Oxophosphonium intermediate

The reaction of phosphines and alkyl halides presents an alternative way to generate phosphonium electrophiles (Scheme 3.8). In particular, the combination of a phosphine and carbon tetrabromide (the Appel reaction) allows for in situ formation of a phosphonium dibromide salt (48, X = Br). Treatment of a hemiacetal donor 1 with the phosphonium halide 48 initially provides the oxophosphonium intermediate 38 (X = Br). However, the oxophosphonium intermediate 38 can react with bromide ion to form the anomeric bromide intermediate 49 (X = Br) with concomitant generation of phosphine oxide. With the aid of bromide ion catalysis (i.e. reversible, catalytic formation of the more reactive P-anomeric bromide 50) [98], the nucleophile displaces the anomeric bromide to form the desired glycoside product 3. The hydrobromic add by-product is typically buffered by the presence of tetramethyl urea (TMU). 

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

Scheme 9 Dehydrative glycosylations via glycosyl oxophosphonium intermediates [26-37]. DEAD = diethyl azodicarboxylate DIAD = diisopropyl azodicarboxylate.

Scheme 10 Dehydrative glycosylations via glycosyl oxophosphonium intermediates [39].

Acylation of the least hindered 6 and 6 hydroxyl groups can be achieved in low to moderate yields using exceptionally mild reaction conditions or the 6-position can be acylated with bulky acid chlorides that is, pivaloyl chloride [8], In a different approach, the application of the Mitsunobu reaction allowed Bottle and Jenkins [9] to prepare bulky oxophosphonium intermediates at the primary 6 and/or 6 -positions. A substitution reaction by palmitate led to the 6-0-palmitoyl sucrose (Fig. 7.5). Interestingly, the 6-position appeared to be more reactive than the 6 but, nevertheless, the 6-6 -dipalmitate could be synthesized by using a 2.6 molar equivalent of palmitic acid. However, the neopentylic-like 1 -position is considerably more hindered in such a substitution process. 

Scheme 22 Mechanism of the Mitsunobu reaction. The essential compounds are a phos-phane and a diazocompound that is able to generate the oxophosphonium intermediate in the presence of alcohols. The SN2-reaction in step III is the rate-determining step. The outcome of the reaction strongly depends on the steric environment of the alcohol and the acidity of the nucleophile. In this case the traditional Mitsunobu reagents diethyla-zodicarboxylate and triphenylphosphane are shown as participants of the reaction [258]...

Mukaiyama reported an alternative method for the generation of oxophosphonium type intermediates using the reaction of tributylphosphine oxide and triflic anhydride, and applied this reaction to the synthesis of ribofuranosides [415]. 

Another variation of the classic Darzens reaction is a one-pot synthesis of dietliyl 1-perfluoro-alkyl-1,2-epoxyalkylphosphonates using the nucleophilic attack of lithium diethyl phosphite on the carbonyl carbon of perfluorinated P-oxophosphonium salts (Scheme 4.8). The resulting intermediate can eliminate in two directions. When the oxygen anion in the least sterically hindered position (R = R = Me) attacks the neighboring carbon atom, diethyl 1-perfluoroalkyl-1,2-epoxyalkylphosphonates aie obtained in moderate yields (42-51%) after elimination of PhjP (anti fashion). The formation of a-(perfluoroalkyl)vinylphosphonates by attack at phosphorus (syn fashion) can be a competing reaction. The results indicate that the selectivity can be controlled to produce exclusively either epoxyphosphonates or vinylphosphonates. ... 

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