Asymmetric Catalysis

Organocatalyzed Asymmetric a-Aminoxylation ofAldehydes and Ketones—An Efficient Access toEnantiomerically Pure a-Hydroxycarbonyl Compounds,Diols, and Even Amino AlcoholsPedro Merino* and Tomas Tejero

Keywords:aldehydes · asymmetric catalysis · ketones ·oxidation · proline

The asymmetric installation of a hy-droxy group at the position a to acarbonyl function is an important C�Obond-forming process in organic syn-thesis.[1] The resulting optically active a-hydroxy carbonyl compounds are ofgeneral interest since they provide di-rect routes to a vast number of bio-logically significant compounds includ-ing carbohydrates, antibiotics, alkaloids,and terpenes. The most widely useddirect procedure for preparing opticallyactive a-hydroxy carbonyl compounds isthe oxidation of enolates with an oxidiz-ing reagent.[2] Asymmetry is induced byusing either chiral nonracemic enolateswith achiral reagents or prostereogenicenolates and enantiomerically pure ox-idizing reagents, typically N-sulfonylox-aziridines.[3] Alternative to these chem-ical methods a variety of a-oxy-func-tionalized carbonyl compounds, includ-ing a-hydroxy, a-hydroperoxy, and a-acetoxy derivatives, can also be pre-pared in enantiomerically pure form bybiocatalytic methods.[4]

Despite the emergence during thetwo last decades of new efficient andconvenient enantioselective catalyticprocesses,[5] not many methods areknown for the catalyzed asymmetric

addition of electrophiles to enolates.[3,6]

The asymmetric a-amination of alde-hydes and ketones provides a usefulreference point for the reaction de-scribed in this account.[7]

Among the electrophiles that can beused to introduce a heteroatom at the aposition of a carbonyl group, nitrosocompounds[8] are particularly attractivebecause of the presence of two differentelectrophilic centers (N and O atoms)that could lead to either N- or O-alkylation, provided the regioselectivityof the reaction can be controlled(Scheme 1).

Yamamoto and co-workers ap-proached this problem by using lithiumand tin enolates, in the absence of anycatalyst, to generate the correspondinga-hydroxyamino carbonyl compounds3.[9] The regiochemical control of the

reaction illustrated in Scheme 1 resultedfrom the Lewis acid catalyst; the bestresults were obtained with Et3SiOTf.

[10]

Under these conditions both silyl and tinenolates provided the a-aminoxy car-bonyl compounds 4. In order to intro-duce asymmetry in the reaction it wasconducted in the presence of (R)-binap(binap = 2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl) and 10 mol% AgOTf.Complete O-selectivity with 91% eewas observed, and of the various silversalts surveyed, the AgOTf and AgClO4

complexes gave the best results in termsof both enantio- and regioselection(Scheme 2).[11] The reaction was testedwith various tin enolates and, in allcases, O-regioselectivity and enantiose-lectivity were maintained. The furthertransformation of a-aminoxy ketone 6into a-hydroxy ketone 7 was smoothly

Scheme 1. N- vs. O-alkylation of carbonylcompounds in the reaction with nitrosoben-zene.

Scheme 2. Asymmetric, catalyzed nitroso-aldolreaction of tin enolate 5 with nitrosoben-zene.[11]

[*] Dr. P. Merino, Dr. T. TejeroLaboratorio de Sintesis AsimetricaDepartamento de Quimica OrganicaFacultad de CienciasUniversidad de Zaragoza50009 Saragossa, Aragon (Spain)Fax: (+34)976-762-075E-mail: pmerino@unizar.es

AngewandteChemie

2995Angew. Chem. Int. Ed. 2004, 43, 2995 –2997 DOI: 10.1002/anie.200301760 � 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

carried out with a catalytic amount(0.3 equiv) of CuSO4 in methanol. Theselectivity found for ketone 7 was97% ee.

During the past five years there hasbeen a dramatic upsurge of interest inasymmetric non-transition-metal-cata-lyzed reactions,[12] particularly thoseconcerning aminocatalysis in which acarbonyl group is activated by a chiralamine.[13] In this context, (S)-proline,which can serve as a ligand in asymmet-ric transition-metal-catalyzed reactions,has been also found to be an excellentcatalyst by itself[14] for reactions ofcarbonyl compounds,[15] including thea-amination of aldehydes and ketones.[7]

Last year several reports appeared inwhich a-aminoxylated aldehydes andketones 4 were prepared in enantiomer-ically pure form from the parent car-bonyl compounds and nitrosobenzenewith (S)-proline as the catalyst(Scheme 1). The advantages of thisorganocatalyzed transformation areclear: 1) the asymmetric reaction iscarried out by a metal-free catalyst,and 2) no enolates must be preformed.The groups of MacMillan[16] and Ha-yashi[17] and also Zhong[18] reported al-most simultaneously the direct (S)-pro-line-catalyzed enantioselective a-amin-oxylation of aldehydes (Scheme 3).

In contrast to other proline-cata-lyzed asymmetric reactions,[15] whichrequire up to 47 mol% catalyst,[19] thereaction outlined in Scheme 3 is effi-ciently catalyzed even with catalystloadings as low as 0.5 mol% as MacMil-lan et al. demonstrated.[16] The use of2 mol% is, however, more advisable inorder to maintain expedient reactiontimes.

Almost as interesting as the highenantioselectivity observed for 9 is thepreferred O-regioselectivity. In princi-

ple, trends similar to those observed fortin enolates in the absence of anycatalyst (N-alkylation) might be expect-ed for the reaction of the intermediateenamine (a masked enolate), which isformed upon activation of the aldehyde.However, only O-alkylation is observedin all cases. This means that additionaldirecting features are needed to ensureattack at the oxygen atom. Prolinemeets such a requirement due to thepresence of the carboxyl group whichmay favor a transition state A with anintramolecular hydrogen bond stabi-lized by the enhanced Brønsted basicityof the nitrogen atom (Scheme 4). ModelA has been proposed essentially in thesame, but independent, way by thegroups of MacMillan,[16] Hayashi,[17]

and Zhong,[18] and it follows the previ-ously reported mechanistic considera-tions for (S)-proline-catalyzed reactions

of ketones and aldehydes with electro-philes.[7, 13] It is important to emphasizethat while model A is consistent withexperimental data collected to date, itstill needs a firmer foundation. Ofcourse, our understanding of the detailsof proline-catalyzed reactions willchange with time and experience.

The reaction appears to be quitegeneral since both aliphatic and aromat-ic aldehydes gave good results. Even thepresence of several functional groups,

such as a C=C bond, Si-protected hy-droxy groups, and N-Boc amino groups,and variation in the steric demand of thealdehyde did not affect the reaction interms of efficiency or enantioselectivity.

A considerable broadening of thescope of the reaction has been recentlyachieved with the extension to ketones.Cordova and co-workers[20] as well asHayashi and co-workers[21] reported si-multaneously the organocatalyzedasymmetric a-aminoxylation of ketones(Scheme 5). Condensation of an excess

(2.0 to 10.0 equiv) ofcyclohexanone 12with 1.0 equiv nitroso-benzene in a highlypolarized solvent suchas DMSO or DMFand in the presenceof a substoichiometricamount (5–30 mol%)of (S)-proline provid-ed opportunities toexamine the behaviorof the reaction undera variety of experi-mental condi-tions.[20,21] Althoughexcellent enantiose-lectivities were ob-served for compound13, low chemicalyields and considera-ble amounts of thecorresponding a,a’-bis(aminoxylated)

product were also obtained. Syntheti-cally useful chemical yields and com-plete a-monoaminoxylation were possi-ble by slow addition (syringe pump) ofnitrosobenzene to the reaction mixture.The extension to other cyclic ketonesresulted in excellent yields as well asalmost complete regio- and enantiose-lectivities. Unfortunately, acyclic ke-tones gave unfavorable mixtures of O-and N-alkylated products; in all cases,with the exception of 3-butenyl methyl

Scheme 3. Enantioselective (S)-proline-cata-lyzed a-aminoxylation of aldehydes. TIPS= tri-isopropylsilyl.[16] Scheme 4. Catalytic cycle for the (S)-proline-catalyzed a-aminoxy-

lation of carbonyl compounds.

Scheme 5. Asymmetric a-aminoxylation ofketones.

Highlights

2996 � 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org Angew. Chem. Int. Ed. 2004, 43, 2995 –2997

ketone, the O-alkylated adduct was themajor product.

a-Aminoxylated carbonyls can betransformed readily into the corre-sponding a-hydroxy carbonyls and thenreduced to diols without any loss inoptical purity.[11] The reduction of thecarbonyl moiety can also be made in situprior to cleavage of the the N�O bond(NaBH4)

[20] or in a simultaneous way(NaBH4, Pd/C, H2),

[16] thus providing analternative, synthetically attractive sol-ution, in the case of a-hydroxy alde-hydes (Scheme 6, R1=H), to the asym-

metric dihydroxylation of terminal ole-fins. Scheme 6 illustrates the potential ofthe enantioselective a-aminoxylation ofaldehydes and ketones for the synthesisof diols and immediate precursors ofamino alcohols like 16.

The asymmetric organocatalyzed a-aminoxylation of aldehydes and ketonesis a powerful, metal-free, direct methodfor the synthesis of a-hydroxy aldehydesand ketones. The reaction with nitro-sobenzene forms the a-phenylaminoxycarbonyl both regio- and enantioselec-tively in good to excellent yields. Thedirectness of the approach to a-hydroxycarbonyls, the generality of the proline-mediated nitrosoaldol reaction, whichpermits great flexibility in selection ofaldehydes and ketones, and the versa-

tility of the reaction are impressiveadvantages that should facilitate thesynthesis of many useful small mole-cules possessing not only the a-hydroxy-carbonyl unit but also other function-alities such as diols or amino alcohols.Undoubtedly, all these possibilitiesshould provide synthetic tools for theasymmetric synthesis of collections ofmolecules with high levels of diversitydirected to the recently proposed “di-versity-oriented synthesis”.[22]

Published Online: May 13, 2004

[1] J. Fuhrhop, G. Penalin, Organic Syn-thesis, 2nd ed., VCH, Weinheim, 1994,chap. 2.

[2] F. A. Davis, B.-C. Chen, Houben Weyl:Methods of Organic Chemistry. Stereo-selective Synthesis, Vol. E21 (Eds.: G.Helmchen, R. W. Hoffmann, J. Mulzer,E. Schaumann), George Thieme, Stutt-gart, 1996, pp. 4497 – 4518.

[3] F. A. Davis, B.-C. Chen, Chem. Rev.1992, 92, 919 – 934.

[4] W. Adam, M. Lazarus, C. R. Saha-MKl-ler, P. Schreier,Acc. Chem. Res. 1999, 32,837 – 845.

[5] a) S. T. Handy, Curr. Org. Chem. 2000, 4,363 – 395; b) Special Issue on Enantio-selective Synthesis: Chem. Rev. 2003,103(8), 2761 – 3400.

[6] a) W. Adam, R. T. Fell, V. R. Stegmann,C. R. Saha-MKller, J. Am. Chem. Soc.

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[7] R. O. Duthaler, Angew. Chem. 2003,115, 1005 – 1008; Angew. Chem. Int.Ed. 2003, 42, 975 – 978.

[8] For reviews on nitroso compounds see:a) P. Zuman, P. Shah, Chem. Rev. 1994,94, 1621 – 1641; b) L. Soghyuk, C. Li,H. W. Ann, Chem. Rev. 2002, 102, 1019 –1066.

[9] N. Momiyama, H. Yamamoto,Org. Lett.2002, 4, 3579 – 3582.

[10] N. Momiyama, H. Yamamoto, Angew.Chem. 2002, 114, 3112 – 3114; Angew.Chem. Int. Ed. 2002, 41, 2986 – 2988;Corrigendum: Angew. Chem. 2002, 114,3459; Angew. Chem. Int. Ed. 2002, 41,3313.

[11] N. Momiyama, H. Yamamoto, J. Am.Chem. Soc. 2003, 125, 6038 – 6039.

[12] P. I. Dalko, L. Moisan, Angew. Chem.2001, 113, 3840 – 3864; Angew. Chem.Int. Ed. 2001, 40, 3726 – 3748.

[13] B. List, Synlett 2001, 1675 – 1686.[14] Although the catalyst activity of (S)-

proline has been known since the 1970s,it was not applied for asymmetric catal-ysis until recently. See: M. Movassaghi,E. N. Jacobsen, Science 2002, 298, 1904 –1905.

[15] B. List, Tetrahedron 2002, 58, 5573 –5590.

[16] S. P. Brown, M. P. Brochu, C. J. Sinz,D. W. C. MacMillan, J. Am. Chem. Soc.2003, 125, 10808 – 10809.

[17] Y. Hayashi, J. Yamaguchi, K. Hibino, M.Shoji, Tetrahedron Lett. 2003, 44, 8293 –8296.

[18] G. Zhong, Angew. Chem. 2003, 115,4379 – 4382; Angew. Chem. Int. Ed.2003, 42, 4247 – 4250.

[19] In fact, most experiments carried out byHayashi and co-workers (see ref. [18])are conducted in the presence of30 mol% (S)-proline. Similarly, Zhong(see ref. [19]) used 20 mol% catalyst.

[20] A. Bøegevig, H. Sunden, A. CMrdova,Angew. Chem. 2004, 116, 1129 – 1132;Angew. Chem. Int. Ed. 2004, 43, 1109 –1112.

[21] Y. Hayashi, S. Yamaguchi, T. Sumiya, M.Shoji, Angew. Chem. 2004, 116, 1132 –1135; Angew. Chem. Int. Ed. 2004, 43,1112 – 1115.

[22] a) S. L. Schreiber, Science 2000, 287,1964 – 1969; b) M. D. Burke, S. L.Schreiber, Angew. Chem. 2004, 116,48 – 60; Angew. Chem. Int. Ed. 2004,43, 46 – 58.

Scheme 6. Synthetic applications of the asymmetric organocatalyzed a-aminoxylation of alde-hydes and ketones.

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