(+)-Taddol

Catalytic Enantioselective Dihalogenation in Total Synthesis.[Pubmed:29664281]

Acc Chem Res. 2018 May 15;51(5):1260-1271.

To date, more than 5000 biogenic halogenated molecules have been characterized. This number continues to increase as chemists explore chloride- and bromide-rich marine environments in search of novel bioactive natural products. Naturally occurring organohalogens span nearly all biosynthetic structural classes, exhibit a range of unique biological activities, and have been the subject of numerous investigations. Despite the abundance of and interest in halogenated molecules, enantioselective methods capable of forging carbon-halogen bonds in synthetically relevant contexts remain scarce. Accordingly, syntheses of organohalogens often rely on multistep functional group interconversions to establish carbon-halogen stereocenters. Our group has developed an enantioselective dihalogenation reaction and utilized it in the only reported examples of catalytic enantioselective halogenation in natural product synthesis. In this Account, we describe our laboratory's development of a method for catalytic, enantioselective dihalogenation and the application of this method to the synthesis of both mono- and polyhalogenated natural products. In the first part, we describe the initial discovery of a (+)-Taddol-mediated dibromination of cinnamyl alcohols. Extension of this reaction to a second-generation system capable of selective bromochlorination, dichlorination, and dibromination is then detailed. This system is capable of controlling the enantioselectivity of dihalide formation, chemoselectivity for polyolefinic substrates, and regioselectivity in the case of bromochlorination. The ability of this method to exert control over regioselectivity of halide delivery permits selective halogenation of electronically nonbiased olefins required for total synthesis. In the second part, we demonstrate how the described dihalogenation has provided efficient access to a host of structurally diverse natural products. The most direct application of this methodology is in the synthesis of naturally occurring vicinal dihalides. Chiral vicinal bromochlorides represent a class of >175 natural products; syntheses of five members of this class, including its flagship member, (+)-halomon, have been accomplished through use of the catalytic, enantioselective bromochlorination. Likewise, enantioselective dichlorination has provided selective access to two members of the chlorosulfolipids, a class of linear, acyclic polychlorides. Synthesis of chiral monohalides has been achieved through solvolysis of enantioenriched bromochlorides; this approach has resulted in the synthesis of five bromocyclohexane-containing natural products through an enantiospecific bromopolyene cyclization. In reviewing these syntheses, a framework for the synthesis of chiral organohalogens mediated by catalytic, enantioselective dihalogenation has emerged. The development of a selective dihalogenation method has been highly enabling in the synthesis of halogenated natural products. In this Account, we detail all examples of catalytic, enantioselective halogenation in total synthesis and encourage the further development of synthetically useful halogenation methodologies.

The resolution of acyclic P-stereogenic phosphine oxides via the formation of diastereomeric complexes: A case study on ethyl-(2-methylphenyl)-phenylphosphine oxide.[Pubmed:29359818]

Chirality. 2018 Apr;30(4):509-522.

As an example of acyclic P-chiral phosphine oxides, the resolution of ethyl-(2-methylphenyl)-phenylphosphine oxide was elaborated with (+)-Taddol derivatives, or with calcium salts of the tartaric acid derivatives. Besides the study on the resolving agents, several purification methods were developed in order to prepare enantiopure ethyl-(2-methylphenyl)-phenylphosphine oxide. It was found that the title phosphine oxide is a racemic crystal-forming compound, and the recrystallization of the enantiomeric mixtures could be used for the preparation of pure enantiomers. According to our best method, the (R)-ethyl-(2-methylphenyl)-phenylphosphine oxide could be obtained with an enantiomeric excess of 99% and in a yield of 47%. Complete racemization of the enantiomerically enriched phosphine oxide could be accomplished via the formation of a chlorophosphonium salt. Characterization of the crystal structures of the enantiopure phosphine oxide was complemented with that of the diastereomeric intermediate. X-ray analysis revealed the main nonbonding interactions responsible for enantiomeric recognition.

Chiral Phosphine-Phosphite Ligands in Asymmetric Gold Catalysis: Highly Enantioselective Synthesis of Furo[3,4-d]-Tetrahydropyridazine Derivatives through [3+3]-Cycloaddition.[Pubmed:29314298]

Chemistry. 2018 Feb 16;24(10):2379-2383.

The Au(I) -catalyzed reaction of 2-(1-alkynyl)-2-alken-1-ones with azomethine imines regio- and diastereoselectively affords furo[3,4-d]tetrahydropyridazines in a tandem cyclization/intermolecular [3+3]-cycloaddition process under mild conditions. By employing a chiral gold catalyst (prepared in situ from a (+)-Taddol-derived phosphine-phosphite ligand, Me2 SAuCl, and AgOTf) high yields and enantioselectivities (up to 94 % yield, up to 96 % ee) are obtained. The method provides an efficient modular route to substituted heterotricyclic furan derivatives and can be easily scaled up (using catalyst loads of only 0.15 mol %).

Chiral 3D Covalent Organic Frameworks for High Performance Liquid Chromatographic Enantioseparation.[Pubmed:29302963]

J Am Chem Soc. 2018 Jan 24;140(3):892-895.

In spite of their great promise for enantioselective processes due to the rich host-guest chemistry, it remains a challenge to construct covalent organic frameworks (COFs) with chiral three-dimensional (3D) structures. Here we report bottom-up synthesis of the first example of 3D chiral COFs by imine condensation of an enantiopure 2-fold symmetric (+)-Taddol-derived tetraaldehyde with a tetrahedral tetra(4-anilyl)methane. After postsynthetic oxidation of imine linkages, the framework is transformed into an amide-linked COF with retention of crystallinity and permanent porosity as well as enhanced chemical stability. The resultant isostructural COFs feature a 4-fold interpenetrated diamondoid open framework with tubular channels decorated with chiral dihydroxy auxiliaries. Both COFs can be used as chiral stationary phases for high performance liquid chromatography to enantioseparate racemic alcohols, and the oxidized COF shows superior separation performance compared to the pristine framework.

Enantioselective Synthesis of [6]Carbohelicenes.[Pubmed:28112916]

J Am Chem Soc. 2017 Feb 1;139(4):1428-1431.

The use of alpha-cationic phosphonites derived from (+)-Taddol as ancillary ligands has allowed a highly regio- and enantioselective synthesis of substituted [6]carbohelicenes by sequential Au-catalyzed intramolecular hydroarylation of diynes. Key for these results is the modular structure of these new ligands, and the enhanced reactivity that they impart to Au(I)-centers after coordination.

Homochiral 2D Porous Covalent Organic Frameworks for Heterogeneous Asymmetric Catalysis.[Pubmed:27618953]

J Am Chem Soc. 2016 Sep 28;138(38):12332-5.

There have been breakthroughs in the development of covalent organic frameworks (COFs) with tunability of composition, structure, and function, but the synthesis of chiral COFs remains a great challenge. Here we report the construction of two-dimensional COFs with chiral functionalities embedded into the frameworks by imine condensations of enantiopure (+)-Taddol-derived tetraaldehydes with 4,4'-diaminodiphenylmethane. Powder X-ray diffraction and computer modeling together with pore size distribution analysis show that one COF has a twofold-interpenetrated grid-type network and the other has a non-interpenetrated grid network. After postsynthetic modification of the chiral dihydroxy groups of (+)-Taddol units with Ti(O(i)Pr)4, the materials are efficient and recyclable heterogeneous catalysts for asymmetric addition of diethylzinc to aldehydes with high enantioselectivity. The results reported here will greatly expand the scope of materials design and engineering for the creation of new types of functional porous materials.

Stereoselective Rh-Catalyzed Hydrogenative Desymmetrization of Achiral Substituted 1,4-Dienes.[Pubmed:27230728]

Org Lett. 2016 Jun 17;18(12):2836-9.

Highly efficient catalytic stereoselective hydrogenative desymmetrization reactions mediated by rhodium complexes derived from enantiopure phosphine-phosphite (P-OP) ligands are described. The highest performing ligand, which contains a (+)-Taddol-derived phosphite fragment [TADDOL = (2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol)], presented excellent catalytic properties for the desymmetrization of a set of achiral 1,4-dienes, providing access to the selective formation of a variety of enantioenriched secondary and tertiary alcohols (six examples, up to 92% ee).

Low-Pressure Cobalt-Catalyzed Enantioselective Hydrovinylation of Vinylarenes.[Pubmed:26998912]

Chemistry. 2016 May 23;22(22):7381-4.

An efficient and practical protocol for the enantioselective cobalt-catalyzed hydrovinylation of vinylarenes with ethylene at low (1.2 bar) pressure has been developed. As precatalysts, stable [L2 CoCl2 ] complexes are employed that are activated in situ with Et2 AlCl. A modular chiral (+)-Taddol-derived phosphine-phosphite ligand was identified that allows the conversion of a broad spectrum of substrates, including heterocyclic vinylarenes and vinylferrocene, to smoothly afford the branched products with up to 99 % ee and virtually complete regioselectivity. Even polar functional groups, such as OH, NH2 , CN, and CO2 R, are tolerated.

TADDOL-based phosphorus(III)-ligands in enantioselective Pd(0)-catalysed C-H functionalisations.[Pubmed:26511604]

Chem Commun (Camb). 2015 Dec 28;51(100):17647-57.

Monodentate (+)-Taddol-derived phosphoramidites and phosphonites are versatile chiral ligands for enantioselective Pd(0)-catalysed C-H functionalisations. They enable highly selective cyclisations to access a wide range of chiral carbo- and heterocycles. The high attractiveness of this ligand class consists in their modular structure, allowing for a quick assembly of a library with variable steric properties. Asymmetric C-H functionalisation methods utilising catalytic systems based on Pd(0) complexes and (+)-Taddol-type ligands are presented and aspects of selectivity are discussed.

(4+1) vs (4+2): Catalytic Intramolecular Coupling between Cyclobutanones and Trisubstituted Allenes via C-C Activation.[Pubmed:26440740]

J Am Chem Soc. 2015 Oct 28;137(42):13715-21.

Herein we describe a rhodium-catalyzed (4+1) cyclization between cyclobutanones and allenes, which provides a distinct [4.2.1]-bicyclic skeleton containing two quaternary carbon centers. The reaction involves C-C activation of cyclobutanones and employs allenes as a one-carbon unit. A variety of functional groups can be tolerated, and a diverse range of polycyclic scaffolds can be accessed. Excellent enantioselectivity can be obtained, which is enabled by a (+)-Taddol-derived phosphoramidite ligand. The bridged bicyclic products can be further functionalized or derivatized though simple transformations.