Mitsunobu Inversion Research Articles

Prins cyclization: new strategy for the stereoselective total synthesis of Polyrhacitide A

A highly stereoselective total synthesis of polyrhacitide A, a polyketide natural product, has been accomplished by means of Prins cyclisation. The key precursor i.e. anti-1,3-diol for polyrhacitide A has been prepared from trans-2,6-disubstituted-3,4-dihydropyrans. In this approach, Prins cyclisation has successfully been utilised twice for the construction of 1,3-diol unit of polyrhacitide A. The key steps involved in this approach are Jacobsen hydrolytic kinetic resolution, Mitsunobu inversion, Prins cyclisation and Ring-closing metathesis (RCM).

Asymmetric total synthesis of diosniponols A and B.

A concise asymmetric total synthesis of diosniponols A and B has been achieved based on an enantioselective Jacobsen kinetic resolution of racemic epoxide and the important 2,3-dihydro-4H-pyran-4-one moiety being installed by the metal-free δ-hydroxyalkynone rearrangement catalyzed by p-TsOH. A diastereoselective catalytic hydrogenation set the required all-syn stereochemistry leading to diosniponol A, which then, under the Mitsunobu inversion conditions, provided diosniponol B. The structure and absolute stereochemistry of the natural products were further confirmed.

Organocatalyzed Protecting-Group-Free Total Synthesis of (S,S)- and (S,R)-Reboxetine, an Antidepressant Drug.

An efficient, simple, and concise organocatalyzed protecting-group-free synthetic approach to the stereoisomers of the antidepressant drug reboxetine and its implementation toward the asymmetric synthesis of (S,S)-reboxetine and (S,R)-reboxetine from commercially available trans-cinnamaldehyde are described. The synthesis features organocatalytic Jørgensen asymmetric epoxidation, epoxide migration, and Mitsunobu inversion as key steps.

Practical access to (S)-heterocyclic aromatic acetates via CAL-B/Na2CO3-deacylation and Mitsunobu reaction protocol

Herein, we report the preparation of enantiomerically pure forms of 2,3-dihydrobenzofuran-3-ol (1), chroman-4-ol (2), thiochroman-4-ol (3), 1-(furan-2-yl) ethanol (5) and 1-(thiophen-2-yl) ethanol (6), through a kinetic resolution catalysed by Candida antarctica lipase B/Na2CO3 hydrolysis sequence in organic media. The (R)-furnished alcohols and the (S)-remained acetates are recovered enantiopures (ee >99%, E ≫ 200, Conv = 50%). Those ideal enzymatic kinetic resolution (EKRs) are well incorporated to the Mitsunobu inversion protocol in a one pot procedure to give (S)-heterocyclic acetates (1a–3a) in good to high enantiomeric excess (88%–92% ee). Whilst, the (S)-heteroaromatic acetates (5a and 6a) are given with moderate enantiomeric excess (51%–62% ee). All the (S)-acetates are given in good isolated chemical yields (>80%) allowing to overcome the maximum of 50% yield which could be usually reached in a regular kinetic resolution processes.

Synthesis of ω‐Muricholic Acid by One‐Pot Enzymatic Mitsunobu Inversion using Hydroxysteroid Dehydrogenases

AbstractThe biocatalyzed conversion of hyocholic acid (3α,6α,7α‐trihydroxy‐5β‐cholan‐24‐oic acid) into ω‐muricholic acid (3α,6α,7β‐trihydroxy‐5β‐cholan‐24‐oic acid) has been obtained exploiting a small library of 7α‐ and 7β‐HSDHs (hydroxysteroid dehydrogenases). The process has been optimized and performed avoiding the isolation of the 7‐oxo intermediate using the appropriate coupled enzymes for the in situ cofactor regeneration. Moreover, the biocatalyzed reduction of 6,7‐dioxolithocholic acid (3α‐hydroxy‐6,7‐dioxo‐5β‐cholan‐24‐oic acid) was also investigated.

A Protecting-Group-Free Synthesis of (-)-Salvinorin A.

A concise enantioselective total synthesis of the neoclerodane diterpene (−)‐salvinorin A is reported. The stereogenic center at C‐12 was installed by catalytic asymmetric propargylation with excellent enantioselectivity, and the remaining six stereogenic centers were set up highly diastereoselectively under substrate control. As for our previous synthesis of racemic salvinorin A, two intramolecular Diels‐Alder reactions were applied to generate the tricyclic core. A chemoselective Mitsunobu inversion of a syn 1,2‐diol allowed for further streamlining of the original reaction sequence by two steps. Overall, (−)‐salvinorin A was synthesized in only 16 steps starting from 3‐furaldehyde with 1.4 % total yield. Furthermore, an alternative intramolecular Diels‐Alder strategy employing a 2‐bromo‐1,3‐diene moiety was investigated.

Development of a robust immobilized organocatalyst for the redox-neutral mitsunobu reaction

An immobilized, recyclable (2-hydroxybenzyl)diphenylphosphine oxide analogue has been synthesized and used in the redox-neutral Mitsunobu inversion of secondary alcohols with nitro substituted benzoic acids (up to 97% yield and 98% specificity).

Synthesis of Isotopically Labelled Disparlure Enantiomers and Application to the Study of Enantiomer Discrimination in Gypsy Moth Pheromone‐Binding Proteins

To study the binding mechanism of disparlure (7,8)‐epoxy‐2‐methyloctadecane enantiomers with pheromone‐binding proteins (PBPs) of the gypsy moth, oxygen‐17 or 18 and 5,5,6,6‐deuterium labelled disparlure enantiomers were prepared in an efficient, enantioselective route. Key steps involve the asymmetric α‐chlorination of dodecanal by SOMO catalysis and Mitsunobu inversion of a 1,2‐chlorohydrin. The pheromone, (+)‐disparlure (7R, 8S), was tested in two infested zones, demonstrating that it is very attractive towards male gypsy moths. Studies of the binding of (+)‐disparlure and its antipode to gypsy moth PBPs by 2H &17O NMR at 600 MHz are reported. Chemical shifts, spin‐lattice relaxation decay times (T1) and transverse relaxation decay times (T2) of deuterium atoms of disparlure enantiomers in 2H NMR show that the binding of disparlure enantiomers to PBP1 differs from binding to PBP2, as expected from their opposite binding preferences (PBP1 binds (–)‐disparlure, and PBP2 binds (+)‐disparlure more strongly). Models of the disparlure enantiomers bound to one internal binding site and two external binding sites of both PBPs were constructed. The observed chemical shift changes of deuterated ligand signals, from non‐bound to bound, T1 and T2 values are correlated with results from the simulations. Together these results suggest that the disparlure enantiomers adopt distinct conformations within the binding sites of the two PBPs and interact with residues that line the sites.

Asymmetric total synthesis of filamentous fungi related resorcylic acid lactones 7-epi-zeaenol and zeaenol

AbstractAn efficient, short and, a convenient asymmetric total synthesis of filamentous fungi related resorcylic acid lactones 7-epi-zeaenol (2) and zeaenol (1) have been achieved in 7 and 9 linear steps with the high overall yield of 32% and 21% respectively, from the known intermediate 13. Mitsunobu inversion, De Brabander’s protocol for macrolactonisation, Heck cross-coupling, diastereoselective alkyne aldehyde coupling and Ohira–Bestmann alkynylation are the key reactions.

Scalable synthesis of cladosporin

Cladosporin, a secondary metabolite isolated from fungal sources like Cladosporium cladosporioides and Aspergillus flavus was found to exhibit selective nano-molar activity against malarial parasite Plasmodium falciparum by inhibiting parasitic protein biosynthesis. In addition, this natural product has a broad range of bioactivities including, antiparasitic, antifungal, antibacterial as well as plant growth inhibition. However, it has limited availability from the natural sources for further development. Herein, we report a modified and improved synthetic route which led us to produce this potent natural product in a gram scale. Conversion of the undesired diastereomer to desired one via Mitsunobu inversion of secondary alcohol and carbon monoxide insertion reaction towards the construction of isocoumarin unit are the key features of the present synthesis.

Stereoinversion of R‐Configured Secondary Alcohols Using a Single Enzymatic Approach

AbstractHere, we achieved a single‐enzymatic stereoinversion of R‐configured alcohols to their corresponding S enantiomers in high percent conversion and high enantioselectivity. A single mutant of Thermoanaerobacter pseudoethanolicus secondary alcohol dehydrogenase (TeSADH) oxidized R alcohols to their corresponding ketones under conditions that allow selectivity mistakes and then reduced them under stereoselective conditions to generate the corresponding S‐configured alcohols. The success of this stereoinversion relies on controlling the stereoselectivity of the oxidation and the reduction reactions by varying the amounts of acetone and 2‐propanol, respectively. Furthermore, the deployment of the TeSADH mutants W110A and W110G led to stereoinversion of enantiopure R alcohols to their S enantiomers in medium to high enantiomeric excess (up to >99% ee). The disclosed approach of single enzymatic stereoinversion presents a biocatalytic alternative to Mitsunobu inversion reaction.

Isolation, Synthesis, and Semisynthesis of Amaryllidaceae Constituents from Narcissus and Galanthus sp.: De Novo Total Synthesis of 2- epi-Narciclasine.

An efficient protocol for the isolation of narciclasine from common Amaryllidaceae bulbs, separation from haemanthamine, and the occurrence of a trace alkaloid, 2- epi-narciclasine, are reported. Attempts to convert natural narciclasine to its C-2 epimer by Mitsunobu inversion or oxidation/reduction sequences were compromised by rearrangement and aromatization processes, through which a synthesis of the alkaloid narciprimine was achieved. The methylation of the 7-hydroxy group of natural narciclasine followed by protection of the 3,4-diol function and oxidation/reduction sequence provided the target C-2 epimer. A de novo chemoenzymatic synthesis of 2- epi-narciclasine from m-dibromobenzene is also described. Haemanthamine and narciprimine were readily detected in the crude extracts of Narcissus and Galanthus bulbs containing narciclasine, and the occurrence of 2- epi-narciclasine as a trace natural product in Galanthus sp. is reported for the first time.

Total Synthesis of the Polyoxygenated Sesquiterpenes Guignarderemophilanes C and D

The total syntheses of the neural anti‐inflammatory agents guignarderemophilanes C and D have been accomplished for the first time starting from γ‐hydroxy carvone in 15 and 14 steps, respectively. The presented synthetic route proceeds via a known intermediate, whose synthesis has been elaborated in our group in the course of the total synthesis of the sesquiterpenoid periconianone A. Key for the successful conversion of this intermediate into both targets was finding a suitable strategy to install the 1,2,3‐trihydroxylated A‐ring scaffold. For this purpose, we effectively employed a Mitsunobu inversion, epoxidation, and regioselective epoxide opening sequence, before the bicyclic ring system was constructed by an aldol condensation reaction on a sterically demanding substrate. Our reported synthesis set the stage for SAR studies to prepare even more potent compounds by modification and derivatization of the natural product's scaffold.

Stereodefined synthesis of the four possible stereoisomers of 5,18-diHETE

Because of the structural similarity between 5,18-diHETE and anti-inflammatory resolvin E2, synthesis of 5,18-diHETE was studied. Methyl (R)-3-hydroxyvalerate was converted to the (R)-C9–C20 phosphonium salt via alkylation of the derived iodide with propargyl alcohol dianion and subsequent Castro-Stephens coupling. The (S)-enantiomer was prepared via Mitsunobu inversion. The (R)- and (S)-enantiomers of the γ-TMS-propargylic alcohol corresponding to the C1–C7 part were constructed by asymmetric hydrogen transfer reaction and converted to the (R)- and (S)-enals by adding the aldehyde carbon using the reaction of the derived TMS-epoxide with Et2AlCN followed by hydride reduction. The (R)-enantiomer of the C1–C8 enal was coupled with the (R)-C9–C20 phosphonium salt by Wittig reaction, and the functional group in the product was transformed to afford 5R,18R-diHETE stereoselectively. Other stereoisomers were synthesized as well.

Bidirectional Synthesis of 6-Acetoxy-5-hexadecanolide, the Mosquito Oviposition Pheromone of Culex quinquefasciatus, from a C2-Symmetric Building Block Using Olefin Metathesis Reactions.

(5R,6S)-6-Acetoxy-5-hexadecanolide (MOP) is the oviposition pheromone of the mosquito Cx. quinquefasciatus, a vector of pathogens causing a variety of tropical diseases. We describe and evaluate herein three syntheses of MOP starting from mannitol-derived (3R,4R)-hexa-1,5-diene-3,4-diol. This C2-symmetric building block is elaborated through bidirectional olefin metathesis reactions into 6-epi-MOP, which was converted into MOP via Mitsunobu inversion. The shortest of the three routes makes use of two sequential cross-metathesis reactions and an assisted tandem catalytic olefin reduction, induced by an in situ conversion of a Ru-carbene to a Ru-hydride.

Stereoselective Total Synthesis of Macrophage-Produced Prohealing 14,21-Dihydroxy Docosahexaenoic Acids.

Synthesis of 14S,21R- and 14S,21S-dihydroxy-DHA (diHDHA) among the four possible stereoisomers of 14,21-diHDHA was studied. Methyl (R)-lactate (>97% ee), selected as a C20-C22 fragment (DHA numbering), was converted to the C17-C22 phosphonium salt, which was subjected to a Wittig reaction with racemic C16-aldehyde of the C12-C16 part with the TMS and TBS-oxy groups at C12 and C14, yielding the C12-C22 derivative with 14R/S and 21R chirality. Kinetic resolution using Sharpless asymmetric epoxidation of the TBS-deprotected allylic alcohol with l-(+)-DIPT/Ti(O-i-Pr)4 afforded 14S-epoxy alcohol and 14R-allylic alcohol with >99% diastereomeric excess (de) for both. The CN group was introduced to the epoxy alcohol by reaction with Et2AlCN. The 14R-allylic alcohol was also converted to the nitrile via Mitsunobu inversion. Reduction of the nitrile with DIBAL afforded the key aldehyde corresponding to the C11-C22 moiety. The Wittig reaction of this aldehyde with a phosphonium salt of the remaining C1-C10 part followed by functional group manipulation gave 14S,21R-diHDHA. Similarly, ethyl (S)-lactate (>99% ee) was converted to 14S,21S-diHDHA. The chiral LC-UV-MS/MS analysis demonstrated that each of these two 14,21-diHDHAs synthesized using the presented total organic synthesis was highly stereoselective and identical to the macrophage-produced counterpart.

Stereoselective Synthesis and Evaluation of C6″-Substituted 5a-Carbasugar Analogues of SL0101 as Inhibitors of RSK1/2.

A convergent synthesis of 5a-carbasugar analogues of the n-Pr-variant of SL0101 is described. The analogues were synthesized in an effort to find compounds with potent in vivo efficacy in the inhibition of p90 ribosomal s6 kinase (RSK1/2). The synthesis derived the desired C-4 L-rhamnose stereochemistry from quinic acid and used a highly selective cuprate addition, NaBH4 reduction, Mitsunobu inversion, and alkene dihydroxylation to install the remaining stereochemistry. A Pd-catalyzed cyclitolization stereoselectively installed the aglycon at the anomeric position. The analogues were evaluated as RSK1/2 inhibitors and found to have 3- to 6-fold improved activity.

A new and expeditious synthesis of all enantiomerically pure stereoisomers of rosaprostol, an antiulcer drug.

Four enantiomerically pure stereoisomers of rosaprostol (1), an antiulcer drug, were efficiently synthesized from the enantiomers of 2-(dimethoxyphosphoryl)-3-hexylcyclopentanone (3) as chiral substrates. The latter were obtained by resolution of racemic 3 with (+)-(R)-1-(1-naphthyl)ethylamine. The conversion of (+)-3 into rosaprostol stereoisomer (−)-1a was accomplished in four steps in 56% overall yield. According to the same protocol, the second stereoisomer (+)-1c was obtained from (−)-3 in 55% overall yield. A slightly improved procedure of the last two steps of the transformation of (+)-3 into (−)-1a allowed an increase in the overall yield to 64%. The remaining two stereoisomers, (−)-1b and (+)-1d, were obtained from (−)-1a and (+)-1c in 71 and 68% yield, respectively, by a two-reaction sequence, in which a Mitsunobu inversion of configuration at C-5 was the key step.

Stereoselective total synthesis of sphingolipids

A novel sphingosine, 1,2-diacetyl D-erythro-sphinganine having a characteristic almond flavour was isolated from the edible mushroom Grifola gargal. We have synthesized this sphinganine along with the three other sphingolipids, such as 1,2-diacetyl L-threo-sphinganine, D-erythro-sphinganine triacetate and L-threo-sphinganine triacetate using Garner aldehyde as the starting material involving the Grignard reaction and Mitsunobu inversion. The sphingolipids 1,2-diacetyl D-erythro-sphinganine and 1,2-diacetyl L-threo-sphinganine have been synthesized for the first time.

Stereoselective synthesis of (+)-decarestrictine L using tandem isomerization followed by C–O and C–C bond formation reaction

A stereoselective synthesis of the (+)-decarestrictine L has been described following our own developed iodine-catalyzed tandem isomerization followed by C–O and C–C bond formation reaction for the construction of trans-2,6-disubstituted dihydropyran as the key step. Other important reactions used for this synthesis are 5-exo-trig-iodolactonization, Mitsunobu inversion, and Wacker’s oxidation. The total synthesis of the target molecule was achieved in 10 linear steps with 28% overall yield.