Carbonyl allenylation/free radical cyclization sequence as a new regio- and stereocontrolled access to bi- and tricyclic beta-lactams

A novel approach to racemic and enantiopure nonconventional fused bi- and tricyclic beta-lactams has been developed by using regio- and stereocontrolled intramolecular free radical reactions in monocyclic 2-azetidinone-tethered allenynes and haloallenes. The access to allene cyclization precursors was achieved by metal-mediated carbonyl allenylation of appropriately substituted 4-oxoazetidine-2-carbaldehydes in an aqueous environment. The tin-promoted radical cyclizations of allene-beta-lactams are totally regioselective for the central allenic carbon, providing bi- and tricyclic beta-lactams containing a seven-membered ring.     

Synthesis of strained tricyclic beta-lactams by intramolecular [2+2] cycloaddition reactions of 2-azetidinone-tethered enallenols: control of regioselectivity by selective alkene substitution

A convenient metal-free methodology for the preparation of structurally novel, strained tricyclic beta-lactams containing a cyclobutane ring has been developed. The first examples accounting for the intramolecular [2+2] cycloaddition reactions in beta-lactams have been achieved by the thermolysis of 2-azetidinone-tethered enallenols, which have been prepared in aqueous media by regio- and diastereoselective indium-mediated carbonyl allenylation of 4-oxoazetidine-2-carbaldehydes. Notably, the regioselectivity of the cycloaddition can be tuned in the allene component just by a subtle variation in the substitution pattern of the alkene component.     

Additions of allenyl/propargyl organometallic reagents to 4-oxoazetidine-2-carbaldehydes: novel palladium-catalyzed domino reactions in allenynes

Metal-mediated carbonyl allenylation and propargylation of 4-oxoazetidine-2-carbaldehydes were investigated in aqueous environment. Different propargyl bromide and metal promoters showed varied regio- and stereoselectivities on product formation. In addition, an unprecedented one-pot stereoselective synthesis of beta-chlorinated allylic alcohols, which can also be considered as functionalized allylsilanes, has been developed, which involves tin(IV) chloride-mediated reaction of propargyltrimethylsilane and 4-oxoazetidine-2-carbaldehydes. Some of the resulting coupling products were submitted to transition metal catalyzed reactions, such as the allenic Pauson-Khand and palladium-catalyzed reactions, leading to novel fused or bridged tricyclic beta-lactams. Remarkably, a novel domino process, namely the allene cyclization/intramolecular Heck reaction was found. A likely mechanism for the cascade reaction should involve an intramolecular cyclization on a (pi-allyl)palladium complex and a Heck-type reaction.     

SmI(2)-mediated cyclizations of derivatized beta-lactams for the highly diastereoselective construction of functionalized prolines

A series of C4-keto-functionalized 1-[(benzoyloxy)(ethoxycarbonyl)methyl]-2-azetidinones were prepared and studied for their tendency to undergo a Reformatsky-type cyclization to fused bicyclic or tricyclic beta-lactams with the single-electron reducing agent samarium diiodide. Whereas the azetidinone 21a underwent reductive cyclization, affording the potent antibiotic sanfetrinem's tricyclic [4.5.6] core structure as the major component, all other examples tested resulted in cyclization followed by an N to O acyl migration involving cleavage of the beta-lactam ring as the favored pathway. Highly functionalized proline derivatives were therefore accessed as single diastereomers through the reductive cyclization of benzoates 21b, 22, 23a,b, 24b, and 25-28. Pertinent for the success of these cyclizations was the addition of 1 equiv of tert-butyl alcohol, allowing for the protonation of the basic amide derivative obtained after the acyl migration step. The diastereoselectivities of these reactions deviate from those of similar cyclizations involving the corresponding lithium enolate. This divergence could be rationalized by the coordination of the metal ion of the samarium(III) enolate intermediate to the beta-lactam amide functionality in the cyclization step, which may not be possible for lithium enolates.     

Divergent synthesis of pseudoenantiomers for ABC-ring moiety of steroids

Steroid family has various bioactivities and characteristic polycyclic structure. Although several synthetic methods have been reported, more efficient way is desired for medicinal chemistry. In this Letter, we synthesized pseudoenantiomers of tricyclic enones toward both enantiomers for ABC-ring moiety of steroids utilizing d-mannitol as a chiral source. The key steps are radical domino cyclization of polyalkenyl-β-keto ester into tricyclic keto ester and subsequent dealkoxycarbonylation.     

Structurally novel Bi- and tricyclic beta-lactams via [2 + 2] cycloaddition or radical reactions in 2-azetidinone-tethered enallenes and allenynes

[reaction: see text] Thermolysis of beta-lactam-tethered enallenyl alcohols gave tricyclic ring structures via a formal [2 + 2] cycloaddition of the alkene with the distal bond of the allene, while the tin-promoted radical cyclization in 2-azetidinone-tethered allenynes proceeded to provide bicyclic beta-lactams containing a medium-sized ring. The access to cyclization precursors was achieved by regio- and stereoselective metal-mediated carbonyl allenylation of 4-oxoazetidine-2-carbaldehydes in an aqueous environment.     

Pathway development and pilot library realization in diversity-oriented synthesis: exploring Ferrier and Pauson-Khand reactions on a glycal template

Through a correlation of the ability of small molecules to bind biological macromolecules and their ability to modulate cellular and organismal processes, chemistry can inform biology and vice versa. Diversity-oriented organic synthesis (DOS), which aims to provide structurally complex and diverse small molecules efficiently, can play a key role in such chemical genetic studies. Here we illustrate the trial-and-error experimentation that can refine an initial pathway-planning exercise and result eventually in an effective diversity pathway. By exploring Ferrier and Pauson-Khand reactions on a glycal template, we have developed efficient and stereoselective syntheses of tricyclic compounds. In this pathway, diversity results from the substituents and their spatial relationships about the tricyclic rings. A pilot split-pool library synthesis of 2500 tricyclic compounds highlights the use of planning considerations in DOS and a "one-bead, one-stock solution" technology platform. Additionally, it illustrates a promising synthetic pathway for future chemical genetic studies.     

Synthesis and antimicrobial activity of some new sugar-based monocyclic beta-lactams

The syntheses of some new sugar-based monocyclic beta-lactams possessing several other functionalities in addition to the carbohydrate moiety are described. The key step was the Staudinger [2+2] cycloaddition of chiral carbohydrate Schiff base 5 with phthalimidoacetyl chloride to yield the sugar-based monocyclic beta-lactam 6 as a single isomer. Treatment of protected beta-lactams 6 and 8 with methylhydrazine afforded the free amino beta-lactams 9 and 10. Acylation of these free amino beta-lactams with benzoyl, phenoxyacetyl, cinnamoyl and phenylacetyl chloride in the presence of pyridine afforded beta-lactams 11a-d and 12a-d. Some of these novel beta-lactams were found to be active against Staphilococcus citrus, Klebsiella pneumoniae, Escherichia coli and Bacillus subtilis.     

1-Boraadamantane blows its top, sometimes. The mono- and polyhomologation of 1-boraadamantane

[reaction: see text] 1-Boraadamantane.THF (3) reacts with 1 equiv of dimethylsulfoxonium methylide (4) to afford a monohomologated product. The polyhomologation of 1-boraadamantane.THF by ylide 4 followed by oxidative cleavage generates star polymethylene polymers incorporating a cyclohexane core. However, only one-third of the initiators lead to product formation, resulting in an observed degree of polymerization three times higher than expected. The polyhomologation of 3 was found to contain branch points after the fourth and fifth methylene insertions. At the branch points, the propagating species either terminate in tricyclic trialkylborane cages with collapsed, pyramidal inverted boron centers that are unreactive toward ylide or they continue in uninterrupted polymerization and eventually result in the formation of giant "tube-like" structures such as 5.     

An anionic nucleophilic catalyst system for the diastereoselective synthesis of trans-beta-lactams

Trans-disubstituted beta-lactams show increasing utility and prominence in numerous pharmaceutical applications, making their asymmetric synthesis an attractive goal for chemists. We introduce an anionic, nucleophilic catalyst system that provides an efficient, diastereoselective route to trans-disubstituted beta-lactams, a complement to our previously described catalytic methodology for generating the corresponding cis diastereomers. This catalytic, "switch mechanism" process allows for flexibility in the stereoselective synthesis of beta-lactams, producing either cis or trans products as desired from the same substrates. [reaction: see text]     

Cu(I)/bis(azaferrocene)-catalyzed enantioselective synthesis of beta-lactams via couplings of alkynes with nitrones

As a consequence of the wide-ranging significance of beta-lactams (e.g., use as drugs and as chiral building blocks), a great deal of effort has been dedicated to the development of methods for their stereoselective synthesis. Although considerable progress has been achieved, nearly all of the approaches that have been described are based on the use of chiral precursors; direct catalytic enantioselective routes to beta-lactams are rare as well as limited in scope. In this communication, we establish that, using a new C2-symmetric planar-chiral bis(azaferrocene) ligand, we can generate beta-lactams with very good enantiomeric excess and cis diastereoselection via catalytic enantioselective Kinugasa reactions (couplings of alkynes with nitrones). Appealing attributes of this process include the ready availability of the starting materials, the functional-group tolerance of the reaction, and the convergency of the approach.     

Circular dichroism and conformational dynamics of cephams and their carba and oxa analogues

The biological activity of bicyclic beta-lactam antibiotics depends strongly on the absolute configuration of the bridgehead carbon atom. Frelek and co-workers proposed an empirical helicity rule relating the configuration of the bridgehead carbon atom to the sign of the 220 nm band in the electronic circular dichroism (CD) spectrum of beta-lactams. Here we use synthetic organic chemistry, CD spectroscopy, and time-dependent density functional theory (TDDFT) to investigate the validity of this structure-property relationship for eight model compounds. For conformationally flexible beta-lactams, substantial thermal effects are found which must be included in calculations. To this end, we combine TDDFT calculations of CD with full quantum-mechanical Born-Oppenheimer molecular dynamics (MD) simulations for the first time. The CD spectra are sampled with ground-state density functional trajectories of up to 60 ps. The MD simulations show a surprisingly high sensitivity of the CD to the molecular conformation. On the other hand, the relation between CD and thermally averaged structural parameters is much less complex. While the helicity rule does not seem to hold for individual conformers, it is confirmed by the calculations for seven out of eight systems studied if thermally averaged CD spectra and structures are considered. Since thermal effects on CD can be larger than typical inherent inaccuracies of TDDFT, our results emphasize the need for a systematic treatment of conformational dynamics in CD calculations even for moderately flexible systems. Temperature-dependent CD measurements are very useful for this purpose. Our results also suggest that CD spectroscopy may be used as a sensitive probe of conformational dynamics if combined with electronic structure calculations.     

Neuroleptic and antidepressant tricyclic compounds: Theoretical study for predicting their biological activity by semiempirical,density functional,and Hartree–Fock methods

The biological activity as antidepressants and/or neuroleptic of tricyclic compounds is investigated by molecular structure calculations. These calculations were carried out with semiempirical, local spin density, and Hartree–Fock methods. Using the computed highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy values, together with their atomic orbital conformation, we have been able to establish a trend to predict the possible biological activity (BA) of tricyclic compounds. We have found that qualitatively it is possible to use any of the applied theoretical methods to obtain a trend for biological activity prediction. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 71: 415–432, 1999     

Lewis acid-promoted intermolecular carbonyl-ene reaction of enantiopure 4-oxoazetidine-2-carbaldehydes. Rapid entry to novel fused polycyclic beta-lactams

Lewis acid-promoted carbonyl-ene reaction of enantiomerically pure 4-oxoazetidine-2-carbaldehydes with various activated alkenes gives 4-[(1'-hydroxy)homoallyl]-beta-lactams with a very high level of syn diastereofacial selectivity. The above homoallylic alcohols are used for the diastereoselective preparation of fused bicyclic, tricyclic, and tetracyclic beta-lactams of nonconventional structure using tandem one-pot radical addition/cyclization or elimination-intramolecular Diels-Alder sequences. In addition, a novel domino process was discovered, the C4-N1 beta-lactam bond breakage/intramolecular Diels-Alder reaction.     

Pyridoxamine,a scavenger agent of carbohydrates

Pyridoxamine has been found to inhibit protein glycation and to avoid the formation of advanced glycation end‐products (AGEs). One of the mechanisms by which pyridoxamine can inhibit glycation involves the scavenger of carbonyl groups with glycation capacity. In this work, we conducted a kinetic study of the reactions of pyridoxamine with various carbohydrates under physiological pH and temperature. The reactions involving hexoses were found to give a tricyclic compound ( 5 ) in addition to pyridoxal and pyridoxine. Such a tricyclic compound inhibits the Amadori rearrangement and the formation of other carbonyl compounds with glycating properties. The reactions involving pentoses gave compound 7 and pyridoxal—by transamination of the Schiff base. The transamination reaction enhances the inhibitory action of pyridoxamine. The formation rate constants for the Schiff base, k₃, were found to be similar to those for the reactions of D ‐glucose with amino acids, which suggests competition between pyridoxamine and terminal amino residues in proteins for glycating sites in sugars. These constants are dependent on the electrophilic character of the carbonyl carbon in the carbohydrate. © 2007 Wiley Periodicals, Inc. 39: 154–167, 2007     

The Intramolecular Aldol Condensation Route to Fused Bi- and Tricyclic beta-Lactams(1)(,)(2)

Staüdinger cycloaddition of activated acid chlorides to 1,3-ketoaldimines, prepared in quantitative yields from 1,3-ketoaldehydes and amino esters, gave in excellent yields cis-2-azetidinones, 6-8, having the adequate functionality to obtain fused bi- and tricyclic beta-lactams. Reaction of compounds 6 with LHMDS at low temperature gave a single diastereomer of fused bicyclic compounds with a carbapenam or carbacefam skeleton. Treatment of diastereomeric cis-2-azetidinones, 7/8, in analogous conditions resulted either in the exclusive cyclization of one of the two diastereomers to form tricyclic [4.n.m] (n = 5, 6; m = 5, 6) compounds, or in the cyclization of both diastereomers to form tricyclic [4.n.7] (n = 5, 6) 2-azetidinones. In all cases the cyclization step was totally stereoselective. Alternatively, trans-carbapenams and one example of a tricyclic system having a trans-2-azetidinone ring have been obtained by using longer reaction times and higher temperatures. Epimerization at C3 of the 2-azetidinone nucleus occurs in these reaction conditions to obtain a single diastereomer of the final products. This approach to fused policyclic 2-azetidinones is one of the scarce syntheses of this kind of compound making use of the aldol condensation.     

A conformationally constrained fused tricyclic nisin AB-ring system mimic toward an improved pyrophosphate binder of lipid II

The bacteria-specific membrane component lipid II is essential for bacterial cell wall synthesis. A tricyclic nisin mimic was designed and synthesized in which both thioether moieties were mimicked by an alkane-bridge, as well as the introduction of a third conformational constraint consisting of a macrocyclic lactam-bridge between the N-terminus and the B-ring. The newly designed tricyclic AB-ring mimic was found to bind lipid II since it was able to inhibit nisin-induced membrane leakage in a dose-dependent manner. These results imply that the tricyclic AB-ring mimic may form a novel class of lead structures for the development of nisin-based peptide antibiotics.     

Synthesis of docetaxel and butitaxel analogues through kinetic resolution of racemic beta-lactams with 7-O-triethylsilylbaccatin III

The kinetic resolution of racemic cis-4-phenyl- and cis-4-tert-butyl-3-hydroxy-beta-lactam derivatives with 7-O-triethylsilylbaccatin III yielded paclitaxel and butitaxel analogues with high diastereoselectivity. The results demonstrated that the tert-butyldimethylsilyl protecting group at the C3-hydroxy group of the beta-lactams provided optimum kinetic resolution in comparison with the sterically less demanding triethylsilyl group and the larger triisopropylsilyl group. In addition, it was found that the C4 beta-lactam substituents also influenced diastereoselectivity. The C4 tert-butyl-beta-lactams provided better diastereoselectivity than the corresponding C4 phenyl beta-lactams.     

Divergent enantioselective synthesis of (-)-galanthamine and (-)-morphine

An efficient divergent synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges by employing a Pd-catalyzed asymmetric allylic alkylation (AAA) to set the stereochemistry. Three generations of syntheses of galanthamine are discussed in detail with particular focus on the scope of the palladium-catalyzed AAA reactions and intramolecular Heck reactions. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine could be formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine.