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"Chiral pool" compounds possessing well defined stereocenters and suitable functionality serve as excellent building blocks for the synthesis of natural products and therapeutically important compounds. Tartaric acid is a C2 -symmetric molecule available in both enantiomeric forms. It was extensively utilized in the synthesis of privileged chiral ligands/catalysts such as TADDOLs, and as a start point in the synthesis of plethora of compounds. The advent of several new C-C bond forming reactions offers opportunity for the development of novel synthetic strategies based on chiral pool compounds. We found that the desymmetrization of the bis-dimethyl amide/Weinreb amide derived from tartaric acid can be accomplished by controlled addition of Grignard /organolithium reagents leading to the mono keto amides, the reduction of which affords the γ-hydroxy amides. This account describes our research efforts of more than a decade on the synthesis and application of diverse γ-hydroxy amides derived from tartaric acid in the total synthesis of structurally simple to complex bio-active natural products.

The addition of lithium anion of (acetylmethylene)triphenylphosphorane to nonracemic sulfinimines was investigated. It was found that the addition proceeded with good diastereoselectivity and further reaction of the formed sulfinimidophosphorane with several aldehydes afforded the β-sulfinamido substituted enones in good yields. The resultant enones were elaborated to the synthesis of alkaloid (+)-241D, to the formal total synthesis of (+)-preussin, and to the synthesis of aminocyclopentenol.

An efficient enantiospecific total synthesis of ent-conduramine F-1 (aminocyclohexenetriol) was accomplished starting from the bis-Weinreb amide of tartaric acid. Key reactions in the synthesis include the desymmetrization of tartaric acid amide with vinylmagnesium bromide and installation of the required amine using Ellman sulfinimine. Ring closing metathesis was used to synthesize the required alkene in the cyclohexene.

Total synthesis of THP tethered pyrone containing natural product cryptopyranmoscatone B2 was accomplished from commercially available 2-deoxyribose. The key THP unit was assembled by FeCl3 catalyzed cyclization of an allyl alcohol. Brown allylation and RCM reactions were employed to construct the lactone unit. The synthesis represents the first total synthesis of the putative structure of the natural product.

A concise total synthesis of the macrolactone natural product Sch 725674 is accomplished starting from commercially available 2-deoxy-o-ribose. Pivotal reactions employed in the synthesis include the addition of 4-pentenylmagnesium bromide to the lactol derived from 2-deoxy-o-ribose, olefin cross metathesis and Yamaguchi macrolactonization. (C) 2018 Elsevier Ltd. All rights reserved.

First total synthesis of the polyhydroxy 5,6-dihydro-2H-pyrone containing natural products monticolide A and B is reported from tartaric acid. Key reaction is the iridium catalysed redox reaction of the Achmatowicz reaction product to the 5,6-dihydro-2H-pyrone moiety and the use of tartaric acid as a four hydroxy four carbon synthon.

Synthesis of chiral tetrols and 1,2,4-triols with varied substitutions was accomplished from tartaric acid. Pivotal reaction in the synthesis was the use of Ley's dithianylation of an alkynyl ketone derived from tartaric acid. Application of the strategy was demonstrated in the total synthesis of decanolactone achaetolide.

The HOIP ubiquitin E3 ligase generates linear ubiquitin chains by forming a complex with HOIL‐1L and SHARPIN in mammals. Here, we provide the first evidence of linear ubiquitination induced by a HOIP orthologue in Drosophila. We identify Drosophila CG11321, which we named Linear Ubiquitin E3 ligase (LUBEL), and find that it catalyzes linear ubiquitination in vitro. We detect endogenous linear ubiquitin chain‐derived peptides by mass spectrometry in Drosophila Schneider 2 cells and adult flies. Furthermore, using CRISPR/Cas9 technology, we establish linear ubiquitination‐defective flies by mutating residues essential for the catalytic activity of LUBEL. Linear ubiquitination signals accumulate upon heat shock in flies. Interestingly, flies with LUBEL mutations display reduced survival and climbing defects upon heat shock, which is also observed upon specific LUBEL depletion in muscle. Thus, LUBEL is involved in the heat response by controlling linear ubiquitination in flies.

Synthesis of novel C2-symmetric 1,2- 1,3- and 1,4- bis-sulfinamides and their use as effective ligands in rhodium (I) catalyzed asymmetric conjugate addition of arylboronic acids to cyclohexenone and cyclopentenones is described. C2-symmetry as well as chirality at the sulfur center in the ligand is crucial for the high enantioselectivity in the 1,4-addition reaction. It was also observed that the conjugate addition proceeded with good selectivity with Wilkinson's catalyst as the rhodium source.

Enantioselective total synthesis of δ-lactone containing natural product (−)-cryptofolione was accomplished from commercially available benzylidene acetone. Key features of the synthesis include lipase mediated resolution of a β-hydroxy ketone intermediate, DBU mediated isomerization of γ,δ-unsaturated aldehyde to α,β-unsaturated aldehyde, Brown allylation and RCM reactions.

The synthesis of 2,3,4,6-tetrasubstituted tetrahydropyran unit of ratjadone A was achieved. Pivotal reaction sequence in the synthesis include non-Evans syn aldol reaction of a chiral aldehyde obtained from l -malic acid and Uenishi’s palladium catalyzed stereoselective intramolecular SN2′ reaction to form the tetrahydropyran ring.

Synthetic efforts towards the total synthesis of the revised structure of marine macrolide palmerolide C is reported. Synthesis of the triol unit present in the C8,C9, C10 positions was achieved from d -ribose while Johnson orthoester rearrangement and a Wittig reaction were used to construct the C1–C7 component of the macrolactone. The key macrolactone unit was assembled using intermolecular Heck coupling reaction and Yamaguchi lactonization.

Stereoselective synthesis of the C9-C22 fragment of pentamycin from the bis-Weinreb amide of d -tartaric acid was accomplished in 12 steps (14% yield). Key reactions in the synthesis include Ley’s dithiaketalization, Narasaka stereoselective reduction of the β-hydroxy ketone and Wittig reaction with a vinylogous phosphonate.

Desymmetrization of the C2-symmetric bis-dimethylamide derived from tartaric acid by controlled addition of alkynyl lithium reagents furnished the mono alkynyl ketones which on reduction produced the corresponding propargyl alcohols with good diastereoselectivity. The propargyl alcohols were transformed to allenes using Claisen rearrangement. The formed allenes serve as a precursor for the synthesis of one of the THP units of the natural product sorangicin and for the synthesis of the polyhydroxy unit present in natural product anamarine.

Formal total synthesis of (+)-stemoamide is accomplished from 5-benzyloxypentanal. Key transformation in the synthesis is the conjugate addition of aza-allylanion obtained from allyl amine to an unsaturated ester.

Enantioselective total synthesis of 2,4,6-trisubstituted pyran natural product diospongin A is accomplished from benzaldehyde in 5 steps. Key reaction in the synthesis is the addition of a silyl enol ether derived from vinylogous aryl methyl ketone to chiral β-alkoxy aldehyde and subsequent oxa-Michael addition.

Total synthesis of (+)-γ-lycorane is accomplished from (S)-ethyl lactate. Key disconnections in the synthesis involve an iterative Claisen and Overman rearrangement reactions to install the chiral centers in the tetrahydroindole moiety while, Pictet-Spengler reaction is used for the synthesis of the isoquinoline unit.

A facile ring opening of furans in furyl propargyl alcohols to the corresponding saturated gamma-keto esters is observed in the gold(III) chloride catalyzed reaction with MeOH. It is found that the ring opening of furan is driven by the intramolecular hydroalkoxylation. Mitigating the intramolecular hydroalkoxylation led to the expected conjugated enyne resulting from the dehydration. (C) 2015 Elsevier Ltd. All rights reserved.

Klebsiella pneumoniae is a significant cause of nosocomial pneumonia and an alarming pathogen owing to the recent isolation of multidrug resistant strains. Understanding of immune responses orchestrating K. pneumoniae clearance by the host is of utmost importance. Here we show that type I interferon (IFN) signaling protects against lung infection with K. pneumoniae by launching bacterial growth-controlling interactions between alveolar macrophages and natural killer (NK) cells. Type I IFNs are important but disparate and incompletely understood regulators of defense against bacterial infections. Type I IFN receptor 1 (Ifnar1)-deficient mice infected with K. pneumoniae failed to activate NK cell-derived IFN-γ production. IFN-γ was required for bactericidal action and the production of the NK cell response-amplifying IL-12 and CXCL10 by alveolar macrophages. Bacterial clearance and NK cell IFN-γ were rescued in Ifnar1-deficient hosts by Ifnar1-proficient NK cells. Consistently, type I IFN signaling in myeloid cells including alveolar macrophages, monocytes and neutrophils was dispensable for host defense and IFN-γ activation. The failure of Ifnar1-deficient hosts to initiate a defense-promoting crosstalk between alveolar macrophages and NK cell was circumvented by administration of exogenous IFN-γ which restored endogenous IFN-γ production and restricted bacterial growth. These data identify NK cell-intrinsic type I IFN signaling as essential driver of K. pneumoniae clearance, and reveal specific targets for future therapeutic exploitations., Author summary The isolation of multidrug-resistant Klebsiella pneumoniae strains has significantly narrowed, or in some settings completely removed, the therapeutic options for the treatment of Klebsiella infections. Therapies targeting the immune system rather than the pathogen represent important alternatives. Despite the clinical relevance, there are still major gaps in our understanding of immune responses which drive the clearance of this pathogen. Type I interferons (IFNs) are known as powerful immune system regulators yet their effects on bacterial infections are disparate and remain elusive. In this study we show that type I IFN signaling is indispensable for mounting a protective and bacterial clearance-promoting immune response against K. pneumoniae. K. pneumoniae-induced type I IFNs launch a crosstalk between alveolar macrophages and NK cells by enabling NK cell IFN-γ production which in turn activates the macrophage anti-microbial armament. Type I IFN-responsive NK cells or IFN-γ administration rescue K. pneumoniae clearance in type I IFN-unresponsive hosts. Our study suggests that manipulation of type I IFN or IFN-γ levels might represent a valid strategy for treatment of drug-resistant K. pneumoniae infections.

The total synthesis of new indole alkaloids henrycinol A and B were accomplished starting from l -tryptophan methyl ester. The key step is a stereochemically flexible Pictet–Spengler reaction governed by the presence or absence of an N-allyl group in the tryptophan precursor. The natural products henrycinol A and B were synthesized in good overall yield in eight and nine steps, respectively.

An enantiospecific total synthesis of polyhydroxy δ-pyrone natural product (+)-anamarine is accomplished. The main features of the synthesis include the stereoselective reduction of the ketone obtained by the desymmetrization of the bis-dimethyl amide of tartaric acid and further elaboration involving asymmetric Brown's allylation and ring closing metathesis.

An enantioselective synthesis of the macrolactone core of natural product Sch725674 was accomplished from furfural. Key reactions in assembly of the macrolactone are the use of furan as a but-2-ene-dione equivalent and ring closing metathesis.

A systematic investigation of the addition of Grignard reagents to sulfinimines derived from tartaric acid diol was undertaken. It was observed that the chirality of the inherent tartrate moiety influences the diastereoselectivity of the resultant sulfinamides formed in the reaction. The formed products serve as excellent building blocks for the synthesis of natural products. This has been demonstrated in the collective total synthesis of lentiginosine, (+)-α-conhydrine and methyldihydropalustramate.

Chiral 2-pyridylsulfinamides were shown to be effective catalysts in the alkylation of aryl and alkyl aldehydes with diethylzinc providing the corresponding alcohols in excellent enantioselectivity. Sulfinamide catalysts possessing solitary chirality at the sulfur center produced the product phenethyl alcohol in good enantioselectivity. Diastereomeric sulfinamides possessing chirality at the carbon-bearing nitrogen and at the sulfur of the sulfinamide increased the enantioselectivity of the product alcohols up to >99%. However, there is no effect of the match-mismatch pair of sulfinamide diastereomers on the outcome of the chiral induction of the product phenethyl alcohols. It was conclusively proved that chirality at the sulfur center is mandatory for obtaining good enantioselectivity in the reaction.

Formation of a 2,3-dihydro-4H-pyran containing 14-membered macrocycle by sequential olefin cross metathesis and a highly regiospecific hetero Diels–Alder reaction was observed in the reaction of a hydroxydienone derived from tartaric acid with Grubbs' second generation catalyst. It was found that the free alcohol in the hydroxyenone led to the macrocycle formation, while protection of the hydroxy group formed the ring closing metathesis product.

An enantiospecific total synthesis of indole alkaloids eburnamonine, aspidospermidine and quebrachamine is described from lactic acid. Synthesis of all three alkaloids is accomplished from a single chiral building block. Johnson–Claisen rearrangement of a chiral allyl alcohol is the main feature for the installation of the required quaternary centre.

Synthesis of isochromanones and isoquinolones comprising a quaternary center with high diastereoselectivity was realized via a AuCl3 catalyzed tandem intramolecular exo-dig heterocyclization/enol isomerization/Claisen rearrangement sequence in excellent yields. The reaction is general and amenable for the synthesis of structurally diverse analogues.

In the search for more efficacious and less toxic cancer drugs, the tumor suppressor p53 protein has long been a desirable therapeutic target. In the recent past, few independent studies have demonstrated that the antitumor activity of wild-type p53 can be restored in cancer cells harboring mutant form of p53 using small molecule activators. In this study, we describe a novel small molecule MPK-09, which is selective and highly potent against allele specific p53 mutations mainly, R175H, R249S, R273H, R273C, and E285K . Except E285K, all other mutations tested are among the six "hot spot" p53 mutations reported in majority of human cancer. Furthermore, our study conclusively demonstrates that the apoptotic activity of the small molecule MPK-09 against cancer cells harboring R273C and E285K mutations is due to restoration of the wild-type conformation to the corresponding mutant form of p53.

Total synthesis of the polyhydroxy caprolactam amide natural product, bengamide E, is accomplished starting from tartaric acid. Key reactions in the synthesis include desymmetrization of the bis(dimethylamide) unit of tartaric acid, Zn(BH(4))(2)-mediated anti-selective reduction, and a Horner-Wadsworth-Emmons olefination.

An enantiospecific total synthesis of polyhydroxy δ-pyrone natural product phomopsolide B is accomplished. The main feature of the synthesis is the installation of the required E-olefin by Horner–Emmons–Wordsworth reaction and the formation of the lactone involving Still–Gennari olefination followed by lactonization.

Enantioselective formal synthesis of macrolactone palmerolide A, a polyketide marine natural product, is described. Key strategies in the synthesis include the oxidative furan ring-opening of a chiral furyl carbinol for the installation of the 1,4-dienol core and a Jung nonaldol-aldol reaction for the dienamide core.

Stereoselective approach for the synthesis of both enantiomers of bio-active decanolactone microcarpalide is described from l-tartaric acid. The synthesis of the key intermediates en route to the natural product is achieved from l-tartaric acid involving the elaboration of γ-hydroxy amide derived from tartaric acid and ring opening of an epoxide derived from tartaric acid.

Enantioselective synthesis of 16-membered trilactone macrolides, macrosphelide A and E from (S)-lactic acid is described. Key features of the synthesis include the utility of a hitherto unexplored β-ketophosphonate derived from lactic acid and Yamaguchi lactonization leading to the title compounds.

The enantiospecific total synthesis of 14-membered macrolactone Sch 725674 was accomplished from tartaric acid. Key reactions in the synthesis include the Ley's dithiaketalization of an alkynone derived from the bis-Weinreb amide of tartaric acid, Boord olefination, and ring-closing metathesis of an acrylate ester.

In the originally published paper, the "before" image for the afatinib condition in Fig. 6c was incorrect. Instead of an image displaying a GBM-3 neoplastic organoid before afatinib treatment, this panel showed an image from the GBM-2 control (DMSO) group before treatment. This error has now been corrected in the HTML and PDF versions of the article; the "before, afatinib" panel in Fig. 6c now shows a representative image from the indicated experiment. The color of all error bars in Fig. 6 has also been changed to black, for consistency. All statistical analysis and all conclusions presented in the article are unaffected by this error. Nevertheless, we apologize for the mistake.

Dimethyl 3-(aryl)-3,6-dihydro-2H-1,3-oxazine4,5-dicarboxylate structure assigned for the products obtained in the Bronsted acid catalyzed reaction of dimethyl but-2-ynoates with anilines and an excess of formaldehyde in methanol has been revised to methyl 1-(aryl)-3-(methoxymethyl)-4,5-dioxopyrrolidine-3-carboxylate. (C) 2010 Elsevier Ltd. All rights reserved.

Stereoselective syntheses of the bio-active styryllactones goniodiol and 9-deoxygoniopypyrone were accomplished from d -(−)-tartaric acid. The key step involves the elaboration of a γ-hydroxy butyramide to the styryllactones via high yielding stereoselective transformations.

γ-Oxo-butyramides derived from tartaric acid serve as excellent precursors for the synthesis of γ-alkyl (aryl)-α,β-dihydroxy-γ-butyrolactones and for the synthesis of tetrols containing three contiguous stereogenic centres. The methodology presented here is general for the synthesis of γ-alkyl (aryl)-α,β-dihydroxy-γ-butyrolactones. Utility of the chiral building block was demonstrated by the synthesis of naturally occurring lipid guggultetrol.

Stereoselective formal synthesis of (−)-centrolobine was achieved from naturally occurring l -(+)-tartaric acid, employing a facile FeCl3 mediated stereoselective formation of a tetrahydropyran as the key step.

An enantiodivergent approach to both antipodes of hydroxy-exo-brevicomin was achieved from a common chiral precursor L-(+)-tartaric acid. The strategy utilizes the elaboration of a keto-Weinreb amide and successive stereoselective reductions.

Sulfinimine-derived polyfunctionalized chiral building blocks, often prepared in one pot, provide efficient access, with a minimum of chemical manipulation, to enantiopure, multifunctional amine derivatives including piperidines and pyrrolidines.

A formal total synthesis of the marine macrolide iriomoteolide 3a is described. Salient features of the synthesis include the elaboration of a β-keto phosphonate derived from D-(-)-tartaric acid and the extension of a chiral butyrolactone derived from L-glutamic acid. Ring-closing metathesis is employed to construct the macrolactone core of the natural product.

A stereoselective approach for the synthesis of the bio-active decanolactone (-)-microcarpalide was achieved from chiral pool tartaric acid. The synthesis of pivotal intermediates en route to the decanolactone was achieved from \alpha-benzyloxy aldehydes derived from L- and D-tartaric acid.

A concise enantiospecific synthesis of the pine beetle pheromone (+)-hydroxy-exo-brevicomin was achieved from l -(+)-tartaric acid in high yield. The key step involves the reduction of a keto-Weinreb amide derived from tartaric acid.

The natural product fumagillin exhibits potent antiproliferative and antiangiogenic properties. The semisynthetic analog PPI-2458, [(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl] N-[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate, demonstrates rapid inactivation of its molecular target, methionine aminopeptidase-2 (MetAP2), and good efficacy in several rodent models of cancer and inflammation with oral dosing despite low apparent oral bioavailability. To probe the basis of its in vivo efficacy, the metabolism of PPI-2458 was studied in detail. Reaction phenotyping identified CYP3A4/5 as the major source of metabolism in humans. Six metabolites were isolated from liver microsomes and characterized by mass spectrometry and nuclear resonance spectroscopy, and their structures were confirmed by chemical synthesis. The synthetic metabolites showed correlated inhibition of MetAP2 enzymatic activity and vascular endothelial cell growth. In an ex vivo experiment, MetAP2 inhibition in white blood cells, thymus, and lymph nodes in rats after single dosing with PPI-2458 and the isolated metabolites was found to correlate with the in vitro activity of the individual species. In a phase 1 clinical study, PPI-2458 was administered to patients with non-Hodgkin lymphoma. At 15 mg administered orally every other day, MetAP2 in whole blood was 80% inactivated for up to 48 hours, although the exposure of the parent compound was only ∼10% that of the summed cytochrome P450 metabolites. Taken together, the data confirm the participation of active metabolites in the in vivo efficacy of PPI-2458. The structures define a metabolic pathway for PPI-2458 that is distinct from that of TNP-470 ([(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl] N-(2-chloroacetyl)carbamate). The high level of MetAP2 inhibition achieved in vivo supports the value of fumagillin-derived therapeutics for angiogenic diseases.

[reaction: see text] N-Sulfinyl beta-amino Weinreb amides are prepared by condensation of sulfinimines with the potassium enolate of N-methoxy-N-methylacetamide. These new chiral building blocks are useful for the asymmetric synthesis of beta-amino carbonyl compounds, as illustrated here by the concise enantioselective syntheses of sedum alkaloids (+)-sedridine and (-)-allosedridine.

[reaction: see text] Diels-Alder reactions of enantiomerically enriched 2H-azirine 3-phosphonates and dienes stereoselectively furnish optically pure, bicyclic aziridine adducts that on hydrogenation afford the first examples of enantiopure quaternary piperidine phosphonates.