Medium-Ring Lactams Research Articles

Counterion-Mediated Enantioconvergent Synthesis of Axially Chiral Medium Rings.

There are few enantioconvergent reactions in which racemic substrates bearing multiple stereochemical features are converted into products with high levels of diastereo- and enantiocontrol. Here, we disclose a process for the highly enantio- and diastereoselective syntheses of medium ring lactams via an intramolecular counterion-directed C-alkylation reaction. The treatment of racemic biaryl anilides that exist as a complex mixture of enantiomers and diastereoisomeric conformers by virtue of multiple axes of restricted rotation with a quinidine-derived ammonium salt under basic conditions affords medium ring lactams bearing elements of both axial and point chirality via an enolate-driven configurational relaxation process. Thermal equilibration of the syn- and anti-product diasteroisomers has demonstrated that the barriers to bowl inversion are >124 kJ mol-1. We propose that the chiral ammonium salt differentiates between a complex and rapidly equilibrating mixture of enolate and rotational isomers, ultimately leading to highly enantioselective alkylative ring closure. This dynamic and enantioconvergent process offers an operationally simple approach to the synthesis of valuable chiral medium ring lactams for which there are few catalytic and enantioselective approaches.

Triarylmethanes and their Medium-Ring Analogues by Unactivated Truce-Smiles Rearrangement of Benzanilides.

Intramolecular nucleophilic aromatic substitution (Truce–Smiles rearrangement) of the anions of 2‐benzyl benzanilides leads to triarylmethanes in an operationally simple manner. The reaction succeeds even without electronic activation of the ring that plays the role of electrophile in the SNAr reaction, being accelerated instead by the preferred conformation imposed by the tertiary amide tether. The amide substituent of the product may be removed or transformed into alternative functional groups. A ring‐expanding variant (n to n+4) of the reaction provided a route to doubly benzo‐fused medium ring lactams of 10 or 11 members. Hammett analysis returned a ρ value consistent with the operation of a partially concerted reaction mechanism.

Triarylmethanes and their Medium‐Ring Analogues by Unactivated Truce–Smiles Rearrangement of Benzanilides

AbstractIntramolecular nucleophilic aromatic substitution (Truce–Smiles rearrangement) of the anions of 2‐benzyl benzanilides leads to triarylmethanes in an operationally simple manner. The reaction succeeds even without electronic activation of the ring that plays the role of electrophile in the SNAr reaction, being accelerated instead by the preferred conformation imposed by the tertiary amide tether. The amide substituent of the product may be removed or transformed into alternative functional groups. A ring‐expanding variant (n to n+4) of the reaction provided a route to doubly benzo‐fused medium ring lactams of 10 or 11 members. Hammett analysis returned a ρ value consistent with the operation of a partially concerted reaction mechanism.

Recent Advances in the Development of Catalytic Methods that Construct Medium-ring Lactams, Partially Saturated Benzazepines and their Derivatives.

Recent catalytic methods to construct medium-sized lactams and partially saturated benzazepines and their derivatives are surveyed. The review is divided into the following sections: 1 Introduction 2 Non-Transition Metal Catalyzed Reactions 2.1 Beckmann Rearrangement 2.2 Non-Beckmann Rearrangement Reactions 2.3 Multi-component reactions 3 Transition Metal-Catalyzed Reactions 3.1 Au-catalyzed reactions to access medium-sized N-heterocycles 3.2 Reactions involving a metal η3-complex catalytic intermediate 3.3 Transition metal-catalyzed reactions of strained cycloalkanes 4 Conclusions.

Synthesis of Benzannulated Medium-ring Lactams via a Tandem Oxidative Dearomatization-Ring Expansion Reaction.

Medium-ring natural products exhibit diverse biological activities but such scaffolds are underrepresented in probe and drug discovery efforts due to the limitations of classical macrocyclization reactions. We report herein a tandem oxidative dearomatization-ring-expanding rearomatization (ODRE) reaction that generates benzannulated medium-ring lactams directly from simple bicyclic substrates. The reaction accommodates diverse aryl substrates (haloarenes, aryl ethers, aryl amides, heterocycles) and strategic incorporation of a bridgehead alcohol generates a versatile ketone moiety in the products amenable to downstream modifications. Cheminformatic analysis indicates that these medium rings access regions of chemical space that overlap with related natural products and are distinct from synthetic drugs, setting the stage for their use in discovery screening against novel biological targets.

ChemInform Abstract: Catalytic Ring Expansion of Cyclic Hemiaminals for the Synthesis of Medium‐Ring Lactams.

A mild and efficient intermolecular ring-expansion approach was developed for the synthesis of medium-ring lactams by using siloxy alkynes. Key to success is the suitable combination of a superior catalyst and an exceptional nitrogen-protecting group. Control experiments indicated that the reaction is remarkably selective toward the desired lactam formation, even with many possible non-productive pathways.

Catalytic Ring Expansion of Cyclic Hemiaminals for the Synthesis of Medium-Ring Lactams.

A mild and efficient intermolecular ring-expansion approach was developed for the synthesis of medium-ring lactams by using siloxy alkynes. Key to success is the suitable combination of a superior catalyst and an exceptional nitrogen-protecting group. Control experiments indicated that the reaction is remarkably selective toward the desired lactam formation, even with many possible non-productive pathways.

Benzoylureas as removable cisamide inducers: synthesis of cyclic amidesviaring closing metathesis (RCM)

Rapid and high yielding synthesis of medium ring lactams was made possible through the use of a benzoylurea auxiliary that serves to stabilize a cisoid amide conformation, facilitating cyclization. The auxiliary is released after activation under the mild conditions required to deprotect a primary amine, such as acidolysis of a Boc group in the examples given here. This methodology is a promising tool for the synthesis of medium ring lactams, macrocyclic natural products and peptides.

Novel synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity that inhibit tumor cell proliferation and are structurally unrelated to existing statins

Pilot-scale libraries of eight-membered medium ring lactams (MRLs) and related tricyclic compounds (either seven-membered lactams, thiolactams or amines) were screened for their ability to inhibit the catalytic activity of human recombinant 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in vitro. A dozen of the synthetic compounds mimic the inhibition of purified HMG-CoA reductase activity caused by pravastatin, fluvastatin and sodium salts of lovastatin, mevastatin and simvastatin in this cell-free assay, suggesting direct interaction with the rate-limiting enzyme of cholesterol biosynthesis. Moreover, several MRLs inhibit the metabolic activity of L1210 tumor cells in vitro to a greater degree than fluvastatin, lovastatin, mevastatin and simvastatin, whereas pravastatin is inactive. Although the correlation between the concentration-dependent inhibitions of HMG-CoA reductase activity over 10 min in the cell-free assay and L1210 tumor cell proliferation over 4 days in culture is unclear, some bioactive MRLs elicit interesting combinations of statin-like (IC50: 7.4-8.0 microM) and anti-tumor (IC50: 1.4-2.3 microM) activities. The HMG-CoA reductase-inhibiting activities of pravastatin and an MRL persist in the presence of increasing concentrations of NADPH. But increasing concentrations of HMG-CoA block the HMG-CoA reductase-inhibiting activity of pravastatin without altering that of an MRL, suggesting that MRLs and existing statins may have different mechanisms of enzyme interaction and inhibition. When tested together, suboptimal concentrations of synthetic MRLs and existing statins have additive inhibitory effects on HMG-CoA reductase activity. Preliminary molecular docking studies with MRL-based inhibitors indicate that these ligands fit sterically well into the HMG-CoA reductase statin-binding receptor model and, in contrast to mevastatin, may occupy a narrow channel housing the pyridinium moiety on NADP+.

Synthesis and conformational analysis of a type VIb β-turn mimetic based on an eight-membered lactam

As part of a programme evaluating medium-ring lactams as peptide conformational constraints the trans-disubstituted lactam dipeptide (3S,8R)-3-acetylamino-8-methoxycarbamoylazocan-2-one (3) was selected as a template to mimic the type VI β-turn conformation of natural polypeptides. The enantioselective synthesis of the eight-membered lactam 3 is discussed. The X-ray crystal structure of the methyl ester precursor of 3 shows a classical type VIb β-turn conformation. Extensive 1H NMR spectroscopic studies of the dipeptide 3 in polar solvents provided evidence for a type VI β-turn. The analysis shows an equilibrium of two folded conformations.

A novel method for the formation of 2-azocanones by lactone-to-lactam ring contraction of 2-oxonanones

As part of project evaluating medium-ring lactams as constrained peptidomimetics, a novel method for the formation of multisubstituted eight-membered lactams has been developed. N-Protected 7-amino- 8-hydroxyoctenoic acids were cyclised to give 8-amino-5,6-dehydro-2-oxocanones which underwent clean intramolecular O-to- N-acyl (lactone-to-lactam) ring contraction to yield 8-hydroxymethyl-6,7-dehydro-2-azocanones, suitable for elaboration to eight-membered lactam dipeptides.

Intramolecular photoaddition reactions of (aminoalkyl)styrylamides

The photochemical reactions of a family of styrene—spacer—amine molecules in which the spacer consists of a rigid amide group in the middle of a flexible alkane chain have been investigated. Our study of the photophysics of these molecules has shown that the amide linker can facilitate intramolecular styrene—amine exciplex formation (J. Phys. Chem., in press). We report here the photochemical behavior of these amide-linked (aminoalkyl) styrylamides. Several tertiary amines are found to undergo regioselective α-C-H addition to the styrene double bond resulting in the formation of medium-ring lactams. A secondary amine undergoes N-H addition yielding an azalactam. The dependence of these reactions upon spacer structure, amine and amide substitution, and solvent polarity is discussed.

New methodology for the synthesis of unsaturated 8-, 9- and 10-membered lactams

Unsaturated 8-, 9- and 10-membered medium ring lactams 1 (n= 1,2,3) have been prepared in good yield by the Claisen rearrangement of the vinyl-substituted precursors 3 in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

Synthesis of medium ring lactams via cyclization reactions using polymer bound HOBT as catalyst

The synthesis of medium ring lactams (7−, 9−, 11− and 13−membered rings) via cyclization reactions mediated by polymer bound 1-hydroxybenzotriazole (HOBT) is reported.

Photocyclization of .GAMMA.-Chlorotiglyl-L-tryptophan Methyl Ester Yields Azocinoindole and Azepinoindole Derivatives.

We aimed to synthesize ten-membered lactams ring-closed at C-4 of the indole by photocyclization reaction of γ-chlorotiglyl L-tryptophan methyl ester 5a for structure-activity study of medium-ring lactams related to indolactams having tumor-promoting activity. However, the 13C-NMR spectra of the products showed that two eight-membered lactams ring-closed at C-4 of the indole, (4S, 7S)-1, 3, 4, 5, 6, 7-hexahydro-4-methoxycarbonyl-7-methyl-6-oxo-7-vinylazocino[4, 5, 6-cd]indole (6a) and its (4S, 7R)-epimer 7a, and a seven-membered lactam ring-closed at C-2 of the indole, (2S, 5S)-1, 2, 3, 4, 5, 6-hexahydro-2-methoxycarbonyl-5-methyl-4-oxo-5-vinylazepino[4, 5-b]indole (8a), were produced rather than the expected ten-membered lactams 3a and 4a. That is, this photocyclization linked the carbon atom adjacent to the amide-carbonyl groups to the indole ring.

Synthesis of monocyclic medium ring lactams

The Claisen rearrangement of the vinyl substituted ketene aminals 4a-c which were generated in situ by selenoxide elimination of the aminal precursors 3a-c in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene gave the monocyclic unsaturated medium ring lactams 5a-c.

Regioselective Functionalization of Medium-Ring Lactams

Regioselective Functionalization of Medium-Ring Lactams

Indolizidine synthesis by transannular cyclization

AbstractBeckmann rearrangement of alkylcyclooctenone oximes VIa and VIb gave corresponding nine‐membered lactams 1,3,4,5,8,9‐hexahydro‐3‐methyl‐2H‐azonin‐2‐one (VIIIa) and 1,3,4,5,8,9‐hexahydro‐3‐butyl‐2H‐azonin‐2‐one (VIIIb), respectively. A stereospecific transannular cyclization was induced by mercuric acetate leading to alkyl indolizinones Xa and Xb. Temperature and solvent dependent nmr spectra of the medium ring lactams indicates the stereochemical control is caused by steric interactions of the alkyl side chain. Lithium aluminum hydride reduced Xa/Xb to cis‐octahydro‐6‐methylindolizidine (XIa) and cis‐octahydro‐3‐n‐butylindolizidine (XIb).

Photochemistry of 4(3H)-pyrimidin-4-ones. Formation of medium-ring lactams

Upon irradiation, 4(3H)-pyrimidin-4-one(1) afforded a di-imine derivative(2) which, when hydrolyzed in an acidic methanol solution, gave N-methyl acetoacetamide(3). On the other hand, the fused 4(3H)-pyrimidin-4-ones, (4) and (5), gave medium-ring lactams(6) and (7), which were hydrolyzed in an acidic methanol solution to give (8) and (9), respectively.

The non-planar amide group

Crystal structures of medium-ring lactams and their crystalline hydrochlorides furnish detailed information on the nature of the out-of-plane distortions of the amide group. Caprylolactam has a non-planar transoid amide group in the crystal but exists in solution as an equilibrium mixture of at least two conformations, one with a nearly planar cis-amide group, one with a non-planar transoid-amide group. The corresponding hydrochloride salt is protonated on oxygen and contains a nearly planar cis-amide group. For non-planar amide groups it is found that out-of-plane bending at nitrogen is about as important as pure twisting, the contribution from out-of-plane bending at the carbonyl carbon being smaller. These results, together with rough data on the energy differences between the lactam conformations, can be used to test various potential functions that have been proposed. It is concluded that although the equilibrium conformation of the amide group may be planar or close to it, out-of-plane deformation can be made at a very modest energy cost. In the construction of models of polypeptide chains or in fitting such models to electron-density maps of protein crystals, the strictly planar peptide unit thus incorporates restrictions that may be rather easily relaxed in the actual molecule.