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Pitt CHEM 2320 - Reagent Controlled Asymmetric Homologation of Boronic Esters

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Reagent-Controlled AsymmetricHomologation of Boronic Esters byEnantioenriched Main-Group ChiralCarbenoidsPaul R. Blakemore,*,†Stephen P. Marsden,‡and Huw D. Vater‡Department of Chemisty, Oregon State UniVersity, CorVallis, Oregon, 97331-4003, andSchool of Chemistry, UniVersity of Leeds, Leeds, West Yorkshire, LS2 9JT, [email protected] December 16, 2005ABSTRACTPutative enantioenriched carbenoid species, (R)-1-chloro-2-phenylethylmagnesium chloride (9) and (S)-1-chloro-2-phenylethyllithium (26), generatedin situ by sulfoxide ligand exchange from (−)-(RS,R)-1-chloro-2-phenylethylp-tolyl sulfoxide (8), effected the stereocontrolled homologation ofboronic esters.sec-Alcohols derived from the product boronates by oxidation with basic hydrogen peroxide exhibited % ee closely approachingthat of sulfoxide 8 in examples employing Li-carbenoid 26.A majority of methods for asymmetric synthesis rely directlyon stereoinduction, viz. new stereogenic elements areintroduced selectively by relay of existing stereochemicalinformation through space across conformationally biasedtransition state assemblies.1Although stereoinduction isundoubtedly an efficient precept for synthesis, emergingstereochemistry is not completely controlled during stereo-inductive events and distinct diastereoisomeric productscannot be targeted with equal facility by a given method.2By contrast, reagents containing preexisting stereogeniccenters, which react via purely stereospecific pathways, mayoffer a trivial means to effect stereocontrol not reliant onstereoinduction at the point of bond formation. The allusionmade here is to a stereospecific reagent control paradigm inwhich stereochemical information contained within thereagent is merely translated into a stereogenic feature of theproduct.In pursuit of a programmable asymmetric method basedfirmly on a principle of stereospecific reagent control, weformulated a hypothetical chain extension process that wouldnot be subject to the vagaries of stereoinduction. Theenvisioned method, stereospecific reagent controlled ho-mologation (SRCH), calls for the stereospecific insertion ofenantioenriched chiral carbenoid reagents 2 into organo-metallic substrates 1 via intermediate ate-complexes 3(Scheme 1; M1,M2) metal, X ) nucleofugal group). 1,2-Metalate rearrangement3of complexes 3 would affordhomologated adducts (4) suitable for direct subjection to†Oregon State University.‡University of Leeds.(1) (a) Catalytic Asymmetric Synthesis; Ojimia, I., Ed.; Wiley: New York,2000. (b) StereoselectiVe Synthesis; Helmchen, G., Hoffmann, R. W.,Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1995. (c) AsymmetricCatalysis in Organic Synthesis; Noyori, R., Ed.; Wiley: New York, 1994.(d) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.(2) The common observation of matching and mismatching of substrate/reagent pairs in “double” asymmetric synthesis is a manifestation of thisfundamental weakness; see: Asymmetric Synthesis; Procter, G., Ed.; OxfordUniversity Press: Oxford, 1996.(3) For recent synthetic applications of 1,2-metalate rearrangements,see: (a) Jarowicki, K.; Kocienski, P. J. Synlett 2005, 167. (b) Abramovitch,A.; Varghese, J. P.; Marek, I. Org. Lett. 2004, 6, 621. (c) Pommier, A.;Stepanenko, V.; Jarowicki, K.; Kocienski, P. J. J. Org. Chem. 2003, 68,4008. (d) Le Menez, P.; Brion, J.-D.; Lensen, N.; Chelain, E.; Pancrazi,A.; Ardisson, J. Synthesis 2003, 2530. (e) Kasatkin, A. N.; Whitby, R. J.Tetrahedron Lett. 2000, 41, 6201. (f) Sidduri, A.; Rozema, M. K.; Knochel,P. J. Org. Chem. 1993, 58, 2694 and references therein.ORGANICLETTERSxxxxVol. 0, No. 0A-D10.1021/ol053055k CCC: $33.50 © xxxx American Chemical SocietyPAGE EST: 3.8Published on Web 01/24/2006further cycles of SRCH. In this manner, iterative SRCH, ifachievable, would allow for the controlled assembly ofpolysubstituted alkyl chains with installation of stereogeniccenters being programmed at each stage of iteration byselection of the appropriate carbenoid enantiomorph. Forexample, in the illustrated notional sequence, either dia-stereoisomer 6 or 7 could be precisely targeted by choice ofcarbenoid reagent, 5 or ent-5.Three conditions require satisfaction for the concept ofSRCH to be fully realized: (1) carbenoid reagents 2 mustpossess configurational and chemical stability under theconditions required for ate-complex formation, (2) ate-complex formation and breakdown must occur via entirelystereospecific processes, and (3) to avoid multiple insertionsper cycle (leading to unwanted oligomerization), the metalaterearrangement step must occur only after any excess car-benoid reagent has suffered immolative deactivation or beenotherwise consumed (i.e., greater stability for 3 vs 2). Herein,we report that these criteria are ostensibly met where M1)B(OR)2and M2) MgCl or Li and describe noniterativeSRCH of boronic esters by enantioenriched R-chloroalkyl-magnesium and R-chloroalkyllithium reagents.4At the outset of our studies, seminal discoveries emanatingfrom the laboratories of Matteson and Hoffmann suggestedthe possibility of a successful SRCH manifold with M1)B(OR)2and M2) MgCl. The early work of Matteson andMah established that R-haloalkyl boronic esters experienceindirect SN2-like displacement of the R-halide atom byGrignard species via intermediate borate complexes 3 (M1) B(OR)2,M2) MgCl).5Of further significance, theHoffmann group recently reported that R-haloalkyl Grignardreagents exhibit good configurational stability (little or noracemization below -60 °C) and demonstrated that thesecarbenoid species can be generated in enantioenriched formby sulfoxide ligand exchange from homochiral R-chloro-sulfoxides.6Cognizant of these results, we reasoned thataddition of a configurationally stable Hoffmann-type car-benoid 2 (M2) MgCl, X ) Cl) to a simple boronic ester 1(M1) B(OR)2) would afford essentially the same type ofborate intermediate to that first encountered by Matteson andMah, the only difference being the order of introduction ofthe participating carbon ligands onto boron. SRCH wouldtherefore be a reasonable expectation providing that elec-trophilic substitution (SE2) of MgCl for B(OR)2occurredstereospecifically.7Eager to test this hypothesis, we preparedknown R-chlorosulfoxide 8 (with dr > 99:1, % ee > 98%)8and verified the efficacy of its sulfoxide ligand exchangereaction with EtMgCl to generate Hoffmann’s carbenoid 9.In agreement with the earlier


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Pitt CHEM 2320 - Reagent Controlled Asymmetric Homologation of Boronic Esters

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