Asymmetric Hydroalkoxylation Research Articles

Formal Synthesis of Amipurimycin and 4'-Deoxymiharamycin B by Way of Sequential Asymmetric Metal Catalysis.

Herein, we describe a highly efficient formal synthesis of nucleoside antibiotics amipurimycin and 4'-deoxymiharamycin B. A signature event is highlighted by the sequential metal catalysis combining (i) Pd-catalyzed asymmetric hydroalkoxylation of an alkoxyallene; (ii) Ru-catalyzed enyne-methathesis, and (iii) Os-catalyzed dihydroxylation. Remarkably, this atom-efficient sequence allows for the construction of a 3'-branched pyranose core structure in only four steps from readily available Garner's aldehyde.

Switchable Chemo‐, Regio‐ and Pseudo‐Stereodivergence in Palladium‐Catalyzed Cycloaddition of Allenes

AbstractHere, we report a strategy enabling triple switchable chemo‐, regio‐, and stereodivergence in newly developed palladium‐catalyzed cycloadditions of allenes. An asymmetric pseudo‐stereodivergent cycloaddition of allenes bearing a primary leaving group at the α‐position, where a dynamic kinetic asymmetric hydroalkoxylation of racemic unactivated allenes was the enantio‐determining step, is realized, providing four stereoisomers [(Z,R), (Z,S), (E,S), and (E,R)] containing a di‐substituted alkene scaffold and a stereogenic center. By tuning reaction conditions, a mechanistically distinctive cycloaddition is uncovered selectively with the same set of substrates. By switching the position of the leaving group of allenes, a cycloaddition involving an intermolecular O‐attack is disclosed. Diverse mechanisms of the cycloaddition reactions of allenes enable rapid access to structurally and stereochemically diverse 3,4‐dihydro‐2H‐1,4‐benzoxazines in high efficiency and selectivity.

Switchable Chemo-, Regio- and Pseudo-Stereodivergence in Palladium-Catalyzed Cycloaddition of Allenes.

Here, we report a strategy enabling triple switchable chemo-, regio-, and stereodivergence in newly developed palladium-catalyzed cycloadditions of allenes. An asymmetric pseudo-stereodivergent cycloaddition of allenes bearing a primary leaving group at the α-position, where a dynamic kinetic asymmetric hydroalkoxylation of racemic unactivated allenes was the enantio-determining step, is realized, providing four stereoisomers [(Z,R), (Z,S), (E,S), and (E,R)] containing a di-substituted alkene scaffold and a stereogenic center. By tuning reaction conditions, a mechanistically distinctive cycloaddition is uncovered selectively with the same set of substrates. By switching the position of the leaving group of allenes, a cycloaddition involving an intermolecular O-attack is disclosed. Diverse mechanisms of the cycloaddition reactions of allenes enable rapid access to structurally and stereochemically diverse 3,4-dihydro-2H-1,4-benzoxazines in high efficiency and selectivity.

Catalytic Asymmetric Hydroalkoxylation and Formal Hydration and Hydroaminoxylation of Conjugated Dienes.

The straightforward construction of stereogenic centers bearing unprotected functional groups, as in nature, has been a persistent pursuit in synthetic chemistry. Abundant applications of free enantioenriched allyl alcohol and allyl hydroxylamine motifs have made the asymmetric hydration and hydroaminoxylation of conjugated dienes from water and hydroxylamine, respectively, intriguing and efficient routes that have, however, been unachievable thus far. A fundamental challenge is the failure to realize transition-metal-catalyzed enantioselective C-O bond constructions via hydrofunctionalization of conjugated dienes. Here, we perform a comprehensive study toward the stereoselective formal hydration and hydroaminoxylation of conjugated dienes by synthesizing a set of new P,N-ligands and identifying an aryl-derived oxime as a surrogate for both water and hydroxylamine. Asymmetric hydroalkoxylation with new P,N-ligands is also elucidated. Furthermore, versatile derivatizations following hydration provide indirect but concise routes to formal hydrophenoxylation, hydrofluoroalkoxylation, and hydrocarboxylation of conjugated dienes that have been unreported thus far. Finally, a ligand-to-ligand hydrogen transfer process is proposed based on the results of preliminary mechanistic experiments.

Catalytic Asymmetric Hydroalkoxylation of C-C Multiple Bonds.

Asymmetric hydroalkoxylation of alkenes constitutes a redox-neutral and 100% atom-economical strategy toward enantioenriched oxygenated building blocks from readily available starting materials. Despite their great potential, catalytic enantioselective additions of alcohols across a C–C multiple bond are particularly underdeveloped, especially compared to other hydrofunctionalization methods such as hydroamination. However, driven by some recent innovations, e.g., asymmetric MHAT methods, asymmetric photocatalytic methods, and the development of extremely strong chiral Brønsted acids, there has been a gratifying surge of reports in this burgeoning field. The goal of this review is to survey the growing landscape of asymmetric hydroalkoxylation by highlighting exciting new advances, deconstructing mechanistic underpinnings, and drawing insight from related asymmetric hydroacyloxylation and hydration. A deep appreciation of the underlying principles informs an understanding of the various selectivity parameters and activation modes in the realm of asymmetric alkene hydrofunctionalization while simultaneously evoking the outstanding challenges to the field moving forward. Overall, we aim to lay a foundation for cross-fertilization among various catalytic fields and spur further innovation in asymmetric hydroalkoxylations of C–C multiple bonds.

Catalytic Asymmetric Synthesis of Hexahydro-furofuran-3-ol and Its Pyran Derivatives.

The catalytic asymmetric synthesis of hexahydro-furofuran-3-ol, a key fragment of HIV protease inhibitors, is reported. A signature event is represented by the sequential metal catalysis that combines the Pd-catalyzed asymmetric hydroalkoxylation of ene-alkoxyallene and ring-closing metathesis (RCM). Notably, this unprecedented and highly chemoselective approach allows for a unified access to pyranofuranol and furopyranol derivatives.

Asymmetric Synthesis of Ethers by Catalytic Alkene Hydro­alkoxy­lation

Many chiral ethers have important physiological activities. Although many asymmetric hydroalkoxylations of olefins with alcohols or phenols have been developed to make chiral ethers, challenges still remain in achieving high reactivity and selectivity over an ever-increasing diversity of alkenes and alcohols. In this review, recent developments on catalytic asymmetric alkene hydroalkoxylations are summarized based on the substitution patterns of alkenes.1 Introduction2 Asymmetric Hydroalkoxylation of Non-Activated Alkenes2.1 Intramolecular Additions2.2 Intermolecular Additions3 Asymmetric Hydroalkoxylation of Enol Ethers3.1 Intramolecular Additions3.2 Intermolecular Additions4 Asymmetric Hydroalkoxylation of α,β-Unsaturated Carbonyl Compounds4.1 α,β-Unsaturated Ketones and Aldehydes as Substrates4.2 α,β-Unsaturated Esters, Amides and Carboxylic Acids as Substrates5 Asymmetric Hydroalkoxylation of Allenes5.1 Intramolecular Additions5.2 Intermolecular Additions6 Conclusion

Axially Chiral 1,1'‐Binaphthyl‐2‐Carboxylic Acid (BINA‐Cox) as Ligands for Titanium‐Catalyzed Asymmetric Hydroalkoxylation

Axially chiral, enantiopure 1,1'‐binaphthyl‐2‐carboxylic acids (BINA‐Cox) have recently been introduced as chiral ligands for transition metal catalysis. Together with equimolar, co‐catalytic amounts of Ti(OiPr)4 and water they form an in situ catalyst that performs the asymmetric catalytic hydroalkoxylation of 2‐allylphenols to 2‐methylcoumarans at high temperature (240 °C, microwave heating). The synthesis of reference ligand 2'‐MeO‐BINA‐Cox (L1) has been optimized and performed at molar scale. Synthetic routes have been developed to access a variety of substituted BINA‐Cox ligands (>30 examples), which have been tested for ligand effects on the reference asymmetric cyclization of 2‐allylphenol. The substrate range of asymmetric catalytic hydroalkoxylation has been explored through systematic substrate structure variations to define scope and limitations of the titanium‐catalyzed process. The new substrates 2‐(1‐vinylcycloalkyl)phenols (1j, 1k), 2‐(2‐vinylphenyl)propan‐2‐ol (1t), and 2'‐vinyl‐[1,1'‐biphenyl]‐2‐ol (1u) are shown to undergo asymmetric catalytic cyclization to benzodihydrofurans and benzo[c]chromene, respectively.

Synthesis of Deoxyaminosugar Cyclohexyl-l-callipeltose and Its Diastereomer Using Pd-Catalyzed Asymmetric Hydroalkoxylation.

Cyclohexyl-l-callipeltose, an aminodeoxysugar subunit of Callipeltoside A, was synthesized in six steps and 40% overall yield from readily available (S)-4-methylpent-4-en-2-ol and cyclohexyloxyallene. The signature step is represented by Pd-catalyzed asymmetric intermolecular hydroalkoxylation that generates the key dihydropyran intermediate upon combination with the ring-closing metathesis reaction. Notably, an unnatural diastereomer of the target compound could also be obtained with comparable efficiency simply by using the enantiomeric ligand.

ChemInform Abstract: Asymmetric Hydroalkoxylation of Non‐activated Alkenes: Titanium‐Catalyzed Cycloisomerization of Allylphenols at High Temperatures.

AbstractA microwave‐assisted enantioselective intramolecular hydroxyalkylation of 2‐allylphenols at high temperatures yields 2‐methylcoumarans.

Asymmetric Hydroalkoxylation of Non-Activated Alkenes at High Temperature

Key words hydroalkoxylation - high-temperature asymmetric catalysis - titanium

Gold(I)-Catalyzed Asymmetric Hydroalkoxylation of Alkynes

Gold(I)-Catalyzed Asymmetric Hydroalkoxylation of Alkynes

Asymmetric Hydroalkoxylation of Non‐Activated Alkenes: Titanium‐Catalyzed Cycloisomerization of Allylphenols at High Temperatures

AbstractThe asymmetric catalytic addition of alcohols (phenols) to non‐activated alkenes has been realized through the cycloisomerization of 2‐allylphenols to 2‐methyl‐2,3‐dihydrobenzofurans (2‐methylcoumarans). The reaction was catalyzed by a chiral titanium–carboxylate complex at uncommonly high temperatures for asymmetric catalytic reactions. The catalyst was generated by mixing titanium isopropoxide, the chiral ligand (aS)‐1‐(2‐methoxy‐1‐naphthyl)‐2‐naphthoic acid or its derivatives, and a co‐catalytic amount of water in a ratio of 1:1:1 (5 mol % each). This homogeneous thermal catalysis (HOT‐CAT) gave various (S)‐2‐methylcoumarans with yields of up to 90 % and in up to 85 % ee at 240 °C, and in 87 % ee at 220 °C.

Asymmetric hydroalkoxylation of non-activated alkenes: titanium-catalyzed cycloisomerization of allylphenols at high temperatures.

The asymmetric catalytic addition of alcohols (phenols) to non-activated alkenes has been realized through the cycloisomerization of 2-allylphenols to 2-methyl-2,3-dihydrobenzofurans (2-methylcoumarans). The reaction was catalyzed by a chiral titanium-carboxylate complex at uncommonly high temperatures for asymmetric catalytic reactions. The catalyst was generated by mixing titanium isopropoxide, the chiral ligand (aS)-1-(2-methoxy-1-naphthyl)-2-naphthoic acid or its derivatives, and a co-catalytic amount of water in a ratio of 1:1:1 (5 mol % each). This homogeneous thermal catalysis (HOT-CAT) gave various (S)-2-methylcoumarans with yields of up to 90 % and in up to 85 % ee at 240 °C, and in 87 % ee at 220 °C.

Chiral palladacycle promoted asymmetric synthesis of functionalized bis-phosphine monoxide ligand

An organopalladium complex containing orthometalated ( R)-(1-(dimethylamino)ethyl)naphthalene as the chiral auxiliary has been used to promote the asymmetric hydroalkoxylation reactions between weak nucleophile methanol and 1,1-bis(diphenylphosphino)ethylene or 1,1-bis(diphenylphosphino)ethylene monoxide in good regio- and stereo-selectivities in the presence of an external base. The major addition product obtained from methanol and 1,1-bis(diphenylphosphino)ethylene monoxide was subsequently isolated in a quantitative yield in its configurationally pure form and characterized by means of two-dimensional rotating-frame nuclear Overhauser enhancement (ROESY) NMR spectroscopy as well as single crystal X-ray diffraction analysis. The enantiomerically pure bis-phosphine monoxide ligand was subsequently liberated in high yield.

Rhodium-catalyzed asymmetric hydroalkoxylation and hydrosulfenylation of diphenylphosphinylallenes

The rhodium-catalyzed intermolecular asymmetric hydroalkoxylation and hydrosulfenylation of diphenylphosphinylallenes gave chiral allylic phosphine oxides substituted with vinyl ether and thioether moieties in high yields with high enantioselectivities.