Boron Reagents for Asymmetric Synthesis Gordon J. Florence University of St Andrews SCI Review Meeting 2009 4th December 2009 London Overview 1) Hydroboration 2) Reductions 3) Aldol Reactions 4) Allylboration Reactions 5) Vinylations and Homologations Hydroboration Hydroboration The Starting Point S H B H H S H O , H H2B H B H 2 2 HO H 3 NaOH R R H HB R R R R R R R R R R R R R R R R R R “In the course of investigating the facile conversion of olefins into trialkylboranes under the influence of the sodium borohydride-aluminum chloride reagent, we have discovered that in the presence of organic ethers diborane adds to olefins with remarkable ease and speed at room temperature to form the corresponding organoboranes in yields of 90-95%.” Brown and Rao, JACS 1956, 78, 5694 JOC 1957, 22, 1136 JOC 1957, 22, 1137 “At the time many individuals expressed scepticism as to the value of devoting so much research effort to this reaction. They took the position that hydroboration, while a clean, simple reaction, produces only organoboranes, compounds of no known use……… We bided our time.” Brown & Ramachandran Pure Appl. Chem, 1991, 63 307 Hydroboration Common Reagents Examples Borane complexes i) BH •THF NHBoc 3 NHBoc ii) MeOH tBuO tBuO O B BH3•THF BH3•DMS B2H6 iii) O O O HO OH Christianson et al. JACS 1997, 119, 8107 Alkylboranes HB S S HB 2 N i) cHex2BH N 9-BBN cHex2BH ii) H2O2, NaOH OTBS OTBS 90% HB H2B 2 OH disiamylborane thexylborane Panek et al. OL 2000, 2, 2575 Dialkyloxyboranes O HB OPMB OH O O OPMB HB HB O C H B C H 10 21 OH O O 10 21 then H2O catecholborane pinacolborane pinBH cross-coupling precursor Kobayashi et al. JOC 2001, 66, 5580 For a recent review, see: Buckhardt and Matos, Chem. Rev. 2006, 106, 2617 Diastereoselective Hydroboration - Acyclic Systems Hydroboration of trisubstituted olefins can be controlled by A(1,3) strain OH B H RL 2 6 RL OH OH H2O2 RM RM R H M H B H Me • A(1,3) strain minimised R H M H CH OR Me R H 2 • Staggered transition state H L CH2OR B H • Sterics : RL vs RM H RL H major minor For detailed TS calculations and discussion, see: Houk et al. Tetrahedron 1984, 40, 2257 Representative Applications E-olefins Z-olefins H2B B2H6 CH2OBn CH2OBn then BH3 TrO OTr O O H2O2 OH TrO OTr work-up OH OH OH dr = 8 : 1 dr = 5 : 1 Kishi et al. JACS 1979, 101, 259 Still & Barrish JACS 1983, 105, 2487 Diastereoselective Hydroboration - Acyclic Systems Hydroboration of acyclic 1,1-disubstituted olefins controlled by A(1,2) strain In general - Houk’s rules BH3 L2BH RL OH RL RL OH H2O2 H2O2 RM RM RM H R H R B H clash B H For boranes RM H RM H For dialkylboranes H TS1 H H Me Me •Small reagent H •Bulky reagent RL RL major •Minimisation of minor •Minimisation of A(1,2) strain H R steric interaction H R favours TS1 H B H B between boron RM H RM H A(1,2) H TS2 H ligand and RM Me H Me H favours TS2 RL RL minor major For detailed TS calculations and discussion, see: Houk et al. Tetrahedron 1984, 40, 2257 Diastereoselective Hydroboration - Acyclic Systems Hydroboration of acyclic 1,1-disubstituted olefins controlled by A(1,2) strain Applications OMe O O OH OH BH3•SMe2 (85%) NO O OMe H OH Bn OH 9-BBN OMe diastereoselectivity OH 92:8 H2O2 O O OH NO O RM = OH OMe H OMe Still & Barrish JACS 1983, 105, 2487 Bn O 9-BBN O OH OH (60%) NO O OMe H Bn diastereoselectivity > 95: 5 Lonomycin: Evans et al. JACS 1995, 117, 2487 PMBO OH OH PMBO OH OH BH3•DMS steps 9-BBN (> 20:1 dr) OH TESO TESO anti H2O2 H H2O2 H O H O H O O OH (> 6:1 dr) MeO MeO syn O O TESO TESO TES TES Spirangien A: Paterson et al. ACIEE 2007, 46, 6699; Chem. Comm. 2008, 6408 Diastereoselective Hydroboration - Cyclic Systems substituted methylenecyclohexanes OH BH •THF NH OSO H; 3 i) LiMe2BH2 2 3 BMe NaOH, H O NH tBu tBu ii) TMSCl 2 2 2 dr = 2.1 : 1 OH Brown et al. JACS 1966, 88, 2870 BH •THF 3 Review, see: Brown & Sinagram Pure. Appl. Chem. 1987, 59, 879 tBu tBu dr = 1.2 : 1 H BH3•THF BH3•DMS B OH tBu tBu dr = 3.3 : 1 (+)-α-pinene (-)-Ipc2BH OH Brown & Zweifel JACS 1961, 83, 486 BH3•THF tBu tBu dr = 2.4 : 1 HO HO OH O O BH3•THF BnO BH3•THF BnO HO HO OH tBu tBu O O dr = 99 : 1 sole product • Largely governed by steric interactions • dr greater when 2-position substituent is axial Fraser-Reid et al. JACS 1984, 106, 731 Senda et al. Tetrahedron 1977, 33, 2933 Asymmetric Hydroboration - Brown’s Ipc reagents H H BH3•DMS B B BH3•DMS (+)-α-pinene (-)-Ipc2BH (+)-Ipc2BH (-)-α-pinene (-)-Ipc2BH OH IpcBH2 - alleviates E-olefin limitation >98.4% ee i) TMEDA ii) BF3 BH2 JACS 1961, 83, 486; JACS 1964, 86, 1076; JOC 1982, 47, 5065 (-)-Ipc2BH OH JOC 1978, 43, 4395; JOC 1982, 47, 5069 (-)-Ipc2BH R X X (-)-IpcBH2 R X = O, >99% ee X = NBn, >99% ee OH X = Cbz, 89% ee R = H, 73% ee OH NB: reversed sense of induction R = Me, 53% ee (-)-Ipc2BH X X (-)-IpcBH2 X = O, >99% ee Ph Ph OH X = S, >99% ee JOC 1986, 51, 4296; Heterocycles 1987, 25, 641 72% ee JOC 1982, 47, 5074 Limitations R •For perspective reviews, see: Pure Appl. Chem. 1991, 63, 316; Pure 14% ee 15% ee R = iPr, 32% ee Appl. Chem. 1987, 59, 879; Acc. Chem. Res. 1988, 21, 287 R = Ph, - •Highlight on asymmetric hydroboration, see: Thomas & Aggarwal ACIEE 2009, 48, 1896 Asymmetric Hydroboration - Masamune’s C2-symmetric borolanes Me Me B H H B Me Me (S,S) (R,R) Advantages: Uniformly high enantioselectivities for all olefins apart from 1,1-disubstituted OH HO (R,R) (R,R) 97.6% ee 95.6% ee R R (R,R) (R,R) HO OH R = H, 99.5% ee 99.3% ee R = Me, 97.6% ee H Selectivity rationalised by TS R model: 2 B R • hydrogen occupies position H R1 closest to Me group of borolane • loss of selectivity when R = H Largely ignored due to one disadvantage: Reagent prepared in seven steps, including: 1. Separation of diastereomers 2. Resolution of racemic trans-borolane Masamune et al. JACS 1985, 107, 4549 Asymmetric Hydroboration: 10-TMS-9-BBD and 10-Ph-9-BBD TMS Ph H H B B (10R)-9-TMS-10-BBD-H (10S)-9-Ph-10-BBD-H Ph Ph OH 10R-TMS 10S-Ph OH B H B H MeH H H 82% ee H 32% ee Me Me H H Favoured clash Me 10R-TMS OH 10S-Ph OH 10S-Ph R R R R R = H, 96% ee R = H, 96% ee R = Me, 84% ee R = Me, 74% ee Ph 10R-TMS OH 10S-Ph OH B H H Ph Ph Ph Ph RS 66% ee 78% ee RL TMS • Good levels of enantioselectivity observed with 1,1-disubstituted olefins using B H H H either reagent system H RS • First real solution to this longstanding hydroboration problem RL 10S-TMS Initial disclosure: Soderquist et al. ACS Symposium Series 783, Organoboranes for Synthesis, P. V. Ramachandran, H. C. Brown, Ed., Ch 13, pp 176-194, American Chemical Society, Washington, DC, 2000. Soderquist et al. JACS 2008, 130, 9218 Catalytic Hydroboration O O HB HB OH O O O O OH 0.5 mol% ClRh(PPh3)3 2h Männig & Nöth ACIEE, 1985, 24, 878 •need to use an unreactive dialkoxyboranes •hydroboration is achieved over ketone reduction by use of Wilkinson’s catalyst Styrene gives reversal of selectivity O HB OH O 1 mol% [Rh(COD) ]BF R 2 4 R Cl P dppb or PPh3 Rh selectivity >99:1 P P or ClRh(PPh3)3 B(OR) Hayashi et al. Tetrahedron Asymmetry 1991, 2, 601 2 Burgess et al. JACS 1992, 114, 9350 Ph Cl HB(OR) Rh P 2 P solv Catalytic cycle with Wilkinson’s catalyst Cl P (RO)2B Rh P Reversal of selectivity rationalised by formation of η3-Rh P H Cl Rh complex with Ph group after insertion of Rh-H Ph B(OR)2 P Wilkinson’s catalyst is highly sensitive to oxygen - Cl (RO) B P significant as slight variation in catalyst structure changes 2 Rh P H Ph reaction outcome - much debate in early studies Ph Reviews, see: Beletskaya & Pelter Tetrahedron 1997, 53, 4957; Crudden & Edwards EJOC 2003, 4695 Catalytic Hydroboration of 1,3-dienes • Regioselective hydroboration of 1,3-diene by choice of Fe(II)-ligand • Sequential hydroboration/crotylation Ritter et al. JACS 2009, 131, 12915 Asymmetric Catalytic Hydroboration O HB OH O PPh2 PPh 1 mol% [Rh(COD) ]BF 2 2 4 R R 2 mol% (+)-BINAP 88-96% ee R = Cl, Me, OMe (+)-BINAP Hayashi et al. JACS 1989,111, 3426 Tetrahedron Asymmetry 1991, 2, 601 Hayashi was first to report catalytic asymmetric hydroboration of styrene with high ee To date, BINAP remains one of the best ligand systems PCy2 Notable ligand systems PCy2 O Ph C2-diphosphane Ph O CF3 70-93% ee N O Ph P Knochel et al.