Recent Developments in Rhodium Carbene and Nitrene Chemistry R1 C H N2 1 LnM R H R2 N2 C R1 R2 2 Metal carbenoid R C-H functionalization LnM LnM "Traditional' C-H activation H C X C H H X C MLn MacMillan Group Meeting February 3, 2010 Brian Ngo Laforteza Rhodium Carbene and Nitrene Chemistry Catalysts ■ Rhodium(II) acetate – prototypical structure of dirhodium carbene/nitrene catalysts Me O O Me O O Rh Rh O O Me O O open coordination site Me Rh2(OAc)4 . “Paddle wheel” catalyst ■ Only one rhodium center functions as carbene binding site . Second acts as electron sink to increase electrophilicity of carbene moiety – additional stabilization R N2 . Catalyst binds carbene through strong σ-acceptor R R M M interactions and weak π-back-donation R N2 Rhodium Carbene and Nitrene Chemistry Catalysts ■ Two widely utilized classes of catalysts R . Symmetry may vary depending X Y R on orientation of ligand binding X Y Rh Rh Y X R Y X Rhodium(II) carboxylates R Rhodium(II) carboxamidates O Rh O Rh X N Rh N O Rh SO2Ar R 4 4 X = O, NCOR . Very active at decomposing diazo compounds . Generally much more rigid than rhodium carboxylates . Optimal for intermolecular C–H insertion reactions . Optimal for enantioselective intramolecular C–H insertion . Later generations possess rigid bridged structure Rhodium Carbene Chemistry The Metal Carbene ■ Control carbene reactivity through substituents - “acceptors” and “donors” Acceptor Acceptor/Acceptor Acceptor/Donor O O O O H Y X X Y X N2 N2 N2 X = R, OR, NR2 X, Y = R, OR, NR2 X = R, OR, NR2 Y = vinyl, aryl . Acceptor/acceptor and acceptor/donor groups stabilize diazo compound – more active catalyst needed for decomposition . Carbenoids formed from acceptor/acceptor diazo compounds very electrophilic . Donor substituent stabilizes carbenoid through resonance Rhodium Carbene Chemistry Trends in C–H Activation ■ Generally believed to occur through concerted (though asynchronous), three-centered transition state A A A H R B C H + B H Rh2L4 D B R + Rh2L4 R C Rh2L4 D R D R R . Build-up of positive charge at carbon undergoing C-H cleavage . C–H activation occurs preferentially at sites that can stabilize δ+ α-hetero C–H, allylic C–H, benzylic C–H preferred sites of activation Reactivity of C–H bonds undergoing insertion methine > methyelene >> methyl . Steric factors, however, can sometimes override this selectivity Rhodium Carbene Chemistry Rh2(DOSP)4 ■ Rhodium(II) carboxylate developed and heavily utilized by Huw M. L. Davies (Emory) SO2Ar H H N O O N Rh O O SO2Ar O Rh O SO2Ar O O N N H H SO2Ar Ar = p-(C12H25)C6H4 ■ Stereochemical model L L H M S S M L MeO2C R L MeO2C R MeO2C R S M S M Rh H Rh . Esther considered sterically demanding group Davies et al. Chem. Rev. 2003, 103, 2861. Davies et al. J. Org. Chem. 2009, 74, 6555. Combined C–H Insertion/Cope Rearrangement Synthesis of 4-Substituted Indoles ■ C–H insertion into 4-methyl-1,2-dihydronaphthalene proceeded with high diastereoselectivity Me Me Ph 95% yield Rh (S-DOSP) (0.5 mol%) Ph N 2 4 + 2 >98% de 2,2-dimethylbutane, 0 °C CO2Me H >99% ee CO2Me . Selectivity unusually high compared to what is known for C–H insertion into cycloalkenes . Mechanism more complex than appears? ■ Proposed combined C–H activation/Cope rearrangement, followed by retro-Cope rearrangement Rh Ph Ph Ph Me CO2Me Me CO2Me Me CO2Me H C-H/Cope Cope H H . Fully conjugated product favored Davies et al. J. Am. Chem. Soc. 2004, 126, 10862. Combined C–H Insertion/Cope Rearrangement Retro-Cope ■ Mechanistic analysis Me Et Me Rh2(S-DOSP)4 (2 mol%) Et N + 2 // 2,2-dimethylbutane, 23 °C CO2Me H CO2Me Et CO Me C-H/Cope 2 110 °C Me >98% de 92%, 98% ee 98% ee ■ Preliminary scope R2 X = CH2, O R1 = H, m-/p-OMe R1 2 X R = OAc, OSiR3 Davies et al. J. Am. Chem. Soc. 2004, 126, 10862. Combined C–H Insertion/Cope Rearrangement Synthesis of 4-Substituted Indoles ■ C–H insertion into dihydroindoles followed by Cope rearrangement and aromatization OAc R CO2Me N2 Rh2(S-DOSP)4 + R CO2Me N DMB, rt Boc N Boc OAc R R R AcO Cope N H Boc N Boc CO2Me Davies et al. J. Am. Chem. Soc. 2006, 128, 1060. Combined C–H Insertion/Cope Rearrangement Synthesis of 4-Substituted Indoles ■ C–H insertion into dihydroindoles followed by Cope rearrangement and aromatization OAc R CO2Me N2 Rh2(S-DOSP)4 + R CO2Me N DMB, rt Boc N Boc Cl MeO Br Cl 65%, 98% ee 52%, 98% ee 53%, 99% ee 45%, 98% ee H3C N Boc 56%, 98% ee 64%, 98% ee 65%, 99% ee 61%, 99% ee Davies et al. J. Am. Chem. Soc. 2006, 128, 1060. Combined C–H Insertion/Cope Rearrangement Application Towards Natural Product Synthesis ■ (+)-erogorgiaene: kinetic enantiodifferentiation Me Me Me (±) H 2 mol% Me Me 2 mol% Me H H Rh (R-DOSP) 2 4 + Rh2(R-DOSP)4 MeO2C Me N Me 2 MeO2C Me Me 48% 48%, 90% ee Me Me H Me Me Me (+)-erogorgiaene Davies et al. Angew. Chem. Int. Ed. 2005, 44, 1733. Combined C–H Insertion/Cope Rearrangement Application Towards Natural Product Synthesis ■ Similar enantiodifferentiating step used in analogous syntheses O Me O Me O Me OH Me HO HO HO HO Me Me Me O H Me H H H O O Me O Me Me H Me Me H Me Me Me Me Me OH (–)-colombiasin A (–)-elisapterosin B (+)-elisabethadione (+)-p-benzoquinone Davies et al. J. Am. Chem. Soc. 2006, 128, 2485. Davies et al. Tetrahedron 2006, 62, 10477. Tandem Cyclopropanation/Cope Rearrangement Formal [4+3] Cycloadditions ■ General idea R3 MeO C R3 2 R4 4 4 N2 MeO2C R MeO2C R R5 Rh(II) 2 5 Cope R2 + R R 2 5 R3 R R 7 6 R1 R R R1 R7 R6 1 R7 R R6 ■ Stereochemical model for cyclopropanation: based on “end-on” approach of olefin H R1 H H R1 2 1 MeO2C R 2 R MeO2C R H H R2 H H Rh Rh MeO2C Davies et al. J. Am. Chem. Soc. 2003, 125, 15902. Tandem Cyclopropanation/Cope Rearrangement Formal [4+3] Cycloadditions ■ Scope of dienes R4 CO Me CO2Me 2 4 R N 1 mol% Rh2(S-PTAD)4 + 2 R2 OTBS R3 OTBS R3 hexanes, –26 °C R1 R1 R2 CO2Me CO2Me TBSO CO2Me OTBS OTBS OTBS Me Ph Me 80% yield 82% yield 70% yield O N O Rh 87% ee 95% ee 99% ee O H O Rh TBSO CO2Me CO2Me 4 CO2Me Rh (S-PTAD) OTBS OTBS 2 4 OTBS Me MeO Me 63% yield 86% yield 57% yield 95% ee 92% ee Davies et al. J. Am. Chem. Soc. 2009, 131, 8329. Tandem Cyclopropanation/Cope Rearrangement Formal [4+3] Cycloadditions ■ Total synthesis of (–)-5-epi-vibsanin E R4 CO Me CO2Me 2 4 R N 1 mol% Rh2(S-PTAD)4 + 2 R2 OTBS R3 OTBS R3 hexanes, –26 °C R1 R1 R2 CO2Me OTBS 65% yield Me Me CO2Me 0.5 mol% Me + N2 90% ee Me OTBS Rh (S-PTAD) 2 4 Me Me O Me O Me O Me Me O Me Me (–)-5-epi-vibsanin E Davies et al. J. Am. Chem. Soc. 2009, 131, 8329. Nucleophilic Attack on Rhodium Carbenes Formal [3+2] Annulation of Indoles ■ Two isomers of annulated product initially observed CO2Me Ph H H N2 Rh2(R-DOSP)4 + + N MeO2C Ph CH2Cl2, –45 °C Ph CO2Me Me N H N H Me Me exo endo 72% yield 17% 80% ee >99% ee ■ Competition between C2- and C3-nucleophilic attack? N2 N2 CO2Me Ph MeO2C Ph Me MeO2C Ph H Me Rh2(S-DOSP)4 Rh2(S-DOSP)4 Me N toluene, –45 °C Ph N toluene, –45 °C CO2Me Me N Me Me N H Me Me exo endo 68% yield 74% yield 97% ee 99% ee Davies et al. J. Am. Chem. Soc. 2010, 132, 440. Nucleophilic Attack on Rhodium Carbenes Formal [3+2] Annulation of Indoles ■ Proposed mechanism MeO2C Ph CO Me CO2Me 2 Rh L 2 4 L4Rh2 H Ph Ph N H N N Me Me Me . Zwitterionic intermediate ■ Stereochemical rationale: configuration of carbene and olefin govern diastereoselectivity NMe MeN Ph Me Me MeO2C Ph exo MeO2C endo Rh Rh s-cis s-trans Davies et al. J. Am. Chem. Soc. 2010, 132, 440. Nucleophilic Attack on Rhodium Carbenes Imines As Nucleophiles ■ Bicyclic pyrrolidines are formed when excess diazo compound is used Ph NO2 N Ar CO2Me N 2 1 mol% Rh2(OAc)4 N 47-66% yield + MeO C Ph up to 98:2 dr 2 CH2Cl2, reflux R NO2 R = H, Cl, Me, OMe ■ Proposed mechanism Ph CO2Me CO2Me Ph CO2Me Rh2L4 Ar N Ar N R N Ar Ph R R Doyle et al. J. Am. Chem. Soc. 2003, 125, 4692. Nucleophilic Attack on Rhodium Carbenes Imines As Nucleophiles ■ Bicyclic pyrrolidines are formed when excess diazo compound is used Y Ph H CO2Me N X N 2 1 mol% Rh2(OAc)4 up to 84% yield + N MeO C Ph Ph ~ 1:1 dr 2 CH2Cl2, reflux CO2Me X 2 eq Y X = H, Cl, Me, NO2 Y = H, OMe, NO2 ■ Proposed mechanism Ar2 Ar2 2 CO Me E Ph Ar Ph CO2Me 2 N Ph N N CHO2Me Ar1 Rh2L4 1 Ar CO2Me Ar1 Ph H Ph Rh2L4 CO2Me Ph Doyle et al.