DOI: 10.1002/cctc.201200926

Asymmetric Copper-catalyzed 1,4-Additions and AllylicSubstitutions with Nucleophiles Formed by theHydrometalation of AlkenesRadovan Sebesta*[a]

The need for enantiomerically pure pharmaceuticals, agro-chemicals, food additives, and other chiral compounds propelsresearch in the area of asymmetric catalysis. Metal catalyzed1,4-addition and allylic substitution of organometallic nucleo-philes to Michael acceptors are among the principal transfor-mations for the synthesis of chiral compounds, applicable alsoat industrial scale.[1] Typically, complexes of soft transitionmetals, such as copper,[2] and rhodium,[3] are used to catalyzethese reactions. Particularly copper-catalyzed conjugate addi-tion and allylic substitution share a number of common fea-tures, because they have similar transition states. A variety ofnucleophiles can be employed, such as organolithium,Grignard, organozinc, organoaluminium, organoboron, andother reagents. However, the majority of these reagents haveto be synthesized prior to conjugate addition or allylic substi-tution itself. In addition, these reagents are usually highly reac-tive and do not tolerate many common functional groups.Practical applications limit also their sensitivity to air and mois-ture or the necessity to work at low temperatures. Therefore,a method that would enable convenient formation of benignorganometallic species from simple and inexpensive precur-sors, and be compatible with metal-catalyzed asymmetric1,4-conjugate addition, would be of great value.

Alkenes are the simplest and most convenient sources ofcarbon synthons. So, are there any methods available to trans-form them into suitable organometallic reagents applicable toasymmetric metal-catalyzed conjugate additions? One canthink of numerous hydrometalation or carbametalation reac-tions, which are quite common among organometallic com-pounds. However, only some of them are of practical syntheticvalue. Furthermore, in comparison to hydrometalations of al-kynes, which leads to alkenyl metal species,[4] alkene hydro-metalations often suffer from rapid b-hydride elimination, a re-verse reaction to hydrometalation. Therefore the choice of suit-able hydrometalating reactions, applicable to alkenes, is limit-ed to hydroboration and hydrozirconation. Although both ofthese reactions have been known for long time, their utiliza-tion for in situ generation of sp3 carbon nucleophiles for asym-

metric 1,4-addition reaction or allylic alkylation has been un-known. There is, undoubtedly, great synthetic potential in thismethodology, as it considerably broadens the scope of theseasymmetric transformations. The primary reason is that othersp3-hybridized carbon nucleophiles such as organolithium,Grignard, organoaluminium, or dialkylzinc reagents are very re-active and, thus, have low tolerance for many functionalgroups. Another important feature of this approach is in-creased effectiveness in terms of step economy, because re-quired organometallic reagent is prepared in situ or at leastwithout the need for its isolation and purification. Therefore,combination of hydrometalation of alkenes with enantioselec-tive Cu-catalyzed 1,4-addition and allylic substitution consti-tutes an important advance in the field of asymmetric catalysis(Scheme 1).

Hydroboration, discovered by Brown already in the 1950s, isa well-known method for the synthesis of organoboron com-pounds.[5] Knochel and co-workers described transmetalationof the resulting alkyl boranes to dialkylzinc reagents,[6] whichwere then used in the Cu-catalyzed 1,4-additions.[7] However,direct use of alkyl boranes is scarce. Only recently, were alkyl-boranes, formed by hydroboration of alkenes, used directly inthe conjugate addition. At first, Sawamura and co-workers de-scribed achiral Cu-catalyzed conjugate addition of alkylboranesgenerated by hydroboration of alkenes with 9-borabicyclo-[3.3.1]-nonane dimer [9-BBN-H]2.[8] N-Heterocyclic carbenesproved to be useful ligands in this reaction. The use of sterical-ly bulky borane is important for ensuring high regioselectivityof the hydroboration toward terminal alkyl borane. Recently,the Sawamura group developed an enantioselective version of

Scheme 1. Alkene hydrometalation followed by asymmetric Cu-catalyzedconjugate addition and allylic substitution.

[a] Dr. R. SebestaDepartment of Organic ChemistryFaculty of Natural SciencesComenius University in BratislavaMlynsk� dolina CH2, SK-84215 Bratislava (Slovakia)Fax: (+ 421) 2-60296337E-mail : radovan.sebesta@fns.uniba.sk

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this process.[9] Several alkyl boranes, obtained by the hydro-boration of terminal alkenes with [9-BBN-H]2, were in this wayadded to unsaturated 1-methylimidazolyl or benzimidazolyl ke-tones. The reaction tolerated various functional groups in thealkene, such as ester, ether, or chloro substituents. High effi-ciency and enantioselectivity of the conjugate addition was en-sured by a Cu-complex of chiral N-heterocyclic carbene ligandL1 (Scheme 2). The ligand structure, in particular its steric

properties, was fine-tuned in order to achieve maximumenantioselectivity.

Alkylboranes produced by hydroboration of alkenes werealso utilized as a source of sp3-carbon nucleophiles for theCu-catalyzed allylic substitution. Allylic phosphates reacted re-gioselectively at the g-position with alkyl-9-BBN reagentsunder catalysis of copper acetate.[10a,b] Further developmentled to the identification of a unique switchable 1,3-anti and1,3-syn substitution.[10c] In related studies, propargylic substitu-tion have also been described. Chiral propargylic phosphateswere, with the help of either Cu-NHC or CuOAc catalyst, trans-formed into chiral allenes.[11] These studies culminated in thedevelopment of the first enantioselective allylic substitution ofprimary allylic chlorides with alkyl-9-BBN reagents.[12] Sawa-mura, Ohmiya, and co-workers showed that the reaction is cat-alyzed by Cu-complex of the DTBM-SEGPHOS ligand (L2)(Scheme 3). The substitution proceeded with high regioselec-tivity (g/a>98:2) and enantioselectivity. The authors also dem-onstrated that a useful array of functional groups is toleratedby the transformation, such as acetal, ester, amide, silyl ether,or even a terminal chloride.

Hydrozirconation is another synthetically useful hydrometa-lation reaction. Schwartz reagent (Cp2ZrHCl) readily adds to al-kenes and alkynes producing alkyl or alkenylzirconium com-pounds.[13] These organozirconium reagents can be transmeta-lated to other organometallic species, such as organozinc re-agents or cuprates. Also direct utilization of thus formedorganozirconium reagents as nucleophiles in conjugate addi-tion is known, but until recently it was possible only in achiralor diastereoselective, substrate controlled way.[14] Successfulutilization of alkenylzirconium reagents in a Rh-catalyzed con-

jugate addition was demonstrated by Oi et al.[15a] Nicolaou andco-workers later utilized the methodology in the constructionof spirocyclic system of Vannusal A, a marine natural pro-duct.[15b]

An important advance in the use of alkylzirconium com-pounds in the enantioselective Cu-catalyzed 1,4-addition hasbeen realized only recently by Fletcher and co-workers.[16] Theysucceeded in performing hydrozirconation of alkenes and sub-sequently combined it with asymmetric Cu-catalyzed 1,4-addi-tion to cyclic enones (Scheme 4).

Several factors seem to contribute to the successful realiza-tion of this strategy. A striking counterion effect was noted,where only CuOTf and CuPF6 gave enantioselectivities higherthan 50 % ee. Also structure of the chiral ligand played crucialrole in achieving high enantioselectivity together with the factthat authors used pre-made air stable Cu-complex of the phos-phoramidite ligand L3. On the other hand, the transformationwas remarkably insensitive to solvent and temperature. Furtherimprovement was achieved by the use of trimethylsilyl chlorideas additive, which is known to speed up conjugate additions.Several alkyl and aryl-substituted alkenes were used in thestudy with good results. Interestingly, also bromo-, chloro-,silyl, and silyloxy-substituted alkenes were tolerated, demon-

Scheme 2. Enantioselective hydroboration and Cu-catalyzed conjugate addi-tion.

Scheme 3. Enantioselective hydroboration and Cu-catalyzed allylic substitu-tion.

Scheme 4. Cu-Catalyzed conjugate addition with alkylzirconium reagents.

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strating great potential of combining the hydrozirconationwith Cu-catalyzed conjugate addition. Recently, Fletcher’s labo-ratory showed applicability of this approach in the synthesis ofstructurally complex molecules.[17]

In conclusion, hydrometalation of alkenes is an interestingand appealing way of producing reactive nucleophiles forasymmetric conjugate additions as well as allylic substitutionreactions. Benign character of nucleophiles, organoboron, andorganozirconium reagents, allows for the use of functionalizedsubstrates, which can be advantageous when using this ap-proach for the synthesis of complex molecules. Further appli-cation of this methodology can be in domino processes basedon conjugate additions, because primary products of hydro-metalations followed by 1,4-additions are either boron or zirco-nium enolates. Therefore, one can envision effective trappingof such enolates with electrophiles, thus further broadeningthe scope of the methodology.

Acknowledgements

Financial support from Slovak Grant Agency VEGA, grant no.1/0623/12 is gratefully acknowledged.

Keywords: 1,4-addition · allylic substitution · asymmetriccatalysis · boron · hydrometalation

[1] G. P. Howell, Org. Process Res. Dev. 2012, 16, 1258 – 1272.[2] For recent reviews on Cu-catalyzed 1,4-additions and allylic substitu-

tions see: a) C. Hawner, A. Alexakis, Chem. Commun. 2010, 46, 7295 –7306; b) A. Alexakis, J. E. B�ckvall, N. Krause, O. P�mies, M. Di�guez,Chem. Rev. 2008, 108, 2796 – 2823; c) S. R. Harutyunyan, T. den Hartog,K. Geurts, A. J. Minnaard, B. L. Feringa, Chem. Rev. 2008, 108, 2824 –2852; d) C. A. Falciola, A. Alexakis, Eur. J. Org. Chem. 2008, 3765 – 3780;e) A. Alexakis, C. Malan, L. Lea, K. Tissot-Croset, D. Polet, C. Falciola,Chimia 2006, 60, 124 – 130; f) H. Yorimitsu, K. Oshima, Angew. Chem.2005, 117, 4509 – 4513; Angew. Chem. Int. Ed. 2005, 44, 4435 – 4439; g) S.Woodward, Angew. Chem. 2005, 117, 5696 – 5698; Angew. Chem. Int. Ed.2005, 44, 5560 – 5562.

[3] For recent reviews on Rh-catalyzed 1,4-additions see: a) P. Tian, H.-Q.Dong, G.-Q. Lin, ACS Catal. 2012, 2, 95 – 119; b) H. J. Edwards, J. D. Har-grave, S. D. Penrose, C. G. Frost, Chem. Soc. Rev. 2010, 39, 2093 – 2105;c) T. Hayashi, Bull. Chem. Soc. Jpn. 2004, 77, 13 – 21.

[4] For an overview of alkenyl nucleophiles in the conjugate additions see:D. M�ller, A. Alexakis, Chem. Commun. 2012, 48, 12037 – 12049.

[5] H. C. Brown—Nobel Lecture: From Little Acorns to Tall Oaks—from Bor-anes through Organoboranes.

[6] F. Langer, A. Devasagayaraj, P. Y. Chavant, P. Knochel, Synlett 1994, 410 –412.

[7] a) R. Naasz, L. A. Arnold, M. Pineschi, E. Keller, B. L. Feringa, J. Am. Chem.Soc. 1999, 121, 1104 – 1105; b) B. L. Feringa, M. Pineschi, L. A. Arnold, R.Imbos, A. H. M. de Vries, Angew. Chem. 1997, 109, 2733 – 2736; Angew.Chem. Int. Ed. Engl. 1997, 36, 2620 – 2623; c) A. H. M. de Vries, A. Meet-sma, B. L. Feringa, Angew. Chem. 1996, 108, 2526 – 2528; Angew. Chem.Int. Ed. Engl. 1996, 35, 2374 – 2376.

[8] a) H. Ohmiya, M. Yoshida, M. Sawamura, Org. Lett. 2011, 13, 482 – 485;b) H. Ohmiya, Y. Shido, M. Yoshida, M. Sawamura, Chem. Lett. 2011, 40,928 – 930.

[9] M. Yoshida, H. Ohmiya, M. Sawamura, J. Am. Chem. Soc. 2012, 134,11896 – 11899.

[10] a) H. Ohmiya, U. Yokobori, Y. Makida, M. Sawamura, J. Am. Chem. Soc.2010, 132, 2895 – 2897; b) K. Nagao, H. Ohmiya, M. Sawamura, Synthesis2012, 44, 1535 – 1541; c) K. Nagao, U. Yokobori, Y. Makida, H. Ohmiya, M.Sawamura, J. Am. Chem. Soc. 2012, 134, 8982 – 8987.

[11] a) H. Ohmiya, U. Yokobori, Y. Makida, M. Sawamura, Org. Lett. 2011, 13,6312 – 6315; b) M. R. Uehling, S. T. Marionni, G. Lalic, Org. Lett. 2012, 14,362 – 365.

[12] Y. Shido, M. Yoshida, M. Tanabe, H. Ohmiya, M. Sawamura, J. Am. Chem.Soc. 2012, 134, 18573 – 18576.

[13] J. Schwartz, J. A. Labinger, Angew. Chem. 1976, 88, 402 – 409; Angew.Chem. Int. Ed. Engl. 1976, 15, 333 – 340.

[14] a) P. Wipf, H. Takahashi, Chem. Commun. 1996, 2675 – 2676; b) A. El-Batta, T. R. Hage, S. Plotkin, M. Bergdahl, Org. Lett. 2004, 6, 107 – 110;c) P. Wipf, J. H. Smitrovich, J. Org. Chem. 1991, 56, 6494 – 6496.

[15] a) S. Oi, T. Sato, Y. Inoue, Tetrahedron Lett. 2004, 45, 5051 – 5055; b) K. C.Nicolaou, W. Tang, P. Dagneau, R. Faraoni, Angew. Chem. 2005, 117,3942 – 3947; Angew. Chem. Int. Ed. 2005, 44, 3874 – 3879.

[16] R. M. Maksymowicz, P. M. C. Roth, S. P. Fletcher, Nat. Chem. 2012, 4,649 – 654.

[17] R. M. Maksymowicz, P. M. C. Roth, A. L. Thompson, S. P. Fletcher, Chem.Commun. 2013, DOI : 10.1039/C1032CC37155C.

Received: December 15, 2012Revised: January 19, 2013Published online on March 25, 2013

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