Mitsunobu reaction 16- member

Another interesting class of five-membered aromatic heterocycles has recently been published by Tron et al. [54]. These compounds have biological activity in the nM range. An example of the formation of these furazan (1,2,5-oxadiazole) derivatives is shown in Scheme 9. The diol 50 was oxidized to the diketone 51 using TEMPO and sodium hypochlorite. Transformation to the bisoxime 52 was performed in an excess of hydroxylamine hydrochloride and pyridine at high temperature for several days. Basic dehydration of 52 formed two products (53a and b). A Mitsunobu reaction was then employed using toluene as solvent to form compound 53b in 24% yield. 

A Mitsunobu reaction then inverts the C-4 configuration to provide compound 151, and subsequent isomerization provides compound 152, which is ready for Lewis acid-mediated cyclization to construct the eight-membered firing. Using MeiAlOTf as a catalyst, intramolecular cyclization occurs, giving product 153 in which A, B, and C rings have been introduced with the desired stereochemistry (Scheme 7-45). 

The diversity-oriented synthesis of enantiomerically pure seven- and eight-membered ring systems was reported from easily accessible naturally occurring. Y-amino acids and their readily prepared derivatives as chiral synthons <2007JC0321>. Intramolecular Mitsunobu reaction was used as a key transformation to construct the 1,4-diazocines 224 (Scheme 27) and 1,4-oxazocines 225 (Scheme 28) <2007JC0321>. 

Eight-membered A,iV -protected cyclic sulfonylamide 89, bearing two different protecting groups, was demonstrated as useful intermediate for preparation of pseudopeptides. Synthesis of 89 was carried out in two steps by an intermolecular Mitsunobu reaction followed by intramolecular N-alkylation (Scheme 20 <2003T6051>). 

The 14-membered ring phosphonate 208 was synthesized via cyclization of the acyclic precursor 207 using the Mitsunobu reaction. Macrocycle 208 was obtained in 82% yield as a mixture of two diastereomers (5 1). The phenyl moiety in 208 was substituted with iV-Cbz-protected aminopentanol, followed by hydrogenolysis in EtOH with hydrogen and 10% Pd/C to afford amine 209 in 50% yield <20010L643, 2002CJC1643>. 

R = Et, Bu , Ph, 2-IC 6H4 Z = CPha, CHPh2, CH2Ph, CHMePh The nine-step synthesis and stereochemical elucidation of a 14-membered cyclic phosphonate (295) has been reported. The key step in the synthesis of the macrolide phosphonate was the cyclization of the acyclic precursor (296) using the Mitsunobu reaction, a mild reaction for the preparation of mixed phosphon-ates (Scheme 79). ... 

The enantioselective total synthesis of the complex bioactive indole alkaloid enf-WIN 64821 was accomplished by L.E. Overman and co-workers." This natural product is a representative member of the family of the C2-symmetric bispyrrolidinoindoline diketopiperazine alkaloids. The stereospecific incorporation of two C-N bonds was achieved using the Mitsunobu reaction to convert two secondary alcohol functionalities to the corresponding alkyl azides with inversion of configuration. The azides subsequently were reduced to the primary amines and cyclized to the desired ib/s-amidine functionality. 

A convergent total synthesis of 15-membered macrolactone, (-)-amphidinolide P was reported by D.R. Williams and coworkers.In their approach, they utilized the Sakurai aiiyiation to introduce the C7 hydroxyl group and the homoallylic side chain. The transformation was effected by BF3-OEt2 at -78 °C to provide the homoallylic alcohol as a 2 1 mixture of diastereomers. The desired alcohol proved to be the major diastereomer, as it resulted from the Felkin-Ahn controlled addition of the allylsilane to the aldehyde. The minor diastereomer was converted into the desired stereoisomer via a Mitsunobu reaction. 

A few well-known and widely used reactions use a cocktail of several different reagents and proceed by multistep mechanisms that are not easily discerned by the beginning student. Two of these reactions, the Swem oxidation and the Mitsunobu reaction, are discussed here. You will find that faculty members enjoy asking graduate students to draw mechanisms for these particular reactions, so you should learn them well ... 

The Mitsunobu reaction of achiral and chiral 3,4-dihydro-2H-l,5-benzoxathiepin-3-ol with aminopurines proceeded via a complete inversion of the stereogenic center of the secondary alcohol giving alkylated purines linked to a homochiral six-membered ring (14ITA22425). 

All characteristic last steps in the synthesis of EDOT, i.e. the ring closure to the dioxane structure, are also sufficient for the formation of the analogous seven-membered rings (1,3-dioxepanes), the 3,4-propylenedioxythiophenes (ProDOTs) Williamson ether synthesis [13], transetherification [30] and Mitsunobu reaction [25]. The analogous basic five-membered ring compound 3,4-methylenedioxythiophene (MDOT, a 1,3-dioxolane derivative) is also accessible by Williamson ether synthesis using bro-mochloromethane [31]. 

Reaction with Di- and Polyols. Although intermolecular dehydration between two molecules of alcohols to afford acyclic ethers usually does not occur with the DEAD-TPP system, intramolecular cyclization of diols to produce three to seven-membered ethers is a common and high yielding reaction. Contrary to an early report, 1,3-propanediol does not form oxetane. Oxetanes can be formed, however, using the trimethyl phosphite modification of the Mitsunobu reaction. The reaction of (5)-1,2-propanediol and ( )-l,4-pentanediol with DEAD and TPP affords the corresponding cyclic ethers with 80-87% retention of stereochemistry at the chiral carbon, while (5)-phenyl-1,2-ethanediol affords racemic styrene oxide. In contrast to the reaction of the same 1,2-diols with benzoic acid (eq 4), oxyphos-phonium salts (25a) and (25b) have been postulated as key intermediates in the present reaction (eq 20). ... 

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