Hydrogen Bonding Assisted Exogenous Nucleophilic Reagent Effect

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Hydrogen Bonding Assisted Exogenous Nucleophilic Reagent Effect for #-Selective Glycosylation of Rare 3-Amino Sugars Jing Zeng, ruobin wang, Shuxin Zhang, Jing Fang, Shanshan Liu, Guangfei Sun, Bingbing Xu, Ying Xiao, Dengxian Fu, Wenqi Zhang, Yixin Hu, and Qian Wan J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 08 May 2019 Downloaded from http://pubs.acs.org on May 8, 2019

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Journal of the American Chemical Society

Hydrogen Bonding Assisted Exogenous Nucleophilic Reagent Effect for -Selective Glycosylation of Rare 3-Amino Sugars Jing Zeng,*,† Ruobin Wang,† Shuxin Zhang,† Jing Fang,† Shanshan Liu,‡ Guangfei Sun,† Bingbing Xu,† Ying Xiao,† Dengxian Fu,† Wenqi Zhang,† Yixin Hu,† Qian Wan*,†,§ Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China. †

‡

The Institute for Advanced Studies, Wuhan University, 299 Bayi Street, Wuhan, Hubei, 430072, China.

§ Institute

of Brain Research, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030,

China. ABSTRACT: Challenges for stereoselective glycosylation of deoxy sugars are notorious in carbohydrate chemistry. We herein report a novel strategy for the construction of the less investigated -glycosidic bonds of 3,5-trans-3-amino-2,3,6-trideoxysuars (3,5-trans-3ADSs) which constitute the core structure of several biologically-important antibiotics. Current protocol leverages a C-3 axial sulfonamide group in 3,5-trans-3-ADSs as a hydrogen-bond (H-bond) donor and repurposes sub-stoichiometric of phosphine oxide as exogenous nucleophilic reagent (exNu) to establish an intramolecular H-bond between the former and the derived oxyphosphonium ion. This pivotal interaction stabilizes the -face covered intermediate to inhibit the formation of the more reactive -intermediate, thereby yielding reversed -selectivity which is unconventional for an exNu-mediated glycosylation system. Wide range of substrates was accommodated and good to excellent -selectivities were insured by this H-bonding-assisted exNu effect. The robustness of current strategy was further attested by the architectural modification of natural products and drugs containing 3,5trans-3-ADSs, as well as the synthesis of a trisaccharide unit in avidinorubicin.

INTRODUCTION

a. Exogenous nucleophilic reagent (exNu) controlled -selectivity

The construction of glycosidic bonds underpins the development of carbohydrate chemistry. The structural diversity and varying properties of mono- or oligosaccharides render the stereoselective glycosylation an arduous task that warrants intensive research efforts.1 Among them, one appealing approach involves the application of exogenous nucleophilic reagent (exNus) effect.2 While this strategy was seminally reported in 1973,3 it has been recently revisited and advanced by Mong4 and Codée,5 et al6 wherein screening of various additives as modulators were mainly embodied in the past decades (Scheme 1a). In general, these protocols necessitate excess or even large excess of additives with prevailing -selectivity.2 The -selectivity was deemed to be engendered from the kinetically controlled -facial attack of acceptors to the more reactive -covalent intermediate (C). 3-Amino-2,3,6-trideoxysugars (3-ADSs)7 belong to a more rarely-encountered class of sugar, typically present in a few anticancer drugs and antibiotics, for instance, saccharomicins,8 avidinorubicin,9 cororubicin10 and lobophorins.11 Significantly, 3-ADSs in these natural products commonly adopt the 3,5-trans configuration and are consistently found to form -glycosidic bonds with other sugars or aglycons. Chemical construction of -O-glycosidic bonds in 3,5-trans-3-ADSs poses extra hurdles due to the lack of C-2 participation group in addition to the exceptional instability of the glycosidic bonds.12 The glycosidic bond was found susceptible to Scheme 1. exNu effect for stereoselective glycosylation.

exNu

O

A oxocarbenium

-covalent intermediates O

-covalent intermediates O

exNu

B more stable less active

O

ROH

C less stable more active



OR

1 -glycosides

exNu: R2S, R2S=O, R3P, R3P=O, DMF related, etc. b. Intramolecular H-bond in 3,5-trans-3-ADS O

AcO

H+

NsNH OMe 2 (  2.7:1)

O

AcO

72%,  > 20:1

NsN

H 3

O

H X-Ray of 3

c. H-bond stabilized oxyphosphonium species for -glycosylation (this work) -oxyphosphonium species O

O

OABz

Au(I)

Ar3P=O (4) ( 0.5 equiv)

ROH NsN

O

Ar

O

OR 

P Ar3P=O NsNH H Ar trans Ar D 6 -glycosides more stable, less active higher selectivity Ns = p-nitrobenzenesulfonyl; OABz = alkynyl benzoate NsNH 5

hydrolysis or isomerization even under weakly acidic conditions.7 Furthermore, although 1,3-diaxial effect exerted by the C-3 axial substituents could promote the -selectivity, the reversed selectivity was favored by anomeric effect, giving rise to anomeric mixtures. Moreover, Finizia13 and Giuliano14 revealed that harnessing the C-3 anchimeric assistance might not be necessarily helpful. Consequently, only two examples

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featuring the stereoselective construction of -O-glycosidic bonds of 3,5-trans-3-ADSs have been documented to-date, in the independent works of McDonald15 and Bennett16 for the synthesis of fragments of saccharomicins.17 In an earlier study on the diversified syntheses of 3,5-trans3-ADSs,7a an -hemiacetal 3 was obtained in excellent selectivity when a methyl O-glycoside 2 was hydrolyzed under acidic conditions. X-ray crystallography analysis revealed that an intramolecular hydrogen-bond (H-bond) was formed between the axial C-3 amide group and the oxygen atom of anomeric hydroxy group, which could have bolstered the formation of -anomer (Scheme 1b). This also hinted to the efficacy of C-3 sulfonamide group as a good H-bond donor.18,19 Inspired by this observation, we envisioned that an intramolecular H-bond could aid to stabilize -covalent intermediate formed between an exNu and activated glycosyl donor. With the assistance of this H-bond arose from the C-3 axial sulfonamide group, the formation of the corresponding covalent intermediate would be largely inhibited to restrict the -facial attack on glycosyl acceptors. Eventually, glycosyl acceptors could only approach from the -face thus deliver a reversed stereo-outcome. Herein, we present our solution to realize the challenging -selective glycosylation of 3,5-trans-3ADSs via a H-bond stabilized -oxyphosphonium intermediate (D) by employing phosphine oxide as exNu (Scheme 1c). Remarkably, only sub-stoichiometric amount of phosphine oxide was required for current method.

a reduced loading of additive 4b to 0.5 equiv (1/3 equiv relative to the donor) conserved the coupling yield and -selectivity (entry 5). Also, Ph3PAuOTf catalyst provided coupling product in lower yield and selectivity, while Ph3PAuBAr4F 23 exhibited similar efficiency as Ph3PAuNTf2 (entries 7, 8). Further investigations revealed that 0.05 equiv of Ph3PAuBAr4F was sufficient to uphold the excellent stereoselectivity (entry 9). In all cases, glycal 8 was identified to be the major byproduct. Table 1. Optimization of reaction conditions.

AcO

NsHN O

OBn

OABz + HO BnO

O BnO

5a (1.5 equiv)

Ph3PAuNTf2 (0.2 equiv) exNu (1.2 equiv)

OMe

Ph3P O

OBn

NHNs

O

AcO

O BnO

DCM (0.05 M), -40 oC

O BnO

6a

7a

OMe

O

exNu MeO

3

4a

Entry 1 2 3 4 5d 6e,f 7d,f 8d,g 9d,h

RESULTS AND DISCUSSION Our studies commenced with screening of exNus (Table 1). In our exploratory studies, it has been verified that the mild Yu glycosylations20 could preserve both the sensitive glycosidic bonds and high glycosylation efficiency. Using Au(I)-catalyzed glycosylation of alkynyl benzoate donor 5a with 7a as model reaction, disaccharide 6a was formed in excellent yield with slight -selectivity in the absence of additive (entry 1). After unsuccessful examination of several types of additives (see the Supporting Information), we turned to phosphine oxides. Mukaiyama and co-workers have elegantly introduced phosphine oxides to modulate the -selectivity of common sugars.21 Very recently, Codée et al. successfully employed this strategy to assemble complex -glucans.5 To our delight, significant increase in -selectivity was observed when the additive was switched to triphenylphosphine oxide (TPPO, 4a) (entry 2). The anomeric proton of -anomer exhibited as double doublet peaks with coupling constant of 9.6 and 2.4 Hz in 1H NMR, indicating the equatorial orientation of the glycosidic bond.22 Among the phosphine oxides surveyed, the electron rich ones forged the glycosidic bond in excellent -selectivity. Remarkably, -isomer was exclusively isolated when 4b was used as an additive due to its increased nucleophilicity (entry 3). In contrast, electron deficient phosphine oxide (4c, entry 4) displayed lower reaction efficiency but yielded a much higher selectivity than the control experiment (entry 1). Interestingly,

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4b

exNu 4a 4b 4c 4b 4b 4b 4b 4b

P O

F

3 4c

6aa 95% 95% 92% 75% 95% 97% 82% 96% 83%

O

P O OAbz

:b 1.6:1 15:1 >20:1 4.8:1 >20:1 >20:1 8.7:1 >20:1 >20:1

Me AcO

NHNs O

8

C5H11

8c 28% 36% 36% 45% 35% 33% 45% 34% 20%

Isolated yields; b  to  ratio was determined by the yields of isolated anomers. c Isolated yields based on 5a. d 0.5 equiv of additive (1/3 equiv related to the donor); e solvent concentration was 0.1 M; f Ph3PAuOTf was used; g Ph3PAuBAr4F was used; h 0.05 equiv of Ph3PAuBAr4F was used. BAr4F = tetrakis[3,5bis(trifluoromethyl)phenyl]borate. a

With these optimized conditions in hand, we then set out to examine the scopes of the stereoselective glycosylation method with Ph3PAuBAr4F as catalyst (Figure 1). As shown in Figure 1, four types of 3-ADS donors (5a-d) reacted well with various acceptors to give products in good to excellent -selectivities. The reaction with bulky primary alcohol furnished 6b in a / ratio of 7.5:1, while the less sterically hindered and electronrich primary alcohols produced lower selectivity (6c). This could be attributed to the secondary role of this glycosyl acceptor as a good H-bond acceptor to compete with the phosphine oxide additive. Correspondingly, an increased steric hindrance or decreased acceptor reactivity could improve the product selectivity, albeit with a compromised reaction yield owing to the significantly temperate donor properties (6d). Acid labile protecting groups such as benzylidene acetal and isopropylidene acetal remained intact under the glycosylation conditions (6b, 6e, 6f, 6h-k). In addition, thioglycosides were well tolerated (6h-j), accentuating the potential of downstream glycosylation by


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Journal of the American Chemical Society

5a-d

+

R-OH

(1.5 equiv)

O

AcO

O

AcO

O

AcO

OR

6 O

AcO Me

OABz NsHN

NsHN

Me 5b

5a

5c

S O

OABz 5d

OPTB

from natural products and drugs

from 5a O

O

O O

O

Ph

O

O O AcO

O

O O

NHNs

O

CbzHN

O 6k, 95%, : = 8:1

O

O

O

O

O

O

O O O

OMe

O OMe

NHNs

R

NHNs 6lc, 68%,  only

O O

O

OH O

R NsHN O AcO

OH O from daunorubicin

O

from NHNs podophyllotoxin 6pc,d, 70%,  only

6o, 83%, : = 5:1

OMe

O O

AcO

H from digoxigenin

OH O

OMe

MeO

O

HO O

AcO

O

H 3C

O O

O

OAc CH3

O

O H

from diosgenin 6ne, 95%, : = 4.2:1

O

AcO

H H

H

NsHN O AcO

H

from simvastatin 6md, 83%, : = 9:1

OMe

rha-sac disaccharide of saccharomicins 6j, 88%,  only

NsHN

H

O

O

NHNs

AcO O

O

O

STol AcO Me

O

O

6g 75%, : = 6:1

Ph O

O O

OMe

O

O

O

O

6h, R'' = OPTB, 85%, : = 7.5:1 6i, R'' = STol, 95%, : = 9:1

NsHN

O

R'' O

NsHN O

38%,  only

6f 82%,  only

from 5b-5d

AcO

6db

O OMe

6e 80%,  only

AcO Me

BnO

6c 94%, : = 3.8:1

AcO OMe

AcO

O

BnO

BnO OMe

6b 95%, : = 7.5:1 O O O

OBn

O

O

BnO BnO

O O

Ph

OABz

NsHN

NsHN O

4 Å MS, DCM, -40 °C

7

OABz

NsHN

Ph3PAuBAr4F (0.1 equiv) 4b (0.5 equiv)

6qc,e, 85%, : = 8:1

AcO

O

NsHN 6rc,e, 83%, : = 3.5:1

Figure 1. Substrate scope.a a Unless otherwise specified, the yields were isolated yields, the / ratios were determined by the isolated isomers separated by column chromatography on silica gel. b Donor (1.0 equiv), acceptor (2.0 equiv), Au(I) cat. (0.07 equiv). cDonor (3.0 equiv), 4b (1.0 equiv). d 4a (0.5 equiv) was used instead of 4b. e 0.2 equiv of Au(I) cat. was used.

activation of thioglycosides (6i, 6j), or the employment of an interrupted Pummerer reaction-mediated (IPRm) glycosylation strategy (6h).24 Encouraged by these observations, we also synthesized the Rha-Sac disaccharide unit (6j) of saccharomicins. Coupling of two molecules of 3-ADS donors with an acceptor possessing two free hydroxy groups maintained a satisfactory yield of 68% of 6l as a single isomer. These successes stimulated us to further extend this strategy to the modification of natural products and drugs containing 3ADSs skeleton (Figure 1). Among the tested natural products and drugs, glycosylation of simvastatin with 5a offered 6m in 83% yield with  to  ratio of 9:1. For chemical modification of podophyllotoxin which constitutes the key pharmacophore of several clinical antitumoral agents,25 the construction of aryltetralin 4-O-glycosidic linkages was conventionally stymied by the high lability of the podophyllotoxin structure towards both acidic and basic conditions.26 With our method, the coupling of podophyllotoxin with 5c provided 6p as a sole anomer in high efficiency by application of the established H-

bonding assisted exNu effect. It should be noted that TPPO (4a) was used instead of 4b in the preparation of 6m and 6p, which otherwise gave rise to extremely low product yields. Our next target was steroid which offer broad-range bioactivities and which the activity profiles vary with the modifications on sugar moieties. We have previously demonstrated the glycosylation of diosgenin and digoxigenin with 3-ADSs in an -favored selectivity.7b,c With the present method, we successfully assembled glycosylated diosgenin 6n and digoxigenin 6o in good -selectivity. Aside from that, anthracyclines possessing 3-ADSs moiety have been widely used for cancer therapy. Of note, Wang and Sun et al have proven that modification of the sugar moieties could augment their antitumor activity and overcome the drug resistance.27 Without much hurdles, current method facilely delivered the -3-ADS analogues of anthracyclines (6q, 6r) in high efficiency. Interestingly, a chiral discrimination was observed in this case: L-3-ADS (6q) was formed in superior selectivity than D-3-ADS (6r).



Encouraged by the high efficiency of this strategy, we proceeded with its employment in the assembly of oligosaccharides (Scheme 2). We were interested to elaborate a diol acceptor 10 with both  and  linkages. Employing Mukaiyama’s -glycosylation protocol20 with TMSI as activator and excess TPPO (4a) as additive, disaccharide 11 was selectively obtained in 61% yield with  to  ratio of 16.5:1. Subsequently, with the same additive 4a but in substoichiometric amount, the coupling reaction between 11 and 5c successfully constructed the -glycosidic bond and the trisaccharide 12 was isolated as a single isomer in 68% yield (80% brsm). This result clearly demonstrated that H-bonding effect participated in the reversion of the selectivity. Given the robustness of gold-catalyzed Yu glycosylation reaction and excellent stereo-control of present methodology, we then contemplated a one-pot synthesis of trisaccharide 15 with Ph3PAuBAr4F as the single catalyst. We envisaged that the coupling reaction between 13 and 14 would occur siteselectively in the presence of gold catalyst on O-6 position of diol 14 with -selectivity. The ensuing addition of 5a and 0.5 equiv of phosphine oxide 4b into the resulting mixture would then promote the introduction of 3-ADS on O-4 position with -orientation. Pleasingly, this two-step one-pot protocol auspiciously produced the trisaccharide 15 in 52% overall yield with absolute stereocontrol. The reaction also showed good compatibility with S-2-[(propan-2-yl)sulfinyl]benzyl (SPTB) glycosides,28 thus bodes well for IPRm glycosylation to elongate the sugar chains.

Page 4 of 8

which was attached to the aminosugars with -orientation. With the phosphine oxide-mediated -glycosylation strategy, the coupling of 3-ADSs 5b and 16 furnished disaccharide 17 in 66% yield with absolute -stereoselective control. Subsequent deprotection of the acetate group produced 18 in 93% yield. The X-ray crystallography analysis of 18 confirmed the -linkage. Finally, subjecting 2,6-dideoxy sugar 19 and disaccharide 18 to Yu glycosylation conditions successfully constructed the protected trisaccharide unit of avidinorubicin 20 in satisfactory reaction outcome. Scheme 3. Synthesis of trisaccharide unit of avidinorubicin. HO Me2N

O



NH2  O O Me O

MeO

O

NH2 O

O O

O

COOH

HO HO OAc + BnO

BnO

BnO 10

9 (1.2 equiv)

TMSI (1.2 equiv) 4a (3.0 equiv)

O

O

Me

5b

5c (3.0 equiv) Ph3PAuBAr4F (0.2 equiv) 4a (0.5 equiv)

O

O OMe



 O

OAc

OAc O

AcO

HO BnO HO OABz

13

O

SPTB

1). Ph3PAuBAr4F (0.3 equiv)

BnO 14

DCM, -78 °C

AcO

O

AcO

2). 5a, 4b (0.5 equiv)

AcO

-40 °C to -20 °C two steps in one-pot one catalyst 52%

NsHN AcO

O

O BnO  O 15

RHN O



O BnO HO

OAc O

O

OABz

+

O

O O 7b

K2CO3 MeOH 93%

OMe

Me

18

NsHN  NsHN O O O O Me Me O  20 avidinorubicin OAc AcO trisaccharide

OMe

O

Ph3PAuBAr4F (0.2 equiv) 4b (0.5 equiv)

AcO

DCM, -40 oC

RHN O

O

6

Yield, : R with 4b

S SPTB

Me

17

SPTB

OBn



OBn

OH

O

5

Entry O

O

NsHN O

OMe

NsHN O O

Table 2. Selectivity variations by modification of the amide group

BnO O O O  BnO BnO NHNs OMe 12

(b)

DCM, -40 °C 86%,  only

AcOOAc 19

O

AcO

Ph3PAuNTf2

OABz

O

BnO

BnO BnO BnO

DCM, -40 °C to -20 °C 68% (80% brsm),  only

BnO O 11 HO BnO

DCM, rt OMe 61%, : 16.5:1



NMe2

OMe PPh3AuNTf2 NsHN  NsHN 4a (0.5 equiv) O O + HO AcO 66%,  only Me Me 16

+

O

O

OABz

NsHN AcO

OH

O HO

HO

BnO BnO BnO

OH

O

Me

O

O

avidinorubicin

NsHN

BnO BnO BnO

OH

Me

Scheme 2. Assembly of trisaccharides. (a)

O

S

SPTB

This -selective glycosylation methodology was further utilized to the construction of trisaccharide unit of avidinorubicin (Scheme 3). Avidinorubicin which was isolated from the cultured broth of Streptomyces avidinii in 1991, exhibited platelet aggregation inhibitory activity.9 It was also recognized as the conceivable biosynthetic precursor of an antitumor antibiotic, decilorubicin.29 The structure complexity of avidinorubicin poses great synthetic challenge, and report of its synthesis is long overdue. The terminal trisaccharide unit of avidinorubicin contains two continuous 3-branched 3,5-trans3-ADSs linked with -glycosidic bond, and a 2,6-dideoxysugar

1 2 3 4

Ns (5a) Ts (5e) Ms (5f) CF3CO (5g)

6b, 95%, 7.5:1 6s, 96%, 3.7:1 6t, 92%, 3.9:1 6u, 95%, 6.3:1

w/o 4b 97%, 1.5:1 95%, 1.5:1 95%, 1.5:1 96%, 3.9:1

The high efficacy of the phosphine oxide-mediated stereoselective glycosylation prompted us to verify the existence of the H-bonding effect by probing the relationship between the selectivity outcome and the H-bond donation capacity of the C-3 amide group (Table 2). A series of 3-ADS donors (5a, 5e-g) possessing different C-3 amide groups were coupled with 7b in the presence of 4b. The selectivity declined significantly from 7.5:1 to 3.7:1 ( to ) as expected, when the Ns group was replaced by the less electron-deficient p-


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Journal of the American Chemical Society toluenesufonyl (Ts, 5e) group which diminished the H-bond donation ability of the amide group (entry 2). Switching the Nprotecting group to methansulfonyl group (Ms, 5g) that presents lower steric encumbrance but higher pKa value as compared to Ns group, also resulted in the erosion of the stereoselectivity (entry 3). When phosphine oxide 4b was excluded in all these cases, the selectivity was lost. These results vigorously implied that the -selectivity arose from the -face shielded H-bonding between the amide group and -oxyphosphonium ion. Interestingly, in contrast to the observations of Finizia13 and Giuliano,14 an improved -selectivity was observed with trifluoroacetate as N-protecting group (5g) when no additive was present (entry4). This implied the plausible existence of a weak C-3 anchimeric assistance. Accordingly, the addition of phosphine oxide further increased the selectivity in this case. Next, the selectivity variations were observed by disruption of the H-bonding (Scheme 4). First, when the hydrogen atom of 4-nitrobenzensulfonylamide was replaced by a methyl group, the conformation of the donor (5h) flipped from 1C4 to 4C1, possibly due to an increased 1,3-diaxial effect. The coupling reaction between the flipped 5h and 7a catalyzed by Ph3PAuNTf2 furnished 6v and 6v in a ratio of 1.25:1, in the absence of additive. Similarly, conformation of the -product 6v also flipped to 4C1 while the conformation of -anomer was generally retained as 1C4 with slight twist. These conformations were confirmed by both the coupling constants of the anomeric proton and the X-ray crystallography analysis (see the supporting information).30 Interestingly, the addition of triphenylphosphine oxide (TPPO, 4a) as additive increased the -selectivity. Since bulkier protecting group might lead to conformation changes, we then considered the installation of azide group on C-3 position of the donor. Unlike the abovementioned amido donors (5a and 5e-h), replacement of the amide group with azide group resulted in the formation of the glycosyl donor 5i as a -anomer, pertaining to the absence of H-bond. The -selectivity of the coupling reaction of 5i was increased in the presence of phosphine oxide, similar to the conventional exNu effect-assisted glycosylations. These results further conformed to the central role of H-bond-assisted exNu effect in imparting -selectivity.31

covered oxyphosphonium intermediate and prevented the formation of the corresponding -intermediate. This primes the -face for glycosyl acceptors for intended -selectivity. Notably, unlike the known exNu reagent effect-mediated glycosylations, only sub-stoichiometric amount of phosphine oxide was required in current protocol. Wide range of substrates including natural products and drugs containing variegated functionalities were well tolerated. In particular, the orthogonality of the present strategy toward the thioglycoside activation method and the IPRm glycosylation method pointed up its vast potential in the assembly of complex oligosaccharides. This strategy offered an expedient solution for the challenging -selective glycosylation of 3,5-trans-3ADSs and paved the way to the synthesis as well as the modification of 3,5-trans-3-ADS-containing naturally occurring oligosaccharides and glycoconjugates.

Scheme 4. Glycosylations without H-bonding.

ACKNOWLEDGMENT

OAc O

NsN Me

AcO

OABz

w/o 4a, 95%,   1.25:1 w 4a, 80%,   1:3.6

5h N3 O

OABz

5i

Me

7a, Ph3PAuNTf2 (0.2 equiv)

AcO

OAc O

+

AcO

N3 O 6w

NsN Me

6v

7b, Ph3PAuBAr4F (0.2 equiv) w/o 4b, 95%,   1:1.4 w 4b, 95%,   1:2.9

NNs O

O

+ AcO

O

O

6v

N3 O

O

6w

Conclusion In summary, we have developed a -selective glycosylation method of 3,5-trans-3-ADSs hinges on a H-bonding-assisted exogenous nucleophilic reagent effect. Unlike the typical exogenous nucleophilic reagents-involved glycosylations which generally prefer -selectivity, the present method provided high level of -selectivity, resulting from the formation of H-bond between the -oxyphosphonium ion and the C-3 amide group of the activated 3,5-trans-3-ADS intermediate. This unique interaction stabilized the -face

ASSOCIATED CONTENT Supporting Information The supporting Information is available free of charge via the Internet at http://pubs.acs.org. Experimental procedures, crystal structures, spectroscopic and analytical data for all compounds (PDF) Crystallographic data for 3 (CIF) Crystallographic data for 6v (CIF) Crystallographic data for S8 (CIF) Crystallographic data for 18 (CIF)

AUTHOR INFORMATION Corresponding Author *[email protected] *[email protected]

ORCID Jing Zeng: 0000-0001-9116-9861 Qian Wan: 0000-0001-9243-8939

Notes The authors declare no competing financial interests.

We greatly appreciated the financial support from National Natural Science Foundation of China (21772050, 21672077, 21761132014), the State Key Laboratory of Bio-organic and Natural Products Chemistry (SKLBNPC13425), Wuhan Creative Talent Development Fund, the Fundamental Research Funds for the Central Universities (2016YXMS137). We thank Analytical and Testing Center of HUST for X-ray and NMR tests. We also thank Dr. Huping Zhu from Shanghai Institute of Organic Chemistry for help on low temperature NMR spectroscopy studies.

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Insert Table of Contents artwork here

O

Ar P Ar O Ar

BnO BnO : 16.5:1 BnO

O HO BnO

more reactive -oxyphosphonium

AcO NsNH

O BnO

Au (I) Ar3P=O (0.16 equiv)

OAbz

 only

AcO

O

Ar O P Ar H Ar H-bond stabilized -oxyphosphonium NsN

O BnO

BnO

BnO

O

O

BnO BnO BnO

AcO

O NHNs

OMe



 O

O BnO

O BnO

OMe

-Glycosylation of 3-amino sugars  H-bonding assisted exogenous nucleophilic reagent effect  Reversal of selectivity  Substoichiometric amount of additive


8

Hydrogen Bonding Assisted Exogenous Nucleophilic Reagent Effect

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