Wieland-Miescher Ketone Research Articles

An Efficient Alternative Synthesis of (+)‐(6S,7S)‐7‐Hydroxy‐6,11‐cyclofarnes‐3(15)‐en‐2‐one, the (S)‐Enantiomer of the Antibacterial Sesquiterpene from Premna oligotricha.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The first total synthesis and determination of the absolute configuration of chapecoderin A, B and C

The seco- and rearranged-labdanes, chapecoderins A 1 , B 2 , and C 3 have been synthesized for the first time starting from ( S)-(+)-Wieland-Miescher ketone analogue 11 . Their absolute configurations have been determined as depicted in the structures 1 , 2 and 3 .

A New Synthesis of 4‐Methylene‐10‐methyl‐Δ8,9‐carbomethoxy‐trans‐decalin.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Total synthesis and structure revision of stachybotrys spirolactams.

The spirolactam structure 1 reported in 1996 by Roggo et al. has been enantioselectively synthesized in 20 steps from (+)-Wieland-Miescher ketone. Spectra of this synthetic lactam differed from those of the natural spirolactam from the Roggo group, leading to the hypothesis that the natural lactam may be the regioisomer 27, a structure previously ascribed by Jarvis et al. to the natural product stachybotrylactam. This hypothesis was confirmed by the first total synthesis of (-)-stachybotrylactam (27). Double reductive amination of two molecules of aldehyde 29 with one molecule of l-lysine led by analogous chemistry to the first synthesis of the pseudosymmetric "dimer" 30, whose spectra corresponded to those of the natural "dimer" originally assigned structure 5 by the Roggo group.

A New Synthesis of 4-Methylene-10-methyl-Δ8,9-carbomethoxy-trans-decalin

A novel synthesis of the title compound has been accomplished starting with alcohol (3) which in turn was prepared from the Wieland-Miescher ketone (1). Alcohol (3) was converted in six steps to ketoester (8) which after reduction, mesylation, and demesylation afforded the unsaturated ester (9). Its conversion to the desired compound (11) was achieved debenzylation followed by oxidation and Wittig reaction.

Enantiomerically Pure Octahydronaphthalenone and Octahydroindenone: Elaboration of the Substrate Overcame the Specificity of Yeast‐Mediated Reduction

AbstractSubstrate specificity on the reduction of bicyclic diketones with a yeast strain, Torulaspora delbrueckii IFO10921, was investigated. Although this yeast efficiently reduces the isolated carbonyl group involved in the (S)‐enantiomer of Wieland–Miescher ketone with high enantioselectivity (E=126), the introduction of a substituent on the octahydronaphthalene skeleton as well as the structural change into an octahydroindene skeleton retarded the enzymatic reduction and the enantioselectivity fell to E=5–16. Further structural variation into a bicyclo[3.3.0] skeleton led to an exclusive 1,4‐conjugate reduction of the α,β‐unsaturated carbonyl group, and the above results suggested the participation of plural oxidoreductive enzymes in the whole cell. In turn, among the 2,2‐disubstituted cycloalkanediones there were found good substrates to give the corresponding hydroxy ketone equivalents by yeast‐mediated reduction. The products were isolated as cyclic hemiacetals, such as (1S,6S)‐3‐ethyl‐3‐hydroxy‐6‐methyl‐2‐oxabicyclo[4.4.0]decan‐7‐one and (1S,6S)‐3‐hydroxy‐3,6‐dimethyl‐2‐oxabicyclo[4.3.0]nonan‐7‐one. In addition, the reduction worked well with use of an air‐dried, long‐term preservable cell preparation. The subsequent chemical transformation warranted the stereochemistry and the stereochemical purity of the products, which are related to octahydronaphthalenone and octahydroindenone systems that, in turn, are of considerable value as starting materials for terpenoid synthesis.

Enantioselective total synthesis and structure revision of spirodihydrobenzofuranlactam 1. Total synthesis of stachybotrylactam.

[reaction: see text] The enantioselective total synthesis and structure revision of spirodihydrobenzofuranlactam 1 and of its regioisomer 25 are presented. Optically pure (+)-Wieland-Miescher ketone was utilized to construct the AB bicyclic core in 10 steps. Introduction of the resorcylate D-ring unit was achieved by use of our tert-butyl ester metalation sequence. Subsequent stereoselective spirocyclization to form the C-ring was followed by regioselective ring cyanation and lactam formation to produce the pentacyclic structure 1 and its regioisomer 25.

An efficient formal synthesis of the sesquiterpenoid longifolene.

Through a convenient ring expansion reaction of key intermediate 1, enone 5, containing the longifolene skeleton, was produced. Elaboration of 5 via hydrogenation, Wittig reaction, Simmons-Smith reaction, and subsequent hydrogenolysis led to ketone 9. Reductive debromination of 9 afforded 10, the penultimate precursor to longifolene. This formal total synthesis was accomplished in 13 steps using commercially available Wieland-Miescher ketone as the starting material.

Novel synthetic approach to the 8,10-dimethyl anti-syn-anti-perhydrophenanthrene skeleton.

[reaction: see text] An efficient and highly stereocontrolled approach to the 8,10-dimethyl anti-syn-anti-perhydrophenanthrene carbon skeleton starting with the Wieland-Miescher ketone is described. The approach centers on a Diels-Alder-angular methylation-deoxygenation sequence.

Chiral HPLC Resolution of the Wieland–Miescher Ketone and Derivatives

The direct HPLC resolution of four structurally related compounds, the Wieland‐Miescher ketone, its C(5) homologue, and their C(1) dioxolane derivatives, was studied on commercially available polysaccharide‐based chiral stationary phases (CSPs) cellulose tris‐(3,5‐dimethylphenylcarbamate) (Chiralcel OD‐H), native β‐cyclodextrin (Cyclobond I), and acetylated, carboxymethylated and permethylated β‐cyclodextrins. The retention, resolution, and elution sequence of the enantiomeric couples were compared using different mobile phases. Baseline enantioseparation of all examined compounds was achieved only on the carboxymethyl‐derivatized β‐cyclodextrin stationary phase that appeared the most effective chiral selector for this class of compounds. Native, acetylated‐, and permethylated‐β‐cyclodextrin CSPs exhibited specific selectivity providing, in general, partial resolution of the compounds under investigation. On Chiralcel OD‐H, only two enantiomeric couples were fully separated. Elution orders depended on CSPs. To optimize chiral separation conditions, the influence of mobile phase composition on column retention and selectivity was also investigated.

Highly Improved Synthesis of (+)-Aureol via (-)-Neoavarone and (-)-Neo­avarol, by Employing Salcomine Oxidation and Acid-Induced Rearrangement/Cyclization Strategy

A short and efficient synthesis of (+)-aureol (1), a structurally novel and biologically important marine natural product, was achieved starting with readily available (+)-Wieland-Miescher ketone analogue 7 via (-)-neoavarone (10) and (-)-neoavarol (11). The method features salcomine oxidation of the phenol derivative 9 to deliver 10 and BF3·OEt2-induced rearrangement/cyclization reaction of 11 to produce 1 as the crucial steps. The improved biomimetic synthesis required only 9 steps and proceeds in 31% overall yield.

Lead Tetraacetate Mediated One-Pot Multistage Transformations: Theoretical Studies on the Diverging Behavior in the Hajos−Parrish and Wieland−Miescher Series

A computational approach to the proposed mechanistic rationale of the lead tetraacetate mediated oxidative cleavage of selected unsaturated diols in the hydrindenediol (derived from the Hajos-Parrish ketone, abbreviated as HP) and octalindiol (derived from the Wieland-Miescher ketone, abbreviated as WM) series is presented. These two unexpected cascade-type transformations have been found to yield structurally different products despite the similarities in the starting compounds 1-HP and 1-WM, which differ only by the number of carbon atoms in the cycloalkane rings. The final product in the HP series is the complex ring-expanded molecule iii-6, while the final product in the WM series is the ring-expanded bisacetoxy diacetal 7. Calculations carried out at the B3LYP/6-31G level have revealed the fact that the transformations of i-6 to ii-6 and of i-7 to ii-7 are endothermic by 19.93 and 4.20 kcal/mol, respectively. The isomerization of compounds i to ii is more endothermic in the case of the HP series. Furthermore, calculations have shown the transformation of i to ii to be kinetically less favored in the HP series than in its analogue WM series. The activation barrier for the transformation of i-6 to ii-6 is calculated to be 22.09 kcal/mol, whereas the corresponding barrier in the WM series is 13.77 kcal/mol. The thermodynamic features of the reactions support the experimental findings as well: 7 is calculated to be more stable than iii-7, and iii-6 is more stable than 6, as expected. The diverging behavior in the mechanism of the interconversion of i to ii has been attributed to the stabilization of the positive charge by a carbonyl oxygen in ii-7 due to the flexibility of the seven-membered ring in contrast to the rigidity of the six-membered ring.

Enantioselective synthesis of the antiinflammatory agent (-)-acanthoic acid.

An enantioselective synthesis of the potent antiinflammatory agent (-)-acanthoic acid (1) is described. The successful strategy departs from (-)-Wieland-Miescher ketone (10), which is readily available in both enantiomeric forms and constitutes the starting point toward a fully functionalized AB ring system of 1. Conditions were developed for a regioselective double alkylation at the C4 center of the A ring, which produced compound 32 as a single stereoisomer. Construction of the C ring of 1 was accomplished via a Diels-Alder reaction between sulfur-containing diene 43 and methacrolein (36), which after desulfurization and further functionalization yielded synthetic acanthoic acid. The described synthesis confirms the proposed stereochemistry of the natural product and represents a fully stereocontrolled entry into an underexplored class of biologically active diterpenes.

First total synthesis of chapecoderin A: absolute configuration of the natural product

A seco-labdane, chapecoderin A 1, has been synthesized starting from (S)-(+)-Wieland–Miescher ketone analogue 9. The absolute configuration has been determined to be 5S,10S.

Studies toward the total synthesis of popolohuanone E: enantioselective synthesis of 8-O-methylpopolohuanone E.

[structure: see text]. 8-O-methylpopolohuanone E (2) was synthesized in a highly convergent manner starting from the cis-fused decalin derivative accessible from the (-)-Wieland-Miescher ketone analogue. The synthetic method features a biogenetic-type annulation of the phenolic and quinone segments to regioselectively construct the central tricyclic ring system as the key step.

ChemInform Abstract: Synthesis of Bioactive Terpenes from Wieland—Miescher Ketone and Its Methyl Analogue

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: A Proline-Catalyzed Asymmetric Robinson Annulation Reaction.

Abstract A single-step enantioselective synthesis of the Wieland–Miescher ketone ( 5 ) is presented. We show that l -proline as well as a number of other chiral amines can act as catalysts of both steps of the Robinson annulation reaction. Other chiral amines are identified as catalysts of Michael and aldol addition reactions.

A proline-catalyzed asymmetric Robinson annulation reaction

A single-step enantioselective synthesis of the Wieland–Miescher ketone ( 5) is presented. We show that l-proline as well as a number of other chiral amines can act as catalysts of both steps of the Robinson annulation reaction. Other chiral amines are identified as catalysts of Michael and aldol addition reactions.

Proline-Catalyzed Direct Asymmetric Aldol Reactions

Most enzymatic transformations have a synthetic counterpart. Often though, the mechanisms by which natural and synthetic catalysts operate differ markedly. The catalytic asymmetric aldol reaction as a fundamental C-C bond forming reaction in chemistry and biology is an interesting case in this respect. Chemically, this reaction is dominated by approaches that utilize preformed enolate equivalents in combination with a chiral catalyst.1 Typically, a metal is involved in the reaction mechanism.1d Most enzymes, however, use a fundamentally different strategy and catalyze the direct aldolization of two unmodified carbonyl compounds. Class I aldolases utilize an enamine based mechanism,2 while Class II aldolases mediate this process by using a zinc cofactor.3 The development of aldolase antibodies that use an enamine mechanism and accept hydrophobic organic substrates has demonstrated the potential inherent in amine-catalyzed asymmetric aldol reactions.4 Recently, the first small-molecule asymmetric class II aldolase mimics have been described in the form of zinc, lanthanum, and barium complexes.5,6 However, amine-based asymmetric class I aldolase mimics have not been described in the literature.7 Here we report our finding that the amino acid proline is an effective asymmetric catalyst for the direct aldol reaction between unmodified acetone and a variety of aldehydes. Recently we developed broad scope aldolase antibodies that show very high enantioselectivities, have enzymatic rate accelerations, and use the enamine mechanism of class I aldolases.4 During the course of these studies, we found that one of our aldolase catalytic antibodies (Aldolase Antibody 38C2, Aldrich) is an efficient catalyst for enantiogroup-differentiating aldol cyclodehydrations of 2,6-heptanediones to give cyclohexenones, including the Wieland-Miescher ketone.8,9 These intramolecular reactions are also catalyzed by proline (Hajos-Eder-Sauer-Wiechert reaction)10 and it has been postulated that they proceed via an enamine mechanism.11 However, the proline-catalyzed direct intermolecular asymmetric aldol reaction has not been described. Further, there are no asymmetric small-molecule aldol catalysts that use an enamine mechanism.7 Based on our own results and Shibasaki’s work on lanthanum-based small-molecule aldol catalysts,4,6 we realized the great potential of catalysts for the direct asymmetric aldol reaction. We initially studied the reaction of acetone with 4-nitrobenzaldehyde. Reacting proline (30 mol %) in DMSO/acetone (4:1) with 4-nitrobenzaldehyde at room temperature for 4 h furnished aldol product (R)-1 in 68% yield and 76% ee (eq 1). This result

Total synthesis of 15-deoxoclerocidin

Enantiomerically pure 15-deoxoclerocidin ( 14), 15-dihydro-12- O-formylclerocidin ( 19) and 12- O-formyl-15,20-tetrahydroclerocidin ( 18) were synthesized from a methyl-substituted Wieland Miescher ketone ( 3).