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Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.

Prospective predictions of human hepatic clearance for anionic/zwitterionic compounds, which are oftentimes subjected to transporter-mediated uptake, are challenging in drug discovery. We evaluated the utility of preclinical species, rats and cynomolgus monkeys [nonhuman primates (NHPs)], to predict the human hepatic clearance using a diverse set of acidic/zwitterionic drugs. Preclinical clearance data were generated following intravenous dosing in rats/NHPs and compared to the human clearance data (n = 18/27). Single-species scaling of NHP clearance with an allometric exponent of 0.50 allowed for good prediction of human clearance (fold error ∼2.1, bias ∼1.0), with ∼86% predictions within 3-fold. In comparison, rats underpredicted the clearance of lipophilic acids, while overprediction was noted for hydrophilic acids. Finally, an in vitro clearance assay based on human hepatocytes, which is routinely used in discovery setting, markedly underpredicted human clearance (bias ∼0.12). Collectively, this study provides insights into the usefulness of the preclinical models in enabling pharmacokinetic optimization for acid/zwitterionic drug candidates.

Preclinical and clinical data suggest that acetyl-CoA carboxylase (ACC) inhibitors have the potential to rebalance disordered lipid metabolism, leading to improvements in nonalcoholic steatohepatitis (NASH). Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein, we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a nonhuman primate model.

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited by the requirement for injection. Here we describe the first effective, orally bioavailable small molecule GLP-1R agonists. A sensitized high-throughput screen identified a series of small molecule GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nM potency. These small molecule agonists increased insulin levels in primates but not rodents, which is explained by a cryo-EM structure that revealed a binding pocket requiring primate-specific tryptophan 33. Importantly, oral administration of agonist PF-06882961 to healthy humans produced dose-dependent declines in serum glucose (NCT03309241). This opens the door to a new era of oral small molecule therapies that target the well-validated GLP-1R pathway for metabolic health.One Sentence SummaryPF-06882961 is an orally administered small molecule that activates the GLP-1 receptor to lower blood glucose in humans.

Studies on indole-3-carboxylic acid derivatives as direct activators of human adenosine monophosphate-activated protein kinase (AMPK) α1β1γ1 isoform have culminated in the identification of PF-06409577 (1), PF-06885249 (2), and PF-06679142 (3) as potential clinical candidates. Compounds 1-3 are primarily cleared in animals and humans via glucuronidation. Herein, we describe the biosynthetic preparation, purification, and structural characterization of the glucuronide conjugates of 1-3. Spectral characterization of the purified glucuronides M1, M2, and M3 indicated that they were acyl glucuronide derivatives. In vitro pharmacological evaluation revealed that all three acyl glucuronides retained selective activation of β1-containing AMPK isoforms. Inhibition of de novo lipogenesis with representative parent carboxylic acids and their respective acyl glucuronide conjugates in human hepatocytes demonstrated their propensity to activate cellular AMPK. Cocrystallization of the AMPK α1β1γ1 isoform with 1-3 and M1-M3 provided molecular insights into the structural basis for AMPK activation by the glucuronide conjugates.

Indole acids 1, 2, and 3 are potent 5′-adenosine monophosphate-activated protein kinase (AMPK) activators for the potential treatment of diabetic nephropathy. Compounds 1–3 were scaled to supply material for preclinical studies, and indole 3 was selected for advancement to first-in-human clinical trials and scaled to kilogram quantities. The progression of the synthesis strategy for these AMPK activators is described, as routes were selected for efficient structure–activity relationship generation and then improved for larger scales. The developed sequences employed practical isolations of intermediates and APIs, reproducible cross-coupling, hydrolysis, and other transformations, and enhanced safety and purity profiles and led to the production of 40–50 g of 1 and 2 and 2.4 kg of 3. Multiple polymorphs of 3 were observed, and conditions for the reproducible formation of crystalline material suitable for clinical development were identified.

Diabetic nephropathy remains an area of high unmet medical need, with current therapies that slow down, but do not prevent, the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both humans and animal models of renal disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing the β1 subunit. After confirming that human and rodent kidney predominately express AMPK β1, we explore the effects of pharmacological activation of AMPK in the ZSF1 rat model of diabetic nephropathy. Chronic administration of these direct activators elevates the phosphorylation of AMPK in the kidney, without impacting blood glucose levels, and reduces the progression of proteinuria to a greater degree than the current standard of care, angiotensin-converting enzyme inhibitor ramipril. Further analyses of urine biomarkers and kidney tissue gene expression reveal AMPK activation leads to the modulation of multiple pathways implicated in kidney injury, including cellular hypertrophy, fibrosis, and oxidative stress. These results support the need for further investigation into the potential beneficial effects of AMPK activation in kidney disease.

Glucagon-like peptide (GLP-1) is an endogenous hormone that induces insulin secretion from pancreatic islets and modified forms are used to treat diabetes mellitus type 2. Understanding how GLP-1 interacts with its receptor (GLP-1R) can potentially lead to more effective drugs. Modeling and NMR studies of the N-terminus of GLP-1 suggest a β-turn between residues Glu9-Phe12 and a kinked alpha helix between Val16-Gly37. N-terminal turn constraints attenuated binding affinity and activity (compounds 1-8). Lys-Asp (i, i+4) crosslinks in the middle and at the C-terminus increased alpha helicity and cAMP stimulation without much effect on binding affinity or beta-arrestin 2 recruitment (compounds 9-18). Strategic positioning of helix-inducing constraints and amino acid substitutions (Tyr16, Ala22) increased peptide helicity and produced ten-fold higher cAMP potency (compounds 19-28) over GLP-1(7-37)-NH2. The most potent cAMP activator (compound 23) was also the most potent inducer of insulin secretion.

Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.

Type 2 diabetes mellitus (T2DM) results from compromised pancreatic β-cell function, reduced insulin production, and lowered insulin sensitivity in target organs resulting in hyperglycemia. The GLP-1 hormone has two biologically active forms, GLP-1-(7-37) and GLP-1-(7-36)amide, which are equipotent at the glucagon-like peptide-1 receptor (GLP-1R). These peptides are central both to normal glucose metabolism and dysregulation in T2DM. Several structurally modified GLP-1 analogues are now approved drugs, and a number of other analogues are in clinical trials. None of these compounds is orally bioavailable and all require parenteral delivery. Recently, a number of smaller peptidomimetics containing 11-12 natural and unnatural amino acids have been identified that have similar insulin regulating profiles as GLP-1. The α-conotoxins are a class of disulfide rich peptide venoms isolated from cone snails, and are known for their highly constrained structures and resistance to enzymatic degradation. In this study, we examined whether 11-residue peptidomimetics incorporated into α-conotoxin scaffolds, forming monocyclic or bicyclic compounds constrained by disulfide bonds and/or backbone cyclization, could activate the GLP-1 receptor (GLP-1R). Several compounds showed potent (nanomolar) agonist activity at GLP-1R, as evaluated via cAMP signaling. In addition, HPLC retention times and in silico calculations suggested that mono- and bicyclic compounds had more favorable n-octanol/water partition coefficients according to the virtual partition coefficient model (vLogP), while maintaining a smaller radius of gyration compared to corresponding uncyclized peptidomimetics. Our findings suggest that cyclic peptidomimetics provide a potential avenue for future design of potent, compact ligands targeting GLP-1R and possessing improved physicochemical properties.

Cyclic constraints are incorporated into an 11-residue analogue of the N-terminus of glucagon-like peptide-1 (GLP-1) to investigate effects of structure on agonist activity. Cyclization through linking side chains of residues 2 and 5 or 5 and 9 produced agonists at nM concentrations in a cAMP assay. 2D NMR and CD spectra revealed an N-terminal β-turn and a C-terminal helix that differentially influenced affinity and agonist potency. These structures can inform development of small molecule agonists of the GLP-1 receptor to treat type 2 diabetes.

Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic acid clinical candidate (1) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds 10 (PF-06679142) and 14 (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3.

The use of peptides in medicine is limited by low membrane permeability, metabolic instability, high clearance, and negligible oral bioavailability. The prediction of oral bioavailability of drugs relies on physicochemical properties that favor passive permeability and oxidative metabolic stability, but these may not be useful for peptides. Here we investigate effects of heterocyclic constraints, intramolecular hydrogen bonds, and side chains on the oral bioavailability of cyclic heptapeptides. NMR-derived structures, amide H-D exchange rates, and temperature-dependent chemical shifts showed that the combination of rigidification, stronger hydrogen bonds, and solvent shielding by branched side chains enhances the oral bioavailability of cyclic heptapeptides in rats without the need for N-methylation.

Development of peptide-based drugs has been severely limited by lack of oral bioavailability with less than a handful of peptides being truly orally bioavailable, mainly cyclic peptides with N-methyl amino acids and few hydrogen bond donors. Here we report that cyclic penta- and hexa-leucine peptides, with no N-methylation and five or six amide NH protons, exhibit some degree of oral bioavailability (4-17%) approaching that of the heavily N-methylated drug cyclosporine (22%) under the same conditions. These simple cyclic peptides demonstrate that oral bioavailability is achievable for peptides that fall outside of rule-of-five guidelines without the need for N-methylation or modified amino acids.

Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays a crucial role in the regulation of fatty acid oxidation. Alterations in lipid metabolism are believed to contribute to insulin resistance; thus inhibition of ACC offers a promising option for intervention in type 2 diabetes mellitus. Herein we disclose a series of ACC inhibitors based on a spirocyclic pyrazololactam core. The lactam series has improved chemical and metabolic stability relative to our previously reported pyrazoloketone series, while retaining potent inhibition of ACC1 and ACC2. Optimization of the pyrazole and amide substituents led to quinoline amide 21, which was advanced to preclinical development.

Diabetic nephropathy remains an area of high unmet medical need, with current therapies that slow down, but do not prevent, the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both humans and animal models of renal disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing the

Glucagon-like peptide-1 (GLP-1) signaling through the glucagon-like peptide 1 receptor (GLP-1R) is a key regulator of normal glucose metabolism, and exogenous GLP-1R agonist therapy is a promising avenue for the treatment of type 2 diabetes mellitus. To date, the development of therapeutic GLP-1R agonists has focused on producing drugs with an extended serum half-life. This has been achieved by engineering synthetic analogs of GLP-1 or the more stable exogenous GLP-1R agonist exendin-4 (Ex-4). These synthetic peptide hormones share the overall structure of GLP-1 and Ex-4, with a C-terminal helical segment and a flexible N-terminal tail. Although numerous studies have investigated the molecular determinants underpinning GLP-1 and Ex-4 binding and signaling through the GLP-1R, these have primarily focused on the length and composition of the N-terminal tail or on how to modulate the helicity of the full-length peptides. Here, we investigate the effect of C-terminal truncation in GLP-1 and Ex-4 on the cAMP pathway. To ensure helical C-terminal regions in the truncated peptides, we produced a series of chimeric peptides combining the N-terminal portion of GLP-1 or Ex-4 and the C-terminal segment of the helix-promoting peptide α-conotoxin pl14a. The helicity and structures of the chimeric peptides were confirmed using circular dichroism and NMR, respectively. We found no direct correlation between the fractional helicity and potency in signaling via the cAMP pathway. Rather, the most important feature for efficient receptor binding and signaling was the C-terminal helical segment (residues 22-27) directing the binding of Phe(22) into a hydrophobic pocket on the GLP-1R.

Platensimycin (1) is the flagship member of a new and growing class of antibiotics with promising antibacterial properties against drug resistant bacteria. The total syntheses of platensimycin and its congeners, platensimycins B1 (7) and B3 (9), platensic acid (2), methyl platensinoate (3), platensimide A (4), homoplatensimide A (5), and homoplatensimide A methyl ester (6) (Figure 1) are described. The convergent strategy developed toward these target molecules involved construction of their cage-like core followed by attachment of the various side chains through amide bond formation. In addition to a racemic synthesis, two asymmetric routes to the core structure are described: one exploiting a rhodium-catalyzed asymmetric cycloisomerization, and another employing a hypervalent iodine-mediated dearomatizing cyclization of an enantiopure substrate. The final two bonds of the core structure were forged through a samarium diiodide-mediated ketyl radical cyclization and an acid-catalyzed etherification. The rhodium-catalyzed asymmetric reaction involving a terminal acetylene was developed as a general method for the asymmetric cycloisomerization of terminal enynes.

The secondary metabolites platensimycin (1) and platencin (2), isolated from the bacterial strain Streptomyces platensis, represent a novel class of natural products exhibiting unique and potent antibacterial activity. Platencin, though structurally similar to platensimycin, has been found to operate through a slightly different mechanism of action involving the dual inhibition of lipid elongation enzymes FabF and FabH. Both natural products exhibit strong, broad-spectrum, Gram-positive antibacterial activity to key antibiotic resistant strains, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, and vancomycin-resistant Enterococcus faecium. Described herein are our synthetic efforts toward platencin, culminating in both the racemic and asymmetric preparation of the natural product. The syntheses demonstrate the power of the cobalt-catalyzed asymmetric Diels–Alder reaction and the one-pot reductive rearrangement of [3.2.1] bicyclic ketones to [2.2.2] bicyclic olefins.

Seit der bahnbrechenden Entdeckung von Penicillin wurde die Vielfalt naturlich vorkommender Molekule ausgiebig hinsichtlich ihrer Eignung als Medikamente sowie zum Auffinden neuer Leitstrukturen beim Wirkstoffdesign untersucht. Die Suche nach Wirkstoffen, mit denen Infektionskrankheiten bekampft werden konnen, war dabei von besonderem Interesse und verlief sehr erfolgreich. Die Erforschung der Antibiotika weist eindrucksvolle Entdeckungen und Geschichten uber die Entwicklung von Wirkstoffen auf, von denen die grose Mehrheit ihren Ursprung in Naturstoffen hat. Die Chemie und besonders die chemische Synthese haben eine bedeutende Rolle dabei gespielt, naturlich vorkommende Antibiotika und deren Derivate fur die medizinische Anwendung bereitzustellen, und zweifellos werden diese Disziplinen auch kunftig Schlusseltechnologien sein. In dieser Ubersicht stellen wir einige der bedeutendsten neueren Entwicklungen und Fortschritte in der Chemie, Biologie und Medizin naturlich vorkommender Antibiotika vor, wobei die Totalsynthese, das Design von Analoga und die biologische Bewertung von Molekulen mit neuartigen Wirkmechanismen im Vordergrund stehen.

The design and implementation of cascade reactions is a challenging facet of organic chemistry, yet one that can impart striking novelty, elegance, and efficiency to synthetic strategies. The application of cascade reactions to natural products synthesis represents a particularly demanding task, but the results can be both stunning and instructive. This Review highlights selected examples of cascade reactions in total synthesis, with particular emphasis on recent applications therein. The examples discussed herein illustrate the power of these processes in the construction of complex molecules and underscore their future potential in chemical synthesis.

Die Entwicklung und Umsetzung von Kaskadenreaktionen hat zu beachtlichen neuartigen, eleganten und effizienten Synthesestrategien gefuhrt. Als besonders anspruchsvoll erwies sich die Anwendung von Kaskadenreaktionen in der Naturstoffsynthese, doch gerade hier winken verbluffende und zugleich aufschlussreiche Ergebnisse als Belohnung. In diesem Aufsatz werden ausgewahlte Kaskadenreaktionen in der Totalsynthese erlautert, wobei neuere Anwendungen besonders hervorgehoben werden. Die erorterten Beispiele sollen die Leistungsfahigkeit dieser Prozesse beim Aufbau von komplexen Molekulstrukturen veranschaulichen und ihr Potenzial fur zukunftige chemische Synthesen verdeutlichen.

Indolosesquiterpenoids are a growing class of natural products that exhibit a wide range of biological activities. Here, we report the total syntheses of xiamycin A and oridamycins A and B, indolosesquiterpenoids isolated from Streptomyces. Two parallel strategies were exploited to forge the carbazole core: 6π-electrocyclization/aromatization and indole C2–H bond activation/Heck annulation. The construction of their trans-decalin motifs relied on two diastereochemically complementary radical cyclization reactions mediated by Ti(III) and Mn(III), respectively. The C23 hydroxyl of oridamycin B was introduced by an sp3 C–H bond oxidation at a late stage. On the basis of the chemistry developed, the dimeric congener dixiamycin C has been synthesized for the first time. Evaluation of the antiviral activity of these compounds revealed that xiamycin A is a potent agent against herpes simplex virus–1 (HSV-1) in vitro., Using a single strategy to make a number of related intermediates is a useful strategy in the total synthesis. Here, the authors report the synthesis of a number of natural products, employing two diastereomerically complementary metal-catalyzed cyclizations as the key step to access a number of frameworks.

Pestalotiopsin A is a structurally unique, caryophyllene-type sesquiterpene which has shown immunosuppressive activity and cytotoxicity in preliminary assays. A stereocontrolled approach to the functionalised 2-oxabicyclo[3.2.0]heptane core of pestalotiopsin A is described. This constitutes the first synthetic studies on pestalotiopsin A. Our approach includes a samarium(II)-mediated 4-exo-trig cyclisation and a trans-lactonisation process triggered by the addition of alkylytterbium reagents to a cyclobutanone intermediate. Further manipulation provides access to advanced intermediates which are excellent precursors for the future construction of the final ring of the target.

[reaction: see text] Pestalotiopsin A is a structurally unique caryophyllene-type sesquiterpene which has shown immunosuppressive activity and cytotoxicity in preliminary assays. A stereocontrolled approach to the functionalized 2-oxabicyclo[3.2.0]heptane core of pestalotiopsin A is described. The approach includes a samarium(II)-mediated 4-exo-trig cyclization and a trans-lactonization process triggered by the addition of alkylytterbium reagents to a cyclobutanone intermediate.

The development of efficient cyclization methods for five-membered ring formation constitutes a continuing challenge in natural and designed molecule construction. Among these methods, the cycloisomerization of 1,6-enynes to form cyclopentane rings has evolved into a powerful technology in chemical synthesis in the past few years. A number of transition metal complexes, such as those of Pd,[1] Ru,[2] Rh[3] and Fe,[4] have proven to be effective catalysts in this transformation. Rh-Based catalytic systems have attracted particular attention as they demonstrated excellent reactivity and enantioselectivity when applied to internal alkyne substrates.[3] However, in some instances an exocyclic methylene group (as opposed to a substituted olefinic bond) is needed on the resulting intermediates for direct elaboration to more advanced products, a condition that requires terminal alkynes as substrates. Although “capped” alkynes with disposable groups have been utilized in this regard, their removal can be laborious and inefficient. Herein we report a Rh-catalyzed asymmetric enyne cycloisomerization reaction using terminal alkynes as substrates and its application to a formal total synthesis of (−)-platensimycin. Scheme 1 shows the proposed mechanism for the Rh-catalyzed cycloisomerization of terminal acetylene (I) to a cyclopentane derivative (IV) through transient species II and III. Scheme 1 Proposed mechanism of Rh-catalyzed asymmetric cycloisomerization of terminal enynes. Employing 1,6-enyne 1 as a substrate we examined a number of Rh-based complexes in order to find the optimum catalytic system; our results are summarized in Table 1. Thus, while the reactivity of [Rh(cod)(MeCN)2]BF4 in the presence of (S)-BINAP was rather modest (36 % yield of product 1a, after 12 h at 23 °C), the product was obtained in promising ee (90 %, Table 1, entry 1). The complex generated in situ by mixing [Rh(cod)Cl]2 and AgOTf in the presence of (S)-BINAP led to a 60 % yield and a comparable ee (91 %, Table 1, entry 2), whereas the combination of [Rh(cod)Cl]2, AgSbF6, and (S)-BINAP employed by Zhang et al. with internal alkynes[3] gave 1a in 65 % yield and 95 % ee (Table 1, entry 3). Finally, it was found that the preformed rhodium catalyst [Rh((S)-BINAP)]SbF6[5] gave the best results, furnishing product 1a in 86 % yield and > 99 % ee (Table 1, entry 4). Table 1 Catalyst screening.a The absolute configuration of product 1a was determined by X-ray crystallographic analysis of its p-bromophenyl carbamate derivative[6] (1b, m.p. 99–101 °C, EtOAc/hexanes 1:1) prepared from 1a through sequential NaBH4 reduction and treatment with p-bromophenyl isocyanate in the presence of Et3N, as shown in Scheme 2. Scheme 2 Preparation and X-ray crystallographic analysis of p-bromophenyl carbamate 1b. Reagents and conditions: a) NaBH4 (1.5 equiv), EtOH, 0 °C, 15 min; b) p-bromophenyl isocyanate (1.05 equiv), Et3N (1.05 equiv), 0 °C, 1 h, 72 % over two steps. ... The generality and scope of the developed asymmetric reaction are demonstrated by the results shown in Table 2. In general, most substrates examined led to good yields and excellent ee’s. The cycloisomerization reaction works well not only with free cis allylic alcohols as demonstrated by most examples in Table 2 (entries 1, 3–11), but also with TBS-protected allylic alcohols, in which case the product with a TBS enol ether moiety is obtained[7] as opposed to the aldehyde (Table 2, entry 2). However, the corresponding trans allylic alcohols are poor substrates as shown with allylic alcohol 3 (Table 2, entry 3). The reaction tolerates a variety of structural motifs, including sulfonamides (Table 2, entries 1–4), lactams (Table 2, entries 5 and 6[8]), 1,1-diesters and sulfones (Table 2, entries 7–9), bis-aromatic moieties (Table 2, entry 10), and dienones (i.e. Table 2, entry 11). Notably, electron withdrawing conjugation is tolerated in either π-system of the substrate (Table 2, entries 5 and 6). The latter example featuring a bromo-acetylene expands considerably the scope of this method due to the fertile chemistry of the stereodefined resulting vinyl bromides (Table 2, entry 11). Table 2 Asymmetric cycloisomerization reactions.a In order to explore the feasibility of this asymmetric cycloisomerization reaction with olefinic side-chains containing other than oxygen substituents, we examined substrates 12 and 13 (Table 2, entries 12 and 13) carrying carbon and nitrogen groups, respectively. Indeed, the reaction performs well in both instances and under similar conditions, leading to cycloisomerized products 12a (Table 2, entry 12, 93 % yield, > 98 % ee)[8] and 13a (Table 2, entry 13, 83 % yield, 94 % ee). The power of the present technology was demonstrated by a formal total synthesis of (−)-platensimycin (18, Scheme 3) from 14, an intermediate previously employed in our synthesis of (±)-platensimycin.[9a] Thus, reduction of 14 with DIBAL-H at −78 °C followed by exposure to aq. HCl at 0 °C led to enone 15 in 88 % overall yield. Conversion of the latter to the corresponding TMS enol ether followed by oxidation with IBX•MPO[10] and desilylation (aq. HCl) furnished bis-enone hydroxy enyne 16 in 68 % overall yield. Delightfully, substrate 16 entered the asymmetric cycloisomerization with 5 mol % catalyst ([Rh((S)-BINAP)]SbF6) to afford the desired spiro dienone aldehyde (−)-17 in 86 % yield and > 99% ee. Notably, the use of the in situ generated catalyst (from [Rh(cod)Cl]2, AgSbF6 and (S)-BINAP) gave erratic results with 10–25 % yield of the desired product. Since (±)-17 and (−)-17 have previously been converted to (±)- and (−)-platensimycin,[9] respectively, this streamlined and highly efficient sequence constitutes a formal total synthesis of (−)-platensimycin (18). Scheme 3 Formal total synthesis of (−)-platensimycin. Reagents and conditions: a) DIBAL-H (1.0 M in hexanes, 1.2 equiv), THF, −78 → −20 °C, 1 h; then 2 N aq. HCl, 0 °C, 30 min, 88 %; b) TMSOTf (1.2 equiv), Et3N (1.5 ... The described catalytic asymmetric synthesis complements and expands the scope of the cycloisomerization of 1,6-enynes by offering efficient and direct entries into enantiopure intermediates for complex natural or designed target molecules of biological and medical interest.

4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP) represents a novel small-molecule activator of the glucagon-like peptide-1 receptor (GLP-1R), and exhibits glucose-dependent insulin secretion in rats following i.v. (but not oral) administration. To explore the quantitative pharmacology associated with GLP-1R agonism in preclinical species, the in vivo pharmacokinetics of BETP were examined in rats after i.v. and oral dosing. Failure to detect BETP in circulation after oral administration of a 10-mg/kg dose in rats was consistent with the lack of an insulinotropic effect of orally administered BETP in this species. Likewise, systemic concentrations of BETP in the rat upon i.v. administration (1 mg/kg) were minimal (and sporadic). In vitro incubations in bovine serum albumin, plasma, and liver microsomes from rodents and humans indicated a facile degradation of BETP. Failure to detect metabolites in plasma and liver microsomal incubations in the absence of NADP was suggestive of a covalent interaction between BETP and a protein amino acid residue(s) in these matrices. Incubations of BETP with glutathione (GSH) in buffer revealed a rapid nucleophilic displacement of the ethylsulfoxide functionality by GSH to yield adduct M1, which indicated that BETP was intrinsically electrophilic. The structure of M1 was unambiguously identified by comparison of its chromatographic and mass spectral properties with an authentic standard. The GSH conjugate of BETP was also characterized in NADPH- and GSH-supplemented liver microsomes and in plasma samples from the pharmacokinetic studies. Unlike BETP, M1 was inactive as an allosteric modulator of the GLP-1R.

This review covers recent (2009–Jan 2013) developments in the field of orally administered glucagon-like peptide 1 receptor (GLP-1R) agonists for the treatment of diabetes. Several approaches are discussed, namely formulation approaches for oral administration of peptides, the use of transporters for active uptake of peptide drugs, and small molecule GLP-1R agonists.

The synthesis of 4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one-based acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown N-2 tert-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate in a streamlined 10-step synthesis requiring only one chromatography procedure. The described synthetic strategy provides pyrazolo-fused spirolactams from halogenated benzylic arenes and cyclic carboxylates. Key steps include a regioselective pyrazole alkylation providing the N-2 tert-butyl pyrazole and a Curtius rearrangement under both conventional and flow conditions to install the hindered amine via a stable and isolable isocyanate. Finally, a Parham-type cyclization was used to furnish the desired spirolactam. An analogous route provided efficient access to the related N-1 isopropyl lactam series. Elaboration of the lactam cores via amidation enabled synthesis of novel ACC inhibitors and the identification of potent analogues.

Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4-formylpiperidine. Enhanced regioselectivity in the condensation between a keto enamine and substituted hydrazines was observed when using toluene as the solvent, leading to selective formation of 1-substituted spiroindazoles. The 2-substituted spiroindazoles were formed selectively from alkyl hydrazones by ring closure with Vilsmeier reagent. The key step in the elaboration to the final products is the conversion of an intermediate olefin to the desired ketone through elimination of HBr from an O-methyl bromohydrin. This methodology enabled the synthesis of each desired regioisomer on 50–75 g scale with minimal purification. Acylation of the resultant spirocyclic amines provided potent ACC inhibitors.

David J. Edmonds,' David M. Dumbrell,2 John G. Primrose,2 Peur McManus,2 Donald J. Birkett) and Vasken Dernirian4 1 Commonwealth Grants Com mission. Canberra. Austra lia' 2 [)(:partment of Health, Housing and Comm unily Services, Canberr.a, ACT, Austra lia 3 [Xpartment of Clinical Pharmacology, Aindcrs Medical Centre. Bedford Park, South AU5lralia. Australia 4 Pharmacy G uild of Australia, Thcsiger Court, Deakin, ACT, Australia

[reaction: see text] Pestalotiopsin A is a structurally unique caryophyllene-type sesquiterpene which has shown immunosuppressive activity and cytotoxicity in preliminary assays. A stereocontrolled approach to the functionalized 2-oxabicyclo[3.2.0]heptane core of pestalotiopsin A is described. The approach includes a samarium(II)-mediated 4-exo-trig cyclization and a trans-lactonization process triggered by the addition of alkylytterbium reagents to a cyclobutanone intermediate.

Platensimycin is the flagship member of a new and growing class of antibiotics with promising antibacterial properties against drug-resistant bacteria. The total syntheses of platensimycin and its congeners, platensimycins B1 and B3, platensic acid, methyl platensinoate, platensimide A, homoplatensimide A, and homoplatensimide A methyl ester, are described. The convergent strategy developed toward these target molecules involved construction of their cage-like core followed by attachment of the various side chains through amide bond formation. In addition to a racemic synthesis, two asymmetric routes to the core structure are described: one exploiting a rhodium-catalyzed asymmetric cycloisomerization, and another employing a hypervalent iodine-mediated de-aromatizing cyclization of an enantiopure substrate. The final two bonds of the core structure were forged through a samarium diiodide-mediated ketyl radical cyclization and an acid-catalyzed etherification. The rhodium-catalyzed asymmetric reaction invo...

The development of efficient cyclization methods for five-membered ring formation constitutes a continuing challenge in natural and designed molecule construction. Among these methods, the cycloisomerization of 1,6-enynes to form cyclopentane rings has evolved into a powerful technology in chemical synthesis in the past few years. A number of transition metal complexes, such as those of Pd,[1] Ru,[2] Rh[3] and Fe,[4] have proven to be effective catalysts in this transformation. Rh-Based catalytic systems have attracted particular attention as they demonstrated excellent reactivity and enantioselectivity when applied to internal alkyne substrates.[3] However, in some instances an exocyclic methylene group (as opposed to a substituted olefinic bond) is needed on the resulting intermediates for direct elaboration to more advanced products, a condition that requires terminal alkynes as substrates. Although “capped” alkynes with disposable groups have been utilized in this regard, their removal can be laborious and inefficient. Herein we report a Rh-catalyzed asymmetric enyne cycloisomerization reaction using terminal alkynes as substrates and its application to a formal total synthesis of (−)-platensimycin. Scheme 1 shows the proposed mechanism for the Rh-catalyzed cycloisomerization of terminal acetylene (I) to a cyclopentane derivative (IV) through transient species II and III. Scheme 1 Proposed mechanism of Rh-catalyzed asymmetric cycloisomerization of terminal enynes. Employing 1,6-enyne 1 as a substrate we examined a number of Rh-based complexes in order to find the optimum catalytic system; our results are summarized in Table 1. Thus, while the reactivity of [Rh(cod)(MeCN)2]BF4 in the presence of (S)-BINAP was rather modest (36 % yield of product 1a, after 12 h at 23 °C), the product was obtained in promising ee (90 %, Table 1, entry 1). The complex generated in situ by mixing [Rh(cod)Cl]2 and AgOTf in the presence of (S)-BINAP led to a 60 % yield and a comparable ee (91 %, Table 1, entry 2), whereas the combination of [Rh(cod)Cl]2, AgSbF6, and (S)-BINAP employed by Zhang et al. with internal alkynes[3] gave 1a in 65 % yield and 95 % ee (Table 1, entry 3). Finally, it was found that the preformed rhodium catalyst [Rh((S)-BINAP)]SbF6[5] gave the best results, furnishing product 1a in 86 % yield and > 99 % ee (Table 1, entry 4). Table 1 Catalyst screening.a The absolute configuration of product 1a was determined by X-ray crystallographic analysis of its p-bromophenyl carbamate derivative[6] (1b, m.p. 99–101 °C, EtOAc/hexanes 1:1) prepared from 1a through sequential NaBH4 reduction and treatment with p-bromophenyl isocyanate in the presence of Et3N, as shown in Scheme 2. Scheme 2 Preparation and X-ray crystallographic analysis of p-bromophenyl carbamate 1b. Reagents and conditions: a) NaBH4 (1.5 equiv), EtOH, 0 °C, 15 min; b) p-bromophenyl isocyanate (1.05 equiv), Et3N (1.05 equiv), 0 °C, 1 h, 72 % over two steps. ... The generality and scope of the developed asymmetric reaction are demonstrated by the results shown in Table 2. In general, most substrates examined led to good yields and excellent ee’s. The cycloisomerization reaction works well not only with free cis allylic alcohols as demonstrated by most examples in Table 2 (entries 1, 3–11), but also with TBS-protected allylic alcohols, in which case the product with a TBS enol ether moiety is obtained[7] as opposed to the aldehyde (Table 2, entry 2). However, the corresponding trans allylic alcohols are poor substrates as shown with allylic alcohol 3 (Table 2, entry 3). The reaction tolerates a variety of structural motifs, including sulfonamides (Table 2, entries 1–4), lactams (Table 2, entries 5 and 6[8]), 1,1-diesters and sulfones (Table 2, entries 7–9), bis-aromatic moieties (Table 2, entry 10), and dienones (i.e. Table 2, entry 11). Notably, electron withdrawing conjugation is tolerated in either π-system of the substrate (Table 2, entries 5 and 6). The latter example featuring a bromo-acetylene expands considerably the scope of this method due to the fertile chemistry of the stereodefined resulting vinyl bromides (Table 2, entry 11). Table 2 Asymmetric cycloisomerization reactions.a In order to explore the feasibility of this asymmetric cycloisomerization reaction with olefinic side-chains containing other than oxygen substituents, we examined substrates 12 and 13 (Table 2, entries 12 and 13) carrying carbon and nitrogen groups, respectively. Indeed, the reaction performs well in both instances and under similar conditions, leading to cycloisomerized products 12a (Table 2, entry 12, 93 % yield, > 98 % ee)[8] and 13a (Table 2, entry 13, 83 % yield, 94 % ee). The power of the present technology was demonstrated by a formal total synthesis of (−)-platensimycin (18, Scheme 3) from 14, an intermediate previously employed in our synthesis of (±)-platensimycin.[9a] Thus, reduction of 14 with DIBAL-H at −78 °C followed by exposure to aq. HCl at 0 °C led to enone 15 in 88 % overall yield. Conversion of the latter to the corresponding TMS enol ether followed by oxidation with IBX•MPO[10] and desilylation (aq. HCl) furnished bis-enone hydroxy enyne 16 in 68 % overall yield. Delightfully, substrate 16 entered the asymmetric cycloisomerization with 5 mol % catalyst ([Rh((S)-BINAP)]SbF6) to afford the desired spiro dienone aldehyde (−)-17 in 86 % yield and > 99% ee. Notably, the use of the in situ generated catalyst (from [Rh(cod)Cl]2, AgSbF6 and (S)-BINAP) gave erratic results with 10–25 % yield of the desired product. Since (±)-17 and (−)-17 have previously been converted to (±)- and (−)-platensimycin,[9] respectively, this streamlined and highly efficient sequence constitutes a formal total synthesis of (−)-platensimycin (18). Scheme 3 Formal total synthesis of (−)-platensimycin. Reagents and conditions: a) DIBAL-H (1.0 M in hexanes, 1.2 equiv), THF, −78 → −20 °C, 1 h; then 2 N aq. HCl, 0 °C, 30 min, 88 %; b) TMSOTf (1.2 equiv), Et3N (1.5 ... The described catalytic asymmetric synthesis complements and expands the scope of the cycloisomerization of 1,6-enynes by offering efficient and direct entries into enantiopure intermediates for complex natural or designed target molecules of biological and medical interest.

Ever since the world-shaping discovery of penicillin, nature's molecular diversity has been extensively screened for new medications and lead compounds in drug discovery. The search for agents intended to combat infectious diseases has been of particular interest and has enjoyed a high degree of success. Indeed, the history of antibiotics is marked with impressive discoveries and drug-development stories, the overwhelming majority of which have their origin in natural products. Chemistry, and in particular chemical synthesis, has played a major role in bringing naturally occurring antibiotics and their derivatives to the clinic, and no doubt these disciplines will continue to be key enabling technologies. In this review article, we highlight a number of recent discoveries and advances in the chemistry, biology, and medicine of naturally occurring antibiotics, with particular emphasis on total synthesis, analogue design, and biological evaluation of molecules with novel mechanisms of action.

Ever since the world-shaping discovery of penicillin, nature’s molecular diversity has been extensively screened for new medications and lead compounds in drug discovery. The search for anti-infective agents intended to combat infectious diseases has been of particular interest and has enjoyed a high degree of success. Indeed, the history of antibiotics is marked with impressive discoveries and drug development stories, the overwhelming majority of which have their origins in nature. Chemistry, and in particular chemical synthesis, has played a major role in bringing naturally occurring antibiotics and their derivatives to the clinic, and no doubt these disciplines will continue to be key enabling technologies for future developments in the field. In this review article, we highlight a number of recent discoveries and advances in the chemistry, biology, and medicine of naturally occurring antibiotics, with particular emphasis on the total synthesis, analog design, and biological evaluation of molecules with novel mechanisms of action.

The molecular design, chemical synthesis and biological evaluation of two distinct series of platensimycin analogs with varying degrees of complexity are described. The first series of compounds (analog series I: 6, 15–18, Figure 3) probes the biological importance of the benzoic acid subunit of the molecule, whilst the second series (analog series II: 2, 3, 9–14) explores the tetracyclic cage domain. The biological data obtained reveal that while the substituted benzoic acid domain of platensimycin is a highly conserved structural motif within the active compounds with strict functional group requirements, the cage domain of the molecule can tolerate considerable structural modifications without losing biological action. These findings refine our present understanding of the platensimycin pharmacophore and establish certain structure activity relationships (SARs) from which the next generation of designed analogs of this new antibiotic may emerge.