Diels–Alder cycloadditions of strained azacyclic allenes

Abstract

For over a century, the structures and reactivities of strained organic compounds have captivated the chemical community. Whereas triple-bond-containing strained intermediates have been well studied, cyclic allenes have received far less attention. Additionally, studies of cyclic allenes that bear heteroatoms in the ring are scarce. We report an experimental and computational study of azacyclic allenes, which features syntheses of stable allene precursors, the mild generation and Diels-Alder trapping of the desired cyclic allenes, and explanations of the observed regio- and diastereoselectivities. Furthermore, we show that stereochemical information can be transferred from an enantioenriched silyl triflate starting material to a Diels-Alder cycloadduct by way of a stereochemically defined azacyclic allene intermediate. These studies demonstrate that heteroatom-containing cyclic allenes, despite previously being overlooked as valuable synthetic intermediates, may be harnessed for the construction of complex molecular scaffolds bearing multiple stereogenic centres.

Cycloadditions of Oxacyclic Allenes and a Catalytic Asymmetric Entryway to Enantioenriched Cyclic Allenes

“…[17] As noted earlier,o ne of the most exciting opportunities regarding cyclic allene chemistry is the possibility of intercepting enantioenriched allenes for the synthesis of enantioenriched cycloadducts.I naseminal study,C hristl and coworkers generated 1-phenyl-1,2-cyclohexadiene in enantioenriched form, as judged by the formation of an enantioenriched cycloadduct, albeit in low yield, likely owing to the necessary use of organolithium reagents. [16] However,i nb oth cases,t he key substrates were only accessible through chiral separation technologies.Acatalytic asymmetric strategy to access enantioenriched cyclic allene precursors has not been reported. [16] However,i nb oth cases,t he key substrates were only accessible through chiral separation technologies.Acatalytic asymmetric strategy to access enantioenriched cyclic allene precursors has not been reported.…”

“…[10a,c,d, 23] TheC =Cb ond length of the allene is 1.32 ,w hich is only slightly longer than the C = Cb ond length in al inear allene. [16] Furthermore,t he internal angle at the central allene carbon is 1338 8,w hich is asignificant deviation from the typical internal angle of 1808 8 seen in linear allenes.T he allene p orbitals in 8 are not perfectly orthogonal, resulting in the CÀHb onds being twisted out of plane (i.e., 388 8 and 418 8). Thus, 8 is inherently chiral, in am anner analogous to linear allenes.T he ground state geometry deviates from C2 symmetry because the molecule adopts an envelope shape;inversion of the envelope requires only 0.8 kcal mol À1 .Interestingly,oxacyclicallene 8 is calculated to possess 31.0 kcal mol À1 of strain energy,which is nearly 4kcal mol À1 more than the azacyclic variant we previously reported.…”

“…[16] Furthermore,t he internal angle at the central allene carbon is 1338 8,w hich is asignificant deviation from the typical internal angle of 1808 8 seen in linear allenes.T he allene p orbitals in 8 are not perfectly orthogonal, resulting in the CÀHb onds being twisted out of plane (i.e., 388 8 and 418 8). [16] This difference can be attributed to the smaller atomic radius of oxygen and the shorter C À O bond length relative to the C À Nbond length in the azacyclic variant. [16] This difference can be attributed to the smaller atomic radius of oxygen and the shorter C À O bond length relative to the C À Nbond length in the azacyclic variant.…”

“…Early efforts in this field relied on harsh reaction conditions; [14,15] however, we recently demonstrated that azacyclic allenes 4 ( Figure 1) can be accessed using mild reaction conditions.M oreover,b yu sing chiral separation technology, enantioenriched 4 was intercepted (R = Cbz, R' = H, R'' = Me), and its stereospecific trapping allowed for au nique approach to access enantioenriched cycloadducts. [16] Given the potential for heterocyclic allenes to provide af acile means to rapidly assemble stereochemically rich scaffolds, [16] we wondered whether oxacyclica llenes 6 could be employed efficiently in cycloadditions to access oxygencontaining heterocycles. [17] Oxygenated heterocycles are often seen in natural products and drugs [18][19][20][21] and are known bioisosteres for their nitrogen-and sulfur-containing counterparts.…”

“…[12,24] Bromoketone 9 (commercially available or readily synthesized from tetrahydro-4-pyranone) was converted into triethylsilyl enol ether 10 upon treatment with DABCO and TESCl. [16] Our three-step scalable [26] synthesis of 12 provides anew strategy to synthesize asilyl ketones en route to cyclic allene precursors.Currently, asilyl ketones are most commonly prepared by 1,4-reduction of the corresponding a,b-unsaturated ketones. [16] Our three-step scalable [26] synthesis of 12 provides anew strategy to synthesize asilyl ketones en route to cyclic allene precursors.Currently, asilyl ketones are most commonly prepared by 1,4-reduction of the corresponding a,b-unsaturated ketones.…”