Mitsunobu condition

The terc-butyldimethylsilyl groups of pyrido[l,2-c]pyrimidine 154 was eliminated with BU4NF to afford 6-hydroxy-8-hydroxymethyl derivative 155 (00TL1849). Compound 155 gave tricyclic derivative 156 under Mitsunobu conditions. 

An 1 5 epimeric mixture of piperidine derivatives 191 was cyclized under Mitsunobu condition to afford a mixture of l-iminoperhydropyrido[l,2-c] pyrimidines 153 and 192 (00TL1849). 

Amino alcohols are also good substrates for aziridination under Mitsunobu conditions. The rfs-1,4-amino alcohols 48, obtained by reductive cleavage of the nitrogen-oxygen bonds of the hetero Diels-Alder adducts 47, underwent syn-SN2 -type displacement on treatment with PPh3 and DEAD to give cyclic vinylaziridines 49 (Scheme 2.15) [27]. 

Sulfonate esters also can be prepared under Mitsunobu conditions. Use of zinc tosylate in place of the carboxylic acid gives a tosylate of inverted configuration. 

The Mitsunobu conditions also can be used to effect a variety of other important and useful nucleophilic substitution reactions, such as conversion of alcohols to mixed phosphite esters.56 The active phosphitylating agent is believed to be a mixed phospho-ramidite. 

Sulfonamides are relatively acidic and their anions can serve as nitrogen nucleophiles.64 Sulfonamido groups can be introduced at benzylic positions with a high level of inversion under Mitsunobu conditions.65... 

The Mitsunobu conditions can be used for alkylation of 2-pyridones, as in the course of synthesis of analogs of the antitumor agent camptothecin. 

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

Methoxyphenyl (PMP) ethers find occasional use as hydroxy protecting groups. Unlike benzylic groups, they cannot be made directly from the alcohol. Instead, the phenoxy group must be introduced by a nucleophilic substitution.185 Mitsunobu conditions are frequently used.186 The PMP group can be cleaved by oxidation with CAN. 

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>. 

To access the calphostins, (S)-16 was subjected to Mitsunobu conditions followed by the two-step dimerization protocol (lithiation, FeCl3) resulting in biaryl (R)-17 as the major diastereomer (Scheme 7.2). In this case, the relative stereochemistry matched the stereochemistry of calphostins A and D. Elaboration following the same protocol as for 5 completed the first total synthesis of calphostin D (4d). Calphostin A (4a) was also synthesized via benzoate protection of the secondary alcohols. 

An application of these rather unusual high-temperature Mitsunobu conditions in the preparation of conformationally constrained peptidomimetics based on the l,4-diazepan-2,5-dione core has recently been disclosed by the group of Taddei (Scheme 6.102b) [208]. Cydization of a hydroxy hydroxamate dipeptide using the DIAD/Ph3P microwave conditions (210 °C, 10 min) provided the desired 1,4-diaze-... 

Thiadiazolidinone 1,1-dioxides 71 undergo O- rather than the expected iV-alkylation under Mitsunobu conditions <1998TL7435>. iV-Acylation can subsequently be performed on the O-alkylated product 72 using acetic anhydride to give thiadiazolines 73 (Scheme 7). 

Cyclodehydration of p-hydroxythioamides under Mitsunobu conditions (Method a) has provided peptide thiazoline in 80% yield with 78 22 ratio of A B and 56% de. Treatment of p-hydroxythioamides with Me02CNS02NEt3,... 

Under cathodic reduction condition, 2-bromo-2-cyanoacetophenone is transformed into 5-amino-4-benzoyl-3-phenylfuran-2-carbonitrile in good yield <00H(53)1337>. Cyanoketones react with glycolate under Mitsunobu conditions to produce vinyl ethers which give rise to 3-... 

Mitsunobu conditions is the key step in the synthesis of / -substituted l,2-benzisoxazolin-3-ones 10 <00TL2295>. Starting from l,2-bis(o-haloaryl)ethanones, 4,5-bis(o-... 

Upon treatment with dibenzyl iminodicarbonate under Mitsunobu conditions, nonracemic w-hydroxy stannanes are converted to a-imino stannanes with inversion of... 

Preparation of the donor 46 was started from 4,6-0-benzylidene protected thiomannoside 47 (Scheme 7.24). Alkylation with p-allyloxybenzyl chloride under phase transfer conditions78 was followed by 3-O-silylation and Pd(0)-mediated deallylation79 to give 48. The phenolic OH group was alkylated with ethyl 6-bromohexanoate and carboxylic acid, liberated by alkaline hydrolysis, was reacted with PEG monomethyl ether (MW -5000) under Mitsunobu conditions to afford 46. 

Scheme 4.28 A modified single-step synthesis of allenes under Mitsunobu conditions.

An alternative strategy for the synthesis of 9-alkoxypurines is via the coupling of a suitably functionalized 9-hydroxypurine with protected alcohols such as 1014 under the Mitsunobu condition or with halides under base-catalyzed conditions to give after deprotection 998 or its adenosine analog 1015 (90TL2185). 

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