Showing papers on "Enone published in 2008"

Efficient visible light photocatalysis of [2+2] enone cycloadditions.

Abstract: We report that Ru(bipy)3Cl2 can serve as a visible light photocatalyst for [2+2] enone cycloadditions. A variety of aryl enones participate readily in the reaction, and the diastereoselectivity in the formation of the cyclobutane products is excellent. We propose a mechanism in which a photogenerated Ru(bipy)3+ complex promotes one-electron reduction of the enone substrate, which undergoes subsequent radical anion cycloaddition. The efficiency of this process is extremely high, which allows rapid, high-yielding [2+2] cyclizations to be conducted using incident sunlight as the only source of irradiation.

Diene Hydroacylation from the Alcohol or Aldehyde Oxidation Level via Ruthenium-Catalyzed C−C Bond-Forming Transfer Hydrogenation: Synthesis of β,γ-Unsaturated Ketones

Abstract: Under the conditions of ruthenium-catalyzed transfer hydrogenation, isoprene couples to benzylic and aliphatic alcohols 1a−g to deliver β,γ-unsaturated ketones 3a−g in good to excellent isolated yields. Under identical conditions, aldehydes 2a−g couple to isoprene to provide an identical set of β,γ-unsaturated ketones 3a−g in good to excellent isolated yields. As demonstrated by the coupling of butadiene, myrcene, and 1,2-dimethylbutadiene to representative alcohols 1b, 1c, and 1e, diverse acyclic dienes participate in transfer hydrogenative coupling to form β,γ-unsaturated ketones. In all cases, complete branch regioselectivity is observed, and, with the exception of adduct 3j, isomerization to the conjugated enone is not detected. Thus, formal intermolecular diene hydroacylation is achieved from the alcohol or aldehyde oxidation level. In earlier studies employing a related ruthenium catalyst, acyclic dienes were coupled to carbonyl partners from the alcohol or aldehyde oxidation level to furnish branch...

Catalytic Enantioselective Intermolecular Hydroacylation: Rhodium-Catalyzed Combination of β-S-Aldehydes and 1,3-Disubstituted Allenes

Abstract: A rhodium(I) catalyst incorporating the Me-DuPhos ligand promotes enantioselective intermolecular hydroacylation between β-S-aldehydes and 1,3-disubstituted allenes. The nonconjugated enone products are obtained in good yields and with high enantioselectivities.

pH‐Dependent Catalytic Activity and Chemoselectivity in Transfer Hydrogenation Catalyzed by Iridium Complex with 4,4′‐Dihydroxy‐2,2′‐bipyridine

Abstract: Transfer hydrogenation catalyzed by an iridium catalyst with 4,4'-dihydroxy-2,2'-bipyridine (DHBP) in an aqueous formate solution exhibits highly pH-dependent catalytic activity and chemoselectivity. The substantial change in the activity is due to the electronic effect based on the acid-base equilibrium of the phenolic hydroxyl group of DHBP. Under basic conditions, high turnover frequency values of the DHBP complex, which can be more than 1000 times the value of the unsubstituted analogue, are obtained (up to 81 000 h(-1) at 80 degrees C). In addition, the DHBP catalyst exhibits pH-dependent chemoselectivity for alpha,beta-unsaturated carbonyl compounds. Selective reduction of the C=C bond of enone with high activity are observed under basic conditions. The ketone moieties can be reduced with satisfactory activity under acidic conditions. In particular, pH-selective chemoselectivity of the C=O versus C=C bond reduction was observed in the transfer hydrogenation of cinnamaldehyde.

Asymmetric Aza‐Michael Reactions of α,β‐Unsaturated Ketones with Bifunctional Organic Catalysts

Abstract: Chiral amine motifs are ubiquitously presented in numerous biologically active and therapeutically important chiral molecules. Consequently chiral amines constitute one of the most important classes of chiral building blocks in organic synthesis. Accordingly, significant efforts have been devoted to the development of catalytic enantioselective transformations of inexpensive achiral precursors into optically active chiral amines. In parallel to enantioselective additions to achiral imines, catalytic asymmetric conjugate additions with nitrogen nucleophiles, or aza-Michael reactions, provide another fundamentally important approach toward optically active chiral amines[1]. Although much progress has been made recently in the development of asymmetric aza-Michael reactions with both chiral metallic[2,3,4] and organic catalysts[5,6,7], highly enantioselective catalytic aza-Michael reactions to simple α,β-unsaturated ketones remain rare. To our knowledge, only three such reactions have been reported, and all are catalyzed by chiral transition-metal complexes.[3] Inanaga and coworkers reported a chiral Sc-complex as a highly effective Lewis acid catalyst for an asymmetric aza-Michael reactions of O-alkoxyhydroxylamines to acyclic enones.[3a] Applying bifunctional catalysis with a chiral Li-Y heterobimetallic complex Shibasaki and coworkers established a highly efficient aza-Michael reaction with a more broad scope, affording high enantioselectivity for a wide range of α,β-unsaturated ketones 1 bearing either an aryl or alkyl β-substituent.[3b,c] However, the ketone substituent (R2) is limited to aromatic rings for both of the aforementioned reactions. More recently, Jacobsen and coworkers reported the conjugate addition of hydrazoic acid to enones catalyzed by a salen-Al complexe.[3d] Notably, this reaction afforded good to excellent enantioselectivity for α,β-unsaturated ketones 1 bearing various alkyl substitutents as both the ketone and the β-substituents. Herein, we wish to report the first highly enantioselective aza-Michael reaction with α,β-unsaturated ketones catalyzed by a chiral organic catalyst. Significantly, this new catalytic asymmetric aza-Michael reaction afforded consistently excellent enantioselectivity for a wide variety of alkyl vinyl ketones bearing either an alkyl or aryl group as the β-substituent, thereby providing a synthetically valuable substrate scope that is complementary to those of existing chiral metal-based methods. MacMillan[6a] first reported the use of chiral secondary amines such as chiral imidazolidinones to activate α,β-unsaturated aldehydes for a highly enantioselective aza-Michael reaction with N-siloxycarbamate via iminium catalysis.[8] Presumably, the steric bulk of the chiral secondary amines renders them highly chemoselective for the nucleophilic attack toward the aldehyde group while minimizing catalyst decomposition via conjugate additions to enals. On the other hand, α,β-unsaturated ketones 1 are sterically more demanding and electronically less active toward iminium formation with chiral amines. The activation of enones for asymmetric aza-Michael reactions by an effective chiral secondary amines has not yet been reported.[9] Recently, 9-amino cinchona alkaloid 4[10] in combination with various acids have been shown to provide an effective catalyst system for the activation of enones 1 for various asymmetric conjugate addition reactions.[11] Presumably, compared to a secondary amine, the sterically less hindered primary amine in 4 reacts more readily with the ketone functionality in 1 to initiate the iminium catalysis. Thus, we reasoned that, while the primary amine activated the enone in the presence of acid via iminium catalysis, the quinuclidine motif of cinchona alkaloid 4, in either the protonated or the free base form, could bind to a nitrogen nucleophiles such as alkoxyamines via hydrogen bonding interactions, thereby activating the nitrogen nucleophile for the nucleophilic attack by bring the nitrogen nucleophile into the approximaty of the activated enone (Scheme 1). We anticipated that this bifunctional catalysis by cinchona alkaloid 4 could be applied to the development of an efficient asymmetric aza-Michael reaction with α,β-unsaturated ketones 1. Scheme 1 Proposed activation modes of aza-Michael addition of α,β-unsaturated ketones 1 with 4. Accordingly, we investigated the aza-Michael reaction of various nucleophiles to enone 1A catalyzed by the 9-amino cinchona alkaloid 4. In the presence of 10 mol% of 4 and 40 mol% of TFA (trifluoroacetic acid), the conversion and the enantioselectivity of the aza-Michael reaction was found to be greatly influenced by the electronic as well as the steric properties of the nitrogen nucleophiles (Table 1). Various alkoxyamines bearing either an N-carbamate or -sulfonamide group were found to be active toward the 4-catalyzed aza-Michael reaction. In particular the reaction with the Boc-protected N-benzyloxyamine 2g afforded the highest enantioselectivity, providing the desired adduct in 84% ee (entry 8). Importantly, when the loading of TFA was decreased from 40 mol % to 20 mol %, the reaction was found to proceed in significantly improved enantioselectivity (entry 9 vs 8). A complete reaction could be attained with 20 mol% of 4 and 40 mol % of TFA to afford the desired aza-Michael adduct 3A in 93% ee (entry 10). Table 1 Asymmetric aza-Michael reaction of α,β-unsaturated ketones 1 with 4. Encouraged by this promising result, we investigated the scope of the 9-amino cinchona alkaloid-catalyzed aza-Michael reaction under the optimal conditions defined through out model studies. As illustrated in Table 2, the high enantioselectivity afforded by catalyst 4 could be extended to a wide range of alkyl vinyl ketones 1A-H. Singnificantly, alterations of the steric properties of the aliphatic ketone substituent did not impact negatively on the enantioselectivity of the reaction. Moreover, catalyst 4 was found to also tolerate a significant range of alkyl groups as the β-substituent in 1. Catalyst 4 was also found to afford excellent enantioselectivity for alkyl vinyl ketones bearing a β-aryl group such as 1I, albeit in drastically decreased activity (entry 9 vs 8). Reaction optimization studies revealed that the cinchonidine-derived catalyst 5 afforded the optimal enantioselectivity for enone 1I, and the enantioselectivity remained high when the reaction was carried out in toluene at 40 °C to provide the corresponding adduct in synthetically useful yield. Utilizing catalyst 5'(C-NH2) derived from cinchonine, the corresponding antipode of 3 were generated in good to excellent optical purity (Table 2). Thus alkyl vinyl ketones 1 bearing both β-aryl and alkyl groups could be employed for this cinchona alkaloid-catalyzed aza-Michael reactions (Table 2). Significantly, among existing highly enantioselective catalytic aza-Michael reactions with enones, the current reactio is unique in its ability to afford high enantioselectivity for alkyl vinyl ketones bearing a β-aryl groups (entries 12-16, Table 2). As illustrated in Scheme 2, the enantiomerically enriched Michael adducts 3G and 3I, which bear substituents of various steric and electronic properties, could be readily converted to the corresponding N-Boc β-amino ketones 6 and 7 without deterioration in optical purity.[12] Scheme 2 Hydrogenation of 3. Table 2 Asymmetric aza-Michael addition of α,β-unsaturated ketones 1 with 4. In summary, we have developed the first highly enantioselective aza-Michael reaction of simple α,β-unsaturated ketones with an organic catalyst. It is particularly noteworthy that this new catalytic asymmetric aza-Michael reaction is effective for a broad range of alkyl vinyl ketones bearing both aryl and alkyl β-substituents. Utilizing a readily available chiral catalyst, commercially available nitrogen nucleophiles and a convenient operation protocol, this asymmetric aza-Michael reaction of general scope should provide a highly promising method for the asymmetric synthesis of a wide range of optically active chiral amines. Current investigations in these laboratories are focused on the elucidation of the mechanism as well as the expansion of the synthetic utility of this reaction.

Total Syntheses and Structural Revision of α‐ and β‐Diversonolic Esters and Total Syntheses of Diversonol and Blennolide C

Abstract: The structures of α- and β-diversonolic esters (1 and 2, Figure 1)[1] define the key structural motifs of a growing family of natural products, some members of which exhibit striking antibiotic activities. Among them are diversonol (3, Figure 1),[2] the first member of the monomeric series within the class, and the rugulotrosins,[3] secalonic acids[4] and hirtusneanoside,[5] all of which are dimeric in nature. Figure 1 Structures of α- and β-diversonolic esters (1, 2, 4 and 5) and diversonol (3). In a program directed towards the total synthesis of these molecules, we focused initially on the development of new synthetic technologies for the synthesis of the basic molecular framework of the class, and, therefore, turned our attention to α- and β-diversonolic esters (1 and 2) and diversonol (3), the simplest members of the family. In this communication we report the development of an expedient synthetic strategy for the construction of the diversonolic architecture, its application to concise total syntheses of all three structures 1–3, and the revision of the originally proposed structures for α- and β-diversonolic esters 1 and 2, to 4 and 5, respectively, through total synthesis. Scheme 1 summarizes the devised synthesis of the originally assigned structures of α- and β-diversonolic esters 1 and 2. Thus, reaction of racemic enone 6 with Et2AlCN followed by trapping with TMSCl in the presence of pyridine furnished the corresponding nitrile TMS enol ether, which was transformed without isolation to nitrile enone 7 through the action of IBX•MPO,[6] in 62 % overall yield. Conversion of the latter to its ester enone counterpart (8) required DIBAL-H reduction (hydroxy aldehyde), DMP oxidation (ketoaldehyde, 83 % yield, two steps), Pinnick oxidation, and treatment with TMSCHN2 (90 % yield, two steps). Ester enone 8 was then converted to bromo hydroxy ester 9 (ca. 1.3:1 dr) through sequential reaction with bromine and Et3N (bromo enone, 94 % yield), followed by reduction with NaBH4-CeCl3 (91 % yield). Deprotonation of bromo hydroxy ester 9 with MeLi (1.1 equiv) followed by sequential treatment with tBuLi and acyl cyanide 10 afforded the expected alcohol (ca. 1.3:1 dr), which was oxidized with IBX to give diketone 11 in 41 % overall yield. Finally, desilylation of 11 (HF•py), followed by deallylation (nBu3SnH, Pd(PPh3)4 cat.), furnished structures 1 and 2 (1:2 ca. 2:1, chromatographically separated), presumably through the intermediacy of 12. The spectroscopic data (1H and 13C NMR) of these compounds, however, did not match those reported[1] for the natural products α- and β-diversonolic esters. The skeletal connectivity of compounds 1 and 2 was established by HMBC studies and their relative stereochemistry was assigned by comparison of NMR data with similar compounds.[7] The structure of 2 (m.p. 183–184 °C, EtOAc:hexanes 1:1) was verified by X-ray crystallographic analysis (see ORTEP drawing, Figure 2).[8] Figure 2 ORTEP drawings of compound 2, 3, 18 and 22 derived from X-ray crystallographic analysis (non-hydrogen atoms are shown as 30 % ellipsoids). Scheme 1 Synthesis of the proposed structures of α- and β-diversonolic esters (1 and 2). Reagents and conditions: a) Et2AlCN (1.0 M in toluene, 1.2 equiv), toluene, 23 °C, 30 min; then pyridine (3.0 equiv), TMSCl (1.8 equiv), 0→23 ... At this stage, and not yet knowing the true structures of α- and β-diversonolic esters, we turned our attention to the synthesis of diversonol (3) through application of the developed synthetic strategy. Thus, substituting the nitrile with a methyl group in the starting enone (now 13, Scheme 2) and following a similar route as before, but proceeding through intermediates 14–19 (17:18 ca. 2:1), we arrived at diversonol (3) in eight steps as summarized in Scheme 2. The spectral data (1H and 13C NMR) of synthetic diversonol matched those reported for the natural substance[2] and those of synthetic diversonol kindly provided by Professor S. Brase, whose group was the first to synthesize this natural product.[9] The structures of synthetic compounds 18 (m.p. 154–155 °C, EtOAc:hexanes 1:1) and 3 were also confirmed by crystallographic analysis (ORTEP drawing, Figure 2).[8] Scheme 2 Total synthesis of diversonol (3). Reagents and conditions: a) Br2 (1.05 equiv), CH2Cl2, 0 °C, 5 min; then Et3N (1.5 equiv), 0 °C, 5 min, 90 %; b) DIBAL-H (1.0 M in hexanes, 1.5 equiv), THF, −78→ −40 °C, ... In what turned out to be a fortunate twist of fate, and aimin improving and streamlining our synthesis of diversonol (3), we decided to employ MOM protecting groups on the aromatic segment of the molecule (aldehyde 20, Scheme 3). We, therefore, proceeded to prepare, by the same route, intermediate 21 (Scheme 3), whose global deprotection under acidic conditions was expected to give compound 17 (Scheme 2) in one step, rather than two, and avoiding the organometallic reagent and catalyst employed in the first route. Upon exposure of 21 to aqueous HClO4, however, we did not observe any of the expected products (i.e. 17 and 18, Scheme 2), but instead obtained two new compounds (ca. 2:1 ratio) isomeric in nature to the previously obtained products (17 and 18) and to each other. Fortunately, one of these compounds (major, less polar, silica gel, hexanes: EtOAc 1:1) crystallized from hexanes: EtOAc (1:1) in beautiful colorless needles (m.p. 175–176 °C, EtOAc:hexanes 1:1). One of these crystals was subjected to X-ray crystallographic analysis (see ORTEP drawing, Figure 2),[8] which revealed its structure as 22, and hence, that of the other isomer as 23 (Scheme 3). Scheme 3 Construction of compounds 22 and 23. Reagents and conditions: a) MeLi (1.6 M in ether, 1.1 equiv), ether, −78 °C, 15 min; then tBuLi (1.7 M in pentane, 2.2 equiv), −78 °C, 15 min; then 20 (1.5 equiv), −78→ ... The proposed mechanism for the formation of compounds 22 and 23 from 21 through postulated intermediates 24–26 (Scheme 4) served as the basis for the total synthesis and structural revision of α- and β-diversonolic esters. Apparently, the initially formed structures undergo skeletal rearrangements to structures such as 22 and 23 under the acidic conditions employed for the deprotection. The similarity of the NMR data of 22 and 23 to those of the natural diversonolic esters led us to propose structures 4 and 5 as the revised structures of 1 and 2, respectively. Scheme 5 summarizes our syntheses of 4 and 5 starting with hydroxy bromo ester 9 and bis-MOM protected acyl cyanide 27 and proceeding through intermediate 28 (4:5 ca. 1:3 dr). The spectral properties of synthetic diversonolic esters 4 and 5 were consistent with their structures and matched those reported[1] for the naturally occurring substances. The structural connectivity of 4 and 5 was established by HMBC studies and their relative stereochemistry was assigned by nOe studies. The revised structures of α- and β-diversonolic esters (4 and 5) also explain the ambiguities in the spectral and chemical properties of these compounds described in the original isolation report.[1] Scheme 4 Postulated mechanism of the formation of 22 and 23. Scheme 5 Total synthesis of the revised structures of α- and β-diversonolic esters (4 and 5). Reagents and conditions: a) MeLi (1.6 M in ether, 1.1 equiv), ether, −78 °C, 15 min; then tBuLi (1.7 M in pentane, 2.2 equiv), −78 ... In a final twist, a naturally occurring compound named blennolide C, bearing the structure of 2, was reported[10] while this manuscript was in preparation. Although a natural product with the structure 1 has not yet been reported, it can be predicted to exist, especially as it is present as a monomeric unit in some dimeric natural products such as the rugulotrosins.[3] Besides uncovering the true structures of α- and β-diversonolic esters and rendering them and diversonol as well as blennolide C readily available, the described chemistry opens an expedient entry into these and the more complex members of this class of natural products, including their enatiomerically pure forms and their analogs. Since both enantiomers of starting materials (6[11] and 13[12]) are known, the as yet undetermined absolute stereochemistry of all three natural products (3–5) should be easily discernable. Finally, biological investigations with the synthesized compounds may reveal interesting properties.

Concise stereocontrolled formal synthesis of (±)-quinine and total synthesis of (±)-7-hydroxyquinine via merged Morita-Baylis-Hillman-Tsuji- Trost cyclization

Abstract: Concise stereoselective syntheses of (±)-quinine and (±)-7-hydroxyquinine are achieved using a catalytic enone cycloallylation that combines the nucleophilic features of the Morita−Baylis−Hillman reaction and the electrophilic features of the Tsuji−Trost reaction. Cyclization of enone−allyl carbonate 11 delivers the product of cycloallylation 13 in 68% yield. Diastereoselective conjugate reduction of the enone 13 (>20:1 dr) followed by exchange of the N-protecting group provides the saturated N-Boc-protected methyl ketone 19, which upon aldol dehydration provides quinoline containing enone 15, possessing all carbon atoms of quinine. Exposure of ketone 15 to L-selectride enables diastereoselective carbonyl reduction (>20:1 dr) to furnish the allylic alcohol 16. Stereoselective hydroxyl-directed epoxidation using an oxovanadium catalyst modified by N-hydroxy-N-Me-pivalamide delivers epoxide 17 (17:1 dr). Cyclization of the resulting amine-epoxide 17 provides (±)-7-hydroxyquinine in 13 steps and 11% overall ...

A General Organocatalytic Enantioselective Malonate Addition to α,β-Unsaturated Enones

Abstract: A general enantioselective organocatalytic conjugate addition procedure of a variety of malonates to alpha,beta-unsaturated enone systems is presented. The reaction is efficiently catalysed by the pyrrolidinyl tetrazole catalyst 1. Cyclic, acyclic and aromatic enones can be used and the reaction with ethyl malonates 3 b provides the Michael addition products in high yields with good to excellent enantioselectivities. Since only 1.5 equivalents of malonate are used as a reagent, the reaction is readily scaled and practical to operate. Furthermore, the malonate addition products can be easily mono decarboxylated without loss in enantiomeric excess by enzymatic or sodium hydroxide mediated methods.

An Expedient Asymmetric Synthesis of Platencin

Abstract: A short and efficient synthesis of enone 3, a key intermediate in the total synthesis of platencin (2), based on an intramolecular Diels−Alder reaction is described.

A novel acetylenic tricyclic bis-(cyano enone) potently induces phase 2 cytoprotective pathways and blocks liver carcinogenesis induced by aflatoxin.

Abstract: A novel acetylenic tricyclic bis-(cyano enone), TBE-31, is a lead compound in a series of tricyclic compounds with enone functionalities in rings A and C. Nanomolar concentrations of this potent multifunctional molecule suppress the induction of the inflammatory protein, inducible nitric oxide synthase, activate phase 2 cytoprotective enzymes in vitro and in vivo, block cell proliferation, and induce differentiation and apoptosis of leukemia cells. Oral administration of TBE-31 also significantly reduces formation of aflatoxin-DNA adducts and decreases size and number of aflatoxin-induced preneoplastic hepatic lesions in rats by >90%. Because of the two cyano enones in rings A and C, TBE-31 may directly interact with DTT and protein targets such as Keap1 that contain reactive cysteine residues. The above findings suggest that TBE-31 should also be tested for chemoprevention and chemotherapy in relevant models of cancer and against other chronic, degenerative diseases in which inflammation and oxidative stress contribute to disease pathogenesis.

α-Olefins as Alkenylmetal Equivalents in Catalytic Conjugate Addition Reactions†

Abstract: First documented over a century ago, conjugate additions are among the most utilized organic reactions. In carbon-carbon bond-forming variants, the nucleophile is typically organometallic in nature. Earlier technology employed enolate, organolithium, Grignard, or organocopper reagents, and more recently organozinc and organoboron compounds have enhanced this transformation significantly.[1,2] Despite increased functional group tolerance, an organometallic or organometalloid is nonetheless required in these powerful methods. Herein we describe a novel conjugate addition reaction in which a simple, unactivated alkene (ethylene, an alpha olefin, or styrene) takes the place of the organometal (eq 1). In other words, although an alkene is not an alkenylmetal reagent per se, it functions as one in this C–C bond-forming process. (1) Catalyzed polymerization of alkenes is one of the most important industrial processes,[3] and Ni-catalyzed two-alkene coupling reactions have also received significant attention, including hydrovinylation.[4] Montgomery has found that nickel complexes catalyze a wide variety of conjugate addition reactions,[5] but the closest precedent to the transformation reported here (catalytic 1,4-addition of simple alkene to unsaturated carbonyl) appears to be Lewis-acid promoted conjugate addition of electron-rich alkenes.[6,7] However, in these cases migration of the double bond of the alkene nucleophile occurs, in contrast to the Ni-catalyzed reactions described below. Ogoshi reported that stoichiometric amounts of Ni(cod)2 and Me3SiOTf effected intramolecular coupling of an alkene and an aldehyde, and shortly thereafter, we reported that alpha olefins are excellent nucleophiles in intermolecular carbonyl addition reactions catalyzed by complex derived from Ni(cod)2 and a phosphine or an N-heterocyclic carbene.[8] Depending on the nature of the ligand, addition at either the terminus or the 2-position of the alkene occurs. The latter provides direct access to allylic alcohol derivatives, and the former yields products of a carbonyl-ene-like reaction. With the aim of broadening the scope of alkenes as nucleophiles in carbon-carbon bond-forming reactions, we turned our attention to electrophiles containing unsaturated carbonyl functional groups. In order to focus on issues of alkene reactivity in initial studies, we selected ethylene as the coupling partner and decided to address issues of regioselectivity in subsequent experiments. As shown in Table 1, Et3SiOTf and catalytic amounts of Ni(cod)2 and Bu3P afford good to excellent yields of the conjugate addition product, isolated as the enolsilane (entries 1–4). Moreover, the stereoselectivity with respect to formation of the enolsilane is at least 92:8. Unsaturated ketones are also effective electrophiles (entries 5–11) but proceed with lower selectivity in some cases. Table 1 Ni-Catalyzed Conjugate Addition Reactions of Alkenes.[a] As demonstrated in entry 9, electron-rich enones are superior electrophiles, and certain heterocycles are also tolerated (entries 10–11). Despite reduced selectivity, reactions with furan- and thiophene-containing enones proceed in high chemical yield. Overall, most of the above cases are highly selective, and thus the transformation represents a direct and stereoselective assembly of tetrasubstituted siloxyalkenes.[9,10] Several observations regarding the optimum reaction conditions are noteworthy. Increasing either the ethylene pressure from 1 atm to 2 atm or the scale of the reaction fourfold resulted in only a marginal reduction in yield (entries 2 and 6). Out of 25 additives investigated (see Supporting Information), Bu3P was by far the most effective for coupling reactions of ethylene. Toluene is the superior solvent; for example, ethereal solvents such as Et2O, THF, and 1,4-dioxane completely suppress the coupling reaction. Significant effort was expended to reduce the rather high catalyst loading (30 mol%); however, small decreases in the amount of Ni(cod)2 resulted in significantly reduced yield. For example, 2b was afforded in 49% yield when 15 mol% Ni(cod)2 was used (76% yield under standard conditions). Similarly, a 63% yield of 2f was obtained at 20% loading, down from 94% yield at 30% loading. Other critical variables are the amounts of Et3N and Et3SiOTf employed. Decreasing or increasing the former lowered the yield or completely suppressed the reaction, and reducing the amount of silyl triflate from 1.75 to 1.25 equiv decreased the yield of 2b from 76% to 47% under otherwise identical conditions. It should also be noted that Me3SiOTf can be used in place of Et3SiOTf, but this substitution tends to diminish the product yield. Unactivated monosubstituted olefins are also good coupling partners in this reaction. For example, 1-octene and 2-hexylacrolein are united in 67% yield, and with very high enolsilane E/Z selectivity (entry 12). Coupling occurs with approximately 4:1 regioselectivity, favoring coupling at the 2-position of the alkene. Since there are comparatively a greater number of general methods for the preparation of 1-alkenyl organometallics (e.g., hydrometalation of terminal alkynes), the fact that 1-octene functions as a 2-alkenyl organometallic reagent highlights a particularly useful aspect of this reaction. Aryl alkenes, on the other hand, afford the opposite alkene regioselectivity (entries 13–14). Coupling at the 2-position of styrene is not observed; carbon-carbon bond formation at 1-position occurs exclusively, whether the electrophile is an enal or an enone. These trends and observations noted above suggest a basic mechanistic framework (Scheme 1). The proposed sequence of events is based largely on a crystal structure of a complex derived from Ni(cod)2, Cy3P, a 1,3-diene, and PhCHO reported recently by Ogoshi.[11] We believe that the alkene (ethylene shown) and the electrophile (enal or enone, 1) afford an oxa-π-allyl nickel complex (A) during the formation of the carbon-carbon bond. The silyl triflate reacts with this species, giving an enolsilane and a Ni(II) complex (B) that undergoes rapid β-H elimination. Product (2) release and Et3N abstraction of TfOH from complex C affords a Ni(0) species (not shown), completing the catalytic cycle. Scheme 1 Proposed Mechanistic Framework The E/Z selectivity thus appears to be dictated by two factors that in most cases reinforce each other. The placement of R2 and R3 away from each other and the chair-like chelation of Ni in complex A are consistent with the observed sense of alkene geometry. The superior performance of electron-rich enals and enones is consistent with the fact that reaction with silyl triflate is a critical step in the cycle. Mackenzie has reported Ni-catalyzed conjugate addition reactions between alkenyltributyltin reagents and α,β-unsaturated aldehydes that are assisted by chlorotrialkylsilanes and likely proceed via 1-((trialkylsilyl)oxy)allyl]nickel(II) intermediates.[7] In this vein, it is possible that the silyl triflate and enal (or enone) first combine, and that the resulting species then undergoes coupling with the alkene. Morken has proposed a similar sequence of events in Ni-catalyzed coupling reactions between allylboron reagents and enones.[12] With the caveat that different ligands are used in coupling reactions of alpha olefins (CyPPh2) and styrene (P(cyclopentyl)3), our working hypothesis for the complementary regioselectivity in these two cases is as follows: It is possible that the regioselectivity observed for styrene (coupling at the alkene 1-position) is due primarily to an electronic consideration, specifically, the formation of a benzylic Ni species. On the other hand, the sense of selectivity in alpha olefin cases is that resulting from avoidance of steric repulsion between the Ni-ligand complex and the alkene substituent. We have proposed an explanation similar to the latter for the behavior of alpha olefins in other Ni-catalyzed coupling reactions that we have developed.[8b–f] Several aspects of this transformation are noteworthy. First, it is a rare example of selective conjugate addition of an alkenyl equivalent to an unsaturated aldehyde. Typically in such reactions 1,2-addition is favored, or complex mixtures are afforded.[1] The high E/Z selectivity in most cases also merits further comment. Enolsilanes are starting materials in a wide range of enantioselective transformations leading to carbonyl compounds with quaternary stereogenic centers in the α-position, in many cases with very high enantioselectivity.[13,14] The double bond configuration is generally critical for high facial selectivity, and thus the nickel-catalyzed conjugate addition reaction provides rapid access to important tri-and tetrasubstituted enolsilanes that would otherwise be difficult to prepare with high selectivity via enolization of an aldehyde or ketone[9] (cf. Table 1, entry 2, (allyl vs. n-hexyl). Finally, the products derived from ethylene possess a monosubstituted alkene that is an excellent substrate for catalytic olefin cross-metathesis.[15] This combination therefore affords products that are regiocomplementary to those of the nickel-catalyzed conjugate addition reaction with aliphatic, monosubstituted alkenes (e.g., 1-octene). Our current efforts expanding the scope and utility of the conjugate addition of monosubstituted alkenes to unsaturated carbonyl compounds. More broadly, we continue to explore catalytic reactions that utilize simple, widely available chemical feedstocks, including alpha olefins, and provide important synthetic intermediates in a single operation.

Total Synthesis of Aburatubolactam A

Abstract: Recently Uemura and co-workers described the structure of aburatubolactam A (1, Figure 1), a macrolactam isolated from the culture broth of a Streptomyces sp. bacterium, SCRC-A20, that was separated from a marine mollusk collected near Aburatubo, Kanagawa Prefecture, Japan.[1a] Aburatubolactam A is a member of a growing class of tetramic acid-containing macrolactams including cylindramide A,[1b] geodin A,[1c] xanthobaccin A,[1d] ikarugamycin,[1e] discodermide,[1f] and the alteramides.[1g] These mixed polyketide-amino acid metabolites have been isolated from a number of sources including sponges, marine bacteria and terrestrial bacteria,[2] and display a diverse range of biological activities including cytotoxicity, anti-microbial activity, and inhibition of superoxide generation. In this Communication we describe a synthesis of aburatubolactam A. Figure 1 Structure of Aburatubolactam A (1) and synthesis strategy. Our strategy for the synthesis of aburatubolactam A is based on the coupling of two domains: a subunit containing the bicyclo[3.3.0]octane (2), and a 3-hydroxyornithine-derived subunit (3, Figure 1). The bicyclo[3.3.0]octane ring system was ultimately envisioned to arise from a ring-opening—ring-closing metathesis of functionalized bicyclo[2.2.1]heptene 4. [3,4] The synthesis commenced with a Diels-Alder reaction of commercially available ketone 6 with cyclopentadiene in the presence of 20 mol % of MacMillan's catalyst 8 to give ketone 7 in 65% yield (endo:exo >98:2, 93% ee, Scheme 1).[5] Conversion to the enone 4 was readily achieved in 80% yield by Saegusa oxidation of the trimethylsilyl enol ether derived from 7.[6] When enone 4 was subjected to 2.5 mol% of Grubbs’ catalyst 9 under an ethylene atmosphere, rapid and smooth reorganization to the desired bicyclo[3.3.0]octene 5 occurred in 90% yield.[7] Scheme 1 Synthesis of the bicyclo[3.3.0]octene. a) 20 mol% 8, H2O, 65%; b) LiHMDS, TMSCl, THF then Pd(OAc)2, MeCN, 80%; c) 2.5% 9, CH2=CH2 (1 atm), CH2Cl2, 90%. LiHMDS=lithiumhexamethyl disilazide, TMS=trimethylsilyl. Further elaboration of 5 was accomplished by reduction of both alkenes (Pd/C, H2) to give fused bicyclic ketone 10 in 94% yield (Scheme 2). Introduction of the C6 and C13 side chains was achieved by a sequence beginning with enolate acylation with Mander's reagent,[8] followed by reduction of the ketone with NaBH4. Elimination of the resultant alcohol by mesylation and treatment with sodium hydride in MeOH-THF (5:1) provided 11 in 64% overall yield from 10. The C13 side chain was introduced by employing Majetich's fluoride-mediated Sakurai allylation9 in DMF-DMPU to give 12 in 78% yield as a 4:1 mixture of inseparable C6 diastereomers favoring the undesired stereochemistry (viz 12a). This ratio could be improved to 2:1 in favor of the desired stereochemistry (viz 12b) by protonation of the silylketene acetal derived from 12a with HCl. Subsequent iodolactonization facilitated separation of the diastereoisomers, and gave 13 in 58% yield for the two steps, along with recovered 12a. This sequence also provided a mechanism for recycling material. Treatment of iodolactone 13 with Zn dust in AcOH/EtOH, followed by reduction of the acid with LAH provided alcohol 14 in 86% yield (2 steps). Scheme 2 Elaboration of the bicyclo[3.3.0]octene. a) 10% Pd/C, EtOAc, H2 (balloon), 94%; b) 1. LDA, NCCO2Me, THF-DMPU then NaBH4, MeOH, 74% (2 steps); 2. MsCl, DMAP, Et3N, CH2Cl2 then NaH, THF-MeOH, 87% (2 steps); c) allyltrimethylsilane, TBAF, THF-DMPU, 78%, ... Advancement of alcohol 14 to 2 involved cross metathesis of butene-1,4-diol derivative 16 catalyzed by 15 to give 13 in 95% yield (Scheme 3). Oxidation with Dess-Martin periodinane, followed by olefination with (iodomethylene)triphenylphosphorane under Stork-Zhao[10] conditions provided vinyl iodide 19 in 82% yield. Conversion of the iodide to the stannane by treatment with tert-BuLi in the presence of tributyltin chloride also resulted in removal of the pivalate to give alcohol 20 in 85% yield. Treatment of this alcohol with Dess-Martin periodinane and subsequent Horner-Wadsworth-Emmons reaction yielded stannyl dioxenone 2 in 60% overall yield (2 steps). Scheme 3 Completion of the carbocyclic domain 2. a) 16, 10% 15, CH2Cl2, 95%; b) 1. Dess-Martin periodinane, CH2Cl2; 2. [Ph3P+ CH2I]I-, NaHMDS, THF, 82% (2 steps); c) t-BuLi, Bu3SnCl (internal quench), THF, 85%; d) 1. Dess-Martin periodinane, CH2Cl2; 2. 17, KHMDS, ... The synthesis of the β-hydroxyornithine subunit 3 began with Sharpless asymmetric dihydroxylation of α,β-unsaturated ester 21 to give diol 22 in 90% yield and >98% ee (Scheme 4). Introduction of the nitrogen was achieved by cyclic sulfite formation and opening with sodium azide. Subsequent silylation provided ether 23 in 80% yield over the three steps. Reduction of the azide and nosylation[11] led to 24 in 94% yield, and was followed by introduction of the methyl group by Mitsunobu reaction to give 25, and removal of the nosyl group with thiophenoxide provided amine 3 (82% from 24). Scheme 4 Synthesis of the β-hydroxyornithine subunit. a) AD mix α, 90%; b) 1. SOCl2, Et3N; 2. NaN3, DMF, 55°C; 3. TBSOTf, 2-6-lutidine, CH2Cl2, 80% (3 steps); c) 1. Pd/C, H2, EtOAc; 2. NsCl, i-Pr2NEt, CH2Cl2, 94% (2 steps); d) MeOH, Ph ... After exploring a number of unsuccessful end game strategies that paralleled those employed for cylindramide, the synthesis was completed as shown in Scheme 5.[12] Coupling of the two halves of the molecule was achieved by heating dioxenone 2 with amine 3 in toluene under reflux for 6 hours (Scheme 5). Subjection of the sensitive β-ketoamide product to Stille coupling with tert-butyl-β-iodoacrylate, followed by Lacey-Dieckmann cyclization, led to tetramic acid 26 in 50% yield (over three steps from 2). Macrocyclization was achieved by simultaneous removal of the Boc carbamate and tert-butyl ester with TFA and treatment of the resulting compound with DEPC[ and Et3N in DMF for 12 hours. Removal of the TBS group with HF provided aburatubolactam A in 46% yield for the 3 steps. Data for an analytical sample of synthetic aburatubolactam A obtained by semi-preparative HPLC matched that obtained for an authentic sample provided by Professor Daisuke Uemura. Scheme 5 Completion of the synthesis. a) 1. PhMe, 110 °C; 2. tert-butyl-β-iodoacrylate, Pd2(dba)3, Ph3As, NMP; 3. NaOMe, MeOH, 50% (3 steps); b) 1. TFA, CH2Cl2; 2. DEPC, Et3N, DMF, rt; 3) HF, MeCN, 46% (3 steps). NMP=N-methylpyrrolidinone, TFA=trifluoroacetic ... In conclusion, we have described a 23 step route that leads to aburatubolactam A and that further highlights the utility of tandem metathesis reactions in a target oriented setting.

A new enone-containing triglyceride derivative as precursor of thermosets from renewable resources

Abstract: A novel triglyceride containing α,β-unsaturated ketone was prepared through photoperoxidation from high oleic sunflower oil by two steps one pot environmentally friendly procedure. This new enone-containing triglyceride was crosslinked with diaminodiphenylmethane (DDM) via aza-Michael addition. A kinetic study of the reaction of p-toluidine with either enone-containing methyl oleate or epoxidized methyl oleate, as model compounds, allowed us to establish the higher reactivity of the former, thus confirming this curing system as an alternative to amine-cured epoxidized vegetable oils. The thermal properties of thermosets from enone- and epoxy-containing triglycerides with DDM have been evaluated. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6843–6850, 2008

Theoretical study of the asymmetric conjugate alkenylation of enones catalyzed by binaphthols.

Abstract: To rationalize the experimental results observed in the asymmetric conjugate addition of alkenylboronates to enones catalyzed by binaphthols and shed light into the factors controlling the rate, the selectivity, and the substituent effects of this process, a theoretical DFT study has been performed. The calculations suggest the catalytic cycle is finely balanced. Reversible exchange of methoxy ligands gives rise to the binaphthol-derived alkenylboronate, which is highly Lewis acidic and strongly coordinates to the enone carbonyl in a reversible fashion, lowering the energy barrier for the subsequent conjugate addition step. The key asymmetric step goes through a sofalike transition structure in which the boron atom is strongly bound to the carbonyl oxygen and lies in the plane of the enone moiety. A steric clash between one of the iodine atoms of the ligand and one face of the enone seems to be responsible for the facial discrimination. The alternative reaction channel in which only one methoxy ligand of the alkenylboronate is exchanged was investigated too and was computed to be disfavored. The [4 + 2] and the [4 + 3] pathways for the competitive hetero-Diels-Alder reaction were also found to be disfavored relative to the conjugate alkenylboration. In addition, the effects of substitution on the enone and the alkenylboronate have been evaluated. Calculations correctly reproduced the experimental reactivity trends and enantiomeric ratios.

Substituted isoxazoline or enone oxime compound, and pest control agent

Abstract: Disclosed is a novel pest control agent, in particular a pesticide or a miticide. Specifically disclosed are a substituted isoxazoline compound or a substituted enone oxime compound represented by the general formula (1) below or the general formula (2) below, and a pest control agent containing any of them. (In the formulae, the symbols are as defined in the description.)

Highly Enantio- and s-trans C=C bond selective catalytic hydrogenation of cyclic enones: alternative synthesis of (-)-menthol.

Abstract: A highly enantioselective catalytic hydrogenation of cyclic enones was achieved by using the combination of a cationic Rh(I) complex, (S)-5,5'-bis{di(3,5-di-tert-butyl-4-methoxyphenylphosphino)}-4,4'-bi-1,3-benzodioxole (DTBM-SEGPHOS), and (CH2CH2PPh3Br)2. The presence of an s-cis C=C bond isopropylidene moiety on the cyclic enone influenced the enantioselectivity of the hydrogenation. Thus, the hydrogenation of 3-alkyl-6-isopropylidene-2-cyclohexen-1-one, which contains both s-cis and s-trans enones, proceeded in excellent enantioselectivity (up to 98 % ee). To obtain high enantio- and s-trans selectivities, the addition of a halogen source to the cationic Rh complex was the essential step. With the key step of the s-trans selective asymmetric hydrogenation of piperitenone, we demonstrated a new synthetic method for optically pure (-)-menthol via three atom-economical hydrogenations. Moreover, we found that the complete s-trans and s-cis C=C bond selective reactions were also realized by the proper choice of both the chiral ligands and halides.

Synthesis of 7-Epineoptilocaulin, Mirabilin B, and Isoptilocaulin. A Unified Biosynthetic Proposal for the Ptilocaulin and Batzelladine Alkaloids. Synthesis and Structure Revision of Netamines E and G

Abstract: Addition of guanidine to a 6-methylhexahydroindenone in MeOH at 85 °C afforded 7-epineoptilocaulin. A similar reaction with a 6-propylhexahydroindenone afforded netamine E. MnO2 oxidation of 7-epineoptilocaulin and netamine E afforded mirabilin B and netamine G, respectively. The netamines have the side chains trans, not cis as was initially proposed. A unified biosynthetic scheme for the batzelladines and ptilocaulin family is proposed. Conjugate addition of guanidine to a bis enone followed by an intramolecular Michael reaction of the enolate to the other enone, aldol reaction, dehydration, and enamine formation will lead to a tricyclic intermediate at the dehydroptilocaulin oxidation state. 1,4-Hydride addition will lead to ptilocaulin or 7-epineoptilocaulin depending on which face the hydride adds to. 1,2-Hydride addition will lead to isoptilocaulin. The key tricyclic intermediate was prepared from a tetrahydroindenone and guanidine and reduced with NaBH4 to give a mixture rich in ptilocaulin and isop...

Selectivity Control in 1,2- and 1,4-Additions of Aluminum Organyls to Carbonyl Compounds

Abstract: Aluminum organyls are valuable reagents for carbon-carbon bond formation as they can either be purchased at low prices or conveniently be prepared, for example, by hydro- or carboalumination of alkenes and alkynes. Although their application in reactions with α,β-unsaturated carbonyl compounds is rather limited, it creates a diverse picture concerning the selectivity of product formation which depends on several factors such as the type of organic residue, the conformation of the enone, the presence of additional functional groups and the donor ability of the solvent. This review describes issues of selectivity of such uncatalyzed transformations as well as conjugate additions catalyzed by achiral copper and nickel catalysts in which alanes can act similarly or even superiorly to the more common lithium or magnesium organyls. Moreover, the rapidly growing field of transition-metal-catalyzed asymmetric 1,2- and 1,4-additions is reviewed, in which aluminum reagents can not only lead to enantioselective alkyl additions, thus substituting zinc organyls, but also afford introduction of aryl, alkenyl and alkynyl groups. 1 Introduction 2 Uncatalyzed Additions to α,β-Unsaturated Carbonyl Compounds- 2.1 Regioselectivity with Plain Enones 2.2 Selective Conjugate Additions to Cyclic Enones 2.3 Conjugate Additions to Carboxylic Compounds 3 Racemic Copper- and Nickel-Catalyzed 1,4-Additions 4 Asymmetric Addition to Carbonyl Compounds 4.1 Enantioselective Conjugate Additions to Enones 4.2 Enantioselective 1,2-Additions 5 Conclusion

An Expedient Route to Montanine-Type Amaryllidaceae Alkaloids: Total Syntheses of (−)-Brunsvigine and (−)-Manthine

Abstract: The first total syntheses of (−)-brunsvigine (1) and (−)-manthine (2) were accomplished in 10 and 18 steps, respectively. (−)-Quinic acid was converted to enone 12 in five steps. Iodination of enone 12 followed by stereoselective reduction yielded α-iodo allylic alcohol 16. Conversion of alcohol 16 into Weinreb amide 11 followed by anionic cyclization gave bicyclic enone 10. Stereoselective reduction of enone 10 and subsequent protection afforded pivaloate 9. Grignard addition of 8 to 9 and detosylation afforded amine derivative 19. Pictet−Spengler cyclization of 19 with Eschenmoser′s salt and subsequent hydrolysis gave enantiomerically pure (−)-brunsvigine (1). For the total synthesis of (−)-manthine (2), the key intermediate 7 was hydrolyzed to diol 21. Conversion of 21 into 22 followed by regioselective cleavage with DIBAL furnished alcohol 25. Alcohol 25 was converted to the corresponding triflate 26, which on treatment with CsOAc and 18-crown-6 gave stereoinverted acetate 27. Hydrolysis of acetate 27...

Mechanistic study of beta-hydrogen elimination from organoplatinum(II) enolate complexes.

Abstract: A detailed mechanistic investigation of the thermal reactions of a series of bisphosphine alkylplatinum(II) enolate complexes is reported. The reactions of methylplatinum enolate complexes in the presence of added phosphine form methane and either free or coordinated enone, depending on the steric properties of the enone. Kinetic studies were conducted to determine the relationship between the rates and mechanism of β-hydrogen elimination from enolate complexes and the rates and mechanism of β-hydrogen elimination from alkyl complexes. The rates of reactions of the enolate complexes were inversely dependent on the concentration of added phosphine, indicating that β-hydrogen elimination from the enolate complexes occurs after reversible dissociation of a phosphine. A normal, primary kinetic isotope effect was measured, and this effect was consistent with rate-limiting β-hydrogen elimination or C−H bond-forming reductive elimination to form methane. Reactions of substituted enolate complexes were also studi...

Oxazaborolidinone-Catalyzed Enantioselective Diels-Alder Reaction of Acyclic α,β-Unsaturated Ketones

Abstract: allo-Threonine-derived O-acyl-B-phenyl-oxazaborolidinones are demonstrated to be powerful and highly enantioselective Lewis acid catalysts for the Diels-Alder reaction of simple acyclic enone dienophiles, expanding the scope of ketone dienophiles and dienes. With 10 to 20 mol % of catalyst, the Diels-Alder adducts are obtained in 76-98% ee with high endo-selectivity. The catalyst exhibits high activity for the reaction with the less reactive beta-substituted dienophiles and the less reactive 1,3-cycohexadiene and 1,3-butadiene derivatives. The application of the catalysts to the Diels-Alder reaction of furan is also described.