Scheme 1: Left: The Mitsunobu reaction is essentially a nucleophilic substitution of alcohols occurring with inversion of configuration at the alcohol stereocenter.
The auxiliary reagents are involved in a redox process. Scheme 1: Left: The Mitsunobu reaction is essentially a nucleophilic substitution of alcohols occurring with Jump to Scheme 1 The reaction proceeds under mild, neutral conditions that are compatible with a wide range of functional groups. In the case where a stereogenic center is involved, the reaction takes place with stereochemical inversion . Otherwise the azo reagent would compete with the acidic nucleophile and participate in the substitution reaction .
Various compounds comply with that condition: carboxylic acids, phenols, hydrazoic acid, some other NH acids, and thiols. However, alternative reagents such as azodicarboxamides [15,16] or stabilized phosphoranes were also developed to allow reaction with nucleophiles of weaker acidity.
The typical phosphine reagents are triphenyl- Ph3P or tributylphosphine n-Bu3P. In recent years, advances have been made using solid supported reagents, thus facilitating work-up conditions [17,18]. The polarity of the commonly aprotic solvents used in the Mitsunobu reaction, including toluene, tetrahydrofuran or dimethylformamide, has been shown to be influential in terms of efficacy and stereoselectivity . Since its infancy, the Mitsunobu reaction has found applications in carbohydrate chemistry, as its broad scope and mild conditions are ideal for the formation of conjugates with sensitive natural products.
Standard applications of the Mitsunobu reaction in glycochemistry have mostly dealt with the functionalization of the primary hydroxy group of sugars and, to a lesser extent, with modifications of the secondary alcohol array in carbohydrate rings  , for example for halogenation .
However, the Mitsunobu reaction can also be profitably utilized for the anomeric modification of carbohydrates. Hence, we have focused this review on the utilization of the Mitsunobu reaction for manipulations of the carbohydrate hemiacetal, where reducing anomerically unprotected sugars react as the alcohol component to be either converted into glycosides or into other anomerically modified carbohydrate derivatives. We intend to provide a critical survey as well as a source of inspiration, even more so as glycosylation remains a challenge in carbohydrate chemistry.
To rationalize the outcome of the Mitsunobu reaction with reducing sugars, special mechanistic considerations have to be taken into account. On the one hand, the equilibrium between the azodicarboxylate, the phosphine, and the acidic component, Nu-OH, is important cf. On the other hand, mutarotation of the sugar hemiacetal has to be discussed to predict the stereochemical outcome of the reaction.
However, full anomerization is often not observed as the rate and the extent of mutarotation depends on various parameters such as anchimeric effects of neighboring groups and the reaction conditions. Another possible explanation for limited anomerization lies in the different stability of anomeric glycosyloxyphosphonium salts, where one anomer can be sterically favored over the other, thereby pushing the equilibrium to a product with the respective anomeric configuration.
Especially when the sugar alcohol is not sterically hindered, phosphorus transfer occurs to yield a phosphine-activated anomeric alcohol a glycosyloxyphosphonium ion, pathway A. This in turn can be attacked by the deprotonated nucleophile resulting in an anomerically modified carbohydrate with inversion of configuration at the anomeric center, according to a SN2 mechanism.
Pathway A can also proceed through a SN1 mechanism when the intermediate glycosyloxyphosphonium ion is less stable. Then, it can decompose into the corresponding anomeric oxocarbenium ion and phosphine oxide. While this would lead to racemization under normal circumstances, in most carbohydrates, participation effects of neighboring groups in the vicinity typically at the 2-position of the sugar ring affect the reaction outcome, favoring nucleophilic attack from a preferred face of the sugar ring [22,23].
In the absence of a substituent at C-2, however, typically poor stereoselectivity is observed in Mitsunobu reactions with carbohydrate hemiacetals, indicating a SN1-type pathway A of the reaction .
Scheme 2: Mechanistic considerations on the Mitsunobu reaction with carbohydrate hemiacetals depicted in simplified form. These can give rise to at least two different reaction pathways, A and B, as explained in the main text. Depending on various parameters, the anomerically modified sugar, a glycoside or an anomeric ester, respectively, is obtained with full inversion of anomeric configuration or as anomeric mixture A , or with retention of the anomeric configuration via O-alkylation B.
For clarity both reaction pathways are exemplified with only one sugar anomer. Scheme 2: Mechanistic considerations on the Mitsunobu reaction with carbohydrate hemiacetals depicted in sim This in turn reacts with the anomeric oxyanion to furnish the anomerically modified sugar with retention of configuration via anomeric O-alkylation.
This mechanistic proposal is in agreement with observations by Lubineau et al. Reactions with protic acids to achieve anomeric esters The first application of the Mitsunobu reaction involved esterification of a secondary alcohol.
Although an anomeric OH group cannot be regarded as a classical secondary alcohol group but as a hemiacetal OH, it can be successfully involved in Mitsunobu reactions to achieve 1-O-acyl glycoses. Thus, searching for an efficient protocol for the preparation of complex, multifunctional glycosyl esters in the context of the total synthesis of phyllanthostatin antitumor agents, A.
Smith and colleagues soundly investigated the suitability of the Mitsunobu reaction . In addition, 4 was also converted with the phyllanthostatin aglycone 8 to give 10 with inversion of anomeric configuration. Extension of this work to other more complex antineoplastic glycosyl esters was successfully investigated by the same group . Scheme 3: Anomeric esterification using the Mitsunobu procedure . Jump to Scheme 3 De Mesmaeker et al. Similarly, regioselective esterification of unprotected allyl glucuronide 11 was performed by Juteau et al.
Scheme 4: Conversion of allyl glucuronate into various 1-O-esterified allyl glucuronates using anomeric Mitsunobu esterification [36,37]. Scheme 4: Conversion of allyl glucuronate into various 1-O-esterified allyl glucuronates using anomeric Mitsu Jump to Scheme 4 Bourhim et al. On the other hand, other authors have reported that the anomeric position can be selectively modified in a Mitsunobu reaction without concomitant modification of the primary 6-OH vide infra.
Apparently, fine-tuning of reaction conditions can alter the selectivity of the Mitsunobu reaction and in addition, different regioselectivities might origin in the structure of the sugar substrate. The produced esters 27—29 were obtained as anomeric mixtures.
Scheme 5: Synthesis of anomeric glycosyl esters as substrates for Au-catalyzed glycosylation . Jump to Scheme 5 Lubineau et al. The authors state that the observed pKa effect is either due to the influence of the acidity of the employed acid on the reaction mechanism or results from the proton-catalyzed change of the anomeric ratio of the starting material 30 in solution. Scheme 6: Correlation between pKa value of the employed acids or alcohol and the favoured anomeric configuration of the respective product.
Scheme 6: Correlation between pKa value of the employed acids or alcohol and the favoured anomeric configur The authors thus considered the Mitsunobu reaction as unsatisfactory for the synthesis of HBP. On the other hand, Inuki et al. Jump to Scheme 7 Reactions with phenols to achieve aryl glycosides Not only anomeric esters, but also glycosides can be obtained through the Mitsunobu reaction.
Dehydrative glycosylation approaches with reducing sugars were previously reviewed [43,44]. As phenols are weak acids, they are suitable reaction partners in the Mitsunobu reaction, leading to aryl glycosides with reducing sugars as the alcohol components.
Grynkiewicz can be called the pioneer of Mitsunobu glycosylation, as having explored the Mitsunobu reaction for the synthesis of various aryl glycosides [24,45]. Scheme 8: Synthesis of phenyl glycosides 44 and 45 from unprotected sugars . Notably, in this reaction, traces of an anomeric mixture of the respective furanoside 48 were detected. Singh, and Xi Chen. Chemical Reviews , 5 , Christine F. Czauderna, Amanda G.
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Bis azide—triphenylphosphine as a reagent for esterification at room temperature. Tetrahedron Letters , 56 50 , Debabrata Bhunia, Preethi M.The authors thus considered the Mitsunobu reaction as unsatisfactory reducing sugars, special mechanistic considerations have to be taken. To rationalize the outcome of the Mitsunobu reaction with glycosyl esters was successfully investigated by the same group. Extension of this work to synthesis more complex antineoplastic to study and build upon so that you're ready. Such Master thesis in public finance was also extended for the synthesis of.
Serrano, and Luis Oriol. Conversion of glycals into vicinal-1,2-diazides and 1,2- or 2,1 -azidoacetates using hypervalent iodine reagents and Me 3 SiN 3. Scheme Synthesis of disaccharides using mercury II bromide as co-activator in the Mitsunobu reaction . Pathway A can also proceed through a SN1 mechanism when the intermediate glycosyloxyphosphonium ion is less stable.
Bis azide—triphenylphosphine as a reagent for esterification at room temperature. Another possible explanation for limited anomerization lies in the different stability of anomeric glycosyloxyphosphonium salts, where one anomer can be sterically favored over the other, thereby pushing the equilibrium to a product with the respective anomeric configuration. Scheme Synthesis of various fructofuranosides according to Mitsunobu and proposed neighbouring group parti Scheme 4: Conversion of allyl glucuronate into various 1-O-esterified allyl glucuronates using anomeric Mitsunobu esterification [36,37].