Diastereoselective Diels-Alder Research Articles

Nickel-Catalyzed Enantioselective Synthesis of Dienyl Sulfoxide.

Sulfoxides are widely used in the pharmaceutical industry and as ligands in asymmetric catalysis. However, the efficient asymmetric synthesis of this structural motif remains limited. In this study, we disclosed a Ni-catalyzed enantioconvergent reaction that utilizes both racemic allenyl carbonates and β-sulfinyl esters. Our method employs cheap and more sustainable Ni(II) as a precatalyst and successfully overcomes the challenging poisoning effect and instability of sulfenate generated in situ. This enables the synthesis of a series of dienyl sulfoxides with enantioselectivity of up to 98 % ee. The product exhibits tremendous potential in various applications, including diastereoselective Diels-Alder reactions, coordination with transition metals, and incorporation into medicinal compounds, among others. Using a combination of experimental and computational methods, we have uncovered an interesting associated outersphere mechanism that contrasts with conventional mechanisms commonly observed in asymmetric transition metal catalysis.

Enantioselective Synthesis of Cassane‐Type Furanoditerpenoids: Total Synthesis of Sucutiniranes C and D

The first enantioselective total synthesis of cassane‐type furanoditerpenoids featuring an aromatic C ring and a substituted B ring is presented. The strategy employed relied on diastereoselective Diels–Alder (DA) reaction of an enantiomerically pure 1,3,3‐trisubstituted‐2‐vinyl‐cyclohexene (sterically demanding diene). It was secured in > 99 % ee through elaboration of enzymatically resolved 3‐ethoxy‐6‐(hydroxymethyl)‐6‐methyl‐cyclohex‐2‐en‐1‐one. Employing hexafluoro‐2‐propanol (HFIP) as the solvent, its DA cycloaddition onto benzo[b]furan‐4,7‐dione proceeded with exquisite endo‐selectivity under ambient temperature and pressure. Subsequent diastereo‐ and regio‐selective methyl Grignard addition provided a pivotal intermediate featuring the complete vouacapane framework. Its versatility and intriguing reactivity were demonstrated by conversion to sucutiniranes C and D.

Diene-Transmissive Enantioselective Diels-Alder Reactions and Sequences Involving Substituted Dendralenes.

Readily available and stable substituted [3]dendralenes undergo highly chemo-, regio-, diastereo-, and enantioselective organocatalyzed Diels-Alder reactions with acrolein to form enantiomerically enriched cycloadducts. These monocycloadducts carry semicyclic dienes that undergo a second, substrate-controlled diastereoselective Diels-Alder reaction with a different dienophile to form 2-fold cycloadducts. Overall, annulated, functional group rich, chiral Δ1(9)-octalin building blocks are accessed in one-pot operations that significantly extend the preparative value of diene-transmissive Diels-Alder sequences since they offer products of regio- and stereochemistry complementary to those generated from the parent, unsubstituted [3]dendralene.

Asymmetric Synthesis of the Tricyclooctane Core of Trachylobane Natural Products and Related Terpenoids.

Enantioselective synthesis of a highly versatile building block en route to trachylobanes and related terpenoids is presented. The synthesis features diastereoselective Diels-Alder cycloaddition reaction, a cyclopropanation/homoquadricyclane rearrangement cascade, and palladium-catalyzed C-H acetoxylation. The targeted tricyclooctane was obtained in 20% yield over 8 steps and in 95% ee. The ketone and alcohol functional groups serve as handles for further elaboration.

Enantio- and Diastereoselective Two-Pot Synthesis of Isoquinuclidines from Glutaraldehyde and N-Aryl Imines with DFT Calculations.

A pot-economic method for the enantio- and diastereoselective synthesis of a [2.2.2] azabicyclic isoquinuclidine system is developed. This protocol involves the proline-catalyzed direct Mannich reaction-cyclization/IBX-mediated site-selective oxidation/NaBH4-reduction sequence between glutaraldehyde and imines to generate in situ chiral 1,2-DHPs, followed by the diastereoselective Diels-Alder reaction with N-aryl maleimides furnishing isoquinuclidines in overall five steps. A variety of isoquinuclidines having five-contiguous chiral centers, including an all-carbon quaternary, were prepared with high yields (up to 78%) and excellent stereoselectivity (>50:1 dr, and up to >99:1 er). DFT calculations support the observed high stereoselective reaction outcome.

Biomimetic Syntheses of (±)-Isopalhinine A, (±)-Palhinine A, and (±)-Palhinine D.

The first total synthesis of isopalhinine A, as well as unified syntheses of palhinine A and palhinine D, were successfully accomplished by means of a biomimetic strategy that proceeds through a bioinspired 5/6/6/9 tetracyclic intermediate, which mimics the amino ketone form of palhinine D. An early-stage direct SN 2 cyclization to construct the nine-membered azonane ring minimized the transannular strain that would otherwise be increased by the twisted nature of the isotwistane skeleton. Then, a diastereoselective Diels-Alder reaction of a masked ortho-benzoquinone using the nine-membered ring as a steric shielding group furnished a functionalized 6/6/9 tricyclic skeleton and established the desired stereochemistry at the C3, C7, C12, and C15 positions in one step. A thiol-mediated acyl radical cyclization gave the bioinspired intermediate bearing three differentiated oxygen-containing functional groups, from which all three total syntheses could be completed in either two or three additional steps.

Synthesis of Allahabadolactone A

A synthesis of allahabadolactone A is described employing diastereoselective Diels-Alder and selenocyclization reactions, starting from (R)-citronellal and propylene oxide. The Diels-Alder substrate is built up in an efficient manner by rhodium-catalyzed alkyne hydroboration and palladium-catalyzed coupling reactions of E-1,2-dichloroethene. It is observed that the Diels-Alder reaction only displays high diastereoselectivity when the diene bears an additional alkene substituent but not an alkyne substituent.

Total synthesis of aspeverin via an iodine(III)-mediated oxidative cyclization.

The first total synthesis of aspeverin, a prenylated indole alkaloid isolated from Aspergillus versicolor in 2013, is described. Key steps utilized to assemble the core structure of the target include a highly diastereoselective Diels-Alder reaction, a Curtius rearrangement, and a unique strategy for installation of the geminal dimethyl group. A novel iodine(III)-initiated cyclization was then used to install the bicyclic urethane linkage distinctive to the natural product.

From Highly Enantioselective Catalytic Reaction of 1,3-Diynes with Aldehydes to Facile Asymmetric Synthesis of Polycyclic Compounds

(S)-1,1'-Binaphth-2-ol (BINOL) in combination with ZnEt(2), Ti(O(i)Pr)(4), and biscyclohexylamine was found to catalyze the highly enantioselective (83-95% ee) addition of various 1,3-diynes to aldehydes of diverse structures. This method provides a convenient pathway to generate a number of optically active dienediynes as the acyclic precursors to polycyclic compounds. The chiral dienediynes undergo highly chemoselective Pauson-Khand (PK) cycloaddition in benzaldehyde by using [Rh(cod)Cl](2) as the catalyst in the presence of rac-BINAP. High diastereoselectivity (up to >20:1) has also been achieved with the chiral dienediyne substrates containing a bulky substituent adjacent to the chiral center. In the presence of the Grubbs II catalyst, ring-closing enyne metathesis of the PK cycloaddition products led to the formation of the desired 5,5,7- and 5,5,8-fused tricyclic compounds. Further highly diastereoselective Diels-Alder reaction of a 5,5,7-tricyclic compound with maleic anhydride produced a 5,5,7,6-polycyclic product. The asymmetric synthesis of polycyclic compounds from optically active dienediynes has established a novel and efficient synthetic route to the structural framework of many biologically significant molecules.

Effect of Counterion Structure on Rates and Diastereoselectivities in α,β-Unsaturated Iminium-Ion Diels–Alder Reactions

The use of cyclic α,β-unsaturated iminium-ion dienophiles is documented in two highly diastereoselective Diels-Alder (DA) reactions. The dienophilic counterion was found to have a significant effect on reactivity.

Optically Pure Fullerodendron Formed by Diastereoselective Diels-Alder Reaction

not Available.

Enantioselective Synthesis of 2,2,5-Tri- and 2,2,5,5-Tetrasubstituted Tetrahydrofurans via [4 + 2] Cycloaddition and Ring-Opening Cross-Metathesis

A chiral vinyl sulfoxide has been developed that undergoes highly diastereoselective Diels-Alder cycloadditions with various substituted furans in excellent yield. The cycloadducts can be stereoselectively transformed into 2,2,5-tri- and 2,2,5,5-tetrasubstituted tetrahydrofurans, which are structural subunits of many natural products, via regioselective ring-opening metathesis/cross-metathesis or oxidative cleavage/refunctionalization.

Synthesis of 4-Aryl- and 4-Alkyl-2-silyl-1,3-butadienes and Their Diels−Alder/Cross-Coupling Reactions

An ene-yne cross methasis of silyl-substituted alkynes and alkenes has been developed as a route to 4-aryl- and 4-alkyl-2-silyl-substituted 1,3-dienes. The dienes prepared were used to affect highly diastereoselective Diels-Alder reactions and then the silicon-substituted Diels-Alder cycloadducts were used in Hiyama cross-coupling reactions. The cross-coupling reactions enable these silicon dienes to be used as synthons for a variety of other dienes one might prepare and need access to. Two of the silicon-substituted Diels-Alder cycloadducts and one of the Hiyama cross-coupling products were also characterized by X-ray crystallography.

Synthesis of enantiopure trans‐N‐Boc‐3‐aminobicyclo[2.2.2]octane‐2‐carboxylic acids and their bicyclic 1,3‐amino alcohol derivatives via the [4+2] cycloaddition of 1,3‐cyclohexadiene to a chiral β‐nitroacrylate

The chiral β-nitroacrylate 2 derived from the (R)- or (S)-4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl) benzoic acid 1 acts as a reactive dienophile in a diastereoselective Diels-Alder reaction with 1,3-cyclohexadiene. The major cycloadducts have been isolated and transformed into enantiopure trans(2S,3S)- or (2R,3R)-N-Boc-3-aminobicyclic[2,2,2]octane-2-carboxylic acids 5. The trans-(2S,3S)- or (2R,3R)-N-Boc 3-(hydoxymethyl)-2-aminobicyclic[2,2,2]octane 6 derivatives were also obtained.

ChemInform Abstract: Diastereoselective Intramolecular Diels-Alder Reaction of N- Alkoxycarbonyl-1-aza-1,3-butadienes and a Total Synthesis of the Piperidine Alkaloid, (.+-.)-Sedridine.

Abstract Total synthesis of (±)-sedridine, the piperidine alkaloid, was accomplished on the basis of diastereoselective intramolecular Diels-Alder reaction of the ψ′,ω′-unsaturated N-alkoxycarbonyl-1-aza-1,3-butadiene generated in situ from N-trimethylsilyl-1-aza-butadiene and the chloroformate of 4-penten-2-ol.

ChemInform Abstract: Diastereoselective Diels-Alder Reactions with Chiral Sulfinyl Derivatives as Dienophiles Under High Pressure.

Abstract Using the high pressure technique, asymmetric Diels-Alder reaction utilizing chiral 2-nitro-1-sulfinylolefins and dienes proceeded smoothly to give highly functionalized cyclohexene derivatives with satisfactory chemical yield and high diastereomeric excess.

ChemInform Abstract: Asymmetric Diels-Alder Reaction of a Chiral Azlactone.

Abstract The chiral Z-azlactone derived from 1,2-O-isopropylidene-D-glyceraldehyde underwent facial diastereoselective Diels-Alder reaction with cyclopentadiene. Catalyst and temperature dependence of the product ratio is described. The absolute configuration of the major compound was established by an X-ray crystallogrophic analysis.

ChemInform Abstract: Stereoselectivities of Diels-Alder Cycloadditions of π-Facially Nonequivalent Dienes to MTAD, PTAD, and N-Methylmaleimide: A Theoretical Study.

Abstract 1,2,3,4,9,9-hexachloro-1α,4α,4aα,8aβ-tetrahydro-1,4-methanonaphthalene (1) and 1,2,3,4,9,9-hexachloro-1α,4α,6,7-tetrahydro-1,4-methanonaphthalene (2) undergo π-facially diastereoselective Diels-Alder reactions with 4-methyl- and 4-phenyl-1,2,4-triazoline-3,5-dione [MTAD and PTAD, respectively] and with N-methylmaleimide (NMM). In contrast with the results of AM1 calculations, those obtained via ab initio calculations performed at the HF/3-21G∗ level of theory predict that the computed Diels-Alder transition states are synchronous in all cases studied. Furthermore, these computational results account quantitatively for: (i) the observed π-facial selectivities of the various Diels-Alder reactions studied, (ii) the observed relative lack of dienophilic reactivity of NMM vis-a-vis MTAD and PTAD, and (ii) the observed enhanced diene reactivity of 1 vs. 2 in the reactions studied.

ChemInform Abstract: Asymmetric Hetero Diels-Alder Reaction of Homochiral Thiabutadienes, 3-(Arylmethylene)thiocamphors.

Abstract The highly diastereoselective hetero Diels-Alder reactions of homochiral camphor-derived thiabutadienes to afford novel, optically active bornene ring-fused dihydrothiopyrans are described.

(1R)-(+)-Camphor and Acetone Derived α′-Hydroxy Enones in Asymmetric Diels−Alder Reaction: Catalytic Activation by Lewis and Brønsted Acids, Substrate Scope, Applications in Syntheses, and Mechanistic Studies

The Diels-Alder reaction constitutes one of the most powerful and convergent C-C bond-forming transformations and continues to be the privileged route to access cyclohexene substructures, which are widespread within natural products and bioactive constituents. Over the recent years, asymmetric catalytic Diels-Alder methodologies have experienced a tremendous advance, but still inherently difficult diene-dienophile combinations prevail, such as those involving dienes less reactive than cyclopentadiene or dienophiles like beta-substituted acrylates and equivalents. Here the main features of alpha'-hydroxy enones as reaction partners of the Diels-Alder reaction are shown, with especial focus on their potentials and limitations in solving the above difficult cases. Alpha'-hydroxy enones are able to bind reversibly to both Lewis acids and Brønsted acids, forming 1,4-coordinated species that are shown to efficiently engage in these inherently difficult Diels-Alder reactions. On these bases, a convenient control of the reaction stereocontrol can be achieved using a camphor-derived chiral alpha'-hydroxy enone model (substrate-controlled asymmetric induction) and either Lewis acid or Brønsted acid catalysis. Complementing this approach, highly enantio- and diastereoselective Diels-Alder reactions can also be carried out by using simple achiral alpha'-hydroxy enones in combination with Evans' chiral Cu(II)-BOX complexes (catalyst-controlled asymmetric induction). Of importance, alpha'-hydroxy enones showed improved reactivity profiles and levels of stereoselectivity (endo/exo and facial selectivity) as compared with other prototypical dienophiles in the reactions involving dienes less reactive than cyclopentadiene. A rationale of some of these results is provided based on both kinetic experiments and quantum calculations. Thus, kinetic measurements of Brønsted acid promoted Diels-Alder reactions of alpha'-hydroxy enones show a first-order rate with respect to both enone and Brønsted acid promoter. Quantum calculations also support this trend and provide a rational explanation of the observed stereochemical outcome of the reactions. Finally, these fundamental studies are complemented with applications in natural products synthesis. More specifically, a nonracemic synthesis of (-)-nicolaioidesin C is described wherein a Brønsted acid catalyzed Diels-Alder reaction involving a alpha'-hydroxy enone substrate is the key step toward the hitherto challenging trisubstituted cyclohexene subunit.