Allylic Alcohol Moiety Research Articles

Synthesis of Indenone-Fused Pyran Derivatives from Aryl Enaminones and Cyclopropenones through Unsymmetrical Relay C-H Bond Activation and Double C-C/C-O Bond Formation.

Presented herein is a novel synthesis of indenone-fused pyran derivatives via the cascade reactions of aryl enaminones with cyclopropenones. The formation of products involves a one-pot cascade procedure consisting of aryl C-H bond and enamine C-H bond functionalization along with C-C bond cleavage of cyclopropenone and 1,3-rearrangement of the in situ-formed allylic alcohol moiety followed by intramolecular O-nucleophilic addition and Me2NH elimination. To our knowledge, this is the first synthesis of indenone-fused pyran derivatives via simultaneous formation of both indenone and pyran scaffolds through concurrent unsymmetrical relay C-H bond activation and double C-C/C-O bond formation. Moreover, the usefulness of this method is further showcased by its suitability for large-scale synthetic scenarios and diverse transformations of products.

Structures and Biosynthesis of Caryoynencins, Unstable Bacterial Polyynes from Pseudomonas protegens Recombinant Expressing the cayG Gene.

Bacteria in certain genera can produce "bacterial polyynes" that contain a conjugated C≡C bond starting from a terminal alkyne. Protegenin A is a derivative of octadecanoic acid that contains an ene-tetrayne moiety. It was discovered in Pseudomonas protegens Cab57 and exhibits strong antioomycete and moderate antifungal activity. By introducing cayG, a cytochrome P450 gene from Burkholderia caryophylli, into P. protegens Cab57, protegenin A was converted into more complex polyynes, caryoynencins A-E. A purification method that minimized the degradation and isomerization of caryoynencins was established. For the first time, as far as we know, the 1H and 13C{1H} NMR signals of caryoynencins were completely assigned by analyzing the NMR data of the isolated compounds and protegenin A enriched with [1-13C]- or [2-13C]-acetate. Through the structural analysis of caryoynencins D/E and bioconversion experiments, we observed that CayG constructs the allyl alcohol moiety of caryoynencins A-C through sequential hydroxylation, dehydration, and hydroxylation. The recombinant strain exhibited a stronger antioomycete activity compared to the wild-type strain. This paper proposes a stable purification and structural determination method for various bacterial polyynes, and P. protegens Cab57 holds promise as an engineering host for the production of biologically active polyynes.

A facile synthesis of (±)-15-deoxy-Δ12,14-prostaglandin J2 methyl ester

A simple and facile synthesis of racemic 15-deoxy-Δ12,14-prostaglandin J2 methyl ester from readily available Corey lactone diol in total eleven steps was suggested. The standard methods provided a pathway to a block with an integrated w w w-chain and further to PGJ2 methyl ester. The latter was smoothly converted to the target prostaglandin in the TsOH–CH2Cl2 medium when allylic alcohol moiety was transformed to exocyclic diene substituent conjugated with endocyclic enone system.

Synthetic route for optically active tetracyclic hexahydrobenzofurobenzopyran skeleton of bisabosquals

In this study, for the first time, we synthesized the optically active form of the hexahydrobenzofurobenzopyran ring, which is found in naturally occurring bisabosquals. This synthetic route involved three key steps: (i) induction of chirality into the allylic alcohol moiety via the Suzuki-Miyaura cross-coupling of an aryl iodide and a chiral alkenyl borate; (ii) transfer of chirality from the optically active allylic ester to the resultant carboxylic acid formed via the Ireland-Claisen rearrangement; and (iii) stepwise construction of the hexahydrobenzofurobenzopyran skeleton from a cyclohexene substrate via an acid-mediated fused furan/pyran ring formation. Using our synthetic route, we obtained both the racemic and optically active hexahydrobenzofurobenzopyrans.

Sequential Allylic Alcohol Formation by a Multifunctional Cytochrome P450 Monooxygenase with Rare Redox Partners.

Caryoynencin is a toxic and antifungal fatty acid derivative produced by a number of plant‐pathogenic and insect‐protective bacteria (Trinickia caryophylli and Burkholderia spp.). In addition to the reactive tetrayne unit, the presence of an allylic alcohol moiety is critical for antimicrobial activities. By a combination of mutational analyses, heterologous expression and in vitro reconstitution experiments we show that the cytochrome P450 monooxygenase CayG catalyzes the complex transformation of a saturated carbon backbone into an allylic alcohol. Unexpectedly, CayG employs a ferritin‐like protein (CayK) or a rubredoxin (CayL) component for electron transport. A desaturation‐hydroxylation sequence was deduced from a time‐course study and in vitro biotransformations with pathway intermediates, substrate analogues, protegencin congeners from Pseudomonas protegens Pf‐5, and synthetic derivatives. This unusual multifunctional oxygenase may inspire future biocatalytic applications.

Sequential Allylic Alcohol Formation by a Multifunctional Cytochrome P450 Monooxygenase with Rare Redox Partners

AbstractCaryoynencin is a toxic and antifungal fatty acid derivative produced by a number of plant‐pathogenic and insect‐protective bacteria (Trinickia caryophylli and Burkholderia spp.). In addition to the reactive tetrayne unit, the presence of an allylic alcohol moiety is critical for antimicrobial activities. By a combination of mutational analyses, heterologous expression and in vitro reconstitution experiments we show that the cytochrome P450 monooxygenase CayG catalyzes the complex transformation of a saturated carbon backbone into an allylic alcohol. Unexpectedly, CayG employs a ferritin‐like protein (CayK) or a rubredoxin (CayL) component for electron transport. A desaturation‐hydroxylation sequence was deduced from a time‐course study and in vitro biotransformations with pathway intermediates, substrate analogues, protegencin congeners from Pseudomonas protegens Pf‐5, and synthetic derivatives. This unusual multifunctional oxygenase may inspire future biocatalytic applications.

Synthesis of (+) and (‐)‐Streptomyces coelicolor Butanolide 5 (SCB‐5)

AbstractVarious 1‐(1‐hydroxyalkyl) paraconyl alcohols are important signaling molecules within antibiotics production in Streptomyces sp. Intending developing a flexible convergent chemical synthesis of such butanolides, a zwitterionic aza‐Claisen rearrangement was chosen as reliable strategy generating the central stereotriad. Reaction of enantiopure N‐allyl pyrrolidines and 4‐phenylbutenoic acid fluoride delivered defined configured amides displaying the 2,3,1’ stereotriads. The configuration was determined by the allyl alcohol moiety indicating a complete remote stereo control. Amide removal by iodolactonization and proceeding reductions, halocyclization and elimination gave key alkylidene tetrahydrofuran derivatives. Stepwise degradation of the olefins through ozonolysis, reductive work‐up and protecting group removal delivered both enantiomers of the target Streptomyces coelicolor butanolide 5.

Total Synthesis of Haliclonin A.

The total synthesis of haliclonin A was accomplished. Starting from 3,5-dimethoxybenzoic acid, a functionalized cyclohexanone fused to a 17-membered ring was prepared through a Birch reduction/alkylation sequence, ring-closing metathesis, intramolecular cyclopropanation, and stereoselective 1,4-addition of an organocopper reagent to an enone moiety. Reductive C-N bond formation via an N,O-acetal forged the 3-azabicyclo[3.3.1]nonane core. The allyl alcohol moiety was constructed by a sequence involving stereoselective α-selenylation of an aldehyde via an enamine, syn-elimination of a selenoxide, and allylation of the aldehyde with an allylboronate. Formation of the 15-membered ring containing a skipped diene was achieved by ring-closing metathesis, and final transformations led to the synthesis of haliclonin A.

Total Synthesis of Haliclonin A

AbstractThe total synthesis of haliclonin A was accomplished. Starting from 3,5‐dimethoxybenzoic acid, a functionalized cyclohexanone fused to a 17‐membered ring was prepared through a Birch reduction/alkylation sequence, ring‐closing metathesis, intramolecular cyclopropanation, and stereoselective 1,4‐addition of an organocopper reagent to an enone moiety. Reductive C−N bond formation via an N,O‐acetal forged the 3‐azabicyclo[3.3.1]nonane core. The allyl alcohol moiety was constructed by a sequence involving stereoselective α‐selenylation of an aldehyde via an enamine, syn‐elimination of a selenoxide, and allylation of the aldehyde with an allylboronate. Formation of the 15‐membered ring containing a skipped diene was achieved by ring‐closing metathesis, and final transformations led to the synthesis of haliclonin A.

Accelerated Development of a Scalable Ring-Closing Metathesis to Manufacture AMG 176 Using a Combined High-Throughput Experimentation and Computational Modeling Approach

AMG 176 is a drug candidate in our oncology pipeline. Ring-closing metathesis (RCM) is a key reaction in the AMG 176 synthesis that is used to construct the 16-membered macrocycle. Process intensification was executed on a compressed timeline by combining high-throughput experimentation and computational analysis using density functional theory, which led to the identification of an optimal 4-bromobenzoate protecting group on the allylic alcohol moiety. Comprehensive process improvements led to a reduction in reaction volume from 800 to 50 L/kg with a >20% yield improvement compared with the discovery route. The RCM process developed from these studies was instrumental in the clinical advancement of the AMG 176 program.

Synthesis and antiproliferative effect of the proposed stereoisomer of the marine sponge metabolite halisphingosine A.

The first synthesis of the proposed natural stereoisomer of halisphingosine A, a metabolite of the marine sponge Haliclona tubifera, was accomplished in 11 steps including an enantioselective Henry reaction, a Weinreb amide - acetylide coupling, and stereoselective reductions of the resulting ynone to afford the R,Z-configured allyl alcohol moiety. The synthetic product differed from the natural isolate in some 13C-NMR data. It showed antiproliferative activity at clinically relevant concentrations against six tumour cell lines including such lacking functional tumor suppressor gene p53.

ChemInform Abstract: Rhodium‐Catalyzed Mild and Selective C—H Allylation of Indolines and Indoles with 4‐Vinyl‐1,3‐dioxolan‐2‐one: Facile Access to Indolic Scaffolds with an Allylic Alcohol Moiety.

AbstractThe efficient and scalable allylation of indolines is performed using an N‐butylcarbamoyl directing group providing the products as an inseparable mixture of E/Z isomers with the (Z)‐isomer being the major product.

Rhodium-catalyzed mild and selective C–H allylation of indolines and indoles with 4-vinyl-1,3-dioxolan-2-one: facile access to indolic scaffolds with an allylic alcohol moiety

The rhodium(III)-catalyzed selective C–H allylations of indolines and indoles with 4-vinyl-1,3-dioxolan-2-one at room temperature are described. These transformations provide the direct and efficient formation of indolic scaffolds containing an allylic alcohol group.

The molecular basis of conjugated polyyne biosynthesis in phytopathogenic bacteria.

Polyynes (polyacetylenes), which are produced by a variety of organisms, play important roles in ecology. Whereas alkyne biosynthesis in plants, fungi, and insects has been studied, the biogenetic origin of highly unstable bacterial polyynes has remained a riddle. Transposon mutagenesis and genome sequencing unveiled the caryoynencin (cay) biosynthesis gene cluster in the plant pathogen B. caryophylli, and homologous gene clusters were found in various other bacteria by comparative genomics. Gene inactivation and phylogenetic analyses revealed that novel desaturase/acetylenase genes mediate bacterial polyyne assembly. A cytochrome P450 monooxygenase is involved in the formation of the allylic alcohol moiety, as evidenced by analysis of a fragile intermediate, which was stabilized by an in situ click reaction. This work not only grants first insight into bacterial polyyne biosynthesis but also demonstrates that the click reaction can be employed to trap fragile polyynes from crude mixtures.

The Molecular Basis of Conjugated Polyyne Biosynthesis in Phytopathogenic Bacteria

AbstractPolyynes (polyacetylenes), which are produced by a variety of organisms, play important roles in ecology. Whereas alkyne biosynthesis in plants, fungi, and insects has been studied, the biogenetic origin of highly unstable bacterial polyynes has remained a riddle. Transposon mutagenesis and genome sequencing unveiled the caryoynencin (cay) biosynthesis gene cluster in the plant pathogen B. caryophylli, and homologous gene clusters were found in various other bacteria by comparative genomics. Gene inactivation and phylogenetic analyses revealed that novel desaturase/acetylenase genes mediate bacterial polyyne assembly. A cytochrome P450 monooxygenase is involved in the formation of the allylic alcohol moiety, as evidenced by analysis of a fragile intermediate, which was stabilized by an in situ click reaction. This work not only grants first insight into bacterial polyyne biosynthesis but also demonstrates that the click reaction can be employed to trap fragile polyynes from crude mixtures.

Identification of novel chromenone derivatives as interleukin-5 inhibitors

A series of (E)-5-alkoxy-3-(3-phenyl-3-oxoprop-1-enyl)-4H-chromen-4-ones (4) and (E)-5-alkoxy-3-(3-hydroxy-3-phenylprop-1-enyl)-4H-chromen-4-ones (5) were synthesized and evaluated for their IL-5 inhibitory activity. Propenone analogs 4 possess some of the structurally important characteristics of isoflavone 2 and chalcone 3 previously known as potent IL-5 inhibitor. However, the inhibitory activity of 4 was weak and therefore this structural hybridization appears to be ineffective for the design of IL-5 inhibitor. Meanwhile the potent activity profile of compounds 5 was discovered. This enhanced activity of 5 compared to 4 could be due to the effective location of hydroxyl group of allylic alcohol moiety of 5 in the 3D structure. The electron withdrawing substituents at position 4 of phenyl ring of 5 enhances the activity possibly due to an increase in the strength of hydrogen bonding property of hydroxyl group of allylic alcohol moiety.

Hydroxy-group effect on the regioselectivity in a photochemical oxetane formation reaction (the Paternò-Büchi Reaction) of geraniol derivatives

The Paternò-Büchi (PB) reaction of geraniol derivatives 1, which contain allylic alcohol functionality and unfunctionalized double bonds, with benzophenone was investigated to see the effect of the hydroxyl group on the regioselectivity of the oxetane formation, i.e., 2/3. At low concentration of geraniol (1a), oxetanes 2a and 3a were formed in a ratio of 2a/3a = ca. 50/50. The oxetane 2a is derived from the PB reaction at the allylic alcohol moiety, whereas the PB reaction at the unfunctionalized double bond produces the oxetane 3a. The PB reaction of the hydroxy-protected methyl ether 1b and acetate 1c gave selectively oxetanes 3b,c derived from the reaction at the more nucleophilic double bond, 2/3∼ 15/85. The hydroxyl-group effect was found to be small, but apparently increased the formation of 2a in the PB reaction with geraniol (1a).

ChemInform Abstract: Intramolecular Heck Reaction with Substrates Possessing an Allylic Alcohol Moiety.

Abstract In this paper we report our investigation on a series of palladium catalysed cyclisations with substrates possessing an allylic alcohol moiety. This methodology provides a good approach to a wide variety of functionalised 5 or 6 membered carbo- or heterocycles. We also demonstrate that it is possible to combine an alkylation and a cyclisation process using the same palladium catalyst system.

Asymmetric Synthesis of the Cytotoxic Marine Natural Product (+)-Awajanomycin and Its C-11 Epimer

Full details of the convergent synthetic approach to awajanomycin, and the first total syntheses of the marine natural product (+)-awajanomycin (1) and its C-11 epimer 38 by an improved 13-step approach, are described. The key elements of the synthetic strategy resided in the use of (R)-18 as the chiral building block to construct the gamma-lactone-delta-lactam core 3 and cross-olefin metathesis as the key reaction to couple the latter with the allylic alcohol segment (R- or S-4). The efficient construction of the core 3 was realized by taking advantage of the inherent multiple reactivities of the chiral building block (R)-18. A highly diastereoselective one-pot transformation of 6 to 26 was achieved in a "one stone four birds" manner. On the other hand, enantioselective synthesis of both enantiomers of the segment 4 has been undertaken by an alternative and more efficient two-step procedure. Both awajanomycin (1) and 11-epi-awajanomycin 38 have been synthesized with overall yields of 3.8% and 3.6%, respectively. Quantum chemical calculations were undertaken to reveal the low reactivity of compound 27 toward methoxycarbonylation and to get an insight into the favored conformations of the intermediates 25-27. In addition, the geometry of the side product 39 arising from the homocoupling of the allylic alcohol moiety 4 was revised as E, and an unusual cyclopropanation reaction was discovered.

A New Access to the 6,8-Dioxabicyclo[3.2.1]octane Ring System Using a Three-Component Reaction: Enantioselective Synthesis of (+)-iso-exo-Brevicomin

The combination of a catalytic hetero-Diels-Alder-­allylboration sequence and a ruthenium-catalyzed isomerization of an allylic alcohol moiety as key steps open a new route for the asymmetric synthesis of 6,8-dioxabicyclo[3.2.1]octane subunits. The application of this strategy to the synthesis of (+)-iso-exo-brevi­comin is also reported.