Asymmetric nucleophilic epoxidation

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Nucleophilic epoxidation is the formation of epoxides from electron-deficient double bonds through the action of nucleophilic oxidants. Nucleophilic epoxidation methods represent a viable alternative to electrophilic methods, many of which do not epoxidize electron-poor double bonds efficiently. [1]

Contents

Although the most commonly used asymmetric epoxidation methods (the Sharpless-Katsuki, [2] and Jacobsen [3] epoxidations) rely on the catalytic reactivity of electrophilic oxidants, nucleophilic oxygen sources substituted with a suitable leaving group can also act as epoxidation reagents. The classic example, the Weitz-Scheffer reaction [4] employs hydrogen peroxide under basic conditions (Z = OH below). Other notable examples have employed hypochlorites (Z = Cl) and chiral peroxides (Z = OR*).

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Asymmetric versions of the above reaction have taken advantage of a number of strategies for achieving asymmetric induction. The highest yielding and most enantioselective methods include:

Although the mechanisms of each of these reactions differ somewhat, in each case the chiral catalyst or reagent must be involved in the enantio determining conjugate addition step. Cis-epoxides are difficult to access using nucleophilic epoxidation methods. Nearly all nucleophilic epoxidations of cis olefins afford trans epoxides.

Mechanism and Stereochemistry

Prevailing Mechanism

The mechanism of nucleophilic epoxidation begins with conjugate addition of the peroxide (or other O-nucleophilic species) to the enone. Metal ions or conjugate acids present in solution coordinate both the peroxide oxygen and the enolate oxygen. Attack of the enolate on the peroxide oxygen generates the epoxide product and releases a leaving group.

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Because the process is stepwise, the configuration of the carbon-carbon double bond is not necessarily preserved. Both cis and trans enones form trans epoxides under nearly all nucleophilic epoxidation conditions (methods employing lanthanide-BINOL systems are the exception).

Stereoselective Variants

How stereoselectivity is achieved in asymmetric nucleophilic epoxidations depends on the method employed. Covered here are various methods for the asymmetric nucleophilic epoxidation of electron-poor olefins. See below for a survey of the substrate scope of the reaction.

When chiral, non-racemic peroxides are used, the two transition states of epoxidation leading to enantiomeric products are diastereomeric. Steric interactions between the peroxide, enone, and templating cation M+ influence the sense of selectivity observed. [9]

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Methods that employ metal peroxides modified by chiral, non-racemic ligands operate by a similar mechanism in which the metal cation plays a templating role. Chiral zinc alkoxides under an oxygen atmosphere have been used to epoxidize some classes of enones (see equation (8) below). The evolution of ethane gas and uptake of oxygen are evidence for ligand exchange followed by oxidation of the intermediate zinc alkoxide species. [10] A catalytic version of this transformation has been achieved using chiral zinc alkylperoxides. [11]

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Lithium, magnesium, and calcium [12] alkylperoxides have also been employed as asymmetric nucleophilic epoxidation reagents. Simple tartrate and pseudoephedrine ligands are effective in combination with these metals; however, little detailed information about the precise mechanisms of these systems is known.

In combination with BINOL ligands and cumene hydroperoxide, lanthanide alkoxides can be used to epoxidize both trans and cis enones with high enantioselectivity. Studies of non-linear effects with these catalyst systems suggest that the active catalyst is oligomeric. [13]

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Homopolymers of amino acids (polypeptides) can also be used to effect enantioselective epoxidations in the presence of an enone and a peroxide. Structure-reactivity relationships have not emerged, but enantioselectivities in these reactions are often high, and polypeptides can often be used when other methods fail. [14]

Phase-transfer catalysis of nucleophilic epoxidation is also possible using cinchona-based alkaloid catalysts. Phase-transfer methods allow some variability in the oxidant used: hydroperoxides, hydrogen peroxide, and hypochlorites have all been used with some success. [15]

Scope and Limitations

Optimal conditions for enantio-selective nucleophilic epoxidation depend on the substrate employed. Although a variety of substrates may be epoxidized using nucleophilic methods, each particular method tends to have limited substrate scope. This section describes asymmetric nucleophilic epoxidation methods, organizing them according to the constitution and configuration of the unsaturated substrate.

Enones

Dialkyl (E)-enones have been most commonly epoxidized using either lanthanide/BINOL systems [16] or a magnesium tartrate catalyst. [17]

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For alkyl aryl (E)-enones, both polypeptides [18] and lanthanide/BINOL catalysts [19] give good yields and enantioselectivities. The most common polypeptide employed is poly-L-leucine.

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Aryl alkyl (E)-enones have been epoxidized with high enantioselectivity using stoichiometric zinc peroxide systems. [6] Polyleucine may be used with these substrates as well; [18] when an existing stereocenter in the substrate biases the sense of selectivity of the epoxidation, polyleucine is able to overcome this bias.

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Phase-transfer catalysis has been applied successfully to epoxidations of diaryl (E)-enones (chalcones). [15] Lanthanide/BINOL is effective for this class of substrates as well. [20]

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(Z)-Enones are difficult to epoxidize without intermediate bond rotation to afford trans-epoxides. Lanthanide catalysts do effectively prevent bond rotation, however, [19] and provide access to cis epoxide products.

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With the lone exception of methylidene tetralone substrates, [10] no general methods are available for the asymmetric nucleophilic epoxidation of trisubstituted double bonds.

Other Electron-poor Alkenes

Unsaturated esters may be epoxidized using either electrophilic or nucleophilic methods. Lanthanide-mediated epoxidation has been successfully applied to cinnamates and β-heteroaryl unsaturated esters. [21] Amides are also epoxidized under lanthanide-mediated conditions. [22]

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Epoxidations of other electron-deficient double bonds (substituted by electron-withdrawing groups other than carbonyls) are limited in scope, although a few examples have been reported. [23] [24] The ability of the carbonyl group to coordinate Lewis acidic functionality is critical for most existing methods.

Comparison with Other Methods

The asymmetric Darzens reaction between aldehydes and (alpha)-haloesters is an effective method for the synthesis of glycidic esters. [25] Chiral auxiliaries, [26] chiral boron enolates, [27] and asymmetric phase transfer catalysis [28] have been used successfully to effect asymmetric induction in the Darzens reaction.

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Diastereoselective epoxidations of chiral, non-racemic alkenes suffer from the limitation that removal of the auxiliary without disturbing the epoxide is often difficult. Nonetheless, diastereoselectivity is high in some cases. [29]

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Oxidation of epoxy alcohols generated via Sharpless epoxidation is a third method for the enantioselective synthesis of chiral α,β-epoxy carbonyl compounds. [30] Swern and Parikh-Doering conditions are most commonly applied to accomplish these oxidations.

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Typical experimental conditions

Generally, nucleophilic epoxidations are carried out under inert atmosphere in anhydrous conditions. For zinc-mediated epoxidations, diethylzinc and ligand are first mixed and oxidized, then the enone is introduced. Lanthanide-mediated epoxidations typically require an additive to stabilize the catalyst; this is most commonly triphenylphosphine oxide or triphenylarsine oxide.

Phase-transfer catalyzed epoxidations may be carried out using one of three possible sets of reaction conditions: (1) sodium hypochlorite at room temperature, (2) freshly prepared 8 M potassium hypochlorite, or (3) trichloroisocyanuric acid in aqueous or non-aqueous conditions.

Among polypeptide-based methods, employing a phase transfer catalyst and triphasic media permits lower catalyst loadings. Biphasic conditions using an organic base in conjunction with urea/H2O2 may also be used.

Related Research Articles

Sharpless epoxidation

The Sharpless epoxidation reaction is an enantioselective chemical reaction to prepare 2,3-epoxyalcohols from primary and secondary allylic alcohols.

Sharpless asymmetric dihydroxylation is the chemical reaction of an alkene with osmium tetroxide in the presence of a chiral quinine ligand to form a vicinal diol. The reaction has been applied to alkenes of virtually every substitution, often high enantioselectivities are realized. Asymmetric dihydroxylation reactions are also highly site selective, providing products derived from reaction of the most electron-rich double bond in the substrate.

Epoxide

An epoxide is a cyclic ether with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for many applications. In general, low molecular weight epoxides are colourless and nonpolar, and often volatile.

Jacobsen epoxidation

The Jacobsen epoxidation, sometimes also referred to as Jacobsen-Katsuki epoxidation is a chemical reaction which allows enantioselective epoxidation of unfunctionalized alkyl- and aryl- substituted alkenes. It is complementary to the Sharpless epoxidation (used to form epoxides from the double bond in allylic alcohols). The Jacobsen epoxidation gains its stereoselectivity from a C2 symmetric manganese(III) salen-like ligand, which is used in catalytic amounts. The manganese atom transfers an oxygen atom from chlorine bleach or similar oxidant. The reaction takes its name from its inventor, Eric Jacobsen, with Tsutomu Katsuki sometimes being included. Chiral-directing catalysts are useful to organic chemists trying to control the stereochemistry of biologically active compounds and develop enantiopure drugs.

Johnson–Corey–Chaykovsky reaction

The Johnson–Corey–Chaykovsky reaction is a chemical reaction used in organic chemistry for the synthesis of epoxides, aziridines, and cyclopropanes. It was discovered in 1961 by A. William Johnson and developed significantly by E. J. Corey and Michael Chaykovsky. The reaction involves addition of a sulfur ylide to a ketone, aldehyde, imine, or enone to produce the corresponding 3-membered ring. The reaction is diastereoselective favoring trans substitution in the product regardless of the initial stereochemistry. The synthesis of epoxides via this method serves as an important retrosynthetic alternative to the traditional epoxidation reactions of olefins.

Shi epoxidation

The Shi epoxidation is a chemical reaction described as the asymmetric epoxidation of alkenes with oxone and a fructose-derived catalyst (1). This reaction is thought to proceed via a dioxirane intermediate, generated from the catalyst ketone by oxone. The addition of the sulfate group by the oxone facilitates the formation of the dioxirane by acting as a good leaving group during ring closure. It is notable for its use of a non-metal catalyst and represents an early example of organocatalysis. The reaction was first discovered by Yian Shi of Colorado State University in 1996.

In organic chemistry, kinetic resolution is a means of differentiating two enantiomers in a racemic mixture. In kinetic resolution, two enantiomers react with different reaction rates in a chemical reaction with a chiral catalyst or reagent, resulting in an enantioenriched sample of the less reactive enantiomer. As opposed to chiral resolution, kinetic resolution does not rely on different physical properties of diastereomeric products, but rather on the different chemical properties of the racemic starting materials. This enantiomeric excess (ee) of the unreacted starting material continually rises as more product is formed, reaching 100% just before full completion of the reaction. Kinetic resolution relies upon differences in reactivity between enantiomers or enantiomeric complexes. Kinetic resolution is a concept in organic chemistry and can be used for the preparation of chiral molecules in organic synthesis. Kinetic resolution reactions utilizing purely synthetic reagents and catalysts are much less common than the use of enzymatic kinetic resolution in application towards organic synthesis, although a number of useful synthetic techniques have been developed in the past 30 years.

Organocatalysis

In organic chemistry, the term organocatalysis refers to a form of catalysis, whereby the rate of a chemical reaction is increased by an organic catalyst referred to as an "organocatalyst" consisting of carbon, hydrogen, sulfur and other nonmetal elements found in organic compounds. Because of their similarity in composition and description, they are often mistaken as a misnomer for enzymes due to their comparable effects on reaction rates and forms of catalysis involved.

Chiral Lewis acids (CLAs) are a type of Lewis acid catalyst that effects the chirality of the substrate as it reacts with it. In such reactions, the synthesis favors the formation of a specific enantiomer or diastereomer. The method then is an enantioselective asymmetric synthesis reaction. Since they affect chirality, they produce optically active products from optically inactive or mixed starting materials. This type of preferential formation of one enantiomer or diastereomer over the other is formally known as an asymmetric induction. In this kind of Lewis acid. the electron-accepting atom is typically a metal, such as indium, zinc, lithium, aluminium, titanium, or boron. The chiral-altering ligands employed for synthesizing these acids most often have multiple Lewis basic sites that allow the formation of a ring structure involving the metal atom.

Jacobsens catalyst

Jacobsen's catalyst is the common name for N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride, a coordination compound of manganese and a salen-type ligand. It is used as an asymmetric catalyst in the Jacobsen epoxidation, which is renowned for its ability to enantioselectively transform prochiral alkenes into epoxides. Before its development, catalysts for the asymmetric epoxidation of alkenes required the substrate to have a directing functional group, such as an alcohol as seen in the Sharpless epoxidation. This compound has two enantiomers, which give the appropriate epoxide product from the alkene starting material.

Oxidation with dioxiranes refers to the introduction of oxygen into organic molecules through the action of a dioxirane. Dioxiranes are well known for their oxidation of alkenes to epoxides; however, they are also able to oxidize other unsaturated functionality, heteroatoms, and alkane C-H bonds.

Epoxidation with dioxiranes refers to the synthesis of epoxides from alkenes using three-membered cyclic peroxides, also known as dioxiranes.

The Juliá–Colonna epoxidation is an asymmetric poly-leucine catalyzed nucleophilic epoxidation of electron deficient olefins in a triphasic system. The reaction was reported by Sebastian Juliá at the Chemical Institute of Sarriá in 1980, with further elaboration by both Juliá and Stefano Colonna.

The Baylis–Hillman reaction is a carbon-carbon bond forming reaction between the α-position of an activated alkene and a carbon electrophile such as an aldehyde. Employing a nucleophilic catalyst, such as a tertiary amine and phosphine, this reaction provides a densely functionalized product. It is named for Anthony B. Baylis and Melville E. D. Hillman, two of the chemists who developed this reaction while working at Celanese. This reaction is also known as the Morita–Baylis–Hillman reaction or MBH reaction, as Morita had published earlier work on it.

The Tsuji–Trost reaction is a palladium-catalysed substitution reaction involving a substrate that contains a leaving group in an allylic position. The palladium catalyst first coordinates with the allyl group and then undergoes oxidative addition, forming the π-allyl complex. This allyl complex can then be attacked by a nucleophile, resulting in the substituted product.

Hydrogen-bond catalysis

Hydrogen-bond catalysis is a type of organocatalysis that relies on use of hydrogen bonding interactions to accelerate and control organic reactions. In biological systems, hydrogen bonding plays a key role in many enzymatic reactions, both in orienting the substrate molecules and lowering barriers to reaction. However, chemists have only recently attempted to harness the power of using hydrogen bonds to perform catalysis, and the field is relatively undeveloped compared to research in Lewis acid catalysis.

In organic chemistry, the Keck asymmetric allylation is a chemical reaction that involves the nucleophilic addition of an allyl group to an aldehyde. The catalyst is a chiral complex that contains titanium as a Lewis acid. The chirality of the catalyst induces a stereoselective addition, so the secondary alcohol of the product has a predictable absolute stereochemistry based on the choice of catalyst. This name reaction is named for Gary Keck.

Phosphoramidite ligand

A phosphoramidite ligand is a chiral monodentate phosphine ligand, widely used for enantioselective synthesis. They were invented by Dutch chemist Ben Feringa. The introduction of phosphoramidite ligands challenged the notion that high flexibility in the metal–ligand complex is detrimental for high stereo control.

In homogeneous catalysis, a C2-symmetric ligands usually describes bidentate ligands that are dissymmetric but not asymmetric by virtue of their C2-symmetry. Such ligands have proven valuable in catalysis. With C2 symmetry, C2-symmetric ligands limit the number of possible reaction pathways and thereby increase enantioselectivity, at least relative to asymmetrical analogues. Chiral ligands combine with metals to form chiral catalyst, which engages in a chemical reaction in which chirality is transfer to the reaction product. C2 symmetric ligands are a subset of chiral ligands.

Heterobimetallic catalysis is an approach to catalysis that employs two different metals to promote a chemical reaction. Included in this definition are cases where: 1) each metal activates a different substrate, 2) both metals interact with the same substrate, and 3) only one metal directly interacts with the substrate(s), while the second metal interacts with the first.

References

  1. ↑ Porter, M.; Skidmore, J. Org. React. 2009, 74, 425. doi : 10.1002/0471264180.or074.03
  2. ↑ Katsuki, T.; Martin, V. S. Org. React.1996, 48, 1.
  3. ↑ Jacobsen, E. N.; Wu, M. H. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin and Heidelberg, 1999; Vol. II, pp 649–678.
  4. ↑ Weitz, E.; Scheffer, A. Chem. Ber.1921, 54, 2327.
  5. ↑ Adam, W.; Rao, P. B.; Degen, H.-G.; Saha-Möller, C. R. J. Am. Chem. Soc.2000, 122, 5654.
  6. 1 2 Enders, D.; Zhu, J. Q.; Raabe, G. Angew. Chem. Int. Ed. Engl.1996, 35, 1725.
  7. ↑ Genski, T.; Macdonald, G.; Wei, X.; Lewis, N.; Taylor, R. J. K. Synlett1999, 795.
  8. ↑ Da, C. S.; Wei, J.; Dong, S. L.; Xin, Z. Q.; Liu, D. X.; Xu, Z. Q.; Wang, R. Synth. Commun.2003, 33, 2787.
  9. ↑ Adam, W.; Rao, P. B.; Degen, H.-G.; Saha-Möller, C. R. Eur. J. Org. Chem.2002, 630.
  10. 1 2 Enders, D.; Zhu, J. Q.; Kramps, L. Liebigs Ann./Recl.1997, 1101.
  11. ↑ Raheem Keeri, Abdul; Justyniak, Iwona; Jurczak, Janusz; Lewiński, Janusz (2016-03-17). "Quest for Efficient Catalysts based on Zinc tert-Butyl Peroxides for Asymmetric Epoxidation of Enones: C2- vs C1-Symmetric Auxiliaries". Advanced Synthesis & Catalysis. 358 (6): 864–868. doi:10.1002/adsc.201500764. ISSN   1615-4169.
  12. ↑ Kumaraswamy, G.; Jena, N.; Sastry, M. N. V.; Rao, G. V.; Ankamma, K. J. Mol. Catal. A: Chem.2005, 230, 59.
  13. ↑ Daikai, K.; Hayano, T.; Kino, R.; Furuno, H.; Kagawa, T.; Inanaga, J. Chirality2003, 15, 83.
  14. ↑ Bickley, J. F.; Hauer, B.; Pena, P. C. A.; Roberts, S. M.; Skidmore, J. J. Chem. Soc., Perkin Trans. 12001, 1253.
  15. 1 2 Corey, E. J.; Zhang, F. Y. Org. Lett.1999, 1, 1287.
  16. ↑ Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc.2001, 123, 2725.
  17. ↑ Jacques, O.; Richards, S. J.; Jackson, R. F. W. Chem. Commun.2001, 2712.
  18. 1 2 Allen, J. V.; Drauz, K. H.; Flood, R. W.; Roberts, S. M.; Skidmore, J. Tetrahedron Lett.1999, 40, 5417.
  19. 1 2 Watanabe, S.; Kobayashi, Y.; Arai, T.; Sasai, H.; Bougauchi, M.; Shibasaki, M. Tetrahedron Lett.1998, 39, 7353.
  20. ↑ Inanaga, J.; Kagawa, T. European Patent 1127616 (2001); Chem. Abstr.2001, 135, 197209.
  21. ↑ Kakei, H.; Tsuji, R.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc.2005, 127, 8962.
  22. ↑ Nemoto, T.; Kakei, H.; Gnanadesikan, V.; Tosaki, S.-Y.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc.2002, 124, 14544.
  23. ↑ Enders, D.; Kramps, L.; Zhu, J. Q. Tetrahedron: Asymmetry1998, 9, 3959.
  24. ↑ Geller, T.; Krüger, C. M.; Militzer, H. C. Tetrahedron Lett.2004, 45, 5069.
  25. ↑ Newman, M. S.; Magerlein, B. J. Org. React.1949, 5, 413.
  26. ↑ Abdel-Magid, A.; Lantos, I.; Pridgen, L. N. Tetrahedron Lett.1984, 25, 3273.
  27. ↑ Corey, E. J.; Choi, S. Tetrahedron Lett.1991, 32, 2857.
  28. ↑ Arai, S.; Shioiri, T. Tetrahedron Lett.1998, 39, 2145.
  29. ↑ Meth-Cohn, W.; Williams, D. J.; Chen, Y. Chem. Commun.2000, 495.
  30. ↑ Baldwin, J. E.; Adlington, R. M.; Godfrey, C. R. A.; Patel, V. K. Tetrahedron1993, 49, 7837.
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