Total syntheses of (±)-rhodonoids A and B and C12-epi-rhodonoid B are described here. A unified strategy employed in these syntheses is an intramolecular oxa-[3 + 3] annulation for accessing the chromene unit. A Fe(OTf)3-promoted diastereoselective cationic [2 + 2] cycloaddition and a photochemical [2 + 2] cycloaddition were featured to construct the cyclobutane core of (±)-rhodonoids A and B and C12-epi-rhodonoid B, respectively. Fe(OTf)3 also leads to an interesting bridged tetracycle, which was unambiguously confirmed by single crystal X-ray analysis.

We report the first experimental evidence for the generation of highly strained cis,trans-cycloheptadienones by electrocyclic ring opening of 4,5-fused cyclobutenamides. In the presence of AlCl3, the cyclobutenamides rearrange to [2.2.1]-bicyclic ketones; DFT calculations provide evidence for a mechanism involving torquoselective 4π-electrocyclic ring opening to a cis,trans-cycloheptadienone followed by a Nazarov-like recyclization and a 1,2-alkyl shift. Similarly, 4,6-fused cyclobutenamides undergo AlCl3-catalyzed rearrangements to [3.2.1]-bicyclic ketones through cis,trans-cyclooctadienone intermediates. The products can be further elaborated via facile cascade reactions to give complex tri- and tetracyclic molecules.

A highly π-facial selective and regioselective fluorination of chiral enamides is described. The reaction involves an enantioselective fluorination exclusively at the electron-rich enamide olefin with N–F reagents such as Selectfluor and N-fluoro-benzenesulfonimide [NFSI] accompanied by trapping of the β-fluoro-iminium cationic intermediate with water. The resulting N,O-hemiacetal could be oxidized using Dess-Martin periodinane, leading to an asymmetric sequence for syntheses of chiral α-fluoro-imides and optically enriched α-fluoro-ketones.

Highly torquoselective electrocyclizations of chiral 1-azatrienes are described. These 1-azatrienes contain an allylic stereocenter that is substituted with a silyl group and are derived in situ from condensation of γ-silyl-substituted enals with vinylogous amides. The ensuing stereoselective ring closures are part of a tandem sequence that constitutes an aza-[3 + 3] annulation method for constructing 1,2-dihydropyridines. Several mechanisms for the formal 1,7-hydrogen shift of these 1-azatrienes were evaluated computationally.

A computational docking study of a series of de novo structural analogs of the highly potent, non-nitrogen containing, acetylcholinesterase inhibitor (+)-arisugacin A is presented. In direct comparison to the recently reported X-ray single-crystal structure of (+)-territrem B bound hAChE, the modeling suggests that there is a unique conformational preference for the E-ring that is responsible for the superior inhibitory activity of (+)-arisugacin A against hAChE relative to (+)-territrem B, and that substitutions on the E-ring also play an important role in the protein–ligand interaction.

The ynamide functional group activates carbon–carbontriple bonds through an attached nitrogen atom that bears an electron-withdrawing group. As a result, the alkyne has both electrophilic and nucleophilic properties. Through the selection of the electron-withdrawing group attached to nitrogen, chemists can modulate the electronic properties and reactivity of ynamides, making these groups versatile synthetic building blocks. The reactions of ynamides also lead directly to nitrogen-containing products, which provides access to important structural motifs found in natural products and molecules of medicinal interest. Therefore, researchers have invested increasing time and research in the chemistry of ynamides in recent years.This Account surveys and assesses new organic transforma-tions involving ynamides developed in our laboratory and in others around the world. We showcase the synthetic power of ynamides for rapid assembly of complex molecular structures. Among the recent reports of ynamide transformations, ring-forming reactions provide a powerful tool for generating molecular complexity quickly. In addition to their synthetic utility, such reactions are mechanistically interesting. Therefore, we focus primarily on the cyclization chemistry of ynamides.This Account highlights ynamide reactions that are useful in the rapid synthesis of cyclic and polycyclic structural manifolds. We discuss the mechanisms active in the ring formations and describe representative examples that demonstrate the scope of these reactions and provide mechanistic insights. In this discussion, we feature examples of ynamide reactions involving radical cyclizations, ring-closing metathesis, transition metal and non-transition metal mediated cyclizations, cycloaddition reactions, and rearrangements. The transformations presented rapidly introduce structural complexity and include nitrogen within or in close proximity to a newly formed ring (or rings). Thus, ynamides have emerged as powerful synthons for nitrogen-containing heterocycles and nitrogen-substituted rings, and we hope this Account will promote continued interest in the chemistry of ynamides.

Electrocyclic ring opening of 4,6-fused cyclobutenamides 1 under thermal conditions leads to cis,trans-cyclooctadienones 2-E,E as transient intermediates, en route to 5,5-bicyclic products 3. Theoretical calculations predict that 4,5-fused cyclobutenamides should likewise undergo thermal ring opening, giving cis,trans-cycloheptadienones, but in this case conversion to 5,4-bicyclic products is thermodynamically disfavored, and these cyclobutenamides instead rearrange to vinyl cyclopentenones.

A highly stereoselective aza-[4 + 2] cycloaddition of chiral cyclic 2-amidodienes with N-sulfonyl aldimines is described. While this Lewis acid promoted heterocycloaddition provides an efficient strategy for constructing optically enriched isoquinuclidines, it is mechanistically intriguing. The cycloaddition favored the endo-II pathway in the absence of a viable bidentate coordination. This represents an unexpected switch from the anticipated endo-I selectivity obtained in the all-carbon cycloaddition.

A strategy for synthesizing highly functionalized cyclohepta[b]indoles through a concise (4 + 3) cycloaddition–cyclization–elimination sequence is described. The cycloaddition features nitrogen-stabilized oxyallyl cations derived from epoxidations of N-aryl-N-sulfonyl-substituted allenamides, while the cyclization and elimination employed an intramolecular Grignard addition and a one-step Chugaev process, respectively.

A concise and stereoselective synthesis of the trioxadispiroketal motif that embodies the DEF-ring of the marine macrolide (+)-spirastrellolide A is described. The synthetic approach features a sequence of cyclic acetal tethered ring-closing metathesis and Suárez oxidative cyclization, thereby constituting a viable strategy for constructing the Northern Half.

Cycloadditions involving oxyallyl intermediates typically require an electron-rich diene or alkene, but we have discovered the first examples of the cycloaddition of heteroatom-stabilized oxyallyls onto carbonyl groups. An oxazolidinone-substituted oxyallyl undergoes chemoselective (3 + 2) cycloaddition onto the carbonyl group of a tethered dienone in preference to formation of the expected (4 + 3) cycloadduct. Density functional theory calculations indicated that the (3 + 2) cycloaddition takes place through a concerted, highly asynchronous mechanism. The transition state features simultaneous interactions of the oxyallyl LUMO with the carbonyl π and lone-pair orbitals, making this reaction “hemipseudopericyclic” (halfway between purely pericyclic and purely pseudopericyclic). Further (3 + 2) cycloadditions involving tethered phenyl ketones and a tethered enone were predicted theoretically and verified experimentally.

Lewis acid promoted Diels–Alder cycloadditions of a series of de novo chiral cyclic 2-amidodienes are described. These cyclic 2-amidodienes are derived from chiral α-allyl allenamides via a sequence of E-selective 1,3-H shift and 6π-electron pericyclic ring closure. With enones serving as effective dienophiles, these cycloadditions can be highly diastereoselective depending upon the chiral amide substituent, thereby representing a facile entry to optically enriched [2.2.2]bicyclic manifolds.

Total syntheses of a series of chromane natural products that contain a cyclobutane ring are described. A unified theme in the strategy employed for all these syntheses is an oxa-[3 + 3] annulation for constructing the chromane nucleus and a stepwise cationic [2 + 2] cycloaddition for the cyclobutane formation. More importantly, the two reactions could be rendered in tandem, thereby providing an expeditious approach to this family of natural products.

A highly diastereoselective addition of lithiated ynamides to Ellman–Davis chiral imines is described. While additions of N-sulfonyl ynamides are highly stereoselective even without Lewis acids, the use of BF3–OEt2 completely reversed the stereoselectivity. In addition, oxazolidinone-substituted ynamides behaved differently and functioned better with BF3–OEt2, and the chirality of the oxazolidinone ring exerts no impact on the selectivity.

Total syntheses of putative (±)-trichodermatides B and C are described. These efficient syntheses feature the oxa-[3+3] annulation strategy, leading to B and C along with their respective C2-epimers. However, these synthetic samples are spectroscopically very different from the natural products. DFT calculations of C13 chemical shifts are conducted and the predicted values are in good agreement with those of synthetic samples, thereby questioning the accuracy of structural assignments of trichodermatides B and C.

The regioselectivities and stereoselectivities of ZnCl2-catalyzed (4 + 3) cycloadditions between chiral oxazolidinone-substituted oxyallyls and unsymmetrical disubstituted furans have been determined. The substitution pattern on the furan is found to provide a valuable tool for controlling the stereochemistry (endo-I or endo-II) of the 7-membered cycloadduct. While cycloadditions with monosubstituted furans usually favor endo-I products, from addition of the furan to the more crowded face of the oxyallyl, cycloadditions with 2,3- and 2,5-disubstituted furans instead favor the endo-II stereochemistry. Density functional theory calculations are performed to account for the selectivities. For monosubstituted furans, the crowded transition state leading to the endo-I cycloadduct is stabilized by an edge-to-face interaction between the furan and the oxazolidinone 4-Ph group, but this stabilization is overcome by steric clashing if the furan bears a 2-CO2R group or is 2,3-disubstituted.

We describe here details of our investigations into Pd-catalyzed and thermal aza-Claisen–carbocyclizations of N-allyl ynamides to prepare a variety of α,β-unsaturated cyclopentenimines. The nature of the ynamide electron-withdrawing group and β-substituent plays critical roles in the success of this tandem cascade. With N-sulfonyl ynamides, the use of palladium catalysis is required, as facile 1,3-sulfonyl shifts dominate under thermal conditions. However, since no analogous 1,3-phosphoryl shift is operational, N-phosphoryl ynamides could be used to prepare similar cyclopentenimines under thermal conditions through zwitter ionic intermediates that undergo N-promoted H-shifts. Alternatively, by employing ynamides bearing tethered carbon nucleophiles, the zwitter ionic intermediates could be intercepted, giving rise rapidly to more complex fused bi- and tricyclic scaffolds.

An imino-Nazarov cyclization using α-aryl-substituted allenamides is described. This gold(I)-catalyzed cascade is efficient and regioselective in constructing a diverse array of synthetically useful aromatic-ring fused cyclopentenamides. The success in this transformation represents a solution to the challenge in establishing an imino-Nazarov cyclization process.

An approach toward the BCD-ring of atropurpuran via a sequence of allenic 1,3-H shift, 6π-electron pericyclic ring closure, and intramolecular Diels–Alder cycloaddition of cyclic 2-amidodiene is described.

A series of carbocyclization cascades of allyl ketenimines initiated through a thermal aza-Claisen rearrangement of N-phosphoryl-N-allyl ynamides is described. Interceptions of the cationic intermediate via Meerwein–Wagner rearrangements and polyene-type cyclizations en route to fused bi- and tricyclic frameworks are featured.

Total syntheses of chelidonine and norchelidonine featuring an enamide–benzyne–[2 + 2] cycloaddition initiated cascade is described. The cascade includes a pericyclic ring-opening and intramolecular Diels–Alder reaction.

A cascade of Pd-catalyzed N-to-C allyl transfer–intramolecular ketenimine–[2 + 2] cycloadditions of N-allyl ynamides is described. This tandem sequence is highly stereoselective and the [2 + 2] cycloaddition could be rendered in a crossed or fused manner depending on alkene substitutions, leading to bridged and fused bicycloimines.

An intermolecular equivalent of Gassman’s cationic [2 + 2] cycloaddition through the use of temporary tethering is described. Notably, hydrazine and hydroxyamide proved to be robust under the acidic conditions required for the cycloaddition, leading to unique cyclobutane manifolds in a highly regio- and stereoselective manner. This development represents a rare usage of hydrazine and hydroxyamide in the capacity as temporary tethers.

Thermal dimerization of N-methyl-flindersine is reported here. This work commenced with the intent to access new Diels–Alder-type dimeric bis-pyranylquinoline alkaloids melicodenines but uncovered and characterized naturally occurring paraensidimerine F, F′and C′, as well as two new bis-quinolone derivatives.

A systematic investigation of the regioselectivities and stereoselectivities of (4 + 3) cycloadditions between unsymmetrical furans and a chiral oxazolidinone-substituted oxyallyl is presented. Cycloadditions were performed using an oxyallyl containing a (R)-4-phenyl-2-oxazolidinone auxiliary (2Ph), under either thermal or ZnCl2-catalyzed conditions. Reactions of 2Ph with 2-substituted furans gave syn cycloadducts selectively, while cycloadditions with 3-substituted furans gave selectively anti cycloadducts. The stereoselectivities were in favor of a single diastereoisomer (I) in all but one case (2-CO2R). Density functional theory calculations were performed to explain the selectivities. The results support a mechanism in which all cycloadducts are formed from the E isomer of the oxyallyl (in which the oxazolidinone C═O and oxyallyl oxygen are anti to each other) or the corresponding (E)-ZnCl2 complex. The major diastereomer is derived from addition of the furan to the more crowded face of the oxyallyl. Crowded transition states are favored because they possess a stabilizing CH−π interaction between the furan and the Ph group.

We describe here the first synthesis of N-phosphoryl ynamides featuring C- and P-chirality via copper(I)-catalyzed amidative cross-couplings between phosphoramidates and phosphordiamidates with alkynyl bromides. Also featured is a tandem aza-Claisen–hetero-[2 + 2] cycloaddition for the synthesis of N-phosphoryl azetidin-2-imines.

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 serve as a basis for the development of AD therapeutics capable of treating the symptomatic aspects of AD, while being neuroprotective with long term efficacy.

Efforts toward achieving a practical and diastereoselective intramolecular [4 + 3] cycloaddition of nitrogen-stabilized oxyallyl cations with tethered dienes are described. Epoxidation of N-sulfonyl substituted allenamides with dimethyldioxirane (DMDO) generates nitrogen-stabilized oxyallyl cations that readily undergo stereoselective [4 + 3] cycloaddition with dienes. Selectivity is found to depend on the tethering length as well as the stability of the oxyallyl cation intermediate, whether generated from N-carbamoyl- or N-sulfonyl-substituted allenamides. The use of chiral N-sulfonyl-substituted allenamides provided minimal diastereoselectivity in the cycloaddition, while high diastereoselectivity can be achieved with a stereocenter present on the tether. These studies provide further support for the synthetic utility of allenamides.

A detailed study of amidine synthesis from N-allyl-N-sulfonyl ynamides is described here. Mechanistically, this is a fascinating reaction consisting of diverging pathways that could lead to deallylation or allyl transfer depending upon the oxidation state of palladium catalysts, the nucleophilicity of amines, and the nature of the ligands. It essentially constitutes a Pd(0)-catalyzed aza-Claisen rearrangement of N-allyl ynamides, which can also be accomplished thermally. An observation of N-to-C 1,3-sulfonyl shift was made when examining these aza-Claisen rearrangements thermally. This represents a useful approach to nitrile synthesis. While attempts to render this 1,3-sulfonyl shift stereoselective failed, we uncovered another set of tandem sigmatropic rearrangements, leading to vinyl imidate formation. Collectively, this work showcases the rich array of chemistry one can discover using these ynamides.

Our struggles and ultimate success in achieving a total synthesis of phomactin A are described. Our strategy features an intramolecular oxa-[3 + 3] annulation to construct its unique ABD-tricyclic manifold. Although the synthesis would constitute a distinctly new approach with the 12-membered D-ring of phomactin A being assembled simultaneously with the 1-oxadecalin at an early stage, the ABD-tricycle represents a unique structural topology that would pose a number of unprecedented challenges. One challenge concerned elaborating this tricycle to have oxygenation at the proper carbon atoms. To overcome this, we would utilize a Kornblum–DeLaMare ring-opening of a peroxide bridge as well as a challenging late-stage 1,3-allylic alcohol transposition. Further, the structural intricacies of the ABD-tricycle were uncovered by a conformational analysis that would be critical for the C5a-homologation.

The (4 + 3) cycloadditions of oxazolidinone-substituted oxyallyls and unsymmetrically substituted furans lead to syn regioselectivity when the furan has a 2-Me or 2-COOR substituent, while anti regioselectivity is obtained with a 3-Me or 3-COOR group. DFT calculations are performed to explain the selectivities. The reactivities and regioselectivities are consistent with the ambiphilic reactivity of amino-oxyallyls with furans.

The Ficini [2 + 2] cycloaddition using N-sulfonyl-substituted ynamides is described, featuring the utility of CuCl2 and AgSbF6 as catalysts. This work represents the first successful example of ynamides participating in a thermal [2 + 2] cycloaddition with enones.

A diastereoselective 6π-electrocyclic ring closure employing halogen-substituted 3-amidotrienes via a 1,6-remote asymmetric induction is described. This new asymmetric manifold for pericyclic ring closure further underscores the significance of the allenamide chemistry.

A new torquoselective ring-closure of chiral amide-substituted 1,3,5-hexatrienes and its application in tandem with [4 + 2] cycloaddition are described. The trienes were derived via either a 1,3-H or 1,3-H−1,7-H shift of α-substituted allenamides, and the entire sequence through the [4 + 2] cycloaddition could be in tandem from allenamides.

A fascinating mechanistic study of ynamido−palladium−π-allyl complexes is described that features isolation of a unique silyl ketenimine via aza-Claisen rearrangement, which can be accompanied by an unusual thermal N-to-C 1,3-Ts shift in the formation of tertiary nitriles and a novel cyclopentenimine formation via a palladium-catalyzed aza-Rautenstrauch-type cyclization pathway.

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 rise to a series of structurally unique amido-cyclopropanes. A plausible mechanistic model is proposed revealing insights into this novel cyclopropanation process.

Covering: up to 2008

Benzyne-[2 + 2] cycloadditions with enamides are described. This effort led to the development of a highly stereoselective tandem [2 + 2] cycloaddition−pericyclic ring-opening−intramolecular-N-tethered-[4 + 2] cycloaddition for rapid assembly of nitrogen heterocycles.

Concise assignments of the C5′ stereochemistry in (+)-lepadin F and (+)-lepadin G and the absolute configuration of (+)-lepadin G via the first total syntheses of (+)-5′-epi-lepadin F, (+)-lepadin G, and (+)-5′-epi-lepadin G are described. This work represents an illustrative example in which a diastereomeric pair can possess sufficient spectroscopic difference for clear assignment despite differing only at a highly insulated acyclic stereocenter.

A total synthesis of (±)-phomactin A is described to highlight the final completion of a complex natural product target that had commenced with an intramolecular oxa-[3 + 3] annulation strategy in the construction of the ABD-tricycle. These efforts reveal structural intricacies of this ABD-tricycle with an illustrative example being the conformational analysis that was ultimately critical for the C5a-homolgation.

A regio- and stereoselective isomerization of allenamides is described, leading to preparations of de novo 2-amido-dienes and a tandem isomerization-6π-electron electrocyclic ring-closure.

A stereoselective intramolecular normal demand [4 + 2] cycloaddition of allenamides under thermal conditions without metal assistance is described. This work led to the development of a stereoselective tandem propargyl amide-isomerization−[4 + 2] cycloaddition sequence amenable for rapid assembly of complex nitrogen heterocycles.

Rh(II)-catalyzed cyclopropenations of ynamides are described. Although an actual amido−cyclopropene intermediate may not be involved, these reactions provide a facile entry to highly substituted 2-amido-furans, thereby formerly constituting a [3 + 2] cycloaddition. An application of these de novo 2-amido-furans in N-tethered intramolecular [4 + 2] cycloadditions is also illustrated, leading to dihydroindoles and tetrahydroquinolines.

A detailed account of Simmons–Smith cyclopropanations of allenamides en route to amido-spiro[2.2]pentanes is described here. While the diastereoselectivity was low when using unsubstituted allenamides, the reaction is overall efficient and general, representing the most direct synthesis of both chemically and biologically interesting amido-spiro[2.2]pentane systems. With α-substituted allenamides, while the diastereoselectivity could be improved significantly based on a series of conformational analyses, both mono- and bis-cyclopropanation products were observed. Consequently, several structurally intriguing amido-methylene cyclopropanes could also be prepared.

The feasibility of trapping the vinyl copper intermediate generated in situ from azide-[3 + 2] cycloadditions and viability of employing these triazoles as unique templates for ring-closing metathesis are described here; this work effectively combines the two powerful reactions for the first time to construct various de novo fused and bridged triazoles that are otherwise not trivial to synthesize.

An unexpected stereoselective anomeric substitution with carbamates promoted by HNTf2 is described here. Our experiments suggest that the observed diastereoselectivity is a result of thermodynamic equilibration of protonated N-acyl aminals.

Tandem azidination– and hydroazidination–Huisgen [3 + 2] cycloadditions of ynamides are described here. These processes are regioselective and chemoselective, leading to the synthesis of chiral amide-substituted triazoles.

The feasibility of trapping the vinyl copper intermediate generated in situ from azide-[3 + 2] cycloadditions and viability of employing these triazoles as unique templates for ring-closing metathesis are described here; this work effectively combines the two powerful reactions for the first time to construct various de novo fused and bridged triazoles that are otherwise not trivial to synthesize.

An unexpected stereoselective anomeric substitution with carbamates promoted by HNTf2 is described here. Our experiments suggest that the observed diastereoselectivity is a result of thermodynamic equilibration of protonated N-acyl aminals.

A detailed account of Simmons–Smith cyclopropanations of allenamides en route to amido-spiro[2.2]pentanes is described here. While the diastereoselectivity was low when using unsubstituted allenamides, the reaction is overall efficient and general, representing the most direct synthesis of both chemically and biologically interesting amido-spiro[2.2]pentane systems. With α-substituted allenamides, while the diastereoselectivity could be improved significantly based on a series of conformational analyses, both mono- and bis-cyclopropanation products were observed. Consequently, several structurally intriguing amido-methylene cyclopropanes could also be prepared.