Mitsunobu glycosylation

FIGURE 3.10 Mitsunobu glycosylation process R side-chain amino acids P protective group or resin linker. 

A synthesis based on a novel Mitsunobu glycosylation procedure as the key step was recently reported by van Boom and co-workers [90]. They reacted the amino acid derived 2-nitrobenzenesulfonamides 81 with 2,3,4,6-tetra-O-acetyl-D-glucose (80) under Mitsunobu conditions (Scheme 25) to obtain fully protected glycosylamines 82, which upon deprotection rearranged to the corresponding Amadori products 73 in overall yields of 70-80%. 

Mitsunobu conditions are effective for glycosylation of weak nitrogen nucleophiles, such as indoles. This reaction has been used in the synthesis of antitumor compounds. 

Since the first examples of lower and upper rim glycocalixarenes were obtained in 1994 by Marra el al.,106 employing the Mitsunobu reaction or copper(II)-catalyzed glycosylation, the development of efficient synthetic methodologies has allowed the emergence of several examples of ()-, N-, or C-glycosyl calix arenes, and these have recently been reviewed (101-106, Fig. 8).107,10X... 

Representative Procedure for Silicon Promoted Glycosylation with Cl-Hemiacetal Donors Using Me3SiBr and CoBr2 129 Representative Procedure for Mitsunobu-Type Glycosylation with Cl-Hemiacetal Donors and Phenol Glycosyl Acceptors 129 Representative Procedure for Appel-Type Glycosylation with Cl-Hemiacetal Donors 129... 

The glycosylation based on the Mitsunobu reaction has been most commonly directed to the synthesis of O-aryl glycosides, a structural motif found in a variety of natural products [80-82], Early work by Grynkiewicz [83,84], among others [85-87], established the viability of triphenylphosphine and diethylazodicarboxylate to promote the glycosylation of phenol acceptors at ambient temperature. More recently, Roush and coworkers have discovered that the glycosylation performed well in the... 

Although aliphatic alcohols are typically poor acceptors in the Mitsunobu-type glycosylation, Szarek and coworkers have highlighted one advance to this end [95]. For the triphenylphosphine and diethylazodicarboxylate promoted glycosylation of a monosaccharide acceptor, the addition of mercuric bromide is necessary to promote the reaction. For example, the (1,6)-disaccharide 44 was obtained in 80% yield using this modified Mitsunobu protocol. Unlike previous examples with phenol or N-acceptors, preactivation of the hemiacetal donor was performed for 10 min at room temperature prior to addition of the aliphatic alcohol nucleophile. 

Representative Procedure for Mitsunobu-Type Glycosylation with Cl-Hemiacetal Donors and Phenol Glycosyl Acceptors [90]... 

Fluoroalkyl Glycosides (RFn-(CH2)2-n-0-sugar) and Perfluor-oalkylidene Acetals Derived from Sugars The very low nucleophilicity of fluoroalcohols makes it difficult to substitute of a hydroxyl (anomeric or not). ° This is the reason why this type of ether is not very common. Such ethers have only been isolated in very small quantities in solvolysis reactions, or in carben insertions, performed in fluorous alcohols.Preparation of these ethers has been solved by means of the Mitsunobu reaction. This reaction is known to be dependent on the pA a of the acceptor of the glycosyl the acidity of fluorous alcohols allows a much easier deprotonation than with non fluorinated alcohols." ... 

The Swiss report3 includes a variation of the Mitsunobu reaction for preparation of acid-sensitive glycosyl fluorides (equation I). 

Next, pyralomicin 2c (38) was synthesized from 32 and 37 (16). The glucosyl donor 37 was prepared from benzyl a-D-glucopyranoside by methoxymethylation followed by hydrogenolysis. The stereoselective N-glycosylation of 37 with 32 was effectively accomplished by using Mitsunobu conditions to give 38, after acidic deprotection. This was identical in all respects with the natural product 38 (16). 

Glycosylations proceeding through oxophosphonium intermediates 186 (Scheme 4.37) frequently rely on the Mitsunobu reaction or some modified version thereof. 

The Mitsunobu protocol has also been investigated in the stereocontrolled synthesis of glycosyl esters (O Scheme 78g) [431]. Complete stereochemical inversion at C-1 of the starting sugar is observed when the esterification is conducted with anomerically pure glycosyl hemiacetals. By corollary, complementary ratios of inverted products are formed when an anomeric mixture of sugars is esterifled. The stereochemical outcome of the esterification is not affected... 

Inversion of configuration (cf Epimerization) of alcohols (Mitsunobu reaction), 160-161, 286 of ally lie acetates with Pd, 27, 164 of allylpalladium with d-synthons, 27, 264 of alkyl halides or sulfonates by 1,3-dithiane anions, 22 by organylcuprates, 36 by tetracarbonylferrate<2 -X 46-47 in triorganylborane rearr., 37-38 of glycosides with free 2-OH by DAST, 272 of glycosyl halides, 271 of oxiranes by 1-alkync anions, 64, 204 by enolate type anions, 63-64 by internal alcoholate addition, 265 Inversion-esterification of alcohols, 160-161, 286 Inverted DNA , 345-346 Iodide, hydrogen porphyrin synthesis with, 255 Iodine = diiodine (Ij) ... 

Mitsunobu type reactions with, 161 Phosphorous tribromide OH/Br exchange, 303 Phosphorous trichloride glycosyl halides, 266 Phosphorus(5 +) chloride ... 

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