- Cyclic Sulfamidite as Simultaneous Protecting Group for Amino Alcohols: Development of a Mild Deprotection Protocol Using Thiophenol
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This study describes the novel utility of cyclic sulfamidite as a simultaneous protecting group for 1,2- or 1,3-amino alcohols. An exceptionally mild and neutral condition for the removal of the cyclic sulfamidite was developed. The deprotection condition demonstrated a broad range of functional-group compatibility, including a substrate bearing a Z-enyne structure without any loss of double-bond stereochemistry.
- Sakata, Juri,Akita, Kazunari,Sato, Manabu,Shimomura, Masashi,Tokuyama, Hidetoshi
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p. 996 - 1000
(2020/11/03)
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- [Co(TPP)]-Catalyzed Formation of Substituted Piperidines
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Radical cyclization via cobalt(III)-carbene radical intermediates is a powerful method for the synthesis of (hetero)cyclic structures. Building on the recently reported synthesis of five-membered N-heterocyclic pyrrolidines catalyzed by CoII porphyrins, the [Co(TPP)]-catalyzed formation of useful six-membered N-heterocyclic piperidines directly from linear aldehydes is presented herein. The piperidines were obtained in overall high yields, with linear alkenes being formed as side products in small amounts. A DFT study was performed to gain a deeper mechanistic understanding of the cobalt(II)-porphyrin-catalyzed formation of pyrrolidines, piperidines, and linear alkenes. The calculations showed that the alkenes are unlikely to be formed through an expected 1,2-hydrogen-atom transfer to the carbene carbon. Instead, the calculations were consistent with a pathway involving benzyl-radical formation followed by radical-rebound ring closure to form the piperidines. Competitive 1,5-hydrogen-atom transfer from the β-position to the benzyl radical explained the formation of linear alkenes as side products.
- Lankelma, Marianne,Olivares, Astrid M.,de Bruin, Bas
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p. 5658 - 5663
(2019/04/08)
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- Formal Total Syntheses of (-)- and (+)-Actinophyllic Acid
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The formal total syntheses of (-)-actinophyllic acid and its enantiomer starting from the same chiral intermediate are reported. The synthesis features a photoredox organocatalytic asymmetric alkylation to generate the original C15 chirality, a photocatalytic C-H functionalization of 3-methylindole in flow for constructing the C16 all-carbon quaternary center, a regioselective 1,3-dipolar cycloaddition, and an intramolecular Henry reaction to assemble the pentacyclic core of the target molecule.
- Xue, Fei,Lu, Huifang,He, Liping,Li, Wenfei,Zhang, Dan,Liu, Xiao-Yu,Qin, Yong
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supporting information
p. 754 - 764
(2018/01/28)
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- Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension
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Prostacyclin controls cardiovascular function via activation of the prostacyclin receptor. Decreased prostacyclin production occurs in several cardiovascular diseases. However, the clinical use of prostacyclin and its analogues is complicated by their chemical and metabolic instability. A medicinal chemistry program searched for novel nonprostanoid prostacyclin receptor agonists not subject to these limitations. A compound with a diphenylpyrazine structural core was synthesized. Metabolic stability and agonist potency were optimized through modification of the linear side chain. Compound 12b (MRE-269, ACT-333679) was identified as a potent and highly selective prostacyclin receptor agonist. Replacement of the terminal carboxyl group with an N-acylsulfonamide group yielded parent compound 26a (selexipag, NS-304, ACT-293987), which is orally active and provides sustained plasma exposure of 12b. Compound 26a was developed for the treatment of pulmonary arterial hypertension and shown to reduce the risk of the composite morbidity/mortality end point in a phase 3 event-driven clinical trial.
- Asaki, Tetsuo,Kuwano, Keiichi,Morrison, Keith,Gatfield, John,Hamamoto, Taisuke,Clozel, Martine
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p. 7128 - 7137
(2015/10/05)
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- Concise, stereodivergent and highly stereoselective synthesis of cis-and trans-2-substituted 3-hydroxypiperidines-development of a phosphite-driven cyclodehydration
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A concise (5 to 6 steps), stereodivergent, highly diastereoselective (dr up to >19:1 for both stereoisomers) and scalable synthesis (up to 14 g) of cis- and trans-2-substituted 3-piperidinols, a core motif in numerous bioactive compounds, is presented. This sequence allowed an efficient synthesis of the NK-1 inhibitor L-733,060 in 8 steps. Additionally, a cyclodehydration-realizing simple triethylphosphite as a substitute for triphenylphosphine is developed. Here the stoichiometric oxidized P(V)-byproduct (triethylphosphate) is easily removed during the work up through saponification overcoming separation difficulties usually associated to triphenylphosphine oxide.
- Huy, Peter H.,Westphal, Julia C.,Koskinen, Ari M.P.
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supporting information
p. 369 - 383
(2014/03/21)
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- Acid promoted cyclodehydration of amino alcohols with amide acetal
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A convenient acid-promoted cyclization protocol for the formation of azaheterocycles from amino alcohols is described. The reaction involves the use of N,N-dimethylacetamide dimethyl acetal (DMADA) as the activating reagent of the hydroxyl group. Using this protocol, pyrrolidines or piperidines with various substituents can be synthesized in good to high yields.
- Hwang, Soonho,Park, Heemin,Kwon, Yongseok,Kim, Sanghee
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p. 60017 - 60024
(2015/02/19)
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- Efficient, stereodivergent access to 3-piperidinols by traceless P(OEt)3 cyclodehydration
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A stereodivergent and highly diastereoselective (dr up to >19:1 for both isomers), step economic (5-6 steps), and scalable synthesis (up to 14 g) of cis- and trans-2-substituted 3-piperidinols, the core motif of numerous bioactive compounds, providing efficient access to the NK-1 inhibitor L-733,060 is presented. Additionally, a "traceless" (referring to the simplified byproduct separation) cyclodehydration realizing simple P(OEt)3 as a substitute for PPh3 is developed.
- Huy, Peter H.,Koskinen, Ari M. P.
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p. 5178 - 5181
(2013/11/06)
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- Reductive hydroxyalkylation/alkylation of amines with lactones/esters
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We have developed a one-pot method for the direct intermolecular reductive hydroxyalkylation or alkylation of amines using lactones or esters as the hydroxyalkylating/alkylating reagents. The method is based on the in situ amidation of lactones/esters with DIBAL-H-amine complex (for primary amines) or DIBAL-H-amine hydrochloride salt complex (for secondary amines), followed by reduction of the amides with an excess of DIBAL-H. Different from the reduction of Weinreb amides with DIBAL-H where aldehydes are formed, the reduction of the in situ formed Weinreb amides yielded amines. Moreover, this method is not limited to Weinreb amides, instead, it also works for other amides in general. A plausible mechanism is suggested to account for the outcome of the reactions.
- Wang, Yu-Huang,Ye, Jian-Liang,Wang, Ai-E,Huang, Pei-Qiang
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experimental part
p. 6504 - 6511
(2012/09/08)
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- CYCLOPROPYL-CONTAINING POLYAMINE ANALOGS AS DISEASE THERAPIES
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This disclosure relates to specific polyamine analogs and methods of treating cancer using polyamine analogs. The polyamine analogs have cyclopropyl groups in their internal segments.
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Page/Page column 27
(2008/12/07)
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- Amine-directed hydroboration: Scope and limitations
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Iodine activation induces intramolecular hydroboration of homoallylic and bis-homoallylic amine boranes with good to excellent control of regiochemistry compared to control experiments using excess THF?BH3. Deuterium labeling and other evidence confirm that the iodine-induced hydroboration reaction of homoallylic amine boranes occurs via an intramolecular mechanism equivalent to the classical 4-center process and without competing retro-hydroboration. Longer carbon chain tethers result in lower regioselectivity, whereas the shorter tether in allylic amines results in a switch to dominant intermolecular hydroboration. Regioselectivity in THF?BH3 control experiments is higher for the allylic amine boranes compared to the iodine activation experiments, whereas the reverse is true for homoallylic amine borane activation.
- Scheideman, Matthew,Wang, Guoqiang,Vedejs, Edwin
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supporting information; experimental part
p. 8669 - 8676
(2009/02/03)
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- Compounds and method for enhancing the efficacy of anti-cancer drugs
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Polyamine compounds, method of synthesis and method of use for anti-cancer purposes, and for enhancing the activity of existing anti-cancer drugs are provided. This disclosure has identified certain polyamine motifs that can be attached to toxic agents to
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Page/Page column 19
(2008/06/13)
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- Stereochemical memory effects in alkene radical cation/anion contact ion pairs: Effect of substituents, and models for diastereoselectivity
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A series of 12 stereochemically defined 2,m-dimethyl- and 2,m,n-trimethyl-6-benzylamino-2-nitro-3-(diphenylphosphatoxy)hexanes have been synthesized and their cyclization reactions leading to di- and trisubstituted N-benzyl pyrrolidines examined in the presence of tributyltin hydride and azoisobutyronitrile in benzene at reflux. The cyclizations are interpreted in terms of generation of an alkyl radical by abstraction of the nitro group with a stannyl radical. The phosphate leaving group is then expelled in a heterolytic cleavage to give a contact alkene radical cation/phosphate anion pair. For the majority of the examples studied, the cyclizations are best understood in terms of nucleophilic attack by the amine on the opposite face of the alkene radical cation to the one shielded by the leaving group, within the confines of the initial contact ion pair, resulting in overall cyclization with inversion of configuration. Dependent on the relative stereochemistry of the substituents, the cyclization is envisaged as taking place through either chair-like or twist-boat-like transition states with the maximum number of substituents pseudo-equatorial. The model breaks down when cyclization on the initial contact ion pair would engender significant destabilizing steric interactions, especially 1,3A strain in the alkene radical cation. In these cases a fully equilibrated Beckwith-Houk-type transition state provides a satisfactory model. Interesting examples of matching and mismatching in the Corey-type oxazaborolidine-mediated reduction of alkyl (methyl-1-nitroethyl) ketones by a β-methyl group in the alkyl chain are reported, and the mismatching is attributed to a developing syn-pentane interaction in the transition state.
- Crich, David,Ranganathan, Krishnakumar
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p. 9924 - 9929
(2007/10/03)
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- Somatostatin analogue compounds
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Compounds having somatostatin activity of the following Formula I, 1wherein, R1 is aryl, substituted-aryl, and aryl-(lower-alkyl)-; R2 is lower alkyl, amino substituted lower alkyl, -carboxy-(lower-alkyl), -carbamic acid-(lower-alkyl) and -carboxy-(lower-alkyl)-aryl; and R3 and R4 are independently, lower-alkyl, aryl, substituted-aryl, (substituted-aryl)-(lower-alkyl)-, heteroaryl, (heteroaryl)-(lower-alkyl)-, substituted-heteroaryl, (substituted heteroaryl)-(lower-alkyl)-, heterocyclic, heterocyclic-(lower-alkyl)-, substituted-heterocyclic, (substituted-heterocylic)-(lower alkyl)-, -carboxy-(lower-alkyl), and -carboxy-(lower-alkyl)-aryl; or a pharmaceutically acceptable, ester, ether, or salt thereof; methods for their use; and preparation.
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- Defining the Molecular Requirements for the Selective Delivery of Polyamine Conjugates into Cells Containing Active Polyamine Transporters
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Several N1-substituted polyamines containing various spacer units between nitrogen centers were synthesized as their respective HCl salts. The N1-substituents included benzyl, naphthalen-1-ylmethyl, anthracen-9-ylmethyl, and pyren-1-
- Wang, Chaojie,Delcros, Jean-Guy,Cannon, Laura,Konate, Fanta,Carias, Horacio,Biggerstaff, John,Gardner, Richard Andrew,Phanstiel IV, Otto
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p. 5129 - 5138
(2007/10/03)
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- A mechanistic alternative for the intramolecular hydroboration of homoallylic amine and phosphine borane complexes
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Intramolecular hydroboration is demonstrated starting from homoallylic amine boranes upon activation by iodine. The process involves a B-iodoborane complex as the intermediate and may occur via internal displacement of iodide by the alkene to generate a cationic borane-alkene π-complex on the way to hydroboration products. The reaction can be carried out using a catalytic amount of iodine. Copyright
- Scheideman, Matthew,Shapland, Peter,Vedejs, Edwin
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p. 10502 - 10503
(2007/10/03)
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- Pyrimidinone-1,3-oxathiolane derivatives with antiviral activity
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Compounds of formula (I) wherein Ra and Rb the same or different, are hydrogen atoms, acyl groups deriving from a lower carboxylic acid or chains of formula (a) useful as reverse transcriptase inhibitors antiviral activity are described.
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- Polyamine derivatives as radioprotective agents
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The present invention relates to polyamine derivatives of the formula RHN-(CH2)m-NH-(CH2)n-NHR wherein m is an integer from 2 to 4, n is an integer from 3 to 10 and R is C2-C6 alkyl or -(CH2)p-Ar wherein Ar is phenyl or naphthyl and p is an integer from 0
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- Synthesis and anti-HIV evaluation of new 2',3'-dideoxy-3'-thiacytidine prodrugs
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A series of anti-HIV prodrugs possessing various polyaminated side arms have been developed. The incorporation of a N-Boc protected monoamine or diamine side arm into the backbone of the 2',3'-dideoxy-3'-thiacytidine 1 (BCH-189) provided an increase in antiviral potency, which could be several orders magnitude greater than the parent drug (1) depending on the cell culture systems used (MT-4 or MDMs). Twenty six 2',3'-dideoxy-3'-thiacytidine prodrugs which differ from each other by the length, the nature of the 5'-O function and the 5'-O or/and N-4 position on the nucleoside moiety were synthesized. Among this new series of prodrugs, several congeners (12c and 12a) were found to inhibit HIV-1 replication in cell culture with 50% effective concentrations EC50 of 10 and 50 nM respectively, in MT-4 cells. Compound 12c was found more active on infected MDMs cells with 50% effective concentration of 0.01 nM. The synthesis and the antiviral properties of these compounds are discussed.
- Mourier, Nicolas,Camplo, Michel,Della Bruna, Giovanna Schioppacassi,Pellacini, Francesco,Ungheri, Domenico,Chermann, Jean-Claude,Kraus, Jean-Louis
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p. 1057 - 1091
(2007/10/03)
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- Method of potentiating cell-mediated immunity utilizing polyamine derivatives
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This invention relates to a method of potentiating cell-mediated immunity which comprises administering to a patient a cell-mediated immunity potentiating amount of a compound of the formula: or a pharmaceutically acceptable salt thereof, wherein m is
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- Total synthesis of NPTX-643, a neurotoxin of the madagascar spider (Nephilengys borbonica) having a novel acylpolyamine structure
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The first total synthesis of NPTX-643, a neurotoxin of the Madagascar spider (Nephilengys borbonica) having a unique cadaverine - nor-putreanine - putreanine acylpolyamine chain, has been achieved by using three key azide intermediates.
- Miyashita, Masaaki,Kanemura, Takanori,Matsushita, Masayuki,Hatakeyama, Susumi,Itagaki, Yasuhiro,Nakajima, Terumi,Miyazawa, Masahiro,Irie, Hiroshi
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p. 171 - 175
(2007/10/03)
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