Enantioselective Synthesis of [b]‐Annulated Azepane Scaffolds

Buschbeck L., Christoffers J.

The 2,5-diaminoterephthalate structural motif is a powerful chromophore with remarkable fluorescence properties. Containing two carboxylate and two amino functions, it defines a colored molecular scaffold which allows for orthogonal functionalization with different functional units. Therefore, different applications in life sciences and materials science could be addressed. In this study, the two amino functions were alkylated by reductive amination with side chains carrying amino (orthogonally protected as Boc or Alloc) and carboxylate functions (orthogonally protected as tBu or allyl ester). After sequential deprotections, functional units were introduced by amidation reactions. As three examples, the chromophore was coupled with retinoic acid and fullerene C60 in order to obtain a triad for studying photoinduced electron transfer processes. Furthermore, cyclooctyne and azide moieties were introduced as functional units, allowing for ligation by click reactions. These two clickable groups were applied in combination with maleimide units which are reactive toward thiol residues. The latter dyes define so-called "turn on" probes, since the fluorescence quantum yields increased by one order of magnitude upon reaction with the molecular target.

Quezada J., Coffman K.A.

Tourette syndrome (TS) is a neurodevelopmental disorder of unknown etiology characterized by spontaneous, involuntary movements and vocalizations called tics. Once thought to be rare, TS affects 0.3–1% of the population. Tics can cause physical discomfort, emotional distress, social difficulties, and can interfere with education and desired activities. The pharmacologic treatment of TS is particularly challenging, as currently the genetics, neurophysiology, and neuropathology of this disorder are still largely unknown. However, clinical experience gained from treating TS has helped us better understand its pathogenesis and, as a result, derive treatment options. The strongest data exist for the antipsychotic agents, both typical and atypical, although their use is often limited in children and adolescents due to their side-effect profiles. There are agents in a variety of other pharmacologic categories that have evidence for the treatment of TS and whose side-effect profiles are more tolerable than the antipsychotics; these include clonidine, guanfacine, baclofen, topiramate, botulinum toxin A, tetrabenazine, and deutetrabenazine. A number of new agents are being developed and tested as potential treatments for TS. These include valbenazine, delta-9-tetrahydrocannabidiol, and ecopipam. Additionally, there are agents with insufficient data for efficacy, as well as agents that have been shown to be ineffective. Those without sufficient data for efficacy include clonazepam, ningdong granule, 5-ling granule, omega-3 fatty acids, and n-acetylcysteine. The agents that have been shown to be ineffective include pramipexole and metoclopramide. We will review all of the established pharmacologic treatments, and discuss those presently in development.

Yoshida M.

Enantioselective α-allylation of α-substituted β-ketoesters with simple allyl alcohols was successfully performed by synergistic catalysis with the catalyst combination of a chiral primary amino acid and an achiral palladium complex without additional promotors like acids or bases. The allylation reaction and generation of a chiral quaternary carbon stereocenter proceeded smoothly to produce α,α-disubstituted β-ketoesters in high yields (91-99%) with high enantioselectivities (90-99% ee).

Geibel I., Christoffers J.

Cyclic β-oxo esters are converted with enol acetates in a cerium-catalyzed, oxidative Umpolung reaction to furnish 1,4-diketones with up to 95 % yield. Atmospheric oxygen is the oxidant in this process, which can be regarded as ideal from economic and ecological points of view. Further advantages of this new C–C coupling reaction are its operational simplicity and the application of nontoxic and inexpensive CeCl3·7H2O as precatalyst.

Penning M., Christoffers J.

Hexahydro-2-oxo-1,4-diazocin-6-carboxylic acid constitutes a conformationally rigid, crown-shaped scaffold. An orthogonally protected (Boc at N-4 and methyl ester at 6-CO2H) representative was prepared by ring expansion of a 3-pyrrolidone-derived 1,4-diketone with MeNH2. After deprotection, this building block was further diversified by reductive aminations and amidations and by sulfonamide and urea formation. Furthermore, the 6-CO2H function was transformed into a 6-NHCbz group in one step by carboxamide degradation in the presence of BnOH. An example of a cyclic tripeptoidic structure was synthesized by amidation with N-Boc-β-alanine and glycine methyl ester. Structural features of the eight-membered heterocycle were established by single-crystal X-ray structure analysis of a 4-bromoaniline derivative.

Uyeda C., Rötheli A.R., Jacobsen E.N.

Uyeda C., Rötheli A.R., Jacobsen E.N.

Claisen rearrangement; organocatalysis; asymmetric catalysis; Density-functional calc; H bondingThe selective construction of contiguous quaternary stereogenic centers, a motif found inmany complex natural products, represents a significant synthetic challenge.[1] Among thelimited number of approaches for the formation of bonds between such sterically-congestedcarbon atoms, intramolecular processes such as polyene cyclizations,[2a,b] intramolecularcycloadditions,[2c] and sigmatropic rearrangements[2d,e] have been particularly effective.For addressing vicinal quaternary carbons, these transformations have only been applied in adiastereocontrolled manner using substrates containing pre-existing stereogenic centers,either as part of cleavable auxiliaries or structural features of the target molecule. Thedevelopment of catalytic asymmetric methods for the direct and selective formation of suchstereochemical arrays represents a highly desirable and challenging goal.Since its discovery in 1912,[3] the [3,3]-sigmatropic rearrangement of allyl vinyl ethers (theClaisen rearrangement) has emerged as a proven strategy for the formation of carbon–carbon bonds between vicinal stereogenic centers.[4] Diastereoselectivity is generallypredictable and high in these processes because of the concerted nature of the C–O bond-breaking and C–C bond-forming events as well as the large energetic preference for chair-like over boat-like transition states. Furthermore, important examples of enantioselectivemethods for Claisen rearrangements involving Lewis acid catalysis[5] have been identifiedrecently for select substrates with chelating functional groups.We reported recently that the achiral guanidinium ion

Frankowski K.J., Golden J.E., Zeng Y., Lei Y., Aubé J.

A tandem Diels–Alder/azido-Schmidt reaction sequence provides rapid access to the core skeleton shared by several Stemona alkaloids including stenine, neostenine, tuberostemonine, and neotuberostemonine. The discovery and evolution of inter- and intramolecular variations of this process and their applications to total syntheses of (±)-stenine and (±)-neostenine are described. The stereochemical outcome of the reaction depends on both substrate type and reaction conditions, enabling the preparation of both (±)-stenine and (±)-neostenine from the same diene/dienophile combination.

Rosiak A., Hoenke C., Christoffers J.

The Shapiro reaction of acetophenone is the key in a convenient three-step access to a divinyl ketone which is further transformed by double aza-Michael reactions with primary amines into N-substituted 3-phenyl-4-piperidones. In the case of N-benzyl and N-allyl derivatives, the piperidine nitrogen atom can be deprotected and further functionalized, for example, by carboxamide, carbamate, or urea formation.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Padwa A., Ginn J.D.

Several cyclic 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMSTF) with beta-alkoxy-gamma-dithiane lactams. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). The resulting oxa-bridge cycloadducts underwent a subsequent 1,2-methylthio shift to form tricyclic lactams in high yield. Furan 9, annealed to an azepine ring, underwent the IMDAF reaction at or below room temperature. Conformational effects imposed by the placement of a carbonyl group within the tether, combined with a rotational bias about the C(2)-N bond, enhances the rate of the IMDAF reaction of the seven-ring system so that it occurs readily at 25 degrees C. The feasibility of using the cascade sequence in the context of a total synthesis of the Stemona alkaloid (+/-)-stenine was explored. The eventual synthesis of (+/-)-stenine was carried out by an intramolecular Diels-Alder reaction of a 2-amido-5-methylthio-substituted furan containing a trans-pent-3-enoic acid methyl ester side chain in order to create the desired azepinoindole skeleton. This was followed by a series of reductions to set the syn-anti stereochemical relationship at the incipient ring fusion sites present in stenine. All six stereocenters at the azepinoindole core were derived in high stereoselectivity from the functionality present in the rearranged cycloadduct 10. Compound 10 was converted to stenine in 11 additional steps via a sequence that features a Crabtree's-catalyst directed hydrogenation, iodolactonization, and a Keck allylation.

Ginn J.D., Padwa A.

[reaction: see text]. The intramolecular [4 + 2]-cycloaddition of a 2-methylthio-5-amidofuran was used to create the azepinoindole skeleton present in the Stemona alkaloid stenine. The rearranged cycloadduct was converted to stenine (1) in 11 additional steps via a sequence that features a Crabtree catalyst directed hydrogenation (9-->10), iodolactonization (2-->11), and a Keck allylation (11-->12).

Carpino L.A., Imazumi H., El-Faham A., Ferrer F.J., Zhang C., Lee Y., Foxman B.M., Henklein P., Hanay C., Mügge C., Wenschuh H., Klose J., Beyermann M., Bienert M.

Carpino L.A., Imazumi H., El-Faham A., Ferrer F.J., Zhang C., Lee Y., Foxman B.M., Henklein P., Hanay C., Mügge C., Wenschuh H., Klose J., Beyermann M., Bienert M.

Morimoto Y., Iwahashi M., Kinoshita T., Nishida K.

The Stemona alkaloid stenine (1), isolated from Stemona tuberosa of physiologically active stemonaceous plants, possesses the structurally novel and unique azepinoindole skeleton (B,C,D-ring system). We have achieved the asymmetric total synthesis of (-)-stenine (1), starting from 1,5-pentanediol (10). The key features are an intramolecular diastereoselective Diels-Alder reaction of the (E,E,E) triene 6, prepared in a convergent fashion from three components--dienyl chloride 7, dithiane 8, and chiral phosphonate 9--and efficient construction of the tricyclic A,B,D-ring system 29 through thermodynamically controlled regioselective enolization of the bicyclic ketone 25. In this article, we describe in detail the highly stereocontrolled total synthesis of (-)-stenine (1). These results should be useful for the asymmetric total synthesis of another, more complex. molecule: tuberostemonine (2), the synthesis of which has never been reported.

Draper R.W., Hou D., Iyer R., Lee G.M., Liang J.T., Mas J.L., Vater E.J.

Two enantioselective syntheses of the fused benzazepine dopamine D1 antagonist (6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H-benzo[d]naphth[2,1-b]azepin-12-ol (1) are described in which the starting material is (+)-l-homophenylalanine (6). In the first approach, methyl (2S)-(1,2,3,4-tetrahydro-1-oxo-2-naphthalenyl)carbamate (5) is prepared by intramolecular Friedel−Crafts cyclization of N-carbomethoxy (+)-l-homophenylalanine (9). Subsequent alkylation of 5 with (4-chloro-3-methoxyphenyl)magnesium bromide, deoxygenation with Et3SiH, reduction, alkylation, and epimerization yields (+)-trans-(1R,2S)-1-(4-chloro-3-methoxyphenyl)-N-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-N-methyl-2-naphthalenamine (2), a key intermediate in the previously described route to 1 (Draper, R. W.; Hou, D.; Iyer, R.; Lee, G. M.; Liang, J. T.; Mas, J. L.; Tormos, W.; Vater, E. J.; Gunter, F.; Mergelsberg, I.; Scherer, D. Org. Process Res. Dev. 1998, 2, XXXXX). A complementary route to 2 is also described in which arylation...

Sanad S.M., Mekky A.E., Hussein R.M., Seif D.S., Hassan F.E., Fekry F.M., Abdellatif N.S., Salama E.A., Elneairy M.A.

Wang X., Wang J., Li X.

A gold-catalyzed asymmetric [8 + 4] cycloaddition was developed to afford highly functionalized furan/pyrrole-fused [5.5.0] polycyclic heterocycles with good diastereo- and enantioselectivity.

Antonova Alexandra S., Zubkov Fedor I.

Catalytic olefin metathesis using Hoveyda-Grubbs type ruthenium complexes is a powerful tool for creating complex molecules possessing a variety of practically useful properties. This method is also applied for obtaining modern polymer materials from low-demand petroleum products. Among all ruthenium complexes containing five- or six-membered chelate rings, the commercially available HG-II catalyst is the most common. In addition, other Hoveyda-Grubbs type complexes, which include a Het→Ru donor–acceptor bond in the chelate ring, often exhibit metathesis activity equal to or superior to that of HG-II. This review considers second-generation N-heterocyclic ruthenium carbene Hoveyda-Grubbs type complexes with donor–acceptor bonds such as O→Ru, S→Ru, Se→Ru, N→Ru, P→Ru and Hal→Ru in the chelate ring. Methods of preparation, analysis of stability and catalytic activity of such complexes are compared, and examples of the application of these organometallic ruthenium derivatives in the synthesis of practically relevant products are provided. The literature from 2010 to 2023 is summarized, making this review useful for a broad audience of chemists working in heterocyclic and organometallic chemistry, as well as practitioners involved in the production of catalysts and polymers.The bibliography includes 174 references.

Tkachenko I.M., Shiryaev V.A., Klimochkin Y.N.

Formal decarbethoxylation of α-quaternary β-ketoesters of homoadamantane series occurs upon treating with nucleophilic agents. Various substituted and heteroannulated homoadamantanes have been synthesized using N-centered nucleophilic agents.