Showing papers on "Bicyclic molecule published in 2010"

Copper-promoted and copper-catalyzed intermolecular alkene diamination.

Abstract: Olefin diamination methods provide powerful access to vicinal diamines useful in drug discovery, materials and catalysis.[1] A number of impressive diastereoselective, enantioselective and catalytic olefin diamination methods have been recently reported.[2–7] The intramolecular olefin diamination forms nitrogen heterocycles directly and has predominantly been accomplished by using tethered amine nucleophiles wherein both amine additions occur in intramolecular fashion (cf. Scheme 1). This olefin diamination strategy has been reduced to practice by using palladium,[4a] nickel[4b] and gold[4c] catalysts and stoichiometric copper reagents[3] and has resulted in the synthesis of a number of interesting compounds such as bicyclic sulfamides, ureas and guanidines. An intra/intermolecular alkene diamination would result in the convergent formation of one new nitrogen heterocycle along with the installation of a differently functionalized amine substituent. In a recent report, Michael and co-workers found that the use of a palladium catalyst, in combination with N-fluorobenzenesulfonimide led to the formation of nitrogen heterocycles with –CH2N(SO2Ph)2 substitution.[5] Herein we report a new copper(II)-promoted and catalyzed intra/intermolecular diamination of alkenes that engages a wide range of internal and external amine sources for the formation of differently functionalized and various nitrogen heterocycles. Importantly, this communication reports the first intramolecular diamination protocol where catalyst-based asymmetric induction has been observed (vide infra). Impressive catalytic enantioselective intermolecular olefin diaminations have been reported,[2] but no enantioselective intramolecular variant has been reported.[8] Herein is reported our progress towards this elusive transformation. Scheme 1 Previous work: Copper-promoted doubly intramolecular alkene diamination. ND = neodecanoate. The copper(II)-promoted and catalyzed intra/intermolecular alkene diamination protocols disclosed herein are an advance on earlier studies by our lab which involved the synthesis of bicyclic sulfamides and ureas via a tethered olefin diamination approach (Scheme 1).[3] We have recently found that we can expand this process to involve the participation of an external amine source in the second C-N bond-forming step (Table 1). Table 1 Copper(II)-promoted intra/intermolecular diamination of N-allyl ureas. Thus, heating 1-allyl-1-benzyl-2-phenyl urea (1a) in the presence of copper(II) 2-ethylhexanoate, Cu(EH)2 (3 equiv), Cs2CO3 and aniline (1.5 equiv) in PhCF3 for 24 h provides imidazolidin-2-one 2a in 92% yield (Table 1, Conditions A). Other copper-promoted processes such as intramolecular carboamination,[9] aminoacetoxylation[9e] and hydroamination[9b] can occur with the substrates used in this study (see Supporting Information), but the intra/intermolecular diamination process appears to be most favorable when the reaction is run in the presence of an external amine nucleophile. A number of substituted anilines (substitutents = Cl, CF3, Me, F, OMe, i-Pr, NO2) also participated as the external amine in this diamination process, providing 2b–2i in good to excellent yield (Table 1). The amount of substituted aniline had to be increased to 3 equiv (Conditions B) in order to minimize competititve formation of 2a, a product that can originate from the creation of PhNH2 from partial decomposition of 1a under the reaction conditions. In addition, at least 2 equiv of Cu(EH)2 is necessary to minimize formation of a hydroamination side product (see Supporting Information for optimization tables). Sodium azide,[10] benzamide and p-toluene sulfonamide were also competent nucleophiles in this diamination reaction (entries 10–12, Table 1). The 4,4-disubstituted imidazolidin-2-one 4 was formed efficiently from diamination/cyclization of the corresponding 1,1-disubstituted alkenyl urea 3 (Scheme 2). Gratifyingly, chiral imidazolidin-2-ones 6 were formed with high 4,5-trans selectivity from the corresponding alkenyl urea substrate 5 (Scheme 3). Formation of the trans diastereomer can be rationalized via cyclic transition state A, where the substituent adopts a pseudo-equatorial position. Scheme 2 Diaminations of a 1,1-disubstituted alkenyl urea. Scheme 3 High diastereoselectivity for allylic substituted ureas. N-aryl-γ-pentenyl amides, and sulfonamides with different γ-alkenyl backbones, were also good substrates in this intra/intermolecular diamination reaction (Table 2). Both 2,5-cis and 2,5-trans pyrrolidines can be formed with high diastereoselectivity (Table 2, entries 10–12). Table 2 Copper(II)-promoted intra/intermolecular diamination of γ-alkenyl amides and sulfonamides.[a] In general it appears that electron-deficient anilines are better coupling partners than electron-rich anilines in this reaction. For example, the electron-deficient p-trifluoromethylaniline provided the highest yield with 1a, giving 97% of 2f (Table 1, entry 6), while only the product of substrate decomposition, 2a, was observed in the attempted diamination with p-methoxyaniline with 1a. p-Methoxyaniline was marginally competent in the diamination reaction with N-tosyl-orthoallylaniline (which cannot undergo the same decomposition), giving 12d in 42% yield (Table 2, entry 7). Electron-rich amines may bind too tightly to the copper promoter, thereby inhibiting either or both of the C-N bond forming steps. To gain insight into the formation of the second C-N bond, we subjected the trans-deuterated alkene d-13[9b] to the diamination reaction (Scheme 4). Partial conversion led to isolation of a 1:1 ratio of diamination diastereomers d-14a (64%) and 25% of d-13, recovered without alkene isomerization. We interpret this to indicate the irreversible formation of a transient primary carbon radical (as in Scheme 5), the result of C-Cu(II) bond homolysis.[3,9b] The radical can then recombine with Cu(II) to generate a C-Cu(III) intermediate which may then undergo RNH2 and reductive elimination to produce the observed diamine product (Scheme 5). Scheme 4 Isotopic labeling experiment. Scheme 5 Origin of 2,5-cis-pyrrolidine diastereoselectivity. We interpret the 2,5-cis-pyrrolidine selectivity shown in products 16 and 18 to be the result of the first C-N bond formation occurring through either the chair-like or boat-like transition states in Scheme 5, where the dominant stereochemistry-determining interaction is avoidance of steric hindrance between the alpha-substituent and the N-substituent.[9] This diastereoselectivity can be switched to favor the 2,5-trans-pyrrolidine (cf. 20) by connecting these two substituents directly to one another.[11] Our initial attempts to render this diamination reaction catalytic in copper(II) using MnO2 as stoichiometric oxidant with either N-allyl urea 1a or N-sulfonyl ortho-allylaniline 11a and aniline or NaN3 as nucleophiles led to no reaction. MnO2 is a competent oxidant in our previously reported copper-catalyzed carboamination reaction.[9c,e] Sulfamide and urea substrates such as those shown in Scheme 1 also failed to undergo copper-catalyzed doubly intramolecular alkene diamination. To our delight, however, when p-TolSO2NH2 was used as the nucleophile with substrates 1a and 11a, the catalytic intra/intermolecular alkene diamination reactions occurred efficiently (Table 3). Superior yields (87% vs 72%, entry 1) were obtained when 2,6-di-tert-butyl-4-methyl pyridine was used as base instead of Cs2CO3. Table 3 Copper(II)-catalyzed intra/intermolecular diamination of alkenes.[a] We next challenged the reaction in the catalytic enantioselective manifold. When copper(II) triflate (30 mol%) complexed with (R)-Ph-bis(oxazoline) ligand (37.5 mol%) was used, diamination adduct 12e was obtained in 51% yield and 71% ee (Scheme 6). The major enantiomer is tentatively assigned S by analogy.[9c] This is a promising lead for development of the elusive catalytic enantioselective intramolecular alkene diamination reaction. Mechanistically, this reaction clearly demonstrates copper is present in the C-N bond-forming step (as indicated in Schemes 3 and ​and5).5). Further optimization of the catalytic enantioselective process is underway in our labs. Scheme 6 Enantioselective copper(II)-catalyzed intra/intermolecular alkene diamination (%ee determined by chiral HPLC).

The synthesis and properties of 1,4‐diketo‐pyrrolo[3,4‐C]pyrroles

Abstract: Syntheses and mechanistic aspects of formation of 1,4-Diketopyrrolo[3,4-c]pyrroles (DPP) are discussed. The chemical reactivity of this novel class of heterocycles is illustrated by specific electrophilic aromatic and N-substitution reactions, as well as by nucleophilic transformations of the bicyclic lactam carbonyl group. X-ray structural analysis of the diphenyl-DPP molecule reveals significant intermolecular hydrogen bonding and π-π interactions in the solid state.

Palladium-Catalyzed Cross-Coupling of Internal Alkenes with Terminal Alkenes to Functionalized 1,3-Butadienes Using C-H Bond Activation: Efficient Synthesis of Bicyclic Pyridones

Abstract: Transition-metal-catalyzed cross-coupling through C H bond activation is emerging as one of the most important tools for carbon–carbon bond formation. In general, vinylogous compounds can be synthesized by Wittig, Heck, and Suzuki reactions, from the condensation of carbonyl compounds, C H addition to alkynes, or by means of organometallic alkenyl compounds, but direct alkenylation using C H bond activation remains particularly attractive for constructing carbon–carbon double bonds owing to their synthetic simplicity and use of readily available reagents. Vinylborates, vinyl halides, alkenyl acetates, and cyclic 1,3-dicarbonyls have been known for the direct alkenylation of arene and (hetero)arene C H bonds. In a more simple and synthetically useful alkenylation, terminal alkenes have been applied as the coupling partners. However, little attention has been paid to the direct alkenylation of alkenyl C H bonds with an alkene as the coupling partner using C H bond activation. 1,3-Butadienes, as a class of versatile organic synthetic reagents, have usually been prepared by indirect methods. To date, only two reports have been documented for their direct synthesis, involving coupling two simple terminal alkenes, owing to the difficulty in activating two alkene substrates at the same time (Scheme 1). Although two examples involving the reaction of 3-methyl-1H-indenes with tert-butyl acrylate were also reported, no work has been directed to the direct alkenylation of open-chain internal alkenes with another alkene as the coupling partner. In order to realize the direct cross-coupling of an internal alkene with a terminal alkene, the low reactivity of an internal alkenyl C H bond should be overcome. We envisioned the introduction of a structural element that could increase the reactivity of an internal alkenyl C H bond. Thus, we hypothesized that a 1,2-dithiane group at the terminal position of an alkene should satisfy the requirement on activating an internal alkenyl C H bond, and a-oxoketene dithioacetals were chosen as the internal alkenes. Herein, we report the palladium(II)-catalyzed direct cross-coupling of a-oxoketene dithioacetals with terminal alkenes as well as the synthesis of bicyclic pyridones [Eq. (1)].

Bicyclic cyclohexose nucleic acid analogs

Abstract: The present invention provides bicyclic cyclohexose nucleoside analogs and oligomeric compounds comprising these nucleoside analogs. These bicyclic nucleoside analogs are useful for enhancing properties of oligomeric compounds including nuclease resistance.

Direct Asymmetric Aldol Reaction of 5H-Oxazol-4-ones with Aldehydes Catalyzed by Chiral Guanidines

Abstract: A new chiral bicyclic guanidine-catalyzed direct catalytic aldol reaction of 5H-oxazol-4-ones with aldehydes has been developed. The present aldol reaction proceeds smoothly with high enantioselectivity using bicyclic guanidines bearing a hydroxy group at the appropriate position, and various combinations of 5H-oxazol-4-ones and aldehydes are applicable. The method provides synthetically useful α,β-dihydroxycarboxylates bearing a chiral quaternary stereogenic center at the α-carbon atom.

Intramolecular oxamidation of unsaturated O-alkyl hydroxamates: a remarkably versatile entry to hydroxy lactams.

Abstract: The development of a versatile method for the preparation of five- to eight-membered hydroxy lactams that involves the iodine(III)-mediated oxamidation of unsaturated O-alkyl hydroxamates is described. This transformation, which is believed to proceed through the intermediacy of singlet nitrenium and bicyclic N-acyl-N-alkoxyaziridinium ions, is both stereospecific and highly regioselective in most of the 22 cases examined.

A Metal-Catalyzed Intermolecular [5+2] Cycloaddition/Nazarov Cyclization Sequence and Cascade

Abstract: The bicyclo[5.3.0]decane skeleton is one of the most commonly encountered bicyclic subunits in nature and the core scaffold of a wide range of targets of structural, biological, and therapeutic importance. Prompted by the interest in such structures, we report the first studies of metal-catalyzed [5+2] cycloadditions of vinylcyclopropanes (VCPs) and enynones. The resultant efficiently formed dienone cycloadducts serve as substrates for subsequent Nazarov cyclizations and as intermediates for single-operation [5+2]/Nazarov serial reactions and catalytic cascades. In many cases the one-flask process can be carried out in shorter reaction times and with comparable or superior yields to the two-flask procedure. Significantly, a single catalyst can be used to mediate both transformations. These [5+2]/Nazarov reaction sequences and cascades collectively provide strategically novel and facile access to the bicyclo[5.3.0]decane skeleton from simple and readily available components.

Novel benzodiazepine derivatives

Abstract: The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepines of formula (I) and (II), in which the diazepine ring (B) is fused with a heterocyclic ring (CD), wherein the heterocyclic ring is bicyclic or a compound of formula (III), in which the diazepine ring (B) is fused with a heterocyclic ring (C), wherein the heterocyclic ring is monocyclic. The invention provides cytotoxic dimers of these compounds. The invention also provides conjugates of the monomers and the dimers. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention. The invention further relates to methods of using the compounds or conjugates for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

Rhodium(I)‐Catalyzed Intramolecular [5+2] Cycloaddition Reactions of Alkynes and Allenylcyclopropanes: Construction of Bicyclo[5.4.0]undecatrienes and Bicyclo[5.5.0]dodecatrienes

Abstract: Highly strained cyclopropane derivatives have served as useful and powerful C3 building blocks [1] for the construction of various ring systems, and the metal-catalyzed cleavage of the activated carbon-carbon s bond of the cyclopropane ring 3] must be one of the most attractive methods from a synthetic point of view. Of particular interest is the Rhcatalyzed [5+2] cycloaddition of vinylcyclopropanes with carbon–carbon p-components for the efficient formation of seven-membered compounds. In 1995, Wender et al. reported the first example of the Rh-catalyzed [5+2] cycloaddition reaction of vinylcyclopropanes with alkynes to provide bicyclo[5.3.0]decadienes. This method was successfully applied to the [5+2] cycloaddition reactions of allenes as well as alkenes 4a] as an alternative carbon–carbon p-counterpart. In sharp contrast to the extensive investigation of vinylcyclopropanes, 3–5] very few examples of the ringclosing reaction of allenylcyclopropane, which is regarded as an alkylidene homologue of vinylcyclopropane, have been reported. Two representative examples are shown in Scheme 1; one involves the Rh-catalyzed cycloisomeriza-

Investigation of the role of bicyclic peroxy radicals in the oxidation mechanism of toluene.

Abstract: The products of the primary OH-initiated oxidation of toluene were investigated using the turbulent flow chemical ionization mass spectrometry technique under different oxygen, NO, and initial OH radical concentrations as well as a range of total pressures. The bicyclic peroxy radical intermediate, a key proposed intermediate species in the Master Chemical Mechanism (MCM) for the atmospheric oxidation of toluene, was detected for the first time. The toluene oxidation mechanism was shown to have a strong oxygen concentration dependence, presumably due to the central role of the bicyclic peroxy radical in determining the stable product distribution at atmospheric oxygen concentrations. The results also suggest a potential role for bicyclic peroxy radical + HO2 reactions at high HO2/NO ratios. These reactions are postulated to be a source of the inconsistencies between environmental chamber results and predictions from the MCM.

Substituted isoquinolinones and quinazolinones

Abstract: The invention relates to substituted nitrogen containing bicyclic heterocycles of the formula (I): wherein Z is CH2 or N-R4 and X, R1, R2, R4, R6, R7 and n are as defined in the description. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of MDM2 and/or MDM4, or variants thereof.

Cysteine protease inhibitors

Abstract: In formula (IV) R1 = R'C(O), R'SO2, R' = a bicyclic, saturated or unsaturated, 8-12 membered ring system containing 0-4 hetero atoms selected from S, O and N, which is optionally substituted with up to four substituents independently selected from groups a), b), and c) below; or R'= a monocyclic, saturated or unsaturated, 5-7 membered ring containing 0-3 hetero atoms selected from S, O and N, which monocyclic ring bears at least one substituent selected from group a) and/or c) and which may optionally bear one or two further substituents selected from group b); R4 = H, C1-7-alkyl, Ar-C1-7-alkyl, Ar, C3-7-cycloalkyl; C2-7-alkenyl; R3 = C1-7-alkyl, C2-C7 alkenyl, C2-C7 alkenyl, C3-7-cycloalkyl, Ar-C1-7-alkyl, Ar; R5 = C1-7-alkyl, halogen, Ar-C1-7-alkyl, C0-3-alkyl-CONR3R4 or a bulky amine, R6 is H, C1-7-alkyl, Ar-C1-7-alkyl, C1-3-alkyl-SO2-Rix, C1-3-alkyl-C(O)-NHRix or CH?2?XAr, q is 0 or 1, have utility as inhibitors of cysteine proteases such as cathepsin K and falcipain.

Enantioselective Intermolecular Aldehyde–Ketone Cross‐Coupling through an Enzymatic Carboligation Reaction

Abstract: Thiamine diphosphate (ThDP)-dependent enzymes are well-established catalysts in the field of asymmetric synthesis.[1] One of the example reactions catalyzed by various types of these enzymes are asymmetric C-C-bond formations of two aldehydes which lead to the formation of 2-hydroxyketones with high enantioselectivity.[2] The exchange of one of the aldehydes in this reaction with a ketone[3] would offer the opportunity for the catalytic asymmetric formation of chiral tertiary alcohols, which are important structural units in natural products and bioactive agents.[4,5] During the last decade different organocatalysts for asymmetric crossed aldehyde-ketone benzoin reaction were developed.[6] Intramolecular variants of this reaction are already described in the literature.[7,8] Most recently, Enders and Henseler described the direct intermolecular cross-benzoin type reaction of aldehydes with trifluoromethyl ketones using a bicyclic triazolium salt as catalyst.[9] Due to the lower electrophilicity of the carbonyl group of ketones and the increased steric hindrance compared to aldehydes, the asymmetric intermolecular non-enzymatic coupling reaction with ketones as acceptors seems to be more difficult and has not been successful yet. Here we present the first example of an asymmetric intermolecular crossed aldehyde-ketone carboligation reaction using a ThDP-dependent enzyme as catalyst (Scheme 1).

Regioselective synthesis of heterocycles containing nitrogen neighboring an aromatic ring by reductive ring expansion using diisobutylaluminum hydride and studies on the reaction mechanism

Abstract: A systematic investigation of the reductive ring-expansion reaction of cyclic ketoximes fused to aromatic rings with diisobutylaluminum hydride (DIBALH) is described. This reaction regioselectively afforded a variety of five- to eight-membered bicyclic heterocycles or tricyclic heterocycles containing nitrogen neighboring an aromatic ring, including indoline, 1,2,3,4,5,6-hexahydrobenz[b]azocine, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine, 1,2,3,4,5,6-hexahydroazepino[3,2-b]indole, 2,3,4,5-tetrahydro-1H-benzothieno[2,3-b]azepine, 2,3,4,5-tetrahydro-1H-benzothieno[3,2-b]azepine, 5,6-dihydrophenanthridine, and 5,6,11,12-tetrahydrodibenz[b, f]azocine. The reaction mechanism leading to the rearrangement was investigated on the basis of the restricted Becke three-parameter plus Lee−Yang−Parr (B3LYP) density functional theory (DFT) with the 6-31G (d) basis set. It was found that the reaction proceeds through a three-centered transition state via a stepwise mechanism because th...

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.

Effect of protonation on the electronic structure of aromatic molecules: naphthaleneH+

Abstract: Protonated naphthalene, the smallest protonated polycyclic aromatic hydrocarbon cation, absorbs in the visible, around 500 nm, which corresponds to an unusually large red shift with respect to the neutral naphthalene counterpart.

Total synthesis of (-)-anominine.

Abstract: The first total synthesis of anominine has been achieved, and the absolute configuration of the product has been determined. The key features include the development of a new, highly efficient organocatalyzed method for the asymmetric synthesis of Wieland-Miescher ketone building blocks, an unusual selenoxide [2,3]-sigmatropic rearrangement, and a ZrCl(4)-catalyzed indole coupling as well as several chemoselective transformations controlled by the structurally congested nature of the bicyclic core.

Total synthesis of the antimitotic bicyclic peptide celogentin C.

Abstract: An account of the total synthesis of celogentin C is presented. A right-to-left synthetic approach to this bicyclic octapeptide was unsuccessful due to an inability to elaborate derivatives of the right-hand ring. In the course of these efforts, it was discovered that the mild Braslau modification of the McFadyen−Stevens reaction offers a useful method of reducing recalcitrant esters to aldehydes. A left-to-right synthetic strategy was then examined. The unusual Leu−Trp side-chain cross-link present in the left-hand macrocycle was fashioned via a three-step sequence comprised of an intermolecular Knoevenagel condensation, a radical conjugate addition, and a SmI2-mediated nitro reduction. A subsequent macrolactamization provided the desired ring system. The high yield and concise nature of the left-hand ring synthesis offset the modest diastereoselectivity of the radical conjugate addition. Formation of the Trp−His side-chain linkage characteristic of the right-hand ring was then accomplished by means of a...

Stereoselective construction of halogenated quaternary stereogenic centers via catalytic asymmetric Diels-Alder reaction.

Abstract: Highly enantioselective Diels-Alder reactions of alpha-halo-alpha,beta-unsaturated ketones with Lewis acid-activated chiral oxazaborolidine 1 are described. The reaction with alpha-fluoroenones provided the corresponding cyclohexane derivatives having a fluorinated quaternary stereogenic center with up to 99% de and 94% ee. The reaction with alpha-bromo cyclic enones provided the corresponding bromo bicyclic adducts with up to 99% de and 95% ee. A brominated cis-fused bicyclic adduct derived from 2-bromocyclopenten-1-one and Dane's diene was converted to the trans-fused bicyclic system via reductive alkylation with the bulky aluminum reagent aluminum tris(2,6-diphenylphenoxide) (ATPH). With this process, formal syntheses of (+)-estrone and norgestrel have been demonstrated.