Mitsunobu Reaction Conditions Research Articles

A benzyloxy group migration under Mitsunobu reaction conditions

When compounds 3a and 3b were subjected to a Mitsunobu reaction with benzoylthymine, the expected substitution products were formed together with the regioisomers corresponding to benzyloxy group migrations.

Synthesis of Acyclic Nitroazole Nucleosides and Their Incorporation into Oligonucleotides, and Their Duplex and Triplex Formation

AbstractAcyclic nucleosides of 4‐nitro‐1H‐imidazole and 4‐nitropyrazole have been synthesized by nucleophilic addition of the appropriate 4‐nitroazole to (−)‐(S)‐(hydroxymethyl)oxirane in the presence of a catalytic amount of potassium carbonate. (+)‐(R)‐3‐(4‐nitro‐1H‐imidazol‐1‐yl)propane‐1,2‐diol and (+)‐(R)‐3‐(2‐methyl‐4‐nitro‐1H‐imidazol‐1‐yl)propane‐1,2‐diol were also obtained in an independent reaction starting from appropriate 1,4‐dinitro‐1H‐imidazole and (+)‐(R)‐3‐aminopropane‐1,2‐diol. (+)‐(R)‐3‐(4‐Nitropyrazol‐1‐yl)propane‐1,2‐diol was also obtained by direct noncatalyzed addition of 4‐nitropyrazole to (−)‐(S)‐(hydroxymethyl)oxirane, whereas the (S)‐enantiomer was obtained by reaction of 4‐nitropyrazole with (+)‐(S)‐1,2‐O‐isopropylideneglycerol under Mitsunobu reaction conditions, followed by a cleavage of the isopropylidene group with 80% AcOH. Racemization during any of these syntheses has not been observed. 3‐(4‐Nitroazol‐1‐yl)propane‐1,2‐diols were incorporated into a 26‐mer oligonucleotide. UV Thermal melting studies of duplexes of the oligonucleotides with 4‐nitropyrazole or 4‐nitro‐1H‐imidazole paired with four natural bases showed moderately decreased stabilities of the duplexes. A narrow range of melting temperatures, typically being within 2° for each acyclic nucleoside, fulfill one of the requirements of using acyclic 4‐nitroazoles as general bases. Single incorporation of 4‐nitroazoles into a 14‐mer triplex forming oligonucleotide resulted in considerably decreased triplex stabilities.

Efficient synthesis of novel cytotoxic cis-fused α-methylene γ-lactones from 7,14-dihydroxy-ent-kaurenes by transformation under Mitsunobu reaction conditions

Facile transformation of 7,14-dihydroxy-ent-kaurenes such as excisanin A (8), kamebanin (9), and kamebakaurin (10), which are abundant in plants of the genus Rabdosia species (Labiatae), to ent-abietanes was accomplished under the Mitsunobu reaction conditions. The δ, ε-unsaturated cis-fused α-methylene γ-lactones (17, 18, and 25) thus prepared showed a moderate cytotoxic activity on P388 murine leukemia cells.

Synthesis of rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol. An unusual double rearrangement leading to the ortho- and para-f oxide-bridged phenylmorphan isomers.

In an attempt to obtain the para-f isomer, rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol, via mesylation of an intermediate 9[small alpha]-hydroxyphenylmorphan, we obtained, instead, a rearranged chloro compound with a 5-membered nitrogen ring, 7-chloro-3a-(2,5-dimethoxyphenyl)-1-methyl-octahydroindole. This indole underwent a second rearrangement to give us the desired para-f isomer. The structures of the intermediate indole and the final product were unequivocally established by X-ray crystallography. A resynthesis of the known rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-8-ol, the ortho-f isomer, was achieved using the reaction conditions for the para-f isomer, as well as under Mitsunobu reaction conditions where, unusually, the oxide-bridge ring in the 5-phenylmorphan was closed to obtain the desired product. The synthesis of the para-f isomer adds an additional compound to those oxide-bridged phenylmorphans that were initially visualized and synthesized; the establishment of the structure and configuration of 8 of the theoretically possible 12 racemates has now been achieved. The X-ray crystallographic structure analysis of the para-f isomer provides essential data that will be needed to establish the configuration of a ligand necessary to interact with an opioid receptor.

Total synthesis of trioxilins 11,12- threo-(8,11,12)-A 3 through type B 3 trioxilins

The total synthesis of trioxilins 11,12-threo-TrXB3 has been extended to the corresponding trioxilins of the (8,11,12)-A3 type. The synthesis involves the allylic rearrangement of a protected TrXB3 derivative with a free 10-hydroxyl group under the Mitsunobu reaction conditions as the key step.

The Synthesis of Azapeptidomimetic β‐Lactam Molecules as Potential Protease Inhibitors.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Flexible Routes to the 5‐Hydroxy Acid Fragment of the Cryptophycins

AbstractTwo solutions to establishing the anti stereochemistry of the vicinal stereocenters in the 5‐hydroxy acid subunit of cryptophycin, based on initial Evans syn aldol reactions between an N‐(propionyl)oxazolidinone 4 and a C3 aldehyde, were developed. In the first route, the secondary hydroxy group was inverted by use of Mitsunobu reaction conditions, whereas the second route features an inversion of the methyl‐bearing stereocenter, achieved by reductive removal of the chiral auxiliary, elimination to afford the terminal alkene, and anti‐selective hydroboration. The aryl part can be attached either by Wittig−Horner olefination or by a modified Julia coupling. Both routes provide the hydroxy acid 16 in a very efficient manner. The substrate for the hydroboration, alkene 22, could also be obtained from (S)‐malic acid. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Synthesis of new arylalkoxy amido derivatives as melatoninergic ligands

Amido derivatives 10– 18 of the corresponding oxyamines were synthesised as melatoninergic ligands by the reaction of hydroxyphtalimide with the halogeno derivatives or the corresponding alcohols using Mitsunobu reaction conditions. The affinity of the compounds for chicken brain melatonin receptors and recombinant human MT 1 and MT 2 receptors was evaluated using 2-[ 125I]-iodomelatonin as the radioligand. Overall, the introduction of an oxygen atom in the amido chain was not a favourable parameter as the compounds were less potent than the corresponding deoxy derivatives. However, nanomolar compounds were obtained with the arylethyloxy derivatives ( 13c (R′=nPr), chicken brain, hMT 1, hMT 2, K i values: 4.8, 3.86, 2.4 nM, respectively) and the 2,7-dimethoxynaphthalene derivatives ( 17c (R′=nPr), chicken brain, hMT 1, hMT 2, K i values: 0.04, 0.13, 0.1 nM, respectively). The functional activity of these compounds was evaluated by the aggregation of melanophores in Xenopus laevis tadpoles and the potency was related to the affinity of the molecules for melatonin receptors. The compounds were found to be full agonists and compound 17a was 20-fold more potent than melatonin in this bioassay.

Total Synthesis of Batzelladine D.

[structure: see text] Stereoselective total synthesis of batzelladine D was accomplished in 15 steps. This synthesis features (i) successive 1,3-dipolar cycloaddition reactions to form the 2,5-disubstituted pyrrolidine ring system, (ii) esterification of the side chain to the bicyclic guanidine carboxylate, a common synthetic intermediate of batzelladine alkaloids, and (iii) tricyclic guanidine formation under the Mitsunobu reaction conditions.

The synthesis of azapeptidomimetic beta-lactam molecules as potential protease inhibitors.

Synthetic methods for the construction of a novel peptidomimetic structure are reported. The structure incorporates a beta-lactam and an azapeptide in a peptide backbone with the intention of generating rationally designed substrate-based protease inhibitors. The beta-lactam is formed by subjecting serine or threonine-azapeptides to Mitsunobu reaction conditions. Importantly, the azapeptidomimetic beta-lactam structure permits extended binding inhibition and the synthetic methods to create tetrapeptidomimetic structures are described.

Total synthesis of batzelladine D.

[structure: see text] Stereoselective total synthesis of batzelladine D was accomplished in 15 steps. This synthesis features (i) successive 1,3-dipolar cycloaddition reactions to form the 2,5-disubstituted pyrrolidine ring system, (ii) esterification of the side chain to the bicyclic guanidine carboxylate, a common synthetic intermediate of batzelladine alkaloids, and (iii) tricyclic guanidine formation under the Mitsunobu reaction conditions.

Facile synthesis of maleimide bifunctional linkers

The synthesis of maleimide containing derivatives capable of serving as linkers for the conjugation of proteins is described. These compounds differ from previously reported linkers by having multiple sites available for drug attachment. Compounds 3a , 3b , and 3d were synthesized from the corresponding amino alcohols by the addition of two equivalents of t-butyl bromoacetate to a series of amino alcohols followed by the introduction of the maleimide under Mitsunobu reaction conditions and ester hydrolysis.

N-Alkylation of 1 H-indoles and 9 H-carbazoles with alcohols

A comparative study of N-alkylation of 1 H-indole and 9 H-carbazole derivatives with alcohol derivatives was performed using classic Mitsunobu reaction conditions, i.e. DEAD/PPh 3, azodicarboxamide derivatives such as TMAD in the presence of PBu 3, or using phosphorane derivatives such as CMMP.

Enantioselective reaction of secondary alcohols with phthalimide in the presence of a chiral tri-coordinate phosphorus reagent in Mitsunobu reaction

The enantioselective reaction of racemic secondary alcohols with phthalimide has been carried out in the presence of a chiral cyclic phosphoramidite (+)- 1/DEAD under Mitsunobu reaction conditions. Phthalimide reacted preferentially with the (−)-enantiomer of the alcohol to give a substituted imide (+)- 2, while the unreacted enantiomeric alcohol, (+)- 3 was obtained in enantiomerically enriched form. Compound (+)- 2 was further treated with hydrazine hydrate to form the product amine, (+)- 4.

Efficient Synthesis of Medium-Sized Cyclic Amines by Means of 2-Nitrobenzenesulfonamide

Construction of medium-sized cyclic amines using 2-nitrobenzenesulfonamides is described. Under either conventional alkylation or Mitsunobu reaction conditions, the cyclization reaction proceeded efficiently to give eight- to ten-membered rings.

Synthesis of functionalised enantiopure steroids from estrone and cholestanone through organolithium intermediates

The reaction of epoxides 1 and 8 derived from estrone and cholestanone, respectively, with an excess of lithium and a catalytic amount of DTBB (7 mol%) in THF at −78°C led to formation of the corresponding β-oxido-functionalised organolithium intermediates 2 and 9, respectively, in a regio- and stereoselective manner. Treatment of these intermediates with different electrophiles [H 2O, D 2O, PhCHO, Me 2CO, Et 2CO, (CH 2) 5CO, CO 2] at −78 to 20°C afforded, after hydrolysis with water, enantiomerically pure derivatives 3 and 10, respectively. When protected ketones 5 and 6 derived from d-glucose and d-fructose were used as the electrophile, the reaction with 2 gave the expected mixed products 3g and 3h, respectively, which consist of a steroid and a carbohydrate fragment. The reaction of O-protected estrone 4 as the electrophilic component and intermediate 2 afforded the C 2-symmetric steroid dimer 3f. The stereochemistry of the products was unambiguously determined by correlation with X-ray data for compound 3d and by comparison with the known compound 6a. Finally, the addition of the dianions 13, resulting from the DTBB-catalysed lithiation of phthalan 12a and isochroman 12b, to the O-protected estrone 4 and to cholestanone 9 led to the formation of the diols 14, 15 and 16. Diols 14 were cyclised under Mitsunobu reaction conditions to the corresponding heterocycles 17.

Novel rearrangement of an isocaryolane sesquiterpenoid under mitsunobu conditions

Under modified Mitsunobu reaction conditions, a novel skeleton rearrangement of terpenes has been obtained. The reactivity of 8, 9-dioxygenated isocaryolane derivatives has been investigated. When either (8R,9R)-8-methoxyisocaryolane-9-ol (7) or (8R, 9R)-isocaryolane-8,9-diol (10) are treated under acidic conditions, isocaryolan-9-one (9) and the rearrangement compound (1S,2S,5R,8S)-1, 4,4-trimethyltricyclo[6.2.1.0(2,5)]undecane-8-carbaldehyde (11) are obtained. Otherwise treatment of compounds 7 and 10 under modified Mitsunobu conditions leads to the novel sesquiterpene derivative (1S, 2S,5R,9R)-1,4,4-trimethyltricyclo[7.2.1.0(2,5)]dodecan-8-one (8). This is the first example, to our knowledge, of a Mitsunobu-induced pinacol rearrangement. The influences of the substrate and reaction conditions on the evolution of the reaction are both explored. This modification of the Mitsunobu reaction conditions introduces a new, one-pot, procedure for preparing this class of rearrangement product.

ChemInform Abstract: An Unexpected Rearrangement During Mitsunobu Epimerization Reaction of Sugar Derivatives.

Mitsunobu reaction on the glucose derivative (3S,4R,5R,6R)-3,4,5,7-tetrabenzyloxy-6-hydroxy-1-heptene yielded an unexpected rearrangement major product. Its structure was determined as (3R,4R,5R,6S)-4,5,6,7-tetrabenzyloxy-3-hydroxy-1-heptene. The suggested rearrangement mechanism involves an initial intramolecular cyclization, followed by ring opening by the nucleophile p-nitrobenzoate. Product distribution of the Mitsunobu reaction was substrate-dependent, with the corresponding mannose derivative (the 3R epimer) giving less of the initial intramolecular reaction products and the corresponding galactose derivative (the 5S epimer) yielding almost exclusively the expected epimerization product. Varying the Mitsunobu reaction conditions (addition of base and using nonpolar solvent) led to the expected epimerization product of the glucose derivative.

An unexpected rearrangement during mitsunobu epimerization reaction of sugar derivatives

Mitsunobu reaction on the glucose derivative (3S,4R,5R,6R)-3,4,5, 7-tetrabenzyloxy-6-hydroxy-1-heptene yielded an unexpected rearrangement major product. Its structure was determined as (3R,4R, 5R,6S)-4,5,6,7-tetrabenzyloxy-3-hydroxy-1-heptene. The suggested rearrangement mechanism involves an initial intramolecular cyclization, followed by ring opening by the nucleophile p-nitrobenzoate. Product distribution of the Mitsunobu reaction was substrate-dependent, with the corresponding mannose derivative (the 3R epimer) giving less of the initial intramolecular reaction products and the corresponding galactose derivative (the 5S epimer) yielding almost exclusively the expected epimerization product. Varying the Mitsunobu reaction conditions (addition of base and using nonpolar solvent) led to the expected epimerization product of the glucose derivative.

Structural modification of carbohydrates via functionalised organolithium intermediates: EPC preparation of branched-chain functionalised sugars

The reductive opening of epoxides 1, 9, 13 derived from d-glucose and 18 derived from d-fructose using lithium and a catalytic amount of 4,4′-di- tert-butylbiphenyl (DTBB) in THF at −78°C allows the formation of β-oxido organolithium derivatives ( 2, 10, 14 and 19), which, by reaction with different electrophiles [H 2O, D 2O, Me 3SiCl, PhCHO, Me 2CO, Et 2CO, (CH 2) 5CO, CO 2] at the same temperature yields, after hydrolysis with water, the expected branched-chain functionalised carbohydrates. An alternative route for compound 11, derived from the epoxide 9, consists of the deprotonation of the chlorohydrin 12 followed by the same protocol of lithiation-reaction with an electrophile. The application of this methodology to the oxetane 4 allows compound 6 to be obtained through the corresponding γ-functionalised organolithium intermediates 5. Finally, the addition of the dianions 25 (resulting from the DTBB-catalysed lithiation of phthalan and isochroman) to the ketones 8 and 23, derived from d-glucose and d-fructose, respectively, allowed the stereoselective functionalisation at the 3-position of the sugars, giving the corresponding diols 26 and 27, which can cyclise to the corresponding heterocycles 28 and 29, respectively, under Mitsunobu reaction conditions.