Showing papers on "Bicyclic molecule published in 2009"

Phage-encoded combinatorial chemical libraries based on bicyclic peptides.

Abstract: Here we describe a phage strategy for the selection of ligands based on bicyclic or linear peptides attached covalently to an organic core. We designed peptide repertoires with three reactive cysteine residues, each spaced apart by several random amino acid residues, and we fused the repertoires to the phage gene-3-protein. Conjugation with tris-(bromomethyl)benzene via the reactive cysteines generated repertoires of peptide conjugates with two peptide loops anchored to a mesitylene core. Iterative affinity selections yielded several enzyme inhibitors; after further mutagenesis and selection, we were able to chemically synthesize a lead inhibitor (PK15; Ki = 1.5 nM) specific to human plasma kallikrein that efficiently interrupted the intrinsic coagulation pathway in human plasma tested ex vivo. This approach offers a powerful means of generating and selecting bicyclic macrocycles (or if cleaved, linear derivatives thereof) as ligands poised at the interface of small-molecule drugs and biologics.

Mn(III)-mediated reactions of cyclopropanols with vinyl azides: synthesis of pyridine and 2-azabicyclo[3.3.1]non-2-en-1-ol derivatives.

Abstract: A Mn(III)-mediated divergent synthesis of substituted pyridines and 2-azabicyclo[3.3.1]non-2-en-1-ol derivatives was exploited using readily available vinyl azides and cyclopropanols with a wide range of substituents. In short, the reactions of vinyl azides with monocyclic cyclopropanol provided pyridines in the presence of Mn(acac)3 (1.7 equiv), whereas those with bicyclic cyclopropanols led to the formation of 2-azabicyclo[3.3.1]non-2-en-1-ol derivatives using a catalytic amount of Mn(acac)3. These reactions may be initiated by a radical addition of β-keto radicals, generated by the one-electron oxidation of cyclopropanols, to vinyl azides to give iminyl radicals, which would cyclize with the intramolecular carbonyl groups. In addition, versatile transformations of 2-azabicyclo[3.3.1]non-2-en-1-ol to 2-azabicyclo[3.3.1]nonane or -non-2-nen frameworks were developed.

Gold-Catalyzed [4C+2C] Cycloadditions of Allenedienes, including an Enantioselective Version with New Phosphoramidite-Based Catalysts: Mechanistic Aspects of the Divergence between [4C+3C] and [4C+2C] Pathways

Abstract: Gold(I) complexes featuring electron acceptor ligands such as phosphites and phosphoramidites catalyze the [4C+2C] intramolecular cycloaddition of allenedienes. The reaction is chemo- and stereoselective, and provides trans-fused bicyclic cycloadducts in good yields. Moreover, using novel chiral phosphoramidite-based gold catalysts it is possible to perform the reaction with excellent enantioselectivity. Experimental and theoretical data dismiss a cationic mechanism involving intermediate II and suggest that the formation of the [4C+2C] cycloadducts might arise from a 1,2-alkyl migration (ring contraction) in a cycloheptenyl Au-carbene intermediate (IV), itself arising from a [4C+3C] concerted cycloaddition of the allenediene. Therefore, these [4C+2C] allenediene cycloadditions and the previously reported [4C+3C] counterparts most likely share such cycloaddition step, differing in the final 1,2-migration step.

Cyclic Guanidine Organic Catalysts: What Is Magic About Triazabicyclodecene?

Abstract: The bicyclic guanidine 1,5,7- triazabicyclo[4.4.0]dec-5-ene (TBD) is an effective organocatalyst for the formation of amides from esters and primary amines. Mechanistic and kinetic investigations support a nucleophilic mechanism where TBD reacts reversibly with esters to generate an acyl-TBD intermediate that acylates amines to generate the amides. Comparative investigations of the analogous bicyclic guanidine 1,4,6-triazabicyclo[3.3.0]oct-4-ene (TBO) reveal it to be a much less active acylation catalyst than TBD. Theoretical and mechanistic studies imply that the higher reactivity of TBD is a consequence of both its higher basicity and nucleophilicity than TBO as well as the high reactivity of the acyl-TBD intermediate, which is sterically prevented from adopting a planar amide structure.

Substituted alpha-l-bicyclic nucleosides

Abstract: The present disclosure describes substituted α-L-bicyclic nucleoside analogs, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, substituted α-L-bicyclic nucleoside analogs are provided, having one or more chiral substituents, that are useful for enhancing properties of oligomeric compounds including binding affinity. In some embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.

Gold‐ and Platinum‐Catalyzed Cycloisomerization of Enynyl Esters versus Allenenyl Esters: An Experimental and Theoretical Study

Abstract: Ester-way to heaven: Unexpected formation of bicyclo[3.1.0]hexene 4 was the main focus of combined experimental and theoretical studies on the Au-catalyzed cycloisomerization of branched dienyne 1 (see scheme), which provided better understanding of the mechanistic details governing the cyclization of enynes bearing a propargylic ester group.Experimental and theoretical studies on Au- and Pt-catalyzed cycloisomerization of a branched dienyne with an acetate group at the propargylic position are presented. The peculiar architecture of the dienyne precursor, which has both a 1,6- and a 1,5-enyne skeleton, leads, in the presence of alkynophilic gold catalysts, to mixtures of bicyclic compounds 3, 4, and 5. Formation of unprecedented bicyclo[3.1.0]hexene 5 is the main focus of this study. The effect of the ancillary ligand on the gold center was examined and found to be crucial for formation of 5. Further mechanistic studies, involving cyclization of an enantioenriched dienyne precursor, (18)O-labeling experiments, and DFT calculations, allowed an unprecedented reaction pathway to be proposed. We show that bicyclo[3.1.0]hexene 5 is likely formed by a 1,3-OAc shift/allene-ene cyclization/1,2-OAc shift sequence, as calculated by DFT and supported by Au-catalyzed cyclization of isolated allenenyl acetate 7, which leads to improved selectivity in the formation of 5. Additionally, the possibility of OAc migration from allenyl acetates was supported by a trapping experiment with styrene that afforded the corresponding cyclopropane derivative. This unprecedented generation of a vinyl metal carbene from an allenyl ester supports a facile enynyl ester/allenenyl ester equilibrium. Further examination of the difference in reactivity between enynyl acetates and their corresponding [3,3]-rearranged allenenyl acetates toward Au- and Pt-catalyzed cycloisomerization is also presented.

An Organocatalytic Asymmetric Tandem Reaction for the Construction of Bicyclic Skeletons

Abstract: Cyclic ketones react with (E)-2-nitroallylic acetates in the presence of catalytic pyrrolidine-thiourea, which affords bicyclic skeletons with four or five stereocenters in one single reaction with up to 98 % ee in moderate to high yields. The cooperative effects of both enamine and the Bronsted acid are found to be crucial for the high reactivity and enantioselectivity of this cascade reaction, which is demonstrated by both theoretical calculation and experimental data.

Bicyclic cyclohexitol nucleic acid analogs

Abstract: The present disclosure provides bicyclic cyclohexitol nucleoside analogs of formula I and oligomeric compounds comprising these nucleoside analogs. These bicyclic nucleoside analogs are expected to be useful for enhancing properties of oligomeric compounds including for example nuclease resistance.

A Stereoselective Synthesis of the Bromopyrrole Natural Product (―)-Agelastatin A

Abstract: Agelastatin A and its congeners are a structurally intriguing class of bromopyrrole-based natural products comprised of a densely functionalized cyclopentane core adorned with four contiguous nitrogen substituent groups (Figure 1).[1] Agelastatin A and B were first isolated in 1993 from the Coral Sea marine sponge Agelas dendromorpha.[2] Subsequently, agelastatin C and D were identified in extracts from the Australian sponge Cymbastela sp.[3] The unique structural features of these compounds together with their powerful cytotoxic activities against certain human cancer cell lines have fueled efforts aimed at their de novo synthesis.[4,5] To date, seven completed syntheses of agelastatin A have appeared, each presenting a decidedly different strategy for assembly of the natural product.[6,7] For our purpose, structures such as agelastatin A serve to inspire the development of new catalytic methods for oxidative C–N bond formation. In this report, we detail an 11-step synthesis of this natural product made possible with the advent of a highly selective and efficient intramolecular olefin aziridination method.[8,9] The unique heterocyclic intermediate generated in this sequence is easily manipulated through two selective nucleophilic ring-opening reactions to afford the substituted cyclopentane core of the target. The finished work offers a flexible and highly efficient preparation of (–)-agelastatin A, easily amenable to analogue design.[10] Figure 1 The agelastatin family of natural products. Recent work from our lab and others has demonstrated that homoallyl and bis-homoallyl sulfamate esters react under oxidative conditions to furnish unique bicyclic aziridine derivatives (Figure 2).[8,11,12] This process generally affords high levels of diastereocontrol with both cyclic and acyclic starting materials. The products can be smoothly converted to polyfunctionalized amine derivatives through sequential, regioselective ring opening. For the purpose of assembling (–)-agelastatin A, an attractive plan emerged that would capitalize on such a sequence of steps to establish the trans-substituted vicinal diamine unit embedded at C4 and C8 (Figure 3). Prior to initiating these investigations, we had little sense if a substrate such as 3 would undergo chemoselective oxidation to generate the unusual tricyclic structure 2 and whether such a product would be isolable. Selectivity in the subsequent aziridine displacement reaction presented an additional concern. This plan, however, could be quickly assessed due to the ready availability of sulfamate 3. Figure 2 Rh-catalyzed aziridination: a versatile method for assembling polyfunctionalized amines. Figure 3 Retrosynthetic analysis of (–)-agelastatin A. Optically enriched lactam 4 is prepared on industrial scale and may be obtained in either antipode at a relatively inexpensive cost (Figure 4).[13] In two high yielding transformations, this material can be converted to alcohol 5, also an item of commerce. Sulfamoylation of 5 following a standard protocol that involves in situ generation of ClSO2NH2 is then easily accomplished.[14] Figure 4 Homoallylic sulfamate synthesis from commercial lactam. Exposure of sulfamate 6 to a dimeric Rh(II) catalyst, 1.1 equiv of PhI(OAc)2, and MgO, affords aziridine 7 as a single diastereomer in 95% yield (Figure 5). Less than 1% of the 5-membered ring product of allylic C–H insertion is obtained in this transformation. By capitalizing on our recently developed Rh2(esp)2 catalyst, loadings as low as 0.06 mol% (>1500 turnovers) can be used, thus enabling the reaction to be easily and inexpensively scaled.[15] The novel tricylic structure is quite stable and can be isolated in pure form following chromatography on silica gel. When treated with NaN3 in aqueous isopropanol, regioselective attack at C4 (agelastatin numbering) proceeds at ambient temperature to yield predominantly the bridging [1,2,3]-oxathiazepane-2,2-dioxide 8 (C4/C8 regioselectivity = 9:1).[16,17] This versatile intermediate incorporates three of the four stereogenic carbamine centers found in the natural product, all differentially masked. Accordingly, this aziridination/ring opening reaction sequence should offer ready access to several derivative forms of agelastatin. Figure 5 Catalytic aziridination and regioselective ring-opening affords the desired oxathiazepane heterocycle 8. Rh2(esp)2 = Rh2(α,α,α’,α’-1,3-benzenediproprionate)2. To forward the synthetic plan, a series of maneuvers was needed that would ultimately enable a single carbon excision and introduction of the C5 ketone (see Figure 3). Six- and seven-membered ring cyclic sulfamates possess intrinsic reactivity as electrophilies, which can be modulated as a result of N-functionalization.[14b,18] Taking advantage of this property, oxathiazepane 8 was first treated with diethyl pyrocarbonate to furnish the N-acylated species 9; subsequent introduction of NaSePh (prepared in a separate reaction vessel) displaces the oxathiazepane C–O bond to afford in a single operation selenide 10 (Figure 6). Access to this product in just 4 steps from 5 underscores the effectiveness of our aziridination process for the rapid assembly of stereochemically complex, orthogonally protected polyamine intermediates. Figure 6 Oxathiazepane 8 activation and ring opening. Oxidation of selenide 10 and elimination of the transient selenoxide was intended to furnish the C5 exo-methylene product 11 (Figure 7). Such a reaction does occur, however, the resulting allylic azide undergoes facile [3,3]-sigmatropic rearrangement to afford cyclopentene 12.[19] As it was not possible to prevent this isomerization process, a decision was made to postpone exo-methylene introduction until the latter steps of the synthesis. Accordingly, we opted to fashion first the requisite pyrrole unit from 10 (Figure 8). Removal of the Boc-group with CF3CO2H precedes an efficient Paal-Knorr condensation, which employs tricarbonyl 13 and mild acid catalysis to forge the heterocycle.[20,21] The desired pyrrole 14 is generated in 85% yield over this two-step sequence. Figure 7 Rearrangement of allylic azide 11 necessitates strategic modification. Figure 8 Paal-Knorr condensation installs pyrrole unit. To complete the agelastatin synthesis, azide 14 is reduced chemoselectively under Staudinger conditions (Me3P, THF/H2O, Scheme 1). Once reduction is complete, MeNCO is added to the reaction flask to produce urea 15. This compound is easily purified by normal-phase silica gel chromatography in spite of the presence of the polar N-methyl urea moiety. Exposure of 15 to m-CPBA induces selenide to selenoxide conversion and subsequent elimination to afford alkene 16. While attempts to cleave the C5 exo-methylene unit under ozonolytic conditions gave only intractable mixtures of products, successful installation of the C5 carbonyl was realized using a combination of 2.5 mol% OsO4 and NaIO4. Once the C5-ketone is exposed, addition of the urea is highly favored and the product is isolated exclusively as hemi-aminal 17. Scheme 1 a) Me3P, THF/H2O; then MeNCO, 81%; b) m-CPBA, DCE, 0 °C; then Et3N, 80 °C, 89%; c) 2.5 mol % OsO4, NaIO4, THF/H2O, 45 °C, 81%; d) KOtBu, tAmOH, 45 °C, 77%; e) NBS, THF/MeOH, 0→25 °C, 75%. m-CPBA = meta-chloroperbenzoic ... The stability of the hemi-aminal in 17 obviates protection as the N,O-acetal. As such, assembly of the final target can be accomplished by first exposing 17 to KOtBu in t-amyl alcohol (Scheme 1).[22] This protocol generates the desired six-membered lactam with concomitant cleavage of the ethyl carbamate. Having intercepted the penultimate intermediate formed in prior syntheses of agelastatin A, a literature procedure using N-bromosuccinimde smoothly and selectively brominates the pyrrole unit and gives the natural product as a white, crystalline solid.[6e] This material matches reported spectral and optical rotation data in all respects.[2,6e] Starting from commercial 5, the 11-step sequence has been executed in a single pass to prepare >200 mg of the natural product (15% overall yield). An efficient, easily scaled, and flexible route to (–)-agelstatin A has been made possible following the development and application of a selective Rh-catalyzed aziridination method. With the aid of Rh2(esp)2, this reaction is made to proceed in high yield at negligible catalyst loadings. The resulting tricyclic product 7 represents a unique heterocyclic structure that is efficiently transformed into a differentially protected cyclopentyltriamine. New protocols for manipulating the intermediate oxathiazepane and for crafting the pyrrole lactam also distill from this work. Overall, the preparation of agelastatin A is illustrative of the manner in which modern oxidative methods for C–N bond formation can alter the retrosynthetic logic of complex chemical synthesis.[23]

Asymmetric synthesis of Nitrogen heterocycles

Abstract: PART 1: Asymmetric Synthesis of Nitrogen Heterocycles Containing Only One Heteroatom ASYMMETRIC SYNTHESIS OF THREE- AND FOUR-MEMBERED RING HETEROCYCLES Substituted Aziridines Substituted Monocyclic Azetidines and Carbocyclic-Fused Systems ASYMMETRIC SYNTHESIS OF FIVE-MEMBERED RING HETEROCYCLES Monocyclic Pyrrolidines and Pyrrolidinones Pyrrolines Fused Bicyclic Systems with Bridgehead Nitrogen ASYMMETRIC SYNTHESIS OF SIX-MEMBERED RING HETEROCYCLES Introduction Dihydropyridines Tetrahydropyridines Monocyclic Piperidines and Carbocyclic Fused Systems Fused Tri- or Bicyclic System with Bridgehead Nitrogen ASYMMETRIC SYNTHESIS OF SEVEN- AND MORE-MEMBERED RING HETEROCYCLES Substituted Azepines Substituted Azocines Substituted Large Nitrogen-Containing Rings PART 2: Asymmetric Synthesis of Nitrogen Heterocycles With More Than One Heteroatom ASYMMETRIC SYNTHESIS OF THREE- AND FOUR-MEMBERED RING HETEROCYCLES WITH MORE THAN ONE HETEROATOM Introduction Three-Membered N-Heterocycles with Two Heteroatoms Four-Membered N-Heterocycles with Two Heteroatoms ASYMMETRIC SYNTHESIS OF FIVE-MEMBERED RING HETEROCYCLES WITH MORE THAN ONE HETEROATOM Five-Membered Heterocycles with N and O Atoms Five-Membered Heterocycles with Two N Atoms Five-Membered Heterocycles with N and S Atoms ASYMMETRIC SYNTHESIS OF SIX-MEMBERED RING NITROGEN HETEROCYCLES WITH MORE THAN ONE HETEROATOM Six-Membered Rings with Another Heteroatom in the Same Ring ASYMMETRIC SYNTHESIS OF SEVEN-MEMBERED RINGS WITH MORE THAN ONE HETEROATOM Diazepines Oxazepines Thiazepines

Gold- or platinum-catalyzed cascade processes of alkynol derivatives involving hydroalkoxylation reactions followed by Prins-type cyclizations.

Abstract: An efficient method for the synthesis of [3.3.1]bicyclic compounds from easily available alkynol derivatives has been developed. The reaction is based on a gold- or platinum-catalyzed tandem process that involves an intramolecular hydroalkoxylation of a triple bond followed by a Prins-type cyclization. The reaction has been carried out with differently substituted alkynol derivatives and oxygen-, nitrogen-, and carbon-centered nucleophiles. The incorporation of halogen atoms as nucleophiles and elimination reactions has also been studied. Enantiomerically pure [3.3.1]bicyclic systems were easily synthesized from the chiral pool.

Total Synthesis of Indolizidine Alkaloid (−)‐209D: Overriding Substrate Bias in the Asymmetric Rhodium‐Catalyzed [2+2+2] Cycloaddition

Abstract: Indolizidine frameworks possessing an alkyl group substituted at the 5-position (indolizidine numbering)[i] represent a large class of naturally occurring compounds[ii] Alkaloids ranging from structurally simple indolizidine 167B and 209D to more complex marine alkaloids such as cylindricines[iii] (Scheme 1) and the immunosuppressant {"type":"entrez-nucleotide","attrs":{"text":"FR901483","term_id":"525229782","term_text":"FR901483"}}FR901483[iv] all contain such ring systems Most recently, Weinreb and coworkers described the first total synthesis of secu'amamine A, a novel tetracyclic alkaloid, via a 5-alkyl indolizinone as a late-stage intermediate[v] Herein, we detail the development of an enantioselective rhodium-catalyzed [2+2+2] cycloaddition of terminal alkyl alkynes and alkenyl isocyanates to generate various 5-alkyl indolizinones (3) As part of a program directed toward developing a universal strategy to indolizidine alkaloids, the synthetic utility here is demonstrated by an expedient synthesis of (−)-209D Scheme 1 [2+2+2] Cycloaddition strategies to the framework of various indolizidine alkaloids We have been exploring the use of neutral rhodium(I)/TADDOL-derived phosphoramidite complexes as enantioselective catalysts for various [2+2+2] cycloadditions, including reactions of terminal alkynes with isocyanates[vi] or carbodiimides[vii] In previous studies, the use of terminal alkyl alkynes with these catalysts provide efficient cycloadditions to afford various bicyclic lactams 4 (Scheme 1) in good yields and enantioselectivities, while the 5-alkyl indolizinone cycloadducts 3, resulting from a CO migration process, can only be observed as minor components In this work, we report a new Rh·L system to achieve a catalyst-controlled cycloaddition en route to 5-alkyl indolizinones 3 To tune product selectivity through ligand design, we began our study by examining the cycloaddition of 1-octyne 1a and alkenyl isocyanate 2 with various phosphoramidite ligands[viii] (Table 1) Switching from TADDOL-derived ligands such as L1 to BINOL-derived L2 led to a complete inversion of product selectivity (entry 1 vs 2) favoring the indolizinone 3a Formation of 3 is thought to proceed through the initial metalacycle I followed by a CO migration process via II to arrive at III Migratory insertion of the pendant alkene into Rh-N bond followed by reductive elimination gives rise to cycloadducts 3 Selectivity in the formation of two initial metalacycles (I vs IV) is reflected in the product selectivity between 3 and 4 Despite the low yield and poor ee, the fundamental difference in product selectivity prompted further investigation into BINOL-derived phosphoramidites Ligands possessing substitution at the 3,3′-positions of the BINOL backbone positively impact reaction efficiency toward the desired indolizinone 3a Further exploration led to the discovery of GUIPHOS (L3) This TMS-substituted phosphoramidite L3 provides a much improved reaction with product selectivity ∼4:1, good chemical yield, and most importantly an excellent 96% ee for 3a (entry 3) Although the TMS-substituted biphenol-derived phosphoramidite L4 behaves no differently than GUIPHOS (entry 4), the corresponding ligand possessing tert-butyl groups at the 3,3′-positions (L5)[ix],[x] proved superior Precatalyst [Rh(C2H4)2Cl]2 modified with L5 provides a clean reaction to furnish the desired indolizinone 3a with a good product ratio (62:1) in excellent yield and enantioselectivity (entry 5) Table 1 Ligand effect on product selectivity and enantioselectivity[a] Indolizidine 209D belongs to a family of 22 natural products, commonly referred to as gephyrotoxins, isolated from the skin secretions of neotropical frogs[xi] Along with indolizidine 167B (Scheme 1), these two structurally simpler alkaloids have only been isolated in minute quantities from unidentified dendrobatid frogs found in a single population Over the years, they have attracted much interest from the synthetic community, both to prepare them in greater quantities as well as a tool to validate new methodologies [xii] In our own effort, the key intermediate 5-hexyl indolizinone 3a can be prepared conveniently by the cycloaddition protocol in one step and is suitable for scale-up (Scheme 2) The resulting vinylogous amide functionality readily undergoes a diastereoselective hydrogenation to afford enantioenriched amino alcohol 5 as a single diastereomer Barton-McCombie deoxygenation via 6 completes the four-step enantioselective synthesis of (−)-209D, which also confirms the absolute configuration of 3a: [α]22D = -665° (c 10, CH2Cl2); lit[10a] [α]26D = -804° (c 10, CH2Cl2) Considering that alkenyl isocyanate 2 can be prepared in one step from commercially available 5-hexenoic acid, this constitutes the shortest synthesis of 209D reported to date[10] Scheme 2 Synthesis of indolizidine (−)-209D The newly developed Rh/phosphoramidite L5 catalyst promotes the enantioselective synthesis of 5-alkyl indolizinones very efficiently (Table 2) Alkyl alkynes bearing an array of functional groups including ester, chloride, silyl ether, Weinreb amide, unprotected terminal alkyne, and phenyl ring all react smoothly to afford cycloadducts in good product ratios and excellent enantioselectivities (entries 2 – 7) The cycloaddition is highly sensitive to both electronic and steric effects on the alkyne partner The product selectivity shifts more toward formation of the bicyclic lactams 4 with electron-withdrawing substituents closer to the alkynyl center For example, cycloaddition of 3-phenyl-1-propyne 1h gave a product ratio of 3:1 favoring the benzyl-substituted indolizinone 3h, instead of the ratio of 5:1 obtained with 1g (entry 8 vs entry 7) In a more extreme case, cycloaddition of TIPS-protected propargyl alcohol 1i furnishes a 16:1 product mixture slightly favoring the indolizinone 3i (entry 9) On the other hand, reaction with the more sterically hindered alkyne 1j improves the product selectivity to provide the desired cycloadduct 3j in a high yield and excellent enantioselectivity (entry 10) In fact, bulky alkynes such as cyclohexyl and cyclopentyl acetylenes are among the best cycloaddition partners The corresponding indolizinone products 3k and 3l can be obtained in high yields and enantioselectivities with excellent product ratios of 14:1 (entries 11, 12) Even more impressively, the rhodium catalyst modified by ligand L5 promotes the cycloaddition of tertiary alkyl-substituted alkynes to gain access to highly congested 5-alkyl indolizinones (entries 13, 14) For example, the MOM-protected cyclopentanol-substituted cycloadduct 3m can be produced in 60% yield with a slightly diminished 81% enantioselectivity as the only product In general, cycloaddition with the tert-butyl substituted phosphoramidite L5 produces the best product selectivity and high overall reactivity, while the use of GUIPHOS (L3) usually gives the best level of enantiocontrol Although GUIPHOS (L3) displays low reactivity toward most sterically hindered alkynes (3k: 44% yield, 95% ee; 3m: 23% yield, 80% ee), it does provide an efficient cycloaddition for the formation of tert-butyl substituted indolizinone 3n in a good chemical yield and enantioselectivity (entry 15) This protocol can also be applied to the synthesis of 5,9-dialkyl indolizinones (eq 1) 1,1-Disubstituted alkenyl isocyanate 7 participates in the cycloadditions with 1-octyne 1a quite efficiently to provide the corresponding cycloadduct 8 in good product ratio and isolated yield Interestingly, while the product selectivity stays relatively unchanged as those obtained with the unsubstituted alkenyl isocyanate 2, a profound effect on the enantioselectivity is observed The use of GUIPHOS (L3) here provides a partial solution, improving the enantioselectivity significantly Table 2 Enantioselective synthesis of 5-alkyl indolizinones[a] (1) In conclusion, we have developed an efficient catalyst system that promotes a cycloaddition between terminal alkyl alkynes and alkenyl isocyanates involving a CO migration process This previously unattainable process allows access to various 5-alkyl indolizinones including an enantioselective synthesis of indolizidine (−)-209D Further studies on the reaction scope as well as applications to the synthesis of alkaloids are ongoing

Palladium(II)-Catalyzed Domino Reaction of 2-(1-Alkynyl)-2-alken-1-ones with Nucleophiles: Scope, Mechanism and Synthetic Application in the Synthesis of 3,4-Fused Bicyclic Tetrasubstituted Furans

Abstract: Described herein is the development of a palladium(II)-catalyzed two- or three-component reaction of 2-(1-alkynyl)-2-alken-1-ones with nucleophiles and allylic chlorides. Various types of nucleophiles such as O-, N-, C-based nucleophiles and olefin-tethered O-, N-, C-based nucleophiles were investigated. The scope, mechanism and application of this Pd(II)-catalyzed domino reaction were studied. In these transformations, the palladium catalyst exhibits a dual role, serving simultaneously as a Lewis acid and a transition metal. Two possible reaction pathways (cross-coupling reaction vs. Heck reaction) from the same intermediate furanylpalladium species were observed. The reaction pathway is dependent on the property of the nucleophile and the length of the tethered chain as well. When olefin-tethered O-based nucleophiles were used, only the cross-coupling reaction pathway was observed, in contrast, both reaction pathways were observed when olefin-tethered C-based nucleophiles were employed. The product ratio is dependent on the length of the tethered chain. Furthermore, ring-closing metathesis (RCM) of corresponding furans with C=C bonds provides an easy method for the preparation of functionalized oxygen-heterocycles - 3,4-fused bicyclic furans. It is also noteworthy that allylic chloride can be as an oxidant besides its well known function as an alkylating reagent.

Structure-activity relationships of antitubercular nitroimidazoles. 2. Determinants of aerobic activity and quantitative structure-activity relationships.

Abstract: The (S)-2-nitro-6-substituted 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines have been extensively explored for their potential use as new antituberculars based on their excellent bactericidal properties on aerobic whole cells of Mycobacterium tuberculosis. An oxygen atom at the 2-position of the imidazole ring is required for aerobic activity. Here, we show that substitution of this oxygen by either nitrogen or sulfur yielded equipotent analogues. Acylating the amino series, oxidizing the thioether, or replacing the ether oxygen with carbon significantly reduced the potency of the compounds. Replacement of the benzylic oxygen at the 6-position by nitrogen slightly improved potency and facilitated exploration of the SAR in the more soluble 6-amino series. Significant improvements in potency were realized by extending the linker region between the 6-(S) position and the terminal hydrophobic aromatic substituent. A simple four-feature QSAR model was derived to rationalize MIC results in this series of bicyclic nitroimidazoles.

Near-Infrared Absorbing Azo Dyes: Synthesis and X-ray Crystallographic and Spectral Characterization of Monoazopyrroles, Bisazopyrroles, and a Boron−Azopyrrole Complex

Abstract: Symmetric 2,5-bisazopyrroles 2(a-d) were synthesized by a one-step reaction of substituted phenyl diazonium salts [R'(Ph)N2(+)Cl-] [a, R' = 4-N(CH3)2; b, R' = 2-OH; c, R' = 2-CO2H; d, R' = 4-NO2] with pyrrole under basic conditions. Asymmetric 2,5-bisazopyrroles 3(a-d) were synthesized by reacting substituted phenyl diazonium salts [R''(Ph)N2(+)Cl-] (a, R'' = 4-OCH(3); b, R'' = H; c, R'' = 4-Br; d, R'' = 4-NO2) with 2-(4-dimethylaminophenylazo)-1H-pyrrole (1a) under the same conditions. The reactions of 2a with boron trifluoride and iodomethane provided a BF2-azopyrrole complex of 1H-pyrrolo[2,1-c]-1,2,4,5-boratriazole (4) and 2,5-bisazo-1-methylpyrrole 5. X-ray crystallographic and spectral analysis of 1a, 2a, 2b, and 4 showed that 1a has three crystal forms: 1a(I), 1a(II), and 1a(III), the latter two bearing a bicyclic ring system formed via intermolecular hydrogen bonding. Complex 4 was found to be the most planar due to a rigid trans-azo configuration and has the longest N horizontal lineN bond distances (1.322 and 1.300 Angstrom) and wavelength of maximum absorption (754 nm). The N horizontal lineN bond distances increase in the sequence of monoazopyrrole [1a(I): 1.253 Angstrom], bisazopyrrole (2a: 1.283 Angstrom), bisazopyrrole with intramolecular hydrogen bonding (2b: 1.293 and 1.293 Angstrom), and the BF2-azopyrrole complex. Their maximum absorptions shift bathochromically in the sequence of monoazopyrrole (1a: 443 nm), bisazopyrroles [2(a-d), 3(a-d), 5: 486-615 nm], and the BF2-azopyrrole complex. These results are important for the design of near-infrared absorbing azo dyes and suggest an efficient path for the preparation of near-infrared absorbing azo dyes by effectively enhancing pi-electron delocalization.

Solution conformation of endothelin-1 by 1H NMR, CD, and molecular modeling.

Abstract: The solution conformation of Endothelin-I, a recently discovered bicyclic, 21 amino acid peptide, has been examined by ‘H NMR in deuterated dimethylsulphoxide and circular dichroism in aqueous and organic solvents. A total of 158 NOES were dctectcd, which were used as distance constraints in the distance geometry program DISGEO. Two families of structures were obtained, both characterized by a helix-like region extending from Lys’ to Cys“, but with opposite “handedness”. Circular dichroism studies of the peptide in both aqueous and trifluoroethanol solutions show a negative shoulder at 224 nm, characteristic of right-handed helices. Molecular dynamics and energy minimization yielded a solution structure for this new peptide compatible with all experimental observations. Endothelin is the name given to a new family of bicyclic, 21 amino acid peptides, whose first member, Endothelin-1 (Fig. I), was isolated and characterized from cultured porcine aortic endothelial cells (1). AIthough initially characterized by their potent vasoconstrictor activity, recent pharmacological studies have shown that the endothelins exert a wide range of biological effects. Indeed, specific endothelin binding sites have now been observed in both the peripheral systems and in the CNS. In view of the potential role(s) that the endothelins may play in the regulation of various mammalian systems, we (2) and others (3) have examined the conformation of Endothelin-1 by ‘H NMR. Our preliminary results suggested that this peptide assumes a compact structure with the C-terminal hexapeptide closely associated with the bicyclic portion of the molecule, while other studies indicate a more flexible role for the last six amino acids (3). We report here a much more detailed study of Endothelin1 in solution by ‘H NMR, circular dichroism, and molecular modeling. COOH

New strategy for the synthesis of substituted morpholines.

Abstract: A four-step synthesis of cis-3,5-disubstituted morpholines from enantiomerically pure amino alcohols is described. The key step in the synthesis is a Pd-catalyzed carboamination reaction between a substituted ethanolamine derivative and an aryl or alkenyl bromide. The morpholine products are generated as single stereoisomers in moderate to good yield. This strategy also provides access to fused bicyclic morpholines as well as 2,3- and 2,5-disubstituted products.

Enantioselective Rhodium-Catalyzed [4+2+2] Cycloaddition of Dienyl Isocyanates for the Synthesis of Bicyclic Azocine Rings

Abstract: A highly enantioselective rhodium-catalyzed [4+2+2] cycloaddition of terminal alkynes and dienyl isocyanates has been developed. The cycloaddition provides a rapid entry to highly functionalized and enantioenriched bicyclic azocines. This reaction represents the first [4+2+2] cycloaddition strategy to construct nitrogen-containing eight-membered rings.