It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.

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Recent data demonstrated that activation of the muscarinic M receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M and M activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M-selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M is sufficient to elicit cholinergic AEs.

A nickel-catalyzed reductive cross-coupling of alkylpyridinium salts and aryl bromides has been developed using Mn as the reductant. Both primary and secondary alkylpyridinium salts can be used, and high functional group and heterocycle tolerance is observed, including for protic groups. Mechanistic studies indicate formation of an alkyl radical, and controlling its fate was key to the success of this reaction.

The development of a convergent fragment coupling strategy for the enantioselective total syntheses of a group of rearranged spongian diterpenoids that harbor the cis-2,8-dioxabicyclo[3.3.0]octan-3-one unit is described. The key bond disconnection relies on a late-stage fragment coupling between a tertiary carbon radical and an electron-deficient alkene to unite two ring systems and form two new stereocenters, one of which is quaternary, in a stereoselective and efficient manner. This strategy is applied toward scalable 14-15 step syntheses of three rearranged spongian diterpenoids, cheloviolenes A and B, and dendrillolide C.

A nickel-catalyzed cross-coupling of benzylic pyridinium salts with arylboronic acids was developed. Coupled with chemoselective pyridinium formation, this method allows benzyl primary amines to be efficiently converted to di(hetero)arylmethanes. Excellent heteroaryl and functional group tolerance is observed, and a one-pot procedure enables benzylic amines to be converted to diarylmethanes directly.

An asymmetric Mannich reaction of phenylacetate thioesters and sulfonylimines using cinchona alkaloid-based amino (thio)urea catalysts is reported that employs proximity-assisted soft enolization. This approach to enolization is based on the cooperative action of a carbonylactivating hydrogen bonding (thio)urea moiety and an amine base contained within a single catalytic entity to facilitate intracomplex deprotonation. Significantly, this allows thioesters over a range of acidity to react efficiently, thereby opening the door to the development of a general mode of enolization-based organocatalysis of monocarboxylic acid derivatives. Soft enolization1,2 provides a mild and operationally simple approach to the deprotonation of certain types of monocarbonyl compounds. In contrast to hard enolization, wherein deprotonation is achieved irreversibly using a very strong base such as LDA, soft enolization occurs when a relatively weak amine base and a carbonyl activating component act in concert to effect reversible deprotonation. We have been investigating this mode of enolization with thioesters in direct carbon-carbon bond formation using Mg 2+ Lewis acids for carbonyl activation.2 Our inspiration for studying thioesters in this context stems from the way in which enolization occurs in the enzyme citrate synthase. 3 Thioester activation in citrate synthase is achieved by hydrogen bonding rather than Lewis-acid coordination (Scheme 1a). While a weaker form of carbonyl activation, it is sufficient to allow deprotonation by a weakly basic carboxylate group.4 This is likely due in large part to the proximity effects imparted to the system as a result of the close spatial arrangement of the ReV. Biophys. Chem. 1986, 15, 97-117. (4) The effect of hydrogen bonding on thioester acidity has been shown for acetyl-CoA dehydrogenase. See: Rudik, I.; Thorpe, C. Arch. Biochem. Biophys. 2001, 392, 341-348. (5) For accounts of proximity accelerated intramolecular transformations in general, see: (a) Menger, F. M.

The total asymmetric synthesis of (+)-and (−)-clusianone and (+)-and (−)-clusianone methyl enol ether is reported. Asymmetric induction is achieved through the use of ACC alkylation, providing the key intermediates with an er of 99:1. The four synthetic compounds were evaluated for their anti-HIV activity. Both (+)-and (−)-clusianone displayed significant anti-HIV activity. KeywordsACC ketone alkylation; Asymmetric synthesis; Polycyclic polyprenylated acylphloroglucinols; Viral infection; Anti-HIV activity Viral infections are a pervasive form of disease that range from the common cold to much more deadly forms such as AIDS. As with antibiotics, 1 current antiviral therapies are becoming less effective due to the development of resistant strains. 2 Consequently, there is an urgent need for new anti-viral agents. (+)-Clusianone (1) (Figure 1) is a member of a large class of biologically active natural products termed the polycyclic polyprenylated acylphloroglucinols (PPAPs). 3 (+)-Clusianone has been shown to possess antiviral activity against both HIV (EC 50 = 0.020 ± 0.003 μM), 4 and Epstein-Barr virus (17.4 ± 1.2% of cells were EBV-EA positive in the presence of 32 nmol of 1). 5 As such, it is a compelling target for further biological investigation as an antiviral agent. Unfortunately, no asymmetric total synthesis is available, as is necessary for further biological testing and medicinal chemistry efforts.Not only do PPAPs generally exhibit biological activity, but they also possess intriguing structures. 3 Consequently, they have attracted considerable interest from the synthetic community. Despite the impressive advances culminating from the synthetic work carried out to date on the PPAPs, asymmetric total syntheses are rare. 6 In the case of clusianone, © 2011 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Supplementary MaterialExperimental procedures and analytical data for all new compounds is available. We recently described a new method for the asymmetric α-alkyation of ketones utilizing chiral N-amino cyclic carbamate (ACC) auxiliaries (cf. 9 and 10, Scheme 1). 12 ACC auxiliaries react readily with ketones to afford the corresponding hydrazones (5 → 6). These undergo rapid deprotonation to the azaenolates, which can be alkylated on up to a multigram scale with excellent stereoselectivity and yield (6 → 7). Moreover, the auxiliaries can be recovered quantitatively and recycled. We realized that this enantio-selective alkylation method could provide the basis for an efficient asymmetric total synthesis of the clusiano...