1.1.5. α-Selective glycosylation by special protecting group
There is no doubt that the nature of protecting groups in glycosides strongly affects the reactive property of either donors or acceptors. In line with this idea, the diol protecting groups, such as the benzylidene, anisylidene, cyclic carbonate, cyclic silyl ethers, oxazolidinones and isopropylidene acetals have been developed in stereoseletive glycosylations.19,20 Fraser-Reid et al. observed that cyclic acetals protecting group on glycosyl donors affect either reactivity or stereoselectivity via a torsional effect.21 To maintain the rigidity of the fixed bicyclic rings, the formation of oxocarbenium ion through a conformational change from chair to boat-like form renders the subsequent glycosylation more difficult (Scheme 4), which further reduce the reactivity of the corresponding glycosyl donor. Furthermore, this feature was successfully applied in orthogonal glycosylations by the use of glycosyl pairs with the same pentenyl leaving group.21
O+
Conf ormational change to f or m pl anar oxocarbenium cation
O
N ot activated no self -cond ensation pr od uct was f ound Tor sional ef fect
Scheme 4 - Torsional effects in donor activation and examples.
The bicyclic protecting group on sugars not only influences the reactivity but also the stereoselectivity. Among the recent advanced developments, Kiso et al. has reported one method so called “di-tert-butylsilylene-(DTBS) directed α-selective glycosylation strategy”.22
O
opening of DT BS X unreacti ve 3-OH group
X = H or protecting group
Scheme 5 - DTBS directed α-selective galactosylation
They demonstrated that the approach of the acceptor from β-face is blocked by the bulky bicyclic silyl group directing the nucleophilic attack more easily from α-face. However, there are some drawbacks for this method. I. The installation of DTBS residue by the expensive silylation reagent makes this process impractical for the route use. II. Methods for
regioselective-opening of silylidene acetal for the following conjugation have not been discovered. III. Due to the bulkiness of the silyl group, glycosylation at 3-hydroxyl position is prevented (Scheme 5).
1.1.6. α-Selective glycosylations by neighboring group participation
Neighboring group participation has long been exploited to control the stereochemistry of glycosylation. In principle, the oxacarbenium ion could react with the participating group to form the more stable intermediate, which enable the nucleophilic attack from the opposite face. The earlier example inspired by this concept was described by Schuerch et al.23 They replaced the 6-O-benzyl group with the ester or carbamate group bringing about the higher α-seletivity in glycosylations. However, they speculated that a substituent with a stronger donating function at C-6 might influence the looseness or tightness of the ion pair. Such an effect can induce α-selectivity but they also mentioned that the tight covalent bonding between the participating group and oxocabenium cation can not be conclusive. The role of neighboring group participation remains controversial until Crich et al. reported a mechanistic study using an isotopic labeling probe towards the influence of esters at the 3-O-axial and -equorial, 4-O-axial and -equatorial, and 6-O-sites (Scheme 6).24 However, they found that no evidence can convince them of the occurrence of the neighboring group participation induced by carbonate esters at these positions, which implied that not only one single factor can induce a certain anomeric selectivity. However, the exemplified cases at other positions are so limited that the current debate over this issue is still going on. In the recent years, the utilization of participating group helping the construction of 1,2-cis-O-glycocidic bond seems prevalent in this field. Thus those advances regarding this strategy will be briefly introduced in the later context.
O+
Scheme 6 - An isotopic labeling probe to investigate the effect of ester participating groups
1,2-ci sglycoside
O
Scheme 7 - Neighboring group participation by a S auxiliary at C-2 leading to 1,2-cis-glycosides
A novel strategy using a chiral auxiliary at the C-2 of a glycosyl donor was reported by Boons et al (Scheme 7).25 They demonstrated that an activated oxocarbenium ion could be associated with the nucleophilic atom of the auxiliary moiety followed by the formation of either a trans- or a cis-decalin system. The trans-decalin conformation dominates due to the favorable steric effect with S-form phenyl substituent. The subsequent attack by a glycosyl
acceptor facilitates the formation of 1,2-cis-α-glycoside, whereas the use of the opposite chiral auxiliary (R form) would lead to 1,2-trans-β-glycoside (Scheme 7).
Lately, based on the “locked-decalin” concept, Turnbull et al. presented that a new oxathiane glycosyl donor involving cyclization of auxiliary chain at C-1 could be formed as a more stable bicyclic thioglycoside as well.26 Upon pre-activation of glycosyl sulfoxide via triflic anhydride (Tf2O) and 1,3,5-trimethoxybenzene, the resulting sulfonium ion intermediate is capable of glycosylation with a variety of acceptors in excellent α-stereoselectivity (Scheme 8).
O
Scheme 8 - Oxathiane glycosyl donors direct α-selective glycosylation
Glycoconjugates incorporating α-sialosides are widely occurred in nature. α-sialylation is usually a challenging task. Gin et al. presented a strategy by installation of N,N-dimethylglycolamide auxiliary (-OCH2-CONMe2) at C-1.27 It was anticipated that the nature of amide can stabilize the oxocarbenium ion to form the two putative intermediates I and II. The predominant intermediate I (due to anomeric effect via oxygen in pyranose ring) is likely more susceptible to the attack of acceptor from α-face, which is believed as a less hindered direction (Scheme 9).
O L = Leaving group
I
II
less hindered face
more hindered face
Scheme 9 - Gin’s proposed mechanism of α-sialylation via the amide auxiliary
The 2-deoxy-2-amino α-gluco- and α-galactosides are prominent components of various biofunctional glycoconjugates. Assembly of 1,2-cis-O-glycosidic linkage for these substrates is challenging.
Scheme 10 - Nguyen’s proposed mechanism of α-selective glycosylation via nickel-mediation
Recently, Nguyen et al. developed a nickel-catalyzed glycosylation to achieve α-selective glycosylations with 2-deoxy-2-amino glycosyl substrates.28 A plausible mechanism is given that nickel metal coordinates the nitrogen atom of the imidate at C-1 and imine at C-2 forming a putative seven-membered ring complex I. They assumed that the
alcohol acceptor leads to formation of oxocarbenium complex II. Followed by departure of imidate gives the oxocarbenium intermediate III, which guides the attack of alcohol from α-face (Scheme 10). In the meantime, Demchenko et al. utilized a coordination chemistry to address the α-selectivity issue.29 Their investigation showed that a suitable multi-dentate metal ligand could strongly coordinate to both of the leaving group and specific atoms of substituent in the C-6 hydroxyl protecting function forming a coordinating complex II (Scheme 11). Subsequent activation via Cu(OTf)2 followed by reacting with nucleophilic acceptors provides α-selective glycosylations. This α-selectivity is ascribed to the more hindered β−face caused by the temporary coordination of metal.
O
Ag[BF4], acetone
AgI
Scheme 11 - Demchenko’s α-selective glycosylation via the metal-coordinated glycosyl donor
1.1.7. α-Selective glycosylation by additives.
Though the use of chiral auxiliary participating group in α-glycosylation is an elegant concept, installation of auxiliary functions is non-trivial that limits its wider application.
Therefore, it is reasonable for developing a more convenient strategy. In this regard, the addition of certain additives to interfere in the glycosylation process may provide an alternative to obtain the desired α-stereochemical outcome.
Entry Additive Yield α/β ratio* DMSO = dimethyl sulfoxide
Sulfone = tetrahydrothiophene 1,1-dioxide
HMPA = hexamethylphosphoric acid (Sulf one) 5 Sulfone 83% 1:1
O
Scheme 12 - Bogusiak’s α-selective glycosylation enhanced by the polar additives
For this purpose, Bogusiak et al. reported that the addition of a stoichiometric amount of hexamethylphosphoramide (HMPA) additive would effect 1,2-cis-α-furanoside formation
when glycosyl xanthates were used as glycosyl donors.30,31 For other additives (DMSO, TMU, sulfone, HMPA), the donicity (DN) of these molecules may provide a rationale towards the higher α-selectivity achieved via addition of additives with a higher DN (HMPA = 38.8). The additive molecules can presumably trap oxocarbenium ion to form intermediate I and II followed by reactions with the alcohol acceptor to form trivalent cations III and IV (Scheme 12). They also conducted quantum chemical calculation, which suggests that the more stable intermediate IV unfavorably proceed via the dissociation of additive leading to the β-furanoside, whereas the α-furanoside is more easily accessed via the intermediate III.
Few years later, Crich et al. adopted the combined reagents of a diaryl sulfoxide (Ar2SO) and triflic anhydride (Tf2O) as a promoting system which was developed by Gin’s group for the activation of thiosialoside.32,33 Interestingly, excessive amount of diaryl sulfoxide was found to play a critical role for α-sialylation. When stoichiometric amount of sulfoxide was used, only the elimination product was found (entry1, Table 2).
Table 2 - Crich’s study: The effect of diaryl sulfoxides for α-sialylation using 2-propanol as an acceptor Entry Ph2SO
Product, yield (α/β ratio)
1 1.0 1.0 2.0 none
TTBP = 2, 4,6-Tri-tert-butylpyrimidine Ph2SO = Diphenyl sulfoxide
*All of the reactions were perf ormed at -78oC.
In contrast, the addition of two more equivalents of diaryl sulfoxide dramatically increased the glycosylation yield but the moderate stereoselectivity obtained (entry 2, Table 2). They concluded that diary sulfoxide not only functions as a promoter but also it would couple with the unstable oxocarbenium ion to form the intermediates V and VI (Scheme 13).
For validation of their assumption, they also screened a panel of sulfoxides and found that dibenzothiophene IV was a better molecule to engage in α-sialylations (entry 3, Table 2).
O CO2Me
Scheme 13 - Crich’s proposed mechanism: Sulfoxide derivatives involving in α-selective sialylation
Recently, Boons et al. utilized a similar approach and demonstrated that the addition of excessive amount of PhSEt or thiophene could induce α-selectivity while 2-azido-2-deoxy glucosyl trichloroacetimidate was used as a donor (Scheme 14).34 With NMR and computa- tional studies, the formation of β-anomeric sulfonium intermediate is favored due to the reverse anomeric effect and steric factor. Thus, the predominant β-species could direct the
incoming acceptor from α−face. However, selectivity of per-O-acetylated 2-azido-2-deoxy glucosyl donor is found higher than that of per-O-benzylated donor. There may be other structural factors affecting the stereochemical outcome.
O+
Scheme 14 - Boon’s method: PhSEt as an additives involved in α-selective glycosylation
Other than Crich and Boons, Kononov et al. reported the influence of the additives on the physical properties of glycosyl donors.35 IR spectroscopy was employed to record the absorption shift of carbonyl group at 5-NAc of sialic acid (Scheme 15).
O weakening of this H bond
change of H-bonding network O
O OCH3
N H
O NIS, TfOH, addtive
CH3CN, -40oC
Scheme 15 - The influence of additives for supramer structures via IR spectroscopy
This result indicated that the H-bonding properties would be altered by the addition of the excessive additives molecules, such as DMF, DMA. The resulting phenomenon affects reaction yields and even the stereoselectivity. However, the trivial difference in yields and α/β−selectivities is hard to draw a conclusion that weakening the hydrogen bonding by additives is a single reason to contribute in α-selective sialylation (Table 3).36
Table 3 - Comparative study of DAMA as an additive in α-O-sialylation Entry Additives
(equiv.)
Time Yield (%)a α/β ratio
1 none 15 min 62 13:1 2 DAMA (1.0) 15 min 64 27:1 3 DAMA (3.0) 15 min 57 18:1 4 none 3 h 69 7:1 5 DAMA (1.0) 3 h 80 8:1
O CO2Me
OAc AcO OAc
AcHNAcO OR
NIS, TfOH, addtive CH3CN, -40oC
OH O O O
OO
O O
O O O
O CO2Me
OAc AcOOAc
AcHNAcO O DAMA
N
O O
additive
6 DAMA (3.0) 3 h 72 7:1
1.1.8. α-Selective O-glycosylation mediated by DMF-type molecules
In June 2009, Muzart published an interesting review article whose title is
“N,N-Dimethylformamide (DMF): much more than a solvent”. He wrote that “The O-atom of DMF can act as a donating moiety. Besides, DMF can react as either an electrophilic or a nucleophilic agent, and, in addition, can be the source of various key intermediates mediating reactions.”37 In his previous work, he found that the 2,3,4-triacetyl-1-bromo-α-D-xylo -pyranose could glycosylate with a serials of terpenols in DMF instead of applying the conventional Koenigs–Knorr conditions (Scheme 16).38 He also referred to 1H-NMR studies conducted by Nishida and co-workers who suggest that the formation of Vilsmeier–Haack
intermediate between glycosyl bromides and DMF make the glycosylation possible even in the absence of any additional promoting reagent, such as Ag, Hg metal.
AcO O
Scheme 16 - Xylosylation of terpenols in DMF
More interestingly, 35 years ago Lemieux has ever reminded us that the addition of the small amount of DMF enable the more efficient halide-catalyzed glycosylations (in situ anomerization process).9 However, no clear explanations were given in his following works until Nishida et al. developed a new dehydrated glycosylation protocol using Appel agents in DMF and further demonstrated the role of DMF in glycosylations.39 According to the evident NMR spectra for these possible intermediates, these signals indicated that the in situ prepared α-glycosyl bromide I by using Appel agent could be transformed to α-glycosyl iminium bromide salt III while DMF is used as a solvent (Scheme 17).
O
Scheme 17 - Nishida’s dehydrative glycosylation method using Appel agents in DMF
Based on Lemieux’s in situ anomerization mechanism, it could be rationalized that the β-glycosyl bromide II derived from α-glycosyl iminium intermdiate would be a real reactive donor for α-selective glycosylation. Furthermore, 2 years later, they made an exhaustive effort to verify the existence of β-substituted donors.40 Unfortunately, they failed to find out the strong evidence for supporting their speculation. Nevertheless, they still suspect that not only β-glycosyl bromide II but also β-glycosyl imidate IV could be the key species to bring about the stereochemical outcome. In contrast to thermodynamically stable α-anomer, they emphasized that the relatively small proportion (ca. 5%) of β-substituted intermediates should be a kinetic moiety and its NMR signal may not be accessible at the ambient temperature due to the rapid equilibration. Moreover, the frozen property of d7-DMF would not allow the further NMR measurement at the low temperature. To date, in terms of mechanistic investigation, the real entity for this reaction is still not successfully identified by any means.
Table 4 - DMA as an additive in α-O-glucosylation
O hemiacetal donor (1.3 eq.)
Acceptor (1.0 eq.) O
OCH3
Entry Acceptor Additive (equiv.) Yield α/β ratio
1 A1 DMFa 58% 77:23
aDMF is used a solvent
8 A4 DMA (5.0) 88% 73:27
Based on the literature reviews, Koto first reported the use of small amide molecules to achieve α−selective glycosylation (Table 4).41 They proposed a mechanism to account for their observatioin. Upon the dehydrative activation of glycosyl hemiacetal donors, the reactive intermediates I and II readily associate with N,N-dimethylacetamide (DMA) forming the glycosyl iminiums III and IV. Coupling with III and IV with the alcohol acceptor gives the glycosylation products (Scheme 18).
O
Scheme 18 - Koto’s plausible mechanism using DMA as an additive in α-O-glucosylation
α-Configuration III is thermodynamically more stable than its β-counterpart. In contrast, β-configuration IV is highly reactive and leading to α-selective glucosylations. Though the operation is simple, no elaborative studies were followed.
However, in our previous works, a good α-selectivity of glycosylation in the aforementioned Chapter 2 (the sequential chlorination-glycosylation protocol) was obtained.
Upon closed examination, it was found that DMF residue in crude glycosyl chloride is the key for α-selectivity observed. This finding sparks our interests to investigate the role, mechanism
and scope of application for DMF additive in α-glycosylation. Some parts of our findings could be very different from others. The more detailed studies would be described in the later sections.
2. Our strategy using DMF as an additive in α-selective glycosylation
As mentioned in the above context, this is certainly not the first time that DMF was used for the stereoselective glycosylation. However, the debates concerning the role of DMF still lie ahead. To clear it up further, a couple of the essential questions should be proposed in advance. I. Does the reaction go through the common β-substituted intermediate or multiple pathways simultaneously? II. Is the excess amount of DMF (even used as a solvent) required for the optimal result? III. Does the reaction need to be carried out at a relatively higher temperature? What effect does the temperature bring out? IV. To date, the reported examples are only limited to the use of glycosyl halides as the reactive donors. We don’t know whether DMF can be applied to other glycosyl donor systems, such as a common-used thioglycoside.
V. The more challenging task is to realize the interactions between DMF, promoter, base and the related counter ions during the reaction course.
Therefore, according to the literature survey and our initial findings, we envisaged that DMF may function as a “brake” molecule to allow the reactions bypass the more reactive pathways via the α/β mixed glycosyl iminium intermediate, which can further result in the improved α-selectivity (Scheme 19).
O RO
Cl
Ag+ AgCl
O RO
O N+ H
O
RO O N+
H main pathway HOR
β−glycoside HOR
I DMF
Ag2CO3 cat. AgOTf
II
α−glycoside
Scheme 19 - DMF-mediated α-selective glycosylation via glycosyl iminium intertemediates
3. Results and discussion
To study the DMF-mediated stereoselective glycosylations, we decided to choose α-glycosyl chlorides as the standard glycosyl donor. In our lab, TCT/DMF chlorination method has been proven being a practical and reliable procedure for the preparation of a wide range of α-glycosyl chlorides. In spite of this advantage, a numbers of other reasons are given that: I. Activation of glycosyl chloride by using the relatively simple promoting system (usually the combinations of AgOTf/Ag2CO3, AgOTf/TMU, or AgClO4/TMU) probably can avoid the potential problem derived from the complex reaction mixtures. II. The configuration of leaving group has been determined as an influential factor in glycosylation processes. The specific α-oriented glycosyl chloride has its merit. III. The compatibility of glycosyl chlorides with other latent leaving groups has been well known with the applications of orthogonal glycosylation strategies.42
Prior to the investigation, we surveyed the typical Koenigs-Knorr glycosylation conditions reported in the literatures and intended to find out the general operations.43-46 However, the versatile procedures can not provide the useful message and rationales for their protocols. For examples, the excess amount of reagents was generally used and the reaction temperature usually varied in a broad range. Thus its paucity of information about the experimental details prompted us to work out this problem. In the absence of the additives, therefore, α-glycosyl chloride 70b was exploited as a testing donor with the more reactive and commercial available diacetone galactosyl acceptor 82 in the preliminary trials. A panel of Koenigs-Knorr conditions was examined to realize which factors significantly contribute to the reactivity and stereoselectivity. Several characteristics for this reaction could be
summarized as below: I. The solid Ag2CO3 provides the source of silver cation for promoting the glycosyl halide and it is also an acid scavenger to neutralize the reaction media. The slightly excessive use of Ag2CO3 is sufficient for the completion of the reactions. Ag2CO3 can be replaced by TMU which usually serves as a base. II. We found that the conversion proceeded very slowly without the treatment of AgOTf. At lower temperature, the increasing amount of AgOTf was required to accelerate the reaction. At ambient temperature the minimum usage of Ag2CO3 (1.6 equiv) and AgOTf (0.05 equiv) as a combined promoting system render this glycosylation protocol inexpensive. III. α-glycosyl chloride 70b can be easily activated under this condition, even at -70 oC. The α/β ratio is highly correlated to the temperature (β-anomer was favorably formed at lower temperature) probably due to the intrinsic stereochemistry of α-halide which may prefer SN2-like glycosylation pathway (entry1-6, Table 5).
Table 5 - Optimization for the conventional Koenigs-Knorr conditions
O
IV. Improving α-stereoselectivity by using the ethereal solvent seems ineffective (entry 7, Table 5). V. The general procedure is conveniently performed by such the adding sequence:
To a mixture of Ag2CO3 (1.6 equiv.), molecular sieve (AW300), the glycosyl acceptor (1.0 equiv.) and glycosyl donor (1.5 equiv.) in DCM was added a catalytic amount of AgOTf (0.05−0.5 equiv) at the given temperature. Upon completion of the reaction, the subsequent treatment of Et3N allows the reaction mixture directly subjected to SiO2 column chromatography. We observed that a modification of the procedure, such as the reverse addition and the slow addition of glycosyl chlorides, could not provide the significant improvement in stereoselectivity. All in all, this protocol would be taken as a standard
To a mixture of Ag2CO3 (1.6 equiv.), molecular sieve (AW300), the glycosyl acceptor (1.0 equiv.) and glycosyl donor (1.5 equiv.) in DCM was added a catalytic amount of AgOTf (0.05−0.5 equiv) at the given temperature. Upon completion of the reaction, the subsequent treatment of Et3N allows the reaction mixture directly subjected to SiO2 column chromatography. We observed that a modification of the procedure, such as the reverse addition and the slow addition of glycosyl chlorides, could not provide the significant improvement in stereoselectivity. All in all, this protocol would be taken as a standard