- An Efficient Stereocontrolled Strategy for the Synthesis of Hydroxyethylene Dipeptide Isosteres
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A novel and practical synthesis of hydroxyethylene dipeptide isostere 9 from L-phenylalanine via the formation and stereospecific reduction of an enaminone is described.
- Stuk, Timothy L.,Haight, Anthony R.,Scarpetti, David,Allen, Michael S.,Menzia, Jerome A.,et al.
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Read Online
- Preparation method of ritonavir and lopinavir intermediates
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The invention discloses a preparation method of ritonavir and lopinavir intermediates. The method comprises the steps: using L-phenylalanine as a raw material to react with benzyl chloride in potassium carbonate and an alkaline aqueous solution to obtain N, N-dimethylformamide; condensing with acetonitrile under the action of sodium amide; carrying out addition reaction with benzyl magnesium chloride; sequentially reducing enamine and carbonyl by using sodium borohydride/methanesulfonic acid and sodium borohydride/trifluoroacetic acid reagents; obtaining a stereoselective product, namely, dibenzylamino-3-hydroxy-5-amino-1, 2, 4-triazole under the induction effect of a chiral inducer; the stereoselective product reacts with di-tert-butyl methyl dicarbonate in a potassium carbonate/tetrahydrofuran solution, ammonium formate and palladium/carbon are used for reduction debenzylation, and the intermediate BDH is obtained. The preparation method is high in stereoselectivity, the diastereomeric excess (de%) value of the chiral product is high, the reaction steps are short, the product yield is high and generated three wastes are few.
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Paragraph 0039-0041
(2020/07/21)
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- Structural Analysis of Potent Hybrid HIV-1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere
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The design, synthesis, and X-ray structural analysis of hybrid HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF) in a pseudo-C2-symmetric dipeptide isostere are described. A series of PIs were synthesized by incorporating bis-THF of darunavir on either side of the Phe-Phe isostere of lopinavir in combination with hydrophobic amino acids on the opposite P2/P2′ position. Structure-activity relationship studies indicated that the bis-THF moiety can be attached at either the P2 or P2′ position without significantly affecting potency. However, the group on the opposite P2/P2′ position had a dramatic effect on potency depending on the size and shape of the side chain. Cocrystal structures of inhibitors with wild-type HIV-1 protease revealed that the bis-THF moiety retained similar interactions as observed in the darunavir-protease complex regardless of the position on the Phe-Phe isostere. Analyses of cocrystal structures and molecular dynamics simulations provide insights into optimizing HIV-1 PIs containing bis-THF in non-sulfonamide dipeptide isosteres.
- Rusere, Linah N.,Lockbaum, Gordon J.,Henes, Mina,Lee, Sook-Kyung,Spielvogel, Ean,Rao, Desaboini Nageswara,Kosovrasti, Klajdi,Nalivaika, Ellen A.,Swanstrom, Ronald,Kurt Yilmaz, Nese,Schiffer, Celia A.,Ali, Akbar
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supporting information
p. 8296 - 8313
(2020/09/22)
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- Molecular tools that block maturation of the nuclear lamin A and decelerate cancer cell migration
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Lamin A contributes to the structure of nuclei in all mammalian cells and plays an important role in cell division and migration. Mature lamin A is derived from a farnesylated precursor protein, known as prelamin A, which undergoes post-translational cleavage catalyzed by the zinc metalloprotease STE24 (ZPMSTE24). Accumulation of farnesylated prelamin A in the nuclear envelope compromises cell division, impairs mitosis and induces an increased expression of inflammatory gene products. ZMPSTE24 has been proposed as a potential therapeutic target in oncology. A library of peptidomimetic compounds were synthesized and screened for their ability to induce accumulation of prelamin A in cancer cells and block cell migration in pancreatic ductal adenocarcinoma cells. The results of this study suggest that inhibitors of lamin A maturation may interfere with cell migration, the biological process required for cancer metastasis.
- Matralis, Alexios N.,Xanthopoulos, Dimitrios,Huot, Geneviève,Lopes-Paciencia, Stéphane,Cole, Charles,de Vries, Hugo,Ferbeyre, Gerardo,Tsantrizos, Youla S.
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supporting information
p. 5547 - 5554
(2018/10/15)
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- A (2 R, 3 S) - 1 - chloro - 3 - tert-butoxy amide - 4 - phenyl - 2 - butanol preparation method
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The invention provides a preparation method for (2R,3S)-1-chlorine-3-tert-butoxycarbonylamino-4-phenyl-2-butanol. The preparation method comprises the steps that L-phenylalanine is taken as raw materials, protected by adopting benzyl, esterified and then catalyzed through NMM to generate a mixed anhydride compound, the mixed anhydride compound reacts with diazomethane to generate diazoketone, a reduction reaction and palladium carbon reduction are performed, and finally the intermediate (2R,3S)-1-chlorine-3-tert-butoxycarbonylamino-4-phenyl-2-butanol is obtained. According to the preparation method, the low-cost benzyl is adopted to protect amidogen, the synthetic route is reasonable, the operation technology is simple, safe and high in yield, industrialization can be well achieved, and the production efficiency is improved.
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Paragraph 0035; 0040; 0056; 0072-0074
(2017/09/26)
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- Method for synthesizing ritonavir intermediate
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The invention relates to a method for synthesizing a ritonavir intermediate. The intermediate is (S,Z)-5-amino-2-(dibenzylamino)-1,6-diphenylhex-4-en-3-one. The method comprises the following steps: mixing L-phenylalanine, water and sodium hydroxide, adding benzyl chloride, adding heptane, washing the above obtained material with a methanol-water solution, and carrying out reduced pressure evaporation to obtain yellow oil benzyl 2-dibenzylamino-3-phenylpropionate; and dissolving the yellow oil in methyl tert-butyl ether under the protection of nitrogen, reacting the obtained solution with anhydrous acetonitrile, adding sodium hydride, stirring all above materials, slowly dropwise adding a Grignard reagent, cooling, adding anhydrous methanol for hydrolyzing superfluous sodium amide, allowing the obtained solution to stand for layering, extracting the obtained water layer with methyl tert-butyl ether, mixing oil layers, concentrating the obtained oil layer mixture, evaporating the obtained concentrate to obtain oil, adding anhydrous methanol, filtering the oil, and carrying out vacuum drying to obtain white powder which is the ritonavir intermediate (S,Z)-5-amino-2-(dibenzylamino)-1,6-diphenylhex-4-en-3-one. Compared with traditional technologies, the method provided by the invention has the advantages of reaction step simplification, reaction cost reduction, and reduction of use of toxic reagents.
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Paragraph 0017
(2017/03/14)
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- A - And B -fluorinated aminophosphonates-Synthesis and properties
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Interest in synthesis of fluorinated aminophosphonates has grown significantly in recent years due to their promising applications in medicinal and bioorganic chemistry. We report herein efficient and general methods for the synthesis of α- and β-monofluo
- Ka?mierczak, Marcin,Kubicki, Maciej,Koroniak, Henryk
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p. 459 - 468
(2016/04/09)
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- Carbohydrates as efficient catalysts for the hydration of α-amino nitriles
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Directed hydration of α-amino nitriles was achieved under mild conditions using simple carbohydrates as catalysts exploiting temporary intramolecularity. A broadly applicable procedure using both formaldehyde and NaOH as catalysts efficiently hydrated a variety of primary and secondary susbtrates, and allowed the hydration of enantiopure substrates to proceed without racemization. This work also provides a rare comparison of the catalytic activity of carbohydrates, and shows that the simple aldehydes at the basis of chemical evolution are efficient organocatalysts mimicking the function of hydratase enzymes. Optimal catalytic efficiency was observed with destabilized aldehydes, and with difficult substrates only simple carbohydrates such as formaldehyde and glycolaldehyde proved reliable.
- Chitale, Sampada,Derasp, Joshua S.,Hussain, Bashir,Tanveer, Kashif,Beauchemin, André M.
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supporting information
p. 13147 - 13150
(2016/11/09)
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- An asymmetric pericyclic cascade approach to 3-alkyl-3-aryloxindoles: Generality, applications and mechanistic investigations
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The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3-alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology.
- Richmond, Edward,Ling, Kenneth B.,Duguet, Nicolas,Manton, Lois B.,elebi-?lcüm, Nihan,Lam, Yu-Hong,Alsancak, Sezen,Slawin, Alexandra M. Z.,Houk,Smith, Andrew D.
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supporting information
p. 1807 - 1817
(2015/02/19)
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- Synthesis of (S,Z)-5-amino-2-(dibenzylamino)-1,6-diphenylhex-4-en-3-one
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L-Phenylalanine taken as a starting material is protected with benzyl chloride and procedure simplified by not charging with ethyl alcohol. Subsequently with the further simplification of skipping the atmospheric distillation of MTBE (methyl tert-butyl ether), (S,Z)-5-amino-2-(dibenzylamino)-1,6-diphenylhex-4-en-3-one, the significant intermediate of Ritonavir and Lopinavir, is obtained from cyanidation, Grignard reaction and reduction.
- Hongmin, Li,Bin, Wang,Shuyong, Mu
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p. 1154 - 1156
(2015/09/28)
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- Chiral Pool-Based Synthesis of Naphtho-Fused Isocoumarins
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A variety of chiral derivatives of benzo[d]naphtho[1,2-b]pyran-6-one were prepared in a single step by Et3N-mediated condensation of homophthalic anhydride with different derivatives of (S)-amino acid chlorides at -5 °C by employing a chiral pool methodology. Chirality 27:951-957, 2015.
- Raza, Abdul Rauf,Saddiqa, Aisha,?akmak, Osman
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p. 951 - 957
(2015/11/16)
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- Chiron based synthesis of isocoumarins: Reactivity of α-substituted carboxylic acids
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The asymmetric synthesis of a novel (S)-isocoumarin has been attempted in a single step by the coupling of homophthalic acid with (S)-N-protected amino acids and α-chloroacids at high temperature by exploiting a chiral pool methodology. The coupling of homophthalic acid with N-protected (S)-amino acids gave exclusion of the carboxyl/alkyl group. However, coupling of homophthalic acid with α-chloroacids afforded asymmetric isocoumarins in high yield.
- Saddiqa, Aisha,Raza, Abdul R.,Black, David Stc.,Kumar, Naresh
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p. 736 - 743
(2014/06/09)
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- A versatile and efficient approach for the synthesis of chiral 1,3-nitroamines and 1,3-diamines via conjugate addition to new (S,E)-Γ-aminated nitroalkenes derived from L-α-amino acids
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New chiral (S,E)-γ-N,N-dibenzylated nitroalkenes 2a-c were synthesized from natural L-(α)-amino acids in five steps with overall yields of 68-88%. The conjugate addition of hydride, methoxide, nitronate and azide nucleophiles to 2a-c led to the corresponding chiral 1,3-nitroamines in 74-90% yield. The conjugate addition of cyanide anion to 2a,b was followed by HNO2 elimination affording chiral aminated acrylonitriles (73-98%). On the other hand, the azide anion reacted with 2a, in acetonitrile, via a [3 + 2]-cycloaddition in which HNO2 was lost, providing the corresponding 1,2,3-triazole derivative. Direct reduction of 1,3- nitroamine derivatives 9a,b produced the corresponding 1,3-diamines in good yields.
- Pereira, Vera Lucia Patrocinio,Da Silva Moura, Andre Luiz,Vieira, Daniel Pais Pires,De Carvalho, Leandro Lara,Torres, Eliz Regina Bueno,Da Silva Costa, Jeronimo
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supporting information
p. 832 - 837
(2013/06/05)
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- DAST mediated preparation of β-fluoro-α-aminophosphonates
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Herein, we report a new and convenient method for the synthesis of β-fluoro-α-aminophosphonates starting from naturally occurring l-amino acids. A key step in the synthetic protocol involves nucleophilic fluorination of N,N-dibenzylated-β-amino alcohols with diethylaminosulfur trifluoride (DAST).
- Ka?mierczak, Marcin,Koroniak, Henryk
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experimental part
p. 23 - 27
(2012/06/30)
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- Remarkable diastereomeric rearrangement of an α-acyloxy β-ketosulfide to an α-acyloxy thioester: A novel approach to the synthesis of optically active (2S,3S) β-amino α-hydroxy acids
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A novel and efficient synthetic method is described for (2S,3S)-3-amino-2-hydroxy-4-phenyl butyric acid derivatives, which are useful intermediates of enzyme inhibitors. This involves a Pummerer rearrangement of a β-ketosulfoxide derived from L-phenylalanine followed by highly stereoselective acyl migration. From these studies, it appears that nitrogen-protecting groups exert a substantial influence over stereoselectivity. The mechanism of the rearrangement is discussed. β-Amino α-hydroxy carboxylic acids are important pharmaceutical intermediates, and this method may provide a versatile synthesis from various amino acids in a few steps.
- Suzuki, Takayuki,Honda, Yutaka,Izawa, Kunisuke,Williams, Robert M.
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p. 7317 - 7323
(2007/10/03)
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- Self-emulsifying drug delivery system
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Oral pharmaceutical formulation which improves the bioavailability of pharmaceuticals which are substantially water and oil insoluble is disclosed. In addition to the pharmaceutical, the formulation includes an emulsifier, an oil and an solubilizer. Alter
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- Diastereoselective reduction of β-ketophosphonates derived from amino acids. A new entry to enantiopure β-hydroxy-γ-aminophosphonate derivatives
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The reduction of γ-N,N-dibenzylamino-β-ketophosphonates 4 derived from readily available (S)-tribenzylated amino acids was achieved with catecholborane at -20°C affording γ-amino-β-hydroxyphosphonates 5 in high diastereoselectivity and good chemical yield. These reactions provide a new entry to enantiomerically pure γ-amino-β-hydroxyphosphonates.
- Ordoez, Mario,De la Cruz, Ricardo,Fernandez-Zertuche, Mario,Muoz-Hernandez, Miguel-Angel
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p. 559 - 562
(2007/10/03)
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- Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
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Selected bis-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.
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Page column 30
(2008/06/13)
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- Novel Lopinavir analogues incorporating non-Aromatic P-1 side chains - Synthesis and structure-activity relationships
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The HIV protease inhibitor Lopinavir has a pseudosymmetric core unit incorporating benzyl groups at both P-1, P-1′ positions. A series of analogues incorporating non-aromatic side chains at the P-1 position were synthesized and the structure-activity relationships explored.
- Sham, Hing L.,Zhao, Chen,Li, Leping,Betebenner, David A.,Saldivar, Ayda,Vasavanonda, Sudthida,Kempf, Dale J.,Plattner, Jacob J.,Norbeck, Daniel W.
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p. 3101 - 3103
(2007/10/03)
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- Retroviral protease inhibiting compounds
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A compound comprising a substituent of the formula (II) is disclosed as an HIV protease inhibitor. Intermediates for making such compounds and processes for making such intermediates are also disclosed.
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- Stereoselective deprotonation of chiral and achiral 2-aminoalkyl carbamates: Synthesis of optically active β-amino alcohols via 1-oxy- substituted alkyllithium intermediates
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A facile protocol for the electrophilic C-substitution (methylation, acylation, α-hydroxyalkylation, and carboxylation) of several 2-(N,N- dibenzylamino)alkan-1-ols via the carbamates 10 is reported. The stereochemistry of the lithiation is greatly influenced by the complexing diamine. The substrate-directed selection between the diastereotopic a-pro-R and pro-S protons in the TMEDA-assisted deprotonation is largely shifted towards pro-S-selectivity in the presence of (-)-sparteine (4). Each of both diastereomeric series is readily accessible in several cases.
- Schwerdtfeger, J?rg,Kolczewski, Sabine,Weber, Berthold,Fr?hlich, Roland,Hoppe, Dieter
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p. 1573 - 1592
(2007/10/03)
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- RETROVIRAL PROTEASE INHIBITING COMPOUNDS
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A compound of the formula: STR1 is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
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- Process for the preparation of substituted keto-enamines
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The present invention discloses a process for the preparation of a compound having formula 4: STR1 The process comprises the step of reacting an enolate having the formula: STR2 with a Grignard reagent. The enolate salt is formed in situ from the reaction of a protected ester wherein M is an alkali metal. R6 and R7 are each hydrogen or are independently selected from STR3 wherein Ra and Rb are independently selected from hydrogen, lower alkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, lower alkyl, trifluoromethyl, alkoxy, halo and phenyl; and STR4 wherein the naphthyl ring is unsubstituted or substituted with one, two or three substitutents independently selected from lower alkyl, trifluoromethyl, alkoxy and halo. Alternatively, R6 is as defined above and R7 is R12 OC(O)-- wherein R12 is benzyl; or R6 and R7 taken together with the nitrogen atom to which they are bonded form STR5 wherein Rf, Rg, Rh and Ri are independently selected from hydrogen, lower alkyl, alkoxy, halogen and trifluoromethyl.
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- Reduction of an enaminone: Synthesis of the diamino alcohol core of ritonavir
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The reduction of (5S)-2-amino-5-dibenzylamino-4-oxo-l,6-diphenylhex-2-ene was optimized for diastereoselectivity and overall conversion to (2S,3S,5S)-5-amino-2-dibenzylamino-3-hydroxy-l,6-diphenylhexane (2a). A two-step reduction sequence is described wherein the enamine is reduced with a borane-sulfonate derivative followed by reduction of the resulting ketone with sodium borohydride. The desired 2a was obtained with 84% diastereoselectivity and an acyclic 1,4 stereoinduction ratio of 14:1. This methodology has been used to produce multikilogram quantities of the diamino alcohol core, of Ritonavir and should be general to the synthesis of related diamino hydroxyethylene isosteres.
- Haight, Anthony R.,Stuk, Timothy L.,Allen, Michael S.,Bhagavatula, Lakshmi,Fitzgerald, Michael,Hannick, Steven M.,Kerdesky, Francis A.J.,Menzia, Jerome A.,Parekh, Shyamal I.,Robbins, Timothy A.,Scarpetti, David,Tien, Jien-Heh J.
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- An Unusual Acyliminium Cyclization and Other Drawbacks during an Attempted Synthesis of a Chiral Primary α-Phosphinoalkanamine
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Studies towards the synthesis of a chiral primary α-phosphinoalkanamine 1a are reported. O-Activated, N-carbamate-protected phenylalaninol 3a did not undergo 5N reaction with KPPh2: instead, after TV-deprotonalion, intramolecular substitution led to formation of the aziridine derivative 5a (Scheme 2). N-Phthalimido-protected. O-activated phenylalaninol 3b also underwent an intramolecular process on treatment with KPPh2, i.e., an unusual aryl-acyliminium cyclization furnishing the (epoxymethano)isoindolo[1,2-a]isoquinolinone 7 (Scheme 3). In a reaction with KPPh2, the N,N-dibenzyl-protected and activated phenylalaninol 3d finally yielded the intermolecular SN reaction product 2a (Scheme 4). However, debenzylation by catalytic hydrogenation turned out to be impossible.
- Christoffers, Jens
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p. 845 - 852
(2007/10/03)
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- Process for producing 3-amino-2-oxo-1-halogenopropane derivatives
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Compounds formed by reacting a protected amino acid with an alkali metal enolate of an alkyl acetate are reacted with a halogenating agent for halogenation of the 2-position, or a protected amino acid is reacted with an alkali metal enolate of an alkyl halogenoacetate, to form a 4-amino-3-oxo-2-halogenobutanoic acid ester derivative, and hydrolysis and decarboxylation are conducted to produce a 3-amino-2-oxo-1-halogenopropane derivative or its salt. The present method is a useful process for producing a 3-amino-2-oxo-1-halogenopropane derivatives which can easily be converted to a 3-amino-1,2-epoxypropane.
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- Investigation of the configurational stability of lithiated phosphine oxides using the Hoffmann test: X-ray structures of (2S*,3S*,4R*)-2-(N,N-dibenzylamino)-4-diphenylphosphinoyl-1- phenylpentan-3-ol and (2S*,4S*)-2-(N,N-dibenzylamino)-4-diphenylphosphinoyl-1- phenylpentan-3-one
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The Hoffmann test (reaction of a racemic organolithium with a phenylalanine-derived aldehyde) is used to show that lithiated diphenylphosphine oxides are not configurationally stable in THF at -78°C (usual reaction conditions) on the timescale of their rate of reaction with the aldehyde. The test is carried out by reacting lithiated ethyldiphenylphosphine oxide with a phenylalanine-derived aldehyde and because all four diastereoisomeric alcohols are obtained, it is necessary to determine the relative stereochemistry of the products. This is done using a combination of synthesis and X-ray crystallography of (2S*,3S*,4R*)-2-(N,N-dibenzylamino)-4-diphenylphosphinoyl-1- phenylpentan-3-ol and(2S*,4S*)-2-(N,N-dibenzylamino)-2-diphenylphosphinoyl-1- phenylpentan-3-one.
- O'Brien, Peter,Powell, Harold R.,Raithby, Paul R.,Warren, Stuart
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p. 1031 - 1039
(2007/10/03)
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- Diastereoselection during 1,2-Addition of the Allylindium Reagent to α-Thia and α-Amino Aldehydes in Aqueous and Organic Solvents
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The stereochemistry of the indium-promoted reaction of allyl bromide with α-thia (PhS and MeS), disubstituted α-amino (Bn2N, Me2N, isoindolyl), and protected α-amino aldehydes (Ac and Boc) in water has been evaluated. The reactions involving the sulfur derivatives are minimally diastereoselective, indicating that the allylindium reagent is not thiophilic. Chelation is not observed and π-facial discrimination is achieved via Felkin - Ahn transition states under the steric control of the substituents. The Garner aldehyde is also anti-diastereoselective. Interestingly, N-acetylmannosamine is appreciably responsive to chelation control and is capable of generating 90% of the syn β-amino alcohol when reacted in a 0.5 M NH4Cl solution. While the α-dibenzylamino substituent is too bulky to enter into complexation, the α-dimethylamino group is not and can lead to high levels (99%) of syn diastereomer. The size of other neighboring substituents does have an impact on π-facial discrimination in these systems and can erode the stereoselectivity accordingly.
- Paquette, Leo A.,Mitzel, Thomas M.,Isaac, Methvin B.,Crasto, Curtis F.,Schomer, William W.
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p. 4293 - 4301
(2007/10/03)
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- Stereoselective synthesis of β-amino alcohols: Diastereoselective reduction of chiral α-amino enones derived from amino acids
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α-Amino acids are doubly benzylated at nitrogen to give N,N-dibenzyl amino acids, which can readily be converted to α'-amino enones 3. The α'-amino enones are very resistant to racemization, and undergo highly diastereoselective reduction to afford chiral amino alcohols upon treatment with L-Selectride under non-chelation control.
- Chung, Sung-Kee,Kang, Dong-Ho
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p. 3027 - 3030
(2007/10/03)
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- Process for the preparation of a substituted 2,5-diamino-3-hydroxyhexane
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A process is disclosed for the preparation of the substantially pure compound of the formula: STR1 comprising catalytic hydrogenation of a compound of the formula: STR2 wherein R6 and R7 are independently selected from STR3 wherein Ra and Rb are independently selected from hydrogen, loweralkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; and STR4 wherein the naphthyl ring is unsubstituted or substituted with one, two or three substitutents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo; or R6 and R7 taken together with the nitrogen atom to which they are bonded are STR5 wherein Rf, Rg, Rh and Ri are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl; or an acid addition salt thereof.
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- Synthesis of phenylalanine-derived β-hydroxy and β-keto phosphine oxides -investigation of the configurational stability of lithiated phosphine oxides using the Hoffmann test
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Reaction between a phenylalanine-derived aldehyde and a lithiated phosphine oxide (the Hoffmann test) has been used to demonstrate that lithiated phosphine oxides are not configurationally stable in THF at -78°C on the timescale of thier reaction with the aldehyde. Additionally, these reactions generate synthetically useful products. Copyright
- O'Brien, Peter,Warren, Stuart
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p. 4271 - 4274
(2007/10/03)
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- Remote asymmetric induction in organocopper conjugate additions to 3-ketoacrylates
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Remote asymmetric induction has been achieved in the conjugate addition of organocopper reagents to a novel 3-ketoacrylate system, 1. Conjugate additions proceed in moderate to good yield and with high regio-and stereoselectivity in the presence of diethylaluminum chloride. Copyright
- Captain, Laura F.,Xia, Xiaoyang,Liotta, Dennis C.
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p. 4293 - 4296
(2007/10/03)
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- Process for the preparation of a substituted 2,5-diamino-3-hydroxyhexane
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Intermediates and processes are disclosed which are useful for the preparation of a substantially pure compound of the formula: STR1 wherein R6 and R7 are each hydrogen or R6 and R7 are independently selected from STR2 wherein Ra and Rb are independently selected from hydrogen, loweralkyl and phenyl and Rc, Rd and Re are independently selected from hydrogen, loweralkyl, trifluoromethyl, alkoxy, halo and phenyl; and STR3 wherein the naphthyl ring is unsubstituted or substituted with one, two or three substitutents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo; or R6 is as defined above and R7 is R7a OC(O)--wherein R7a is loweralkyl or benzyl; or R6 and R7 taken together with the nitrogen atom to which they are bonded are STR4 wherein Rf, Rg, Rh and Ri are independently selected from hydrogen, loweralkyl, alkoxy, halogen and trifluoromethyl and R8 is hydrogen or --C(O)R" wherein R" is loweralkyl, alkoxy, benzyloxy or phenyl wherein the phenyl ring is unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, trifluoromethyl, alkoxy and halo; or an acid addition salt thereof.
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- A Practical Synthesis of an HIV Protease Inhibitor Intermediate - Diastreoselective Epoxide Formation from Chiral α-Aminoaldehydes
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A practical and efficient synthesis of an HIV protease inhibitor intermediate has been developed based on the diastereoselective epoxide formation from a chiral α-aminoaldehyde and an in situ generated halomethyllithium reagent.
- Ng, John S.,Przybyla, Claire A.,Liu, Chin,Yen, Joe C.,Muellner, Frank W.,Weyker, Cara L.
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p. 6397 - 6410
(2007/10/02)
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- Acyclic stereoselection in the tertiary amine-catalysed addition of activated vinyl systems (Baylis-Hillman reaction) to protected chiral α-hydroxy and α-amino aldehydes
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The non chelation-controlled aldol-type addition of the ambident vinyl α anions derived from acrylic esters and methyl vinyl ketone to a series of protected chiral α-hydroxy and α-amino aldehydes has been investigated in order to assess some of the factors which contribute to the control of the diastereofacial selectivity.Whlist the α-methylene-β,γ-disubstituted carbonyl products showed a general preference for selectivity, some examples of syn predominance were made possible via a 'substituent tuning'approach.The observed diastereomer ratios have been interpreted in terms of the Felkin model and the Anh-Eisenstein proposals for 1,2-asymmetric induction.Simple steric effects appear to be as important as ?-orbital energies in the designation of the large 'anti group' for the application of these transition-state interpretations.Attempts to improve the overall induction via double diastereoselection approach, which combines the 1,5-induction of chiral acrylates with the 1,2-induction already present, were largely inconclusive.Methods for the routine NMR assignment of the relevant stereo-substructures have been assessed and the use of novel complementary technique is described.
- Manickum, Thavrin,Ross, Gregory H. P.
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- Optically active α-amino aldehydes, process for the preparation thereof, and the use thereof for the stereoselective preparation of optically active β-amino alcohols
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The invention relates to new optically active α-amino aldehydes of the formulae STR1 in which R1 represents an optionally substituted alkyl, alkenyl, aralkyl or aryl radical, and R2 and R3, independently of one another, denote an optionally substituted alkyl, alkenyl, cycloalkyl or aralkyl group, together form an optionally substituted phenylene-(1,2)-bis-methylene radical, or R2 is an optionally substituted, alkyl, cycloalkyl or aralkyl radical, and R3 forms together with R1 a 1,3-propylene radical. a process for the preparation thereof, and the use thereof for the stereoselective preparation of optically active β-amino alcohols.
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