Mitsunobu reaction catalytic reactions

A double reduction was achieved under catalytic hydrogenation conditions to open the epoxide and reduce the nitro group to an amino group in 90% yield. The aniline thus afforded was reacted with diethylethoxymethylenemalonate to give 92. 92 was next cyclized to the 1,4-benzoxazine 93 via a Mitsunobu reaction in the absence of a Lewis acid, unlike Kim s approach (Kang et al., 1996). Completion of the tricycle core was ultimately achieved in PPE at 140-145°C to furnish the LVX core in 85% yield. The core was converted to LVX (1) in two precedented steps. 

Alcohol inversion. Elimination competes with S, 2 substitution in the inversion of secondary alcohols by the Mitsunobu reaction or by reaction of mesylates with cesium propionate or cesium acetate. Elimination in the inversion of cyclopentyl and cyclohexyl alcohols can be largely suppressed by reaction of the mesylate with cesium acetate (excess) and a catalytic amount of l8-crown-6 in refluxing benzene. Even inversion of an ally lie alcohol can be effected in moderate yield under these conditions (equation I). ... 

Phenylacetaldehyde was readily converted into allylic alcohol 81 by a standard olefination and reduction protocol. Epoxidation with t-BuOOH and catalytic Ti(OPr-i)4 in the presence of catalytic (-)-DIPT gave (2R, 3R)-3-benzylglycidol 82 in >99% e.e. Addition of diphenyl-methanamine and Ti(OPr-i)4 in refluxing 1,2-dichloroethane led to aminodiol 83, from which aminoepoxide (S,S)-84 was obtained by hydrogenolysis and /V-protection followed by an intramolecular Mitsunobu reaction [76]. 

A further chemical synthesis (93) (Scheme 22) relied on catalytic cis reduction of the (Z)-olefin 81, yielding the protected serine 82. This was resolved using hog renal acylase (EC 3.5.1.4), and BBrj treatment gave (2S, 3/ )-[2,3- H2]serine 60e contaminated with (2S)-[2,3,3- H3]serine. The (2S, 3S)-isomer could be obtained by a Mitsunobu reaction (93). 

Catalytic Mitsunobu reactions in which substoichiometric amounts of phosphine or azodicarboxylate are used require much more work to find a workable solution. Some initial work in this area has been carried out by Toy and his group. Use of stoichiometric iodosobenzene diacetate as an oxidant to oxidize the reduced azodicarboxylate allowed the use of 10 mol% of DEAD or an equivalent reagent. How to use only catalytic amounts of phosphine in Mitsunobu reactions remains an unsolved problem. 

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>. 

The preparation and reaction of 1-alkylthioisoquinolinium salts with active methylene compounds was studied <02CPB225>. The selective N- and O-alkylation of 1-isoquinolones using Mitsunobu conditions was also studied <02JCS(P1)335>. Additionally, the oxidation of isoquinoline derivatives to the corresponding isoquinolones using iodosobenzene and catalytic tetrabuty(ammonium iodide was reported <02HCA1069>. 

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