Probes for Narcotic Receptor Mediated Phenomena

The synthesis of a series of epoxy 5‐phenylmorphans is being explored in order to determine the conformational requirements of the phenolic ring in a phenylmorphan molecule that may be needed both for binding to a specific opioid receptor and for exhibiting opioid agonist or antagonist activity. Of the twelve possible ortho‐ and para‐bridged isomers (a–f) (Fig. 1), we now report the synthesis of the para‐d isomer, rac‐(3R,6aS,11aR)‐2‐methyl‐1,3,4,5,6,11a‐hexahydro‐2H‐3,6a‐methanobenzofuro[2,3‐c]azocin‐8‐ol ( 3 ). Compound 3 was synthesized via construction of the 5‐phenylazabicyclo[3.3.1]non‐3‐ene skeleton (Scheme 1) and subsequent closure of the epoxy bridge (Scheme 2). As determined by an X‐ray diffraction study, the epoxy bridge, restricting the phenyl‐ring rotation, fixed the dihedral angle between the least‐squares planes through the phenyl ring and atoms N(2), C(3), C(11a), and C(6a) of the piperidine ring (Fig. 2) at 43.0°, and the torsion angle C(12)? C(6a)? C(6b)? C(10a) at ?95.0°.     

First Total Synthesis of N‐(3‐Guanidinopropyl)‐2‐(4‐hydroxyphenyl)‐2‐oxoacetamide

The first total synthesis of the α‐oxo amide‐based natural product, N‐(3‐guanidinopropyl)‐2‐(4‐hydroxyphenyl)‐2‐oxoacetamide ( 3 ), isolated from aqueous extracts of hydroid Campanularia sp., has been achieved. The α‐oxo amide 12 , prepared via the oxidative amidation of 1‐[4‐(benzyloxy)phenyl]‐2,2‐dibromoethanone ( 9a ) with 4‐{[(tert‐butyl)(dimethyl)silyl]oxy}butan‐1‐amine ( 10a ), has been used as the key intermediate in the total synthesis of 3 as HBr salt. On the way, an expeditious total synthesis of polyandrocarpamide C ( 2c ), isolated from marine ascidian Polyandrocarpa sp., was carried out in four steps.     

Illicium Sesquiterpenes: Divergent Synthetic Strategy and Neurotrophic Activity Studies

Majucin‐type sesquiterpenes from Illicium sp., such as jiadifenolide ( 2 ), jiadifenin ( 3 ), and (1R,10S)‐2‐oxo‐3,4‐dehydroxyneomajucin ( 4 , ODNM), possess a complex caged chemical architecture and remarkable neurotrophic activities. As such, they represent attractive small‐molecule leads against various neurodegenerative diseases. We present an efficient, enantioselective, and unified synthesis of 2 , 3 , and 4 and designed analogues that diverge from tetracyclic key intermediate 7 . The synthesis of 7 is highlighted by the use of an enantioselective Robinson annulation reaction (construction of the AB rings), a Pd‐mediated carbomethoxylation reaction (construction of the C ring), and a one‐pot oxidative reaction cascade (construction of the D ring). Evaluation of the neurotrophic activity of these compounds led to the identification of several highly potent small molecules that significantly enhanced the activity of nerve growth factor (NGF) in PC‐12 cells. Moreover, efforts to define the common pharmacophoric motif suggest that substitution at the C‐10 center significantly affects bioactivity, while the hemiketal moiety of 2 and 3 and the C‐1 substitution might not be critical to the neurotrophic activity.     

Total Synthesis of the Spermidine Alkaloid 13‐Hydroxyisocyclocelabenzine

A convergent total synthesis of 13‐hydroxyisocyclocelabenzine was developed. (3S)‐Methyl 3‐amino‐3‐phenylpropanoate ( 4 ) was used as the chiral building block. The 3,4‐dihydro‐4‐hydroxyisoquinolin‐1(2H)‐one derivative ( 5 ), the key fragment for the total synthesis, was prepared by a novel base‐catalyzed lactone‐lactam ring enlargement (Scheme 3). The resulting target C(13) epimers 3a / 3b from macrocyclization (Scheme 4) were separated by repeated flash chromatography. The absolute configuration of the synthetic alkaloid was determined by an X‐ray crystal‐structure analysis, which enabled us to determine the absolute configuration (9S,13R) for natural 3a with positive [α]_D.     

群柱虫内酯官能团化的C2-C10片段的立体选择性合成

本文以廉价的消旋甲基戊二酸酐为起始原料,完成了具有抗肿瘤活性的海洋天然产物群柱虫内酯（Clavulactone）官能团化的C2-C10片段的立体选择性合成。使用的关键方法包括不对称去对称化获得光学纯手性孤立甲基,和RCM方法构建顺式烯烃。该片段的获得为群柱虫内酯的全合成提供了基础。     

Transition‐Metal Complexes Based on the 1,3,5‐Triethynyl Benzene Linking Unit

The synthesis of a unique series of heteromultinuclear transition metal compounds is reported. Complexes 1‐I‐3‐Br‐5‐(FcC≡C)‐C₆H₃ ( 4 ), 1‐Br‐3‐(bpy‐C≡C)‐5‐(FcC≡C)‐C₆H₃ ( 6 ), 1,3‐(bpy‐C≡C)₂‐5‐(FcC≡C)‐C₆H₃ ( 7 ), 1‐(XC≡C)‐3‐(bpy‐C≡C)‐5‐(FcC≡C)‐C₆H₃ ( 8 , X = SiMe₃; 9 , X = H), 1‐(HC≡C)‐3‐[(CO)₃ClRe(bpy‐C≡C)]‐5‐(FcC≡C)‐C₆H₃ ( 11 ), 1‐[(Ph₃P)AuC≡C]‐3‐[(CO)₃ClRe(bpy‐C≡C)]‐5‐(FcC≡C)‐C₆H₃ ( 13 ), 1‐[(Ph₃P)AuC≡C]‐3‐(bpy‐C≡C)‐5‐(FcC≡C)‐C₆H₃ ( 14 ), [1‐[(Ph₃PAuC≡C]‐3‐[{[Ti](C≡CSiMe₃)₂}Cu(bpy‐C≡C)]‐5‐(FcC≡C)‐C₆H₃]PF₆ ( 16 ), and [1,3‐[(tBu₂bpy)₂Ru(bpy‐C≡C)]₂‐5‐(FcC≡C)‐C₆H₃](PF₆)₄ ( 18 ) (Fc = (η⁵‐C₅H₄)(η⁵‐C₅H₅)Fe, bpy = 2,2′‐bipyridiyl‐5‐yl, [Ti] = (η⁵‐C₅H₄SiMe₃)₂Ti) were prepared by using consecutive synthesis methodologies including metathesis, desilylation, dehydrohalogenation, and carbon–carbon cross‐coupling reactions. In these complexes the corresponding metal atoms are connected by carbon‐rich bridging units comprising 1,3‐diethynyl‐, 1,3,5‐triethynylbenzene and bipyridyl units. They were characterized by elemental analysis, IR and NMR spectroscopy, and partly by ESI‐TOF mass spectrometry., The structures of 4 and 11 in the solid state are reported. Both molecules are characterized by the central benzene core bridging the individual transition metal complex fragments. The corresponding acetylide entities are, as typical, found in a linear arrangement with representative M–C, C–C_C≡C and C≡C bond lengths.     

Site‐Selective and Metal‐Free Aliphatic CH Oxidation Enabled Synthesis of [5,24,25‐D3]‐(25S)‐Δ7‐Dafachronic acid

Steroid hormones play significant roles in both worms and mammalians. (25S)‐Δ⁷‐Dafachronic acid (Δ⁷‐DA, 1 ) is a member of the dafachronic acid hormonal series that regulates both development and lifespan of C. elegans. Despite its importance, effective tools for the illumination of its mode of action are lacking. Herein, we report an efficient synthesis of trideuterated Δ⁷‐DA, [5,24,25‐D3]‐(25S)‐Δ⁷‐dafachronic acid ([D₃]‐Δ⁷‐DA, 2 ), as a useful chemical tool for subsequent biological studies. Key steps for this bioinspired synthesis approach include site‐selective aliphatic C?H oxidation mediated by methyl(trifluoromethyl)dioxirane (TFDO), and the iridium/phosphine‐oxazoline‐catalyzed late‐stage asymmetric deuterium reduction.     

A Novel Asymmetric Synthesis of 3‐(1H‐Pyrrol‐1‐yl)‐Substituted β‐Lactams via a Bismuth Nitrate‐Catalyzed Reaction

The reaction of racemic α‐keto β‐lactams 5a – 5c with the commercially available chiral compound trans‐4‐hydroxy‐L ‐proline ( 6 ) in the presence of a catalytic amount of Bi(NO₃)₃?5 H₂O in EtOH gave a diastereoisomer mixture of β‐lactams with a pyrrole ring at C(3) ( 7 to 12 ). This is the first enantioselective synthesis of optically active β‐lactams (=azetidin‐2‐ones) that possess a pyrrolyl residue at C(3), in a single step.     

A [4+1] Cyclative Capture Approach to 3H‐Indole‐N‐oxides at Room Temperature by Rhodium(III)‐Catalyzed CH Activation

The rhodium(III)‐catalyzed [3+2] C? H cyclization of aniline derivatives and internal alkynes represents a useful contribution to straightforward synthesis of indoles. However, there is no report on the more challenging synthesis of pharmaceutically important N‐hydroxyindoles and 3H‐indole‐N‐oxides. Reported herein is the first rhodium(III)‐catalyzed [4+1] C? H oxidative cyclization of nitrones with diazo compounds to access 3H‐indole‐N‐oxides. More significantly, this reaction proceeds at room temperature and has been extended to the synthesis of N‐hydroxyindoles and N‐hydroxyindolines.     

A [4+1] Cyclative Capture Approach to 3H‐Indole‐N‐oxides at Room Temperature by Rhodium(III)‐Catalyzed C?H Activation

The rhodium(III)‐catalyzed [3+2] C H cyclization of aniline derivatives and internal alkynes represents a useful contribution to straightforward synthesis of indoles. However, there is no report on the more challenging synthesis of pharmaceutically important N‐hydroxyindoles and 3H‐indole‐N‐oxides. Reported herein is the first rhodium(III)‐catalyzed [4+1] C H oxidative cyclization of nitrones with diazo compounds to access 3H‐indole‐N‐oxides. More significantly, this reaction proceeds at room temperature and has been extended to the synthesis of N‐hydroxyindoles and N‐hydroxyindolines.     

Practical Synthesis of (20S)‐10‐(3‐Aminopropyloxy)‐7‐ethylcamptothecin,a Water‐Soluble Analogue of Camptothecin

A robust, practical synthesis of (20S)‐10‐(3‐aminopropyloxy)‐7‐ethylcamptothecin (T‐2513, 5 ), which is a water‐soluble analogue of camptothecin, has been developed. The key step in this synthesis is a highly diastereoselective ethylation at the C20 position by using N‐arylsulfonyl‐(R)‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid ester as a chiral auxiliary, which affords the key intermediate ethyl‐(S)‐2‐acyloxy‐2‐(6‐cyano‐5‐oxo‐1,2,3,5‐tetrahydroindolizin‐7‐yl)butanoate ( 8 k ) in 93 % yield and 87 % de. Optically pure compound 8 k was obtained by a single recrystallization from acetone and its further elaboration through Friedlander condensation afforded compound 5 . This synthesis does not require any chromatographic purification steps and can provide compound 5 on a multi‐gram scale in 6.3 % overall yield (16 steps).     

Synthesis of Enantiopure C3‐Symmetric Triangular Molecules

An asymmetric synthesis of C ₃‐symmetric triangular macrocycles is reported. 1‐Methylsulfonyl‐4‐(4‐vinylphenyl)‐1,2,3‐triazole undergoes a rhodium(II)‐catalyzed cyclotrimerization to establish an enantiopure C ₃‐symmetric triangular macrocycle motif. This method can be applied to the synthesis of an enantiopure hydrocarbon, which owes its chirality to asymmetric distribution of H/D atoms on the benzene rings.     

A Convenient Synthesis of 2,3‐Dihydro‐3‐methylidene‐1H‐isoindol‐1‐ones by Reaction of 2‐Formylbenzo­nitriles with Dimethyloxosulfonium Methylide

A facile method for the synthesis of 2,3‐dihydro‐3‐methylidene‐1H‐isoindol‐1‐one and its derivatives carrying substituent(s) at C(5) and/or C(6) has been developed. The reaction of 2‐formylbenzonitrile ( 1a ) with dimethyloxosulfonium methylide, generated by the treatment of trimethylsulfoxonium iodide with NaH in DMSO/THF at 0°, resulted in the formation of 2,3‐dihydro‐3‐methylidene‐1H‐isoindol‐1‐one ( 2a ) in 77% yield. Similarly, six 2‐formylbenzonitriles carrying substituent(s) at C(4) and/or C(5), i.e., 1b – 1g , also gave the corresponding expected products 2b – 2g in comparable yields.     

Stereoselective Total Synthesis of Stagonolide C

A convergent and efficient total synthesis of stagonolide C ( 1 ), a phytotoxic metabolite, was achieved (Schemes 2 and 3) The synthesis exploited the high configuration control in the Prins cyclization along with alkene rearrangement and ring‐closing metathesis as key steps.     

Asymmetric α‐Hydroxylation of a Lactone with Vinylogous Pyridone by Using a Guanidine–Urea Bifunctional Organocatalyst: Catalytic Enantioselective Synthesis of a Key Intermediate for (20S)‐Camptothecin Analogues

We have developed a catalytic asymmetric synthesis of (S)‐4‐ethyl‐6,6‐(ethylenedioxy)‐7,8‐dihydro‐4‐hydroxy‐1H‐pyrano[3,4‐f]indolizine‐3,10(4H)dione ( 5 a ), a synthetic intermediate for (20S)‐camptothecin analogues. A key step in this synthesis is an asymmetric α‐hydroxylation of a lactone with a vinylogous pyridone structure ( 8 a ) by using a guanidine–urea bifunctional organocatalyst. The present oxidation was successfully applied to the synthesis of C20‐modified derivatives of (+)‐C20‐desethylbenzylcamptothecin ( 13 ).     

Spontaneous Aminoacylation of a RNA Sequence Containing a 3′‐Terminal 2′‐Thioadenosine

We report the synthesis of a modified 8mer RNA sequence, (C‐C‐C‐C‐A‐C‐C‐(2′‐thio)A)‐RNA 5′‐(dihydrogen phosphate) ( 9 ) containing a 3′‐terminal 2′‐thioadenosine (Schemes 2 and 3), and its spontaneous and site‐specific aminoacylation with the weakly activated amino acid thioester H Phe SPh ( 12 ). This reaction, designed in analogy to the ‘native chemical ligation’ of oligopeptides, occurs efficiently in buffered aqueous solutions and under a wide range of conditions (Table). At pH values between 5.0 and 7.4, two products, the 3′‐O‐monoacylated and the 3′‐O,2′‐S‐diacylated RNA sequences 10 and 11 are formed fast and quantitatively (Scheme 4). At pH 7.4 and 37°, the 3′‐O‐monoacylated product 10 is formed as major product in situ by selective hydrolysis of the O,S‐diacylated precursor 11 . Additionally, the preparation and isolation of the relevant 3′‐O‐monoacylated product 10 was optimized at pH 5. The here presented concept could be employed for a straightforward aminoacylation of analogously modified tRNAs.     

The ‘Azirine/Oxazolone Method’ on Solid Phase: Introduction of Various α,α‐Disubstituted α‐Amino Acids

Peptides containing various α,α‐disubstituted α‐amino acids, such as α‐aminoisobutyric acid (Aib), 1‐aminocyclopentane‐1‐carboxylic acid, α‐methylphenylalanine, and 3‐amino‐3,4,5,6‐tetrahydro‐2H‐pyran‐3‐carboxylic acid have been synthesized from the N‐ to the C‐terminus by the ‘azirine/oxazolone method’ under solid‐phase conditions. In this convenient method for the synthesis of sterically demanding peptides on solid‐phase, 2H‐azirin‐3‐amines are used to introduce the α,α‐disubstituted α‐amino acids without the need for additional reagents. Furthermore, the synthesis of poly(Aib) sequences has been explored.     

Total Synthesis of the Marine Sesquiterpene Quinones Hyatellaquinone and Spongiaquinone

The synthesis of the marine sesquiterpene quinone (+)‐hyatellaquinone ( 1 ) was achieved starting from the sesquiterpene aldehyde (+)‐albicanal ((+)‐ 3 ) (Schemes 3 and 4). Coupling of (+)‐albicanal with 2,3,5,6‐tetramethoxyphenyllithium led to the aryl‐sesquiterpene system, which was modified to the target molecule. Furthermore, the first total synthesis of the marine compound spongiaquinone ( 2 ) was carried out starting from ((?)‐albicanal (?)‐ 3 ) in a reaction sequence encompassing a stereoselective C?C bond hydrogenation and a one‐pot AcOH elimination/demethylation reaction (Schemes 7 and 10). The occurrence of 1,2‐ and 1,4‐benzoquinone forms of 1 and 2 depends on the pH of the solvent system.     

Practical Synthesis of anti‐β‐Hydroxy‐α‐Amino Acids by PdII‐Catalyzed Sequential C(sp3)H Functionalization

An improved and practical procedure for the stereoselective synthesis of anti‐β‐hydroxy‐α‐amino acids (anti‐βhAAs), by palladium‐catalyzed sequential C(sp³)?H functionalization directed by 8‐aminoquinoline auxiliary, is described. followed by a previously established monoarylation and/or alkylation of the β‐methyl C(sp³)?H of alanine derivative, β‐acetoxylation of both alkylic and benzylic methylene C(sp³)?H bonds affords various anti‐β‐hydroxy‐α‐amino acid derivatives. As an example, the synthesis of β‐mercapto‐α‐amino acids, which are highly important to the extension of native chemical ligation chemistry beyond cysteine, is described. The synthetic potential of this protocol is further demonstrated by the synthesis of diverse β‐branched α‐amino acids. The observed diastereoselectivities are strongly influenced by electronic effects of aromatic AAs and steric effects of the linear side‐chain AAs, which could be explained by the competition of intramolecular C?OAc bond reductive elimination from Pd^IV intermediates vs. intermolecular attack by an external nucleophile (AcO^?) in an S_N2‐type process.     

Sequential Ugi Four‐Component Reaction (4‐CR)/CH Activation Using (Diacetoxyiodo)benzene for the Synthesis of 3‐(Diphenylmethylidene)‐2,3‐dihydro‐1H‐indol‐2‐ones

A sequential Ugi four‐component reaction (4‐CR)/C? H activation using (diacetoxyiodo)benzene is reported. This process is a five‐component reaction of aromatic aldehydes, aniline derivatives, isocyanides, phenylpropiolic acid (3‐phenylprop‐2‐ynoic acid), and (diacetoxyiodo)benzene for the synthesis of 3‐(diphenylmethylidene)‐2,3‐dihydro‐1H‐indol‐2‐ones. This procedure offers several advantages such as good yields, high bond‐forming efficiency, selectivity, and short reaction times.