Catalytic enantioselective Michael reaction

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The catalytic, enantioselective Michael reaction involves the combination of a nucleophile with an electron-deficient alkene in the presence of a chiral, nonracemic catalyst (either a metal complex or organocatalyst). Addition of the nucleophile to the β-carbon of the electrophilic olefin generates at least one new stereogenic center.[1]

Introduction

The Michael reaction consists of the addition of a stabilized carbon nucleophile (i.e. an enolate or enolate equivalent) to the β-carbon of an electron-deficient alkene (Eq. 1).[2][3] Protonation or treatment with an electrophile converts the resulting stabilized anion into a product in which the alkenic carbons bear two new bonds. This article covers reactions in which only one carbon-carbon bond forms (at the β-carbon); vicinal difunctionalization of electron-poor alkenes is covered in a related Organic Reactions chapter.[4] The reaction may establish stereocenters at the nucleophilic carbon or the α- or β-carbons of the electrophile. Catalytic, enantioselective Michael reactions include a chiral nonracemic catalyst that promotes formation of a single enantiomeric product selectively.

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In Michael reactions, the nucleophile may be generated by treatment of a pronucleophile such as a ketone, malonate, or nitroalkane with base or may be prepared in advance as an enoxysilane. The former are used in direct Michael reactions while the latter are the nucleophilic species in Mukaiyama-Michael reactions. Catalytic, enantioselective variants of these reactions employ metal complexes, Lewis acids, or organic species in chiral nonracemic form as catalysts. An enormous variety of catalysts have been developed for enantioselective Michael reactions, but the catalyst of choice for a given pair of substrates depends strongly on substrate structure. Typically the catalyst enforces selectivity by blocking one face of the prochiral nucleophile and/or electrophile during the carbon-carbon bond-forming step, although more complex mechanistic scenarios have been observed in some cases (see below).

Mechanism and Stereochemistry

Types of Stereoselectivity

Enantioselective Michael reactions can be classified according to the prochirality of the nucleophile and the electrophile.[5][6] This classification is important because the number of stereocenters set in the reaction and their locations in the product dictate the types of stereodiscrimination in which the catalyst must engage (Eq. 2).

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If the reaction establishes only one stereocenter (that is, if only one of the substrates is prochiral), the chiral catalyst must control only the facial selectivity at either the nucleophile or electrophile, depending on which of the two is prochiral. If both substrates are prochiral, the catalyst must control facial selectivity at both the nucleophile and electrophile and thereby exhibit simple diastereoselection. In the latter case, the selectivity induced by the catalyst may oppose the "natural" diastereoselectivity observed in the uncatalyzed reaction.

Prevailing Mechanisms

Metal or Lewis Acid Catalysis

In metal-catalyzed direct Michael reactions, the nucleophile (generated by deprotonation of a highly acidic pronucleophile such as a 1,3-dicarbonyl compound or nitroalkane) coordinates to a chiral metal complex, forming an intermediate in which the faces of the nucleophilic carbon are heterotopic (Eq. 3). The electrophile approaches the more accessible face of this intermediate selectively, which leads to the formation of a stabilized anion in enantioenriched form. Proton transfer and exchange of the product for a nucleophile molecule then occurs.[7]

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Mukaiyama-Michael reactions involve the use of an enoxysilane nucleophile prepared in advance from a carbonyl compound. The electrophile coordinates to the Lewis acidic catalyst, which promotes addition by the relatively weak enoxysilane nucleophile and blocks one of the faces of the electrophile (Eq. 4).[8] A hetero-Diels-Alder mechanism, in which the electrophile acts as diene and the nucleophile as dienophile, has also been observed.[9]

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Organocatalysis

In contrast to the metal- or Lewis acid-catalyzed Michael reactions described above, organocatalyzed reactions often involve the formation of a covalent bond between the catalyst and one of the substrates. Activation of the nucleophilic species involves the formation of an enamine from a chiral amine catalyst and a carbonyl compound. Activation of the electrophile involves the formation of an iminium ion from a chiral amine catalyst and an α,β-unsaturated carbonyl compound.

Studies of reactions involving enamine activation have demonstrated that the first irreversible step of the mechanism is not carbon-carbon bond formation, but protonation of the substituted enamine formed after the addition step (Eq. 5).[10] As a result, stereoselectivity depends on the relative rates of protonation of diastereomeric enamines.

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Iminium ions formed from α,β-unsatured aldehydes and chiral amines are more electrophilic than the starting aldehydes. Thus, amines can be used as electrophile-activating catalysts in certain types of Michael reactions. Nucleophilic addition at the β position of the conjugated iminium ion affords an enamine, which undergoes hydrolysis to form the product and regenerate the amine catalyst (Eq. 6).[11]

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Organic molecules that form hydrogen bonds to the nucleophile and/or electrophile can also act as organocatalysts of the Michael reaction. Thioureas have emerged as privileged structures in this context. In the example shown in Eq. 7, the pendant amine base deprotonates the pronucleophile. In the stereodetermining transition state, two hydrogen bonds between the nucleophile and catalyst and a secondary interaction between the nitro group in the electrophile and the ammonium group result in strong facial discrimination.[12]

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Scope and Limitations

Coordination complexes that catalyze enantioselective Michael reactions may be mono- or polymetallic. Among monometallic catalysts, ruthenium amido complex 1 is effective for the addition of ethyl acetoacetate or malonates to cyclic enones (Eq. 8).[13] Complexes of rare earth elements have also been used with success.[14]

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One of the most useful examples of a heterobimetallic catalyst for the Michael reaction contains a rare earth metal surrounded by naphthoxide ligands and alkali metal cations. This catalyst promotes additions of nitromethane, β-keto esters, or malonates to cyclic or acyclic enones. In particular, it catalyzes the addition of β-keto esters to methyl vinyl ketone (Eq. 9).[15]

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Mukaiyama-Michael reactions, in which an enoxysilane serves as the nucleophile, are most commonly catalyzed by metal complexes. The copper(II)-bisoxazoline family of catalysts exhibits wide substrate scope in this reaction, but only N-enoyloxazolidinones may be used as electrophiles because bidentate coordination of the electrophile to the catalyst is necessary (Eq. 10).[16]

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Because enamines are relatively weak nucleophiles, organocatalyzed Michael reactions that proceed via enamine activation are limited to very strong electrophiles such as nitroalkenes. Tripeptide catalyst 3 includes a proline residue that participates in enamine formation and a terminal carboxy group that is believed to bind the nitro group in the electrophile (Eq. 11).[17]

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α,β-Unsaturated aldehydes are problematic electrophiles in Michael reactions catalyzed by Lewis acidic metal complexes. However, iminium activation offers an attractive alternative that is both atom economical and operationally simple. Silyl prolinol catalysts such as 4 control the intermediate iminium ion geometry effectively and block one of its faces (Eq. 12).[18] Only highly acidic pronucleophiles (1,3-dicarbonyl compounds or nitroalkanes) may be used because of the neutral or slightly acidic conditions required for formation of the iminium ion.

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Organic molecules that form hydrogen bonds to the electrophile can catalyze conjugate addition by lowering its LUMO. Bifunctional thioureas operate in this manner and demonstrate wide substrate scope.[19] Rigid squaramide catalysts were developed later and exhibit a more optimal orientation of N-H groups for hydrogen bonding to the Michael acceptor. Catalyst 5 includes an additional basic site and catalyzes the reaction of 1,3-diketones with nitroalkenes in short reaction times with good yields and high enantioselectivity (Eq. 13).[20]

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Chiral ammonium or phosphonium salts have been employed as phase-transfer catalysts in enantioselective Michael reactions. After deprotonation of the nucleophile in the aqueous phase, ion pairing and migration to the organic phase leads to addition to the organic-soluble electrophile. This method is limited by the requirement that the nucleophile be generated in the aqueous phase, as no base stronger than hydroxide may be used. Glycinate-benzophenone imines, the most common pronucleophiles, react efficiently with a diverse group of Michael acceptors in the presence of chiral ammonium catalyst 6 under phase-transfer conditions (Eq. 14).[21]

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Bifunctional catalysts such as 5 often include a basic group that participates in catalysis. However, chiral Brønsted bases have themselves been employed as enantioselective catalysts for the Michael reaction. Alkaloid-based catalyst 7 catalyzes the reaction of 1,3-diketones with alkynones (Eq. 7).[22] This reaction affords a mixture of (E) and (Z) isomers, which is converted almost exclusively to the (E) isomer via treatment with triphenylphosphine.

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Synthetic Applications

The extreme diversity of catalysts available for enantioselective Michael reactions has resulted in the application of this reaction as a key step in a number of syntheses of natural products. Often, the reaction is used to set a stereocenter at an early stage that is maintained throughout the remainder of the synthesis. For example, enamine catalysis was applied in an enantioselective Michael reaction between propanal and methyl vinyl ketone during a synthesis of (–)-bitungolide F, a cytotoxic polyketide (Eq. 16).[23]

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A reported synthesis of (S)-warfarin uses a catalytic, enantioselective Michael reaction under iminium ion catalysis as a key step (Eq. 17).[24] Although the reaction exhibits moderate enantioselectivity, recrystallization from acetone/water increases the purity of the (S)-enantiomer to greater than 99.9%. Furthermore, the synthesis of (R)-warfarin can be realized by a simple switch in the absolute configuration of the catalyst.

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Comparison to Other Methods

Alternative methods for the construction of 1,5-dicarbonyl compounds are very limited, particularly if a chiral product is desired in nonracemic form. For example, ozonolysis of cyclopentenes is one possibility, but the starting material must already be enantiopure (Eq. 18).[25]

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Michael reactions employing chiral auxiliaries are an alternative to enantioselective catalysis, although additional steps to install and remove the auxiliary are necessary and a stoichiometric amount of the chiral auxiliary must be used. Amide enolates derived from Evans oxazolidinones react with Michael acceptors with high diastereoselectivity and good yield (Eq. 19).[26] Electrophiles generally must be unsubstituted at the β-position and nucleophiles are limited to carboxylic acid derivatives.

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When a ketone or aldehyde is the desired Michael donor, SAMP/RAMP hydrazines[27] or α-methylbenzylamine[28] may be used as chiral auxiliaries. The latter is an attractive choice because the auxiliary is removed via simple hydrolysis (Eq. 20).

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Experimental Conditions and Procedure

Typical Conditions

Michael reactions catalyzed by metal complexes generally require the use of inert atmosphere and dry solvents. Organocatalyzed reactions, on the other hand, are often carried out with reagent-grade solvents in the open air. Catalyst loadings are usually higher in organocatalyzed reactions, although hydrogen-bonding catalysts may be effective in slightly lower amounts than enamine and iminium catalysts. Importantly, reactions proceeding via iminium activation of the electrophile require a Brønsted acid co-catalyst. Michael reactions under phase-transfer catalysis typically involve the preparation of a biphasic mixture from an aqueous solution of the base and an organic solution of the pronucleophile, electrophile, and catalyst.

Example Procedure[29]

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Propanal (10 mmol, 0.75 mL, 10 equiv) was added to a solution of trans-β-nitrostyrene (1.0 mmol, 154 mg, 1.0 equiv) and (S)-2-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine (0.1 mmol, 34 mg, 0.10 equiv) in hexane (1.0 mL) at 0 ºC. After the mixture had been stirred for 5 h at 0 ºC, the reaction was quenched by the addition of aqueous 1 N HCl (2.0 mL). The mixture was extracted with EtOAc (3 x 5 mL), the combined organic phases were dried (Na2SO4) and concentrated, and the residue was purified by preparative TLC (CHCl3) to give the title compound (0.85 mmol, 183 mg, 85%, syn 94.0:6.0 er, anti 99.5:0.5 er) as a clear oil: tR (2R,3S) 19.7 min (major), tR (2S,3R) 14.5 min (minor) (Daicel Chiralcel-ODH, hexanes/i-PrOH, 10:1, 1.0 mL/min, 254 nm). The remaining analytical data matched that previously published[30]: 1H NMR (CDCl3, 500 MHz) δ 9.72 (d, J = 1.5 Hz, 1H), 7.36–7.29 (m, 3H), 7.17–7.16 (m, 2H), 4.80 (dd, J = 12.9, 5.5 Hz, 1H), 4.69 (dd, J = 12.9, 9.2 Hz, 1H), 3.81 (ddd, J = 9.2, 9.2, 5.5 Hz, 1H), 2.80–2.75 (m, 1H), 1.01 (d, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 202.2, 136.5, 129.1, 128.1, 128.0, 78.1, 48.4, 44.0, 12.1; HRMS (m/z): [M + H]+ calcd for C11H13NO3, 207.0817; found, 207.0812. Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76. Found: C, 63.42; H, 6.27; N, 6.43.

References

  1. ↑ Reyes, E.; Uria, U.; Vicario, J. L.; Carrillo, L. Org. React. 2016, 90, 1. (link)
  2. ↑ Michael, A. J. Prakt. Chem. 1887, 35, 349.
  3. ↑ Bergmann, E. D.; Ginsburg, D.; Papp, R. Org. React. 1959, 10, 179. (link)
  4. ↑ Chapdelaine, M. J.; Hulce, M. Org. React. 1990, 38, 227. (link)
  5. ↑ Oare, D. C.; Heathcock, C. H. Top. Stereochem. 1989, 19, 227.
  6. ↑ Oare, D. C.; Heathcock, C. H. Top. Stereochem. 1991, 20, 87.
  7. ↑ Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240.
  8. ↑ Liu, D.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 8160.
  9. ↑ Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
  10. ↑ Patora-Komisarska, K.; Meryem, B.; Ishikawa, H.; Seebach, D.; Hayashi, Y. Helv. Chim. Acta 2011, 94, 719.
  11. ↑ Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416.
  12. ↑ Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119.
  13. ↑ Watanabe, M.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2003, 125, 7508.
  14. ↑ Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506.
  15. ↑ Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 5561.
  16. ↑ Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480.
  17. ↑ Wiesner, M.; Revell, J. D.; Wennemers, H. Angew. Chem., Int. Ed. 2008, 47, 1871.
  18. ↑ Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307.
  19. ↑ Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119.
  20. ↑ Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416.
  21. ↑ Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347.
  22. ↑ Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 5672.
  23. ↑ ElMarrouni, A.; Joolakanti, S. R.; Colon, A.; Heras, M.; Arseniyadis, S.; Cossy, J. Org. Lett. 2010, 12, 4074.
  24. ↑ Halland, N.; Hansen T.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 4955.
  25. ↑ de Mayo, P. Acc. Chem. Res. 1971, 4, 41
  26. ↑ Evans, D. A.; Bilodeau, M. T.; Somers, T. C.; Clardy, J.; Cherry, D.; Kato, Y. J. Org. Chem. 1991, 56, 5750.
  27. ↑ Enders, D.; Papadopoulus, K. Tetrahedron Lett. 1983, 24, 4967.
  28. ↑ Pfau, M.; Revial, G.; Guingant, A.; d’Angelo, J. J. Am. Chem. Soc. 1985, 107, 273.
  29. ↑ Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212.
  30. ↑ Betancort, J. M.; Barbas, C. F., III Org. Lett. 2001, 3, 3737.
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