hz, 1H), 4.51 (d, J ¼ 6.8 Hz, 1H), 4.26 (d, 1H, J ¼ 8.0 Hz), 4.11 (2H, s), 4.10 –4.17 (m, 2H), 3.97 (dd, 1H, J ¼ 5.2, 1.6 Hz), 3.79– 3.82 (m, 1H), 3.70 (t, 1H, J ¼ 8.0 Hz), 3.65 (s, 3H), 3.58 – 3.63 (m, 2H), 3.34 (s, 3H), 3.52 (t, 1H, J ¼ 8.8 Hz), 2.29 (t, 2H, J ¼ 7.2 Hz), 1.49 –1.60 (m,
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6H), 1.53 (s, 3H), 1.39 (d, 3H, J ¼ 6.4 Hz), 1.32 (s, 3H), 1.24 –1.36 (m, 18H), 1.22 (d, 3H, J ¼ 6.4 Hz), 0.91 (t, 3H, J ¼ 6.8 Hz), 0.85 (s, 9H), 0.00 (s, 3H), 2 0.08 (s, 3H); 13 C NMR (100 Hz, CDCl3): d 170.3, 99.5, 97.9, 96.1, 80.1, 78.5, 78.1, 76.7, 74.4, 73.0, 70.9, 68.7, 68.6, 68.4, 56.7, 51.4, 34.6, 34.1, 33.4, 32.0, 30.0, 29.8, 29.7, 29.6, 29.3, 29.2, 28.1, 26.4, 25.9, 25.1, 24.9, 24.5, 18.2, 16.6, 14.1, 2 3.8, 2 4.5; HRESIMS: m/z 799.6089 [M þ Na]þ (calcd for C40H76NaO12Si, 799.6098). 3.7 Synthesis of 1-(hydroxycarbonyl) pentadec-10(S)-yl 2-O-methyloxymethyl4-O-tert-butyldimethylsilyl-a-L rhamnopyranosyl-(1→2)-3,4-Oisopropylidene-b-D -fucopyranoside (11) A mixture of 10 (155 mg, 0.20 mmol) and KOH (183 mg, 3.27 mmol) in THF – H2O (9:1, v/v, 7.0 ml) was stirred at 558C for 6 h. Then, the reaction was neutralized with acetic acid and extracted with CH2Cl2 (20 ml £ 3). The combined organic extracts were washed with brine (20 ml), dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by CC (3:1, petroleum ether – EtOAc) to afford 11 as a colorless syrup (137 mg, 90%). Rf 0.38 (2:1, petroleum ether – EtOAc); ½a20 D 2 30.2 (c ¼ 1.1, CHCl3); 1H NMR (400 MHz, CDCl3): d 5.44 (s, 1H), 5.20 (s, 1H), 4.59 (d, J ¼ 6.8 Hz, 1H), 4.51 (d, J ¼ 6.8 Hz, 1H), 4.26 (d, 1H, J ¼ 8.0 Hz), 4.11 (2H, s), 4.10– 4.17 (m, 2H), 3.97 (dd, 1H, J ¼ 1.6, 5.2 Hz), 3.79– 3.82 (m, 1H), 3.70 (t, 1H, J ¼ 8.0 Hz), 3.58– 3.63 (m, 2H), 3.34 (s, 3H), 3.52 (t, 1H, J ¼ 8.8 Hz), 2.29 (t, 2H, J ¼ 7.2 Hz), 1.49– 1.60 (m, 6H), 1.53 (s, 3H), 1.39 (d, 3H, J ¼ 6.4 Hz), 1.32 (s, 3H), 1.24– 1.36 (m, 18H), 1.22 (d, 3H, J ¼ 6.4 Hz), 0.91 (t, 3H, J ¼ 6.8 Hz), 0.85 (s, 9H), 0.00 (s, 3H), 2 0.08 (s, 3H); 13C NMR (100 Hz, CDCl3): d 170.3, 99.5, 97.9, 96.1, 80.1, 78.5, 78.1, 76.7, 74.4, 73.0, 70.9, 68.7, 68.6, 68.4, 56.7, 34.6, 34.1, 33.4, 32.0, 30.0, 29.8, 29.7, 29.6,
29.3, 29.2, 28.1, 26.4, 25.9, 25.1, 24.9, 24.5, 18.2, 16.6, 14.1, 2 3.2, 2 4.2; HRESIMS: m/z 785.5956 [M þ Na]þ (calcd for C39H74NaO12Si, 785.5943). 4. General procedure for the ringclosing step using a Keck macrolactonization approach A stirred mixture of DCC (10.1 equiv), DMAP (102 equiv), and PPTS (10.1 equiv) in DCE (40 ml) was stirred under reflux. To the mixture was added dropwise a 3.5 £ 10 23 M solution of seco-acid (1.0 equiv.) in DCE by a syringe pump over 2 h. The reaction mixture was stirred for an additional 1 h, then it was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by CC to afford the desired macrolactone products. 4.1 Synthesis of 1,20 -lactone of (S)-1(hydroxycarbonyl)pentadec-10-yl 3-O-pmethoxybenzyl-4-O-tertbutyldiphenylsilyl-a-L rhamnopyranosyl-(1→2)-3,4,6-tri-O-pmethoxybenzyl-b-D -glucopyranoside (1) Compound 1 was prepared from 2 (91 mg, 0.07 mmol), DCC (146 mg, 0.71 mmol), DMAP (872 mg, 7.15 mmol), and PPTS (178 mg, 0.71 mmol). The residue was purified by CC (10:1, petroleum ether –EtOAc) to afford macrolactone 1 (62 mg, 92%) as a colorless syrup. Product 1 is a known compound and its spectroscopic data matched the reported data [10]. 4.2 Synthesis of 1,30 -lactone of (S)-1(hydroxycarbonyl)pentadec-10-yl 2-Omethyloxymethyl-4-O-tertbutyldimethylsilyl-a-L rhamnopyranosyl-(1→2)-3,4-Oisopropylidene-b-D -fucopyranoside (3) Compound 3 was prepared from 11 (61 mg, 0.08 mmol), DCC (146 mg,
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Journal of Asian Natural Products Research 0.71 mmol), DMAP (872 mg, 7.15 mmol), and PPTS (178 mg, 0.71 mmol). The residue was purified by CC (10:1, petroleum ether – EtOAc) to afford macrolactone 3 (49 mg, 82%) as a colorless syrup. Rf 0.26 (2:1, petroleum ether – EtOAc); ½a20 D þ 20.7 (c ¼ 1.2, CHCl3); 1 H NMR (400 MHz, CDCl3): d 5.45 (s, 1H), 5.22 (s, 1H), 4.58 (d, J ¼ 6.8 Hz, 1H), 4.52 (d, J ¼ 6.8 Hz, 1H), 4.26 (d, 1H, J ¼ 8.0 Hz), 4.10 (2H, s), 4.10 –4.17 (m, 2H), 3.97 (dd, 1H, J ¼ 5.2, 1.6 Hz), 3.77– 3.84 (m, 1H), 3.70 (t, 1H, J ¼ 8.0 Hz), 3.55 –3.62 (m, 2H), 3.32 (s, 3H), 3.52 (t, 1H, J ¼ 8.8 Hz), 2.29 (t, 2H, J ¼ 7.2 Hz), 1.49 –1.60 (m, 6H), 1.53 (s, 3H), 1.39 (d, 3H, J ¼ 6.4 Hz), 1.31 (s, 3H), 1.24 – 1.36 (m, 18H), 1.22 (d, 3H, J ¼ 6.4 Hz), 0.91 (t, 3H, J ¼ 6.8 Hz), 0.85 (s, 9H), 0.00 (s, 3H), -0.08 (s, 3H); 13C NMR (100 Hz, CDCl3): d 165.3, 99.5, 97.9, 96.1, 80.1, 78.5, 78.1, 76.6, 76.7, 74.4, 73.0, 70.9, 68.7, 68.6, 56.6, 34.4, 34.1, 33.4, 32.0, 30.0, 29.8, 29.7, 29.6, 29.3, 29.2, 28.1, 27.4, 25.9, 25.1, 24.9, 24.4, 18.2, 16.6, 14.1, 2 3.5, 2 4.3; HRESIMS: m/z 767.5809 [M þ Na]þ (calcd for C39H72NaO11Si, 767.5831). 4.3 Synthesis of 1,2 000 -lactone of (S)-1(hydroxycarbonyl)pentadec-10-yl 3,4-diO-benzyl-b-D -quinovosyl-(1→2)-3,4,6tri-O-benzyl-b-D -glucopyranosyl-(1→2)3,4-O-isopropylidene-b-D fucopyranoside (12) Compound 12 was prepared from 13 (85 mg, 0.07 mmol), DCC (146 mg, 0.71 mmol), DMAP (872 mg, 7.15 mmol), and PPTS (178 mg, 0.71 mmol). The residue was purified by CC (7:1, petroleum ether – EtOAc) to afford macrolactone 12 (63 mg, 75%) as a colorless syrup. Product 12 is a known compound and its spectroscopic data matched the reported data [12]. Disclosure statement No potential conflict of interest was reported by the authors.
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Funding The financial support from the NSFC [grant number 81373381] is highly appreciated.
References [1] R. Pereda-Miranda and M. Bah, Curr. Top. Med. Chem. 3, 111 (2003). [2] Sh.F. Lu, Z.W. Guo, Q.Q. O’yang, and Y.Z. Hui, Youji Huaxue 17, 488 (1997) and references cited therein. [3] E.M.M. Gaspar, Eur. J. Org. Chem., 369 (2001). [4] L. Che´ rigo, R. Pereda-Miranda, M. Fragoso-Serrano, N. Jacobo-Herrera, G.W. Kaatz, and S. Gibbons, J. Nat. Prod. 71, 1037 (2008). [5] I. Kitagawa, K. Ohashi, H. Kawanishi, H. Shibuya, K. Shinkai, and H. Akedo, Chem. Pharm. Bull. 37, 1679 (1989). [6] I. Leo´n, R.G. Enrı´quez, D. Gnecco, M.L. Villarreal, D.A. Corte´ s, W.F. Reynolds, and M. Yu, J. Nat. Prod. 67, 1552 (2004). [7] For a review on synthesis of resin glycosides, see: A. Fu¨rstner, Eur. J. Org. Chem. 2004, 943 (2004). [8] Z.H. Jiang, A. Geyer, and R.R. Schmidt, Angew. Chem. Int. Ed. Engl. 34, 2520 (1995). [9] S.F. Lu, Q.Q. O’Yang, Z.W. Guo, B. Yu, and Y.Z. Hui, Angew. Chem. Int. Ed. Engl. 36, 2344 (1997). [10] L. Xie, S.Y. Zhu, X.Q. Shen, L.L. He, and J.S. Yang, J. Org. Chem. 75, 5764 (2010). [11] D.P. Larson and C.H. Heathcock, J. Org. Chem. 62, 8406 (1997). [12] M. Brito-Arias, R. Pereda-Miranda, and C.H. Heathcock, J. Org. Chem. 69, 4567 (2004). [13] J. Furukawa, S. Kobayashi, M. Nomizu, N. Nishi, and N. Sakairi, Tetrahedron Lett. 41, 3453 (2000). [14] A. Fu¨rstner and T. Nagano, J. Am. Chem. Soc. 129, 1906 (2007). [15] M.H.D. Postema, K. TenDyke, J. Cutter, G. Kuznetsov, and Q.-L. Xu, Org. Lett. 11, 1417 (2009). [16] S.Y. Zhu, J.S. Huang, S.S. Zheng, K. Zhu, and J.S. Yang, Org. Lett. 15, 4154 (2013). [17] Y.Q. Yin, J.S. Wang, J.G. Luo, and L.Y. Kong, Carbohydr. Res. 344, 466 (2009). [18] C. Escobedo-Martı´nez and R. PeredaMiranda, J. Nat. Prod. 70, 974 (2007). [19] E. Escalante-Sa´nchez and R. PeredaMiranda, J. Nat. Prod. 70, 1029 (2007).
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[20] L.A. Mulard, M.J. Clement, A. Imberty, and M. Delepierre, Eur. J. Org. Chem. 2002, 2486 (2002). [21] Q. Yang, M. Lei, Q.J. Yin, and J.S. Yang, Carbohydr. Res. 342, 1175 (2007). [22] R.R. Schmidt and K.H. Jung, in Preparative Carbohydrate Chemistry, edited
by S. Hanessian (Dekker, New York, 1997). [23] R.R. Schmidt, Angew. Chem. Int. Ed. Engl. 25, 212 (1986). [24] H. Weiss and C. Unverzagt, Angew. Chem. Int. Ed. 42, 4261 (2003). [25] M. Bah and R. Pereda-Miranda, Tetrahedron 52, 13063 (1996).
Journal of Asian Natural Products Research Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ganp20
Synthesis of key macrolactone structure of resin glycosides using a Keck macrolactonization method ab
ab
ab
Hong Huang , Chun-Song Yang , Li-Nan Zeng
& Ling-Li Zhang
ab
a
Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu 610041, China b
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Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China Published online: 08 Jan 2015.
To cite this article: Hong Huang, Chun-Song Yang, Li-Nan Zeng & Ling-Li Zhang (2015): Synthesis of key macrolactone structure of resin glycosides using a Keck macrolactonization method, Journal of Asian Natural Products Research, DOI: 10.1080/10286020.2014.998653 To link to this article: http://dx.doi.org/10.1080/10286020.2014.998653
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Journal of Asian Natural Products Research, 2015 http://dx.doi.org/10.1080/10286020.2014.998653
Synthesis of key macrolactone structure of resin glycosides using a Keck macrolactonization method Hong Huanga,b, Chun-Song Yanga,b, Li-Nan Zenga,b and Ling-Li Zhanga,b*
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a
Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu 610041, China; bKey Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China (Received 27 October 2014; final version received 10 December 2014) We present in this paper the efficient synthesis of three macrocyclic lactone units which are core structures of natural resin glycosides by the use of a Keck macrolactonization approach. Keywords: resin glycoside; Keck macrolactonization; macrolactone; synthesis
1.
Introduction
Resin glycosides are a type of amphiphilic glycolipids with a characteristic macrolactone backbone [1,2]. They are often isolated from the morning glory family (Convolvulaceae) plants most of which are widely used in folk medicine for treating various diseases. The hydrophobic aglycons found in resin glycosides are chiral hydroxyaliphatic acids mainly including jalapinolic acid (11(S)-hydroxyhexadecanoic acid) and convolvulinolic acid (11(S)hydroxytetradecanoic acid). However, the hydrophilic oligosaccharide portions are typically composed of four to six monosaccharides such as D -glucose, D -fucose, L -rhamnose, and D -quinovose. These sugar moieties are often substituted with fatty acids. Moreover, it is reported that resin glycosides possess a wide range of bioactivities such as cytotoxic activity against human cancer cell lines [3], antibacterial activity [4], and ionophoretic activity [5], as well as plant growthcontrolling effects [3,6]. Analysis of the structure – activity relationships showed that the macrocycle is an essential structural feature for all the bioactivities
of these plant glycolipids. Cleavage of the lactone bond leads to lose of activity [1]. To further study the structure –activity relationship and search for potential medicinal molecule, we set out to synthesize resin glycosides and their structural analogs. In this study, we report the highly efficient synthesis of the core macrolactone structures of resin glycosides by use of a Keck macrolactonization method.
2.
Results and discussion
Constructing the unique macrocyclic lactone core in resin glycosides has been considered a major synthetic challenge. In this aspect, two methods have been adopted so far [7]. One is a macrolactonization method. For instance, the Corey – Nicolaou macrolactonization protocol was used, respectively, by Schmidt [8], Yu [9], and Yang [10] for the total synthesis of calonyctin A1, tricolorin A, and batatoside L. Besides, the Yamaguchi approach was applied by the groups of Heathcock [11,12] and Sakairi [13], respectively, in the synthesis of tricolorin A and other resin glycosides. But this strategy suffers from
*Corresponding author. Email: [email protected]; [email protected] q 2015 Taylor & Francis
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H. Huang et al.
either long reaction times (5 –7 days) [8 – 10] or modest cyclization yields (60 – 71%) [11 – 13]. The other protocol is an olefin ring-closing metathesis (RCM) method, by which the Fu¨rstner group [14] and later a team from the Eisai Research Institute [15] assembled the macrolidic systems and realized the synthesis of a set of complex resin glycosides. But in this approach, the need to selectively reduce the formed disubstituted CvC double bond in the tether without affecting the unsaturated ester substituents on the carbohydrate chain required careful planning. Recently, Yang and co-workers [16] reported a highly convergent synthesis of the proposed structure of batatin VI, an architecturally novel ester-type resin glycoside dimer. In their elegant work, a Keck macrolactonization method was introduced to the production of the crucial 18membered macrolactone core and the ringclosing process was greatly improved. This strategy facilitates the final total synthesis of the target octasaccharide glycolipid. Here, we sought to apply the Keck macrolactonization approach to the synthesis of three macrolactone backbones of resin glycosides. Our first synthetic target is the protected macrolactone 1 (Scheme 1) which represents the core structure of tetrasaccharide resin glycosides batatosides J– N. These natural products were isolated by Kong and co-workers from the tuber of Ipomoea batatas (L.) Lam. PMBO PMBO PMBO
(Convolvulaceae) [17], a plant with the common name of sweet potato. Among these glycolipids, batatoside L possesses significant cytotoxicity against laryngeal carcinoma cells. As mentioned above, the Yang group previously employed a Corey – Nicolaou macrolactonization method to create such 18-membered macrolactone 1 and eventually succeeded in the total synthesis of batatoside L [10]. Thus, the known ring-closing precursor seco-acid 2 [10] was first prepared according to the literature procedures. Then, 2 was subjected to cyclization under Keck macrolactonization conditions (Scheme 1). In the event, treatment of 2 with a combination of N,N0 -dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP), and pyridinium 4toluenesulfonate (PPTS) in highly dilute 1,2-dichloroethane (DCE) solution (3.5 £ 1023 M) under reflux for 3 h gave the desired cyclized product 1 in a good 91% yield. Compared with the previous method reported by Yang et al. [10], a more reliable approach to get access to the macrocyclic framework of batatoside L via a Keck macrolactonization protocol has been established. This protocol offers a significant advantage over the previous method in terms of shorter reaction time, simpler operation, and higher yield. In order to further demonstrate the viability of the Keck macrolactonization reaction in the construction of macrolactone structure of resin glycoside, a 19membered macrocycle 3 was prepared
C5H11 O
DCC (10 equiv) DMAP (100 equiv) PPTS (10 equiv)
O
O
PMBO PMBO PMBO
C5H11 O O
TBDPSO
O
DCE, reflux, 3 h 91%
PMBO OH
TBDPSO PMBO
HO 2
O O
1 O
Scheme 1. Synthesis of macrolactone 1.
O
O
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Journal of Asian Natural Products Research utilizing the developed Keck macrolatonization approach as key cyclization strategy. This compound represents the common macrocyclic subunit of the pescaprein-type resin glycosides [18] and dimeric glycolipids batatins I and II [19]. As shown in Scheme 2, the synthesis began with the known allyl 3-O-PMB-a-L -rhamnopyranoside (4) [20]. Treatment of 4 with chloroacetyl chloride (ClCH2COCl) via a Ag2O-mediated regioselective monoacylation methodology [21] and followed by 4O-silylation with t-butyldimethylsilyl chloride (TBSCl) afforded L -rhamnose derivative 5 in 65% yield over two steps. Then, the anomeric hydroxyl group of 5 was unmasked by a PdCl2-catalyzed deallylation of the allyl ether. Activation of the resulting crude hemiacetal was completed by treatment with trichloroacetonitrile (CCl3CN) and 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) [22] to give the desired trichloroacetimidate 6 in 62% yield over two steps. Utilizing the Schmidt glycosylation conditions [23], donor 6 was easily coupled to the known 7 [9] in CH2Cl2 at 2 78 → 08C promoted by a catalytic amount of trimethylsilyl trifluoromethanesulfonate (TMSOTf), furnishing disaccharide lipid 8 in 97% yield. Conversion of 8 to 9 was realized via selective removal of the 20 -O-chloroacetyl group by mild saponification with K2CO3 in MeOH/CH2Cl2 (1:10) [24] and re-protection of the 20 position with a methyloxymethyl (MOM) group, thereby giving 9 in 65% over two steps. Subsequent removal of p-methoxybenzyl (PMB) of 9 with 2,3-dichloro-5,6dicyano-p-benzoquinone (DDQ) in CH2Cl2 afforded alcohol 10 in 80% yield. This compound was readily saponified with KOH in a THF/H2O (9:1) cosolvent at 558C for 6 h to liberate the aglycon carboxyl group, leading to hydroxy acid 11 in 90% yield. With this ring-closing precursor in hand, the key cyclization procedure was run according to the conditions described above to give 82% yield of the target disaccharide macrocycle 3.
3
The usefulness of this efficient synthetic technique is also proved by construction of a protected trisaccharide glycolipid 12 with a larger 21-membered macrolide ring (Scheme 3). Compound 12 represents the backbone of natural tricolorin f which was isolated by Bah and Pereda-Miranda from Mexican herb Ipomoea tricolor [25]. Previously, in the total synthesis of tricolorin f, 12 was assembled in a moderate 60% yield by Heathcock and co-workers via cyclization of 13 under a Yamaguchi macrolactonization protocol [12]. Here, hydroxyl acid 13 was subjected to the aforementioned Keck macrolactonization conditions (DCC, DMAP, PPTS, DCE, reflux, 5 h). As a result, the desired cyclized product 12 was obtained in an improved 75% yield. We noticed a good relationship between the yield of the Keck macrolactonization reaction and the size of each macrocycle. Namely, the yield of 1 with a 18-membered ring is higher than that of 3 with a 19-membered ring, while the yield of the latter is higher than that of 12 having a 21-membered ring (91% vs 82% vs 75%, Schemes 1, 2, and 3, respectively). In conclusion, three macrolactones which represent the core structures of natural resin glycosides have been efficiently constructed based on the use of a Keck macrolactonization approach. These compounds can be utilized as advanced intermediates in the final total synthesis of the corresponding resin glycosides. Further application of the Keck macrolactonization approach to the synthesis and structural modification of resin glycosides is currently underway. 3. 3.1
Experimental General experimental procedures
Optical rotations were measured with a PE-314 automatic polarimeter (PerkinElmer, Waltham, MA, USA) at 20 ^ 18C for solutions in a 1.0-dm cell. The HRESI-MS were measured by a Micromass
OH
O
O
O
O
C5H11
Scheme 2. Synthesis of macrolactone 3.
9 R = MOM
8 R = COCH2Cl
O
OR
O
O
2) TBSCl imidazole, DMAP CH2Cl2 65% over 2 steps
H3CO
TBSO PMBO
4
O
1) K2CO3, MeOH/CH2Cl2 2) MOMCl, DIPEA, CH2Cl2 65% over 2 steps
HO PMBO
1) ClCH2COCl OAll Ag2O, KI, n-Bu4NI CH2Cl2
5
OCOCH2Cl
OAll
80%
TBSO R1O
O O
O
C5H11
11 R1 = R2 = H
6
O CCl3
DCE, reflux, 3 h 82%
O
OH
O
7
O
O
O
O
O O
3
OMOM
O
O
O
C5H11
C5H11
TMSOTf, CH2Cl2 –78 to 0 °C, 2 h 97%
H3CO
TBSO
OCOCH2Cl
O
DCC, DMAP PPTS
TBSO PMBO
10 R1 = H, R2 = CH3
O
OMOM
O
O
R2O
O
2) CCl3CN, DBU, rt 62% over 2 steps
1) PdCl2, NaOAc AcOH-H2O, 30 °C
KOH, THF/H2O 55°C, 6 h 90%
DDQ, CH2Cl2 30 °C, 20 h
TBSO PMBO
O
NH
O O
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4 H. Huang et al.
Journal of Asian Natural Products Research O BnO BnO BnO BnO BnO
O O
O
O
DCC, DMAP PPTS DCE, reflux, 5 h 75%
O
O
O
C5H11
O
OH
BnO BnO BnO BnO BnO
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O
O O O
C5H11 O
O
O
O
HO 13
5
O
12
O
Scheme 3. Synthesis of macrolactone 12.
Q-TOF mass spectrometer (Waters Corporation, Milford, MA, USA). 1H and 13C NMR spectra were recorded on a Varian Inova-400/54 spectrometer (Varian, Palo Alto, CA, USA) in CDCl3 with tetramethylsilane (TMS) as the internal reference. Chemical shifts (d) are expressed in parts per million downfield from the internal TMS absorption. Standard splitting patterns are abbreviated: s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). J values are given in Hertz. All nonaqueous reactions were performed under a nitrogen atmosphere and monitored by thin-layer chromatography (TLC) using silica gel GF254 plates from Merck (Darmstadt, Germany) with detection by charring with 10% (v/v) H2SO4 in EtOH or by UV detection. Column chromatography (CC) was carried out on silica gel (200 – 300 mesh, Qingdao Haiyang Chemical Group Co., Qingdao, China) or Sephadex LH-20 (GE Healthcare, Uppsala, Sweden). Solvents used in the reactions were distilled from appropriate drying agents prior to use. 3.2 Synthesis of allyl 2-O-chloroacetyl3-O-p-methoxybenzyl-4-O-tertbutyldimethylsilyl-a-L rhamnopyranoside (5) A mixture of 4 (1.1 g, 3.39 mmol), Ag2O (1.83 g, 7.89 mmol), and Bu4NI (127 mg, 0.35 mmol) in CH2Cl2 (34.0 ml) was stirred for 20 min at room temperature.
Then, to the mixture were added KI (227 mg, 1.37 mmol) and ClCH2COCl (310 ml, 3.70 mmol). After being stirred at room temperature for 12 h, the reaction mixture was filtered. The filtrate was concentrated to dryness, and the resulting residue was purified by CC (8:1, petroleum ether –EtOAc) to afford the corresponding regioselective acylation product as a colorless syrup. To a solution of the obtained syrup (103.8 mg, 0.26 mmol) in CH2Cl2 (1.21 ml) were added imidazole (114 mg, 1.48 mmol), DMAP (8.8 mg, 0.08 mmol), and TBSCl (0.25 ml, 1.16 mmol). The reaction mixture was stirred overnight at room temperature. Then, it was filtered and the filtrate was concentrated to dryness. The resulting residue was purified by CC (11:1, petroleum ether–EtOAc) to afford compound 5 as a colorless syrup (1.13 g, 65% over two steps). Rf 0.55 (5:1, petroleum ether – EtOAc). [a ]20 D 2 57.9 (c ¼ 1.8, CHCl3); 1 H NMR (400 MHz, CDCl3): d 7.21, 6.85 (each 2H, J ¼ 8.4 Hz), 5.85 – 5.95 (m, 1H), 5.36 (s, 1H), 5.31 (ddd, 1H, J ¼ 1.2, 2.4, 16.0 Hz), 5.24 (d, 1H, J ¼ 10.8 Hz), 4.75 (s, 1H), 4.58 (d, 1H, J ¼ 10.8 Hz), 4.36 (d, 1H, J ¼ 10.8 Hz), 4.14– 4.18 (m, 1H), 4.12 (2H, s), 3.94 –3.99 (m, 1H), 3.80 (s, 3H), 3.68 –3.69 (m, 1H), 3.65– 3.67 (m, 1H), 3.57 (t, 1H, J ¼ 8.8 Hz), 1.29 (t, 3H, J ¼ 7.2 Hz), 0.87 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (100 Hz, CDCl3): d 2 4.7, 2 3.7, 18.2, 18.4, 55.2, 67.4, 68.1, 68.6, 69.2, 70.8, 73.0, 77.5, 96.9, 113.5,
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117.6, 129.5, 130.1, 133.6, 158.9, 170.4; HRESIMS: m/z 537.3155 [M þ Na]þ (calcd for C25H39ClNaO7Si, 537.3147).
2 4.6; HRESIMS: m/z 640.1944 [M þ Na]þ (calcd for C24H35Cl4NNaO7Si, 640.1931).
3.3 Synthesis of 2-O-chloroacetyl-3-Op-methoxybenzyl-4-O-tertbutyldimethylsilyl-a-L -rhamnopyranosyl trichloroacetimidate (6)
3.4 Synthesis of 1-(methoxycarbonyl) pentadec-10(S)-yl 2-O-chloroacetyl-3-Op-methoxybenzyl-4-O-tertbutyldimethylsilyl-a-L rhamnopyranosyl-(1→2)-3,4-Oisopropylidene-b-D -fucopyranoside (8)
A mixture of 5 (514 mg, 1.00 mmol), PdCl2 (356 mg, 2.01 mmol), and NaOAc (674 mg, 8.22 mmol) in AcOH – H2O (9:1, v/v, 6.4 ml) was stirred overnight at 308C. Then, the insoluble material was filtered off. The filtrate was concentrated in vacuo to give a residue which was extracted with EtOAc (20 ml £ 2). The combined organic extracts were washed with water (10 ml £ 2), saturated aqueous NaHCO3 (15 ml £ 2), and brine (15 ml), dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by CC (6:1, petroleum ether– EtOAc) to afford the desired lactol as a colorless syrup which was directly used for the next step without further purification. To a solution of the obtained lactol (460 mg, 0.97 mmol) in CH2Cl2 (9.56 ml) were added CCl3CN (750 ml, 7.05 mmol) and catalytic DBU at 08C. The mixture was stirred for 5 h during which time it was gradually warmed to ambient temperature, and then concentrated to give a residue which was purified by CC (8:1, petroleum ether – EtOAc) to afford compound 6 as a colorless syrup (382 mg, 62% over two steps). Rf 0.60 (3:1, petroleum ether – EtOAc). [a ]20 D 2 48.0 (c ¼ 2.3, CHCl3); 1H NMR (400 MHz, CDCl3): d 8.64 (s, 1H), 7.23 (d, 2H, J ¼ 8.4 Hz), 6.85 (d, 2H, J ¼ 8.4 Hz), 6.14 (d, 1H, J ¼ 1.2 Hz), 5.43 (t, 1H, J ¼ 2.4 Hz), 4.59 (d, 1H, J ¼ 11.2 Hz), 4.43 (d, 1H, J ¼ 10.8 Hz), 4.12(2H, s), 3.80 –3.84 (m, 1H), 3.79 (s, 3H), 3.62– 3.71 (m, 2H), 1.31 (d, 3H, J ¼ 6.4 Hz), 0.88 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); 13C NMR (100 Hz, CDCl3): d 170.0, 160.1, 159.1, 129.8, 129.5, 113.6, 95.3, 76.6, 72.4, 72.3, 71.2, 67.4, 67.2, 55.2, 25.9, 18.3, 2 3.7,
A mixture of donor 6 (210 mg, 0.34 mmol), ˚ acceptor 7 (90 mg, 0.19 mmol), and 4 A molecular sieves (350 mg) in CH2Cl2 (3.0 ml) was stirred for 10 min at room temperature and then cooled to 2 788C. To the slurry was added a solution of TMSOTf (12.4 ml, 0.068 mmol) in CH2Cl2 (0.5 ml). The reaction mixture was stirred at 2 788C for 1 h. Then, the reaction was allowed to warm to 08C over 1 h, quenched with triethylamine and filtered. The combined filtrates were concentrated in vacuo to give a residue, which was purified by CC (8:1, petroleum ether – EtOAc) to afford 8 as a colorless syrup (306 mg, 97%). Rf 0.55 (4:1, petroleum ether – EtOAc); 0 1 ½a20 D 2 15.8 (c ¼ 1.1, CHCl3); H NMR (400 MHz, CDCl3): d 7.19 (d, 2H, J ¼ 8.8 Hz), 6.84 (d, 2H, J ¼ 8.0 Hz), 5.44 (s, 1H), 5.20 (s, 1H), 4.60 (d, 1H, J ¼ 10.8 Hz), 4.26 (d, 1H, J ¼ 8.0 Hz), 4.24 (d, 1H, J ¼ 10.8 Hz), 4.11 (2H, s), 4.10 –4.17 (m, 2H), 3.97 (dd, 1H, J ¼ 1.6, 5.2 Hz), 3.79– 3.82 (m, 1H), 3.79 (s, 3H), 3.70 (t, 1H, J ¼ 8.0 Hz), 3.65 (s, 3H), 3.58 – 3.63 (m, 2H), 3.52 (t, 1H, J ¼ 8.8 Hz), 2.29 (t, 2H, J ¼ 7.2 Hz), 1.49 –1.60 (m, 6H), 1.53 (s, 3H), 1.39 (d, 3H, J ¼ 6.4 Hz), 1.32 (s, 3H), 1.24– 1.36 (m, 18H), 1.22 (d, 3H, J ¼ 6.4 Hz), 0.91 (t, 3H, J ¼ 6.8 Hz), 0.85 (s, 9H), 0.00 (s, 3H), 2 0.08 (s, 3H); 13C NMR (100 Hz, CDCl3): d 174.3, 170.3, 158.9, 130.3, 129.4, 113.4, 109.9, 99.5, 96.1, 80.1, 78.5, 78.1, 76.7, 74.4, 73.0, 70.9, 68.7, 68.6, 68.4, 67.1, 55.2, 51.4, 34.6, 34.1, 33.4, 32.0, 30.0, 29.8, 29.7, 29.6, 29.3, 29.2, 28.1, 26.4, 25.9, 25.1, 24.9, 24.5, 22.6, 18.2, 16.6,
Journal of Asian Natural Products Research
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14.1, 2 3.7, 2 4.4; HRESIMS: m/z 951.6119 [M þ Na]þ (calcd for C48H81ClNaO13Si, 951.6129). 3.5 Synthesis of 1-(methoxycarbonyl) pentadec-10(S)-yl 2-O-methyloxymethyl3-O-p-methoxybenzyl-4-O-tertbutyldimethylsilyl-a-L rhamnopyranosyl-(1→2)-3,4-Oisopropylidene-b-D -fucopyranoside (9) A mixture of 8 (928 mg, 1.00 mmol) and K2CO3 (276 mg, 2.0 mmol) in MeOH – CH2Cl2 (1:10, v/v, 6.0 ml) was stirred 5 h at 308C. Then, the insoluble material was filtered off. The filtrate was concentrated in vacuo to give a residue which was extracted with EtOAc (20 ml £ 2). The combined organic extracts were washed with water (10 ml £ 2), saturated aqueous NaHCO3 (15 ml £ 2), and brine (15 ml), dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by CC (4:1, petroleum ether – EtOAc) to afford the desired alcohol as a colorless syrup. To a solution of the obtained alcohol (827 mg, 0.97 mmol) in dry CH2Cl2 (24 ml) were added DIPEA (1.21 ml, 6.79 mmol) and MOMCl (0.29 ml, 2.91 mmol). The solution was stirred at room temperature for 22 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (1 ml). The aqueous phase was extracted with CH2Cl2 (3 £ 10 ml). The combined organic phases were dried over anhydrous Na2SO4 and concentrated. The crude residue was purified by CC (7:1, petroleum ether – EtOAc) to afford MOM ether 9 as a colorless syrup (583 mg, 65% over two steps). Rf 0.65 (4:1, petroleum ether – EtOAc); [a ]20 D 2 40.1 (c ¼ 1.1, CHCl3); 1 H NMR (400 MHz, CDCl3): d 7.19 (d, 2H, J ¼ 8.8 Hz), 6.84 (d, 2H, J ¼ 8.0 Hz), 5.44 (s, 1H), 5.20 (s, 1H), 4.60 (d, 1H, J ¼ 10.8 Hz), 4.59 (d, J ¼ 6.8 Hz, 1H), 4.51 (d, J ¼ 6.8 Hz, 1H), 4.26 (d, 1H, J ¼ 8.0 Hz), 4.24 (d, 1H, J ¼ 10.8 Hz), 4.11 (2H, s), 4.10 –4.17 (m, 2H), 3.97 (dd,
7
1H, J ¼ 1.6, 5.2 Hz), 3.79– 3.82 (m, 1H), 3.79 (s, 3H), 3.70 (t, 1H, J ¼ 8.0 Hz), 3.65 (s, 3H), 3.58 –3.63 (m, 2H), 3.34 (s, 3H), 3.52 (t, 1H, J ¼ 8.8 Hz), 2.29 (t, 2H, J ¼ 7.2 Hz), 1.49 –1.60 (m, 6H), 1.53 (s, 3H), 1.39 (d, 3H, J ¼ 6.4 Hz), 1.32 (s, 3H), 1.24 – 1.36 (m, 18H), 1.22 (d, 3H, J ¼ 6.4 Hz), 0.91 (t, 3H, J ¼ 6.8 Hz), 0.85 (s, 9H), 0.00 (s, 3H), 2 0.08 (s, 3H); 13 C NMR (100 Hz, CDCl3): d 170.3, 158.9, 130.3, 129.4, 113.4, 109.9, 99.5, 97.9, 96.1, 80.1, 78.5, 78.1, 76.7, 74.4, 73.0, 70.9, 68.7, 68.6, 68.4, 67.1, 56.7, 55.2, 51.4, 34.6, 34.1, 33.4, 32.0, 30.0, 29.8, 29.7, 29.6, 29.3, 29.2, 28.1, 26.4, 25.9, 25.1, 24.9, 24.5, 18.2, 16.6, 14.1, 2 3.6, 2 4.8; HRESIMS: m/z 919.6670 [M þ Na]þ (calcd for C48H84NaO13Si, 919.6675). 3.6 Synthesis of 1-(methoxycarbonyl) pentadec-10(S)-yl 2-O-methyloxymethyl4-O-tert-butyldimethylsilyl-a-L rhamnopyranosyl-(1→2)-3,4-Oisopropylidene-b-D -fucopyranoside (10) To a solution of 9 (500 mg, 0.56 mmol) in CH2Cl2 – H2O (17:1, v/v, 6.0 ml) was added DDQ (191 mg, 0.84 mmol) at 08C. The mixture was stirred for 8 h at 308C, then the reaction was quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 (10 ml £ 3). The combined organic extracts were washed with water (15 ml £ 3) and brine (15 ml), dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by CC (6:1, petroleum ether –EtOAc) to afford 10 as a white solid (348 mg, 80%). Rf 0.45 (5:1, petroleum ether – EtOAc); ½a20 D 2 25.5 (c ¼ 1.1, CHCl3); 1H NMR (400 MHz, CDCl3): d 5.44 (s, 1H), 5.20 (s, 1H), 4.59 (d, J ¼ 6.8 Hz, 1H), 4.51 (d, J ¼ 6.8 Hz, 1H), 4.26 (d, 1H, J ¼ 8.0 Hz), 4.11 (2H, s), 4.10 –4.17 (m, 2H), 3.97 (dd, 1H, J ¼ 5.2, 1.6 Hz), 3.79– 3.82 (m, 1H), 3.70 (t, 1H, J ¼ 8.0 Hz), 3.65 (s, 3H), 3.58 – 3.63 (m, 2H), 3.34 (s, 3H), 3.52 (t, 1H, J ¼ 8.8 Hz), 2.29 (t, 2H, J ¼ 7.2 Hz), 1.49 –1.60 (m,
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6H), 1.53 (s, 3H), 1.39 (d, 3H, J ¼ 6.4 Hz), 1.32 (s, 3H), 1.24 –1.36 (m, 18H), 1.22 (d, 3H, J ¼ 6.4 Hz), 0.91 (t, 3H, J ¼ 6.8 Hz), 0.85 (s, 9H), 0.00 (s, 3H), 2 0.08 (s, 3H); 13 C NMR (100 Hz, CDCl3): d 170.3, 99.5, 97.9, 96.1, 80.1, 78.5, 78.1, 76.7, 74.4, 73.0, 70.9, 68.7, 68.6, 68.4, 56.7, 51.4, 34.6, 34.1, 33.4, 32.0, 30.0, 29.8, 29.7, 29.6, 29.3, 29.2, 28.1, 26.4, 25.9, 25.1, 24.9, 24.5, 18.2, 16.6, 14.1, 2 3.8, 2 4.5; HRESIMS: m/z 799.6089 [M þ Na]þ (calcd for C40H76NaO12Si, 799.6098). 3.7 Synthesis of 1-(hydroxycarbonyl) pentadec-10(S)-yl 2-O-methyloxymethyl4-O-tert-butyldimethylsilyl-a-L rhamnopyranosyl-(1→2)-3,4-Oisopropylidene-b-D -fucopyranoside (11) A mixture of 10 (155 mg, 0.20 mmol) and KOH (183 mg, 3.27 mmol) in THF – H2O (9:1, v/v, 7.0 ml) was stirred at 558C for 6 h. Then, the reaction was neutralized with acetic acid and extracted with CH2Cl2 (20 ml £ 3). The combined organic extracts were washed with brine (20 ml), dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by CC (3:1, petroleum ether – EtOAc) to afford 11 as a colorless syrup (137 mg, 90%). Rf 0.38 (2:1, petroleum ether – EtOAc); ½a20 D 2 30.2 (c ¼ 1.1, CHCl3); 1H NMR (400 MHz, CDCl3): d 5.44 (s, 1H), 5.20 (s, 1H), 4.59 (d, J ¼ 6.8 Hz, 1H), 4.51 (d, J ¼ 6.8 Hz, 1H), 4.26 (d, 1H, J ¼ 8.0 Hz), 4.11 (2H, s), 4.10– 4.17 (m, 2H), 3.97 (dd, 1H, J ¼ 1.6, 5.2 Hz), 3.79– 3.82 (m, 1H), 3.70 (t, 1H, J ¼ 8.0 Hz), 3.58– 3.63 (m, 2H), 3.34 (s, 3H), 3.52 (t, 1H, J ¼ 8.8 Hz), 2.29 (t, 2H, J ¼ 7.2 Hz), 1.49– 1.60 (m, 6H), 1.53 (s, 3H), 1.39 (d, 3H, J ¼ 6.4 Hz), 1.32 (s, 3H), 1.24– 1.36 (m, 18H), 1.22 (d, 3H, J ¼ 6.4 Hz), 0.91 (t, 3H, J ¼ 6.8 Hz), 0.85 (s, 9H), 0.00 (s, 3H), 2 0.08 (s, 3H); 13C NMR (100 Hz, CDCl3): d 170.3, 99.5, 97.9, 96.1, 80.1, 78.5, 78.1, 76.7, 74.4, 73.0, 70.9, 68.7, 68.6, 68.4, 56.7, 34.6, 34.1, 33.4, 32.0, 30.0, 29.8, 29.7, 29.6,
29.3, 29.2, 28.1, 26.4, 25.9, 25.1, 24.9, 24.5, 18.2, 16.6, 14.1, 2 3.2, 2 4.2; HRESIMS: m/z 785.5956 [M þ Na]þ (calcd for C39H74NaO12Si, 785.5943). 4. General procedure for the ringclosing step using a Keck macrolactonization approach A stirred mixture of DCC (10.1 equiv), DMAP (102 equiv), and PPTS (10.1 equiv) in DCE (40 ml) was stirred under reflux. To the mixture was added dropwise a 3.5 £ 10 23 M solution of seco-acid (1.0 equiv.) in DCE by a syringe pump over 2 h. The reaction mixture was stirred for an additional 1 h, then it was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by CC to afford the desired macrolactone products. 4.1 Synthesis of 1,20 -lactone of (S)-1(hydroxycarbonyl)pentadec-10-yl 3-O-pmethoxybenzyl-4-O-tertbutyldiphenylsilyl-a-L rhamnopyranosyl-(1→2)-3,4,6-tri-O-pmethoxybenzyl-b-D -glucopyranoside (1) Compound 1 was prepared from 2 (91 mg, 0.07 mmol), DCC (146 mg, 0.71 mmol), DMAP (872 mg, 7.15 mmol), and PPTS (178 mg, 0.71 mmol). The residue was purified by CC (10:1, petroleum ether –EtOAc) to afford macrolactone 1 (62 mg, 92%) as a colorless syrup. Product 1 is a known compound and its spectroscopic data matched the reported data [10]. 4.2 Synthesis of 1,30 -lactone of (S)-1(hydroxycarbonyl)pentadec-10-yl 2-Omethyloxymethyl-4-O-tertbutyldimethylsilyl-a-L rhamnopyranosyl-(1→2)-3,4-Oisopropylidene-b-D -fucopyranoside (3) Compound 3 was prepared from 11 (61 mg, 0.08 mmol), DCC (146 mg,
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Journal of Asian Natural Products Research 0.71 mmol), DMAP (872 mg, 7.15 mmol), and PPTS (178 mg, 0.71 mmol). The residue was purified by CC (10:1, petroleum ether – EtOAc) to afford macrolactone 3 (49 mg, 82%) as a colorless syrup. Rf 0.26 (2:1, petroleum ether – EtOAc); ½a20 D þ 20.7 (c ¼ 1.2, CHCl3); 1 H NMR (400 MHz, CDCl3): d 5.45 (s, 1H), 5.22 (s, 1H), 4.58 (d, J ¼ 6.8 Hz, 1H), 4.52 (d, J ¼ 6.8 Hz, 1H), 4.26 (d, 1H, J ¼ 8.0 Hz), 4.10 (2H, s), 4.10 –4.17 (m, 2H), 3.97 (dd, 1H, J ¼ 5.2, 1.6 Hz), 3.77– 3.84 (m, 1H), 3.70 (t, 1H, J ¼ 8.0 Hz), 3.55 –3.62 (m, 2H), 3.32 (s, 3H), 3.52 (t, 1H, J ¼ 8.8 Hz), 2.29 (t, 2H, J ¼ 7.2 Hz), 1.49 –1.60 (m, 6H), 1.53 (s, 3H), 1.39 (d, 3H, J ¼ 6.4 Hz), 1.31 (s, 3H), 1.24 – 1.36 (m, 18H), 1.22 (d, 3H, J ¼ 6.4 Hz), 0.91 (t, 3H, J ¼ 6.8 Hz), 0.85 (s, 9H), 0.00 (s, 3H), -0.08 (s, 3H); 13C NMR (100 Hz, CDCl3): d 165.3, 99.5, 97.9, 96.1, 80.1, 78.5, 78.1, 76.6, 76.7, 74.4, 73.0, 70.9, 68.7, 68.6, 56.6, 34.4, 34.1, 33.4, 32.0, 30.0, 29.8, 29.7, 29.6, 29.3, 29.2, 28.1, 27.4, 25.9, 25.1, 24.9, 24.4, 18.2, 16.6, 14.1, 2 3.5, 2 4.3; HRESIMS: m/z 767.5809 [M þ Na]þ (calcd for C39H72NaO11Si, 767.5831). 4.3 Synthesis of 1,2 000 -lactone of (S)-1(hydroxycarbonyl)pentadec-10-yl 3,4-diO-benzyl-b-D -quinovosyl-(1→2)-3,4,6tri-O-benzyl-b-D -glucopyranosyl-(1→2)3,4-O-isopropylidene-b-D fucopyranoside (12) Compound 12 was prepared from 13 (85 mg, 0.07 mmol), DCC (146 mg, 0.71 mmol), DMAP (872 mg, 7.15 mmol), and PPTS (178 mg, 0.71 mmol). The residue was purified by CC (7:1, petroleum ether – EtOAc) to afford macrolactone 12 (63 mg, 75%) as a colorless syrup. Product 12 is a known compound and its spectroscopic data matched the reported data [12]. Disclosure statement No potential conflict of interest was reported by the authors.
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Funding The financial support from the NSFC [grant number 81373381] is highly appreciated.
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