Mitsunobu with acetic acid

Hydration or elimination of glycals. Glycals can undergo hydration or elimination when treated with HgS04 in dilute sulfuric acid or aqueous acetic acid.1 However, D-glucal 1 is converted only into the (l,2-dihydroxyethyl)furan (2).2 This product has been used for a short synthesis of L-hexoses. Thus 2 can be converted to the monobenzoate 3 with inversion (Mitsunobu). This product is converted into... 

Zinc and acetic acid reduced the 1,4-naphthoquinone E into hydroquinone F with concomitant removal of the protective group. Ring closure of F was effected under the Mitsunobu conditions to give G. Barton s benzeneseleninic anhydride [(PhSe0)20] smoothly oxidized G to furnish (R)-ent-nocardione B (143 ) as dextrorotatory needles with orange color. Naturally occurring (—)-nocardione B (143) was therefore shown to possess (/ -configuration.35... 

A modified Mitsunobu procedure in which 63 is first treated with the preformed complex 68 (prepared by reaction of triphenylphosphine and diisopropyl azodicarboxylate) and then cesium thioacetate leads to significant racemization [17]. However, if the free acid is reacted instead with an appropriate thioacid (rather than the ester and a cesium salt), optical yields improve significantly. Thus, thioacetylation of (S)-l can be accomplished by treating it with 68 followed by the addition of thioacetic acid in THF to provide in 48% yield (5)-2-(acet-ylthio)-2-phenylacetic acid (69) with 84% ee after recrystallization. The low yield is due in part to the unavoidable formation to the extent of at least 50% of a viscous, polymeric material. The reaction is complete in minutes, however, and proceeds with retention of configuration. Presumably this is a result of a double inversion mechanism that passes through an a-lactone. Interestingly, the corresponding reaction with lactic acid does occur with inversion [18]. 

D-Xylose has been converted to (25)-3-(indol-3-yl)propane-l,2-diol 237 by two different routes, one involving direct Fischer indolization of 238. The dibenzyl-dithioacetal 239 was elaborated to the fused triazoline 240 following reaction with MCPBA. Initial oxidation was followed by elimination of acetic acid allowing intramolecular 1,3-dipolar cycloaddition reaction to construct the triazole ring. The bicyclic iV,S -acetals 242 and 241 were prepared by reaction of the 2,3-0-isopropylidene-D-ribofuranose with 2-aminoethane thiol followed by Mitsunobu reaction. These products are considered analogues of castanosper-mine and australine. ... 

Hitherto unreported (— )-conduramine E (170) was synthesized from 169 in ca. 50% overall yield as outlined in Scheme 27. Enzyme (esterase) induced monodeacetylation was followed by Mitsunobu-type inversion with an AT-nucleophile in the presence of acetic acid. endo-Cyclization with concomitant epoxide-opening produced a urethane bearing the correct stereochemistry at the four chiral centres. Base treatment revealed the (—)-conduramine [for (+)-conduramine E see Vol. 29, p. 

The synthesis of the second building block [62] for meropenem starts from trans-hydroxyproline. First, the amino acid is protected on both, the amino and the carboxyl group. By reaction with thioacetic acid m a Mitsunobu esterification, the thiol ftmction is introduced, and the carboxyl group is then selectively deprotected with trifluoroacetic add. The dimethylamino-group is introduced with the aid of isopropyl chloroformate, and the thiol acetate is finally hydrolysed with aqueous sodium hydroxide. 

Willoughby and coworkers reported a solid-phase strategy for the preparation of 2-arylindole combinatorial libraries in a split-and-pool format (Figure 11.61). Twenty different arylalkyl ketoacids were immobilized onto a sulfonamide resin, mixed, and separated into twenty equal portions. The Fischer indole cyclization was carried out with 20 arylhydrazines in the presence of ZnCl2 and acetic acid. The resin was mixed, separated into 80 equal portions, and finally alkylated under Mitsunobu conditions. A library of 12,800 compounds was generated, and led to the discovery of potent ligands for a variety of G-protein coupled receptors. 

During an exploration of practical syntheses of a GnRH antagonist, Farr et al. examined two key substrates for the Mitsunobu reaction.Both reactions were carried out at kilo-scale. Typically, four equivalents of the pyridyl ethanol 181 were required to drive the reaction to completion. Since the dinitrosulfonamide product 182 proved to be labile during the hydrolysis of the methyl ester, further exploratory work was carried out with the p-nitrosulfonamide 183. The nosyl group of the crude reaction product 184 was removed with thioglycolic acid. After an aqueous workup, the desired product 185 was obtained in 58% yield over three steps after recrystallisation from ethyl acetate. Eventually, this route was abandoned due to supply issues with the pyridyl ethanol and byproduct removal issues arising firom the Mitsunobu reaction and the nosyl deprotection. 

A similar strategy served to carry out the last step of an asymmetric synthesis of the alkaloid (—)-cryptopleurine 12. Compound 331, prepared from the known chiral starting material (l )-( )-4-(tributylstannyl)but-3-en-2-ol, underwent cross-metathesis to 332 in the presence of Grubbs second-generation catalyst. Catalytic hydrogenation of the double bond in 332 with simultaneous N-deprotection, followed by acetate saponification and cyclization under Mitsunobu conditions, gave the piperidine derivative 333, which was transformed into (—)-cryptopleurine by reaction with formaldehyde in the presence of acid (Scheme 73) <2004JOC3144>. 

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." ... 

One of the early syntheses of orlistat (1) by Hoffmann-La Roche utilized the Mukaiyama aldol reaction as the key convergent step. Therefore, in the presence of TiCU, aldehyde 7 was condensed with ketene silyl acetal 8 containing a chiral auxiliary to assemble ester 9 as the major diastereomer in a 3 1 ratio. After removal of the amino alcohol chiral auxiliary via hydrolysis, the a-hydroxyl acid 10 was converted to P-lactone 11 through the intermediacy of the mixed anhydride. The benzyl ether on 11 was unmasked via hydrogenation and the (5)-7V-formylleucine side-chain was installed using the Mitsunobu conditions to fashion orlistat (1). 

The successful synthesis of optically active 7 then led to the first synthesis of verrucarin A (8), a macrotrilactone with significant cytostatic activity. The synthesis involved esterification of the primary alcohol of verrucarol (the tricyclic fragment) with the acetate of 7 (DCC, 4-pyrrolinopyridine) and then with a protected derivative of (E, Z)-muconic acid. After deprotection (Bu4NF), lactonization was effected by the Mitsunobu procedure (7,405-406). 

Mitsunobu reaction as well as by mesylation and subsequent base treatment failed, the secondary alcohol was inverted by oxidation with pyridinium dichromate and successive reduction with sodium borohydride. The inverted alcohol 454 was protected as an acetate and the acetonide was removed by acid treatment to enable conformational flexibility. Persilylation of triol 455 was succeeded by acetate cleavage with guanidine. Alcohol 456 was deprotonated to assist lactonization. Mild and short treatment with aqueous hydrogen fluoride allowed selective cleavage of the secondary silyl ether. Dehydration of the alcohol 457 was achieved by Tshugaejf vesLCtion. The final steps toward corianin (21) were deprotection of the tertiary alcohols of 458 and epoxidation with peracid. This alternative corianin synthesis needed 34 steps in 0.13% overall yield. 

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