Total synthesis of caminoside B, a novel antimicrobial glycolipid isolated from the marine sponge Caminus sphaeroconia

Carbohydrate Research 345 (2010) 750–760

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Total synthesis of caminoside B, a novel antimicrobial glycolipid isolated from the marine sponge Caminus sphaeroconia Zaihong Zhang a, Chengli Zong a, Gaopeng Song a, Guokai Lv a, Yuexing Chun a, Peng Wang a, Ning Ding b, Yingxia Li b,* a b

School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China School of Pharmacy, Fudan University, Shanghai 201203, China

a r t i c l e

i n f o

Article history: Received 14 October 2009 Received in revised form 21 January 2010 Accepted 25 January 2010 Available online 29 January 2010

a b s t r a c t The first total synthesis of caminoside B, a novel marine antimicrobial glycolipid isolated from the marine sponge Caminus sphaeroconia, was developed. This marine small molecule inhibitor (IC50 = 20 lM) targeting type III secretory pathway of bacterial pathogenesis was assembled in good yield via a ‘2+2+1’ strategy based on stereocontrolled construction of the four glycosidic linkages. Ó 2010 Elsevier Ltd. All rights reserved.

Keywords: Caminoside B Regioselective glycosylation Antimicrobial glycolipid Type III secretory pathway

1. Introduction Knowledge of type III secretory pathway in various gram-negative organisms was accumulated in the late 1980s and early 1990s.1 This secretory system is found in disease-causing bacteria, but not in their non-pathogenic counterparts. Notably, pathogens use the type III secretory system to deliver different effectors that influence host cells in a variety of ways.2 The virulence mechanism of pathogens such as enteropathogenic Escherichia coli (EPEC) and enterohemorragic E. coli 0157:H7 (EHEC) that are deadly toward children and the elderly is mainly dependent on E. coli type III secretion system, while benign commensal strains do not bear such organization.3 So, components of this system might be good targets for novel antimicrobial agents and selective type III secretory system inhibitors are potential antimicrobials. Recently, a screening program aimed at discovering inhibitors of the bacterial type III secretory system was developed. A bioassay-guided isolation of the methanol extract of the Caribbean sponge Caminus sphaeroconia led to the discovery of caminosides A to D, a new family of antimicrobial glycolipids, which are the first marine small molecule inhibitors (IC50 = 20 lM) targeting the type III secretory pathway of bacterial pathogenesis and which show reasonably potent in vitro inhibition of certain gram-positive pathogens.4 Caminosides display a number of unique structural features: a fully substituted glucose residue (sugar B), a 6-deoxyta* Corresponding author. Tel./fax: +86 21 51980127. E-mail address: [email protected] (Y. Li). 0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2010.01.015

lose residue (sugar C), and L-quinovose (sugar D), which are rare in nature, and an unprecedented aglycon in sponge glycolipids which bears a C19 linear chain and a methyl ketone terminus. Thus, a total synthesis of the first known caminoside A4a was initially achieved by the Yu group,5 but there are still some aspects to improve in the synthesis, for example, to stereoselectively construct the R-configured secondary alcohol of the aglycon, to improve the synthetic procedure, and to get the natural glycolipid instead of the peracetate derivative. In an effort to carry SAR studies and identify compounds with improved activity, we now report a facile synthesis of the fascinating compound caminoside B with an improved biological activity as compared to A. 2. Results and discussion As could be expected from the structural similarity between caminosides A and B, the total synthesis of caminoside B presents similar difficulties in that it requires considerable forethought in the orchestration of the orthogonal protections of the carbohydrate. Therefore, in our synthesis of caminoside B, besides utilizing the advantages in total synthesis of caminoside A,5 we further optimized the synthetic route. As outlined in Scheme 1, synthesis of caminoside B was planned to be accomplished via a ‘2+2+1’ strategy. Building block 2 as a glycosyl acceptor could result from the glycosylation of (10R)-10-hydroxy-1-octadecane (6), in which the absolute configuration at C-10 could be introduced via 2,3-O-isopropylidene-D-glyceraldehyde and glucosyl donor 7. Building block 3, as a disaccharide donor, could be obtained by regioselective

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Z. Zhang et al. / Carbohydrate Research 345 (2010) 750–760

HO

O OBn O

BnO BnO

OH HO

O

HO HO

OH O

A

2

B

O

OBn OH O BnO O

O O

3

O O O O O

O

BnO

CCl3

NH OAzmb

CCl3 NH

O STol OLev 9 HO O

HO O

O

D

O

OAc

OBn

O HO

7

O

O RO

BnO BnO

O

O

C

OBn O

O

OH

OH

6

O

OH

OMP

OAzmb 8

HO Caminoside A R=Ac Caminoside B (1) R=CH3(CH2)2CO

O O

BnO BnO 4

STol OBn or

O

BnO BnO

OBn

CF3 NPh

5

Scheme 1. Retrosynthetic analysis of caminoside B.

glycosylation of 1-thiofucopyranoside 9 with a monosaccharide acceptor 8 bearing two free hydroxyl groups at C-4 and C-6. The sterically less hindered primary hydroxyl group at C-6 would be the main glycosylation site. Then condensation of 2 and 3 could afford the trisaccharide backbone. Lastly, coupling of the trisaccharide acceptor with donors 4 and 5 could provide the tetrasaccharide which could produce target compound 1 by hydrogenolysis of the O-benzyl groups. Our study began with the preparation of the building block 2 which could be obtained by coupling of acceptor 6 with donor 7. As outlined in Scheme 2, Wittig reaction of (S)-2,3-O-isopropylidene-D-glyceraldehyde with 1-octyltriphenylphosphonium bromide gave the cis-alkene 10 in 86% yield.6 Reduction of the unsaturated carbon–carbon bond was realized by a simple heterogeneous (Pd/C)-catalyzed hydrogenolysis to provide (R)-alcohol 11 in 91% yield. Acidic deprotection of the 1,2-O-isopropylidene group

Me

Me O

O S

Me a

Me O

Me

O

CHO

b

in 11 smoothly gave diol 12 (82%). Then selective tosylation of the primary hydroxyl group in 12 was accomplished in a good yield (97%) by using the method of Martinelli et al.7 involving Bu2SnO/ TsCl, and the tosylate was in turn converted into the epoxide 13 in an excellent yield (99%).8 The epoxide was opened to form the (R)-alcohol 6 (81%) by reaction with the Grignard reagent prepared from 8-bromo-1-octene.9 Reaction of 2-O-acetyl-3,4,6-tri-O-benzyl-D-glucose10 with CCl3CN and 1,8-diazabicyclo[5.4.0]undec-7ene (DBU) gave trichloroacetimidate 7 in 99% yield. Then glycosylation of 7 with the acceptor 6 using TMSOTf as promoter was carried out smoothly to give pure b-isomer 14 (JH-1,H-2 7.7 Hz) in 87% yield. To our delight, removal of the 2-O-acetyl group (99%), followed by Wacker oxidation of the terminal C@C double bond provided the methyl ketone 2 in 82% yield.4,11 The next effort was to construct disaccharide 3 (Scheme 5). For this purpose, acceptor 8 was prepared from the known methoxy-

Me O 11

O

e R

13 BnO BnO

6 g

OBn O

OH

f

BnO BnO 7

HO HO R 12

R 10

d

c

O

R

OBn O

h O

14 OAc

OAc 16

BnO BnO

OBn O

O

i

2

OH

15 Scheme 2. Reagents and conditions: (a) BuLi, Ph3P+(CH2)7CH3Br, THF, 86%; (b) H2, Pd–C, EtOH, 91%; (c) PPTs, MeOH, 82%; (d) (i) Bu2SnO, TEA, p-TsCl, CH2Cl2, 97%; (ii) KOH, PhCH3, 99%; (e) 8-bromo-1-octylene, magnesium, I2, Cu2Br2, THF, 81%; (f) CCl3CN, DBU, CH2Cl2, 99%; (g) TMSOTf, 4 Å MS, CH2Cl2, 87%; (h) MeONa, MeOH, 99%; (i) PdCl2, Cu(OAc)2, O2 (1 atm), DMA–H2O, 82%.

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O

Ph

O

O O

O

O HO 17

OMP

O

O O

OH

O

18

O

Ph

O

O

Ph

OMP

OMP

OAzmb 8

20

a

c

b

OH Ph

O O HO

O 19

O

O O AzmbO

Ph

OMP O

O O 21

HO HO AzmbO

OMP O

O

OMP

O

O

22

Scheme 3. Reagents and conditions: (a) n-Butyryl chloride, CuCl2, NaH, THF, 79%; (b) AzmbOH, DMAP, EDCHCl, CH2Cl2, 96%; (c) 80% HOAc, 47% for 8, 38% for 22.

phenyl glucoside 1712 in three steps (Scheme 3). Regioselective protection of the C-3 hydroxyl group of 4,6-O-benzylidene-b-D-glycopyranosides with a butyryl group could be proved to be a challenging task because the butanoyl substituent must be kept in the target compound 1 and the C-2 hydroxyl must also be protected by a participating group in order to control formation of the b-glycosidic linkage in the subsequent glycosylation step. Using the same procedure as reported by Osborn’s group13, however, a mixture of C-2- and C-3-protected products (79%) was obtained after scaling up the reaction to one gram. Furthermore, chromatography was found useless as 18 and 19 have the same Rf-values. The mixture of compounds were then coupled with 2-(azidomethyl)benzoic acid (AzmbOH) in the presence of EDCHCl and 4-N,N-dimethylaminopyridine (DMAP) to afford a mixture of 20 and 21 in 96% yield, which have also the same Rf-values.14 Removal of the 4,6-O-benzylidene group in 20/21 (80% AcOH, 80 °C) produced diols 8 (47%) and 22 (38%) in a pure form after chromatographic purification. Donor 9 (Scheme 4) was prepared from acetobromofucose 23, which was readily obtained by C-6 deoxygenation of D-galactose in five steps.15 Conversion of 23 into 25 was achieved through a one-pot sequence of anomeric bromination, halide-promoted orthoesterification, deacetylation, benzylation, acid-catalyzed ring opening, and then acylation to afford an anomeric mixture of 24 and 24a. This anomeric mixture was directly converted into the corresponding thioglycoside 25 in a satisfactory yield (74% overall yield for six steps).10 Subsequently, the C-2 acetyl group of 25 was removed by Zemplén deacetylation, followed by protection of the corresponding C-2 position with a levulinoyl group providing the donor 9 in an excellent yield in two steps (99%). Regioselective glycosylation of acceptor 8 and donor 9 in the presence of NIS and AgOTf as promoter was carried out smoothly to afford the b-D-Fuc-(1?6)-b-D-Glc-disaccharide 26 (86%) with complete C-6 selectivity (Scheme 5). The regioselectivity was com-

pletely supported by its subsequent reaction product, the C-4 butyryl derivative 27. Peaks at d 5.02 ppm (t, 1H, J 9.9 Hz, H-4) and 3.85 ppm (d, 1H, J 9.9 Hz, H-6a), 3.66 ppm (dd, 1H, J 11.0, 8.3 Hz, H-6b) in the 1H NMR spectrum of 27, in comparison to those for 26 at 3.51–3.47 ppm (m, 1H, H-4), 3.98 ppm (d, 1H, J 11.0 Hz, H6a), and 3.86 ppm (d, 1H, J 2.2 Hz, H-6b), confirmed the (1?6)linkage in its precursor 26. Then, selective removal of the levulinoyl group with hydrazine acetate without destroying the Azmb and butanoyl groups proceeded smoothly to give compound 28 in 85% yield. Net inversion at C-2 from the equatorial 2-OH to the axial one can be accomplished successfully by oxidation to a 2-keto-b-galactoside followed by stereoselective reduction to the 2b-alcohol 29 in 96% yield in two steps (no equatorial isomer was detected in the reduction step).5,16 The stereoselectivity of the reduction was further evidenced by the signal for H-10 in the 1 H NMR spectrum which appeared as a singlet at d 4.26 ppm. Finally, oxidative removal of the anomeric methoxyphenyl group with ammonium cerium(IV) nitrate in wet methyl cyanide (5:1 MeCN–water), followed by treatment with CCl3CN and DBU gave the disaccharide trichloroacetimidate 3 in 87% yield in two steps. With the required building blocks 2 and 3 in hand, a TMSOTfpromoted selective coupling of these entities was carried out to afford b-D-Tal-(1?6)-b-D-Glc-(1?2)-b-D-Glc-trisaccharide 30 in 76% yield (JH-10 ,H-20 7.4 Hz). No glycosylation took place on the free axial 2-OH of the talose moiety. This selectivity can be explained by the fact that the equatorial 2-OH of a glucoside is less hindered than the axial 2-OH of a taloside and that the presence of the hydrogen bond between the axial 2-OH and the axial 4-OBn of the taloside residue could reduce the reactivity at O-2. Thus, the glucoside 2-OH of block 2 and disaccharide trichloroacetimidate may be more in line with the ‘matching’ acceptor and donor reactivities. Then, exhaustive benzylation of 30 (10 equiv of BnOC(@NH)CCl3, catalytic TfOH, 1:1 CH2Cl2–cyclohexane, 1 h, 79%)17 followed by OBn

OAc a

O AcO

O

Br

Me

23

OAc

BnO

AcO

O O OEt

Me

OAc

BnO O

O

AcO

O

OBn

OAc

O OEt

24 OBn

b O

BnO AcO 24-a

OAc

OBn O BnO

STol

c 9

OAc 25 Scheme 4. Reagents and conditions: (a) (i) TBAI, CH3CN, CH3C(OEt)3; (ii) MeONa, MeOH, rt; (iii) BnBr, NaH, DMF; (iv) 1 M HCl; (v) Ac2O, pyridine; (b) p-TolSH, BF3Et2O, 74% for six steps; (c) (i) MeOH, MeONa; (ii) levulinic acid, EDCHCl, DMAP, CH2Cl2, 99% for two steps.

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deprotection of the C-2 azidomethylbenzoyl group of 31 provided the trisaccharide acceptor 32 (85%).5,14 Two monosaccharide donors 4 and 5 were designed for the investigation of the later coupling of trisaccharide 32 and quinovose donor. The preparation of 4 (Scheme 6) started with the 6-deoxy-1-thio-b-L-glucoside perbenzoate 33,18 treatment with BF3Et2O and p-TolSH to afford thioglycoside 34 (63%), and MeONa-induced elimination of Bz and benzylation which smoothly gave the desired donor 4 in a satisfactory overall yield (59% in two steps). Hydrolysis of 4 with N-bromosuccinimide (NBS) in wet acetone (9:1 acetone–water) gave compound 35 in 94% yield, which can be transformed into trifluoroacetimidate 5 by treatment with CF3C(Cl)@NPh and K2CO3.5 When 2.0 equiv of thioglycoside donors 4 was employed in the presence of NIS-AgOTf in CH2Cl2, tetrasaccharide 36 was obtained in a poor yield as outlined in Scheme 7 (23%). However, coupling of the newly prepared perbenzyl L-quinovosyl trifluoroacetimidate 5 and 32 in the presence of TMSOTf as reported by Yu and co-workers5 gave 36 in a moderate yield (39%). The stereochemistry of the newly formed glycosidic linkage was determined to be the desired a-form by 1H NMR spectroscopy (JH-1000 , H-2000 3.3 Hz). Finally, catalytic hydrogenation of the

O-benzyl-protecting groups over Pd/C did not meet any difficulty providing the target caminoside B (1) in 88% yield. The physical data obtained were in full agreement with those reported for the natural product.4b In conclusion, a facile synthesis of the marine antimicrobial glycolipid caminoside B was achieved successfully via a ‘2+2+1’ strategy based on the stereocontrolled construction of the four glycosidic linkages. With donors equipped with appropriate neighboring participating groups, the 1,2-trans b-glucopyranoside linkage was formed conveniently. Under the influence of the anomeric effect and with a donor bearing a non-participating 2-O-Bn group, the 1,2-cis a-quinovopyranoside was obtained easily, while the 1,2-cis b-mannopyranoside-type linkage of the 6-deoxy-talose moiety, the most challenging work of the total synthesis, was installed by stereoselective elaboration at position 2 of 6-deoxy-b-D-galactopyranoside. The major novelty of our work, with respect to the previously reported caminoside A, is that the R-configured secondary alcohol of the aglycon has been stereoselectively constructed. Furthermore, we got the pure targeted natural isomer caminoside B, instead of the peracetate derivative, which could not allow access to the natural glycolipid since the acetyl group cannot be selectively

OBn

OBn O 8+

BnO

a

9

LevO

O

O

BnO

O

LevO O

b HO O O

O

OMP

O

O O

OAzmb

O

26

OMP

OAzmb 27 c

OBn OH OBn OH O BnO O O

O BnO

O

OBn O

O

O

BnO O

O

O

O AzmbO

O

e

NH

O

O

CCl3

d

OMP

O

O

OAzmb

O O

HO O O O

29

3

OMP

OAzmb 28

O

O

f 2 BnO

OBn O

BnO BnO HO

O

O

O

BnO

OAzmb O

BnO

O O

BnO

O

O

O

g

O

O

OBn O

BnO BnO O

O

OR O

BnO

O O

O

30

O

31 R=Azmb h

32 R=H

Scheme 5. Reagents and conditions: (a) NIS, AgOTf, 4 Å MS, CH3CN–CH2Cl2, 0 °C to rt, 86%; (b) n-Butyryl chloride, pyridine, 88%; (c)H2NNH2HOAc, MeOH–CH2Cl2, 85%; (d) (i) Dess–Martin periodinane, CH2Cl2, rt; (ii) NaBH4, CH2Cl2–CH3OH, 96% for two steps; (e) (i) CAN, CH3CN–H2O; (ii) CCl3CN, DBU, CH2Cl2, 87% for two steps; (f) TMSOTf, 4 Å MS, CH2Cl2, 76%; (g) BnOC(@NH)CCl3, TfOH, 4 Å MS, CH2Cl2–cyclohexane, 79%; (h) Bu3P, THF–H2O, 85%.

O

BzO BzO 33

OBz OBz

a

O

BzO BzO 34

STol OBz

b

4

c

O

BnO

OH OBn

d

5

BnO 35

Scheme 6. Reagents and conditions: (a) BF3Et2O, TolSH, CH2Cl2, 63%; (b) (i) MeONa, MeOH; (ii) BnBr, NaH, TBAI, DMF, 59% for two steps; (c) NBS, acetone–H2O, 94%; (d) CF3C(Cl)@NPh, K2CO3, acetone, rt, 90%.

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Z. Zhang et al. / Carbohydrate Research 345 (2010) 750–760

O

O OBn O

BnO BnO

BnO

BnO

BnO

O

OH O

a 4 or 5

BnO

O O

O

32

BnO

BnO

O

O

O

O O

O

OBn O

BnO BnO

O

O

O

b O

O

O O

O

O

BnO

36

1

BnO

OBn

Scheme 7. Reagents and conditions: (a) NIS, AgOTf, 4 Å MS, CH2Cl2–Et2O, 0 °C to rt, 23% for 4 as donor; TMSOTf, 4 Å MS, Et2O, 0 °C to rt, 39% for 5 as donor; (b) Pd/C, EtOH– EtOAc, 50 °C, 88%.

removed in the presence of a butanoyl group. This result should provide a practical approach to other analogues of caminoside B, which are useful substrates for biological examinations in the type III secretory inhibitor domain.

3. Experimental section 3.1. General methods Solvents were purified in a conventional manner. Thin layer chromatography (TLC) was performed on precoated E. Merck Silica Gel 60 F254 plates. Flash column chromatography was performed on silica gel (200–300 mesh, Qingdao, China). Optical rotations were determined with a Perkin–Elmer Model 241 MC polarimeter. 1 H and 13C NMR spectra were taken on a JEOL JNM-ECP 500 or 600 spectrometer with tetramethylsilane as the internal standard, and chemical shifts are recorded in d values. Mass spectra were recorded on a Q-TOF Ultima Global mass spectrometer in a positive ion mode. 3.2. (R, E)-2,2-Dimethyl-4-(non-1-enyl)-1,3-dioxolane (10) Octyl triphenylphosphonium bromide (20.0 g, 44.0 mmol) was suspended in dry THF (300 mL). The mixture was cooled to 0 °C and n-BuLi (14.4 mL, 23.0 mmol) (1.6 M in hexane) was added dropwise. The red solution was stirred for 30 min, and then (S)-2,3-O-isopropylidene-D-glyceraldehyde (1.5 g, 11.5 mmol) in THF (6 mL) was added slowly. The reaction mixture was allowed to warm to room temperature while stirred overnight and was monitored by TLC. For workup, the reaction mixture was quenched with 10 mL MeOH. Afterward 80% MeOH in water was added and the reaction mixture was extracted with hexane. The combined hexane layers were dried over Na2SO4 and evaporated. The resulting residue was subjected to column chromatography (50:1, petroleum ether–EtOAc) to yield compound 10 as a colorless oil (2.23 g, 86%): Rf 0.65 (20:1 petroleum 1 ether–EtOAc); ½a22 D 6.9 (c 0.17, CHCl3); H NMR (600 MHz, CDCl3): d 5.63 (dt, 1H, J 13.0, 7.8 Hz, @CH), 5.40 (dd, 1H, J 11.0, 8.7 Hz, @CH), 4.87–4.83 (m, 1H, CHO), 4.06 (dd, 1H, J 7.8, 6.0 Hz, OCHH), 3.51 (t, 1H, J 8.3 Hz, OCHH), 2.15–2.02 (m, 2H, @CHCHH), 1.43, 1.40 (2s, 6H, 2  Me), 1.31–1.27 (m, 2H, @CHCH2CHH), 1.25 (br s, 8H, 4  CH2), 0.88 (t, 3H, J 6.9 Hz, CH3). 13C NMR (125 MHz, CDCl3): d 133.6, 130.0, 114.0, 76.2, 69.5, 33.8, 31.9, 29.7–29.3, 22.7, 14.1. 3.3. (R)-2,2-Dimethyl-4-nonyl-1,3-dioxolane (11) Compound 10 (845.5 mg, 3.7 mol) was dissolved in MeOH (50 mL) and then 10%-Pd/C (500 mg) was added. After stirring

for 24 h at room temperature under H2 atmosphere, the mixture was filtered through a Celite pad and the filtrate was concentrated. The resulting residue was subjected to column chromatography (25:1 petroleum ether–EtOAc) to yield 11 (777.5 mg, 91%) as a colorless oil: Rf 0.65 (25:1 petroleum ether–EtOAc); 1 ½a22 D 36.9 (c 0.07, CHCl3); H NMR (600 MHz, CDCl3): d 4.10– 4.02 (m, 2H, OCHH), 3.50 (t, 1H, J 7.3 Hz, OCH), 1.67–1.62 (m, 1H, OCH2CHH), 1.51–1.46 (m, 1H, OCH2CHH), 1.41 (s, 3H, Me), 1.36 (s, 3H, Me), 1.33–1.27 (m, 2H, OCH2CH2CHH), 1.26 (br s, 12H, 6  CH2), 0.88 (t, 3H, J 6.9 Hz, CH3); 13C NMR (150 MHz, CDCl3): d 108.5, 76.2, 69.5. 33.6, 31.9, 29.7–29.4. 22.7, 14.1. 3.4. (R)-Undecane-1,2-diol (12) To a solution of 11 (134.0 mg, 0.6 mmol) in MeOH (10 mL) was added pyridinium p-toluenesulfonate (45.2 mg, 10% w/w) at ambient temperature under N2. The reaction mixture was stirred for 12 h until completion as judged by TLC. Then the mixture was concentrated and purified by silica gel column chromatography (1:1 petroleum ether–EtOAc) to give diol 12 (90.3 mg, 82%) as a white solid: Rf 0.45 (1:1 petroleum ether–EtOAc); ½a22 D +5.8 (c 0.06, CHCl3); 1H NMR (600 MHz, CDCl3): d 3.71 (br s, 1H, OCHH), 3.66 (d, 1H, J 11.0 Hz, OCHH), 3.44(t, 1H, J 9.2, 8.7 Hz, OCH), 2.32 (br s, 2H, 2  OH), 1.45–1.41 (m, 2H, OCH2CHH), 1.31–1.28 (m, 2H, OCH2CH2CHH), 1.26 (br s, 12H, 6  CH2), 0.88 (t, 3H, J 7.1 Hz, CH3); 13C NMR (150 MHz, CDCl3): d 72.3, 66.8, 33.2, 31.9, 29.6– 29.3, 25.5, 22.6, 14.1. 3.5. (R)-1,2-Nonyloxirane(13) To a solution of diol 12 (1.0 g, 5.4 mmol), dibutyltin oxide (134.9 mg, 0.5 mmol), and triethylamine (1.5 mL, 10.8 mmol) in CH2Cl2 (50 mL) was added p-toluenesulfonyl chloride (1.5 g, 8.1 mmol) in one portion. The reaction mixture was stirred at ambient temperature for 16 h and then the reaction was quenched with aq saturated NaHCO3 (50 mL) and the reaction mixture was extracted with EtOAc (2  100 mL). The EtOAc layer was washed with brine (2  100 mL), dried over MgSO4, filtered, and concentrated under diminished pressure. The residue was purified by silica gel column chromatography (10:1 petroleum ether–EtOAc) to give the tosylate (1.8 g, 97%) as a white solid; Rf 0.50 (4:1 petroleum ether–EtOAc); 1 ½a22 D 6.2 (c 0.06, CHCl3); H NMR (600 MHz, DMSO-d6): d 7.79 (d, 2H, J 8.3 Hz, Ph), 7.48 (d, 2H, J 6.7 Hz, Ph), 4.97 (br s, 1H, OH), 2.91– 2.89 (m, 1 H, OCH), 3.85 (dd, 1H, J 9.7, 4.1 Hz, OCHH), 3.80 (dd, 1H, J 10.1, 5.9 Hz, OCHH), 3.57–3.54 (m, 1H, OCH), 2.42 (s, 3H, PhCH3), 1.31–1.23 (m, 2H, OCHCHH), 1.20 (br s, 14H, 7  CH2), 0.85 (t, 3H, J 7.1 Hz, CH3); 13C NMR (150 MHz, CDCl3): d 145.0, 132.6, 129.9, 127.9, 74.0, 69.5, 32.6, 31.8, 29.5–29.2, 25.2, 22.6, 21.6, 14.1.

Z. Zhang et al. / Carbohydrate Research 345 (2010) 750–760

To a solution of the monotosyl compound (0.3 g, 0.9 mmol) in PhCH3 (10 ml), powdered KOH (59 mg, 1.0 mmol) was added and the suspension was stirred under N2 for 45 min till the starting material was not detectable on TLC (20:1 petroleum ether–EtOAc). The reaction mixture was then filtered and concentrated. The residue was purified by silica gel column chromatography (50:1 petroleum ether–EtOAc) to give compound 13 (148.9 mg, 99%) as a colorless oil: Rf 0.70 (30:1 petroleum ether–EtOAc); ½a22 D +8.6 (c 0.09, CHCl3); 1H NMR (600 MHz, CDCl3): d 2.91–2.89 (m, 1 H, OCH), 2.75 (dd, 1H, J 4.7, 4.0 Hz, OCHH), 2.46 (dd, 1H, J 4.8, 2.6 Hz, OCHH), 1.54–1.51 (m, 2H, OCHCHH), 1.48–1.39 (m, 2H, OCHCH2CHH), 1.27 (br s, 12H, 6  CH2), 0.85 (t, 3H, J 6.9 Hz, CH3); 13C NMR (150 MHz, CDCl3): d 52.4, 47.1, 32.5, 31.9, 29.5– 29.3, 25.9, 22.7, 14.1. 3.6. (R)-Nonadec-1-en-10-ol (6) A solution of 8-bromo-1-octylene (250 lL, 1.5 mmol) was added dropwise to a suspension of magnesium turnings (50 mg, 2.0 mmol) and a catalytic amount of I2 in Et2O (10 mL) under N2. The mixture was refluxed for 2 h, then cooled to room temperature, and added dropwise to a stirred solution of purified copper iodide (33.6 mg, 0.2 mmol) in dry THF (5 mL) at 20 °C. After 10 min, a solution of 13 (60 mg, 0.35 mmol) in THF (2 mL) was added dropwise. Then the mixture was stirred at 0 °C for an additional 30 min while warming to room temperature. The product was extracted with EtOAc (3  50 mL). The combined organic layers were washed with brine (50 mL), dried, and evaporated. The residue was purified by silica gel column chromatography (80:1 petroleum ether– EtOAc) to give compound 6 (80.3 mg, 81%) as a white solid: Rf 1 0.40 (15:1 petroleum ether–EtOAc); ½a22 D 1.5 (c 0.11, CHCl3); H NMR (600 MHz, DMSO-d6): d 5.82–5.75 (m, 1H, @CH), 5.01–4.97 (m, 1H, @CHH), 4.94–4.92 (m, 1H, @CHH), 4.19 (d, 1H, J 5.4 Hz, OH), 3.32 (br s, 1H, CH), 2.01–1.98 (m, 2H, @CHCH2), 2.01–1.98 (m, 2H, @CHCH2), 1.24 (br s, 28H, 14  CH2), 0.85 (t, 3 H, J 7.2 Hz, CH3); 13C NMR (150 MHz, CDCl3): d 139.2, 114.1, 72.0, 37.5, 33.8, 31.9, 29.7–28.9, 25.6, 22.7, 14.1. 3.7. 2-O-Acetyl-3,4,6-tri-O-benzyl-a-D-glucopyranosyl trichloroacetimidate (7) To a stirred solution of 2-O-acetyl-3,4,6-tri-O-benzyl-D-glucose 16 (5.0 g, 10.0 mmol) and CCl3CN (6.2 mL, 60.9 mmol) in CH2Cl2 (100 mL) at 0 °C was added DBU (780 lL, 5.0 mmol). After 2 h, the solution was concentrated and the residue was purified by silica gel column chromatography (10:1 petroleum ether–EtOAc) to afford 7 (6.4 g, 99%) as a syrup: Rf 0.52 (6:1 petroleum ether– 1 EtOAc); ½a20 D +120.8 (c 0.13, CHCl3); H NMR (600 MHz, CDCl3): d 8.56 (s, 1H, NH), 7.33–7.16 (m, 15 H, Ph), 6.52 (d, 1H, J 3.7 Hz, H1), 5.07 (dd, 1H, J 9.9, 3.7 Hz, H-2), 4.86 (d, 1H, J 11.8 Hz, PhCHH), 4.83 (d, 1H, J 10.6 Hz, PhCHH), 4.77 (d, 1H, J 11.3 Hz, PhCHH), 4.63 (d, 1H, J 12.1 Hz, PhCHH), 4.57 (d, 1H, J 10.6 Hz, PhCHH), 4.50 (d, 1H, J 12.1 Hz, PhCHH), 4.09 (t, 1H, J 9.7 Hz, H-3), 4.02– 3.99 (m, 1H, H-5), 3.88 (t, 1H, J 9.5 Hz, H-4), 3.81 (dd, 1H, J 11.0, 3.3 Hz, H-6a), 3.69 (dd, 1H, J 11.0, 1.9 Hz, H-6b), 1.93 (s, 3H, COCH3); 13C NMR (150 MHz, CDCl3): d 170.0, 163.4, 160.9, 138.2, 137.7, 128.4–127.6, 93.9, 79.4, 75.4, 75.3, 73.4, 73.3, 72.3, 67.8, 60.3, 20.5, 14.1. ESIMS: calcd for [MCCl3CN+Na]+ m/z 515.2; found: 515.2. 3.8. (10R)-Nonadec-1-en-10-yl 2-O-acetyl–3,4,6-tri-O-benzyl-bD-glucopyranoside (14) To a mixture of 7 (236.9 mg, 0.37 mmol), 6 (60.0 mg, 0.21 mmol), and 4 Å molecular sieves in dry CH2Cl2 (5 mL), TMSOTf (5 lL, 0.03 mmol) was added at 20 °C under argon. The reaction

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mixture was stirred under these conditions for 30 min and then neutralized with Et3N. The solid was filtered off, and the filtrate was concentrated under diminished pressure. The resulting residue was purified by silica gel column chromatography (50:1 petroleum ether–EtOAc) to give 14 (138.8 mg, 87%) as a syrup: Rf 0.39 1 H (15:1 petroleum ether–EtOAc); ½a22 D 11.4 (c 0.06, CHCl3); NMR (600 MHz, CDCl3): d 7.33–7.19 (m, 15H, Ph), 5.83–5.76 (m, 1H, @CH), 4.99–4.91 (m, 3H, @CHH and H-2), 4.79 (d, 2H, J 11.4 Hz, PhCHH), 4.66 (d, 1H, J 11.4 Hz, PhCHH), 4.64 (d, 1H, J 12.0 Hz, PhCHH), 4.59 (d, 1H, J 10.8 Hz, PhCHH), 4.56 (d, 1H, J 12.0 Hz, PhCHH), 4.36 (d, 1H, J 7.8 Hz, H-1), 3.72–3.64 (m, 4H, H3, H-4, H-5 and H-6a), 3.51 (dd, 1H, J 12.0, 6.0 Hz, H-6b), 3.47– 3.44 (m, 1H, CHO), 2.03–1.99 (m, 2H, @CHCHH), 1.99 (s, 3H, COCH3), 1.56 (br s, 10H, (CH2)5), 1.42–1.40 (m, 2H, CHHCHO), 1.34–1.29 (m, 2H, CHOCHH), 1.25(br s, 14H, (CH2)7), 0.88 (t, 3H, J = 6.9 Hz, CH3); 13C NMR (150 MHz, CDCl3): d 169.4, 139.2, 138.3, 138.2, 137.9, 128.4, 128.3, 128.1, 127.8, 127.7, 127.6, 127.5, 114.15, 114.0, 100.8, 83.1, 80.8, 78.1, 75.2, 75.0, 74.9, 73.6, 73.5, 69.0, 34.9, 34.1, 33.8, 31.9, 29.9–28.9, 25.3, 25.0, 22.7, 20.9, 14.1; ESIMS: calcd for [M+Na]+ m/z 779.5; found: 779.5. 3.9. (10R)-Nonadec-1-en-10-yl 3,4,6-tri-O-benzyl-b-Dglucopyranoside (15) To a solution of compound 14 (337.0 mg, 0.4 mmol) in dry MeOH (5 mL) and CH2Cl2 (5 mL) was added NaOMe until pH 8.5. The reaction mixture was stirred at 35 °C for 30 h, after which the reaction mixture was neutralized with Dowex 50  8(H+) resin until pH 7.0, filtered, and concentrated. The residue was purified by silica gel column chromatography (50:1 petroleum ether–EtOAc) to give 15 (318.0 mg, 99%) as a white solid: Rf 0.39 (20:1 petroleum 1 ether–EtOAc); ½a22 D 9.3 (c 0.3, CHCl3); H NMR (600 MHz, CDCl3): d 7.39–7.20 (m, 15H, Ph), 5.83–5.77 (m, 1H, @CH), 5.00–4.97 (m, 1H, @CHH), 4.96 (d, 1H, J 11.0 Hz, PhCHH), 4.94–4.91 (m, 1H, @CHH), 4.84 (d, 1H, J 11.0 Hz, PhCHH), 4.83 (d, 1H, J 11.6 Hz, PhCHH), 4.62 (d, 1H, J 12.7 Hz, PhCHH), 4.58 (d, 1H, J 9.4 Hz, PhCHH), 4.56 (d, 1H, J 12.1 Hz, PhCHH), 4.28 (d, 1H, J 7.7 Hz, H1), 3.73 (dd, 1H, J 11.0, 2.2 Hz, H-6a), 3.70 (dd, 1H, J 11.0, 4.4 Hz, H-6b), 3.66–3.62 (m, 1H, OCH), 3.61–3.52 (m, 3H, H-3, H-4 and H-2), 3.48–3.45 (m, 1H, H-5), 2.34–2.18 (m, 2H, @CHCHH), 2.06– 2.00 (m, 2H, OCHCHH), 1.68–1.21 (m, 26H, 13  CH2), 0.88 (t, 3H, J 6.9 Hz, CH3); 13C NMR (150 MHz, CDCl3): d 139.2, 138.7, 138.3, 138.1, 129.7–127.6, 114.1, 114.0, 102.0, 84.7, 80.1, 75.2, 75.0, 73.6, 69.1, 34.8, 34.1, 33.8, 31.9, 29.7–28.9, 25.2, 22.7, 14.1. 3.10. (10R)-2-Nonadecanone-10-yl 3,4,6-tri-O-benzyl-b-Dglucopyranoside (2) To a mixture of 15 (277.8 mg, 0.4 mmol) in N,N-dimethylacetamide (3 mL) and water (0.3 mL), PdCl2 (18.6 mg, 0.1 mmol) and Cu(OAc)2H2O (155.7 mg, 0.8 mmol) were added. The mixture was stirred at 50 °C under oxygen for 7 h until the reaction was complete as judged by TLC. Then it was diluted with CH2Cl2 (100 mL), washed with saturated aq NaHCO3 (2  50 mL), water (50 mL), and brine (2  50 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (10:1 petroleum ether–EtOAc) to give 2 (233.3 mg, 82%) as a syrup: Rf 0.31 (6:1 petroleum ether–EtOAc); ½a22 D 11.8 (c 0.1, CHCl3); 1H NMR (600 MHz, CDCl3): d 7.38–7.19 (m, 15H, Ph), 4.95 (d, 1H, J 11.5 Hz, PhCHH), 4.84 (d, 1H, J 11.0 Hz, PhCHH), 4.83 (d, 1H, J 11.0 Hz, PhCHH), 4.62 (d, 1H, J 12.4 Hz, PhCHH), 4.57 (d, 1H, J 10.5 Hz, PhCHH), 4.55 (d, 1H, J 11.9 Hz, PhCHH), 4.28 (d, 1H, J 7.8 Hz, H-1), 3.72 (dd, 1H, J 11.0, 2.3 Hz, H-6a), 3.70 (dd, 1H, J 11.0, 4.1 Hz, H-6b), 3.65–3.61 (m, 1H, OCH), 3.60–3.57 (m, 2H, H-3 and H-4), 3.53 (t, 1H, J 9.1 Hz, H-2), 3.48–3.45 (m, 1H, H-5), 2.37 (t, 2H, J 7.32 Hz, COCHH), 2.11 (s, 3H, COCH3),

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1.58–1.26 (m, 28 H, 14  CH2), 0.88 (t, 3H, J 6.9 Hz, CH3); 13C NMR (150 MHz, CDCl3): d 138.8, 138.4, 138.3, 128.4–127.5, 102.0, 84.7, 79.9, 77.7, 75.3–75.0, 73.6, 69.3, 43.8, 34.8, 34.1, 31.9, 29.8–29.2, 25.3, 25.2, 23.9, 22.7, 14.1; ESIMS: calcd for [M+Na]+ m/z 753.5; found: 753.6. 3.11. 4-Methoxyphenyl 2-O-[2-(azidomethyl)benzoyl]-3-Obutyryl-b-D-glucopyranoside (8) 4-Methoxyphenyl 4,6-O-benzylidene-b-D-glucopyranoside (250 mg, 0.67 mmol) was dissolved in anhyd THF (25 mL THF) and NaH (83.2 mg, 1.9 mmol) was added. The formation of the disodium alcoholate was complete in 1 h at room temperature to give a thick white slurry. Anhydrous copper(II) chloride (88.4 mg, 0.67 mmol) was added to the alcoholate slurry which went to dissolution as a dark green solution. To the green chelate solution was added butyryl chloride (83.0 lL, 0.8 mmol) and the reaction mixture was left to stir under N2 for 5 h. To the solution were added water (3 mL) and 3% aq NH3 (3 mL) to give a dark blue solution. The organic layer was separated and the water layer was extracted with EtOAc (5  50 mL). The organic fractions were combined, dried with MgSO4, and the excess solvent was removed under diminished pressure to yield a pale yellow oil which when subjected to column chromatography (8:1 petroleum ether–EtOAc) yielded the mixture of 18 and 19 (233.4 mg, 79%) as a white solid: Rf 0.51 (3:1 petroleum ether– EtOAc); ESIMS: calcd for [M+Na]+ m/z 467.2; found: 467.3; HRESIMS: m/z calcd for C24H28O8Na+ 467.1682; found 467.1687. To a solution of the mixture 18 and 19 (233.4 mg, 0.53 mmol) in dry CH2Cl2 (30 mL), AzmbOH (139.5 mg, 0.79 mmol), EDCHCl (201.3 mg, 1.1 mmol), and DMAP (128.1 mg, 1.1 mmol) were added under argon. The mixture was stirred for 12 h, diluted with CH2Cl2 (100 mL), washed with water (50 mL), 1 M HCl (2  50 mL), saturated aqueous NaHCO3 (2  50 mL), and brine (2  50 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (6:1 petroleum ether–EtOAc) to give a mixture of 20 and 21 (305.4 mg, 96%) as a white solid: Rf 0.40 (4:1, petroleum ether–EtOAc); ESIMS: calcd for [M+Na]+ m/z 626.2; found: 626.3; HRESIMS: m/z calcd for C32H33N3O9Na+ 626.2114; found 626.2094. The mixture of 20 and 21 (305.4 mg, 0.50 mmol) was dissolved in 80% AcOH (30 mL) and stirred for 2 h at 80 °C, then the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (2:3 petroleum ether–EtOAc) to give compound 8 as a colorless oil (123.6 mg, 47%): Rf 0.46 (2:3 petro1 leum ether–EtOAc); ½a22 D +14.7 (c 0.2, CHCl3); H NMR (600 MHz, DMSO-d6): d 7.81 (d, 1H, J 7.1 Hz, Ph), 7.65 (t, 1H, J 7.7 Hz, Ph), 7.56 (d, 1H, J 7.1 Hz, Ph), 7.50 (t, 1H, J 7.7 Hz, Ph), 6.92 (d, 2H, J 8.8 Hz, Ph), 6.82 (d, 2H, J 8.8 Hz, Ph), 5.61 (d, 1H, J 5.5 Hz, 4-OH), 5.40 (d, 1H, J 8.3 Hz, H-1), 5.31 (t, 1H, J 9.3 Hz, H-3), 5.14 (dd, 1H, J 9.9, 8.2 Hz, H-2), 4.79 (t, 1H, J 6.1 Hz, 6-OH), 4.74 (s, 2H, PhCH2), 3.75 (dd, 1H, J 11.0, 5.5 Hz, H-4), 3.67 (s, 3H, OMe), 3.65–3.55 (m, 3H, H-6 and H-5), 2.28–2.18 (m, 2H, COCH2), 1.44–1.40 (m, 2H, CH2CH3), 0.72 (t, 3H, J 7.1 Hz, CH3); 13C NMR (150 MHz, DMSOd6): d 172.2, 164.9, 154.7, 150.6, 136.4, 133.1, 130.6, 130.3, 128.5, 128.4, 117.5, 114.5, 98.4, 76.7, 74.6, 72.2, 67.5, 60.1, 55.3, 51.7, 35.4, 17.8, 13.1; ESIMS: calcd for [M+Na]+ m/z 538.2; found: 538.2. 3.12. 4-Methoxyphenyl 3-O-[2-(azidomethyl)benzoyl]-2-Obutyryl-b-D-glucopyranoside (22) Compound 22 as a filiation of compound 8 was obtained as a white solid (99.8 mg, 38%): Rf 0.51 (2:3 petroleum ether–EtOAc); 1 ½a22 D +51.8 (c 0.05, CHCl3); H NMR (600 MHz, DMSO-d6): d 7.92 (d, 1H, J 7.7 Hz, Ph), 7.67 (t, 1H, J 7.7 Hz, Ph), 7.57 (d, 1H, J 7.7 Hz, Ph), 7.53 (t, 1H, J 7.7 Hz, Ph), 6.96 (d, 2H, J 9.4 Hz, Ph), 6.87 (d, 2H, J 9.3 Hz, Ph), 5.70 (d, 1H, J 6.1 Hz, 4-OH), 5.39 (t, 1H, J 9.3 Hz,

H-3), 5.32 (d, 1H, J 8.2 Hz, H-1), 5.07 (dd, 1H, J 9.3, 8.8 Hz, H-2), 4.80 (d, 1H, J 13.7 Hz, PhCH2), 4.80 (t, 1H, J 5.5 Hz, 6-OH), 4.69 (d, 1H, J 13.7 Hz, PhCH2), 3.76–3.73 (m, 1H, H-4), 3.71 (s, 3H, OMe), 3.70–3.64 (m, 2H, H-6), 3.59–3.55 (m, 1H, H-5), 2.25–2.14 (m, 2H, COCH2), 1.45–1.40 (m, 2H, CH2CH3), 0.71 (t, 3H, J = 7.7 Hz, CH3); 13C NMR (150 MHz, DMSO-d6): d 171.7, 163.4, 154.7, 150.7, 136.3, 132.8, 130.6, 130.4, 128.9, 128.4, 117.7, 114.5, 98.5, 76.5, 76.0, 71.2, 67.5, 60.0, 55.3, 51.7, 35.2, 17.8, 13.0; ESIMS: calcd for [M+Na]+ m/z 538.2; found: 538.2. 3.13. p-Tolyl 3,4-di-O-benzyl-2-O-acetyl-1-thio-b-Dfucopyranoside (25) To a suspension of acetobromofucose 23 (3 g, 8.8 mmol) in dry MeCN (50 mL), triethylorthoacetate (3.0 mL, 17.6 mmol) was added, followed by the addition of tetrabutylammonium iodide (1.6 g, 4.4 mmol). The mixture was allowed to stir for 12 h. When the reaction was complete (TLC 3:1 petroleum ether–EtOAc), Et3N was added to neutralize the solution and the mixture was evaporated to dryness. To a dry methanolic solution (25 mL) of the residue was added NaOMe at 0 °C until pH 8.5. The reaction mixture was stirred at room temperature for 30 min, after which the reaction mixture was concentrated. The residue was dried under diminished pressure to give a crude product. To a solution of the crude product in dry DMF (20 mL) was added NaH (985.6 mg, 24.6 mmol) at 0 °C. The mixture was stirred under these conditions for 30 min and then BnBr (4.2 mL, 35.2 mmol) was added dropwise. The mixture was allowed to stir for 2 h at room temperature. When TLC (3:1 petroleum ether– EtOAc) showed complete conversion, MeOH (2 mL) was carefully added to destroy excess NaH, and the mixture was diluted with CH2Cl2 (50 mL). The organic layer was shaken with 1 M HCl (3  50 mL) followed by washing with saturated aq NaHCO3 solution (3  50 mL) and water (3  50 mL). Finally, the organic layer was separated, dried over Na2SO4, and evaporated to give a syrup. The residue was dissolved in dry CH2Cl2 (50 mL) at 0 °C. To this cold suspension was added Ac2O (1.7 mL, 17.6 mmol), and then triethylamine (1.7 mL, 12.3 mmol) was added dropwise over a period of 30 min, and the mixture was stirred for 30 min. Then, DMAP (59.8 mg, 0.5 mmol) was added in one portion. The reaction mixture was stirred for 4 h while warming to room temperature. The reaction was quenched with MeOH (5 mL) and concentrated. The residue was diluted with CH2Cl2 (50 mL), washed with 1 M HCl (2  50 mL), saturated aq NaHCO3 (2  50 mL), and brine (50 mL), dried over Na2SO4, filtered, and concentrated under diminished pressure. The crude product was dissolved in CH2Cl2 (50 mL) and p-TolSH (1.7 g, 13.6 mmol) was added at 0 °C. To the cold solution, BF3Et2O (1.7 mL, 13.6 mmol) was added dropwise over a period of 30 min. The reaction mixture was allowed to stir for another 2 h while warming to room temperature. After the reaction was complete as judged by TLC, it was quenched by the addition of aq NaHCO3 (25 mL). The mixture was extracted with CH2Cl2 (100 mL). The organic layer was washed with saturated aq NaHCO3 (2  50 mL), water (2  50 mL), brine (2  50 mL), dried over Na2SO4, filtered, and concentrated under diminished pressure. Purification of the crude reaction product by column chromatography on silica gel (10:1?2:1 petroleum ether–EtOAc) furnished pure p-tolyl 3,4-diO-benzyl-2-O-acetyl-1-thio-b-D-fucopyranoside (25) as a colorless oil (2.4 g, 74% for six steps): Rf 0.51 (4:1 petroleum ether–EtOAc); 1 ½a22 D +17.2 (c 0.2, CHCl3); H NMR (600 MHz, CDCl3): d 7.41–7.26 (m, 12H, Ph), 7.06 (d, 2H, J 7.8 Hz, Ph), 5.39 (t, 1H, J 9.6 Hz, H-2), 4.98 (d, 1H, J 11.5 Hz, PhCHH), 4.68 (d, 1H, J 12.4 Hz, PhCHH), 4.64 (d, 1H, J 11.5 Hz, PhCHH), 4.56 (d, 1H, J 12.0 Hz, PhCHH), 4.53 (d, 1H, J 9.6 Hz, H-1), 3.65 (d, 1H, J 2.7 Hz, H-4), 3.56 (dd,

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1H, J 9.6, 2.7 Hz, H-3), 3.53 (q, 1H, J 6.6 Hz, H-5), 2.31 (s, 3H, PhCH3), 2.06 (s, 3H, COCH3), 1.26 (d, 3H, J 6.6 Hz, 6-Me). 13C NMR (150 MHz, CDCl3): d 169.5, 138.4, 137.9, 137.5, 132.4, 129.9, 129.4, 128.4–127.4, 86.8, 81.9, 75.5, 74.8, 74.3, 72.0, 69.7, 21.1, 17.2. ESIMS: calcd for [M+Na]+ m/z 515.2; found: 515.2. 3.14. p-Tolyl 3,4-di-O-benzyl-2-O-levulinyl-1-thio-b-Dfucopyranoside (9) To a solution of 25 (0.96 g, 3.6 mmol) in dry MeOH (25 mL) and CH2Cl2 (25 mL) was added NaOMe until pH 8.5–9.0. The reaction mixture was stirred at room temperature for 30 h, after which the reaction mixture was neutralized with Dowex 50  8(H+) resin until pH 7.0, filtered, and concentrated. To a solution of the residue in dry CH2Cl2 (50 mL), levulinic acid (0.5 g, 2.9 mmol), EDCHCl (0.3 g, 2.9 mmol) and DMAP (61.0 mg, 0.5 mmol) were added under argon. The mixture was stirred for 12 h, diluted with CH2Cl2 (50 mL), washed with water (50 mL), 1 M HCl (2  50 mL), saturated aq NaHCO3 (2  50 mL), and brine (2  50 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (10:1 petroleum ether–EtOAc) to give 9 (0.9 g, 99% for two steps) as a white solid: Rf 0.42 (3:1 petroleum 1 ether–EtOAc); ½a22 D +23.2 (c 0.1, CHCl3); H NMR (600 MHz, CDCl3): d 7.40–7.25 (m, 12H, Ph), 7.05 (d, 2H, J 8.2 Hz, Ph), 5.37 (t, 1H, J 9.9 Hz, H-2), 4.97 (d, 1H, J 11.5 Hz, PhCHH), 4.67 (d, 1H, J 12.1 Hz, PhCHH), 4.62 (d, 1H, J 11.6 Hz, PhCHH), 4.59 (d, 1H, J 12.7 Hz, PhCHH), 4.52 (d, 1H, J 9.9 Hz, H-1), 3.62 (d, 1H, J 2.2 Hz, H-4), 3.55 (dd, 1H, J 9.4, 2.8 Hz, H-3), 3.51 (q, 1H, J 6.6 Hz, H-5), 2.81– 2.56 (m, 4H, COCH2CH2CO), 2.30 (s, 3H, PhCH3), 2.17 (s, 3H, COCH3), 1.24 (d, 3H, J 6.6 Hz, 6-CH3); 13C NMR (150 MHz, CDCl3): d 206.4, 171.4, 138.4, 138.0, 137.5, 129.4, 128.4, 128.1, 127.7, 127.6, 127.4, 86.9, 81.8, 75.6, 74.8, 74.3, 72.2, 70.1, 37.9, 29.9, 28.1, 21.1, 17.2; ESIMS: calcd for [M+Na]+ m/z 571.2; found: 571.2. 3.15. 4-Methoxyphenyl 3,4-di-O-benzyl-2-O-levulinoyl-b-Dfucopyranosyl-(1?6)-2-O-[2-(azidomethyl)benzoyl]-3-Obutyryl-b-D-glucopyranoside (26) To a mixture of 8 (281.5 mg, 0.55 mmol), 9 (359.5 mg, 0.66 mmol), and 4 Å molecular sieves in dry CH2Cl2 (15 mL) and MeCN (15 mL), NIS (198.9 mg, 0.88 mmol) and AgOTf (28.3 mg, 0.11 mmol) were added at 0 °C under argon. The mixture was stirred for an additional 12 h while warming to room temperature. After the reaction was complete as judged by TLC, the mixture was filtered and concentrated. Then the resulting residue was diluted with CH2Cl2 (50 mL) and washed with 10% aq Na2S2O3 (25 mL) and brine (2  25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (3:1 petroleum ether– EtOAc) to give 26 (440.8 mg, 86%) as a syrup: Rf 0.34 (1:1 petro1 leum ether–EtOAc); ½a22 D 5.7 (c 0.25, CHCl3); H NMR (600 MHz, DMSO-d6): d 7.81 (d, 1H, J 7.7 Hz, Ph), 7.65 (t, 1H, J 7.7 Hz, Ph), 7.55 (d, 1H, J 7.7 Hz, Ph), 7.50 (t, 1H, J 7.7 Hz, Ph), 7.37–7.30 (m, 10H, Ph), 6.91 (d, 2H, J 9.3 Hz, Ph), 6.81 (d, 2H, J 9.3 Hz, Ph), 5.65 (d, 1H, J 6.1 Hz, 4-OH), 5.38 (d, 1H, J 8.3 Hz, H-1), 5.32 (t, 1H, J 9.4 Hz, H-3), 5.12 (dd, 1H, J 9.9, 8.3 Hz, H-2), 4.99 (dd, 1H, J 9.9, 8.2 Hz, H-20 ), 4.83 (d, 1H, J 11.6 Hz, PhCH2), 4.74 (s, 2H, PhCH2), 4.71 (d, 1H, J 12.1 Hz, PhCH2), 4.59 (d, 1H, J 11.5 Hz, PhCH2), 4.56 (d, 1H, J 12.1 Hz, PhCH2), 4.46 (d, 1H, J 7.7 Hz, H-10 ), 3.98 (d, 1H, J 11.0 Hz, H-6a), 3.86 (d, 1H, J 2.2 Hz, H-6b), 3.82 (t, 1H, J 8.8 Hz, H-40 ), 3.64 (s, 3H, OMe), 3.63–3.59 (m, 3H, H-30 , H-50 , and H-5), 3.51–3.47 (m, 1H, H-4), 2.62–2.18 (m, 6H, 3  COCH2), 2.07 (s, 3H, COCH3), 1.45–1.38 (m, 2H, CH2CH3), 1.17 (d, 3H, J = 6.6 Hz, 6Me), 0.71 (t, 3H, J = 7.7 Hz, CH3); 13C NMR (150 MHz, CDCl3): d 206.4, 172.6, 172.3, 171.5, 165.0, 155.5, 151.2, 138.3, 138.0, 137.5, 133.0, 131.0, 129.7, 128.5–127.5, 118.0, 114.9, 100.9, 99.9,

757

80.9, 75.4, 74.5, 74.2, 72.6, 72.2, 72.0, 71.5, 70.7, 68.8, 67.3, 55.6, 52.8, 37.8, 35.9, 29.6, 28.0, 18.2, 16.7, 13.6, 13.4. ESIMS: calcd for [M+Na]+ m/z 962.4; found: 962.5. 3.16. 4-Methoxyphenyl 3,4-di-O-benzyl-2-O-levulinoyl-b-Dfucopyranosyl-(1?6)-2-O-[2-(azidomethyl)benzoyl]-3,4-di-Obutyl-b-D-glucopyranoside (27) Compound 26 (54.7 mg, 0.06 mmol) was dissolved in pyridine (5 mL) and butyryl chloride (12.4 lL, 0.12 mmol) was added dropwise at 0 °C. The solution was stirred for 2 h while warming to room temperature. After the reaction was complete as judged by TLC, the mixture was diluted with CHCl3 (20 mL) and washed consecutively with water (20 mL), HCl (3  20 mL), saturated aq NaHCO3 (2  10 mL), and brine (20 mL). The organic layer was dried (Na2SO4) and filtered. Purification of the residue on a silica gel column (10:1?3:1 petroleum ether–EtOAc) gave 27 (52.0 mg, 88%) as a syrup: Rf 0.52 (2:1 petroleum ether–EtOAc); ½a22 D 7.7 (c 0.3, CHCl3); 1H NMR (600 MHz, CDCl3): d 7.89 (d, 1H, J 7.1 Hz, Ph), 7.55 (t, 1H, J 7.7 Hz, Ph), 7.49 (d, 1H, J 7.7 Hz, Ph), 7.38–7.26 (m, 11H, Ph), 6.93 (d, 2H, J 8.8 Hz, Ph), 6.82 (d, 2H, J 8.8 Hz, Ph), 5.48 (t, 1H, J 9.9 Hz, H-3), 5.44 (t, 1H, J 9.4 Hz, H-2), 5.37 (dd, 1H, J 9.4, 8.2 Hz, H-20 ), 5.14 (d, 1H, J 7.7 Hz, H-1), 5.02 (t, 1H, J 9.9 Hz, H-4), 4.97 (d, 1H, J 11.6 Hz, PhCH2), 4.79 (d, 1H, J 14.9 Hz, PhCH2), 4.75 (d, 1H, J 14.3 Hz, PhCH2), 4.66 (d, 2H, J 13.2 Hz, PhCH2), 4.60 (d, 1H, J 12.1 Hz, PhCH2), 4.42 (d, 1H, J 8.3 Hz, H-10 ), 3.99 (t, 1H, J 8.8 Hz, H-5), 3.85 (d, 1H, J 9.9 Hz, H-6a), 3.74 (s, 3H, OMe), 3.66 (dd, 1H, J 11.0, 8.3 Hz, H-6b), 3.57 (br s, 1H, H-40 ), 3.48 (dd, 1H, J 9.9, 2.7 Hz, H-30 ), 3.43 (q, 1H, J 6.1 Hz, H-50 ), 3.63–3.59 (m, 3H, H-30 , H-50 , and H-5), 2.52–2.17 (m, 8H, 4  COCH2), 2.06 (s, 3H, COCH3), 1.61–1.57 (m, 2H, CH2CH3), 1.50–1.47 (m, 2H, CH2CH3), 1.17 (d, 3H, J 6.1 Hz, 6-Me), 0.91 (t, 3H, J 7.7 Hz, CH3), 0.78 (t 3H, J 7.7 Hz, CH3); 13C NMR (150 MHz, CDCl3): d 207.0, 173.7, 171.7, 165.2, 155.6, 151.2, 138.2, 137.5, 132.9, 131.1, 129.6, 128.5– 127.6, 118.5, 114.7, 100.9, 100.4, 80.6, 75.5, 75.2, 74.8, 74.6, 72.5, 72.0, 71.3, 71.1, 69.8, 67.4, 55.6, 52.9, 37.9, 36.1, 30.8, 29.8, 29.7, 28.0, 18.3, 16.8, 14.1, 13.4; ESIMS: calcd for [M+Na]+ m/z 1032.4; found: 1032.7. 3.17. 4-Methoxyphenyl 3,4-di-O-benzyl-b-D-fucopyranosyl(1?6)-2-O-[2-(azidomethyl)benzoyl]-3,4- di-O-butyryl-b-Dglucopyranoside (28) To a stirred solution of 27 (340.1 mg, 0.34 mmol) in CH2Cl2 (10 mL) and MeOH (10 mL) was added NH2NH2AcOH (309.8 mg, 3.4 mmol). After 2 h, the solution was concentrated and the residue was purified by silica gel column chromatography (3:1 petroleum ether–EtOAc) to afford 28 (260.8 mg, 85%) as a syrup: Rf 0.42 (3:1 +5.4 (c 0.5, CHCl3); 1H NMR petroleum ether–EtOAc); ½a22 D (600 MHz, DMSO-d6): d 7.82 (d, 1H, J 7.1 Hz, Ph), 7.66 (t, 1H, J 7.7 Hz, Ph), 7.56 (d, 1H, J 7.7 Hz, Ph), 7.50 (t, 1H, J 7.7 Hz, Ph), 7.43–7.26 (m, 10H, Ph), 6.97 (d, 2H, J 8.8 Hz, Ph), 6.82 (d, 2H, J 9.4 Hz, Ph), 5.64 (t, 1H, J 9.8 Hz, H-3), 5.48 (d, 1H, J 8.2 Hz, H-1), 5.30 (dd, 1H, J 9.3, 8.3 Hz, H-2), 5.09 (d, 1H, J 4.9 Hz, 20 -OH), 5.04 (t, 1H, J 9.9 Hz, H-4), 4.83 (d, 1H, J 11.0 Hz, PhCH2), 4.77–4.71 (m, 4H, PhCH2), 4.59 (d, 1H, J 11.5 Hz, PhCH2), 4.22 (d, 1H, J 7.7 Hz, H-10 ), 4.20–4.18 (m, 1H, H-5), 3.75–3.73 (m, 2H, H-6a and H-40 ), 3.62 (s, 3H, OMe), 3.62–3.53 (m, 3H, H-6b, H-20 and H-50 ), 3.39 (dd, 1H, J 9.9, 2.8 Hz, H-30 ), 2.32–2.14 (m, 4H, 2  COCH2), 1.53– 1.47 (m, 2H, CH2CH3), 1.42–1.36 (m, 2H, CH2CH3), 1.15 (d, 3H, J 6.5 Hz, 6-Me), 0.85 (t, 3H, J 7.7 Hz, CH3), 0.70 (t, 3H, J 7.7 Hz, CH3); 13C NMR (150 MHz, CDCl3): d 172.7, 172.4, 165.0, 155.7, 150.9, 138.4, 137.6, 133.0, 131.0, 129.7, 128.4–127.6, 118.5, 114.7, 103.6, 100.0, 82.2, 76.2, 74.7, 74.0, 72.9, 72.3, 72.0, 71.5, 70.9, 68.8, 68.1, 55.6, 52.8, 35.9, 35.8, 30.8, 18.2, 16.8, 13.6, 13.4; ESIMS: calcd for [M+Na]+ m/z 934.4; found: 934.5.

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Z. Zhang et al. / Carbohydrate Research 345 (2010) 750–760

3.18. 4-Methoxyphenyl 3,4-di-O-benzyl-6-deoxy-b-Dtalopyranosyl-(1?6)-2-O-[(2-azidomethyl)benzoyl]-3,4-di-Obutyryl-b-D-glucopyranoside (29) A solution of 28 (324.9 mg, 0.36 mmol) in CH2Cl2 (5 mL) was added to a stirred solution of Dess–Martin periodinane (755.7 mg, 1.8 mmol) in CH2Cl2 (20 mL) at room temperature. Then the solution was stirred for 4 h. After the reaction was complete as judged by TLC, the mixture was diluted with CH2Cl2 (50 mL) and washed with 10% aq Na2S2O3 (30 mL), saturated aq NaHCO3 (30 mL), and brine (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under diminished pressure. The crude compound was dissolved in CH2Cl2 (10 mL) and MeOH (10 mL). Then NaBH4 (136.0 mg, 3.6 mmol) was added at 0 °C. After 0.5 h, the reaction was complete as judged by TLC. The mixture was diluted with CH2Cl2 (50 mL), and washed with water (30 mL), 1 M HCl (30 mL), saturated aq NaHCO3 (30 mL), and brine (30 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel column chromatography (4:1 petroleum ether–EtOAc) to afford 29 (309.3 mg, 96%) as a syrup: Rf 0.38 (2:1 petroleum ether–EtOAc); ½a18 D 10.8 (c 0.35, CHCl3); 1H NMR (600 MHz, DMSO-d6): d 7.82 (d, 1H, J 7.8 Hz, Ph), 7.66 (m, 1H, Ph), 7.56 (d, 1H, J 6.8 Hz, Ph), 7.50 (t, 1H, J 7.8 Hz, Ph), 7.43–7.26 (m, 10H, Ph), 6.94 (dd, 2H, J 6.9, 2.3 Hz, Ph), 6.83 (dd, 2H, J 6.9, 2.3 Hz, Ph), 5.65 (t, 1H, J 9.6 Hz, H3), 5.56 (d, 1H, J 7.7 Hz, H-1), 5.29 (dd, 1H, J 10.1, 8.3 Hz, H-2), 5.04 (t, 1H, J 10.1 Hz, H-4), 4.89 (d, 1H, J 11.5 Hz, PhCH2), 4.77– 4.71 (m, 2H, PhCH2), 4.64 (d, 1H, J 11.9 Hz, PhCH2), 4.59 (d, 1H, J 11.0 Hz, PhCH2), 4.54 (d, 1H, J 11.9 Hz, PhCH2), 4.26 (s, 1H, H-10 ), 4.19–4.16 (m, 1H, H-5), 3.87 (br d, 1H, J 8.7 Hz H-20 ), 3.82 (dd, 1H, J 11.5, 1.9 Hz, H-6a), 3.77 (br s, 1H, H-40 ), 3.63 (s, 3H, OMe), 3.58–3.55 (m, 2H, H-6b and OH), 3.52–3.49 (m, 1H, H-5), 3.48 (t, 1H, J 2.8 Hz, H-30 ), 2.34–2.15 (m, 4H, 2  COCH2), 1.52–1.47 (m, 2H, CH2CH3), 1.41–1.36 (m, 2H, CH2CH3), 1.13 (d, 3H, J 6.0 Hz, 6Me), 0.84 (t, 3H, J 7.3 Hz, CH3), 0.70 (t, 3H, J 7.3 Hz, CH3); 13C NMR (150 MHz, CDCl3): 206.6, 172.6, 172.3, 165.0, 155.5, 150.9, 137.8, 137.5, 133.0, 131.1, 129.7, 128.5–127.6, 117.7, 114.7, 102.3, 99.4, 77.7, 75.7, 74.4, 72.3, 71.9, 71.1, 69.8, 69.0, 68.9, 68.4, 55.6, 52.8, 35.9, 30.8, 29.6, 18.2, 16.7, 13.6, 13.4; [M+Na]+ m/z 934.4; found: 934.5. 3.19. 3,4-Di-O-benzyl-6-deoxy-b-D-talopyranosyl-(1?6)-2-O[(2-azidomethyl)benzoyl]-3,4-di-O-butyryl-b-D-glucopyranosyl trichloroacetimidate (3) To a solution of 29 (309.3 mg, 0.34 mmol) in MeCN (15 mL) and water (3 mL) was added ammonium cerium(IV) nitrate (930.3 mg, 1.69 mmol) and the mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with EtOAc (40 mL), successively washed with saturated aq NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated. The resulting residue was purified by flash column chromatography (1:1 petroleum ether–EtOAc) to give a syrup (263.0 mg, 96%) which was used directly for the preparation of donor 3. To a stirred solution of it (263.0 mg, 0.32 mmol) and CCl3CN (197.4 lL, 2.0 mmol) in CH2Cl2 (20 mL) at 0 °C was added DBU (24.7 lL, 0.16 mmol). After 1 h, the solution was concentrated. The residue was purified by silica gel column chromatography (10:1 petroleum ether–EtOAc) to afford 3 (280.8 mg, 91%) as a syrup: Rf 0.44 (2:1 petroleum ether–EtOAc); 1 ½a20 D +19.1 (c 0.22, CHCl3); HNMR (600 MHz, CDCl3): d 8.49 (s, 1H, NH), 7.95 (dd, 1H, J 7.7, 1.3 Hz, Ph), 7.57–7.31 (m, 13H, Ph), 6.61 (d, 1H, J 3.7 Hz, H-1), 5.79 (t, 1H, J 9.9 Hz, H-3), 5.29 (dd, 1H, J 10.1, 3.7 Hz, H-2), 5.14 (t, 1H, J 10.1 Hz, H-4), 5.01 (d, 1H, J 11.0 Hz, PhCHH), 4.84 (d, 1H, J 11.9 Hz, PhCHH), 4.83 (d, 1H, J 14.6 Hz, PhCHH), 4.77 (d, 1H, J 14.6 Hz, PhCHH), 4.63 (d, 1H, J 11.0 Hz, PhCHH), 4.56 (d, 1H, J 11.9 Hz, PhCHH), 4.35–4.32 (m, 2H, H-5

and H-10 ), 4.07–4.05 (m, 1H, H-40 ), 3.96 (dd, 1H, J 11.9, 1.3 Hz, H6a), 3.86–3.85 (m, 1H, H-30 ), 3.69 (dd, 1H, J 11.9, 6.9 Hz, H-6b), 3.59 (br s, 1H, OH), 3.43–3.40 (m, 2H, H-50 and H-20 ), 2.27–2.25 (m, 2H, COCH2), 2.18 (t, 2H, J 7.5 Hz, COCH2), 1.61–1.56 (m, 2H, COCH2CH2), 1.52–1.46 (m, 2H, COCH2CH2), 1.25 (d, 1H, J 6.9 Hz, 6-Me), 0.90 (t, 3H, J 7.3 Hz, CH3), 0.77 (t, 3H, J 7.3 Hz, CH3); 13CNMR (150 MHz, CDCl3): d 172.5, 172.4, 171.2, 160.8, 138.2, 137.9, 137.5, 133.5, 131.6, 129.5, 128.7–127.6, 126.7, 101.5, 92.8, 75.6, 72.6, 71.1, 70.6, 69.5, 69.2, 68.2, 68.0, 67.5, 60.4, 52.9, 35.8, 29.7, 21.0, 18.3, 18.2, 16.6, 14.2, 13.6, 13.4; ESIMS: calcd for [M-CCl3CN+Na]+ m/z 828.3; found: 828.5. 3.20. p-Tolyl 2,3,4-tri-O-benzoyl-6-deoxy-1-thio-b-Lglucopyranoside (34) 6-Deoxy-b-L-glucoside perbenzoate18 33 (4.6 g, 7.9 mmol) was dissolved in CH2Cl2 (100 mL) and p-TolSH (2.0 g, 15.8 mmol) was added at 0 °C. To the cold solution, BF3Et2O (2.0 mL, 15.9 mmol) was added dropwise over a period of 30 min and the reaction mixture was allowed to stir for another 2 h while warming to room temperature. The reaction was quenched by the addition of saturated aq NaHCO3 (100 mL) and the mixture was extracted with CH2Cl2 (150 mL). The organic layer was washed with water (100 mL), saturated aq NaHCO3 (100 mL), and brine (100 mL), dried over Na2SO4, and concentrated under diminished pressure. Purification of the crude reaction product by column chromatography on silica gel (50:1 ether–EtOAc) furnished pure 34, which could be crystallized from petroleum ether–EtOAc; (2.9 g, 63%): Rf +0.57 (3:1 petroleum ether–EtOAc); mp 149–150 °C; ½a18 D 6.0 (c 0.2, CHCl3); 1H NMR (600 MHz, CDCl3): d 7.97 (dd, 2H, J 9.6, 0.9 Hz, Ph), 7.92 (dd, 2H, J 8.2, 0.9 Hz, Ph), 7.78 (dd, 2H, J 8.3, 0.9 Hz, Ph), 7.54–7.49 (m, 2H, Ph), 7.42–7.35 (m, 7H, Ph), 7.23 (t, 2H, J 8.2 Hz, Ph), 7.13 (d, 1H, J 7.7 Hz, Ph), 5.81 (t, 1H, J 9.6 Hz, H3), 5.42 (t, 1H, J 9.6 Hz, H-2), 5.29 (t, 1H, J 9.6 Hz, H-4), 4.93 (d, 1H, J 10.1 Hz, H-1), 3.88 (qd, 1 H, J 9.6, 5.9 Hz, H-5), 1.39 (d, 3H, J 6.4 Hz, 6-Me); 13C NMR (150 MHz, DMSO-d6): d 165.8, 165.4, 165.0, 138.6, 133.8, 133.3, 133.2, 129.8–128.2, 86.1, 74.9, 74.2, 73.6, 70.9, 21.2, 17.8; HRESIMS: calcd for C34H30O7SNa+ [M+Na]+ m/z 605.1610; found: 605.1602. 3.21. p-Tolyl 2,3,4-tri-O-benzyl-6-deoxy-1-thio-b-Lglucopyranoside (4) Compound 34 (1.00 g, 1.7 mmol) was dissolved in MeOH (25 mL) and NaOMe was added to the solution until pH 8.5. The mixture was stirred at room temperature for about 1 h, and then it was neutralized with Dowex 50  8(H+) resin until pH 7.0, filtered, and concentrated. The dried residue was dissolved in DMF (20 mL) and cooled to 0 °C. Sodium hydride (60%, 247.3 mg, 6.0 mmol) was added, followed by benzyl bromide (1.8 mL, 10.2 mmol). As shown by TLC, the reaction was complete after 4 h at 0 °C. The mixture was diluted with water (100 mL) and extracted with CH2Cl2 (3  100 mL). The combined organic extracts were combined, dried over MgSO4, and concentrated. Silica gel column chromatography of the crude product (100:1 petroleum ether–EtOAc) furnished 4 (549.0 mg, 59%) as a colorless oil: Rf 1 0.53 (10:1, petroleum ether–EtOAc); ½a22 D 13.8 (c 0.2, CHCl3); H NMR (600 MHz, CDCl3): d 7.45 (d, 2H, J 7.8 Hz, Ph), 7.40 (dd, 2H, J 8.2, 1.4 Hz, Ph), 7.35–7.28 (m, 13H, Ph), 7.11 (d, 1H, J 7.8 Hz, Ph), 4.91 (d, 1H, J 9.6 Hz, PhCHH), 4.90 (d, 1H, J 10.1 Hz, PhCHH), 4.86 (d, 1H, J 10.5 Hz, PhCHH), 4.84 (d, 1H, J 10.5 Hz, PhCHH), 4.90 (d, 1H, J = 10.1 Hz, PhCHH), 4.74 (d, 1H, J 10.1 Hz, PhCHH), 4.65 (d, 1H, J 10.9 Hz, PhCHH), 4.59 (d, 1H, J 9.6 Hz, H-1), 3.66 (t, 1H, J 9.1 Hz, H-3), 3.46 (t, 1H, J 9.6 Hz, H-2), 3.39 (qd, 1 H, J 9.6, 6.0 Hz, H-5), 3.20 (t, 1H, J 9.2 Hz, H-4), 2.34 (s, 3H, PhCH3), 1.34 (d, 3 H, J 6.4 Hz, 6-Me); 13C NMR (150 MHz, DMSO-d6): d 138.4, 138.1,

Z. Zhang et al. / Carbohydrate Research 345 (2010) 750–760

138.0, 137.7, 132.6, 129.6, 128.4–127.7, 87.8, 86.6, 83.3, 81.2, 75.5, 18.1. ESI-MS: calcd for [M+Na]+ m/z 563.2; found: 563.2.

759

71.7, 70.5, 69.1, 69.0, 52.7, 43.7, 35.8, 35.0, 34.2, 31.9, 30.9, 30.0– 29.2, 25.3, 24.9, 23.8, 22.7, 18.3, 18.1, 16.8, 14.1, 13.6, 13.4. ESIMS: calcd for [M+Na]+ m/z 1631.9; found:1632.0.

D-talopyranosyl-(1?6)-

3.22. (10R)-2-Nonadecanone-10-yl 3,4-di-O-benzyl-6-deoxy-b2-O-[(2-azidomethyl)-benzoyl]-3,4-di-Obutyryl-b-D-glucopyranosyl(1?2)-3,4,6-tri-O-benzyl-b-Dglucopyranoside (30)

3.24. (10R)-2-Nonadecanone-10-yl 2,3,4-tri-O-benzyl-6-deoxyb-D-talopyranosyl-(1?6)-3,4-di-O-butyryl-b-D-glucopyranosyl(1?2)-3,4,6-tri-O-benzyl-b-D-glucopyranoside (32)

To a solution of 2 (162.0 mg, 0.22 mmol), 3 (285.4 mg, 0.30 mmol), and 4 Å molecular sieves in dry CH2Cl2 (15 mL), TMSOTf (8 lL, 0.04 mmol) was added at 0 °C under argon. The reaction mixture was stirred for 1 h until TLC indicated that the reaction was complete. The reaction was quenched by the addition of Et3N (two drops) and concentrated. The residue was purified by silica gel column chromatography (4:1 petroleum ether–EtOAc) to give 30 (254.1 mg, 76%) as a syrup: Rf 0.39 (4:1 petroleum ether– 1 EtOAc); ½a22 D 16.0 (c 0.2, CHCl3); HNMR (600 MHz, CDCl3): d 7.72 (d, 1H, J 6.8 Hz, Ph), 7.49–7.15 (m, 31H, Ph), 7.72 (dd, 1H, J 7.8, 1.9 Hz, Ph), 5.32 (t, 1H J 9.6 Hz, H-30 ), 5.21–5.16 (m, 2H, H-10 and H-20 ), 4.97 (d, 1H, J 11.0 Hz, PhCH2), 4.91 (t, 1H J 9.6 Hz, H40 ), 4.87 (d, 1H, J 14.2 Hz, PhCH2), 4.84 (d, 1H, J 11.4 Hz, PhCH2), 4.62–4.55 (m, 7H, PhCH2), 4.43 (d, 1H, J 11.0 Hz, PhCH2), 4.37 (d, 1H, J 11.0 Hz, PhCH2), 4.30 (d, 1H, J = 7.3 Hz, H-1), 4.27 (d, 1H, J = 11.9 Hz, H-6a0 ), 4.22 (s, 1H, H-100 ), 4.21 (d, 1H, J 12.4 Hz, H6b0 ), 3.90 (d, 1H, J 11.0 Hz, H-6a), 3.79–3.72 (m, 2H, H-50 and H6b), 3.66–3.34 (m, 9H, H-2, H-3, H-4, H-5, H-200 , H-300 , H-400 , H-500 and OCH), 2.37 (t, 2H, J 7.40 Hz, COCH2), 2.24–2.21 (m, 2H, COCH2), 2.14–2.11 (m, 2H, COCH2), 2.10 (s, 3H, COCH3), 1.62–1.23 (m, 35H, 2  CH2CH2CO, 14  CH2 and 600 - Me); 0.91–0.86 (m, 6H, 2  CH3), 0.73 (t, 3H, J = 7.6 Hz, CH3). 13C NMR (150 MHz, CDCl3): 209.1, 172.6, 172.3, 164.7, 138.6, 138.0, 137.7, 137.6, 137.4, 132.7, 130.8, 129.8, 128.4–126.9, 102.1, 101.8, 99.6, 85.8, 82.2, 78.6, 78.1, 77.9, 77.6, 75.5, 75.0, 74.7, 74.6, 74.3, 73.0, 72.3, 70.8, 70.0, 69.2, 69.1, 68.5, 68.4, 52.7, 43.7, 35.8, 31.9, 30.9, 30.0–29.2, 25.5, 24.8, 23.8, 22.7, 18.3, 18.2, 16.7, 14.1, 13.6, 13.4; ESIMS: calcd for [M+Na]+ m/z 1540.8; found: 1541.2.

To a solution of 31 (10 mg, 0.006 mmol) in THF (5 mL), Bu3P (10 mg) and water (0.1 mL) were added at 50 °C under argon. The reaction mixture was stirred under these conditions for 1 h, until TLC indicated that the reaction was complete. The reaction mixture was diluted with EtOAc, washed with saturated aq NaHCO3 (5 mL) and brine (5 mL), dried over Na2SO4, and concentrated under diminished pressure. The residue was purified by silica gel column chromatography (6:1 petroleum ether–EtOAc) to give 32 (7.6 mg, 85%) as a syrup: Rf 0.50 (3:1 petroleum ether–EtOAc); 1 ½a22 D 12.6 (c 0.07, CHCl3); H NMR (600 MHz, CDCl3): d 7.76 (d, 1H, J 7.7 Hz, Ph), 7.49–6.97 (m, 33H, Ph), 5.07 (t, 1H J 9.4 Hz, H30 ), 5.04 (d, 1H, J 12.6 Hz, PhCH2), 4.96 (d, 1H, J 12.1 Hz, PhCH2), 4.93 (t, 1H J 9.8 Hz, H-40 ), 4.87 (d, 1H, J 11.7 Hz, PhCH2), 4.85 (d, 1H, J 11.2 Hz, PhCH2), 4.78 (d, 1H, J 11.5 Hz, PhCH2), 4.72–4.69 (m, 3H, H-10 and PhCH2), 4.55 (d, 1H, J 12.1 Hz, PhCH2), 4.53 (d, 1H, J 10.4 Hz, PhCH2), 4.49 (d, 1H, J 12.1 Hz, PhCH2), 4.44 (d, 1H, J 10.6 Hz, PhCH2), 4.42 (d, 1H, J 6.6 Hz, H-1), 4.34 (d, 1H, J 12.1 Hz, PhCH2), 3.99–3.97 (m, 1H, H-50 ), 3.84 (s, 1H, H-100 ), 3.73–3.49 (m, 9H, H-20 , H-4, H-6, H-500 , H-60 , H-3, H-200 , H-300 , H-400 ), 3.45–3.31 (m, 3H, H-2, H-5 and OCH), 2.36 (t, 2H, J 7.70 Hz, COCH2), 2.24– 2.20 (m, 4H, 2  COCH2), 2.04 (s, 3H, COCH3), 1.67–1.22 (m, 35H, 2  CH2CH2CO, 14  CH2 and 600 -Me); 0.92–0.87 (m, 9H, 3  CH3); 13 C NMR (150 MHz, CDCl3): d 209.2, 173.2, 172.7, 166.1, 139.6, 139.2, 138.4, 138.3, 138.0, 137.9, 128.6–127.2, 102.8, 102.3, 101.0, 84.8, 80.0, 79.9, 79.0, 78.8, 76.2, 74.9, 74.2, 74.0, 73.7, 73.6, 73.3, 71.9, 70.5, 69.0, 68.6, 66.2, 60.5, 43.9, 36.3, 36.1, 34.7, 33.9, 30.0–29.3, 25.3, 23.9, 22.8, 18.5, 18.4, 14.3, 14.2, 13.7. ESIMS: calcd for [M+Na]+ m/z 1471.8; found:1471.8.

3.23. (10R)-2-Nonadecanone-10-yl 2,3,4-tri-O-benzyl-6-deoxyb-D-talopyranosyl-(1?6)-2-O-[(2-O-azidomethyl)benzoyl]-3,4di-O-butyryl-b-D-glucopyranosyl-(1?2)-3,4,6-tri-O-benzyl-b-Dglucopyranoside (31)

3.25. (10R)-2-Nonadecanone-10-yl 2,3,4-tri-O-benzyl-6-deoxya-L-glucopyranosyl-(1?2)- [2,3,4-tri-O-benzyl-6-deoxy-b-Dtalopyranosyl-(1?6)]-3,4-di-O-butyryl-b-D-glucopyranosyl(1?2)-3,4,6-tri-O-benzyl-b-D-glucopyranoside (36)

To a solution of 30 (99.0 mg, 0.06 mmol), BnO(CCl3)C@NH (100 mg, 0.30 mmol), 4 Å molecular sieves in dry CH2Cl2 (3 mL), and cyclohexane (3 mL), TfOH (5 lL) was added at room temperature under argon. The reaction mixture was stirred under these conditions for 1 h, then neutralized with Et3N (two drops). The solid was filtered off, and the filtrate was concentrated under diminished pressure. The resulting residue was purified by silica gel column chromatography (4:1, petroleum ether–EtOAc) to give 31 (108.9 mg, 79%) as a syrup: Rf 0.40 (4:1 petroleum ether–EtOAc); 1 ½a20 D 7.0 (c 0.1, CHCl3); H NMR (600 MHz, CDCl3): d 7.76 (d, 1H, J 7.7 Hz, Ph), 7.49–6.97 (m, 33H, Ph), 5.33 (t, 1H J 9.4 Hz, H-30 ), 5.21–5.16 (m, 2H, H-10 and H-20 ), 5.07 (d, 1H, J 12.7 Hz, PhCH2), 4.99 (d, 1H, J 12.1 Hz, PhCH2), 4.94 (t, 1H J 9.9 Hz, H-40 ), 4.85 (d, 1H, J 14.3 Hz, PhCH2), 4.78 (d, 2H, J 12.1 Hz, PhCH2), 4.64 (d, 1H, J 14.3 Hz, PhCH2), 4.61–4.36 (m, 9H, PhCH2 and H-6a0 ), 4.30 (d, 1H, J 7.13 Hz, H-1), 4.02 (s, 1H, H-100 ), 3.94–3.90 (m, 1H, H-6b0 ), 3.69– 3.31 (m, 12H, H-2, H-3, H-4, H-5, H-6a, H-6b, H-50 , H-200 , H-300 , H400 , H-500 and OCH), 2.35 (t, 2H, J 7.70 Hz, COCH2), 2.27–2.23 (m, 2H, COCH2), 2.15–2.12 (m, 2H, COCH2), 2.10 (s, 3H, COCH3), 1.67– 1.22 (m, 35H, 2  CH2CH2CO, 14  CH2 and 600 - Me), 0.94–0.86 (m, 6H, 2  CH3), 0.74 (t, 3H, J 7.4 Hz, CH3). 13C NMR (150 MHz, CDCl3): 206.9, 172.7, 172.2, 164.7, 139.6, 138.5, 138.1, 138.0, 137.7, 137.4, 132.8, 130.8, 129.8, 128.5–126.9, 102.4, 101.5, 99.5, 85.8, 81.0, 78.7, 77.7, 75.0, 74.7, 74.6, 74.3, 73.7, 73.2, 72.5, 72.4,

To a mixture of 32 (20.0 mg, 0.01 mmol), 4 (15.0 mg, 0.02 mmol), and 4 Å molecular sieves in dry CH2Cl2 (3 mL), NIS (4.0 mg, 0.016 mmol) and AgOTf (1.0 mg, 0.002 mmol) were added at 0 °C under argon. The reaction mixture was stirred for an additional 12 h while allowed to warm to room temperature. After the reaction was complete as judged by TLC, the reaction mixture was filtered and concentrated. Then the residue was diluted with CH2Cl2 (20 mL), and washed with 10% aq Na2S2O3 (15 mL), aq NaHCO3 (15 mL), and brine (2  15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (6:1 petroleum ether–EtOAc) to give 36 (6.0 mg, 23%) as a syrup: Rf 0.55 (3:1 petroleum ether– 1 EtOAc); mp 149.1–150.0 °C ½a22 D 15.7 (c 0.2, CHCl3); H NMR (600 MHz, CDCl3): d 7.46–7.04 (m, 45 H), 5.29 (t, 1H, J 9.3, 7.7 Hz, H-30 ), 5.23 (d, 1H, J 3.3 Hz, H-1000 ), 5.14 (d, 1H, J 11.5 Hz, PhCH2), 5.13 (t, 1H J 8.3 Hz, H-40 ), 5.03–4.63 (m, 17 H, H-10 , H-20 and 7  PhCH2), 4.60 (d, 1H, J 11.5 Hz, PhCH2), 4.55 (d, 1H, J 10.4 Hz, PhCH2), 4.54 (d, 1H, J 11.0 Hz, PhCH2), 4.50 (d, 1H, J 11.0 Hz, PhCH2), 4.44–4.42 (m, 1H, H-6a0 ), 4.37–4.32 (m, 1H, H-6b0 ), 4.25 (d, 1H, J 7.7 Hz, H-1), 4.07 (t, 1H, J 9.3 Hz, H-4), 3.98 (s, 1H, H-100 ), 3.81–3.77 (m, 2H, H-3 and H-50 ), 3.74 (t, 1H, J 8.8 Hz, H-2), 3.56– 3.37 (m, 10H, H-6, H-5, H-200 , H-300 , H-400 , H-2000 , H-3000 , H-4000 , H-500 and OCH), 3.29–3.26 (m, 1H, H-5000 ), 3.16 (dd, 1H, J = 9.4, 8.8 Hz, H-4000 ), 2.36–2.32 (m, 2H, COCH2), 2.23–2.13 (m, 4H, 2  COCH2),

760

Z. Zhang et al. / Carbohydrate Research 345 (2010) 750–760

2.09 (s, 3H, COCH3), 1.65–1.18 (m, 37H, 2  CH2CH2CO, 14  CH2, 600 -Me and 6000 -Me); 0.94–0.83 (m, 9H, 3  CH3); 13C NMR (150 MHz, CDCl3): 172.5 172.2, 139.7, 139.4, 138.7–137.8, 128.6– 126.9, 102.4, 102.1, 99.6, 96.2, 91.1, 86.5, 84.4, 83.7, 83.5, 82.2, 81.7, 81.5, 80.3, 78.9, 75.7–73.2, 72.6, 71.6, 70.5, 69.8, 69.2, 68.1, 67.0, 66.9, 43.7, 36.2, 35.8, 35.1, 34.3, 31.9, 30.1–29.2, 25.3, 25.0, 23.8, 22.7, 18.2, 18.0, 14.1, 13.7, 13.6; ESIMS: calcd for [M+H]+ m/ z 1867.0; found: 1867.6; HRESIMS: m/z calcd for C34H30O7SNa+ 605.1610; found 605.1602. 3.26. (10R)-2-Nonadecanone-10-yl 6-deoxy-a-L-glucopyranosyl(1?2)-[6-deoxy-b-D-talopyranosyl-(1?6)]- 3,4-di-O-butyryl-b-Dglucopyranosyl-(1?2)-b-D-glucopyranoside (1)

Acknowledgments This work was supported by a grant from the Ph.D. Programs Foundation of Ministry of Education of China (No. 20070423001) and the National Natural Science Youth Foundation (No. 30701046). Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.carres.2010.01.015.

References Compound 36 (6 mg) was dissolved in MeOH (5 mL) and then 10%-Pd/C (50 mg) was added. After stirring at 50 °C for 4 h under H2, the mixture was filtered through a Celite pad and the filtrate was concentrated. The resulting residue was subjected to Sephadex LH-20 chromatography (1:1 MeOH–CH2Cl2) to yield 1 (3.0 mg, 88%) as a colorless glass: Rf 0.33 (2:1 CHCl3–CH3OH-1% AcOH); 4b 1 ½a25 ½a25 D 24 (c 0.175, MeOH), (Lit. D 22 (c 0.17, MeOH); HNMR (600 MHz, DMSO-d6): d 5.17 (t, 1H, J 10.2 Hz, H-30 ), 5.04 (d, 1H, J 7.7 Hz, H-10 ), 4.63 (s, 2H, H-100 and H-1000 ), 4.57 (t, 1H, J 9.9 Hz, H40 ),4.39–4.37 (m, 3H, 3  OH), 4.22(t, 1H, J 6.8, 6.4 Hz, 6-OH), 4.13 (d, 1H, J 6.8 Hz, H-1), 4.01–3.95 (m, 1H, H-5000 ), 3.90–3.85 (m, 1H, OH), 3.68–3.57 (m, 4H, H-6a, H-6a0 , H-50 and OCH), 3.50– 3.30 (m, 8H, H-6b, H-6b0 , H-200 , H-300 , H-400 , H-500 , H-20 , H-3000 ), 3.16–3.11 (m, 2H, H-2000 and H-4), 3.03–2.99 (m, 1H, H-5), 2.94 (t, 1H, J 9.6 Hz, H-3), 2.71 (t, 1H, J 9.3 Hz, H-4000 ), 2.39 (t, 2H, J 7.7 Hz, COCH2), 2.34–2.12 (m, 4H, 2  COCH2), 2.05 (s, 3H, COCH3), 1.68– 1.18 (m, 32H, 2  CH2CH2CO and 14  CH2); 1.14 (d, 3H, J 6.4 Hz, 600 -Me), 1.09 (d, 3H, J 5.9 Hz, 6000 -Me), 0.84 (t, 9H, J 7.8 Hz, 3  CH3); 13C NMR (150 MHz, DMSO-d6): d 208.4, 171.8, 171.4, 101.4, 101.2, 100.0, 99.4, 80.8, 77.0, 76.9, 76.5, 75.6, 73.6, 73.3, 72.6, 72.3, 72.0, 71.8, 71.3, 70.7, 69.9, 69.5, 68.3, 67.2, 60.6, 42.6, 35.3, 35.0, 34.2, 33.7, 31.3, 29.7–28.5, 23.1, 22.1, 17.9, 17.6, 17.5, 16.4, 13.8, 13.3, 13.2. ESIMS: calcd for [M+Na]+ m/z 1077.6; found:1077.7. HRESIMS: m/z calcd for C51H90O22Na+ 1077.5821; found 1077.5853. (Lit.4b 1HNMR (800 MHz, DMSO-d6): d 5.17 (H-30 ), 5.04 (H-10 ), 4.65 (H-1000 ) 4.64 (H-100 ), 4.57 (H-40 ), 4.13 (H-1), 3.92 (H-5000 ), 3.66 (H-50 ), 3.64 (H-200 ), 3.63 (H-6a0 ) 3.62 (H-6a) 3.44 (OCH), 3.48 (H6b), 3.42 (H-6b0 ), 3.40 (H-20 ), 3.39 (H-500 ), 3.34 (H-3000 ), 3.16 (H-4), 3.13 (H-2000 ), 3.03 (H-5), 2.75 (H-4000 ), 2.37 (COCH2), 2.27 (2  COCH2), 2.04 (COCH3), 1.47 (2  CH2CH2CO), 1.19 (CH2), 1.13 (d, 3H, J = 6.4 Hz, 600 -Me), 1.08 (6000 -Me), 0.84, (2  CH3) 0.83 (CH3); 13C NMR (100 MHz, DMSO-d6): d 208.0, 171.5, 171.0, 101.2, 101.0, 99.7, 99.2, 80.8, 77.1, 77.0, 76.5, 75.6, 73.7, 73.4, 72.6, 72.1, 71.7, 71.3, 70.9, 69.9, 69.5, 68.4, 67.0, 60.7, 42.7, 35.4, 35.1, 34.3, 33.7, 29.7, 29.6, 29.5, 29.3, 29.1, 29.0, 28.8, 28.7, 28.5, 23.0, 17.9, 17.6, 17.5, 16.4, 13.9, 13.4, 13.3.)

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