Stereodirecting Effect of C5-Carboxylate Substituents on the Glycosylation Stereochemistry of 3-Deoxy- d - Manno -oct-2-ulosonic Acid (Kdo) Thioglycoside Donors: Stereoselective Synthesis of α- And β-Kdo Glycosides

Article abstract of DOI:10.1021/jacs.7b09461

The stereodirecting effect of C5-ester functions on the glycosylation stereoselectivity of 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) ethyl thioglycoside donors is presented. The coupling of 5-O-arylcarbonyl or acetyl protected Kdo thioglycosides with acceptors proceeds in an α-selective and high-yielding manner, leading to formation of α-linked Kdo glycosides products. On the other hand, the glycosylation stereoselectivity of the 5-O-2-quinolinecarbonyl (Quin) or 4-nitropicoloyl substituted Kdo thioglycoside donors is switchable: (1) The glycosylation of the 5-O-Quin carrying Kdo donors with primary glycosyl acceptors shows complete β-stereoselectivity, furnishing the corresponding β-glycosides in good-to-excellent yield. (2) The stereochemical outcome of the secondary acceptors with these Kdo donors is determined mainly by the stereoelectronic nature of the acceptor. Only or predominant α anomeric products are obtained when the Kdo donors couple with the disarmed or highly crowded secondary carbohydrate acceptors, while the selectivity may switch to predominant β in the glycosylation of the 5-O-4-nitropicoloyl carrying donor with more reactive secondary alcohols. The synthetic use of the newly developed Kdo donors 1c and 7b has been demonstrated by facile preparation of a structurally unique trisaccharide motif 19 which possesses both α- and β-Kdo glycosidic bonds.

Full text of DOI:10.1021/jacs.7b09461

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Article
Stereodirecting Effect of C5-Carboxylate Substituents on the Glycosylation
Stereochemistry of 3-Deoxy-D-manno-oct-2-ulosonic Acid (Kdo)
Thioglycoside Donors: Stereoselective Synthesis of #- and #-Kdo Glycosides
Wei Huang, Ying-Yu Zhou, Xing-Ling Pan, Xian-Yang Zhou,
Jin-Cai Lei, Dong-Mei Liu, Yue Chu, and Jin-Song Yang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b09461 • Publication Date (Web): 26 Feb 2018
Downloaded from http://pubs.acs.org on February 26, 2018
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Stereodirecting Effect of C5ꢀCarboxylate Substituents on the Glycosylation
Stereochemistry of 3ꢀDeoxyꢀDꢀmannoꢀoctꢀ2ꢀulosonic Acid (Kdo) Thioglycoside
Donors: Stereoselective Synthesis of αꢀ and βꢀKdo Glycosides
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Wei Huang, YingꢀYu Zhou, XingꢀLing Pan, XianꢀYang Zhou, JinꢀCai Lei, DongꢀMei Liu, Yue Chu,
and JinꢀSong Yang*
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Department of Chemistry of Medicinal Natural Products, Key Laboratory of DrugꢀTargeting and Drug Delivery
System of the Ministry of Education, West China School of Pharmacy, and State Key Laboratory of Biotherapy,
West China Hospital, Sichuan University, Chengdu 610041, China
ABSTRACT: The stereodirecting effect of C5ꢀester functions on the glycosylation stereoselectivity of 3ꢀDeoxyꢀDꢀ
mannoꢀoctꢀ2ꢀulosonic acid (Kdo) ethyl thioglycoside donors is presented. The coupling of 5ꢀOꢀarylcarbonyl or
acetyl protected Kdo thioglycosides with acceptors proceeds in an αꢀselective and highꢀyielding manner, leading to
formation of αꢀlinked Kdo glycosides products. On the other hand, the glycosylation stereoselectivity of the 5ꢀOꢀ2ꢀ
quinolinecarbonyl (Quin) or 4ꢀnitropicoloyl substituted Kdo thioglycoside donors is switchable: (1) the
glycosylation of the 5ꢀOꢀQuin carrying Kdo donors with primary glycosyl acceptors shows complete βꢀ
stereoselectivity, furnishing the corresponding βꢀglycosides in goodꢀtoꢀexcellent yield. (2) the stereochemical
outcome of the secondary acceptors with these Kdo donors is determined mainly by the stereoelectronic nature of
the acceptor. Only or predominant α anomeric products are obtained when the Kdo donors couple with the disarmed
or highly crowded secondary carbohydrate acceptors, while the selectivity may switch to predominant β in the
glycosylation of the 5ꢀOꢀ4ꢀnitropicoloyl carrying donor with more reactive secondary alcohols. The synthetic use of
the newly developed Kdo donors 1c and 7b has been demonstrated by facile preparation of a structurally unique
trisaccharide motif 19 which possesses both αꢀ and βꢀKdo glycosidic bonds.
INTRODUCTION
3ꢀDeoxyꢀDꢀmannoꢀoctꢀ2ꢀulosonic acid (Kdo), a acidic eightꢀcarbon saccharide, is a characteristic component of
bacterial lipopolysaccharide (LPS) and capsular polysaccharide (CPS).1 Kdo glycosides can exist in nature as both
αꢀ and βꢀanomers at C2ꢀpositions (Figure 1). Bacterial LPS and CPS are known to be closely connected with the
pathogenicity and survival of pathogenic bacteria. Chemical synthesis of Kdoꢀcontaining portions of LPSs and CPSs
in pure and homogeneous forms has attracted great attention since these molecules will benefit the development of
potential carbohydrateꢀbased vaccines or therapeutics against bacterial pathogens.2 However, the stereoselective and
highꢀyielding synthesis of a Kdo glycoside poses a great challenge in carbohydrate chemistry owing to (1) the lack
of C3ꢀparticipating group which hampers the stereocontrol of product formation, (2) the presence of C1ꢀelectronꢀ
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withdrawing carboxylic group that heavily deactivates the anomeric center, and (3) the formation of a significant
amount of 2,3ꢀdehydro byproduct during glycosylation reaction.3
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Figure 1. Structures of αꢀ and βꢀKdo glycosides
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A number of studies have focused on the development of Kdo glycosyl donors for efficient αꢀglycosylation,
including the utility of various anomeric activating groups, such as halides,4 Nꢀphenyltrifluoroacetimidates,5
glycals,6 thioglycosides,7 as well as the installment of C3ꢀstereodirecting auxiliary groups.8 Among the Kdo donors
reported to date, the cyclic 4,5ꢀOꢀisopropylidene acetal or 4,5ꢀdiꢀOꢀtertꢀbutyldimethylsilyl (TBS) ether protected
Kdo fluorides or Nꢀphenyltrifluoroacetimidates exhibited special validity and have been applied to the synthesis of
LPSꢀrelated αꢀKdoꢀcontaining carbohydrates.4aꢀd,5b Besides, in the preceding paper,7e our group have studied the
effect of cyclic 5,7ꢀOꢀacetals on the Kdo glycosylation stereoselectivity and developed an efficient methodology for
the assembly of αꢀKdo glycoside employing bulky 5,7ꢀOꢀdiꢀtertꢀbutylsilylene (DTBS) protected Kdo thioglycosides
as glycosyl donors. The approach allows a wide range of acceptors to be used, producing diverse Kdo glycosides
including the naturally occurring αꢀ(2→4)ꢀ, (2→5)ꢀ, and (2→8)ꢀlinked KdoꢀKdo dimers in goodꢀtoꢀexcellent yields
with complete αꢀstereoselectivity.
Compared to the considerable progress on the synthesis of αꢀKdo glycosides, fewer synthetic studies of βꢀKdo
glycosides have been reported so far. In 2012, Ling et al. discovered that a class of Kdo 1ꢀCꢀarylglycals could
undergo βꢀglycosylation with alcohols when mediated by Nꢀiodosuccinimide (NIS) to give 2ꢀiodoꢀβꢀDꢀ
ketopyranosides.9 These intermediates were in turn subjected to deiodination and followed by oxidization of the C1ꢀ
aryl group to give the corresponding βꢀKdo glycosides. Later, the Mong group described that the 4,5,7,8ꢀdiꢀOꢀ
isopropylidene protected Kdo glycal donor showed excellent βꢀstereoselectivity of glycosylation in a CH2Cl2ꢀ
CH3CN coꢀsolvent, giving high yields of 2ꢀiodoꢀβꢀKdo glycosides which could be converted into the desired βꢀKdo
glycosides after reductive removal of the 2ꢀiodide.10 Gauthier et al. developed the peracetylated Kdo thioglycosides
equipped with a 4’ꢀmethoxyphenacyl (Phen) group at C1ꢀposition with which a series of βꢀKdo glycosides were
synthesized in good yield but with moderate βꢀselectivity only. Additionally, the Phen auxiliary group has to be
cleaved after the glycosylation, thereby lowering the synthetic efficiency.11 More recently, Yang et al. reported a
Gold(I)ꢀcatalyzed synthesis of βꢀKdo glycosides using Kdo orthoꢀhexynylbenzoate as donor. Despite the fact that
complete βꢀselectivity was realized in this direct glycosylation reaction, only one pyranosyl alcohol especially no
Kdo alcohol was used as acceptor, which limits the application of the method.12
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Scheme 1. 2ꢀQuinolinecarbonylꢀDirected Formation of βꢀKdo Glycoside
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Recently, a facile hydrogenꢀbondꢀmediated aglycone delivery (HAD) approach was uncovered by Demchenko
and coꢀworkers to synthesize stereoselectively various challenging 1,2ꢀcisꢀpyranosides.13 Relying on such a concept,
our group developed a novel 2ꢀquinolinecarbonyl (Quin)ꢀassisted 1,2ꢀcisꢀfuranosylation method for efficient
preparation of βꢀarabinoꢀ and αꢀgalactofuranosides.14 The Quin group, serving as a hydrogen bond acceptor, shows
a strong stereocontrolling ability in the condensation of furanosyl thioglycoside donors with a wide range of
carbohydrate and nonꢀcarbohydrate alcohols. In this work, we sought to expand the Quinꢀdirected stereoselective
glycosylation strategy to the synthesis of the relevant Kdo glycoside. As shown by Scheme 1, we envisioned that, in
a typical glycosylation course of a Quin substituted Kdo donor, the hydrogen bond tethering between the Quin group
and the acceptor is over the sugar ring and thereby would be likely to offer a βꢀfacial selectivity for the attack of the
acceptor. As a consequence, a βꢀKdo glycoside product would be formed. In order to test the effectiveness of
hydrogen bond as a stereocontrolling factor on the construction of βꢀKdo glycoside, a series of Kdo donors
including 4ꢀ, 5ꢀ, 7ꢀ, and 8ꢀOꢀquinolineꢀ2ꢀcarbonylated ethyl thioglycosides 1aꢀe (Table 1) were synthesized (see
Supporting Information) and their glycosylation behaviors were examined by reaction with model glucosyl acceptor
2.15 All glycosylations were run with 2 equiv of the donor and 1 equiv of the acceptor in the presence of NIS (3.0
equiv), catalytic triflic acid (TfOH), and 4 Å molecular sieve (MS) at –78 to –20 °C in CH2Cl2 (Table 1). The
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anomeric configuration of Kdo glycosides with a C2 conformation is confirmed based on the coupling constant
between the axial proton at C3ꢀposition and the 13C carbon at C1ꢀposition in the undecoupled 13C NMR spectra. For
the αꢀKdo anomer, the 3JCꢀ1/Hꢀ3ax value is less than 1.5 Hz, while for the βꢀKdo anomer, the 3JCꢀ1/Hꢀ3ax is about 5.0ꢀ6.0
Hz.4e,16
RESULTS AND DISCUSSION
As shown in Table 1, entries 1ꢀ5, the reactions of 1aꢀe with 2 provided the corresponding glycoside products 3aꢀe
in satisfactory 75ꢀ88% chemical yields but with quite different degree of anomeric selectivity. The coupling of donor
1a carrying a Quin substituent at the equatorial C4ꢀposition showed a poor βꢀanomeric selectivity (α/β 1:3, entry 1).
Gratifyingly, donors 1b,c both with an axially oriented C5ꢀQuin group exhibited excellent stereocontrolling property
in the glycosylations with 2 and complete βꢀstereoselectivities were obtained for the products 3b,c (entries 2 and 3).
Furthermore, the reactions of the 7ꢀ and 8ꢀOꢀQuin substituted 1d,e displayed no or little βꢀselectivity, respectively
(entries 4 and 5), which might be due to the flexibility of the C7ꢀ and C8ꢀpositions. Of note is that though
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elimination byproducts (4aꢀe) were obtained in 40ꢀ53% yield together with the Kdo disaccharides in each case, these
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byproducts could be conveniently isolated from the expected Kdo glycosides by silica gel column chromatography.
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Table 1. Glycosylation of Quin Substituted Kdo Donors (1aꢀe)a
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a Glycosylations were run with donor 1aꢀe (2 equiv, 60 mM), acceptor (1 equiv), NIS (3 equiv)/TfOH (0.2 equiv), 4
Å molecular sieves (MS) in anhydrous CH2Cl2 at –78 → –20 °C for 2ꢀ3 h. b Isolated yield based on the acceptor. For
c
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entries 1, 4, and 5, the yield is combined yield of α/βꢀisomers. Determined by H NMR of the corresponding
isomer mixture. d Based on the donor.
Table 2. Stereoselective Glycosylation of 1c with Various Acceptorsa
Yieldc (α/β)d
87% (β only)
Entry
1
Acceptor
Conditions
Product
5a
NIS/TfOH, CH2Cl2
–78 → –20 °C
6a
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NIS/TfOH, CH2Cl2
–78 → 0 °C
6b
82% (β only)
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5c
5d
5d
5e
5f
NIS/TfOH, CH2Cl2
–78 → –15 °C
6c
6d
6d
6e
6f
80% (β only)
12% (α only)
71% (α only)
72% (α only)
85% (α only)
82% (α only)
67% (α only)
NIS/TfOH, CH2Cl2
–78 → –15 °C
IBr/AgOTf, CH2Cl2
–80 °C
IBr/AgOTf, CH2Cl2
–80 °C
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IBr/AgOTf, CH2Cl2
–80 °C
5g
5h
IBr/AgOTf, CH2Cl2
–80 °C
6g
6h
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IBr/AgOTf, CH2Cl2
–80 °C
a
Glycosylations were run with Kdo thioglycoside donor (2 equiv), acceptor (1 equiv), NIS (3 equiv)/TfOH (0.2
b
equiv) (for entries 1ꢀ4) or IBr (2.4 equiv)/AgOTf (3 equiv) (for entries 5ꢀ9), 4 Å MS in anhydrous CH2Cl2. The
yield of 4c was based on donor 1c and was about 40ꢀ76%. c Isolated yield based on the acceptor. d Determined by 1H
NMR of the corresponding isomer mixture.
After investigating the effect of the substituting position of Quin group on the glycosylation selectivity, we next
surveyed the glycosylation reaction of the C5ꢀQuin substituted donor 1c with diverse glycosyl acceptors. For this
purpose, a set of representative alcohols (5aꢀh, Table 2) were synthesized. As summarized in Table 2, we were
pleased to find that, upon treatment with NIS/TfOH (cat.) in CH2Cl2, primary sugar alcohols, including galactose
(Gal) 6ꢀOH acceptor 5a, Nꢀacetylglucosamine (GlcNAc) 6ꢀOH acceptor 5b7e as well as Kdo 8ꢀOH acceptor 5c7e
coupled very well to donor 1c, giving rise to the corresponding disaccharides 6aꢀc in 80ꢀ87% yields as exclusively
βꢀisomers (entries 1ꢀ3). However, we met great difficulties in the reaction of the secondary 2,4,6ꢀtriꢀOꢀbenzylated
Gal alcohol 5d17 with 1c. In the event, only 12% yield of the desired disaccharide 6d was obtained under the
NIS/TfOH promotion and to our surprise the glycosylation stereochemistry completely reversed to α (Table 2, entry
4). Our explanation to the reversal of the selectivity is that due to the steric hindrance of the secondary hydroxyl
group of the acceptor, there is probably no hydrogen bond between the Quin group and the acceptor but the remote
participation of the carbonyl or the sp2ꢀhybridized nitrogen of the Quin group becomes the stereodirecting factor in
the glycosylation, thus resulting in an αꢀlinked product. In fact, a similar remote neighboring group participating
phenomenon of the axial 4ꢀOꢀcarboxylate ester groups in Gal donors had been observed by Boons et al., which led
to preferential formation of 1,2ꢀcisꢀαꢀgalactosides.18 To improve the glycosylation efficiency of the secondary
alcohol 5d with 1c, a number of thioglycoside promoters, such as NIS/sliver triflate (AgOTf), iodobromide
(IBr)/AgOTf, and the oneꢀelectron oxidizing agent tris(4ꢀbromophenyl)ammoniumyl hexachloroantimonate
(TBPA)19 were screened. Consequently, we found that when the glycosylation was catalyzed with IBr (2.4
equiv)/AgOTf (3.0 equiv) reagent system in CH2Cl2 at –80 °C, previously utilized by Oscarson and coꢀworkers for
the activation of Kdo ethyl thioglycosides,7d the product 6d was obtained in an elevated 71% yield as αꢀanomer only
(Table 2, entry 5). Then, the optimized reaction conditions were further applied to the coupling of other secondary
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glycosyl nucleophiles, including the disarmed peracetylated Gal alcohol 5e,20 rhamnose (Rha) 4ꢀOH acceptor 5f,21
Kdo 4ꢀ and 7ꢀOH acceptors 5g,h.22 As a result, the reaction of these substrates with 1c proceeded smoothly to yield,
respectively, disaccharides 6e,f, (2→4)ꢀ and (2→7)ꢀlinked Kdo disaccharides 6g,h in good yield and also as a single
αꢀketoside (Table 2, entries 6ꢀ9).
In order to verify the remote participation effect of the sp2ꢀhybridized nitrogen at the C5ꢀposition, we carried out a
glycosylation between 4ꢀOꢀBnꢀ5ꢀOꢀpicolinyl (Pic) substituted Kdo thioglycoside donor 1f and the secondary Rha
alcohol 5f under the activation of IBr/AgOTf in CH2Cl2. As shown in Scheme 2, the reaction still exhibits high αꢀ
stereoselectivity, affording disaccharide product 6i in 75% yield as a separable α/β (>15:1) mixture. This provides an
indication that the participation of the Pic’s nitrogen on the donor’s anomeric center may exist.23
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Scheme 2. Glycosylation of 5ꢀOꢀPic Substituted Kdo Donor 1f with Secondary Acceptor 5f
Moreover, the factors that influence the glycosylation stereoselectivity of the secondary acceptor were studied in
more detail and the results were summarized in Table 3. We first investigated the steric effect of the C4ꢀprotecting
group of the Kdo donor on the glycosylation. Thus, the 4ꢀOꢀBn and Me substituted donors 1b and 1g were reacted
with Rha alcohol 5f under the promotion of IBr (2.4 equiv)/AgOTf (3 equiv) in CH2Cl2. As a result, similar to the
glycosylation of the 4ꢀOꢀTBS substituted donor 1c with 5f (Table 2, entry 7), the two glycosylations still afforded
glycoside products with high αꢀselectivity (Table 3, entries 1 and 2). Next, we examined the influence of the
acceptor alcohol and the substituents on the C5ꢀNꢀheterocyclic ring of the donor. Similar to the reactions of the
2,4,6ꢀtriꢀOꢀBn/Bz protected Gal 3ꢀOH alcohol 5d/e with donor 1c where only αꢀanomeric products were formed
(Table 2, entries 5 and 6), the reaction of the 2ꢀOꢀBzꢀ4,6ꢀOꢀbenzylidene protected Gal 3ꢀOH substrate 5i24 with 1c
also provided high αꢀselectivity (Table 3, entry 3, α/β >10:1), but the reaction of the 2ꢀOꢀBnꢀ4,6ꢀOꢀbenzylidene
protected counterpart 5j25 with 1c showed a significant drop in αꢀselectivity (Table 3, entry 4, α/β 3:1). In contrast,
when the conformationally locked 5j was condensed with the 5ꢀOꢀ3ꢀmethylpicoloyl or 4ꢀnitropicoloyl substituted
donors 1h,i, the glycosylation stereoselectivity reversed, yielding the disaccharide products 6n,o in good yields with
low or excellent βꢀselectivities (Table 3, entry 5, α/β 1:3 and entry 6, α/β <1:10, respectively). Finally, we further
assessed the effect of the acceptor on the stereochemical outcome by reaction of the 5ꢀOꢀ4ꢀnitropicoloyl carrying 1i
with alcohols 5kꢀm. As outlined in Table 3, entry 7, the reaction of 1i with small isopropanol 5k showed excellent
βꢀselectivity, delivering the corresponding βꢀlinked Kdo glycoside 6p in good yield. However, in the couplings of 1i
with more sterically hindered adamantanols 5l,m, only αꢀanomeric products were observed (Table 3, entries 8 and
9). Taken together, these experiments reveal that (1) the electronic and steric nature of the secondary acceptors is the
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crucial factor affecting the glycosylation stereoselectivity. The decrease in steric hindrance of the secondary alcohols
is beneficial to the improvement of the βꢀanomeric product formation, while the glycosylation of disarmed or highly
crowded acceptors tends to form the products with high or complete αꢀselectivity. (2) the bulkiness at the C4
position of Kdo donor has no effect on the diastereoselectivity of the glycosylation. But the electronꢀwithdrawing
substituent on the C5ꢀNꢀheterocyclic ring of the donor may elevate the βꢀselectivity. High βꢀstereocontrol can be
achieved in the couplings between the C5ꢀ4ꢀnitropicoloylated donor 1i and the secondary acceptors with relatively
low steric hinderance.
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Table 3. Glycosylation of Various Secondary Acceptors with Kdo Donorsa
a
Glycosylations were run using Kdo thioglycoside donor (2 equiv) and acceptor (1 equiv) under the activation of
b
IBr (2.4 equiv)/AgOTf (3 equiv) in anhydrous CH2Cl2 at –80 °C for 2ꢀ3 h. The yields of glycals 4b,c, 4gꢀi were
based on the corresponding donors 1b,c, 1gꢀi and were about 30ꢀ45%. c Combined yield of α/βꢀisomers based on the
acceptor. d Determined by 1H NMR of the corresponding isomer mixture.
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We continued to study the remote participating effect of carbonyl group at C5ꢀposition on the glycosylation
selectivity. Thus, a set of 5ꢀOꢀarylcarbonyl or acetyl substituted Kdo thioglycoside substrates 7aꢀg were prepared
and reacted with model compound 2 under the catalysis of NIS/TfOH (cat.) in CH2Cl2 (Table 4). As expected, these
donors exerted goodꢀtoꢀexcellent αꢀstereoselectivities in all glycosylations with 2, affording the corresponding
disaccharide products 8aꢀg as sole or major αꢀanomers in satisfactory yields (Table 4, entries 1ꢀ7). These
experiments obviously illustrate the strong αꢀdirecting ability of the C5ꢀacyl substitutions. In general, the
glycosylations of 5ꢀOꢀarylcarbonylated donors 7aꢀd led to higher αꢀanomeric selectivity than that of 5ꢀOꢀacetylated
donor 7e (Table 4, entries 1ꢀ4 vs entry 5). In addition, the electron density of the ketone functionality significantly
affects the stereochemical outcome. For instance, compared to the benzoyl (Bz) group (7b), the more electronꢀrich
pꢀmethoxybenzoyl group (7c) provided a much greater αꢀstereocontrol, enhancing the α/β ratio from 15:1 to 25:1
(entry 2 vs entry 3), whereas the more electronꢀdeficient pꢀnitrobenzoyl substituent (7d) brought a lower αꢀ
selectivity (α/β 12:1, entry 4 vs α/β 15:1, entry 2). Also examined was the influence of the C4ꢀprotecting group on
the reaction. As depicted by entries 6 and 7 in Table 4, the couplings of 4ꢀOꢀBn and Nap (2ꢀnaphthylmethyl) donors
7f,g with 2 were much less stereoselective (α/β 6:1 and 8:1, respectively) than that of 4ꢀOꢀTBS counterparts 7aꢀe
(Table 4, entries 6, 7 vs entries 1ꢀ5). To further understand the impact of the substituting position of acyl group on
the reaction, we evaluated the glycosylating behaviors of donors 7hꢀj carrying a Bz moiety at C4ꢀ, C7ꢀ, and C8ꢀ
position, respectively. As indicated in Table 4, the reaction of the 4ꢀOꢀbenzoylated 7h with 2 showed slight αꢀ
stereocontrol (α/β 2:1, entry 8), but in contrast the reactions of the 7ꢀ and 8ꢀOꢀbenzoylated 7i,j favored production of
βꢀanomers (α/β 1:5, entries 9, 10).
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The reaction scope of the 4ꢀOꢀTBSꢀ5ꢀOꢀBz protected Kdo donor 7b was further investigated. The glycosylations
of 7b with the primary sugar alcohols 5aꢀc proceeded in an αꢀselective and highꢀyielding manner, furnishing
disaccharide glycosides 10a,b, and (2→8)ꢀlinked Kdo dimer 10c in excellent yield (85ꢀ89%) and high αꢀselectivity
(Table 5, entries 1ꢀ3). Furthermore, 7b was also proved to be an efficient glycosyl donor in the IBr/AgOTfꢀpromoted
couplings with sterically demanding secondary Gal (5e), Rha (5f), and Kdo (5n) acceptors and the corresponding
disaccharide products 10e,f, and 10n were isolated in 75%, 91%, and 71% yield with complete αꢀselectivity (Table 5,
entries 4ꢀ6, respectively). However, in the IBr/AgOTfꢀcatalyzed reaction of Kdo alcohol 5o,7e a difficult glycosyl
acceptor because of the poor nucleophilicity of its 5ꢀOH group, only a small amount of the desired αꢀ(2→5)ꢀbound
KdoꢀKdo disaccharide 10o was isolated (entry 7). To our delight, the yield of 10o was improved to 50% (entry 8)
when the coupling was carried out upon activation with TBPA (1.2 equiv) in CH3CN, which was previously
employed by us in the condensation of the 5,7ꢀOꢀDTBS protected Kdo thioglycosides with Kdo 5ꢀOH alcohol.7e
Table 4. Glycosylation of Kdo Donors (7aꢀj)a
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a
Glycosylations were run using Kdo thioglycoside donor (2 equiv) and acceptor (1 equiv) under the activation of
NIS (3 equiv)/TfOH (0.2 equiv) in anhydrous CH2Cl2 at –78 → –50 °C for 2ꢀ3 h. b Combined yield of α/βꢀisomers
based on the acceptor. c Determined by 1H NMR of the corresponding isomer mixture. d Based on the donor.
Table 5. αꢀSelective Glycosylation of 7b with Various Acceptorsa
Yieldc (α/β)d
Entry
Acceptor
Conditions
Product
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5a
5b
5c
5e
NIS/TfOH, CH2Cl2
–78 → –50 °C
10a
10b
10c
10e
85% (12:1)
NIS/TfOH, CH2Cl2
–78 → –50 °C
86% (>15:1)
89% (>15:1)
75% (α only)
NIS/TfOH, CH2Cl2
–78 °C
IBr/AgOTf, CH2Cl2
–80 °C
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5f
IBr/AgOTf, CH2Cl2
–80 °C
10f
91% (α only)
71% (α only)
ꢀ
5n
5o
5o
IBr/AgOTf, CH2Cl2
–80 °C
10n
10o
10o
IBr/AgOTf, CH2Cl2
–80 °C
TBPA, CH3CN
–30 → –20 °C
50% (α only)
a
Glycosylations were run using Kdo thioglycoside donor (2 equiv) and acceptor (1 equiv) under the activation of
NIS (3 equiv)/TfOH (0.2 equiv) (for entries 1ꢀ3) or IBr (2.4 equiv)/AgOTf (3 equiv) (for entries 4ꢀ7) in CH2Cl2 or
b
c
TBPA (1.2 equiv) in CH3CN (for entry 8). The yield of 9b was based on donor 1c and was about 40ꢀ60%.
Isolated yield based on the acceptor. For entries 1ꢀ3, the yield is combined yield of α/βꢀisomers. d Determined by 1H
NMR of the corresponding isomer mixture.
Scheme 3. Synthesis of βꢀKdoꢀ(2→7)ꢀαꢀHepꢀ(1→5)ꢀαꢀKdo Trisaccharide (19)
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To demonstrate the utility of these methods in the synthesis of Kdoꢀcontaining oligosaccharides, we targeted the
assembly of trisaccharide 19 (Scheme 3). This trisaccharide motif, possessing a linear βꢀKdoꢀ(2→7)ꢀαꢀHepꢀ(1→5)ꢀ
αꢀKdo backbone, corresponds to the part structure of the LPS from marine bacterium Alteromonas macleodii ATCC
27126T.26 Its unique structural features include: (1) it comprises both αꢀ and βꢀKdo glycosidic linkages, which is
rarely found in natural LPS. (2) the LꢀglyceroꢀDꢀmannoꢀheptopyranose (Hep) residue attaches to the inert 5ꢀOH of
the Kdo unit, which brings extra difficulty in creating the trisaccharide.6b Here, we decided to adopt the newly
developed Kdo donors 1c and 7b as key building blocks for the construction of the βꢀ and αꢀKdo linkages,
respectively. As shown by Scheme 3, the target compound, equipped with an αꢀpropyl amino linker at the reducing
end, would be synthesized by a stepwise approach. The amino linker will facilitate the subsequent application in
neoglycoconjugate preparation. Thus, the synthesis of 19 started with the glycosylation between the αꢀdirecting
donor 7b and alcohol 11 according to the aforementioned conditions to furnish the glycoside 12 in 90% yield as a
separable α/β (8:1) diastereomixture. Pure αꢀ12 was easily converted to azide 13 (90% yield), which was then
subjected to selective removal of the 5ꢀOꢀBz protecting group. However, attempted deprotection under basic
conditions such as sodium methoxide (NaOMe) in MeOH and sodium hydroxide (NaOH) in THF/H2O led to
simultaneous cleavage of C4ꢀ and C5ꢀprotecting groups. In the end, 13 was successfully converted to the required
Kdo 5ꢀOH alcohol 14 via a threeꢀstep sequence: (i) deprotection of 4ꢀOꢀTBS with tetrabutylammonium fluoride
(TBAF) in THF, (ii) Zemplén deacylation of 5ꢀOꢀbenzoate group with NaOMe in MeOH, and (iii) reꢀintroduction of
a TBS group on C4 with TBSCl and imidazole in DMF, delivering 14 in 56% yield for three steps. This Kdo
derivative was then condensed with Hep thioglycoside building block 15 in Et2O/CH2Cl2 (1:1) coꢀsolvent under NIS
(2 equiv)/TfOH (cat.) activation at –20 °C for 1 h to generate the challenging (1→5)ꢀlinked HepꢀKdo disaccharide
16 as a separable mixture of α/βꢀanomers (α/β 6:1, 86% combined yield). The αꢀconfiguration of the newly formed
Hep glycoside was confirmed by the coupling constant between C1 and H1 of the Hep residue (1JC1/H1 = 170.4 Hz).27
Subsequent removal of the C4ꢀ and C7’ꢀTBS groups of the resulting αꢀ16 upon treatment with TBAF in THF gave
cleanly disaccharide alcohol 17 (85% yield). Then, using the same NIS/TfOHꢀmediated protocol, 17 was coupled
readily and stereospecifically with the βꢀdirecting donor 1c and produced the desired trisaccharide 18 in a good 88%
yield (β only) without formation of αꢀanomeric byproduct. The global deprotection of 18 was fulfilled in the
following order: removal of the TBS group with TBAF in THF, cleavage of the isopropylidene functionalities with
acetic acid (AcOH) in water, removal of all the ester groups via hydrolysis with NaOMe in MeOH, release of the
carboxylic group via saponification with NaOH in a dioxane/MeOH (3:1) coꢀsolvent, and finally deprotection of the
Bn ethers and reduction of the azide to amine by catalytic hydrogenolysis over Pd/C. Purification of the deprotected
trisaccharide was performed using gel filtration chromatography on Sephadex LHꢀ20 column with water as eluent to
produce 19 as a white solid in 50% yield over five steps. The structure of trisaccharide 19 was verified through the
use of NMR and ESIMS spectral analysis. The αꢀ and βꢀconfigurations of the reducing and nonreducing end Kdo
units in 19 were determined on the basis of the undecoupled 13C NMR analysis (3JCꢀ1/Hꢀ3ax = 0 and 6.0 Hz,
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respectively).16 Further support for the structure came from the highꢀresolution MS data, which provided an (M +
Na)+ signal at m/z 730.2383 (calcd 730.2376).
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CONCLUSIONS
In conclusion, the tuning effect of carboxylate ester groups at C5ꢀposition on the glycosylation stereoselectivity of
Kdo thioglycoside donors has been investigated. On one hand, the glycosylations of the Kdo thioglycosides having
5ꢀOꢀbenzoate or acetate groups with various acceptors are found to be highly αꢀselective, affording αꢀglycoside
products in good yields. On the other hand, the glycosylation stereochemistry of the 5ꢀOꢀQuin or 4ꢀnitropicoloyl
substituted Kdo donors is switchable: (1) exclusive βꢀselectivity is realized when the 5ꢀOꢀQuin Kdo donor reacts
with primary sugar alcohols. (2) the glycosylation selectivity of the secondary acceptors mainly depends on the
stereoelectronic effect of the acceptor. Only or predominant α anomeric products are obtained when these donors
glycosylate with the secondary acceptors possessing low nucleophilicity, while the selectivity is likely to switch to
predominant β when the 5ꢀOꢀ4ꢀnitropicoloyl carrying donor reacts with more reactive secondary alcohols. By
combined use of the donors 1c and 7b, we have accomplished the stereocontrolled preparation of the trisaccharide
19 with an unusual structure. Currently, we are exploring the use of the novel donors to promote the synthesis of
complex Kdoꢀcontaining carbohydrates.
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ASSOCIATED CONTENT
1
Supporting Information. Experimental details, H and 13C NMR spectra for all new compounds, and 2D NMR
spectra for 18 and 19. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*yjs@scu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We appreciate National Natural Science Foundation (21772132, 21572145, 21372166) and Ministry of Science and
Technology (2017ZX09101003ꢀ005ꢀ004) of China for financial support.
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