Excellent Dr Research Articles

Oxidant controlled regio- and stereodivergent azidohydroxylation of alkenes via I2 catalysis.

A novel, I2 catalyzed regio- and stereodivergent vicinal azidohydroxylation of alkenes leading to 1,2-azidoalcohols in high yields (up to 92%) and excellent dr (up to 98%) has been developed. This unprecedented transformation employs NaN3 and DMF as N- and O-nucleophiles respectively. The role of DMF as the O-source in the reaction has been unequivocally proven by (18)O labelling studies.

ChemInform Abstract: Rapid Construction of (‐)‐Paroxetine and (‐)‐Femoxetine via an N‐Heterocyclic Carbene Catalyzed Homoenolate Addition to Nitroalkenes.

Due to their abundance in natural products and medicinal agents, the rapid, stereodefined construction of piperidines has received considerable attention from the synthetic community. 1, 2 Specifically, the pursuit of methodologies to furnish 3- and 4- substituted piperidine rings has been the subject of particularly intense focus due to its application in the synthesis of paroxetine. Paroxetine (Paxil) is a selective serotonin reuptake inhibitor (SSRI) that was discovered in 1970 and introduced to market in 1992 as a treatment for depression, anxiety, and panic disorder. 3 A related SSRI, femoxetine, was discovered concurrently with paroxetine, but was not pursued.3 Since the initial report, many syntheses of paroxetine have appeared relying upon the establishment of a single enantiomer of N-protected trans-4-(4-fluorophenyl)-3-piperidinemethanol II, followed by coupling with sesamol and deprotection. Approaches to set the stereochemistry often depend on the chiral pool, 4 resolution, 5 chiral auxiliaries, 6 chiral base, 7 and asymmetric catalysis. 8 These methods have proven effective and are represented in the literature accordingly. However, a highly convergent synthesis in which all the carbons of paroxetine are introduced in a single stereocontrolled step is lacking. Recently, we reported a N-heterocyclic carbene (NHC) catalyzed homoenolate addition of enals to nitroalkenes allowing access to syn δ-nitroesters in good yield, excellent dr, and excellent ee.9,10 Furthermore, we developed a protocol for the in situ reduction of the syn δ-nitroesters to the corresponding trans δ-lactam. This method provides rapid access to trans 3,4-disubstituted piperidones. We envisioned that utilization of this method would allow for exceptional levels of efficiency in the syntheses of paroxetine and femoxetine. Our method is notable, as it allows for the concomitant formation of the piperidine ring and establishment of the contiguous stereocenters in a single reaction (Scheme 1). Scheme 1 NHC-Catalyzed Nitroester/Lactam Formation We began our synthesis of paroxetine by forming requisite nitro alkene 3 (Scheme 2). From commercially available aldehyde 2 we performed a Henry reaction with nitromethane followed by elimination with trifluoroacetic anhydride to furnish nitroalkene 3 in 68 % yield over two steps. With this nitroalkene in hand we were ready to attempt the key NHC-catalyzed step. Using conditions we optimized and reported in our previous publication using catalyst 1a we observed no desired lactam product 5. We hypothesized that the bulky bis-butyl/OTMS moiety of the catalyst may be too large to facilitate the reaction and explored other catalyst scaffolds (Table 1). We found that fluorinated catalyst 1b11 provides the desired lactam 5 in 82 % ee, 10:1 dr, and 58 % yield. Satisfied with these results we scaled the reaction to 9 mmol and were pleased to find the reaction proceeds smoothly, delivering 1.8 grams of product in predictable yield and selectivities. We then subjected 1.2 grams (3.55 mmol) of the lactam precursor 5 to a LAH reduction, which delivered paroxetine (Paxil) 6 in 88 % yield (1.0 grams, 3.13 mmol), for an overall yield of 35 % over 4 steps in 82 % ee. Scheme 2 Preparation of paroxetine. Reagents and conditions: a) CH3NO2, KOtBu (20 mol%), tBuOH/THF, 0 to 23 °C, quantitative; b) trifluoroacetic anhydride, Et3N, CH2Cl2, 0 °C, 68 %; c) NHC 1b, NaOAc (50 mol%), EtOH, 23 °C, 12 h, then Zn ... Table 1 Chiral Catalyst Screen. Due to its structural similarity with paroxetine, we also explored a short synthesis of femoxetine. We first synthesized nitroalkene 8 from a two-step Henry/elimination sequence to furnish nitroalkene 8 in 20 % yield over two steps (Scheme 3). We then subjected nitroalkene 8 and cinnamaldehyde to the key NHC-catalyzed step followed by in situ reduction and were pleased to observe lactam 10 in 53 % yield, 7:1 dr, and 82 % ee. Methylation of the lactam with methyl iodide followed by LAH reduction completes our synthesis of femoxetine 11 in 5 steps and 82 % ee. Scheme 3 Preparation of femoxetine. Reagents and conditions: a) CH3NO2, KOtBu (20 mol%), tBuOH/THF, 0 to 23 °C, quantitative; b) trifluoroacetic anhydride, Et3N, CH2Cl2, 0 °C, 20 %; c) NHC 1b, NaOAc (50 mol%), EtOH, 23 °C, 12 h, then Zn ... In conclusion, we have developed rapid syntheses of (-)-paroxetine and (-)-femoxetine by employing a NHC catalyzed coupling of enals and nitroalkenes. The use of fluorinated NHC catalyst 1b in a one-pot sequence provides access to lactam products in moderate yield and good stereoselectivities, which were quickly elaborated to both paroxetine and femoxetine. Further, we have demonstrated that this approach is amenable to gram scale. To the best of our knowledge, this work represents the shortest synthesis of paroxetine to date.

ChemInform Abstract: Novel Sulfonylpolystyrene‐Supported Prolinamides as Catalysts for Enantioselective Aldol Reaction in Water.

Abstract Five novel prolinamides derived from 1,n-diamines supported on commercially available sulfonylpolystyrene have been synthesized and successfully applied in diastereo- and enantioselective aldol reaction in water or, in one case, neat conditions. Excellent dr and er were obtained by reaction of different cyclohexanone derivatives with aromatic and heteroaromatic aldehydes in the presence of the catalysts and AcOH as co-catalyst. The supported organocatalysts work in low loading (5 mol %) exhibiting similar performances than homogeneous prolinamides, and can be reused, after activation, without loss of activity.

ChemInform Abstract: List—Barbas—Mannich Reaction Catalyzed by Modularly Designed Organocatalysts.

The List–Barbas–Mannich reaction of ethyl (p-methoxyphenylimino)acetate (p-methoxyphenyl = PMP) with unmodified aldehydes or ketones catalyzed by modularly designed organocatalysts (MDOs) that are self-assembled from proline and cinchona alkaloid thioureas (such as a quinidine-derived thiourea) produces the corresponding γ-oxo-α-amino acid derivatives in high yields and excellent stereoselectivities. No solvent is necessary for this reaction. Aldehydes are especially good substrates for this reaction: The reaction takes only a few minutes to yield the corresponding List–Barbas–Mannich products in excellent dr (up to >99:1) and ee values (up to >99% ee).

Novel sulfonylpolystyrene-supported prolinamides as catalysts for enantioselective aldol reaction in water

Five novel prolinamides derived from 1,n-diamines supported on commercially available sulfonylpolystyrene have been synthesized and successfully applied in diastereo- and enantioselective aldol reaction in water or, in one case, neat conditions. Excellent dr and er were obtained by reaction of different cyclohexanone derivatives with aromatic and heteroaromatic aldehydes in the presence of the catalysts and AcOH as co-catalyst. The supported organocatalysts work in low loading (5 mol %) exhibiting similar performances than homogeneous prolinamides, and can be reused, after activation, without loss of activity.

List–Barbas–Mannich Reaction Catalyzed by Modularly Designed Organocatalysts

The List-Barbas-Mannich reaction of ethyl (p-methoxyphenylimino)acetate (p-methoxyphenyl = PMP) with unmodified aldehydes or ketones catalyzed by modularly designed organocatalysts (MDOs) that are self-assembled from proline and cinchona alkaloid thioureas (such as a quinidine-derived thiourea) produces the corresponding γ-oxo-α-amino acid derivatives in high yields and excellent stereoselectivities. No solvent is necessary for this reaction. Aldehydes are especially good substrates for this reaction: The reaction takes only a few minutes to yield the corresponding List-Barbas-Mannich products in excellent dr (up to >99:1) and ee values (up to >99% ee).

A Highly Diastereo- and Enantioselective Synthesis of Tetrahydroquinolines: Quaternary Stereogenic Center Inversion and Functionalization

Tetrahydroquinolines containing two quaternary stereogenic centers were synthesized with excellent ee and dr via a four-component cyclization reaction catalyzed by a chiral phosphoric acid. High chemoselectivity was achieved by differentiating anilines with similar reactivities to yield diverse "hybrid" products. The chirality of the quaternary C4 atom of the 4-aminotetrahydroquinoline products was found to undergo highly stereoselective inversion, enabling facile functionalization using a wide range of nucleophiles (C, O, N, and S).

A Highly Diastereoselective and Enantioselective Synthesis of Polysubstituted Pyrrolidines via an Organocatalytic Dynamic Kinetic Resolution Cascade

Highly functionalized pyrrolidine and piperidine analogues, with up to three stereogenic centers, were synthesized in good yield (50-95%), excellent dr (single isomer), and high ee (>90%) using a Cinchona alkaloid-derived carbamate organocatalyst. High stereoselective synergy was achieved by combining a reversible aza-Henry reaction with a dynamic kinetic resolution (DKR)-driven aza-Michael cyclization. Whereas both reactions proceed with moderate enantioselectivities (50-60% for each step), high enantioselectivities are obtained for the overall products devoid of dr sacrifice.

One-pot synthesis of 2,3,4,5,6-pentasubstituted tetrahydropyrans using lithiation–borylation, allylation and Prins cyclisation reactions

2,3,4,5,6-Pentasubstituted tetrahydropyrans have been prepared in good yield (42–57%) with excellent dr (>95:5) and er (>95:5) using a one-pot lithiation–borylation, allylation and Prins cyclisation reaction.

Spiking venom with rVes v 5 improves sensitivity of IgE detection in patients with allergy to Vespula venom

Spiking venom with rVes v 5 improves sensitivity of IgE detection in patients with allergy to Vespula venom

A Formal Synthesis of (−)-Cyanolide A Featuring a Stereoselective Mukaiyama Aldol Reaction and Oxocarbenium Reduction

The formal synthesis of the marine natural product (-)-cyanolide A is presented. The synthetic strategy is centered on two acyclic diastereoselective reactions and a single cyclic reaction with modest to excellent dr based on an initial stereocenter. Most notable is a highly stereoselective oxocarbenium reduction based on a "mismatched" reactive conformer to afford the β-C-glycoside subunit leading to an efficient synthesis of the diolide aglycon in 12 overall steps.

Diastereoselective Tin-Free Tandem Radical Additions to 3-Formylchromones

A tin-free tandem radical addition methodology onto 3-formylchromones is presented. This radical process yields functionalized chromone structures via two carbon-carbon bond-forming steps. These products contain up to three contiguous stereocenters with good to excellent dr's and yields.

Catalytic Asymmetric Vinylogous Mannich-type (AVM) Reaction of Nonactivated α-Angelica Lactone

A direct highly diastereo- and enantioselective asymmetric vinylogous Mannich-type (AVM) reaction of aldimines with nonactivated natural α-angelica lactone has been successfully developed. It was demonstrated that the nonactivated natural α-angelica lactone is a useful vinylogous nucleophile to give the chiral δ-amino γ,γ-disubstituted butenolide carbonyl derivatives. The N,N'-dioxide L2-Sc(III) complex is efficient toward the obtention of a range of corresponding products with adjacent quaternary and tertiary stereocenters in excellent dr and ee values.

Asymmetric Synthesis of α-Alkyl α-Selenocarbonyl Compounds Catalyzed by Bifunctional Organocatalysts

A new organocatalytic approach for the synthesis of a variety of α-alkyl, α-phenylselenyl ketones as well as their corresponding esters and amides, by the addition of α-selenocarbonyl derivatives to nitroalkenes catalyzed by thiourea or squaramide cinchona catalysts, is presented. This catalytic system allows the preparation in high yields of enantiomerically enriched selenocarbonyl derivatives bearing two chiral centers with excellent ee's and dr's by using catalytic loadings of 3 mol%.

Acyclic Stereocontrol in the Catalytic C−H Amination of Benzylic Methylene Groups

Diastereotopos-differentiation is the key feature of the catalytic C-H amination at the benzylic position of substrate 1. Essentially independent of the functional group X (X = COOMe, PO(OEt)(2), SO(2)Ph, NO(2), CN, OAc), the depicted products 2 are formed with good (dr = 80/20) to excellent (dr > 95/5) diastereoselectivity. The reaction proceeds without racemization and possesses potential for the C-H amination of open-chain substrates.

Borobox Ligands for Asymmetric Henry Reactions

The Pfaltz group has extended the scope and applications of its borabox ligand which was first introduced in 2005 for asymmetric cyclopropanation and desymmetrization of meso diols (Angew. Chem. Int. Ed. 2005, 44, 4888). Asymmetric Henry reaction of several nitro­methane derivatives with a wide range of aromatic and aliphatic aldehydes catalyzed by a copper-borabox complex gave addition products in good yields with modest to excellent dr and ee values.

De Novo Synthesis of 2‐Substituted syn‐1,3‐Diols via an Iterative Asymmetric Hydration Strategy.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Legal considerations of clinical guidelines

In their otherwise excellent review Dr Samanta and his colleagues (March 2003 JRSM1) assert that ‘clinical guidelines are systematically developed, evidence-based, clinically workable statements that aim to provide consistent and high quality care for patients’, and that because ‘guidelines from NICE... may be seen as the creme de la creme of authoritative bodies' it follows that their pronouncements are increasingly likely to inform the standard of care in negligence’. This is a dangerously illogical assumption to make: for all the diversity of lay and medical expertise available to NICE, the content of their guidelines is becoming increasingly proscriptive, and, in some cases, advocates a radical departure from pragmatic medical practice. The recent furore over the use of ultrasound locating devices for placing central venous catheters is a case in point.2, 3, 4 There are any number of criticisms that could be made of this document and its practical implementation,5 but with regard to the quasilegal nature of the guidelines, several important questions arise. Who owes the duty of informing doctors of new guidelines? Who is responsible for their execution—the hospital, the doctor, or both? Who is responsible for failing to follow the guidelines—the doctor, the hospital (either primarily, or vicariously), or both? Does obtaining specific consent from the patient vitiate the pseudo-legal requirement to follow the guideline? What is the legal recourse open to doctors who do not accept that the guidelines are ‘systematically developed, evidence-based or clinically workable’? Finally, should the courts be asked in every case to determine whether the guidelines are reasonable and rational before relying on them as the standard of acceptable medical practice? NICE and CHAI are valuable agencies for improving the quality of care in the NHS, but their authority depends on the soundness of their decrees. It is ultimately for the courts to decide, case by case, whether such decrees should inform the standard of care in negligence. Guidelines should continue to inform, rather than prescribe, medical practice.

Rheumatic Fever in Warm Climates-Reply

In Reply.— Dr Garcia-Palmieri has very properly emphasized that the epidemiology of acute rheumatic fever relates to the intensity and severity of streptococcal disease, whether it be in the tropics or in temperate climates. Wherever the predisposing factors of inadequate primary medical treatment with crowded living conditions, close person-to-person contact, inadequate nutritional intake, and lowered host defenses exist, acute rheumatic fever can be expected—and the prevalence of rheumatic fever and rheumatic heart disease will not be related to climate, per se, nor to any particular racial or ethnic group. For further information, the reader is referred to the very excellent monographRheumatic Fever and Streptococcal Infectionby Dr Gene H. Stollerman (New York, Grune & Stratton Inc, 1975).

Immunity of rats and mice following injection with 60Co irradiated Babesia rodhaini infected red cells.

Babesia rodhainiinfected mouse and rat red cells were non-infective after receiving 40 or 60 krad irradiation from a60Co source.Rats inoculated with irradiated infected red cells were subsequently found to show strong resistance to homologous challenge.Mice, which are more susceptible toB. rodhaini, showed less resistance to challenge, following immunization with irradiatedB. rodhainiinfected red cells.Splenectomized rats were immunized with irradiated infected blood. There was a delay compared with the controls in the onset of acute fatal parasitaemias in these rats. A population of parasites was isolated by taking and mixing blood from each of the splenectomized rats during the patent parasitaemia following challenge. This population appeared to be an antigenic variant of the original immunizing population.I thank Mrs J. Page for excellent technical assistance and Dr K. N. Brown for criticizing the manuscript.