A highly regio-, diastereo-, and enantioselective desymmetrization of five-, six-, and seven-membered meso-cyclic allylic bis-diethyl phosphates (2a, 2b, and 2c, respectively) was obtained with diethylzinc, using catalytic amounts of [Cu(OTf)](2).C6H6 and phosphoramidite ligands 5. Enantiomeric excesses of up to 87, 94, and >98% were obtained for the addition of diethylzinc to cyclopentene, cyclohexene, and cycloheptene bis-diethyl phosphates, respectively

Claverie, C

Daubos, P

Feringa, B. L.

Gennari, C

Minnaard, A. J.

Piarulli, Umberto

A highly regio-, diastereo-, and enantioselective desymmetrization of five-, six-, and seven-membered meso-cyclic allylic bis-diethyl phosphates (2a, 2b, and 2c, respectively) was obtained with diethylzinc, using catalytic amounts of [Cu(OTf)](2).C6H6 and phosphoramidite ligands 5. Enantiomeric excesses of up to 87, 94, and &gt;98% were obtained for the addition of diethylzinc to cyclopentene, cyclohexene, and cycloheptene bis-diethyl phosphates, respectively.</p

Claverie, Christelle

Daubos, Philippe

Gennari, Cesare

Minnaard, Adriaan J.

Feringa, Bernard

Dissertations of the University of Groningen

English

Copper phosphoramidite-catalyzed enantioselective desymmetrization of meso-cyclic allylic bisdiethyl phosphates

PIARULLI, UMBERTO

CLAVERIE C

DAUBOS P

GENNARI C

MINNAARD A. J.

FERINGA B. L.

Archivio istituzionale della ricerca - Università dell'Insubria

Copper Phosphoramidite-CatalyzedEnantioselective Desymmetrization ofmeso-Cyclic Allylic BisdiethylPhosphatesUmberto Piarulli,*,†,‡ Christelle Claverie,‡ Philippe Daubos,‡ Cesare Gennari,*,‡Adriaan J. Minnaard,§ and Ben L. Feringa§Dipartimento di Scienze Chimiche, Fisiche e Matematiche, UniVersita` dell’Insubria,Via Valleggio 11, I- 22100 Como, Italy, Dipartimento di Chimica Organica eIndustriale, Centro di Eccellenza C.I.S.I., UniVersita` di Milano, Via G. Venezian 21,I-20133 Milano, Italy, and Department of Organic and Molecular InorganicChemistry, Stratingh Institute, UniVersity of Groningen, Nijenborgh 4,9747 AG Groningen, The Netherlandsumberto.piarulli@uninsubria.it; cesare.gennari@unimi.itReceived September 19, 2003ABSTRACTA highly regio-, diastereo-, and enantioselective desymmetrization of five-, six-, and seven-membered meso-cyclic allylic bis-diethyl phosphates(2a, 2b, and 2c, respectively) was obtained with diethylzinc, using catalytic amounts of [Cu(OTf)]2âC6H6 and phosphoramidite ligands 5.Enantiomeric excesses of up to 87, 94, and >98% were obtained for the addition of diethylzinc to cyclopentene, cyclohexene, and cycloheptenebis-diethyl phosphates, respectively.meso-Cyclic allylic diols are powerful substrates for theconstruction of enantiomerically enriched functionalizedproducts. Their desymmetrization has been realized byacylation or by allylic substitution, which can occur via SN2or SN2′ (allylic displacement) mechanisms, with eitherretention or inversion.1 The palladium-catalyzed desymme-trization, pioneered by Trost, is usually performed with softnucleophiles and takes place via the SN2 mechanism.2 Asomewhat related enantioselective ring opening of meso-oxabicyclic alkenes with organometallic reagents was re-ported by Lautens and co-workers (palladium-catalyzedaddition of alkylzinc reagents and RhI-catalyzed addition ofarylboronic acids)3 and by Pineschi, Feringa, and co-workers(CuI-catalyzed addition of alkylzinc reagents).4 Whereas in† University of Insubria.‡ University of Milano.§ University of Groningen.(1) For a recent review, see: Willis, M. C. J. Chem. Soc., Perkin Trans.1 1999, 1765-1784.(2) For recent accounts, see: (a) Graening, T.; Schmalz, H.-G. Angew.Chem., Int. Ed. 2003, 42, 2580-2584. (b) Trost, B. M.; Crawley, M. L.Chem. ReV. 2003, 103, 2921-2944.(3) (a) Lautens, M.; Renaud, J.-L.; Hiebert, S. J. Am. Chem. Soc. 2000,122, 1804-1805. (b) Lautens, M.; Hiebert, S.; Renaud, J.-L. Org. Lett.2000, 2, 1971-1973. (c) Lautens, M.; Hiebert, S.; Renaud, J.-L. J. Am.Chem. Soc. 2001, 123, 6834-6839. (d) Lautens, M.; Dockendorff, C.;Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311-1314 and referencestherein.(4) Bertozzi, F.; Pineschi, M.; Macchia, F.; Arnold, L. A.; Minnaard, A.J.; Feringa, B. L. Org. Lett. 2002, 4, 2703-2705.ORGANICLETTERS2003Vol. 5, No. 234493-449610.1021/ol035807l CCC: $25.00 © 2003 American Chemical SocietyPublished on Web 10/11/2003the first case the reaction occurs via the SN2′ mechanismwith retention (the nucleophile attacks from the same sideof the allylic leaving group),3 in the second case the allylicdisplacement reaction takes place with inversion.4 Piarulli,Gennari, and co-workers have recently disclosed a newhighly regio-, diastereo-, and enantioselective desymmetri-zation of meso-cyclic allylic bisdiethyl phosphates withorganozinc reagents5 catalyzed by copper(I) complexes ofchiral Schiff base ligands 1 (Scheme 1).6 In the case of meso-4-cyclopentene-1,3-bisdiethyl phosphate (2a), only the prod-uct arising from the allylic displacement (SN2′) mechanismwith inversion (3a) was obtained with excellent yield andenantiomeric excess (ee) up to 88% after screening a libraryof 125 Schiff-base ligands 1. Reaction of diethylzinc withmeso-2-cyclohexene-1,4-bisdiethyl phosphate (2b), on thecontrary, gave the allylic displacement products originatingfrom either inversion (3b) or retention (4b) with gooddiastereoselectivity (81:19-4:96), depending on the solventand the ligand used. However, very low ees were obtained.The reaction of meso-2-cycloheptene-1,4-bisdiethyl phos-phate (2c) afforded only the product arising from the allylicdisplacement with inversion (3c), albeit with modest ee (upto 56%).The Groningen group has demonstrated that phosphora-midites of general structure 5 serve as very effective ligandsin a number of catalytic asymmetric carbon-carbon bond-forming reactions.7 These include the already mentionedcopper-catalyzed ring opening of oxabicyclic alkenes,4 theconjugate addition of dialkylzincs to enones8 and nitroalkenes,9 the ring opening of vinyl epoxides,10 the desym-metrization of methylidene cycloalkene oxides,11 the allylicalkylation of cinnamyl derivatives,12 and the rhodium-catalyzed addition of arylboronic acids.13In this paper we report a highly enantioselective desym-metrization of meso-4-cyclopentene-1,3-bisdiethyl phosphate(2a), meso-2-cyclohexene-1,4-bisdiethyl phosphate (2b), andmeso-2-cycloheptene-1,4-bisdiethyl phosphate (2c) with di-ethylzinc catalyzed by copper(I) complexes of phosphora-midite ligands 5 (Figure 1).Copper complexes of ligands 5a-f were obtained in situby stirring CuIOTf with 2 equiv of the appropriate ligand intoluene (45 min, rt). Reaction of meso-4-cyclopentene-1,3-bisdiethyl phosphate (2a), readily obtained from com-mercially available meso-4-cyclopentene-1,3-diol,14 with 2.0equiv of Et2Zn in the presence of 10 mol % of the copper-phosphoramidite complexes afforded the product arising fromallylic displacement with inversion (3a, R ) Et) in variableyields and enantiomeric excesses (Table 1). In particular,the screening of the ligands revealed that good yields andenantiomeric excesses were obtained when phosphoramiditeligands with bulkier secondary amine substituents were used(entries 2-4). Varying the temperature with the best ligand(5b) increased the enantiomeric excess to 87% at -40 °C(entry 7). Dimethylzinc was considerably less reactive thandiethylzinc; the reaction had to be run at 0 °C to obtain 3a(R ) Me) with a fair conversion (54%), still associated witha good ee (87%, Table 1, entry 10).15meso-2-Cyclohexene-1,4-bisdiethyl phosphate (2b) wasobtained starting from cyclohexadiene via a palladium-(5) Piarulli, U.; Daubos, P.; Claverie, C.; Roux, M.; Gennari, C. Angew.Chem., Int. Ed. 2003, 42, 234-236.(6) (a) Chataigner, I.; Gennari, C.; Piarulli, U.; Ceccarelli, S. Angew.Chem., Int. Ed. 2000, 39, 916-918. (b) Ongeri, S.; Piarulli, U.; Jackson,R. F. W.; Gennari, C. Eur. J. Org. Chem. 2001, 803-807. (c) Chataigner,I.; Gennari, C.; Ongeri, S.; Piarulli, U.; Ceccarelli, S. Chem. Eur. J. 2001,7, 2628-2634.(7) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353.(8) (a) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem.,Int. Ed. Engl. 1996, 35, 2374-2376. (b) Feringa, B. L.; Pineschi, M.; Arnold,L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int. Ed. Engl. 1997,36, 2620-2622. (c) Imbos, R.; Brilman, M. H. G.; Pineschi, M.; Feringa,B. L. Org. Lett. 1999, 1, 623-626.(9) (a) Duursma, A.; Minnaard, A. J.; Feringa, B. L. Tetrahedon 2002,58, 5773-5778. (b) Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am.Chem. Soc. 2003, 125, 3700-3701.(10) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Feringa, B. L.Angew. Chem., Int. Ed. 2001, 40, 930-932.(11) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Arnold, A.;Feringa, B. L. Org. Lett. 2000, 2, 933-936.(12) Malda, H.; van Zijl, A. W.; Arnold, L. A.; Feringa, B. L. Org. Lett.2001, 3, 1169-1171.(13) Boiteau, J. G.; Imbos, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett.2003, 5, 682-685 and 1385.(14) cis-4-Cyclopentene-1,3-diol was transformed into the correspondingbisdiethyl phosphate (2) by deprotonation with n-BuLi and reaction withdiethylchlorophosphate in THF/TMEDA (4/1); see: Yu, K. L.; Ko, K. Y.;Fraser-Reid, B. Synth. Commun. 1988, 465-468.(15) Reactions at -40 or -20 °C showed poor conversions (15-20%)associated with slightly better ees (90-93%).Scheme 1. Desymmetrization of meso-Cyclic AllylicBisdiethyl Phosphates with Organozinc Reagents Catalyzed byCopper(I) Complexes of Chiral Schiff Base Ligands 1Figure 1. Structure of the phosphoramidite ligands 5.4494 Org. Lett., Vol. 5, No. 23, 2003catalyzed 1,4-diacetoxylation,16 followed by hydrolysis andphosphorylation using the same procedure as for the five-membered substrate 2a.14 Reaction with Et2Zn affordedvariable proportions of two products, namely, those arisingfrom the allylic displacement (SN2′) with either inversion(3b) or retention (4b) (Table 2). In particular, small ligands(e.g., 5a, entry 1) and higher reaction temperatures (cf. entries7-9, 10-11) afforded larger proportions of product 4b,whereas ligands bearing bulkier amine substituents and lowertemperatures favored the formation of product 3b. Anenantiomeric excess of up to 82% was obtained for theproduct arising from allylic displacement (SN2′) with inver-sion, using ligand 5b at -60 °C, albeit in rather low yield(entry 2). Increasing the reaction temperature to -40 °Cimproved both the yield (77%) and the enantiomeric excess(90%, entry 7). Interestingly, ligand 5c comprising S-BINOLand the S,S-diamine moiety afforded a very promising 76%ee at -60 °C (entry 3), which could be improved to 94%,with 69% yield, by increasing the temperature to -40 °C(entry 10). It should be noted that this is one of the fewcases where the matched combination arises in 5 fromS-BINOL and the S,S-diamine.10,11 Product 4b, on the otherhand, was always isolated as a racemic mixture.Reaction of the seven-membered-ring substrate 2c (Table3), obtained following the same route as for 2b, affordedonly the product arising from allylic displacement (SN2′) withinversion (3c) with excellent enantiomeric excess (>98%)and isolated yield (85-86%) using ligands 5b and 5c (entries4, 5). This is a case of very remarkable chemo-, regio-,stereo-, and enantiocontrol, where the potential competitionof several reaction pathways might in principle lead to upto 15 different reaction products and only one is obtained.17Product 3c was reduced to the corresponding alcohol withLiAlH4 in diethyl ether (quantitative yield). The enantiomericexcess was measured by 1H NMR spectroscopy, afterderivatization of the resulting alcohol with (R)-(+)-R-methoxy-R-(trifluoromethyl) phenylacetic acid, DCC, and4-DMAP in dichloromethane (quantitative yield).18 Theabsolute configuration of product 3c was also assigned fromthe NMR data of its Mosher ester derivatives.19,20 The esterswere assumed to adopt a conformation with the H-C-O-(16) Ba¨ckvall, J. E.; Bystro¨m, S. E.; Nordberg, R. E. J. Org. Chem. 1984,49, 4619-4631.(17) In particular, SN2′ and SN2 substitutions could occur, and both witheither retention or inversion of configuration. In the case of the SN2, wherean allylic alcohol derivative is obtained, a second allylic substitution couldoccur, via the SN2′ or SN2 mechanism, with either retention or inversion.On the basis of this complex scenario, up to 15 different reaction products(7 pairs of enantiomers and 1 meso-compound) could in principle beobtained.(18) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519. (b) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973,38, 2143-2147.(19) Diastereomeric esters were prepared using (R)-(+)-R-methoxy-R-(trifluoromethyl) phenylacetic acid with an unbalanced mixture of enan-tiomeric alcohols 3c.(20) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.Soc. 1991, 113, 4092-4096.Table 1. Allylic Alkylation of 2a with R2Zn in the Presence ofCopper Complexes of Phosphoramidites 5a-faentry ligand RT(°C)productyield(%)bee %c(configuration)d1 5a Et -60 10 24 (R,R)2 5b Et -60 >98 74 (R,R)3 5c Et -60 20 60 (R,R)4 5d Et -60 30 58 (R,R)5 5e Et -60 65 10 (R,R)6 5f Et -60 13 07 5b Et -40 >98 87 (R,R)8 5b Et -20 >98 84 (R,R)9 5b Et 0 >98 81 (R,R)10 5b Me 0 54 87 (R,R)a Reaction conditions: [CuOTf]2âC6H6 (0.05 equiv), ligand 5 (0.2 equiv),R2Zn (2.0 equiv), 2a (1.0 equiv), toluene, 15 h. b GC yield. c Determinedby GC: MEGADEX DMEPEâ, OV 1701, 25 m, film 0.25 ím, carrier H2(70 kPa). d Absolute configuration was determined as previously described.5Table 2. Allylic Alkylation of 2b with Et2Zn in the Presenceof Copper Complexes of Phosphoramidites 5a-faentry ligandT(°C)productyield(%)b 3b/4bee % of 3bc(configuration)d1 5a -60 13 31/69 35 (R,R)2 5b -60 35 76/24 82 (R,R)3 5c -60 16 87/13 76 (R,R)4 5d -60 3 79/21 68 (R,R)5 5e -60 10 69/31 48 (R,R)6 5f -60 07 5b -40 77 87/13 90 (R,R)8 5b -20 89 67/33 84 (R,R)9 5b 0 85 44/56 52 (R,R)10 5c -40 69 85/15 94 (R,R)11 5c -20 88 68/32 93 (R,R)a Reaction conditions: [CuOTf]2âC6H6 (0.05 equiv), ligand 5 (0.2 equiv),Et2Zn (2.0 equiv), 2b (1.0 equiv), toluene, 15 h. b Isolated yield. c Deter-mined by GC: MEGADEX DMEPEâ, OV 1701, 25 m, film 0.25 ím,carrier H2 (70 kPa), after reduction of the phosphate ester to alcohol withLiAlH4 in diethyl ether (quantitative yield). d Absolute configuration wasdetermined by reduction of 3b to the corresponding alcohol (LiAlH4, Et2O)and comparison of the optical rotation ([R]D) with the literature value.10Org. Lett., Vol. 5, No. 23, 2003 4495(CdO)-C-CF3 fragment in one plane. The signals assignedto the methyl group of the ethyl substituent in the 2-positionand to the vinylic proton in the 3-position of the seven-membered ring appeared at a higher field in the moreabundant diastereomeric ester than the signals of the corre-sponding protons in the minor diastereomer; therefore, theabsolute configuration of the major ester was assigned as(R,R)-.20To test the applicability of this synthetic methodology tomore functionalized substrates, we performed the reactionon compound 6,21 a derivative of conduritol A, using 5b asthe ligand (Scheme 2).Much to our delight, compound 7, derived from allylicdisplacement (SN2′) with inversion, was obtained in 52%yield (74% based on recovered 6) as a single diastereomer,in 86% enantiomeric excess.22,23 It is worth noting that afully functionalized cyclohexane derivative, containing fourcontiguous stereocenters and a double bond, was obtainedas a single diastereomer and in high enantiomeric excess froman achiral starting material.In summary, we have developed a highly regio-, diastereo-,and enantioselective desymmetrization of five-, six-, andseven-membered meso-cyclic allylic bis-diethyl phosphates(2a, 2b, and 2c, respectively) with diethylzinc using catalyticamounts of [Cu(OTf)]2âC6H6 and phosphoramidite ligands5. Studies toward the extension of the scope of this reaction,using different organozinc reagents and other functionalizedsubstrates, are currently underway in our laboratories.Acknowledgment. We thank the European Commission(IHP Network Grant “CombiCat” HPRN-CT-2000-00014)for financial support and for postdoctoral fellowships to C.Claverie (HPRN-CT-2000-00014) and P. Daubos (“MarieCurie” HPMF-CT-2001-01318). We also thank “MerckResearch Laboratories” (Merck’s Academic DevelopmentProgram Award to C. Gennari, 2002) and MIUR COFIN2002 (2002031849) for financial support. U. Piarulli thanksthe Dipartimento di Chimica Organica e Industriale (Uni-versity of Milano) for the hospitality.Supporting Information Available: Experimental detailsand characterization data, including 1H, 31P, and 13C NMR,IR, MS, and HRMS spectra and GC conditions. This materialis available free of charge via the Internet at http://pubs.acs.org.OL035807L(21) Johnson, C. R.; Ple´, P. A.; Adams, J. P. J. Chem Soc., Chem.Commun. 1991, 1006-1007.(22) Absolute configuration of compound 7 has not yet been assigned.(23) Reaction performed at -40 °C gave compound 7 in higher isolatedyield (78%) but with lower ee (65%).Table 3. Allylic Alkylation of 2a with Et2Zn in the Presenceof Copper Complexes of Phosphoramidites 5a-caentry ligandT(°C)productyield(%)bee %c(configuration)d1 5a -60 5 nd2 5b -60 81 98 (R,R)3 5c -60 75 >98 (R,R)4 5b -40 85 >98 (R,R)5 5c -40 86 >98 (R,R)a Reaction conditions: [CuOTf]2âC6H6 (0.05 equiv), ligand 5 (0.2 equiv),Et2Zn (2.0 equiv), 2c (1.0 equiv), toluene, 15 h. b Isolated yield. c Deter-mined by 1H NMR analysis of the Mosher esters, after reduction of thephosphate ester to alcohol with LiAlH4 in diethyl ether (quantitative yield).d Absolute configuration was determined by analysis of the Mosher ester(see text).Scheme 2. Desymmetrization of Functionalized Substrate 6aa Reaction conditions: [CuOTf]2âC6H6 (0.05 equiv), ligand 5b(0.2 equiv), Et2Zn (2.0 equiv), 6 (1.0 equiv).4496 Org. Lett., Vol. 5, No. 23, 2003

University of Groningen

   University of GroningenCopper phosphoramidite-catalyzed enantioselective desymmetrization of meso-cyclic allylicbisdiethyl phosphatesPiarulli, Umberto; Claverie, Christelle; Daubos, Philippe; Gennari, Cesare; Minnaard, AdriaanJ.; Feringa, BernardPublished in:Organic lettersDOI:10.1021/ol035801lIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2003Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Piarulli, U., Claverie, C., Daubos, P., Gennari, C., Minnaard, A. J., & Feringa, B. (2003). Copperphosphoramidite-catalyzed enantioselective desymmetrization of meso-cyclic allylic bisdiethyl phosphates.Organic letters, 5(23), 4493-4496. https://doi.org/10.1021/ol035801lCopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-11-2019Copper Phosphoramidite-CatalyzedEnantioselective Desymmetrization ofmeso-Cyclic Allylic BisdiethylPhosphatesUmberto Piarulli,*,†,‡ Christelle Claverie,‡ Philippe Daubos,‡ Cesare Gennari,*,‡Adriaan J. Minnaard,§ and Ben L. Feringa§Dipartimento di Scienze Chimiche, Fisiche e Matematiche, UniVersita` dell’Insubria,Via Valleggio 11, I- 22100 Como, Italy, Dipartimento di Chimica Organica eIndustriale, Centro di Eccellenza C.I.S.I., UniVersita` di Milano, Via G. Venezian 21,I-20133 Milano, Italy, and Department of Organic and Molecular InorganicChemistry, Stratingh Institute, UniVersity of Groningen, Nijenborgh 4,9747 AG Groningen, The Netherlandsumberto.piarulli@uninsubria.it; cesare.gennari@unimi.itReceived September 19, 2003ABSTRACTA highly regio-, diastereo-, and enantioselective desymmetrization of five-, six-, and seven-membered meso-cyclic allylic bis-diethyl phosphates(2a, 2b, and 2c, respectively) was obtained with diethylzinc, using catalytic amounts of [Cu(OTf)]2âC6H6 and phosphoramidite ligands 5.Enantiomeric excesses of up to 87, 94, and >98% were obtained for the addition of diethylzinc to cyclopentene, cyclohexene, and cycloheptenebis-diethyl phosphates, respectively.meso-Cyclic allylic diols are powerful substrates for theconstruction of enantiomerically enriched functionalizedproducts. Their desymmetrization has been realized byacylation or by allylic substitution, which can occur via SN2or SN2′ (allylic displacement) mechanisms, with eitherretention or inversion.1 The palladium-catalyzed desymme-trization, pioneered by Trost, is usually performed with softnucleophiles and takes place via the SN2 mechanism.2 Asomewhat related enantioselective ring opening of meso-oxabicyclic alkenes with organometallic reagents was re-ported by Lautens and co-workers (palladium-catalyzedaddition of alkylzinc reagents and RhI-catalyzed addition ofarylboronic acids)3 and by Pineschi, Feringa, and co-workers(CuI-catalyzed addition of alkylzinc reagents).4 Whereas in† University of Insubria.‡ University of Milano.§ University of Groningen.(1) For a recent review, see: Willis, M. C. J. Chem. Soc., Perkin Trans.1 1999, 1765-1784.(2) For recent accounts, see: (a) Graening, T.; Schmalz, H.-G. Angew.Chem., Int. Ed. 2003, 42, 2580-2584. (b) Trost, B. M.; Crawley, M. L.Chem. ReV. 2003, 103, 2921-2944.(3) (a) Lautens, M.; Renaud, J.-L.; Hiebert, S. J. Am. Chem. Soc. 2000,122, 1804-1805. (b) Lautens, M.; Hiebert, S.; Renaud, J.-L. Org. Lett.2000, 2, 1971-1973. (c) Lautens, M.; Hiebert, S.; Renaud, J.-L. J. Am.Chem. Soc. 2001, 123, 6834-6839. (d) Lautens, M.; Dockendorff, C.;Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311-1314 and referencestherein.(4) Bertozzi, F.; Pineschi, M.; Macchia, F.; Arnold, L. A.; Minnaard, A.J.; Feringa, B. L. Org. Lett. 2002, 4, 2703-2705.ORGANICLETTERS2003Vol. 5, No. 234493-449610.1021/ol035807l CCC: $25.00 © 2003 American Chemical SocietyPublished on Web 10/11/2003the first case the reaction occurs via the SN2′ mechanismwith retention (the nucleophile attacks from the same sideof the allylic leaving group),3 in the second case the allylicdisplacement reaction takes place with inversion.4 Piarulli,Gennari, and co-workers have recently disclosed a newhighly regio-, diastereo-, and enantioselective desymmetri-zation of meso-cyclic allylic bisdiethyl phosphates withorganozinc reagents5 catalyzed by copper(I) complexes ofchiral Schiff base ligands 1 (Scheme 1).6 In the case of meso-4-cyclopentene-1,3-bisdiethyl phosphate (2a), only the prod-uct arising from the allylic displacement (SN2′) mechanismwith inversion (3a) was obtained with excellent yield andenantiomeric excess (ee) up to 88% after screening a libraryof 125 Schiff-base ligands 1. Reaction of diethylzinc withmeso-2-cyclohexene-1,4-bisdiethyl phosphate (2b), on thecontrary, gave the allylic displacement products originatingfrom either inversion (3b) or retention (4b) with gooddiastereoselectivity (81:19-4:96), depending on the solventand the ligand used. However, very low ees were obtained.The reaction of meso-2-cycloheptene-1,4-bisdiethyl phos-phate (2c) afforded only the product arising from the allylicdisplacement with inversion (3c), albeit with modest ee (upto 56%).The Groningen group has demonstrated that phosphora-midites of general structure 5 serve as very effective ligandsin a number of catalytic asymmetric carbon-carbon bond-forming reactions.7 These include the already mentionedcopper-catalyzed ring opening of oxabicyclic alkenes,4 theconjugate addition of dialkylzincs to enones8 and nitroalkenes,9 the ring opening of vinyl epoxides,10 the desym-metrization of methylidene cycloalkene oxides,11 the allylicalkylation of cinnamyl derivatives,12 and the rhodium-catalyzed addition of arylboronic acids.13In this paper we report a highly enantioselective desym-metrization of meso-4-cyclopentene-1,3-bisdiethyl phosphate(2a), meso-2-cyclohexene-1,4-bisdiethyl phosphate (2b), andmeso-2-cycloheptene-1,4-bisdiethyl phosphate (2c) with di-ethylzinc catalyzed by copper(I) complexes of phosphora-midite ligands 5 (Figure 1).Copper complexes of ligands 5a-f were obtained in situby stirring CuIOTf with 2 equiv of the appropriate ligand intoluene (45 min, rt). Reaction of meso-4-cyclopentene-1,3-bisdiethyl phosphate (2a), readily obtained from com-mercially available meso-4-cyclopentene-1,3-diol,14 with 2.0equiv of Et2Zn in the presence of 10 mol % of the copper-phosphoramidite complexes afforded the product arising fromallylic displacement with inversion (3a, R ) Et) in variableyields and enantiomeric excesses (Table 1). In particular,the screening of the ligands revealed that good yields andenantiomeric excesses were obtained when phosphoramiditeligands with bulkier secondary amine substituents were used(entries 2-4). Varying the temperature with the best ligand(5b) increased the enantiomeric excess to 87% at -40 °C(entry 7). Dimethylzinc was considerably less reactive thandiethylzinc; the reaction had to be run at 0 °C to obtain 3a(R ) Me) with a fair conversion (54%), still associated witha good ee (87%, Table 1, entry 10).15meso-2-Cyclohexene-1,4-bisdiethyl phosphate (2b) wasobtained starting from cyclohexadiene via a palladium-(5) Piarulli, U.; Daubos, P.; Claverie, C.; Roux, M.; Gennari, C. Angew.Chem., Int. Ed. 2003, 42, 234-236.(6) (a) Chataigner, I.; Gennari, C.; Piarulli, U.; Ceccarelli, S. Angew.Chem., Int. Ed. 2000, 39, 916-918. (b) Ongeri, S.; Piarulli, U.; Jackson,R. F. W.; Gennari, C. Eur. J. Org. Chem. 2001, 803-807. (c) Chataigner,I.; Gennari, C.; Ongeri, S.; Piarulli, U.; Ceccarelli, S. Chem. Eur. J. 2001,7, 2628-2634.(7) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353.(8) (a) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem.,Int. Ed. Engl. 1996, 35, 2374-2376. (b) Feringa, B. L.; Pineschi, M.; Arnold,L. A.; Imbos, R.; de Vries, A. H. M. Angew. Chem., Int. Ed. Engl. 1997,36, 2620-2622. (c) Imbos, R.; Brilman, M. H. G.; Pineschi, M.; Feringa,B. L. Org. Lett. 1999, 1, 623-626.(9) (a) Duursma, A.; Minnaard, A. J.; Feringa, B. L. Tetrahedon 2002,58, 5773-5778. (b) Duursma, A.; Minnaard, A. J.; Feringa, B. L. J. Am.Chem. Soc. 2003, 125, 3700-3701.(10) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Feringa, B. L.Angew. Chem., Int. Ed. 2001, 40, 930-932.(11) Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Arnold, A.;Feringa, B. L. Org. Lett. 2000, 2, 933-936.(12) Malda, H.; van Zijl, A. W.; Arnold, L. A.; Feringa, B. L. Org. Lett.2001, 3, 1169-1171.(13) Boiteau, J. G.; Imbos, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett.2003, 5, 682-685 and 1385.(14) cis-4-Cyclopentene-1,3-diol was transformed into the correspondingbisdiethyl phosphate (2) by deprotonation with n-BuLi and reaction withdiethylchlorophosphate in THF/TMEDA (4/1); see: Yu, K. L.; Ko, K. Y.;Fraser-Reid, B. Synth. Commun. 1988, 465-468.(15) Reactions at -40 or -20 °C showed poor conversions (15-20%)associated with slightly better ees (90-93%).Scheme 1. Desymmetrization of meso-Cyclic AllylicBisdiethyl Phosphates with Organozinc Reagents Catalyzed byCopper(I) Complexes of Chiral Schiff Base Ligands 1Figure 1. Structure of the phosphoramidite ligands 5.4494 Org. Lett., Vol. 5, No. 23, 2003catalyzed 1,4-diacetoxylation,16 followed by hydrolysis andphosphorylation using the same procedure as for the five-membered substrate 2a.14 Reaction with Et2Zn affordedvariable proportions of two products, namely, those arisingfrom the allylic displacement (SN2′) with either inversion(3b) or retention (4b) (Table 2). In particular, small ligands(e.g., 5a, entry 1) and higher reaction temperatures (cf. entries7-9, 10-11) afforded larger proportions of product 4b,whereas ligands bearing bulkier amine substituents and lowertemperatures favored the formation of product 3b. Anenantiomeric excess of up to 82% was obtained for theproduct arising from allylic displacement (SN2′) with inver-sion, using ligand 5b at -60 °C, albeit in rather low yield(entry 2). Increasing the reaction temperature to -40 °Cimproved both the yield (77%) and the enantiomeric excess(90%, entry 7). Interestingly, ligand 5c comprising S-BINOLand the S,S-diamine moiety afforded a very promising 76%ee at -60 °C (entry 3), which could be improved to 94%,with 69% yield, by increasing the temperature to -40 °C(entry 10). It should be noted that this is one of the fewcases where the matched combination arises in 5 fromS-BINOL and the S,S-diamine.10,11 Product 4b, on the otherhand, was always isolated as a racemic mixture.Reaction of the seven-membered-ring substrate 2c (Table3), obtained following the same route as for 2b, affordedonly the product arising from allylic displacement (SN2′) withinversion (3c) with excellent enantiomeric excess (>98%)and isolated yield (85-86%) using ligands 5b and 5c (entries4, 5). This is a case of very remarkable chemo-, regio-,stereo-, and enantiocontrol, where the potential competitionof several reaction pathways might in principle lead to upto 15 different reaction products and only one is obtained.17Product 3c was reduced to the corresponding alcohol withLiAlH4 in diethyl ether (quantitative yield). The enantiomericexcess was measured by 1H NMR spectroscopy, afterderivatization of the resulting alcohol with (R)-(+)-R-methoxy-R-(trifluoromethyl) phenylacetic acid, DCC, and4-DMAP in dichloromethane (quantitative yield).18 Theabsolute configuration of product 3c was also assigned fromthe NMR data of its Mosher ester derivatives.19,20 The esterswere assumed to adopt a conformation with the H-C-O-(16) Ba¨ckvall, J. E.; Bystro¨m, S. E.; Nordberg, R. E. J. Org. Chem. 1984,49, 4619-4631.(17) In particular, SN2′ and SN2 substitutions could occur, and both witheither retention or inversion of configuration. In the case of the SN2, wherean allylic alcohol derivative is obtained, a second allylic substitution couldoccur, via the SN2′ or SN2 mechanism, with either retention or inversion.On the basis of this complex scenario, up to 15 different reaction products(7 pairs of enantiomers and 1 meso-compound) could in principle beobtained.(18) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519. (b) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973,38, 2143-2147.(19) Diastereomeric esters were prepared using (R)-(+)-R-methoxy-R-(trifluoromethyl) phenylacetic acid with an unbalanced mixture of enan-tiomeric alcohols 3c.(20) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.Soc. 1991, 113, 4092-4096.Table 1. Allylic Alkylation of 2a with R2Zn in the Presence ofCopper Complexes of Phosphoramidites 5a-faentry ligand RT(°C)productyield(%)bee %c(configuration)d1 5a Et -60 10 24 (R,R)2 5b Et -60 >98 74 (R,R)3 5c Et -60 20 60 (R,R)4 5d Et -60 30 58 (R,R)5 5e Et -60 65 10 (R,R)6 5f Et -60 13 07 5b Et -40 >98 87 (R,R)8 5b Et -20 >98 84 (R,R)9 5b Et 0 >98 81 (R,R)10 5b Me 0 54 87 (R,R)a Reaction conditions: [CuOTf]2âC6H6 (0.05 equiv), ligand 5 (0.2 equiv),R2Zn (2.0 equiv), 2a (1.0 equiv), toluene, 15 h. b GC yield. c Determinedby GC: MEGADEX DMEPEâ, OV 1701, 25 m, film 0.25 ím, carrier H2(70 kPa). d Absolute configuration was determined as previously described.5Table 2. Allylic Alkylation of 2b with Et2Zn in the Presenceof Copper Complexes of Phosphoramidites 5a-faentry ligandT(°C)productyield(%)b 3b/4bee % of 3bc(configuration)d1 5a -60 13 31/69 35 (R,R)2 5b -60 35 76/24 82 (R,R)3 5c -60 16 87/13 76 (R,R)4 5d -60 3 79/21 68 (R,R)5 5e -60 10 69/31 48 (R,R)6 5f -60 07 5b -40 77 87/13 90 (R,R)8 5b -20 89 67/33 84 (R,R)9 5b 0 85 44/56 52 (R,R)10 5c -40 69 85/15 94 (R,R)11 5c -20 88 68/32 93 (R,R)a Reaction conditions: [CuOTf]2âC6H6 (0.05 equiv), ligand 5 (0.2 equiv),Et2Zn (2.0 equiv), 2b (1.0 equiv), toluene, 15 h. b Isolated yield. c Deter-mined by GC: MEGADEX DMEPEâ, OV 1701, 25 m, film 0.25 ím,carrier H2 (70 kPa), after reduction of the phosphate ester to alcohol withLiAlH4 in diethyl ether (quantitative yield). d Absolute configuration wasdetermined by reduction of 3b to the corresponding alcohol (LiAlH4, Et2O)and comparison of the optical rotation ([R]D) with the literature value.10Org. Lett., Vol. 5, No. 23, 2003 4495(CdO)-C-CF3 fragment in one plane. The signals assignedto the methyl group of the ethyl substituent in the 2-positionand to the vinylic proton in the 3-position of the seven-membered ring appeared at a higher field in the moreabundant diastereomeric ester than the signals of the corre-sponding protons in the minor diastereomer; therefore, theabsolute configuration of the major ester was assigned as(R,R)-.20To test the applicability of this synthetic methodology tomore functionalized substrates, we performed the reactionon compound 6,21 a derivative of conduritol A, using 5b asthe ligand (Scheme 2).Much to our delight, compound 7, derived from allylicdisplacement (SN2′) with inversion, was obtained in 52%yield (74% based on recovered 6) as a single diastereomer,in 86% enantiomeric excess.22,23 It is worth noting that afully functionalized cyclohexane derivative, containing fourcontiguous stereocenters and a double bond, was obtainedas a single diastereomer and in high enantiomeric excess froman achiral starting material.In summary, we have developed a highly regio-, diastereo-,and enantioselective desymmetrization of five-, six-, andseven-membered meso-cyclic allylic bis-diethyl phosphates(2a, 2b, and 2c, respectively) with diethylzinc using catalyticamounts of [Cu(OTf)]2âC6H6 and phosphoramidite ligands5. Studies toward the extension of the scope of this reaction,using different organozinc reagents and other functionalizedsubstrates, are currently underway in our laboratories.Acknowledgment. We thank the European Commission(IHP Network Grant “CombiCat” HPRN-CT-2000-00014)for financial support and for postdoctoral fellowships to C.Claverie (HPRN-CT-2000-00014) and P. Daubos (“MarieCurie” HPMF-CT-2001-01318). We also thank “MerckResearch Laboratories” (Merck’s Academic DevelopmentProgram Award to C. Gennari, 2002) and MIUR COFIN2002 (2002031849) for financial support. U. Piarulli thanksthe Dipartimento di Chimica Organica e Industriale (Uni-versity of Milano) for the hospitality.Supporting Information Available: Experimental detailsand characterization data, including 1H, 31P, and 13C NMR,IR, MS, and HRMS spectra and GC conditions. This materialis available free of charge via the Internet at http://pubs.acs.org.OL035807L(21) Johnson, C. R.; Ple´, P. A.; Adams, J. P. J. Chem Soc., Chem.Commun. 1991, 1006-1007.(22) Absolute configuration of compound 7 has not yet been assigned.(23) Reaction performed at -40 °C gave compound 7 in higher isolatedyield (78%) but with lower ee (65%).Table 3. Allylic Alkylation of 2a with Et2Zn in the Presenceof Copper Complexes of Phosphoramidites 5a-caentry ligandT(°C)productyield(%)bee %c(configuration)d1 5a -60 5 nd2 5b -60 81 98 (R,R)3 5c -60 75 >98 (R,R)4 5b -40 85 >98 (R,R)5 5c -40 86 >98 (R,R)a Reaction conditions: [CuOTf]2âC6H6 (0.05 equiv), ligand 5 (0.2 equiv),Et2Zn (2.0 equiv), 2c (1.0 equiv), toluene, 15 h. b Isolated yield. c Deter-mined by 1H NMR analysis of the Mosher esters, after reduction of thephosphate ester to alcohol with LiAlH4 in diethyl ether (quantitative yield).d Absolute configuration was determined by analysis of the Mosher ester(see text).Scheme 2. Desymmetrization of Functionalized Substrate 6aa Reaction conditions: [CuOTf]2âC6H6 (0.05 equiv), ligand 5b(0.2 equiv), Et2Zn (2.0 equiv), 6 (1.0 equiv).4496 Org. Lett., Vol. 5, No. 23, 2003

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Copper phosphoramidite-catalyzed enantioselective desymmetrization of meso-cyclic allylic bisdiethyl phosphates

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