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In the presence of different nucleophilic Knoevenagel competitors, cyclic and acyclic ketones have been shown to undergo highly chemoselective aldol reactions with aldehydes. In doing so, the substrate breadth for this emerging methodology has been significantly broadened. The method is also no longer beholden to proline-based catalyst templates, e.g. , commercially available O- t -Bu-L-threonine is advantageous for acyclic ketones. The key insight was to exploit water-based mediums under conventional (in-water) and non-conventional (deep eutectic solvents) conditions. With few exceptions, high aldol-to-Knoevenagel chemoselectivity (>10:1) and good product profiles (yield, dr , and ee ) were observed, but only in DESs (deep eutectic solvents) in conjunction with ball milling did short reaction times occur.

Site selectivity, differentiating instances of the same functional group type on one substrate, represents a forward-looking theme within chemistry: reduced dependence on protection/deprotection protocols for increased overall yield and step-efficiency. Despite these potential benefits and the expanded tactical advantages afforded to synthetic design, site selectivity remains elusive and especially so for ketone-based substrates. Herein, site-selective intermolecular mono-aldolization has been demonstrated for an array of prochiral 4-keto-substituted cyclohexanones with concomitant regio-, diastereo-, and enantiocontrol. Importantly, the aldol products allow rapid access to molecularly complex ketolactones or keto-1,3-diols, respectively containing three and four stereogenic centers. The reaction conditions are of immediate practical value and general enough to be applicable to other reaction types. These findings are applied in the first enantioselective, formal, synthesis of a leading Alzheimer's research drug, a γ-secretase modulator (GSM), in the highest known yield., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The default explanation for good to high diastereomeric excess when reducing N-chiral imines possessing only mediocre cis/trans-imine ratios (>15% cis-imine) has invariably been in situ cis-to-trans isomerization before reduction; but until now no study unequivocally supported this conclusion. The present study co-examines an alternative hypothesis, namely that some classes of cis-imines may hold conformations that erode the inherent facial bias of the chiral auxiliary, providing more of the trans-imine reduction product than would otherwise be expected. The ensuing experimental and computational (DFT) results favor the former, pre-existing, explanation.

Here, we present the new UCL Bioinformatics Group's PSIPRED Protein Analysis Workbench. The Workbench unites all of our previously available analysis methods into a single web-based framework. The new web portal provides a greatly streamlined user interface with a number of new features to allow users to better explore their results. We offer a number of additional services to enable computationally scalable execution of our prediction methods; these include SOAP and XML-RPC web server access and new HADOOP packages. All software and services are available via the UCL Bioinformatics Group website at http://bioinf.cs.ucl.ac.uk/.

Here we report on inroads concerning increased substrate breadth via the picolylamine organocatalyst template, a vicinal chiral diamine based on a pyridine-primary amine motif. The addition of cyclohexanone to β-nitrostyrene has many catalyst solutions, but cyclopentanone and isobutyraldehyde additions continue to be challenging. PicAm-3 (10 mol%) readily allows the Michael addition of cyclopentanone or isobutyraldehyde (5.0 equiv.) to β-nitrostyrene derivatives. By contrast, PicAm-1 (7.0 mol%) is optimal for catalyzing the aldol reaction of cyclohexanone or cycloheptanone (3.3 equiv.) with aromatic aldehydes. Eighteen products are reported and for each reaction type new products are reported (4b-d, 9c). Very good yields and stereoselectivities are generally noted. The reactions, which require an acid additive, proceed via a transient chiral enamine and a mechanistic case is put forth for a bifunctional catalysis model.

Relying on the assembly of commercially available catalyst building blocks, highly stereocontrolled quaternary carbon (all carbon substituted) formation has been achieved with unmatched substrate diversity. For example, the in situ assembly of a tricomponent catalyst system allows α-branched aldehyde addition to nitroalkene or maleimide electrophiles (Michael products), while addition to an α-iminoester affords Mannich reaction products. Very good yields are observed and for fifteen of the eighteen examples 96-99 % ee is observed. Using racemic α-branched aldehydes, two contiguous (quaternary-tertiary) stereogenic centers can be formed in high diastereo- and enantiomeric excess (eight examples) via an efficient in situ dynamic kinetic resolution, solving a known shortcoming for maleimide electrophiles in particular. The method is of practical value, requiring only 1.2 equiv of the aldehyde, a 5.0 mol % loading of each catalyst component, for example, O-tBu-L-threonine (O-tBu-L-Thr), sulfamide, DMAP or O-tBu-L-Thr, KOH, and room temperature reactions. As a highlight, the first demonstration of ethylisovaleraldehyde (7) addition is disclosed, providing the most congested quaternary stereogenic carbon containing succinimide product (8) known to date. Finally, mechanistic insight, via DFT calculations, support a noncovalent assembly of the catalyst components into a bifunctional catalyst, correctly predict two levels of product stereoselectivity, and suggest the origin of the tricomponent catalyst system's exceptionality: an alternative hydrogen bond motif for the donor-acceptor pair than currently suggested for non-assembled catalysts., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A three component catalyst system entailing an amino acid (O(t)Bu-L-threonine), a hydrogen bond donor (sulfamide), and an amine base (DMAP) allows α-branched aldehyde addition to nitroalkenes in good to high yield and excellent ee. Importantly, the lowest reported catalyst loading (5.0 mol%) and aldehyde stoichiometry (1.2-2.0 equiv) is demonstrated and in most instances the best current product profile is observed.

A pyridine based 1,2-diamine containing only one stereogenic center has been identified for fast aldol reactions (16-48 h). Using 2-5 mol% of (R)- or (S)-PicAm-2, cyclohexanone (3.3 equiv) readily undergoes aldol reactions with o-, m-, and p-substituted aromatic aldehyde partners (limiting reagent), including the poor electrophile 4-methylbenzaldehyde (95-99% ee). Furthermore, functionalized cyclic ketone substrates have been converted into four aldol products 9-12 using the lowest catalyst loading (5.0 mol%) to date with the highest yield and enantioselectivity.

The UCL Bioinformatics Group web portal offers several high quality protein structure prediction and function annotation algorithms including PSIPRED, pGenTHREADER, pDomTHREADER, MEMSAT, MetSite, DISOPRED2, DomPred and FFPred for the prediction of secondary structure, protein fold, protein structural domain, transmembrane helix topology, metal binding sites, regions of protein disorder, protein domain boundaries and protein function, respectively. We also now offer a fully automated 3D modelling pipeline: BioSerf, which performed well in CASP8 and uses a fragment-assembly approach which placed it in the top five servers in the de novo modelling category. The servers are available via the group web site at http://bioinf.cs.ucl.ac.uk/.

Reductive amination of prochiral unhindered 2-alkanones 1 with (R)- or (S)-alpha-MBA in the presence of Yb(OAc)3 (50-110 mol %), Raney-Ni, and hydrogen (120 psi) results in increased diastereoselectivity for the amine products 2 (80-89% de) with good yield (80-87%). The increased de is based on comparison with the best previously reported de's when using (R)- or (S)-alpha-MBA, regardless of the strategy employed [stepwise (isolation of ketimines) or one-pot (reductive amination)], reducing agent examined, or achiral Lewis acid or Brønsted acid examined. An in situ cis- to trans-ketimine isomerization mechanism, promoted by Yb(OAc)3, has been proposed to account for the observed increase in diastereoselectivity and suggests a new entry into the control of ketimine geometry.

[reaction: see text] A new method for the one-pot asymmetric reductive amination of prochiral aliphatic ketones has been developed. The previously unexplored reagent combination of Ti(O(i)Pr)(4)/Raney Ni/H(2) in the presence of (R)- or (S)-alpha-methylbenzylamine provides good to excellent yield (76-90%) and diastereomeric excess (72-98%). The second step, hydrogenolysis, provides the corresponding primary amine in high yield (88-93%) and with uncompromised enantiomeric excess.

Advantageous use of homochiral cyclohexadiene-cis-1,2-diol 2, available by means of biocatalytic oxidation of chlorobenzene with toluene dioxygenase, has enabled the synthesis of all four enantiomerically pure C(18)-sphingosines 1. The four requisite diastereomers of azido alcohols 4a-d were accessed by regioselective opening of epoxides 7 and 8 with either azide or halide ions. The configuration of C4 and C5 in azides 4 defines the stereochemistry of the incipient sphingosine chain, liberated from 4 by the oxidative cleavage of the C1-C6 olefin. For L-threo-sphingosine (1b), lactol 20b generated by this cleavage was converted by periodate oxidation to azido deoxy L-threose 22b, which gave 1b upon Wittig olefination and reduction. Similarly, D-erythro-sphingosine (1a) and L-erythro-sphingosine (1c) were generated from 4a,c, respectively. The last sphingosine (1d) was synthesized from the silyl-protected azido alcohol 29d. Subsequent transformations provided silyl-protected azido deoxy D-threose 32d, which upon Wittig olefination and reduction gave D-threo-sphingosine (1d). Experimental and spectral data are provided for all new compounds.