Subject Mitsunobu reactions

Similarly, fV-BOC-aminoalcohols can be subjected to Mitsunobu reaction conditions to yield the piperidine structure 10 (Equation 26) <2004JOC2229>, which is an intermediate in the synthesis of galactohomonojirimycin (BOC = /-butoxycarbonyl). Cyclization of an iV-BOC derivative of an aminoalcohol mesylate was reported in the synthesis of enantiopure 3-hydroxy-4-phenylpiperidine derivatives starting from L-phenylglycine <2004TL987>. 

In the asymmetric synthesis of axially chiral biaryls, the formation of two C-O bonds is the key step in the etherification of 2,2, 6,6 -tetrahydroxybiphenyl 187 (Scheme 21). Sequential etherification of the biaryl 187 with 1,4-di-O-benzyl-L-threitol 188 under the Mitsunobu conditions afforded the monoether 189. After deprotection of the /-butyldimethylsilyl (TBDMS) group with Bu4NF, the intermediate alcohol was again subjected to the Mitsunobu reaction in situ. The intramolecular cyclization proceeded smoothly to give 190 in high yield (for R= Bn, m.p. 138-139°C) <2000JOC1335>. 

The mild conditions required for the Mitsunobu reaction make it one of the best methods for inverting the configuration of an alcohol or subjecting a 2° alcohol to nucleophilic substitution. Normally, E2 elimination competes with Sn2 substitution at 2° C(sp3), but little or no elimination occurs in the Mitsunobu reaction. 

Amines. Chiral a-amino acids are obtained from cyanohydrins via a Mitsunobu reaction employing A-f-butoxycarbonyl-A-(2-trimethylsilyl)ethylsulfonamide as the nucleophile. The a-aminonitrile derivatives thus generated are hydrolyzed with acid. By means of an intramolecular displacement (3-hydroxy acids are transformed into (3-amino acids. Thus, subjecting the derived 0-benzylhydroxamides to Mitsunobu reaction conditions leads to (3-lactams which are readily processed (LiOH H, Pd/C). 

An alternative is the attachment of ketones to the solid support via thioacetals. Such a linker has been used in fhe form of an a-lipoic acid for fhe attachment of aryl ketones, which were then subjected to Suzuki and Mitsunobu reactions (Scheme 32) [80]. 

The Mitsunobu reaction has been used by It6 and co-workers as a key step in the synthesis of unnatural (+)-a-skytanthine (184) (196). The chiral amide 210 (197) was subjected to an aza-Claisen rearrangement, and the resulting amide 211 was reduced with LiAlU to afford the amine 212 in 80% yield. A hydroboration-oxidation sequence led to a mixture of amino alcohols 213, which was heated at 100°C for 24 h in the presence of cyanomethylene-trimethylphosphorane (CMMP) to yield a 92 8 mixture of cis- and rrans-fused isomers 214 and 215 in 81% yield from 212. 

Isopropylidene-D-erythrose (104) was treated with Wittig reagent to give the olefin 110. This was subjected to a Mitsunobu reaction to afford the azide intermediate 111, whose intramolecular cycloaddition in refluxing benzene produced the bicyclic iminium ion 112. Treatment of 112 with tm-butylamine gave 113, which upon hydroboration using the modification of Schultz method " afforded the acetonides 48 as a major product in addition to 114 (7%). Aqueous acid hydrolysis of 48 afforded 1 in 39% overall yield from 104. 

The highly substituted 5,6-dihydro-4//-l,3,4-oxadiazine (264 R = Pr") is formed as a by-product (20%) along with benzil monoxime (40%) on subjecting the O-benzylated monoxime of benzoin (PhCH(OH)C(Ph)=NOCH2Ph) to a Mitsunobu reaction (PhjP and diisopropyl azodicarboxylate) <87JOC4978>, Substitution of the diisopropyl by the diethyl ester raises the yield of oxadiazine (264 R = Et) to 50%,... 

Cyclization of the A -Boc derivative of an aminoalcohol mesylate was used in a synthesis of enantiopure 3-hydroxy-4-phenylpiperidine derivatives from i-phenylglycine <04TL987>. Alternatively, such 77-Boc-aminoalcohol derivatives may be subjected to Mitsunobu reaction conditions, as in the preparation of 142, an intermediate in a route to 1-deoxy-D-galactohomonojirimycin <04JOC2229>. 

The Mitsunobu alkylation conditions of 48 also exhibit high chemoselectivity when subjected to reaction with diol 4731 In this example, judicious choice of phosphine and diazo compound dictate which alcohol is activated. Using h-Bu3P in combination with TMAD (TV,N,V, /V -tetramethylazodicarboxamide) gives primarily reaction with the primary alcohol yielding 49. Whereas, Me3P and ADDP (l,l -(azodicarbonyl)-dipiperidide) allow for reaction at the secondary alcohol with another equivalent of 48 giving a fully protected di-amine 50. 

Scheme 9 Santonin (41) was converted to the derivative (99), whose conversion to alcohol (100) by metal hydride reduction and Mitsunobu reaction. Diol (102), prepared from (100), on acid catalysed cyclization and followed by subjection to Mitsunobu reaction, gave (104), which was converted to ketone (106), whose transformation to homoallylic alcohol (108), was achieved by standard organic reactions. Phenylselenylation afforded (110), which was finally converted to phytuberin.

Acetylation of the secondary alcohol and deprotection of the silyl group of the primary alcohol in 59, followed by replacement of the resulting hydroxy group at C-9 with 2-nitrobenzenesulfonamide under Mitsunobu conditions and removal of the acetyl group of the secondary hydroxy group at C-13, afforded sulfonamide 76 (Scheme 14). Compound 76 was subjected to the intramolecular Mitsunobu reaction with di-lcrl-butyl azodicarboxylate (DTAD) and PPhs in THF to give cw-decahydroquinoline 77. 

The total synthesis of ditryptophenaline (651) used stereoisomer 637, which was oxidized (—> 645) and reduced to give diol 646 (Scheme 10.5). Analogous to the previously described synthesis, 646 was subjected to a Mitsunobu reaction and reduction to furnish cyclization product 647. Benzyl deprotection and coupling with a Fmoc-protected W-methyl-(5)-phenylalanine derivative yielded tetrapeptide 648. TMSE-deprotection, two oxidations (—> 650), Fmoc-deprotection, and DCC-mediated cyclization finally led to the natural product ditryptophenaline (651). 

The synthesis of 252 began with Brown s asymmetric crotylation to aldehyde 261. The resulting homoallyl alcohol was converted benzyl ester 262, which was reduced to give lactol acetate 263. Axial allylation to 263 formed 2,6-trans-tetrahydropyran 264, which was subjected to ozonolysis to give an aldehyde. Addition of alkenylzinc, prepared by hydrozircona-tion of an alkyne 265, to the aldehyde mediated by chiral ligand 266 yielded allyl alcohol 267 with a 5.1 1 diastereoselectivity [110]. The stereochemistry of the major isomer was found, unexpectedly, to be the S-form at Cl7, which rendered the macrolactonization to adopt the Mitsunobu reaction. The iodide 252, prepared from 267 in three steps, reacted with... 

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