Luche Reduction Research Articles

Continuous Flow Process for Carbonyl and α,β-Unsaturated Carbonyl Compounds Reduction Using NaBH4 Solutions: Toward Implementation of Luche Reduction in Flow

Continuous Flow Process for Carbonyl and α,β-Unsaturated Carbonyl Compounds Reduction Using NaBH₄ Solutions: Toward Implementation of Luche Reduction in Flow

Asymmetric Total Synthesis of Cryptorigidifoliol I.

An efficient asymmetric total synthesis of cryptorigidifoliol I based on an unusual Luche reduction leading to bicyclic etherification and acid hydrolysis to a thermodynamically less stable 4-hydroxy-2,6-trans-disubstituted-THP moiety has been achieved. The easy setup of trans-2,6-substitution on the core pyran ring through bicyclic etherification would enable the synthesis of various THP and bicyclic-THP-lactone natural products.

Unanticipated Bicyclic Etherification in Luche Reduction: Asymmetric Total Syntheses of Diospongins A and B and Tetraketide.

In the synthesis of diospongin B based on rearrangement of δ-hydroxyalkynone to 2,3-dihydro-4H-pyran-4-one, we discovered an unanticipated beguiling reaction giving a thermodynamically less stable 4-hydroxy-2,6-trans-disubstituted-THP moiety via bicyclic etherification under Luche reduction conditions and simple acid hydrolysis. The practical applicability of this method is exemplified by the asymmetric total syntheses of diospongins A and B, several analogues, and tetraketide.

Two Total Syntheses of Trigoxyphins K and L.

Two total syntheses are presented for trigoxyphins K and L, tricyclic terpenoids from Trigonostemon xyphophylloides. The first proceeds via electrophlic cyclization in A/C-ring substrates to close the B ring at C4-C5 and then 1O2-mediated hydroxybutenolide formation to trigoxyphin L, with Luche reduction leading to trigoxyphin K. The second route develops from tetralone ring expansion to a B/C-ring intermediate that, by one-step O-demethylation-lactonization-isomerization, affords trigoxyphin K and then trigoxyphin L following enolate oxygenation.

Unified Divergent Total Synthesis of Discorhabdin B, H, K, and Aleutianamine via the Late-Stage Oxidative N,S-Acetal Formation.

This study achieved the total syntheses of (+)-discorhabdin B, (-)-discorhabdin H, (+)-discorhabdin K, and (-)-aleutianamine. A phenethylamine fragment bearing a o-pivaloylthio group, corresponding to the D/E/G ring moiety, was prepared from benzothiophen-2-carboxylic acid methyl ester and condensed with a known pyrroloiminoquinone derivative. The adduct was subjected to [bis(trifluoroacetoxy)iodo]benzene (PIFA)-promoted oxidative spirocyclization to furnish the A/B/C/D/E spirocyclohexadienone fused with pyrroloiminoquinone. The total synthesis of (±)-discorhabdin B was completed via the key construction of the highly strained G ring with the N,S-acetal moiety featuring a newly developed CuBr2-mediated oxidative cascade cyclization. The stereocontrolled total synthesis of (+)-discorhabdin B was accomplished by a diastereoselective PIFA-promoted oxidative spirocyclization using a chiral thioester. (-)-Disocrhabdin H and (+)-discorhabdin K were synthesized by the site- and face-selective thia-Michael addition of l-ovothiol A to (+)-N-Ts-discorhabdin B with the concomitant formation of the F ring by forming the C2-N18 bond. The total synthesis of (-)-aleutianamine was achieved via a skeletal rearrangement initiated by the Luche reduction of the dienone moiety of (+)-N-Ts-discorhabdin B.

Synthesis of (±)-Ingenol

Key words (±)-ingenol - De Mayo reaction - Corey–Posner–Whitesides–House reaction - Upjohn Dihydroxylation - Dess–Martin oxidation - Luche reduction

Synthesis of highly deuterated coniferyl alcohol for silencing of NMR signals in the resulting dehydrogenative polymer

To establish a facile methodology for the elucidation of the lignin chain-growth mechanism, the preparation of monolignol that does not show NMR signals in the dehydrogenative polymer (DHP) was attempted. As a monolignol of which aliphatic moieties were deuterated, coniferyl alcohol-d7 was successfully synthesized from protocatechualdehyde and malonic acid via the modified Knoevenagel–Doebner reaction and the Luche reduction. The process achieved high to excellent deuteration efficiencies at the aimed positions (i.e., methoxy: > 99%D, α: > 99%D, β: 92%D, and γ: 98%D). DHP was prepared solely from coniferyl alcohol-d7, and its NMR spectra were compared with those from coniferyl alcohol. The results indicated that: (1) the deuterium atoms at methoxy group, α- and β-positions were highly retained even in the DHP, and their signals were effectively suppressed; (2) a part of the deuterium at γ-position was replaced with H through the reaction; (3) meanwhile, the formation of γ-CH2 was negligible. This study demonstrated that coniferyl alcohol-d7 could “silence” the majority of the signals even when converted to DHP. Highly deuterated monolignols can be a unique molecular tool that can differentiate the signals of interest from those derived from monolignols.

Synthesis of Immucillins BCX‐1777 and BCX‐4430 from a Common Precursor

AbstractA convergent route for the synthesis of BCX‐1777 and BCX‐4430 from a Boc‐protected 2‐pyrrolidinone, derived from 2,3,5‐tri‐O‐benzyl‐d‐ribonolactone, and a dihalogenated pyrrolopyrimidine as the key starting materials is reported. A chemoselective cross‐coupling was achieved from the two key starting materials in 79 % yield. Luche reduction and mesylation resulted in the stereoselective formation of an advanced intermediate in 77 % yield over two steps, which served as a precursor for synthesizing BCX‐1777 and BCX‐4430 in 38 % (over 10 steps) and 32 % (over 11 steps) overall yields, respectively, from 2,3,5‐tri‐O‐benzyl‐d‐ribonolactone.

Stereoselective Total Synthesis of (±)-Pleurospiroketals A and B.

A full account of our efforts toward the stereoselective total synthesis of sesquiterpenoid-derived natural products (±)-pleurospiroketals A and B is described. Commercially available 3-methyl-2-cyclohexenone and 2,2-dimethyloxirane were used as key building blocks, and the substrate-controlled stereoselection was exploited to access the entire stereochemistry of these natural products. Initially, a planned synthetic route involving a [6,5]-bicyclic lactone intermediate was found to be insurmountable, and the later strategy comprising OsO4-NMO-mediated dihydroxylation of 3-methyl-2-cyclohexenone, followed by Luche reduction, Eschenmoser methylenation, and Brønsted acid-induced spiroketalization steps, was ultimately identified as the reliable strategy.

Selective synthesis of the two main progesterone metabolites, 3α-hydroxy-5α-pregnanolone (allopregnanolone) and 3α-hydroxypregn-4-en-20-one, and an assessment of their effect on proliferation of hormone-dependent human breast cancer cells

A directed synthesis of two progesterone metabolites, allopregnanolone and 3a-hydroxy-pregn-4-en-20-one, from Δ16-pregnanolone and progesterone, respectively, was carried out by a reduction of the carbonyl groups in positions 3 and subsequent inversion of the configuration of the resulting alcohols by the Mitsunobu reaction. The selectivity of the reduction of the conjugated carbonyl group in position 3 of progesterone with sodium borohydride in the presence of cerium(III) chloride (Luche reduction) was demonstrated. The ef ect of the obtained metabolites on the proliferation of breast cancer cells of the MCF-7 and T47D lines under normal and steroid-free conditions was studied. It is shown that the ef ect of these compounds on the proliferation depends on the presence of additional steroids in the culture medium. Metabolites exerted small cytostatic ef ects on the growth of the MCF-7 cells under standard conditions, while the transfer of the cells to a steroid-free medium weakened these cytotoxic ef ects. In the experiments with the T47D line cells, the cell growth was stimulated under both standard and steroid-free conditions. Allopregnanolone and progesterone stimulate the growth to a greater extent under steroid-free conditions than under standard ones.

Synthesis, structural assignments and antiinfective activities of 3-O-benzyl-carvotacetone and 3-hydroxy-2-isopropyl-5-methyl-p-benzoquinone

In an attempt to synthesize carvotacetone analogues, new 3-O-benzyl-carvotacetone (10) and previously reported 3-hydroxy-2-isopropyl-5-methyl-p-benzoquinone (11) were synthesized from piperitone (7). In this work, we describe the synthesis of 10 and other analogues from 7. Luche reduction of 7 to cis-piperitol (8), followed by benzylation yielded 3-O-benzyl-piperitol (9). Riley oxidation of 9 afforded corresponding ketone 10, 11 and 3-benzyloxy-4-isopropylcyclohex-1-enecarbaldehyde (12). Structures of these compounds were determined based on NMR, IR and LC-MS spectral data. Compound 11, exhibited antiplasmodial activities against chloroquine-sensitive (D6) and resistant (W2) strains of Plasmodium falciparum with IC50 values of 0.697 and 0.653 µg/mL, respectively. In addition, compound 11 was active against Cryptococcus neoformans with an IC50 value of 3.11 µg/mL, compared to reference standard fluconazole (IC50 value of 1.87 µg/mL), while 10 and 12 were inactive against both organisms. This is the first report of the antiplasmodial and anticryptococcal activity of compound 11.

Synthesis of Bradyrhizose from d-Glucose.

We describe the synthesis of the unusual bicyclic sugar bradyrhizose in 14 steps and a 6% overall yield from d-glucose. The synthesis involves the elaboration of a trans-fused carbocyclic ring onto the preexisting glucopyranose framework followed by adjustment of the oxidation levels. Key steps include radical extension of the glucopyranose side chain, ring closing metathesis, allylic oxidation, Luche reduction, hydroxy-directed epoxidation, and acid-catalyzed epoxide opening at the more substituted position.

Synthesis of α/β dipeptides containing linear or cyclic α-dehydro-β-amino acids as scaffolds for bioactive compounds.

The synthesis of α/β dipeptides containing linear or cyclic α-dehydro-β-amino acids has been performed starting from alkylidene acetacetamides, which were obtained from α-amino esters via Ir-catalyzed allylic amination. Differently hindered carbonates were synthesized via a protocol involving chemoselective Luche's reduction, acylation, and allylic amination. Depending on the nature of the selected α-amino acid, we observed strong influence on the product regiochemistry due to the carbonate size and the amino-acid side chain. In particular, complete regioselectivity was observed in the aminic allylation of carbonates deriving from amino acids possessing a methylene unit in β-position. On the contrary, methyl carbonates deriving from β-branched amino acid afforded different results depending on the hindrance of the carbonate. Moreover, spontaneous cyclization was observed for carbamate-containing intermediates, allowing to obtain peptidomimetic polyfunctionalized dihydropyrimidine-2,4-dione. Finally, by inverting the order of reduction/acylation steps on the starting alkylidene acetoacetamides, the formation of polyfunctionalized 1,3-oxazinane-2,4-dione was obtained demonstrating the wide applications of these substrates for the preparation of bioactive peptidomimetics.

Improved stereoselective synthesis of 3-methoxy- and 3-benzyloxy-16-hydroxymethyl-13α-estra-1,3,5(10)-trien-17-ol isomers by transfer hydrogenation using chiral Ru catalysts

The Noyori-type (1S,2S)- and (1R,2R)-N-(para-tosyl)-1,2-diphenylethylene-1,2-diamine ligands complexed with ruthenium have been found to be effective catalysts for the regiospecific transfer hydrogenation of 3-methoxy- and 3-benzyloxy-(Z)16-hydroxymethylidene-13α-estra-1,3,5(10)-trien-17-ones to 3-methoxy- and 3-benzyloxy-16-hydroxymethyl-13α-estra-1,3,5(10)-trien-17-one diastereomers. The ratio of the diastereomers depends on the catalyst used. Further reduction of the isolated products with NaBH4 in the presence of cerium(III) chloride (Luche reduction conditions) yielded the corresponding diols. In contrast to the previous preparation methods, this two-step simple hydrogenation/reduction protocol afforded all four possible isomers in almost equal amounts.

Repetition of chemistry from a recently retracted paper. A cautionary note

The base-catalyzed condensation reaction between (E)-4-phenylbut-2-enal and phenylpropargyl aldehyde recently reported in the literature to provide formylcyclobutadiene was repeated under the published conditions. The product obtained was identified as (E)-5-phenyl-2-((E)-styryl)pent-2-en-4-ynal rather than the reported 2-phenyl-3-styrylcyclobutadiene-1-carboxaldehyde. The structure assignment is supported by NMR and IR data and a x-ray structure of the crystalline alcohol obtained by Luche reduction.

Stereoselective Total Syntheses of Acutifolone A, Bisacutifolone A and B, Pinguisenol, and Isonaviculol.

Stereoselective total syntheses of pinguisane type of sesquiterpenoids are described following a unified approach using a chiral building block derived from (R)-pulegone. The functionality embodied in the key intermediate enables their facile elaboration into more complex structures of biological relevance such as acutifolone A (9 steps, 22% overall yield) and bisacutifolone A and B (6 and 8%, respectively) following Furukawa’s modified Simmons–Smith cyclopropanation, Luche reduction, Saegusa–Ito oxidation, pyridinium chlorochromate-mediated 1,3-oxidative transposition, and Diels–Alder dimerization as key steps.

Porphyrin Arch-Tapes: Synthesis, Contorted Structures, and Full Conjugation.

Porphyrin tapes possessing meso-meso β-β β-β triple direct linkages have been targets of extensive studies because of their fully conjugated characteristic π-electronic networks. In this paper, we report porphyrin arch-tapes that bear additional carbonyl group(s) or methylene group(s) inserted between one of the β-β linkage(s) of the porphyrin tapes. The carbonyl-inserted porphyrin arch-tapes were efficiently synthesized by double fusion reactions of β-to-β carbonyl-bridged porphyrin oligomers with DDQ and Sc(OTf)3, and were converted to the methylene-bridged porphyrin arch-tapes via Luche reduction with NaBH4 and CeCl3 followed by ionic hydrogenation with HBF4·OEt2 and BH3·NEt3. While the conventional porphyrin tapes display rigid and planar structures and low solubilities, these porphyrin arch-tapes show remarkably contorted structures, flexible conformations, and improved solubilities because of the presence of the incorporated seven-membered ring(s). Interestingly, the methylene-inserted arch-tapes exhibited conjugative electronic interactions that were comparable to those of porphyrin tapes probably owing to through-space interaction in the contorted conformations. The carbonyl-inserted arch-tapes displayed distinctly larger conjugative interactions owing to an active involvement of the carbonyl group(s) in the electronic conjugation. A similar trend was observed in the nonlinear optical properties, as evidenced by their two-photon absorption cross sections. Furthermore, as a benefit of the contorted structures, these porphyrin arch-tapes can catch C60 fullerene effectively. Naturally, the electron-rich methylene-bridged arch-tapes exhibited larger association constants than the electron-deficient carbonyl-bridged arch-tapes. Among these arch-tapes, a methylene-bridged syn-Ni(II) porphyrin trimer recorded the largest association constant of (1.5 ± 0.4) × 107 M-1 in toluene at 25 °C.

Synthetic Route Development for the Laboratory Preparation of Eupalinilide E.

Following the discovery that the guaianolide natural product eupalinilide E promotes the expansion of hematopoietic stem and progenitor cells; the development of a synthetic route to provide laboratory access to the natural product became a priority. Exploration of multiple synthetic routes yielded an approach that has permitted a scalable synthesis of the natural product. Two routes that failed to access eupalinilide E were triaged either as a result of providing an incorrect diastereomer or due to lack of synthetic efficiency. The successful strategy relied on late-stage allylic oxidations at two separate positions of the molecule, which significantly increased the breadth of reactions that could be used to this point. Subsequent to C-H bond oxidation, adaptations of existing chemical transformations were required to permit chemoselective reduction and oxidation reactions. These transformations included a modified Luche reduction and a selective homoallylic alcohol epoxidation.

Toward the Stereoselective Synthesis of Arthrobotrisin A: Fragment Synthesis and Coupling Studies

A route towards the stereocontrolled synthesis of arthrobotrisin A based on a Nozaki–Hiyama–Kishi (NHK) coupling strategy was developed. Highlights of the fragment synthesis include enzyme-catalyzed kinetic resolution, Negishi carbometalation–iodination, quinone formation through oxidation with hypervalent iodine, chiral oxazaborolidine-catalyzed asymmetric Diels–Alder reaction with cyclopentadiene, regio- and stereoselective epoxidation, Noyori reduction, retro-Diels–Alder reaction, diastereoselective Luche reduction, and, finally, a Nozaki–Hiyama–Kishi (NHK) coupling of the vinyl iodide fragment.

First DMAP-mediated direct conversion of Morita-Baylis-Hillman alcohols into γ-ketoallylphosphonates: Synthesis of γ-aminoallylphosphonates.

An efficient synthesis of a series of γ-ketoallylphosphonates through a direct conversion of both primary and secondary Morita–Baylis–Hillman (MBH) alcohols by trialkyl phosphites with or without DMAP, used as additive, and under solvent-free conditions, is described herein for the first time. Subsequently, a highly regioselective Luche reduction of the primary phosphonate 2a (R = H) gave the corresponding γ-hydroxyallylphosphonate 5 that further reacted with tosylamines in the presence of diiodine (15 mol %) as a catalyst, affording the corresponding SN2-type products 6a–d in 63 to 70% isolated yields. Alternatively, the alcohol 5 produced the corresponding acetate 7 which, mediated by Ce(III), was successfully converted into the corresponding γ-aminoallylphosphonates 8a–d.