Desymmetrization Strategy Research Articles

Catalytic Desymmetrization by C-H Functionalization as a Solution to the Chiral Methyl Problem.

Breaking the mirror (plane): A palladium-catalyzed desymmetrization strategy via β C-H activation provides an alternate approach for solving the age-old challenge of introducing an α-methyl stereocenter to a molecule.

The Construction of Chiral Fused Azabicycles Using a Pd-Catalyzed Allylic Substitution Cascade and Asymmetric Desymmetrization Strategy.

A highly enantioselective Pd-catalyzed asymmetric allylic substitution cascade of cyclic N-sulfonylimines with an accompanying asymmetric desymmetrization has been developed for the construction of fused tetrahydroindole derivatives bearing two chiral centers. Mechanistic studies confirmed that the cascade reaction proceeds by initial allylic alkylation and subsequent allylic amination. The first alkylation is a chirality-control step and represents an asymmetric desymmetrization of cis-cyclic allyl diacetates. The reaction has been performed on a gram scale, and the desired products can take part in several transformations.

Copper‐Catalyzed Intramolecular Desymmetric Aryl CO Coupling for the Enantioselective Construction of Chiral Dihydrobenzofurans and Dihydrobenzopyrans

AbstractO‐Heterocyclic structures such as 2,3‐dihydrobenzofurans are key motifs in many natural compounds and pharmaceuticals. Enantioselective formation of chiral dihydrobenzofurans and analogues was achieved through a copper‐catalyzed desymmetrization strategy with a chiral cyclic 1,2‐diamine. A broad range of substrates are compatible with this CuI‐diamine catalytic system and afford the desired coupling products with chiral tertiary or quaternary carbon centers in high yields and good to excellent enantioselectivities under mild conditions.

Copper-Catalyzed Intramolecular Desymmetric Aryl C-O Coupling for the Enantioselective Construction of Chiral Dihydrobenzofurans and Dihydrobenzopyrans.

O-Heterocyclic structures such as 2,3-dihydrobenzofurans are key motifs in many natural compounds and pharmaceuticals. Enantioselective formation of chiral dihydrobenzofurans and analogues was achieved through a copper-catalyzed desymmetrization strategy with a chiral cyclic 1,2-diamine. A broad range of substrates are compatible with this Cu(I)-diamine catalytic system and afford the desired coupling products with chiral tertiary or quaternary carbon centers in high yields and good to excellent enantioselectivities under mild conditions.

Total synthesis of clostrubin.

Clostrubin is a potent antibiotic against methicillin- and vancomycin-resistant bacteria that was isolated from a strictly anaerobic bacterium Clostridium beijerinckii in 2014. This polyphenol possesses a fully substituted arene moiety on its pentacyclic scaffold, which poses a considerable challenge for chemical synthesis. Here we report the first total synthesis of clostrubin in nine steps (the longest linear sequence). A desymmetrization strategy is exploited based on the inherent structural feature of the natural product. Barton–Kellogg olefination forges the two segments together to form a tetrasubstituted alkene. A photo-induced 6π electrocyclization followed by spontaneous aromatization constructs the hexasubstituted B ring at a late stage. In total, 200 mg of clostrubin are delivered through this approach.

Pd-catalyzed asymmetric intramolecular aryl C-O bond formation with SDP(O) ligand: enantioselective synthesis of (2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanols.

Employing a chiral spirodiphosphine monoxide ligand with 1,1'-spirobiindane backbone (SDP(O)), a desymmetrization strategy of Pd-catalyzed intramolecular asymmetric aryl C-O coupling of 2-(2-halophenoxy)propane-1,3-diols, was developed. The SDP(O) ligand shows much better results than its SDP counterpart. The protocol provides an efficient and highly enantioselective method for the synthesis of 2-hydroxymethyl-1,4-benzodioxanes. Density functional theory studies provide a model that accounts for the origin of the enantioselectivity.

Copper-catalyzed enantioselective intramolecular aryl C-N coupling: synthesis of enantioenriched 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamides via an asymmetric desymmetrization strategy.

The differentiation of two nucleophilic amide groups in malonamides through a copper-catalyzed enantioselective intramolecular aryl C-N coupling reaction is demonstrated based on an asymmetric desymmetrization strategy. Such a method afforded enantioenriched 2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamides in high yields and moderate to good enantioselectivity.

Enantioselective formation of cyano-bearing all-carbon quaternary stereocenters: desymmetrization by copper-catalyzed N-arylation.

The enantioselective construction of all-carbon quaternary stereocenters is one of the most challenging fields in asymmetric synthesis. An asymmetric desymmetrization strategy offers an indirect and efficient method for the formation of all-carbon stereocenters. An enantioselective formation of cyano-bearing all-carbon quaternary stereocenters in 1,2,3,4,-tetrahydroquinolines and 2,3,4,5-tetrahydro-1H-benzo[b]azepines by copper-catalyzed desymmetric N-arylation is demonstrated. The cyano group at the prochiral center plays a key role for the high enantioselectivity and works as an important functional group for further transformations. DFT studies provide a model which successfully accounts for the origin of enantioselectivity.

Studies in symmetry-driven synthesis of ryanodol: application of nucleophilic alkynylation for regio- and stereoselective desymmetrization

We developed a simple and novel desymmetrization strategy toward the total synthesis of ryanodol. The advanced intermediate 1 with six contiguous tetrasubstituted carbons was synthesized from the previously reported 3 by employing two key nucleophilic reactions. The first nucleophilic reaction to C2-symmetric tetraketone 2 installed the C6-tetrasubstituted carbon in a regio- and stereoselective fashion, leading to desymmetrized mono-alkynylated 8 without forming C2-symmetric bis-alkynylated 9. The second addition to triketone 8 also proceeded regio- and stereoselectively to construct the C2-tetrasubstituted stereocenter of 10.

An iterative, facile stereoselective synthesis of C1-C11 fragment of borrelidin via enzymatic desymmetrization strategy

A highly stereoselective and general method for the synthesis of the C1-C11 fragment of borrelidin has been achieved. The main feature of our synthetic route is enzymatic desymmetrization to create two methyl bearing chiral centres, use of Evans auxiliary to introduce two other methyl groups and creation of C3 stereocentre by regioselective opening of an epoxide arising from Sharpless epoxidation protocol. The synthesis of the C1-C11 subunit was achieved in gram scale by a linear synthetic sequence in an overall yield of 18.4%.

Synthesis of the C1–C15 fragment of elaiolide

The synthesis of the C1–C15 fragment of elaiolide was achieved by successfully utilizing the desymmetrization strategy, zirconium catalyzed C–C bond formation and double stereodifferentiating aldol reactions.

Development and Challenges in Copper-Catalyzed Asymmetric Ullmann-Type Coupling Reactions

Ullmann-type coupling is one of the most powerful methods for the formation of aryl C–C, C–N, and C–O bonds. Yet asymmetric Ullmann coupling has received little attention because of the great challenges in both ligand and reaction designs. The success of the first catalytic enantioselective intramolecular Ullmann C–N coupling reaction through an asymmetric desymmetrization strategy offers a new way to develop enantioselective variants of such reactions. This paper addresses the importance of the desymmetrization strategy in Ullmann-type couplings and outlines some future directions in this field.

Construction of Contiguous Tetrasubstituted Carbon Stereocenters by Intramolecular Crossed Benzoin Reactions Catalyzed by N‐Heterocyclic Carbene (NHC) Organocatalyst

AbstractBicyclic compounds with two contiguous tetrasubstituted carbon stereocenters at bridgehead positions were synthesized by N‐heterocyclic carbene (NHC)‐catalyzed intramolecular crossed benzoin reactions of symmetrical compounds. This desymmetrization strategy was applied to asymmetric synthesis with chiral NHC organocatalysts. Transition‐state models were proposed to explain the enantioselectivity. A tricyclic compound with three contiguous tetrasubstituted carbon stereocenters was synthesized by a stepwise strategy. The molecular structure and absolute configuration of the (+)‐enantiomer of this tricyclic compound were determined by X‐ray crystallographic analysis.

Stereoselective synthesis of methyl branched chiral deoxypropionate units: a new route for synthesis of insect pheromone (−)-lardolure and (2R,4R,6R,8R) 2,4,6,8-tetramethylundecanoic acid

(−)-Lardolure and (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic acid have been synthesized via lipase catalyzed desymmetrization strategy to create two methyl chiral centers. Other key steps involved in the synthesis are Wittig reaction, Evan’s asymmetric alkylation, Grignard reaction, Pd-catalyzed isomerization of primary allylic alcohol to corresponding saturated aldehyde, and PhNO/proline catalyzed MacMillan α-hydroxylation.

Enantioselective Total Synthesis of (+)- and (-)-Vittatalactone

The asymmetric total synthesis of both enantiomers of (+)- and (-)-vittatalactone has been achieved using a desymmetrization strategy to create three methyl chiral centers. The key steps in these total syntheses are Myers asymmetric alkylation, copper-­catalyzed alkylation, 2,2,6,6-tetramethyl-1-piperidinyloxyl-(diacet­oxyiodo)benzene [TEMPO-PhI(OAc2)] promoted oxidation and p-toluenesulfonyl chloride mediated lactonization. The products are obtained in good overall yields employing linear synthetic sequences.

Synthesis of (4R,6S,7R)-7-hydroxy-4,6-dimethyl-3-nonanone and (3R,5S,6R)-6-hydroxy-3,5-dimethyl-2-octanone

The synthesis of (4R,6S,7R)-7-hydroxy-4,6-dimethyl-3-nonanone and (3R,5S,6R)-6-hydroxy-3,5-dimethyl-2-octanone is described as their acetates using a desymmetrization strategy as well as an Evans syn aldol strategy.

Studies towards the total synthesis of (−)-callystatin A

The synthesis of C1–C12 and C13–C22 fragments of (−)-callystatin A is accomplished employing desymmetrization strategy for the creation of five chiral centres of the polypropionate fragment and application of cross-metathesis (CM) reaction for the first time for this molecule.

Stereoselective Synthesis of the C1-C11 Tetrahydropyran Core Unit of (+)-Zincophorin

Synthesis of the C1-C11 tetrahydropyran core unit of (+)-zincophorin using a desymmetrization strategy is reported. Horner­-Wadsworth-Emmons (HWE) and Mitsunobu cyclization reactions are the key transformations.

Desymmetrization of (R,R)-Hexa-1,5-diene-3,4-diol via Monofunctionalization and Rhodium-Catalyzed Allylic Substitution

A sequence of selective monoprotection and Rh-catalyzed enantioconservative allylic substitution is established as a desymmetrization strategy for C(2)-symmetric hexa-1,5-diene-3,4-diol. A benzyl protecting group and ethyl carbonate as a leaving group emerged as the most useful combination with respect to reproducibility, stereoselectivity, and yield. A remarkable deviation from the normally observed regiospecificity of Rh-catalyzed allylic alkylations was observed for unprotected carbonates. In this case, a linear, rather than a branched alkylation product was obtained exclusively.

Enantioselective Rhodium‐Catalyzed Allylic CH Activation for the Addition to Conjugated Dienes

Transition-metal-catalyzed C H activation has the potential to streamline organic synthesis because it can provide novel disconnections in the retrosynthetic analysis of a target molecule. A synthetically useful C H activation method should be diastereoselective and more importantly, enantioselective, if one or more stereocenter is generated in this process. Although significant progress has been made in transition-metal-catalyzed C H activation reactions, the progress of enantioselective C H activation and subsequent C C bond formations through metal insertion has lagged behind. Several impressive examples in this area have emerged. For example, the research groups of Mikami, Murai, and Bergman and Ellman have all reported pioneering work on the enantioselective coupling reactions of vinylic and aromatic C H bonds with alkenes. Enantioselective hydroacylation reactions of alkenes and ketones through the cleavage of an acyl C H bond have also been reported. Yu and co-workers have developed an elegant palladium(II)-catalyzed enantioselective coupling reaction of aromatic C H bonds with boronic acids and styrenes using a desymmetrization strategy. By using a similar approach, Albicker and Cramer achieved enantioselective palladiumcatalyzed direct arylations. Despite these notable advances in the enantioselective sp C H activation reactions, the enantioselective sp C H activation/C C bond formation through the intermediate formation of carbon–metal bonds remains elusive. The lack of progress may be attributed to the limited methods for sp C H activation, the harsh reaction conditions required for the cleavage of an sp C H bond, and the paucity of ligands available for enantioselective C H activations. One example of an enantioselective sp C H activation/C C bond formation came from Yu and coworkers, who reported a palladium(II)-catalyzed pyridinedirected reaction that occurred with a promising 37% ee. For enantioselective allylic C H oxidations, White and coworkers achieved a 63% ee for the palladium(II)-catalyzed allylic oxygenation of terminal olefins. Even though it is challenging to achieve asymmetric sp C H activation with high enantioselectivity, considering its synthetic importance, continuous endeavors to meet such a challenge are required. Recently, our research group has developed a conjugateddiene-assisted, rhodium-catalyzed addition of allylic C H bonds to conjugated dienes to furnish multifunctional tetrahydropyrrole, tetrahydrofuran, and cyclopentane compounds. The two new stereogenic centers in the final products had good to excellent diastereoselectivity (see the reaction shown in Table 1). We were eager to develop an asymmetric version of this allylic C H activation/C C bond formation reaction, which would provide efficient and easy access to the multifunctional chiral tetrahydropyrrole, tetrahydrofuran, and cyclopentane compounds. The two challenges for this enantioselective reaction are the asymmetric allylic C H activation/C C bond formation, and the asymmetric synthesis of a quaternary carbon center, which has been a longstanding challenge in organic synthesis. Herein, we report the first example of a highly enantioselective allylic C H activation/ C C bond formation reaction through metal insertion. We show that the present reaction provides an easy route to the asymmetric synthesis of two adjacent sp carbon centers, one of which is a quaternary carbon center. Our study began with the identification of an effective chiral ligand for the target reaction (Table 1). We found that chelating diphosphines such as binap inhibited the reaction, therefore we focused our effort on screening themonodentate ligands. Chiral phosphoramidites, which are a class of easily accessible and highly modulable ligands, were tested. Fortunately, the application of phosphoramidite ligandAunder our previous reaction conditions gave a high yield and a promising ee value (Table 1, entry 1). This encouraging result led us to further optimize the reaction conditions. We observed that changing the silver source from AbSbF6 to AgOTf improved the enantioselectivity (entry 2). Better enantioselectivity was obtained when DME or benzene were used as the solvent (entries 3 and 4, respectively) compared with DCE (entry 2), although the reaction in benzene was slower. The use of [{Rh(coe)2Cl}2] as a catalyst precursor provided a faster reaction rate (entry 5), presumably as a result of the faster dissociation of the coe ligand from the catalyst precursor. Next, we tested a variety of phosphoramidite ligands. A slight increase of the steric bulk on the nitrogen center improved the ee value, for example, phosphoramidites bearing diethyl amine (B), diisopropyl amine (C), piperidine (D), and morpholine (E) gave 90%, 89%, 87%, and 90% ee, respec[*] Q. Li, Prof. Dr. Z.-X. Yu Beijing National Laboratory of Molecular Sciences (BNLMS) Key Laboratory of Bioorganic Chemistry and Molecular Engineering College of Chemistry, Peking University, Beijing, 100871 (China) Fax: (+86)10-6275-1708 E-mail: yuzx@pku.edu.cn