Efficient and practical access to chiral aminocyclopropanes is secured by the title reaction (see example). Both E and Z enamides undergo the cyclopropanation with high diastereoselectivity (d.r. up to >95:5). The application of this methodology to the synthesis of biologically significant aminocyclopropanes illustrates the potential of chiral enamides as useful building blocks for stereoselective organic synthesis.
A de novo preparation of α-keto-imides via ynamide oxidation is described. With a number of alkyne oxidation conditions screened, a highly efficient RuO2-NaIO4 mediated oxidation and a DMDO oxidation have been identified to tolerate a wide range of ynamide types. In addition to accessing a wide variety of α-keto-imides, the RuO2-NaIO4 protocol provides a novel entry to the vicinal tricarbonyl motif via oxidation of push-pull ynamides, and imido acylsilanes from silyl-substituted ynamides. Chemoselective oxidation of ynamides containing olefins can be achieved using DMDO, while the RuO2-NaIO4 protocol is not effective. These studies provide further support for the synthetic utility of ynamides.
1 H and 13 C NMR chemical shifts were measured for a set of six isomers-the cis and trans 2-, 3-, and 4-methylcyclohexanols. 1 H and 13 C NMR chemical shifts were computed at the B3LYP, WP04, WC04, and PBE1 density functional levels for the same compounds, taking into account the Boltzmann distribution among conformational isomers (chair-chair forms and hydroxyl rotamers). The experimental versus computed chemical shift values for proton and carbon were compared and evaluated (using linear correlation (r 2 ), total absolute error (jDdj T ), and mean unsigned error (MUE) criteria) with respect to the relative ability of each method to distinguish between cis and trans stereoisomers for each of the three constitutional isomers. For 13 C shift data, results from the B3LYP and PBE1 density functionals were not sufficiently accurate to distinguish all three pairs of stereoisomers, while results using the WC04 functional did do so. For 1 H shift data, each of the WP04, B3LYP, and PBE1 methods was sufficiently accurate to make the proper stereochemical distinction for each of the three pairs. Applying a linear correction to the computed data improved both the absolute accuracy and the degree of discrimination for most of the methods. The nature of the cavity definition used for continuum solvation had little effect. Overall, use of proton chemical shift data was more discriminating than use of carbon data.
Cholinergic synaptic transmission often requires extremely rapid hydrolysis of acetylcholine by acetylcholinesterase (AChE). AChE is inactivated by organophosphates (OPs) in chemical warfare nerve agents. The resulting accumulation of acetylcholine disrupts cholinergic synaptic transmission and can lead to death. A potential long-term strategy for preventing AChE inactivation by OPs is based on evidence that OPs must pass through a peripheral site or P-site near the mouth of the AChE active site gorge before reacting with a catalytic serine in an acylation site or A-site at the base of the gorge. An ultimate goal of this strategy is to design compounds that bind tightly at or near the P-site and exclude OPs from the active site while interfering minimally with the passage of acetylcholine. However, to target the AChE P-site with ligands and potential drugs that selectively restrict access, much more information must be gathered about the structure-activity relationships of ligands that bind specifically to the P-site. We apply here an inhibitor competition assay that can correctly determine whether an AChE inhibitor binds to the P-site, the A-site, or both sites. We have used this assay to examine three uncharged, natural product inhibitors of AChE, including aflatoxin B1, dihydrotanshinone I, and territrem B. The first two of these inhibitors are predicted by the competition assay to bind selectively to the P-site, while territrem B is predicted to span both the P- and A-sites. These predictions have recently been confirmed by X-ray crystallography. Dihydrotanshinone I, with an observed binding constant (KI) of 750 nM, provides a good lead compound for the development of high-affinity, uncharged inhibitors with specificity for the P-site.
[3 + 3] Annulations of exo-cyclic vinylogous amides and urethanes with vinyl iminium salts are described here. We observed an intriguing dichotomy in their reaction pathways. For pyrrolidineand azepane-based vinylogous amides or urethanes, aza-[3 + 3] annulation would dominate to give tetrahydroindolizidines, whereas, unexpectedly, for piperidine-based vinylogous amides or urethanes, carbo-[3 + 3] annulation was the pathway, leading to hexahydroquinolines. The origin for such a contrast is likely associated with a switch in the initial reaction pathway between C-1,2-addition and C-1,4-addition.
A computation docking study of the highly potent, non-nitrogen containing, acetylcholinesterase inhibitor (+)-Arisugacin A is presented. The model suggests that (+)-arisugacin A is a dual binding site covalent inhibitor of AChE. These findings are examined in the context of Alzheimer's disease-modifying therapeutic design. (+)-Arisugacin A's revealed mode of action is unique, and may serves as a basis for the development of AD therapeutics capable of treating the symptomatic aspects of AD, while being neuroprotective with long term efficacy. KeywordsArisugacin A; Acetylcholinesterase inhibitor; Alzheimer's disease; Dual binding site; Covalent inhibitor Alzheimer's disease [AD]1 affects well over 24 million people worldwide.2 -3 It is one of the most degenerative and devastating syndromes affecting mostly the geriatric population, causing loss of memory and cognitive abilities. The exact pathogenic mechanism of AD still remains unknown, however tremendous progress has been made in understanding the biochemical events involved. Through this understanding, targets and theories have emerged as to how to best combat this disease. The current leading theory in disease-modifying therapeutic research is the amyloid cascade hypothesis focusing on β-amyloid peptide (Aβ), a primary component of the neurotoxic senile plaques that are a major hallmark of AD.4 These efforts focus on inhibiting Aβ production, preventing Aβ aggregation, or altering Aβ metabolism and clearance.5 The long standing cholinergic deficiency hypothesis3 , 6 has served almost exclusively as the rational basis in the development of known drugs ( Figure 1). This hypothesis links the loss of acetylcholine, a neurotransmitter responsible for memory and cognitive functions, to AD. To maintain concentrations of acetylcholine in AD patients, current treatment involves the use of reversible and competitive inhibitors of acetylcholinesterase [AChE], a classical serine protease that catalyzes the hydrolysis of acetylcholine.6 Treatments using cholinesterase [ChE] NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptRecent findings show the cholinergic and amyloid hypotheses are not independent of one another. Namely, acetylcholine activation of the muscarinic receptors leads indirectly to increases in the non-amyloidogenic β-secretase processing of Aβ precursor protein (APP),11 thus linking AChE inhibition with the diversion of APP away from Aβ formation. Another key connection has been the identification and mechanistic elucidation of the proaggregating action of AChE on Aβ.12 This secondary activity of AChE involves the enzyme's peripheral anionic site (PAS) located at the entrance of the catalytic gorge. AChE inhibitors able to bind to the PAS have been found to inhibit this pro-aggregating activity. 12a These connections point to the disease-modifying potential of AChE inhibitors.In light of these findings there has been a re-emerging interest in AChE inhibitor-based drug development, and their extension to molecules that serv...
A stereoselective halo-etherification of chiral enamides is described here. This work provides an approach to halogen containing cyclic ethers and reveals further mechanistic insights to the chemistry of chiral enamides.With elegant advances in metal-catalyzed N-alkenylations, 1-4 chiral enamides should emerge as versatile building blocks for developing stereoselective synthetic methods. [5][6][7][8][9][10][11][12] We encountered an interesting phenomenon involving enamides when we attempted years ago to transform enamides 1 to chiral ynamides 13 via a sequence of bromination-elimination of the intermediate β-bromo-enamides 3 and 4 [Scheme 1]. 14 Two intriguing observations were made. First, the bromination behaved differently from a standard bromination of olefins. It was reversible with or without an amine base, and 3 and 4 were obtained only if the reaction was heated at ≥80 °C without base. Although upon its addition the bromine color disappeared rapidly in a colormetric titration manner, the color returned upon warming to rt. Second, when R is a TBSO or TIPSO group, the bromination led to a completely different product, thereby failing to access ynamides 5 via this protocol. While we suspected the N-acyl iminium salt intermediate 2 to be responsible for the reversibility issue [see blue arrows], we recently resolved the mystery product in the second observation. We reported here a stereoselective halo-etherification of chiral enamides in the synthesis of halogen containing cyclic ethers.When chiral enamide 6 15 was subjected to bromination conditions in which 1.33 equiv of Br 2 was added at −35 °C and the resulting mixture was heated at 83 °C in ClCH 2 -CH 2 Cl for 20 h, pyran 7-Br was isolated in 43% yield as a single isomer. Its relative stereochemistry was unambiguously assigned via single-crystal X-ray structure [Scheme 2]. No β-bromoenamides related to 3 and 4 were found, and pyran 7-Br implies a bromine-promoted desilylative cyclization had taken place instead.© 2007 American Chemical Society rhsung@wisc.edu. Supporting Information Available: Experimental details, characterization data, X-ray structural analysis, and NMR spectral for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. With these protocols in hand, we investigated the effect of the chiral auxiliary on the stereoselectivity. The diastereomeric ratio appears to be sensitive to the types of auxiliary used [ Figure 1]. In comparison to Evans' auxiliaries, 20 Seebach's auxiliary 21 appears to be better giving 12-Br in a 7.7:1 ratio, although the ratio was lower when using Close's auxiliary 22 for the preparation of 13-Br. Interestingly, an additional substituent such as OBz [at C5] eroded the ratio 14-Br/14-Br′. NIH Public AccessThe best result came when using Sibi's auxiliary. As shown in Scheme 3, in a sequence that is intended to demonstrate the synthetic potential of this method in conjunction with Nalkenylation via amidative cross-coupling, 1,2 enamide 17 substituted with Sibi's...
This work describes the first examples of diastereoselective intramolecular cyclopropanations of a de novo class of push-pull carbenes derived from DMDO-epoxidations of chiral ynamides. This reaction sequence essentially constitutes a tandem epoxidation-cyclopropanation that effectively gives arise to a series of structurally unique amido-cyclopropanes. A plausible mechanistic model is proposed revealing insights into this novel cyclopropanation process.
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