Showing papers on "Enone published in 2010"

Brønsted Base-Catalyzed One-Pot Three-Component Biginelli-Type Reaction: An Efficient Synthesis of 4,5,6-Triaryl-3,4-dihydropyrimidin-2(1H)-one and Mechanistic Study

Abstract: An efficient one-pot synthesis of 4,5,6-triaryl-3,4-dihydropyrimidin-2(1H)-ones via a three-component Biginelli-type condensation of aldehyde, 2-phenylacetophenone, and urea/thiourea in the presence of a catalytic amount of t-BuOK (20 mol %) is described. The reactions proceeded efficiently at 70 °C to afford the desired products in moderate to good yields. Detailed mechanistic study shows that the Biginelli-type reaction using urea and thiourea proceeds through two totally different pathways. Enone 5 and bis-urea 8 were highly suggested as respective reaction intermediates for reactions involving thiourea and urea as substrates.

Enantioselective Synthesis of Trifluoromethyl‐Substituted 2‐Isoxazolines: Asymmetric Hydroxylamine/Enone Cascade Reaction

Abstract: The title reaction consists of an addition/cyclization/dehydration sequence and affords the biologically important chiral 3,5-diaryl-5-(trifluoromethyl)-2-isoxazolines in excellent yields with high e.e.

Palladium-catalyzed carbonylative Heck-type reactions of alkyl iodides.

Abstract: A palladium-catalyzed carbonylative Heck-type cyclization of alkyl halides is described. Treatment of a range of primary and secondary alkyl iodides with catalytic palladium(0) under CO pressure forms a variety of synthetically versatile enone products. The reactivity described represents a rare example of a palladium-catalyzed Heck-type cyclization involving unactivated alkyl halides with β-hydrogens. Alkene substitution is well tolerated, and mono- and bicyclic carbocycles may be easily accessed.

Expanding the Scope of Enantioselective FerroPHANE-Promoted [3+2] Annulations with α,β-Unsaturated Ketones

Abstract: The planar chiral 2-phospha[3]ferrocenophane I has been shown to be the first efficient nucleophilic organocatalyst for the enantioselective synthesis of cyclopentenylphosphonates, through [3+2] cyclizations between diethyl allenylphosphonate and alpha,beta-unsaturated ketones. The same catalyst has also been applied to the highly enantioselective [3+2] cyclizations of allenic esters with dibenzylideneacetone and analogous bis-enones, leading to functionalised cyclopentenes with either monocyclic or spirocyclic structures (ee 84-95 %). It has been shown that the residual enone functions in the resulting cyclopentenes can be involved in subsequent cyclization steps to afford unprecedented C(2)-symmetric bis-cyclopentenylketones. In order to provide insight into the behaviour of FerroPHANE I as a chiral catalyst in [3+2] cyclisations, the energetically most favoured isomers of the key phosphine-allene adduct have been calculated by DFT methods. Factors likely to control the chiral induction process are highlighted.

Diastereo‐ and Enantioselective Reductive Aldol Reaction with Trichlorosilane Using Chiral Lewis Bases as Organocatalysts

Abstract: The catalytic enantioselective tandem reaction is an efficient synthetic methodology in which optically active compounds are assembled from simple prochiral substrates via two (or more) distinct catalytic processes taking place under the same conditions. The synthetic efficiency is enhanced by avoiding the time-intensive and yield-reducing isolation and purification of synthetic intermediates and by decreasing the amounts of chemicals and solvents used. The asymmetric catalytic reductive aldol reaction is an efficient tandem transformation involving conjugate reduction of a,b-unsaturated carbonyl compounds followed by aldol reaction of the enolate intermediate with aldehydes or ketones. Chiral transition-metal catalysts have been used to control the stereochemistry of these transformations. We recently reported that achiral phosphorus oxides function as Lewis base organocatalysts to promote both the conjugate reduction of enones with trichlorosilane and the reductive aldol reaction of enones with aldehydes. Herein we report that enantioselective catalysis of this tandem reaction by chiral Lewis bases provides good to high diastereoand enantioselectivities. Scheme 1 outlines the current catalytic method. Our previous study had shown that the Lewis base catalyzed conjugate reduction with trichlorosilane proceeds via a six-membered transition state with an enone in the s-cis conformation to give the (Z)-trichlorosilyl enolate exclusively. Therefore, high syn selectivity is expected for the subsequent aldol process, assuming that the reaction proceeds through a chair-like cyclic transition state. Moreover, high enantioselectivity could also be achieved by judicious selection of chiral Lewis base catalysts (LB*). We first examined various chiral Lewis base catalysts (Figure 1) for the reductive aldol reaction of chalcone (1a) and benzaldehyde (2a) with trichlorosilane at 78 8C (Table 1). With (S)-BINAPO, the reaction in dichloromethane gave aldol adduct 3a with respectable stereoselectivities (Table 1, entry 1). By simply changing the solvent from dichloromethane to propionitrile, both the stereoselectivities and chemical yield dramatically improved (Table 1, entry 2). Other Lewis base catalysts were then examined using this solvent (Table 1, entries 3–6). (R,R)-DIOPO showed a comparable activity to BINAPO to afford similar enantioselectivity with a slight loss of diastereoselectivity (Table 1, entry 3). Although structurally similar to BINAPO, (S)[a] Prof. Dr. M. Sugiura, N. Sato, Y. Sonoda, Prof. Dr. M. Nakajima Graduate School of Pharmaceutical Sciences Kumamoto University 5-1 Oe-honmachi, Kumamoto 862-0973 (Japan) Fax: (+81)96-362-7692 E-mail : msugiura@kumamoto-u.ac.jp (M. Sugiura) nakajima@gpo.kumamoto-u.ac.jp (M. Nakajima) [b] Prof. Dr. S. Kotani Priority Organization for Innovation and Excellence Kumamoto University 5-1 Oe-honmachi, Kumamoto 862-0973 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.200900450. Scheme 1. The enantioselective reductive aldol reaction with trichlorosilane catalyzed by a chiral Lewis base catalyst.

Stereoselective Phosphine-Catalyzed Synthesis of Highly Functionalized Diquinanes

Abstract: In 2003, Tomita reported an intriguing P(n-Bu)3-catalyzed diastereoselective cyclization of certain yne-diones to form bicyclic furanones that bear two new stereocenters (Figure 1).[1] He proposed that conjugate addition of the phosphine to the alkyne is followed by tautomerization, which furnishes zwitterionic enolate A. Next, an intramolecular aldol reaction provides B, and then a second conjugate addition generates bicycle C (the conversion of A to C via a concerted cycloaddition may also be considered). Tautomerization and then elimination of the phosphine affords the bicyclic furanone. Tomita’s investigation focused on symmetrical substrates (i.e., R1 = –C≡CR), although he did report reactions of two unsymmetrical yne-diones, which cyclized in relatively modest yield (41–50%). Figure 1 Phosphine-catalyzed reaction of yne-diones to form bicyclic furanones (for the sake of simplicity, the steps are drawn as irreversible). This study by Tomita provides an excellent illustration of how the use of a nucleophilic catalyst can open the door to new modes of reactivity.[2] Surprisingly, to the best of our knowledge there have been no subsequent investigations that further develop this interesting reaction manifold (i.e., conjugate-addition/cross-tautomerization to generate a dipolar intermediate such as A). In this report, we exploit this reactivity to achieve phosphine-catalyzed diastereoselective transformations of acyclic precursors into highly functionalized diquinanes that bear multiple (three or four) contiguous stereocenters [Eq. (1)].[3] (1) Not only are diquinanes (including bicyclo[3.3.0]octan-2-ones) subunits of a wide array of bioactive compounds, but they are also versatile intermediates in organic synthesis.[4,5] We envisioned that a phosphine-catalyzed method for the generation of such structures might be viable (Krische has also developed a powerful phosphine-catalyzed approach to the synthesis of diquinanes[6]), if a zwitterion derived from 1 (analogous to A in Figure 1) could be induced to undergo an intramolecular Michael, rather than an aldol, reaction. Unfortunately, when subjected to the conditions developed by Tomita, compound 1 was not transformed into the target diquinane in significant yield [<10% yield; Eq. (2)]. (2) Upon investigating a variety of reaction parameters (e.g., catalyst, temperature, solvent, and concentration), we determined that the desired reaction manifold can be achieved through the appropriate choice of solvent and concentration. Thus, by conducting the cyclization in CH2Cl2/EtOAc (9/1) under more dilute conditions, we can efficiently generate the target diquinane, which bears three new contiguous stereocenters and an E double bond, as a single diastereomer [89% yield; Eq. (2)].[7] This phosphine-catalyzed reaction can be applied to the stereoselective synthesis of an array of diquinanes (Table 1; in each case, a single diastereomer is produced).[8] For example, the alkyne subunit can include an aromatic, alkenyl, or alkyl group (see R in Table 1); the ability to achieve cyclizations of alkyl-substituted compounds (entries 4, 7, 8, and 11) is noteworthy, since β-alkyl-substituted ynones are susceptible to phosphine-catalyzed isomerization to conjugated dienones.[9] The linker between the ynone and the enoate can bear substituents (e.g., entries 5–9) or include an aromatic ring (entries 10 and 11). Furthermore, an existing stereocenter can control the stereochemistry of the three newly created stereocenters [Eq. (3)]. Table 1 Phosphine-catalyzed stereoselective synthesis of highly functionalized diquinanes at room temperature (20% P(n-Bu)3, CH2Cl2/EtOAc). (3) The diquinanes produced via our phosphine-catalyzed double cyclization process can be functionalized with high stereoselectivity. Thus, new stereocenters can be introduced at the α or the β position of the enone [Eq. (4) and Eq. (5)],[10] as well as at the carbonyl group itself [Eq. (6)]. (4) (5) (6) We have initiated an investigation of an enantioselective variant of this phosphine-catalyzed diquinane synthesis. We anticipated that this challenge might be comparatively difficult, due to issues such as the potential generation of mixtures of E/Z isomers in key intermediates and the distance between the phosphine subunit and the site(s) of carbon–carbon bond formation. In view of such complications, we were pleased to determine that phosphepine 3 can catalyze the synthesis of a diquinane with promising enantioselectivity [60% ee; Eq. (7)].[11,12,13] (7) We have begun to explore the application of our method to the synthesis of other classes of fused carbocycles. Hydrindanes are an important family of targets,[14] and in a preliminary study we have determined that, without separate optimization, the method that we developed for the formation of diquinanes can be employed for the generation of 6,5 ring systems with promising yield and excellent stereoselectivity [Eq. (8) and Eq. (9)]. (8) (9) In summary, building on a powerful but largely unexploited mode of reactivity discovered by Tomita (phosphine catalysis via conjugate addition then cross tautomerization of an unsaturated carbonyl compound), we have developed a versatile new method for the room-temperature synthesis of diquinanes from acyclic precursors, thereby generating two rings, three stereocenters, and an olefin with high selectivity. The products of the double cyclization can be derivatized with excellent diastereoselection into an array of highly functionalized compounds. Preliminary studies suggest that an enantioselective variant can be achieved and that the method can be applied to the synthesis of other fused ring systems. Future investigations will further explore the scope of novel modes of reactivity furnished by phosphines and other nucleophilic catalysts.

Catalytic Asymmetric Synthesis of R207910

Abstract: The first asymmetric synthesis of a very promising antituberculosis drug candidate, R207910, was achieved by developing two novel catalytic transformations; a catalytic enantioselective proton migration and a catalytic diastereoselective allylation of an intermediate α-chiral ketone. Using 2.5 mol % of a Y-catalyst derived from Y(HMDS)3 and the new chiral ligand 9, 1.25 mol % of p-methoxypyridine N-oxide (MEPO), and 0.5 mol % of Bu4NCl, α-chiral ketone 3 was produced from enone 4 with 88% ee. This reaction proceeded through a catalytic chiral Y-dienolate generation via deprotonation at the γ-position of 4, followed by regio- and enantioselective protonation at the α-position of the resulting dienolate. Preliminary mechanistic studies suggested that a Y: 9: MEPO = 2: 3: 1 ternary complex was the active catalyst. Bu4NCl markedly accelerated the reaction without affecting enantioselectivity. Enantiomerically pure 3 was obtained through a single recrystallization. The second key catalytic allylation of ketone...

Zinc-mediated asymmetric additions of dialkylphosphine oxides to α,β-unsaturated ketones and N-sulfinylimines.

Abstract: A catalyst was synthesized on the basis of Trost's dinuclear catalyst characterized by working well without pyridine in the present phospha-Michael reaction. Nevertheless, the presence of pyridine is still advantageous in the present system. The substrate scope was successfully extended to enones employing diallyl phosphine oxide as a nucleophile. Excellent yields and enantioselectivities (up to >99% ee) were achieved for a wide scope of enones employing the catalyst under mild conditions. The detailed reaction mechanism is also discussed herein. Finally, the unprecedented asymmetric additions of dialkylphosphine oxides to N-sulfinylimines were achieved by using Et(2)Zn as a base.

Regioselective and stereoselective copper(I)-promoted allylation and conjugate addition of N-Boc-2-lithiopyrrolidine and N-Boc-2-lithiopiperidine.

Abstract: Copper salts have been screened for transmetalation and electrophilic quench of N-tert-butoxycarbonyl-2-lithiopyrrolidine (N-Boc-2-lithiopyrrolidine) and N-Boc-2-lithiopiperidine, formed by deprotonation of N-Boc-pyrrolidine and N-Boc-piperidine, respectively. Transmetalation with zinc chloride then (lithium chloride solubilized) copper cyanide followed by allylation typically gives mixtures of regioisomers (S(N)2 and S(N)2' products), whereas transmetalation with copper iodide.TMEDA then allylation occurs regioselectively (S(N)2 mechanism). Addition to an enone or alpha,beta-unsaturated ester occurs by 1,4-addition. Asymmetric deprotonation of N-Boc-pyrrolidine or dynamic resolution in the presence of a chiral ligand of N-Boc-2-lithiopiperidine followed by the zinc/copper chemistry was successful and gave the allylated pyrrolidine and piperidine products with good enantioselectivity, although use of the copper iodide chemistry resulted in some loss of enantiopurity. The chemistry provides formal syntheses of (+)-allosedridine, (+)-lasubine II, and (+)-pseudohygroline and has been used for the synthesis of (+)-coniine, (-)-pelletierine, (+)-coniceine, (-)-norhygrine, and the ant extract alkaloids cis- and trans-2-butyl-5-propylpyrrolidine.

Understanding the mechanism of stereoselective synthesis of cyclopentenes via N-heterocyclic carbene catalyzed reactions of enals with enones.

Abstract: The N-heterocyclic carbene (NHC) catalyzed addition of enals to enones to yield trans-cyclopentenes has been investigated using DFT methods at B3LYP/6-31G** computational level. This NHC catalyzed reaction comprises several steps. The first one is the formation of a Breslow intermediate, which nucleophilically attacks to the conjugated position of the enone to yield an enol-enolate. This second step is responsible for the trans relationship at the final cyclopentene. An intramolecular aldolic condensation allows for the formation of the alkoxy cyclopentane intermediate, that by intramolecular nucleophilic attack on the carbonyl group yields a bicyclic ether. The extrusion of the NHC catalyst affords a bicyclic lactone, yielding by CO2 elimination, the final trans-cyclopentene.

Total synthesis of (+)-nankakurines A and B and (±)-5-epi-nankakurine A.

Abstract: The first total syntheses of the Lycopodium alkaloids (+)-nankakurine A (2), (+)-nankakurine B (3), and the originally purported structure 1 of nankakurine A were accomplished. The syntheses of 2 and 3 feature a demanding intramolecular azomethine imine cycloaddition as the key step for generating the octahydro-3,5-ethanoquinoline moiety and installing the correct relative configuration at the spiropiperidine ring juncture. The cyclization precursor was prepared from octahydronaphthalene ketone 50, which was assembled from enone (+)-9 and diene 48 by a cationic Diels−Alder reaction. The Diels−Alder reactants were synthesized from 5-hexyn-1-ol (16) and (+)-pulegone (49), respectively. The tetracyclic ring system of 1 was generated using an unprecedented nitrogen-terminated aza-Prins cyclization cascade. The enantioselective total syntheses of (+)-nankakurine A (2) and (+)-nankakurine B (3) establish the relative and absolute configuration of these alkaloids and are sufficiently concise that substantial qua...

Diastereoselective [2+2] Photocycloaddition of Chiral Cyclic Enone and Cyclopentene Using a Microflow Reactor System

Abstract: Diastereoselective [2 + 2] photocycloaddition of chiral cyclohexenone 1 with cyclopentene was conducted using a continuous microflow reactor. This reaction led to photoadducts 2 and 3 in a shorter ...

Reversal of stereoselectivity in the Cu-catalyzed conjugate addition reaction of dialkylzinc to cyclic enone in the presence of a chiral azolium compound.

Abstract: Reversal of enantioselectivity in a Cu-catalyzed asymmetric conjugate addition reaction of dialkylzinc to cyclic enone with use of the same chiral ligand was successfully achieved. The reaction of 2-cyclohexen-1-one (30) with Et(2)Zn catalyzed by Cu(OTf)(2) in the presence of an azolium salt derived from a chiral beta-amino alcohol gave (S)-3-ethylcyclohexanone (31) in good enantioselectivity. Among a series of chiral azolium compounds examined, the benzimidazolium salt (10) having both a tert-butyl group at the stereogenic center and a benzyl substituent at the azolium ring was found to be the best choice of ligand in the Cu(OTf)(2)-catalyzed reaction. Good enantioselectivity was observed when the reaction was conducted by employing a benzimidazolium derivative rather than an imidazolium derivative. The influence of the substituent at the azolium ring on the stereoselectivity of the reaction was also examined. In addition, from the results of the reaction catalyzed by Cu(OTf)(2) combined with an azolium compound derived from (S)-leucine methyl ester, it was found that the hydroxy side chain in the chiral ligand is probably crucial for the enantiocontrol of the conjugate addition reaction. On the other hand, it was discovered from a screening test of copper species that the reversal of enantioselectivity was realized by allowing 30 to react with Et(2)Zn in the presence of Cu(acac)(2) combined with the same ligand precursor to afford (R)-31 as a major product. The influence of the stereodirecting group at the chiral ligand on the stereoselectivity in the Cu(acac)(2)-catalyzed reaction differed completely from that observed in the Cu(OTf)(2)-catalyzed reaction. Reaction with a cyclic enone consisting of a seven-membered ring such as 2-cyclohepten-1-one (40) resulted in increasing the enantioselectivity of the reaction. Thus, treatment of 40 with Et(2)Zn catalyzed by Cu(OTf)(2) combined with a benzimidazolium salt produced the corresponding (S)-conjugate adduct in a 92:8 enantiomer ratio (er), while the Cu(acac)(2)-catalyzed reaction with the same ligand afforded (R)-product in a 9:91 er.

A tandem reaction initiated by 1,4-addition of bis(iodozincio)methane for 1,3-diketone formation.

Abstract: Treatment of an γ-acyloxy-α,β-unsaturated ketone with bis(iodozincio)methane leads to a novel tandem reaction consisting of three steps: (1) 1,4-addition of the dizinc reagent to the enone, which affords the corresponding zinc enolate of the β-zinciomethylated ketone; (2) intramolecular nucleophilic attack by the enolate on the ester group; and (3) Grob-type fragmentation of the adduct, accompanied by elimination of the zinc alkoxide of allyl alcohol. The overall reaction gives 1,3-diketones efficiently.

An Enantioselective Total Synthesis of (+)‐Peloruside A

Abstract: Peloruside A (1), a potent microtubule stabilizer that acts in a manner synergistic to that of paclitaxel, was first isolated in 2000 by Northcote and coworkers from a marine sponge of the Pelorus Sound in New Zealand.[1] The absolute stereochemistry of 1 was established in De Brabander’s initial total synthesis in 2003,[2] and since then three other total syntheses have been reported.[3–5] Herein, we describe a convergent total synthesis of peloruside A in which three different enantioenriched epoxides (8, 9, and 11, Figure 1) obtained using asymmetric catalytic methodologies serve as the key building blocks for the stereochemically complex macrocyclic framework. A second key strategic feature is a chiral catalyst-controlled diastereoselective hetero-Diels–Alder reaction for the construction of intermediate 7. The application of direct catalyst control represents a complement to the previous synthetic approaches to peloruside A, which relied primarily on substrate- and auxiliary-based diastereocontrol to establish the relative and absolute stereochemical features of the natural product.[2–5] Figure 1 Retrosynthetic analysis of peloruside A Dissection of the seco ester form of peloruside A into fragments of roughly equal size and complexity suggested aldehyde 3 and enone 4 as potentially useful late-stage intermediates (Figure 1).[6] The synthesis of enone 4 began with a highly enantioselective Payne rearrangement of meso-epoxy diol 12, available in one step from commercial cis-2,3-butenediol, to enantioenriched terminal epoxide 14 (Scheme 1).[7] This transformation was catalyzed by oligomeric cobalt salen catalyst 13,[8] which establishes an equilibrium favoring terminal epoxide 14 over meso epoxide 12 in a 7:3 ratio. Epoxide 14 was unstable to purification, but protection as the primary silyl ether in situ and subsequent alkylation of the secondary alcohol provided the functionally-rich bis-protected epoxide 11 in good overall yield.[9] Scheme 1 Asymmetric Payne rearrangement and elaboration. Reagents and conditions: a) CuBr (10 mol%), vinyl magnesium bromide, −40 °C, 2 h; then HMPA, Me2SO4, rt, 48 h; b) O3, CH2Cl2, −78 °C; then PPh3, rt, 3 h; c) CuBr (10 mol%), ... Epoxide 11 was subjected to a one-pot vinyl cuprate addition/methylation, followed by ozonolysis to provide aldehyde 15 in 66% overall yield. In an analogous manner, enantiopure aldehyde 16 was obtained from racemic epoxide 9 via a high-yielding hydrolytic kinetic resolution (HKR)/vinylation/alkyation/ozonolysis sequence. Aldehyde 15 was then engaged in a hetero-Diels–Alder (HDA) reaction with trioxy-substituted diene 10, available in two steps from methyl benzyloxyacetate (see Supporting Information). Diene 10 proved highly sensitive to decomposition in the presence of strong Lewis acids, but cycloadditions catalyzed by (Schiff-base)chromium complexes were found to proceed cleanly. The degree of intrinsic substrate diastereocontrol was poor, as reaction with achiral chromium catalyst 17 afforded cycloadduct in 1:2 dr favoring the undesired isomer. However, the chiral chromium Schiff-base complex (1R,2S)-18[10] catalyzed formation of the desired product 7 in good yield and 7:1 dr favoring the desired isomer. Conversely, the enantiomeric catalyst (1S,2R)-18 provided the undesired diastereomer in high (1:11) selectivity. This represents one of the most demanding applications reported to date of the application of catalyst 18 in an HDA reaction between stereochemically and functionally complex substrates.[11] Hydrogenation of hetero-Diels–Alder adduct 7 took place diastereoselectively, and concomitant hydrogenolysis of the O-benzyl acetal provided 19 in 69% yield and in 10:1 dr.[12] Oxidation of lactol 19 and opening of the resulting lactone with N,O-dimethylamine hydrochloride afforded Weinreb amide 20, which was protected as the secondary TBS ether. Addition of isopropenylmagnesium bromide occurred with cleavage of the C8 acetate ester to provide hydroxyenone 21, which was purified chromatographically to >20:1 dr. The C8 hydroxyl group was then re-protected as the TBS ether to provide aldol coupling partner 4 (Scheme 3). Scheme 3 Elaboration of the hetero-Diels–Alder adduct 7 to enone 4. Reagents and conditions: a) Pd/C, i-PrOH, pH 7 buffer, H2 (200 psi), 48 h; b) KBr, TEMPO, NaOCl, pH 7 buffer, CH2Cl2, 0 °C, 90 min; c) N,O-dimethylamine hydrochloride, AlMe3, toluene, ... In the approach to aldehyde 3, epoxide 8 was prepared in high ee from enyne 24, available in two steps from commercial 3-pentyn-1-ol,[13] via a (salen)Mn-catalyzed epoxidation[14]/hydrolytic kinetic resolution (HKR) sequence.[15] Epoxide 8 was then opened stereospecifically and regioselectively at the propargylic position, and the resulting primary alcohol was protected as the triisopropylsilyl ether to provide alkyne 25 in 72% yield over two steps (Scheme 4). This strategy of opening a terminal epoxy-alkyne at the internal position with a simple Grignard reagent provides a concise and convenient method for the stereocontrolled synthesis of homopropargylic primary alcohols. Scheme 4 Synthesis of key aldehyde fragment 3. Reagents and conditions: a) 22 (5.0 mol%), NaOCl, CH2Cl2, 0 °C, 6.5 h;b) 23 (0.50 mol%), H2O, Et2O, 0 °C to rt, 24 h; c) ethylmagnesium chloride, THF, −78 °C to rt, 4 h; d) TIPSCl, ... Silyl ether 25 was further elaborated to vinyl bromide 5 via a one-pot hydroboration/bromination/elimination/silyl-deprotection sequence (Scheme 4).[16] Protection of the resultant primary alcohol as the benzyl ether provided compound 5 in 69% overall yield from 25.[17] This protecting-group exchange on the C20 hydroxyl proved advantageous because a large silyl protecting group was required for attaining high regioselectivity (9:1) in the hydroboration of compound 25, while the presence of a benzyl protecting group led to improved diastereoselctivity in the addition of the vinyl lithium reagent derived from 5 into aldehyde 17. In this manner, alcohol 26 was obtained in 5:1 dr and isolated in 64% yield following chromatographic purification. In contrast, analogous silyl-protected vinyl bromides (TIPS, TBDPS) led to the corresponding allylic alcohols in only 2:1 dr. Alcohol 26 was then protected as the paramethoxybenzyl ether, and the primary alcohol was selectively unmasked and oxidized with the Dess-Martin periodinane to provide aldehyde 3 in 58% yield over the 3 steps. Enone 4 and aldehyde 3 were coupled via a reductive aldol reaction similar to that utilized in the Ghosh synthesis of peloruside A[4] to afford 2 in 1.7:1 dr. Despite the modest stereoselectivity in this step, 2 could be isolated in diastereomerically pure form and in 52% yield following chromatographic purification (Scheme 5). The primary TBS ether was then removed selectively using buffered HF·pyridine and the resulting alchol oxidized to provide aldehyde 27 in 74% yield over the 2 steps. Aldehyde 27 was then oxidized to the corresponding acid, and the crude reaction mixture was subjected to pH 7 buffered DDQ to cleave the C15 PMB ether and afford the macrolaconization substrate. The seco acid was subjected without purification to Yamaguchi conditions to provide macrolactone 28 in 52% yield for the 3 steps from aldehyde 27. This macrolactonization strategy drew direct inspiration from the Evans approach to peloruside A employing a similarly protected seco acid,[5] wherein differentiation between free hydroxyl groups at C11 and C15 was also observed. Finally, the benzyl protecting group at the C20 hydroxyl was removed under transfer hydrogenolysis conditions, and a subsequent global deprotection of the remaining protecting groups under strongly acidic conditions[18] afforded (+)-peloruside A (1) in 57% isolated yield, with characterization data matching those reported for the natural product.[1] Scheme 5 Synthesis of (+)-peloruside A. Reagents and conditions: a) L-Selectride, THF, −78 °C, 2 h; then −40 °C, 2 h; b) HF·pyridine, pyridine, THF, 0 °C to rt, 2 h; c) bis-acetoxyiodobenzene, TEMPO, CH2Cl2, rt, ... This convergent synthesis of (+)-peloruside A required 20 steps in the longest linear sequence from commercially available materials. The approach relies on the availability of both simple (e.g. 8 and 9) and relatively complex (i.e., 11) terminal epoxides via (salen)Co-catalyzed ring-opening reactions, and on chiral catalyst-induced diastereocontrol in a key hetero-Diels–Alder cycloaddition reaction between advanced intermediates. The route provides a useful illustration of the applicability of modern asymmetric catalytic methods in the total synthesis of stereochemically complex polyketides.

Asymmetric Conjugate Addition of Nitromethane to Enones Catalyzed by Chiral N,N′-Dioxide–Scandium(III) Complexes

Abstract: The catalytic conjugate addition of nitroalkanes to a,b-unsaturated ketones is one of the most important processes in organic synthesis, since the corresponding products are very useful intermediates for the synthesis of a variety of more elaborate structures, such as amino alkanes, amino carbonyls, lactones, and pyrrolidines. In the past decades, tremendous effort has been devoted to this area; however, to the best of our knowledge, most of these syntheses are promoted by organocatalysts or phase-transfer catalysts, although reactions catalyzed by chiral metal complexes, such as heterobimetallic chiral catalysts, lanthanum trisbinaphthoxide, and a salen–Al complex, have also been reported. Furthermore, catalysts in previous studies generally suffer from limitations in substrate scope that mean they are only effective for one particular type of enone and catalysts with high efficiency for both chalcone and “cinnamone” derivatives have rarely been reported. Therefore, finding a simple, efficient synthesis for both of these types of enone, with high enantioselectivity and broad substrate scope, is still challenging and interesting. Herein, we report that a ScACHTUNGTRENNUNG(OTf)3/N,N’-dioxide complex efficiently promotes the Michael addition of nitromethanes to enones, providing the desired adducts in excellent yields (up to 99%) and excellent enantiomeric excesses (up to>99% for chalcone and up to 98% for “cinnamone” derivatives). The reaction between chalcone and nitromethane was selected as the model reaction for optimizing the conditions. A screening of different metals revealed that Sc ACHTUNGTRENNUNG(OTf)3 was superior to any other at giving the product (Table 1, entry 5 vs. 1–4). Subsequently, the structure of the N,N’-dioxide ligand was studied (L1–L5). It was shown that ligands with bulky groups at the ortho position of the aniline functionality, such as isopropyl groups, provide good results (Table 1, entry 8 vs. 6 and 7). As for the chiral backbone, if an (S)ramipril-derived N,N’-dioxide was used instead of those derived from l-proline or (S)-pipecolic acid, the result was slightly improved (>99% ee ; Table 1, entry 9). To further improve the efficiency of the reaction, several other reaction conditions, such as additives and solvents, [a] L. Wang, Q. Zhang, X. Zhou, Dr. X. Liu, Dr. L. Lin, Dr. B. Qin, Prof. Dr. X. Feng Key Laboratory of Green Chemistry & Technology Ministry of Education, College of Chemistry Sichuan University, Chengdu 610064 (China) Fax: (+86)28-8541-8249 E-mail : xmfeng@scu.edu.cn qinbo@163.com Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201000688. Table 1. Asymmetric Michael addition of nitromethane to chalcone.

Circular dichroism, optical rotation and absolute configuration of 2-cyclohexenone-cis-diol type phenol metabolites: redefining the role of substituents and 2-cyclohexenone conformation in electronic circular dichroism spectra

Abstract: The absolute configurations of 2-cyclohexenone cis-diol metabolites resulting from the biotransformation of the corresponding phenols have been determined by comparison of their experimental and calculated circular dichroism spectra (TDDFT at the PCM/B2LYP/Aug-cc-pVTZ level), optical rotations (calculated at the PCM/B3LYP/Aug-cc-pVTZ level) and by stereochemical correlation. It is found that circular dichroism spectra and optical rotations of 2-cyclohexenone derivatives are strongly dependent on the ring conformation (M or P sofa S(5) or half-chair), enone non-planarity and the nature and positions of the hydroxy and alkyl substituents. The effect of non-planarity of the enone chromophore, including the distortion of the CC bond, is determined for the model structures by TDDFT calculations at the PCM/B2LYP/6-311++G(2d,2p) level. Non-planarity of the CC bond in the enone chromophore is commonly encountered in 2-cyclohexenone derivatives and it is a source of significant rotatory strength contribution to the electronic circular dichroism spectra. It is shown that the two lowest-energy transitions in acrolein and 2-cyclohexenone and its derivatives are nCO–πCO* and πCC–πCO*, as expected, while the shorter-wavelength (below 200 nm) transitions are of more complex nature. In 2-cyclohexenone and its alkyl derivatives it is predominantly a mixture of πCC–πCC* and πCC–σ* transitions, whereas the presence of hydroxy substituent results in a dominant contribution due to the nOH–πCO* transition. A generalized model for correlation of the CD spectra of 2-cyclohexenones with their structures is presented.

Rhodium‐Catalysed Intermolecular Alkyne Hydroacylation: The Enantioselective Synthesis of α‐ and β‐Substituted Ketones by Kinetic Resolution

Abstract: Chemical Equation Presented Cleared up! Intermolecular alkyne hydroacylation represents a new addition to the range of transition- metalcatalysed hydroacylation reactions that can be performed in an enantioselective manner. By using a kinetic resolution procedure, both racemic α- and βsubstituted aldehydes can be converted into the corresponding enantiomerically enriched substituted enone products (see scheme). © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Conjugate Addition of Lithiated Methyl Pyridines to Enones

Abstract: Preparatively useful conjugate addition of lithiated methyl pyridines to cyclic and acyclic enones is reported. Addition of 2-picoline to 3-penten-2-one led to a concise synthesis of the alkaloids (±)-senepodine G and (±)-cermizine C.

Asymmetric construction of quaternary stereocenters by direct conjugate addition of oxindoles to enone

Abstract: Chiral cinchona-based primary amine A was found to catalyze the asymmetric direct conjugate addition of prochiral 3-oxindoles with enones to afford 3,3-disubstituted oxindoles in good yields, moderate to high diastereoselectivities, and excellent enantioselectivities.

Quinoline‐containing networks from enone and aldehyde triglyceride derivatives

Abstract: The crosslinking reaction of a triglyceride derivative containing α,β-unsaturated ketones with diaminodiphenylmethane via aza-Michael addition has been extensively studied. First, a model study with monofunctional compounds showed that the conjugated addition product undergoes a series of transformations leading to formation of a substituted quinoline. The proposed reaction pathway is presented as a variation of the Skraup-Doebner-Von Miller quinoline synthesis. The presence of quinolines as crosslinking points in the cured materials has been proved by means of different characterization techniques, and the properties derived from this aromatization process have been described. This new crosslinking approach has been successfully applied to an aldehyde-containing triglyceride to obtain quinoline-containing thermoses.

Regioselective Nickel-Catalyzed Reductive Couplings of Enones and Allenes

Abstract: Catalytic reductive coupling processes have been developed in numerous contexts as a strategy for the regioand stereoselective installation of alkenes. The direct coupling of a polar p system with a relatively nonpolar p system is often a successful strategy for selectively accomplishing synthetically desirable heterocouplings while avoiding undesired homocoupling of either reagent. For example, reductive couplings of aldehydes, enones, enals, or imines paired with alkynes, alkenes, or allenes have been extensively developed in recent years. Processes of this type are often highly effective in controlling both the position and stereochemistry of di-, tri-, and tetrasubstituted alkenes within polyfunctional molecules. Among these methods, the preparation of g,dunsaturated carbonyl groups by nickeland cobalt-catalyzed processes has been the subject of considerable study. The catalytic strategies developed for synthesis of g,d-unsaturated carbonyl groups by the coupling of two p-containing components include enone–alkyne additions in work reported by our group and by Cheng and co-workers, and enone–alkene additions in work reported by Jamison and co-workers, and Ogoshi et al. (Scheme 1). Processes of this type provide an important counterpart to organocuprate technology and hydrometallative processes, while having the advantage of not requiring the stoichiometric preparation of an alkenyl metal species. Stereodefined trisubstituted alkenes 1, trans-disubstituted alkenes 2, and monosubstituted alkenes 3 may be readily prepared by the above-mentioned enone–alkyne and enone– alkene coupling processes. However, a general strategy for the preparation of 1,1-disubstituted alkenes 4 by these methods has not been developed. Since terminal alkyne reductive coupling strategies and hydrometallative processes typically favor formation of the conjugate addition product 2 with a 1,2-disubstituted alkene, the 1,1-disubstituted alkene 4 is considerably more difficult to prepare. As depicted below (Scheme 2), regiocontrolled reductive coupling of an

Organocatalytic Enantioselective Michael Additions of Malonates to 2-Cyclopentenone

Abstract: The Michael reaction of a dialkyl malonate to a cyclic enone using a chiral diamine/acid combination catalyst gave the desired Michael adduct in high yield with excellent enantiomeric excess in a protic solvent such as methanol and ethanol. The methanol molecule participates in a proton relay system in which the dialkyl malonate is activated through hydrogen bonding to afford the Michael adduct with excellent enantioselectivity.