Lithiation-Borylation Methodology and Its Application in Synthesis Literature Seminar 2018/06/23 Hongyu CHEN (M1) Contents • Introduction • Part 1 : Factors responsible for the 1,2-migration • Part 2 : Factors responsible for stereocontrol • Part 3 : Application of lithiation-borylation reaction in synthesis • Summary Contents • Introduction • Part 1 : Factors responsible for the 1,2-migration • Part 2 : Factors responsible for stereocontrol • Part 3 : Application of lithiation-borylation reaction in synthesis • Summary Anatomy of The Lithiation-Borylation Reaction R3 B(OR)2 Stereoretentive B(OR)2 R2 R Borylation 2 1,2-Metallate R3 OLG R1 R1 Rearrangement R Homologated X Li 3 Boronate complex B(OR)2 product R2 R2 OLG Lithiation OLG R1 R1 OLG = OCb or OTIB Lithium carbenoid R2 X = H or SnR OLG R2 3 Stereoinvertive R 1 R3 R1 Borylation B(OR)2 1,2-Metallate R B(OR)2 3 Rearrangement Boronate complex Homologated product ・ R1, R2 and R3 = Alkyl, Alkenyl or Aryl ・ Reagent Control ・ Complete Stereospecificity Arylation ・ Contiguous Stereocenters Alkynylation ・ Quaternary Stereocenters Oxidation Fluorination ・ Natural Product Synthesis Assembly-Line Synthesis ・ Assembly-Line Synthesis http://www.chm.bris.ac.uk/org/aggarwal/research.php#li-b The First Nonenzymatic Asymmetric Synthesis (H. C. Brown, 1961) DG )2BH [O] + BH3 )2B 0 ℃ H HO H 90% yield, 87% ee cis, cis; cis, trans; trans, trans etc. R*CHCHCHCHR’ R*OH R* R' R*CO2H R* R’ R' R*D R*CHO General Asymmetric Synthesis R* R* R' R*CH OH via Chiral Organoboranes 2 R*NH2 R*CH2CHCH2 R* B R*R’NH R*R’CHNH2 R*CCR’ R*CCH R*COR’ R*CH2COR’ R*R’CHOH R*CH2CN R*COCCR’ R*CH2CO2Et R*R ’COH Brown, H. C. et al. Pure & Appl. Chem., 1991, 63, 307. R*CH(CN)2 2 Complementary Routes to Chiral Boronic Esters A) Matteson: Stepwise substrate-controlled approach R Cl R R R O 1 LiCHCl O 1 R -MgBr 2 O 1 R B 2 B 2 B O R O R O R1 R1 R1 B) Hoppe: Stepwise reagent-controlled approach R Li B(Oi-Pr)3 B(pin) R2-MgBr 2 R OCb then pinacol R OCb R B(pin) C) Lithiation-Borylation: Iterative reagent-controlled approach Li R2 Li R -B(pin) R2 2 R3 OCb B(pin) R R OCb R B(pin) R3 Aggarwal, V. K. et al. Acc. Chem. Res., 2014, 47, 3174. Prof. Varinder Kumar Aggarwal 1980-1983 BA, University of Cambridge 1983-1986 PhD, University of Cambridge (Prof. Stuart Warren) 1986-1988 Postdoctoral Position, Columbia University (Prof. Gilbert Stork) 1988-1991 Lecturer in Chemistry, University of Bath 1991-1995 Lecturer in Chemistry, University of Sheffield 1995-1997 Reader in Chemistry, University of Sheffield 1997-2000 Professor in Chemistry, University of Sheffield 2000-present Professor in Synthetic Chemistry, University of Bristol Current Research Interests: Stereoselective synthesis / Mechanistic studies / Total synthesis of natural and non-natural products “Our current focus is in the field of organoboron chemistry, since boron seems to possess a unique ability to orchestrate many processes cleanly and with high stereochemical fidelity.” Contents • Introduction • Part 1 : Factors responsible for the 1,2-migration • Part 2 : Factors responsible for stereocontrol • Part 3 : Application of lithiation-borylation reaction in synthesis • Summary What Affects the Migratory Aptitude of Alkyl Groups ? (Steric & Electronic Factors) 1,2-Rearrangement oF borate complexes Migrating terminus R1 R2 R1 R B X B X + Y 2 Y R R3 3 Migrating origin 1. Steric hindrance around boron. 2. Steric hindrance around the migrating terminus. 3. Compression of the bond angles in the migrating group at the transition state for migration. 4. Nonbonded interactions of the substituents at the migrating terminus with the substituents attached to boron. 5. The stability of the migrating group which carries partial negative charge. Aggarwal, V. K. et al. Pure & Appl. Chem., 2006, 78, 215. Example 1. Iodine-Induced Rearrangement of Ethynyltrialkylborates (1) I R2 R1 R1 R2 I B I2 R B B + R3R2BI R3 2 R R3 R3 R1 1 I I S. W. Slayden. J. Org. Chem., 1981, 46, 2311. Example 1. Iodine-Induced Rearrangement of Ethynyltrialkylborates (2) ・ A partial relative migratory aptitude order: bicyclooctyl > n-butyl > cyclohexyl, isobutyl, sec-butyl > thexyl. Generally 1° > 2° > 3° (except for bicyclo group). ・ Inexact ordering of the cyclohexyl, isobutyl, and sec-butyl groups. Can be explained by the stability of the migrating goup that carries partial negative charge (factor 5). S. W. Slayden. J. Org. Chem., 1981, 46, 2311. Example 1. Iodine-Induced Rearrangement of Ethynyltrialkylborates (3) For 4-6, An approximate two- fold increase in M in the series n-butyl < sec-butyl < isobutyl but no such regularity for 7-9. Can be explained by the steric acceleration due to B strain (factor 1). S. W. Slayden. J. Org. Chem., 1981, 46, 2311. Example 2. Rearrangement of 9-BBN Derivatives Migrating group H n-C H OC COn-C8H17 IPh 8 17 PhI H n-C H OC O R R 8 17 PhI H n-C H OC R IPh B B 8 17 B n-C8H17 H B H H H H BR-9-BBN H R R = c-C5H9, c-C6H11, n-C6H13 Conformation of the ate complex dominates outcome (factor 4). M. Ochiai. et al. Org. Lett., 2004, 6, 1505. I2 Nonmigrating group H R R1 I2 B R R R Br R B 1 B 1 H H H H Br BR-9-BBN R B-9-BBN R = n-Butyl, sec-Butyl, isobutyl R1 = COR2, CO2R3, CN Torsional strain in expansion of 9-BBN. H. C. Brown. et al. J. Am. Chem. Soc., 1969, 91, 6852. H. C. Brown. et al. J. Am. Chem. Soc., 1969, 91, 6854. H. C. Brown. et al. J. Am. Chem. Soc., 1969, 91, 6855. Example 3. Oxidation of Trialkylborane with TMANO t-Hx c-Hx n-Hx t-Hx B TMANO B O c-Hx NMe n-Hx 3 c-Hx n-Hx n-Hx t-Hx t-Hx c-Hx NMe3 Me3N NMe3 OH OH n-HxOH relative yield 78% 20% 2% The bulkier groups are preferentially Can be accounted for the preferred oxidized (migratory aptitude decreases conformation of the ate complex in the order 3° > 2° > 1°). (factor 4). [O] H O The intermediate alkoxyboranes R B R BOR 2 R BOH 3 2 2 + ROH are easy to be hydrolyzed. TMANO (1eq), 0 ℃ R2BOR TMANO (2eq), 25 ℃ The oxidation process can be controlled R3B RB(OR)2 depending on the stoichiometry and reaction conditions. TMANO (3eq), reflux, 24h B(OR)3 J. A. Soderquist. et al. J. Org. Chem., 1986, 51, 1330. Example 4. Carbonylation of Organoboranes R1 O O CO R1 R B C O R1R2R3B 2 R3B [O] R2R3B R1 R2 R3 O R1 R1 R R R1 R1 O R2 1 2 KCN TFAA R R R R B R B CN R B C N 2 N N [O] 1 2 3 2 2 B R B CF 3 R3 R3 3 R3 O O CF3 CF3 O Ph O (1) CO H Ph (1) NaCN H B B (2) [O], pH 8 (2) TFAA (3) [O], pH 8 60% yield, 99% ee, >99% trans 75% yield, 99% ee, 99% trans Suggesting that the 1,2-migration is No ketones bearing the most hindered dominated by electronic factors relating group were isolated. The order in the to the ability of the migrating group to migration step is 1° > 2° > 3°. carry negative charge (factor 5). H. C. Brown. et al. J. Am. Chem. Soc., 1988, 110, 1529. Short Summary • Several factors should be considered when thinking about which group will migrate preferentially. • There is no migrating / nonmigrating group absolutely. • A consideration of the conformation required for migration of the ate complex is important. Contents • Introduction • Part 1 : Factors responsible for the 1,2-migration • Part 2 : Factors responsible for stereocontrol • Part 3 : Application of lithiation-borylation reaction in synthesis • Summary Stereocontrol: Substrate Control VS Reagent Control Complementary routes to homochiral organoboranes involving 1,2-metallate rearrangement Substrate control (Matteson) OR* LiCHCl2 Cl OR* R M Cl OR* -LiCl * 2 R1 B B * B M OR* OR* R1 OR* R -MCl 1 R2 R2 OR* Reagent control (Aggarwal) B * R OR* M 1 OR * LG OR R1 LG -MLG R2 B * B M OR OR R 1 R2 V. K. Aggarwal. et al. Chemical Record., 2009, 9, 24. Substrate Control: Anatomy And Application Matteson homologation-alkylation sequence Cl R Cl R Cl R Cl ZnCl Zn O 2 Zn O LiCHCl2 H ZnCl2 Cl O Cl R B O R H O R Cl R 1 B O r.t. R Cl B THF, -78℃ Cl B O B O O Cl O Cl R R R H R 1 R R R1 1 1 Cl H 1 2 3 3 4 Favoured Disfavoured X R Cl Cl R Cl MgX R R O R MgX M 1 O 2 H O MgX X O B R H O Cl R B B O R B O R1 B O O O R1 R R1 H R2 R R2 R R R2 R 2 R1 5 6 7 7 8 Synthetic Applications O O OH OH O OH O O O HO O C8H17 OH Me Japonilure (2S,3R,1’R)-Stegobinone L-(+)-ribose Serricornin D. S. Matteson. et al. J. Org. Chem., 2013, 78, 10009. Limitations of the Matteson-type Homologation-Alkylation (1) Reaction of diastereomeric boronic esters with grignard reagents lead to different outcome. X Mg O MeMgBr O X O B Cl B O Ph O B H O Ph Me Cl Bn Me 9 10 11 X Mg O MeMgBr O X O B Cl B O Ph O B Bn O Ph Me Cl H Me 12 13 14 MeMgBr X X Mg Mg Cl X O Me B X H H O O Cl R O B Bn Ph O B Bn R Me O H Me 15 15 16 D.