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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).
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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.
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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.
REFERENCES (1) Das, R.; Mukhopadhyay, B. Chemical O-Glycosylations: An Overview. ChemistryOpen 2016, 5, 401-433. (b) Demchenko, A. V. General Aspects of the Glycosidic Bond Formation. In Handbook of Chemical Glycosylation; Demchenko, A. V. Ed.; Wiley-Ver & Co. KGaA: Weinheim, 2008. (c) Zhu, X.; Schmidt, R. R. New Principles for GlycosideBond Formation. Angew. Chem. Int. Ed. 2009, 48, 1900-1934. (d) Ranade, S. C.; Demchenko, A. V. Mechanism of Chemical Glycosylation: Focus on the Mode of Activation and Departure of Anomeric Leaving Groups. J. Carbohydr. Chem. 2013, 32, 1-43. (e) Bennett, C. S. Selective Glycosylations: Synthetic Methods and Catalysts, Wiley VCH Verlag GmbH: Weinheim, 2017. (f) Peng, P.; Schmidt, R. R. Acid-Base Catalysis
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in Glycosidations: A Nature Derived Alternative to the Generally Employed Methodology. Acc. Chem. Res. 2017, 50, 1171-1183. (2) For recent reviews, see: (a) Mulani, S. K.; Hung, W.-C.; Ingle, A. B.; Shiau, K.-S.; Mong, K.-K. T. Modulating Glycosylation with Exogenous Nucleophiles: An Overview. Org. Biomol. Chem. 2014, 12, 1184-1197. (b) Yao, H.; Vu, M. D.; Liu, X.-W. Recent Advances in Reagent-controlled Stereoselective/stereospecific Glycosylation. Carbohydr. Res. 2019, 473, 72-81. (3) West, A. C.; Schuerch, C., Reverse anomeric effect and the synthesis of -glycosides. J. Am. Chem. Soc. 1973, 95, 1333-1335. (4) (a) Lu, S.-R.; Lai, Y.-H.; Chen, J.-H.; Liu, C.-Y.; Mong, K.-K. T. Dimethylformamide: An Unusual Glycosylation Modulator. Angew. Chem. Int. Ed. 2011, 50, 7315-7320. (b) Lin, Y. H.; Ghosh, B.; Mong, K.-K. T, In Situ Formation of β-Glycosyl Imidinium Triflate from Participating Thioglycosyl Donors: Elaboration to Disarmed–armed Iterative Glycosylation. Chem. Commun. 2012, 48, 10910-10912. (c) Ingle, A. B.; Chao, C.-S.; Hung, W.-C.; Mong, K.-K. T. Tuning Reactivity of Glycosyl Imidinium Intermediate for 2-Azido-2-deoxyglycosyl Donors in αGlycosidic Bond Formation. Org. Lett. 2013, 15, 5290-5293. (5) (a) Wang, L.; Overkleeft, H. S.; van der Marel, G. A.; Codée, J. D. C. Reagent Controlled Stereoselective Synthesis of α-Glucans. J. Am. Chem. Soc. 2018, 140, 4632-4638. (b) Wang, L.; Overkleeft, H. S.; van der Marel, G. A.; Codée, J. D. C. Reagent Controlled Stereoselective Assembly of α(1,3)-Glucans. Eur. J. Org. Chem. 2019, 2019, 1994-2003. (6) For selected recent examples, see: (a) Garcia, B. A.; Gin, D. Y. Dehydrative Glycosylation with Activated Diphenyl Sulfonium Reagents. Scope, Mode of C(1)-Hemiacetal Activation, and Detection of Reactive Glycosyl Intermediates. J. Am. Chem. Soc. 2000, 122, 4269-4279. (b) Park, J.; Kawatkar, S.; Kim, J.-H.; Boons, G.-J. Stereoselective Glycosylations of 2-Azido-2-deoxy-glucosides Using Intermediate Sulfonium Ions. Org. Lett. 2007, 9, 1959-1962. (c) Nokami, T.; Shibuya, A.; Manabe, S.; Ito, Y.; Yoshida, J.-i. α- and β-Glycosyl Sulfonium Ions: Generation and Reactivity. Chem. Eur. J. 2009, 15, 2252-2255. (d) Crich, D.; Li, W. Efficient Glycosidation of a Phenyl Thiosialoside Donor with Diphenyl Sulfoxide and Triflic Anhydride in Dichloromethane. Org. Lett. 2006, 8, 959-962. (e) Qin, Q.; Xiong, D.-C.; Ye, X.-S. Additive-controlled stereoselective glycosylations of 2,3-oxazolidinone protected glucosamine or galactosamine thioglycoside donors with phenols based on preactivation protocol. Carbohydr. Res. 2015, 403, 104-114. (f) Gu, Z.-Y.; Zhang, J.-X.; Xing, G.-W. N-Acetyl-5-N,4-O-oxazolidinone-Protected Sialyl Sulfoxide: An α-Selective Sialyl Donor with Tf2O/(Tol)2SO in Dichloromethane. Chem. Asian J. 2012, 7, 1524-1528. (g) Oka, N.; Kajino, R.; Takeuchi, K.; Nagakawa, H.; Ando, K. α-Selective Ribofuranosylation of Alcohols with Ribofuranosyl Iodides and Triphenylphosphine Oxide. J. Org. Chem. 2014, 79, 7656-7664. (h) Matsumura, F.; Oka, N.; Wada, T., Stereoselective Synthesis of α-Glycosyl Phosphites and Phosphoramidites via O-Selective Glycosylation of H-Phosphonate Derivatives. Org. Lett. 2008, 10, 52975300. (7) (a) Zeng, J.; Sun, G.; Yao, W.; Zhu, Y.; Wang, R.; Cai, L.; Liu, K.; Zhang, Q.; Liu, X.-W.; Wan, Q. 3-Aminodeoxypyranoses in Glycosylation: Diversity-Oriented Synthesis and Assembly in Oligosaccharides. Angew. Chem. Int. Ed. 2017, 56, 5227-5231. (b) Zeng, J.; Sun, G.; Wang, R.; Zhang, S.; Teng, S.; Liao, Z.; Meng, L.; Wan, Q. Gold-catalyzed Diversified Synthesis of 3-Aminosugar Analogues of Digitoxin and Digoxin. Org. Chem. Front. 2017, 4, 2450-2454. (c) Zeng, J.; Wang, R.; Yao, W.; Zhang, S.; Sun, G.; Liao, Z.; Meng, L.; Wan, Q. Diversified Synthesis and αSelective Glycosylation of 3-Amino-2,3,6-trideoxy sugars. Org. Chem. Front. 2018, 5, 3391-3395. (8) Kong, F.; Zhao, N.; Siegel, M. M.; Janota, K.; Ashcroft, J. S.; Koehn, F. E.; Borders, D. B.; Carter, G. T. Saccharomicins, Novel Heptadecaglycoside Antibiotics Effective against Multidrug-Resistant Bacteria. J. Am. Chem. Soc. 1998, 120, 13301-13311. (9) Aoki, M.; Shirai, H.; Nakayama, N.; Itezono, Y.; Mori, M., Satoh, T., Ohshima, S.; Watanabe, J.; Yokose, K.; Seto, H. Structural Studies on Avidinorubicin, a Novel Anthracycline with Platelet Aggregation Inhibitory Activity. J. Antibiot. 1991, 44, 635. (10) Ishigami, K.; Hayakawa, Y.; Seto, H. Cororubicin, a New Anthracycline Antibiotic Generating Active Oxygen in Tumor Cells. J. Antibiot. 1994, 47, 1219. (11) (a) Jiang, Z.-D.; Jensen, P. R.; Fenical, W. Lobophorins A and B, new antyinflammatory macrolides produced by a tropical marine bacterium. Bioorg. Med. Chem. Lett. 1999, 9, 2003-2006. (b) Wei, R.-B.; Xi, T.; Li, J.; Wang, P.; Li, F.-C.; Lin, Y.-C.; Qin, S. Lobophorin C and D, New Kijanimicin Derivatives from a Marine Sponge-Associated Actinomycetal Strain AZS17. Mar. Drugs 2011, 9, 359-368. (c) Niu, S.; Li, S.; Chen, Y.;
Tian, X.; Zhang, H.; Zhang, G.; Zhang, W.; Yang, X.; Zhang, S.; Ju, J.; Zhang, C. Lobophorins E and F, New Spirotetronate Antibiotics from a South China Sea-derived Streptomyces sp. SCSIO 01127. J. Antibiot. 2011, 64, 711-716. (d) Braña, A.; Sarmiento-Vizcaíno, A.; Osset, M.; PérezVictoria, I.; Martín, J.; de Pedro, N.; de la Cruz, M.; Díaz, C.; Vicente, F.; Reyes, F.; García, L.; Blanco, G. Lobophorin K, a New Natural Product with Cytotoxic Activity Produced by Streptomyces sp. M-207 Associated with the Deep-Sea Coral Lophelia pertusa. Mar. Drugs 2017, 15, 144. (12)For recent reviews on -selective glycosylation of 2-deoxy sugars, see: (a) Borovika, A.; Nagorny, P. Recent Advances in the Synthesis of Natural 2-Deoxy-β-glycosides. J. Carbohydr. Chem. 2012, 31, 255−283. (b) Zeng, J.; Xu, Y.; Wang, H.; Meng, L.; Wan, Q., Recent Progress on the Synthesis of 2-Deoxy Glycosides. Science China Chem. 2017, 60, 1162-1179. (c) Bennett, C. S.; Galan, M. C., Methods for 2-Deoxyglycoside Synthesis. Chem. Rev. 2018, 118, 7931-7985. (13) Finizia, G. On the Synthesis of Aminoglycosides of Cardioactive Steroids: A Study Directed Towards β-Selective Glycosylations of 3Aminodigitoxose with Digitoxigenin Analogues. J. Carbohydr. Chem. 1998, 17, 75-98. (14) Dulin, M. L.; Noecker, L. A.; Kassel, W. S.; Giuliano, R. M. An Unusual Course of Thioglycoside Activation with Bromine: Synthesis and Crystal Structure of 4-O-Acetyl-2-bromo-2,3,6-trideoxy-3-C-methyl-3trifluroacetamido-α-L-altropyranosyl Bromide. Carbohydr. Res. 2003, 338, 1121-1125. (15) Balthaser, B. R.; McDonald, F. E. Brønsted Acid-Promoted Glycosylations of Disaccharide Glycal Substructures of the Saccharomicins. Org. Lett. 2009, 11, 4850-4853. (16) (a) Bylsma, M.; Bennett, C. S. Stereospecific Synthesis of the Saccharosamine-Rhamnose-Fucose Fragment Present in Saccharomicin B. Org. Lett. 2018, 20, 4695-4698. For precedent example, see: (b) Daley, L.; Guminski, Y.; Demerseman, P.; Kruczynski, A.; Etiévant, C.; Imbert, T.; Hill, B. T.; Monneret, C. Synthesis and Antitumor Activity of New Glycosides of Epipodophyllotoxin, Analogues of Etoposide, and NK 611. J. Med. Chem. 1998, 41, 4475-4485. (17) Mendlik, M. T.; Tao, P.; Hadad, C. M.; Coleman, R. S.; Lowary, T. L., Synthesis of L-Daunosamine and L-Ristosamine Glycosides via Photoinduced Aziridination. Conversion to Thioglycosides for Use in Glycosylation Reactions. J. Org. Chem. 2006, 71, 8059-8070. (18) Selected examples of H-bong mediated aglycon delivery: (a) Yasomanee, J. P.; Demchenko, A. V. Effect of Remote Picolinyl and Picoloyl Substituents on the Stereoselectivity of Chemical Glycosylation. J. Am. Chem. Soc. 2012, 134, 20097-20102. (b) Liu, Q.-W.; Bin, H.-C.; Yang, J.-S. β-Arabinofuranosylation Using 5-O-(2-Quinolinecarbonyl) Substituted Ethyl Thioglycoside Donors. Org. Lett. 2013, 15, 3974-3977. (c) Le Mai Hoang, K.; Liu, X.-W. The Intriguing Dual-directing Effect of 2-Cyanobenzyl Ether for a Highly Stereospecific Glycosylation Reaction. Nature Commun. 2014, 5, 5051. (d) Ruei, J.-H.; Venukumar, P.; Ingle, A. B.; Mong, K.-K. T. C6 Picoloyl Protection: a Remote Stereodirecting Group for 2-Deoxy-β-glycoside formation. Chem. Commun. 2015, 51, 5394-5397. (19) Precedents of sulfonamide directed glycosylation: (a) Ding, F.; Ishiwata, A.; Ito, Y. Bimodal Glycosyl Donors Protected by 2-O-(orthoTosylamido)benzyl Group. Org. Lett. 2018, 20, 4384-4388. (b) Ding, F.; Ishiwata, A.; Ito, Y. Stereodivergent Mannosylation Using 2-O-(orthoTosylamido)benzyl Group. Org. Lett. 2018, 20, 4833-4837. (20) (a) Yu, B. Gold(I)-Catalyzed Glycosylation with Glycosyl OAlkynylbenzoates as Donors. Acc. Chem. Res. 2018, 51, 507-516. (b) Yu, B.; Sun, J.; Yang, X. Assembly of Naturally Occurring Glycosides, Evolved Tactics, and Glycosylation Methods. Acc. Chem. Res. 2012, 45, 1227-1236. (c) Li, Y.; Yang, Y.; Yu, B. An Efficient Glycosylation Protocol with Glycosyl ortho-Alkynylbenzoates as Donors Under the Catalysis of Ph3PAuOTf. Tetrahedron Lett. 2008, 49, 3604-3608. (21) (a) Kobashi, Y.; Mukaiyama, T. Highly -Selective Glycosylation with Glycosyl Acetate via Glycosyl Phosphonium Iodide. Chem. Lett. 2004, 33, 874-875. (b) Mukaiyama, T.; Kobashi, Y. Highly -Selective Synthesis of Disaccharide Using Glycosyl Bromide by the Promotion of Phosphine Oxide. Chem. Lett. 2004, 33, 10-11. (c) Mukaiyama, T.; Kobashi, Y.; Shintou, T. A New Method for -Selective Glycosylation Using a Donor, Glycosyl Methyldiphenylphosphonium Iodide, without Any Assistance of Acid Promoters. Chem. Lett. 2004, 32, 900-901. (d) Kobashi, Y.; Mukaiyama, T. Glycosyl Phosphonium Halide as a Reactive Intermediate in Highly -Selective Glycosylation. Bull. Chem. Soc. Jpn. 2005, 78, 910916. (22)The conformation was further confirmed by the crystal structure of compound 18. See the Supporting Information.
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Journal of the American Chemical Society (23) (a) Zhu, Y.; Yu, B. Highly Stereoselective β-Mannopyranosylation via the 1-α-Glycosyloxy-isochromenylium-4-gold(I) Intermediates. Chem. Eur. J. 2015, 21, 8771-8780. (b) Zhu, Y.; Shen, Z.; Li, W.; Yu, B., Stereoselective Synthesis of β-Rhamnopyranosides via Gold(I)-catalyzed Glycosylation with 2-Alkynyl-4-nitro-benzoate Donors. Org. Biomol. Chem. 2016, 14, 1536-1539. (24) (a) Shu, P.; Xiao, X.; Zhao, Y.; Xu, Y.; Yao, W.; Tao, J.; Wang, H.; Yao, G.; Lu, Z.; Zeng, J.; Wan, Q. Interrupted Pummerer Reaction in Latent-Active Glycosylation: Glycosyl Donors with a Recyclable and Regenerative Leaving Group. Angew. Chem. Int. Ed. 2015, 54, 1443214436. (b) Shu, P.; Yao, W.; Xiao, X.; Sun, J.; Zhao, X.; Zhao, Y.; Xu, Y.; Tao, J.; Yao, G.; Zeng, J.; Wan, Q. Glycosylation via Remote Activation of Anomeric Leaving Groups: Development of 2-(2-propylsulfinyl)benzyl Glycosides as Novel Glycosyl Donors. Org. Chem. Front. 2016, 3, 177183. (c) Meng, L.; Zeng, J.; Wan, Q. Interrupted Pummerer Reaction in Latent/Active Glycosylation. Synlett, 2018, 29, 148-156. (d) Zeng, J.; Liu, Y.; Chen, W.; Zhao, X.; Meng, L.; Wan, Q. Glycosyl Sulfoxides in Glycosylation Reactions. Top. Curr. Chem. 2018, 376, 27. (25) Bruno, B.; Giulliano Delle, M.; Domenico, M.; Alberto, V.; Giovanni, Z. Aryltetralin Lignans: Chemistry, Pharmacology and Biotransformations. Curr. Med. Chem. 2001, 8, 1363-1381. (26)(a) Liu, H.; Liao, J.-X.; Hu, Y.; Tu, Y.-H.; Sun, J.-S. A Highly Efficient Approach to Construct (epi)-Podophyllotoxin-4-O-glycosidic Linkages as well as Its Application in Concise Syntheses of Etoposide and Teniposide. Org. Lett. 2016, 18, 1294-1297. (b) Wan, J.-H.; Hu, Y.; Liu, H.; Tu, Y.-H.; He, Z.-Y.; Sun, J.-S., The Catalytically Lignan-Activation-Based Approach for the Synthesis of (epi)-Podophyllotoxin Derivatives. J. Org. Chem. 2017, 82, 5652-5662. and references cited therein. (27) (a) Zhang, G.; Fang, L.; Zhu, L.; Zhong, Y.; Wang, P. G.; Sun, D. Syntheses and Biological Activities of 3’-Azido Disaccharide Analogues of Daunorubicin against Drug-Resistant Leukemia. J. Med. Chem. 2006, 49, 1792-1799. (b) Zhang, G.; Fang, L.; Zhu, L.; Aimiuwu, J. E.; Shen, J.;
Cheng, H.; Muller, M. T.; Lee, G. E.; Sun, D.; Wang, P. G., Syntheses and Biological Activities of Disaccharide Daunorubicins. J. Med. Chem. 2005, 48, 5269-5278. (c) Fang, L.; Zhang, G.; Li, C.; Zheng, X.; Zhu, L.; Xiao, J. J.; Szakacs, G.; Nadas, J.; Chan, K. K.; Wang, P. G.; Sun, D., Discovery of a Daunorubicin Analogue That Exhibits Potent Antitumor Activity and Overcomes Pgp-Mediated Drug Resistance. J. Med. Chem. 2006, 49, 932941. (28) Xiao, X.; Zhao, Y.; Shu, P.; Zhao, X.; Liu, Y.; Sun, J.; Zhang, Q.; Zeng, J.; Wan, Q. Remote Activation of Disarmed Thioglycosides in Latent-Active Glycosylation via Interrupted Pummerer Reaction. J. Am. Chem. Soc. 2016, 138, 13402-13407. (29) Ishii, K.; Kondo, S.; Nishimura, Y.; Hamada, M.; Takeuchi, T.; Umezawa, H. Decilorubicin, a New Anthracycline Antibiotic. J. Antibiot. 1983, 36, 451-453. (30) CCDC 1889014 (3), 1889018 (18), 1889013 (6v) and 1889006 (S8) contain the supplementary crystallographic data for this paper. These data are provided free of charge by The Cambridge Crystallographic Data Centre. (31) Although it is difficult to confirm the exact structure of the proposed glycosyl oxyphosphonium ion intermediate through low-temperature NMR spectroscopy studies at this stage, several weak signals possibly attributed to the interactions between the P atom to the anomeric proton and the P atom to the C3 NsN-H were observed in the 1H/31P HMBC spectrum. For details, see the Supporting Information. For NMR studies on glycosyl oxyphosphonium ions, see: (a) Mukaiyama, T.; Suda, S. Diphosphonium Salts as Effective Reagents for Stereoselective Synthesis of 1,2-cisRiboruranosides. Chem. Lett. 1990, 19, 1143-1146. (b) Mossotti, M.; Panza, L. Dehydrative Glycosylation with the Hendrickson Reagent. J. Org. Chem. 2011, 76, 9122-9126. For reviews, see: Frihed, T. G.; Bols, M.; Perdersen, C. M. Mechanisms of Glycosylation Reactions Studied by LowTemperature Nuclear Magnetic Resonance. Chem. Rev. 2015, 115, 49635013.
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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
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