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. N tBu PPh P O Ph N 2 ACIEE 2001, 40, 1235 2 O N PPh Fe CF3 2 PPh2 Ph O tBu Josiphos-derivative Ph O QUINAP Pyphos 98.5% ee Taddol-based phosphane-phosphite O 78-94% ee 90% ee 91% ee Ph Togni et al. P O Ph J. M. Brown et al. Chan et al. Schmalz et al. JACS 1994, 116, 4062 N Chem. Comm. 1993, 1673 JOC 2002, 67, 2769 Adv. Synth. Catal. 2002, 344, 868 ACIEE, 1995, 34, 931; Bn Ph monodentate-Taddol 90-96% ee Takacs et al. OL 2006, 8, 3097
Reviews, see: Beletskaya & Pelter Tetrahedron 1997, 53, 4957; Crudden & Edwards EJOC 2003, 4695 Asymmetric Catalytic Hydroboration
Mes NNMes
CuCl 0.5 mol%
0.5 mol% NaOtBu Bpin O selectivity > 98% HB Hoveyda et al. O JACS 2009, 131, 3160
Hoveyda has recently established the catalytic hydroboration of 1,2-disubstituted olefins Use Cu-NHC complex and pinacolborane for regioselective hydroboration
Substrate Scope Enantioselective variant
OH O Ph Ph OMe OH S iPr Bpin O NN 76%, 96% ee 96% yield O iPr iPr OMe Bpin OH 7.5 mol% CuCl, 30 mol% KOtBu Bpin B pin , MeOH (2 eq), THF, -50°C, 2 d 51%, 89% ee X 2 2 80%, 98% ee after oxidative workup X= CH2, 97% Ph Ph X= O, >98% Ph NN O BF O OMe 4 Ph Bpin Bpin 76% yield X 7.5 mol% CuCl, 30 mol% KOtBu X B2pin2, MeOH (2 eq), THF, -50°C, 2 d X = CH2, 63%, 72% ee X = O, 98%, 89% ee
Hoveyda et al. JACS 2009, 131, 3160 Reductions Reductions with Borane Reagents
O O B2H6 "B2H6" "B2H6" CN Ph OH Ph OH H OH diglyme Ph diglyme Ph NH2 H. C. Brown PhD thesis, University of Chicago diborane generated in situ from NaBH4 and BF3•OEt2 Brown, Schlesinger & Burg JACS 1939, 61, 673 Brown & Rao JOC 1957, 22, 1135
Commercial Boranes
t Primary Applications BH3•THF BH3•DMS B2H6 BH3•pyr BH3•NEt3 BH3•NH2 Bu Carboxylic acid reduction Reductive amination Amide reduction enamine reduction Oxime reduction
NH R1 HArMe Ar Me O BH •DMS HO O 3 BH3•pyr HO C O N R N R 2 O O N RT 76%, >1kg O O O N 100% 1 2 O2N R Hoffman-La Roche: US Patent 4112225, 1978 Parker et al. Org. Proc. Res. Dev. 2003, 7, 67
Cl Cl MeO MeO O H H BH •THF H2N OMe 3 OMe O2N NBn O2N NBn H H O i) OMe N reflux OMe H H H O 90% t ii) BH3•NH2 Bu AcOH, PhMe Pfizer: US Patent 5256791, 1993 Draper et al. Org. Proc. Res. Dev. 1998, 2, 175
For review, see: Buckhardt & Matos Chem. Rev. 2006, 106, 2617 Reductions with Borohydride Reagents
O NaBH4, MeOH H OH
Chaikin & W. C. Brown JACS 1949, 71, 122 H.C. Brown, Mead & Rao JACS 1955, 77, 6209
A selection of some commercial borohydrides and applications
NaBH4 LiBH4 LiBH(Et)3 Met-BH(sBu)3
Super Hydride Met = Li, Na, K Met-Selectride
ketone/aldehydes + esters Hindered ketones Stereoselective reductions of ketones Enone reductions - 1,2 or 1,4 acid chlorides directed ketone reductions SN2 - Ts/Ms displacement Amide to alcohol Lactones to lactols
O HO O OH 7 7 O O K-Selectride, 79% O O LiBH(Et)3 9 : 1 dr at C7 PhHN 1 5 1 PhHN NH PhHN NH
OTBS OTBS Killigore et al. WO Appl. 0140184, 2001 Smith et al. JACS 2000, 122, 8654
NaBH3(CN) NaBH(OAc)3 Me4NBH(OAc)3
reductive amination directed ketone reductions Directed Reductions of β-Hydroxy Ketones
1,3-syn reduction - Narasaka-Prasad
H Et Et2BOMe; H R OH O O NaBH4 H OH OH O O B Ph OMe Et Ph OMe THF/MeOH O H 1,3-syn diol, 98% ds
• Formation of intermediate boron aldolate • Axial addition of hydride from lowest energy half-chair • Reaction can be done in situ following boron aldol reaction
With trialkylboranes: Narasaka & Pai Tetrahedron 1984, 40, 2233 Modification with alkoxyboranes: Prasad et al. TL 1987, 28, 155
1,3-anti reduction of β-hydroxy ketones - Evans-Saksena Reduction
H H OAc OH OH O O+ Major B - R1 O OAc OMe H R2 1,3-anti OH O O Me4NBH(OAc)3 Favoured OMe
H OAc OH OH O R2 B- Minor R1 O OAc OMe H O H + 1,3-syn Disfavoured
1,3-directed reductions with NaBH4 / AcOH: Saksena & Mangiaracina TL 1983, 24, 273 Optimisation and utility in polyketide synthesis: Evans et al. JACS 1988, 110, 3560 Asymmetric Borane Reductions
Brown’s Ipc-based Boranes O chiral borane H OH
OBn
+ + B Li B Li B H H
Alpine-Borane Alpine-Hydride NB-Enantride Brown et al. JOC 1977, 42, 2534 Midland et al. JOC 1982, 47, 2495 20% ee 1% ee
effective for ynones (99% ee) - effective for straight chain ketones (68-79% ee) Midland et al. JACS 1980, 102, 867 Cl Cl Cl B B B
(-)-Ipc2BCl (+)-Ipc2BCl Eap2BCl Brown et al. JACS 1988, 110, 1539 Brown et al. Pure. Appl. Chem. 1991, 63, 307
98% ee >99% ee
(+)-Ipc2BCl reduction L s RL Rs R R Me H • boron chloride reagents work by de- O hydroboration and loss of pinene O H B B Me H Me H Cl Cl (-)-α-pinene
For a comparative study with various classes of ketones prior to CBS, see: Brown et al. J. Org. Chem. 1987, 52, 5406 Asymmetric Borane Reductions
Itsuno’s Reagent O OH O (S), BH •THF OH (S), BH3•THF 3 R = Me, 94% ee R = Et, 94% ee L s L Rs H Ph R R R Ph R Ph R R = Pr, 96% ee Ph
HN O O OH B (R), BH3•THF OR N (S), BH3•THF NH2 RL Rs L s R = Me, 99% ee H R R R = Bn, 95% ee (S) Ph Ph Itsuno's reagent • reagent and BH3•THF mixed in situ to form diborane complex • stoichiometric reagent system works well for ketones with defined large and small groups • catalytic version developed by Corey (see below) • oxime ether reduction gives reversal of facial selectivity Itsuno et al. J. Chem. Soc. Chem. Comm. 1983, 469 J. Chem. Soc. Perkin Trans. 1, 1985, 2039 Corey’s CBS Reagent
H Ph H Ph Me Ph Ph O 5-10 mol% (S)-MeCBS OH Ph R = tBu, 94% ee R = Ph, 94% ee H N N O R Me R Me B N O 0.6-1 eq BH3•THF H B B B H Ph Me Me H O Rs (S)-MeCBS (R)-MeCBS •Corey proposed mechanistic rationale for observed selectivity •Optimised catalytic version of reaction RL •Both (R)- and (S)-MeCBS commercially available Corey et al. JACS 1987, 109, 5551
O O O OH O O (R)-MeCBS •Utility has been demonstrated in process N O N O chemistry - 50 kg scale BH3•THF •Remains a go to reagent for many total synthesis F Ph F Ph 97% yield, 95% de campaigns for tricky reductions 15-50 kg scale Schering-Plough: Fu et al. TL 2003, 44, 801; Wu et al. JOC 1999, 64, 3714 Aldol Reactions Boron Reagents for Aldol Reactions
Focus of intense interest over last 30 or so years due to its primary utility in the synthesis of polyketide natural products OH O OH O
R3 R1 R3 R1 syn O O aldol R2 R2 + reaction R3 H R1 R2 OH O OH O anti R3 R1 R3 R1 R2 R2
1) Mukaiyama TMS O O LA O OH R3 R1 H R4 R1 R4 R2 R2 R3
Lewis acid promoted (e.g. BF3•OEt2)
2) Boron-mediated
O L2BX OBL O OH 2 O R3N + R1 R1 R1 R3 H R3 R2 R2 R2
Formation of boron enolate and reaction with aldehyde Mukaiyama Aldol Reactions
TMS Mukaiyama et al. O O O OH TiCl4 Chem. Lett. 1973, 1011 JACS 1974, 96, 7503 Ph H Ph Ph Ph Reviews: Org. React. 1994, 46, 1
• Reaction of silyl enol ether and aldehyde in presence of Lewis acid promoter (e.g. TiCl4, BF3•OEt2) • Proceeds via open transition state
LA R1 LA TMS O O O O LA O OH R2 R3 R2 R3 TMSO R1 H R4 R1 R4 H R4 H R4 3 R2 R2 R3 R R1 OTMS antiperiplanar synclinal "Favoured"
Possible to control relative and absolute stereochemistry by use of: 1) Chiral silyl enol ether (limited application) 2) Chiral aldehydes 3) Chiral Lewis acid
1) Chiral silyl enol ether TMS TMS TBSO O TBSO O OH TBSO O TBSO O OH BF3•OEt2 BF3•OEt2 + anti + anti iPrCHO iPrCHO
dr = 59 : 41 dr = 95 : 5 Evans: JACS 1995, 117, 9598 enolsilane facial selectivity = 95 : 5 enolsilane facial selectivity = 90 : 10
Reviews, see: Mahrwald, Chem. Rev. 1999, 99, 1095; Nelson, Tetrahedron: Asymmetry 1998, 9, 357 Mukaiyama Aldol Reaction: Chiral Aldehydes
α-chiral aldehydes F B TBS 3 H O L Me O O BF3•OEt2 O OH RL R Ph Ph Me Nu R H R H O H Nu H F3B R = Me, dr = 91 : 9 Favoured R = tBu, dr = 96: 4 Anh & Eisenstein Noveau J. Chim. 1977,1, 61 • Mukaiyama aldol reactions with α-chiral aldehydes proceed with high levels of Felkin-Anh induction • Increasing size of nucleophile leads to increased selectivity for Felkin-Anh product β-oxygenated aldehydes
TMS F3B H H O O OP BF3•OEt2 O OH OP O H PO PO H R F B R H 3 O Nu Nu P = PMB, dr = 92 : 8 P = TBS, dr = 80 : 20 Favoured dipole destabilization
•Mukaiyama aldol reactions with β-OPMB proceed with high levels of 1,3-anti induction (also OBn), according to Evans’ 1,3-polar model
Merging stereochemical models O OPMB BF3•OEt2 O OH OPMB O OH OPMB
O OPMB BF3•OEt2 O OH OPMB H TMS R R O H TMS R O R Felkin anti-Felkin R = Me, dr = 17 : 83 R R = Me, dr = 97 : 3 R = iPr, dr = 56 : 44 R = tBu, dr = 99 : 1 R = tBu, dr = 96 : 4 anti diastereomer syn diastereomer α and β reinforcing α and β non-reinforcing Small nuceophile - 1,3-control Large nucleophile - Felkin control
Evans et al. JACS 1996, 118, 4322; JACS 2001, 123, 10840 Mukaiyama Aldol Reaction: Chiral Boron Lewis Acids
Yamamoto’s Chiral (Acyloxy)Boranes
OTMS O OH OTMS 20 mol% CAB O OH 20 mol% CAB i PhCHO O Pr O CO2H nBu PhCHO nBu Ph PhO PhO Ph O 81%, 85% ee 63%, 84% ee O O O OiPr B OTMS O OH OTMS 20 mol% CAB O OH 20 mol% CAB H CAB Et Et Ph PhO Pr PhO Pr PhCHO OHC
94%, 94% ds, 96% ee 97%, 96% ds, 97% ee
•Yamamoto’s tartrate-derived CAB give high levels of ee •substituted silyl enol ethers/ketene acetals give syn adduct regardless of starting geometry Yamamoto et al. JACS 1991, 113, 1041; Synlett 1991, 439; Bull. Chem. Soc. Jpn. 1993, 66, 3483; JACS 1993, 115, 10412
Masamune’s Oxaborolidine Catalysts
Me OTMS 20 mol% 1 O OH OTMS 20 mol% 1 O OH O PhCHO EtO Ph PhCHO PhO Ph iPr EtO PhO p N O TolO2S B 77%, 93% ee 83%, 91% ee H OTMS 20 mol% 1 O OH
tBuS PhCHO tBuS Ph
94% ds, 82% ee Masamune et al. JACS 1991, 113, 9365; TL 1992, 33, 1729
Reviews, see: Mahrwald, Chem. Rev. 1999, 99, 1095; Nelson, Tetrahedron: Asymmetry 1998, 9, 357 Mukaiyama Aldol Reaction: Chiral Boron Lewis Acids
Corey’s Oxaborolidine Catalyst:
O OTMS 20 mol% OXB-Bu O OH OTMS 20 mol% OXB-Bu N O H Ph PhCHO Ph Ph MeO PhCHO; then TFA O Ph p N O TolO2S B 82%, 89% ee 100%, 82% ee n Bu aldol - cyclisation: formal hetero-Diels Alder Corey: TL 1992, 33, 6907 Derivatives and related applications
O OH OTMS O OH N O OTBS 5 mol% 2 H 20 mol% 1 MeO Ph PhCHO Ph Ph MeO iPrCHO p N O TolO2S B 99%, 94% ee 75%, 98% ee R vinylogous aldol reaction: Yamamoto et al. JOC, 2000, 65, 9125 1: R = Ph, Kalesse et al. OL 2007, 9, 5637 2: R = 3,5-(CF3)2C6H3
Diels-Alder reactions Origin of facial selectivity
π−π interaction between OTIPS OTIPS HN carbonyl of aldehyde and indole 10 mol% OXB-Bu R H ring of catalyst CHO -78 °C O O O Nu Cl CHO B •Only re-face exposed for 94% ee R nucleophile addition Ts Corey: JACS 1994, 116, 3611 JACS, 1991, 113, 8966; JACS 1992, 114, 8290 Boron-mediated Aldol Reaction
Focus of intense interest over last 30 or so years due to its primary utility in the synthesis of polyketide natural products OH O OH O
R3 R1 R3 R1 syn O O aldol R2 R2 + reaction R3 H R1 R2 OH O OH O anti R3 R1 R3 R1 R2 R2
General mechanism L H X O L B L2B L2B O 3 O O O 3 O R L2BX R3N R H H R1 R1 R1 R1 R2 R2 R2 R2
L L B O O workup O OH R1 R3 R1 R3 R2 R2
Stereochemical issues to consider: 1) relative stereocontrol - selective enolization 2) absolute stereocontrol - π-facial selectivity Why Boron?
Comparison of Group I, II and III enolates
O M O O O OH O OH M O O OH R3 H O OH 3 R3 H X X R3 X R 3 R3 R M syn anti
Li >98 2 M syn anti X = CMe3 MgBr >95 5 BBu2 >97 3 Li 48 52 AlEt2 50 50 Li 80 20 BBu2 17 83 X = C6H5 BBu2 >97 3
X = Et Li 80 20 BBu2 >97 3
cHex BCl O 2 BcHex2 O • stereocontrol with Li- and Mg-enolates optimal with Et3N O OH “large” X Ph H Ph Ph Ph • high levels of selectivity maintained with use of B-enolates O 95% anti Ph • B-O bond length < M-O bond length - tighter transition B-9-BBN O state - higher levels of stereocontrol from metal centre O O OH Ph H 9-BBN-OTf Ph Ph Ph iPr2NEt MO BO MC BC 98% syn
1.9-2.2 Å 1.4-1.5 Å 2.0-2.2 Å 1.5-1.6 Å In general Boron chloride → (E)-enolate → anti aldol
Boron triflate → (Z)-enolate → syn aldol Controlling Enolate Geometry
L2BCl O L2BOTf
i Et3N R Pr2NEt
cis trans R L B deprotonation + TfO – L deprotonation L2B O 2 O O – L Me + B H B R L Cl L O R R Favoured H Me Favoured for electronic H for steric reasons :NEt ABH reasons (E)-enolate 3 (Z)-enolate i proton activated :NEt Pr2 by cis B–Cl
trans Cl L cis L B L2B O deprotonation R deprotonation 2 O B O + R + – Me L O L H B – R R Disfavoured H Me TfO L Disfavoured H (Z)-enolate H (E)-enolate
• sterically demanding ligands (e.g. cHex) • small ligands (e.g. n-butyl, 9-BBN) • poor leaving group (e.g. chloride) • good leaving group (e.g. triflate)
• small amine base (e.g. Et3N, Me2NEt) • bulky amine base (e.g. iPr2NEt) Relative Stereocontrol
H L 1 O OH R + 3 M R O L 1 3 H R R O R2 2 R TS-1 1,2-syn OBL2 R2 clash R1 3 R L O OH (Z)-enolate R1 + M H O L 1 3 H R R O R2 R2 TS-2
H L O OH R1 3 + M R O L 1 3 R2 R R O R2 TS-3 H 1,2-anti OBL2 clash R1 3 R L 2 R R1 O OH + M (E)-enolate H O L 1 3 R2 R R O R2 H TS-4
• enolate geometry faithfully transferred by 6-membered Zimmerman-Traxler TS (for R2 ≠ H)
• rationalizes observed relative stereochemistry
• widely accepted but is this really the case? Relative Stereocontrol: Revised
DFT Transition state calculations - Jaguar v4.2, 6-31G** basis set, B3LYP
H H H B O B O B O O O O
chair chair chair 0 +0.55 +1.46
O H O H O H B B B O O O
Boat A Boat A Boat A +1.30 0 0
O O O B B B O H O H O H
Boat B Boat B Boat B +3.37 +0.67 +0.93
relative energies in kcal mol-1
For Z-enolborinates - boat A and B destabilized by 1,4-steric interactions between Me and ligand - Chair favoured
For E-enolborinates - chair destabilized by 1,3-diaxial repulsion (ligand ↔ enolate sidechain) - Boat A favoured
For unsubstituted enolborinate - chair disfavoured strongly (ligand ↔ enolate sidechain) - Boat A favoured
Goodman and Paton, Chem Comm 2007, 2124 Absolute Stereocontrol in Boron Aldol Reactions
Selection of one diastereomer over an other
OBL O 2 OH O OH O R2 + 1 R 3 1 3 1 R3 H R R R R R2 R2
L2BOTf iPr2NEt
O
R1 R2
L2BCl Et3N
OBL2 O OH O OH O + 1 3 R R H R3 R1 3 1 R2 R R R2 R2
• Use of chiral aldehydes where R3 is a stereogenic group • Use of auxillary control where R1 is a stereogenic group and is subsequently removed • Use of substrate control where R1 is a stereogenic group which is retained • Use of reagent control by using chiral boron reagents α-chiral aldehydes and (Z)-enolates
O OML2 + R2 R1 H (Z) 23 Normal 'Felkin' Anti-Felkin conformer conformer 1 R1 R L L H L H H R2 M M R1 O L O L Me M H H O L O 2 O H H R2 A R Me O Me Me H Me TS-6 Me TS-5 H gauche Favoured for R2 > Me syn pentane
O OH O OH R2 R2 R1 R1
Felkin product Anti-Felkin product Minor Major
O OBBu2 O O O OH
O N H O N
62% ds
Evans & Bartoli TL 1982, 23, 807 α-chiral aldehydes and E-enolates
H R1 L O OH Me O H B R2 Me R1 O L H R2 Anti-Felkin product gauche OBL O Anti-Felkin transition state 2 Minor (E) R2 R1 + H
R1 H L O OH O B R2 Me R1 O H R2 L H Felkin product Me Felkin transition state Major
Example: Spongistatin C15-C16 bond construct
O H O O HO OAc OMe TESO TESO O OMe OH OMe cHex2BCl O O Et3N O O O O O O AcO HO O O O O O O AcO TBSO AcO TBSO HO OH O OPMB OPMB O OCH CCl O OCH2CCl3 O OH 2 3 H OH Cl OH 89%, 90% ds spongistatin 1 (altohyrtin A)
Paterson: ACIEE, 2001, 40, 4055 See also: Evans: Tetrahedron 1999, 55, 8671 (Spongistatin 2) Chiral Auxiliaries: Evans’ Oxazoladinones
Bu Bu O O B O O nBu2BOTf O O O OH iPr2NEt R H O N O N O N R
i i Pr iPr Pr >99 : 1 for achiral aldehydes
• The benchmark - reliable 1,2-syn aldol product via Z-enolate • Facial bias of enolate overides any inherent selectivity of chiral aldehydes • Auxillary readily available from parent amino acid (or Aldrich) • Readily removed by hydrolysis, formation of Weinreb amide
Transition states
O O H O N L N QuickTime™ and a L O QuickTime™ and a decompressor H B H decompressor are needed to see this picture. O B are needed to see this picture. L O O L O R R
Favoured
References Evans et al. JACS 1981, 103, 2127; Pure Appl. Chem. 1981, 53, 1109 Calculations: Goodman and Paton, Chem Comm 2007, 2124 Chiral Auxiliaries: Evans’ Oxazoladinones
Auxiliaries
O O O O
O NH O NH O NH O NH
iPr Bn Ph Bn
Evans et al. JACS 1981, 103, 2127; Pure Appl. Chem. 1981, 53, 1109 SuperQuat: Davies et al. Tetrahedron 2004, 60, 7553; OBC 2004, 2, 3385
Applications
O O O O O O O O O O
Cl OBn NBn2 O N O N O N O N O N
Bn Bn Bn Bn Bn propionate crotyl imide α-chloro glycolate-type α-amino
O O O O
H Et H H Ph H Ph
O O O O OH O O OH O O OH O OH O OH
O N R O N Et O N O N Ph O N Ph Cl OBn NBn2 Bn Bn Ph Bn Bn TL 1986, 27, 4957 TL 1987, 28, 39 Tetrahedron 2004, 60, 7553 Chiral Auxiliaries: Evans’ Oxazoladinones
Limitations - the acetate aldol O BBu2 O O O O H O OH O OH
O N O N O N
i i iPr Pr Pr Ratio = 52 : 48
QuickTime™ and a QuickTime™ and a •Competing boat transition states decompressor decompressor are needed to see this picture. are needed to see this picture. •TS1 - iPr group occupies position pointing away from TS •TS2 - iPr group occupies position pointing towards TS •Energy difference between TSs is negligible •No selectivity
Auxiliary-based Solutions 1. Introduce temporary group 2. Nagao Sn(II) acetate aldol O S O Sn(OTf) S O OH BBu2 2 O O H O O OH O O OH N-Et-piperidine O N R SMe RaNi O N O N O N O N O i SMe iPr Pr i H R Pr iPr iPr 93-97% ds 98% ds Nagao et al. Chem. Soc., Chem. Commun. 1985, 1418 Pure Appl. Chem. 1981, 53, 1109 Nagao et al. J. Org. Chem. 1986, 51, 2391. Chiral Auxiliaries: α-oxygenated ketones
O OR O O O O O RO TBSO TBSO TBSO OR OTBS TBS R = Bn R = Bn R = Bz R = Bz
Masamune Enders Heathcock Paterson Cardo, Marco Romea JACS 1981, 103 1566 ACIEE 1988, 27, 581 JOC 1991, 56, 2499 TL 1994, 35, 9083 & 9087 TL 1999, 40, 6845 OL 2000, 2, 2599
• Simple chiral ketones • Use α-substituent to dictate π-facial selectivity • Aldol products are the manipulated to excise directing group
Syn aldols L L O PO H H L O B O R1 O OH 2 PO L BX, R N PO H R B PO 2 3 R2 O 2 H L R O R1 X = OTf or Cl R1 R1 1 R = C6H11, tBu, Me, CH2OBn Me 92-99% ds P = TBS, TMS, Bn
• Preferential formation of (Z)-enolate due to chelation of reagent with α-alkoxy/siloxy group, independent of reagent
• Chair TS, in which alkoxy group aligned to oppose dipole of enolate oxygen and alkyl group is positioned to avoid steric congestion Chiral Auxiliaries: α-oxygenated ketones
Paterson anti aldols
O O cHex2BCl OBL2 O OH Me NEt BzO 2 BzO H R BzO R
95-99% ds
• selective E-enolisation - α-oxygen of benzoate unable to chelate boron reagent • high levels of selectivity for anti-anti diastereomer • Enolate induction normally overides any other stereodifferentiating factors
Ph Ph O H-bond L O H O O H Me Me H H B O R L O L Me B Me O O R H L H
chair boat
• Both chair and revised boat TSs account for π-facial selectivity • Boat TS - significantly less congested • A13 strain minimised between Me of enolate and α-stereocentre • Contrasteric - large OBz directed in to TSs • Electronic effect - lone pair repulsion between n(O) enolate and Bz group minimised and TS stabilised by H-bonding of C=O to formyl H,
Paterson et al. Tetrahedron Lett. 1994, 35, 9083 & 9087; Synthesis 1998, 639 Chiral Auxiliaries: α-oxygenated ketones
Manipulation of α-oxygenated aldol adducts
TBSO H cHex BCl, Et N + OBz H 2 3 + OBn O O O O cHex2BCl 99% cHex BCl 85% Me2NEt >97% ds 2 OBn Et3N 90% ds O O B TBSO L2 OBz OBn EtMgBr 92% OH O 90% ds OH O a) PMBTCA, H+ a) TBSOTf b) NaBH4; K2CO3 b) SmI2 OBn c) NaIO4 OH OH
TBSO H a) LiDBB b) NaIO TBSO O 4 PMBO O
JACS 2001,123,9535 TL 1994, 35, 9087 OH O • useful tool to incorporate anti-aldol motif • complimentary to Evans syn-aldol • products readily manipulated to remove superfluous stereodirecting group • ketones readily available from cheap (R)- and (S)-lactate esters • not limited to ethyl ketones
O O O O BzO BzO BzO BzO
C6H13 OMe OP P = Bn: TL 1994, 35, 9087 TL 1994, 35, 9083 TL 1999, 40, 393 ACIEE 2000, 39, 1308 P = PMB: Shiori et al. TL 1999, 40, 3187 Reagent Control
Concept : Control absolute configuration by using chiral ligands on boron
OH O OH O
R3 R1 R3 R1 O O 2 2 L* BX, R N R R + 2 3 R1 R3 H L* = chiral ligand R2 OH O OH O
R3 R1 R3 R1 R2 R2
First example - Meyers and Yamamoto JACS 1981, 103, 4278
O (-)-Ipc2BOTf O tBuCHO OH O
N iPr2NEt N i) workup tBu OMe + BH ii) H ; CH2N2 29% (based on boron reagent) 94% ds, 79% ee Reagent Control: Isopinocampheyl Boron Reagents
X X B B
(-)-Ipc2BX (+)-Ipc2BX X = Cl or OTf X = Cl or OTf
• Most common chiral reagents for asymmetric boron aldols
• Ipc2BCl introduced by Brown for asymmetric reduction of ketones in 1985 • Reagents readily prepared from (+)- or (-)-α-pinene by hydroboration
• Ipc2BCl is commercially available from Aldrich, (+)- or (-)-DIPCl
• Ipc2BOTf prepared in situ from the corresponding Ipc2BH
Application of Ipc-reagents for aldol reactions by Paterson
OHC O OBL* 2 O OH (-)-Ipc2BOTf
iPr2NEt
L* = (-)-Ipc 78% 98% ds, 91% ee
Paterson et al. Tetrahedron Lett. 1986, 27, 4787; Tetrahedron 1990, 46, 4663; Pure Appl. Chem. 1992, 64,1821 Reagent Control: Isopinocampheyl Boron Reagents
Origin of facial selectivity Me Me R O O L H L H O R O O B B OBL* H 2 O OH Me H R H R Me Me Me Me Me L* = (-)-Ipc Me Me Si-face FAVOURED Re-face •Competing chair transition states •Attack on Re-face leads to unfavourable interaction between enolate sidechain and Me of pseudoaxial Ipc ligand •Calculations predict Si-face addition (88% ee) - consistent with experimental observations (66-93% ee)
Methyl ketones
H L L O H O OHC B B O OBL*2 O OH R (-)-Ipc2BOTf O O R iPr2NEt Me Me Me L* = (-)-Ipc 59%, 73% ee Me Me Me
•Facial selectivity is opposite Re-face Si-face •Attributed to boat-like transition state FAVOURED •Confirmed by calculations
Paterson et al. Tetrahedron Lett. 1986, 27, 4787; Tetrahedron 1990, 46, 4663; Pure Appl. Chem. 1992, 64,1821 Reagent Control: C2-symmetric borolanes
Me Ph
B OTf B Cl
Me Ph
Masamune Reetz JACS 1986, 108, 8279 Tetrahedron Lett. 1986, 27, 4721 Pure Appl. Chem. 1988, 60, 1587 Pure Appl. Chem. 1988, 60, 1607 Me
B OTf
Me B B OH O O OH O O O RCHO RCHO R SCEt3 SCEt SCEt R SCEt3 SCEt3 3 iPr2NEt 3 71 - 95% yield 71 - 95% yield syn : anti = >30 : 1 90-98% ee H >98% ee R O H Me Me O B H •Enolisation of alkylthioester gives E-enolate, exclusively Me Favoured SCEt •Selectivity rationalised by chair transition state 3 H •Essentially perfect stereocontrol in anti-aldol products •Comparable levels of stereocontrol are achieved in thioacetate aldol reaction clash H H Me SCEt3 • Why is this reagent overlooked? B R O Me Me O H Practicality: Advantage of high ee outweighed by the 7-step reagent H synthesis (including diastereomer separation and a resolution) Reagent Control: C2-symmetric diazaborolidines
CF3 CF3 CF3 CF3 Ph Ph Ph Ph Ph Ph
Ar N N Ar S S S N N S N N B F3C B CF3 F3C S B S CF3 O O O O O O O O O O O O Br Br Br (R,R)-2 (R,R)-1 (S,S)-1 Corey JACS 1989, 111, 5493; JACS 1990, 112, 4976; TL. 1991, 32, 2857; TL 1993, 34, 1737 thiopropionate
Ph BL*2 OH O O O 71 - 95% yield S Ph L B S Ph (S,S)-1 RCHO S R3N 2 syn : anti = >30 : 1 - O L2B O Br O SPh R SPh >98% ee L B SPh iPr2NEt 2 Br diethyl ketone • enolisation of aryllthiopropionate/ OH O diethylketone gives Z-enolates, attributed O 68-91% yield (R,R)-2 RCHO syn : anti = >94 : 6 to dissociation of bromide following ate >95% ee Et R Et iPr2NEt R= Ph, Et, iPr formation
Ar = p-NO2-C6H4 • high levels of induction thioacetate • acetate gives reverse sense of induction with high ee O OH O 82-84% yield (S,S)-1 RCHO 91% ee: R = Ph • t-butyl propionate enolisation gives 83% ee: R = iPr SPh R SPh iPr2NEt “expected” E-enolate t-butyl-propionate All propionate diastereomers are accessible simply by choice of starting BL*2 ester and ligand O (S,S)-1 O RCHO OH O 82-93% yield syn : anti = >96 : 4 t t t O Bu Et3N O Bu R O Bu 75-98% ee Substrate Control: Syn aldol reactions of α-chiral ethyl ketones
Substrate Control: Use stereogenic centre in a chiral ketone to control facial selectivity, which is then retained in subsequent steps Syn aldol reactions
OBL O OH 2 RCHO R RL L R
RM RM
RL = large group, RM = medium group
Me Me R R O O L H O OH H L O OH O O R B RL B L H R vs H R RM RL L R L RM H M H RL RM FAVOURED
In general,
• reaction of α-chiral (Z)- boron enolates governed by sterics to give syn-syn adduct
• favoured TS, A(1,3) strain and steric interactions are minimised by RL pointing away from chair TS
• also applicable to titanium aldols (TiCl4, Hunig’s base)
Evans, JACS 1991, 113, 1047 Substrate Control: Syn aldol reactions of α-chiral ethyl ketones
Examples
O O OH nBu BOTf iPrCHO TBS 2 TBS iPr2NEt Enders 90% ds ACIEE 1988, 27, 581
OHC O TBSO O TBSO O OH 9-BBNOTf steps OH O O
iPr2NEt 83%, 95% ds ebelactone A Paterson and Hulme JOC, 1995, 60, 3288
Comparison of metal (Z)-enolates
M M Yield (%) SS : SA TBSO O TBSO O OH TBSO O OH iPrCHO TiCln 96 96 : 4 9-BBN 66 92 : 8 Li 85 17 : 76 : 7(anti) SS SA
M TBSO O TBSO O OH iPrCHO
M = TiCln: 95% ds M = 9-BBN: 92% ds Titanium: Evans JACS 1991, 113, 1047 Boron: Evans TL, 1995, 36, 9245 Lithium: McCarthy JOC 1987, 52, 4681 •configuration of β-silyloxy has limited effect on selectivity Substrate Control: Anti aldol reactions of α-chiral ethyl ketones
In general OBL O OH 2 RCHO R RL L R
RM RM SA
RL = large group, RM = medium group
Anti aldol with (E)-enolate under steric control gives syn-anti diastereomer
H H R R O O L Me O OH Me L O OH O O B RL B RL H R H R H H L RM L RM RM R R R L L SA M AA FAVOURED
•A(1,3) strain is minimised between α-substituent and Me group of enolate in proposed chair TSs •large group orientated away in favoured TS (chair) •Boat-type TS can also be envisaged - same stereochemical outcome
L L H B R O OH O Me RL O R H H RM
RM SA RL
Evans: Tetrahedron 1992, 48, 2127; JACS 1995, 117, 6619 Substrate Control: Anti aldol reactions of α-chiral ethyl ketones
Examples: Steric Control
TBSO O TBSO O OH TBSO O TBSO O OH cHex2BCl iPrCHO cHex2BCl iPrCHO
Et3N Et3N 90%, 94% ds 75%, 96% ds
Evans: Tetrahedron 1992, 48, 2127
With α-chiral aldehydes O OPMB
BL2 TBSO O H TBSO O OH OPMB
matched
L = cHex 85%, >99% ds
O OPMB
BL2 TBSO O H TBSO O OH OPMB
mismatched
L = cHex 79%, 81% ds
Evans: JACS 1995, 117, 6619 Substrate Control: Anti aldol reactions of α-chiral ethyl ketones
Paterson’s α-chiral ethyl ketone building blocks
BL PO O PO O 2 PO O OH cHex2BCl RCHO R Et3N
P = Bn, PMB, DMB L = cHex AA : >95% ds
• Anti-anti diastereomer formed with high selectivity • Proven building block for assembly of polypropionate units in natural products • Both enantiomers readily available from commerical (R)- or (S)-Roche ester • Does not follow steric TS model - electronic effect
OBn
H L H Me L Me H BnO H + B - R O - B + Me L O R O L Me O H H
Favoured Disfavoured re-face si-face
TL 1989, 30, 7121; Pure Appl. Chem. 1992, 64,1821; JACS 1994, 116, 11287 Modeling: Tetrahedron 1993, 49, 685 Substrate Control: Anti aldol reactions of α-chiral ethyl ketones
Applications in synthesis Sug O O OTBS
H I O DMBO O DMBO O OH OTBS H OH cHex BCl 2 MeO O O I Et3N 99%, 95% ds callipeltoside Cl OL 2003, 5, 4477 Formaldehyde aldol Pure Appl. Chem. 2008, 80, 1773
PMBO O PMBO O OH cHex2BCl HCHO discodermolide OL, 2003, 5, 35; Et3N JOC 2005, 70, 150 96%, 93% ds
OMe Propyl ketone with in-situ reduction OH O L L Sugar OHC OH O O BnO O B OH BnO O O BnO OH OH cHex2BCl LiBH4 HO O concanamycin A Et3N OMe TL 1997, 38, 4183 94%, 95% ds ACIEE 2000, 39,1308 In situ reduction: TL 1992, 33,801; Tetrahedron 1996, 52, 811 Benzyloxymethyl-ketone
PMBO O OH PMBO O cHex BCl MeCHO 2 spongistatin 1 Et3N TL 1997, 38, 5727 OBn OBn ACIEE, 2001, 40, 4055 93%, >97% ds Substrate Control: Aldol reactions of α-chiral methyl ketones
BL H BnO O BnO O 2 BnO O OH L2BCl PrCHO Pr H Et3N PO L 1,4-syn O H B L = cHex: 88% ds L = (-)-Ipc: 92% ds O L R' • Boron aldol reaction of methyl ketone gives 1,4-syn adduct • Level of selectivity can be increased by using chiral ligand system • Sense of induction in line with analogous ethyl ketone Paterson, Goodman, Isaka, TL 1989, 30, 7121 • Rationalised by boat TS- formyl H-bond stabilises favoured TS TS Calculations: Goodman and Paton OL, 2006,8, 4299
Application OH O MeO OMe O OH O ODMB O O H ODMB
OTES OTES steps O H OH MeO OTBS cHex2BCl, Et3N MeO OTBS MeO O O Br Br (89%; >95 : 5 dr) Br dolastatin 19
OL, 2006, 8, 2131; Tetrahedron 2007, 63,5806 Pure Appl. Chem. 2008, 80, 1773 Substrate Control - β-oxygenated methyl ketones
1,5-anti induction
BnO BnO BnO L BCl, Et N iPrCHO 2 3 5 1 L = c-Hex TESO OP O TESO OP OBL2 TESO OP O OH or (-)-Ipc
1 : P = PMB P = PMB 2 : P = TBS P = TBS entry ketone L dsa (yield)
1 1 c-Hex 92 (78) 2 1 (-)-Ipc 96 (71) 3 2 c-Hex 77 (80) 4 2 (-)-Ipc 95 (84) Paterson et al. TL 1996 37, 8585
OTr OTr OTr i Bu2BOTf, Pr2NEt Ph(CH2)2CHO 5 1 R
O O O O O OBL2 O O O OH
Ph Ph Ph
R R = (CH2)2Ph (70%, >95% ds) H PO L Evans et al. JOC 1997, 62, 788; JACS 2003, 125, 10893 O H B •High levels of 1,5-anti induction from methyl ketones with bearing β-alkoxy group O L R' •Numerous applications in polyacetate natural products since discovery 1,5-Anti •Rationalised by boat TS - formyl H-bond and R group points away Favoured Goodman and Paton OL, 2006, 8, 4299 Substrate Control: 1,6-induction - the limit of induction?
γ−methyl-(Z)-enones RL Me RL Me H L O (c-Hex)2BCl, Et3N; 6 H L H O B H B OH O 1 O L L iPrCHO O O TBSO OTBS TBSO OTBS R R 99%, 81% ds chair boat working models
dienolate in s-trans conformation A(1,3) strain minimised sterics control facial selectivity Application
cHex2BCl O Et3N O H MeO C O O O 2 TBS TBSO NH 2 OTBS
O
HO O O O MeO2C TBS OTBS NH2
OTBS 64%, 95% ds at C5
Paterson et al. OL 2003, 5, 35; JOC, 2005, 70, 160 Allylboration Reactions Allylboration and Crotylboration: Introduction
General process
H L R3 O B 5 4 2 6 R R R 3 R O L R OH 1 5 6 R R H R 5 1 R via R B R 6 2 R 2 R4 3 R R R4 R2 R1 MC BC
2.0-2.2 Å 1.5-1.6 Å
• Transfer of allyl group to an aldehyde via highly ordered cyclic TS • Reaction proceeds via 6-membered Zimmerman-Traxler transition state • High levels of relative stereocontrol from tight TS - short B-C bonds • Control of absolute stereochemistry typically by using chiral boron ligands Typical applications
Allylation O OH H R R2B R
Crotylation O O OH OH H R H R R2B R R2B R
(E)-crotylborane anti-product (Z)-crotylborane syn-product
First examples reported by R. W. Hoffmann in late 70’s Developments through 80’s - 90’s paralleled those in asymmetric aldol methodology and continue today Resulting terminal olefin can then be elaborated or retained as a masked functionality to be revealed at a later point Using pinacol-based reagents: Hoffmann & Zeiß ACIEE 1979, 18, 306; JOC 1981, 46, 1309 Asymmetric Allylboration: Chiral Boronic Esters
Hoffmann - 1979
OH O O i) MeCHO steps O B O Ph ii) N(CH2CH2OH)3 O 93%, 60-70% ee ent-stegobinone
First example of asymmetric allylboration using camphor-based scaffold
Hoffmann et al. ACIEE 1978, 17, 768; TL 1979, 48, 4653
Hall redesign - 2003
OH O 10 mol% Sc(OTf)3 OH B O R O 10 mol% Sc(OTf)3 RCHO O B R Ph RCHO up to 96% ee Ph 94 - 97% ee
OH O 10 mol% Sc(OTf)3 O B R RCHO Ph 70-97% ee
• Subtle redesign of original Hoffmann system • Movement of Ph-group and use of catalytic scandium triflate boosts ee Hall et al. JACS 2003, 125, 10160; Synthesis 2004, 1290 Asymmetric Allylboration: Chiral Boronic Esters
Roush’s tartrate-derived systems - 1985
iPrO2C OH O cHexCHO iPrO2C OH iPrO2C B cHex O O cHexCHO iPrO2C B cHex O 90%, 83% ee
iPrO2C 72%, 87% ee OH O cHexCHO iPrO C B 2 O cHex
O >99%, 91% ee iPrO O iPrO
i O H PrO O iPrO B H O O R B O Me O O Me O Favoured R
• Practical and predictable system using tartrate ester derivatives • available in either enantiomeric form •Favoured transiton state minimises interaction of aldehyde and ester lone pairs
Roush et al. JACS 1985, 107, 8186; TL 1988, 29, 5579
Variations
iPrO2C iPrO2C OH O RCHO OH O RCHO KH R iPrO2C B iPrO2C B TMS R O R O 56%, 92% ee TMS Z-diene >20:1 Yamamoto et al. JACS 1982, 104, 7667 Roush et al. TL 1990, 31, 7563; TL 1992, 48, 1981 Myles et al. JOC 2003, 68, 6646 Asymmetric Allylboration: Brown’s Ipc-Reagents
Allylation H
OH L H BOMe BrMg B MeCHO O R B 2 2 BF •OEt Me 3 2 H Me (-)-Ipc2BOMe >99% ee Me
Me Crotylation
K OH BOMe B MeCHO • Deprotonation of (Z)- or (E)-2-butene with 2 2 BF •OEt Me Schlosser’s base at -78 °C gives respective 3 2 anion
(-)-Ipc2BOMe 99% ds, 96% ee • Formation of reagent by addition of
Ipc2BOMe, followed by BF3•OEt2 to break- up ate complex BOMe K B MeCHO OH 2 2 Me • Reaction with aldehydes proceeds with BF3•OEt2 high selectivities
(-)-Ipc2BOMe 99% ds, 96% ee • Ipc2BOMe commercially available from Aldrich in either enantiomeric form
Brown et al. Allylation: JACS 1983, 105, 2092; JOC 1991, 56, 401 Crotlyation: JACS 1986, 108, 293; JACS 1988, 110, 1535 Full paper: JOC 1986, 51, 432 Asymmetric Allylboration: Soderquist’s 10-TMS-9-BBD Reagents
Allylations
Ph Ph O TMS Me TMS TMS O B B BrMg B OH Me N RCHO MeHN OH R H R 96-99% ee O air stable x-tals TMS B R recycled reagent H 10R proposed TS
• Treatment of precursor 10R with allylMgBr generates allylborane reagent in situ • allylation of aldehyde proceeds through proposed TS • allyl group points away from 10-TMS group • R group of aldehyde minimises steric interaction with BBD ring system • 10R recovered by refluxing with (S,S)-pseudoephedrine
Crotylations
TMS K OH TMS OH B K B RCHO RCHO R 10R R
>98% ds >98% ds 94-95% ee 96-99% ee Using (S,S)-pseudoephedrine reagent recovery
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 2005, 127,8044 Asymmetric Allylboration: Soderquist’s 10-Ph-9-BBD Reagents
Ketone Allylations
Ph
O Me O O Ph Ph Ph BrMg HO RL Me N B B tBu B H tBu Rs
70% yield 10R-Ph 99% ee
• 10R-Ph adopts chair-like conformation on side of Ph-group - larger chiral pocket for small group of ketone • Allows ketone allylation- phenyl group is smaller than corresponding 10R-TMS • 10R recovered by refluxing with (S,S)-pseudoephedrine Soderquist et al. JACS 2005, 127,11572
Ketimine allylation
Ph TMS Me O N Ph Ph TMS BrMg Me Me N B B NH2 Ph R R N H R B Me 50-82% yield 10R-Ph 60-94% ee
• 10R-Ph allylation used to prepare series of enantiomeric enriched 3° carbamines • Powerful solution to access rare motif • NB - sense of induction opposite to carbonyl additions • Ketimine approaches trans to Ph group
Soderquist et al. JACS 2006, 128, 8712 Asymmetric Allylboration: Soderquist’s Double Allylation
O TMS Ph H B B B TMS 1 B R B O Ph -78°C, 12 h R1 Ph TMS B 10S-TMS 10S-Ph trans-10-SS
rearrangement
BBDPh BBDPh O Me O OH OH O OBBDTMS R1 R1 = iPr, R2 = Ph, 71%, 98% ee H2O2, NaOH RH 1 2 1 2 R = Ph, R = iBu, 63%, 98% ee R R2 R1 R
B
TMS
• Hydroboration of 10S-TMS with 10S-Ph gives diboron reagent • Ketone allylation followed by borotropic rearrangent • Subsequent aldehyde allylation and oxidative work-up gves 1,3-diols with essentially complete ds and ee • Variation of reagent configuration gives access to further diastereomers by design
Soderquist et al. JACS 2009, 131, 1269 Catalytic Asymmetric Ketone Allylboration
Last decade has seen significant advances in catalytic asymmetric protocols Aldehyde allylation dominated by use of Ti-BINOL-type catalysis with allylsilanes or allylstannanes O OH H R TMS R Ti-BINOL or Tagliavini et al. Org Lett 1999,1,1061 >97% ee Bu3Sn Maruoka et al. TL 2001, 42,1935
Ketone allylation remained a significant hurdle until 2006: Schaus’s organocatalytic allylboration
O O 2 mol% S-3,3-Br2-BINOL OH B Ar Me O t-BuOH, RT Ar >96% ee Br O O 4 mol% S-3,3-Br2-BINOL OH B OH Ph Me O t-BuOH, RT Ph OH
97% ds, 98% ee Br O O OH 4 mol% S-3,3-Br2-BINOL S-3,3-Br -BINOL B 2 Ph Me O t-BuOH, RT Ph
96% ds, 94% ee
Schaus et al. Shibasaki reported CuF2-DUPHOS system in 2004 (~80% ee) Original report: JACS 2006, 128, 12660 JACS 2004, 126, 8910; For review, see: Chem. Rev. 2008, 108, 2853 Optimised reaction: ACIEE, 2009, 48, 1 Schaus’s organocatalytic allylboration
Catalytic Cycle O O Br 2 mol% S-3,3-Br2-BINOL OH B Ar Me O t-BuOH, RT Ar OH >96% ee OH
OH O Br B Ph HO O S-3,3-Br2-BINOL HO
HO H O HO O H Me B O O O O B Ph O
with OiPr HO H B Ph O OiPr O O Me B O Schaus et al. O Original report: JACS 2006, 128, 12660 Ph Optimised reaction: ACIEE, 2009, 48, 1
With acyl imines
O
N Ph OiPr 15 mol% S-3,3-Ph2-BINOL NHBz • NB - reversal of facial selectivity B i R H O Pr PhMe, RT R • High ee’s R= alkyl, aryl • Crotylations also very efficient 91-98% ee Original report: JACS 2007, 129, 15398 Substrate-directed allylborations R. W. Hoffmann intramolecular allylations
MeO OMe LiBF X 4 X Bpin MeCN OH H X = O X = O, >98% ds X = NCO2Me X = NCO2Me, >98% ds O O B O OH MeO OMe >98% ds Bpin OH LiBF4 X X Liebigs Ann. Chem. 1993, 1185 MeCN X = O X = O, 94% ds X = NBoc X = NBoc, >98% ds Liebigs Ann. Chem. 1996, 1283
OMe OMe OMe MeO H Bpin MeO Bpin LiCH2Cl MeO Yb(OTf)3 O O O Bpin HO O Rh(PPh3)3Cl
Matteson: Organometallics 1985, 4, 1687 Brown: JOC 1986, 51, 3150 Synthesis of medium ring ethers
N(Me)OMe
O DIBAL; s-BuLi pinB-OiPr O HO
then pH7 O OTBS O OTBS O OTBS pinB laurencin core JACS 1997, 119, 7499
For an overview, see: Hoffmann et al. ACS Symposium Series 783, Organoboranes for Synthesis, P. V. Ramachandran, H. C. Brown, Ed., Ch 12, pp 160-175, American Chemical Society, Washington, DC, 2000 Substrate-directed allylborations Hall’s sequential HDA-allylation
Bpin Bpin Jacobsen-HDA RCHO QuickTime™ and a R decompressor O OEt are needed to see this picture. O OEt O OEt OH >99% ds, 96%ee R = aryl, alkyl
JACS 2003, 125, 9308 Chem. Eur. J. 2006, 12, 3132 Jacobsen HDA, see: ACIEE 2002, 41, 3059
Application in Synthesis Bpin O Bpin Bpin OPMB Jacobsen-HDA HO pinB O OEt pinB O O OEt O O OEt O OEt EDCI OH PMBO O 84%, 96 % ee LDA, TMSCl•NEt3
pinB OPMB OPMB O OEt H2O2, NaOH [3,3] MeO HO O O OEt O OEt PMBO then CH2N2 O OH O Bpin OTMS 55%, >98% ds • HDA-allylation with aldehyde then sets stage for B-Ireland-Claisen • Allows hydroxyl differentiation and rapid assembly of carbon framework palmerolide A JACS 2009, 131, 14216 Vinylations and Homologations Petasis Reaction
General Scheme 1 R1 R1 O OH heat R H OH 4 R transfer 4 N O N R N B B 2 R2 H R3 H R4 OH R2 OH R 3 3 R R4 R R1 = alkyl R3 = alkyl, COOH, aryl R4 = alkenyl, aryl, R2 = alkyl, OH, heteroaryl O-alkyl, NHBoc
• Formation of hemiaminal, followed by ate formation • Transfer of alkenyl or aryl group from intermediate ate complex gives allylic/benzylic amine products • Mechanism remains a point of discussion TL, 1993, 34, 583; Tetrahedron 1997, 53, 16463; JACS 1997, 119, 445 Modifications Hydroxyl-Directed 1 2 1 2 R R O R R N R1 OH heat N 4 3 R transfer 3 R 3 R N H B R R4 R2 H R4 OH H OH OH R4 O 1 3 4 B R = H, alkyl, benzyl R = alkyl, CH2OH R = alkenyl, aryl, OH R2 = alkyl, benzyl heteroaryl OH >99% de
JACS 1998, 120, 11798
Cyclic N-acyliminium
OH OH OH HO H O OH BF3•OEt2 N OH B O OAc N OAc N Cbz Cbz 6-deoxycastanospermine
Batey et al. JACS 1999, 121, 5075; TL 2000, 41, 9935 Asymmetric Petasis Reactions
Takemoto - 2007 CF3 CF3 S S
1 2 F3C N N R R OH F3C N N H H H H N 1 N B 1 2 R HO Ar OH R R O N 10 mol% B HO O Ar N OPh O N CO2Ph Ph Cl OPh R2 82-96% ee TS-concept •Vinylation of N-acylated quinolines catalysed by isothiourea
Takemoto et al. JACS 2007, 129, 6687
Schaus - 2008
R1 Bn O N R1 OEt 15 mol% (S)-VAPOL OEt OEt N H B R2 Bn H R2 OEt 3A MS, -15 °C, PhMe O O Ph OH 1 Ph OH R = alkyl, benzyl R2 = aryl, alkyl 78-94% ee
• First asymmetric variant of classical Petasis reaction catalysed by chiral biphenol • Need to use ethyl glyoxalate to achieve high ee’s (S)-VAPOL • Tolerates range of FGs in both amine and vinyl boronate
Lou & Schaus JACS 2008, 130, 6922 Rh-mediated 1,4-addition of Boronic Acids
Miyaura-Hayashi 1997 O O Rh(acac)(CO)2 / dppb (3 mol%) Ph B(OH)2 cyclohexane/ H2O ( 6 : 1) 50°C, 16h Ph 52% Asymmetric: Miyaura-Hayashi 1998 Miyaura, Hayashi et al. Organometallics 1997, 16, 4229
O Rh(acac)(C H ) / (S)-BINAP O 2 4 2 O Rh(acac)(C H ) / (S)-BINAP O (3 mol%) 2 4 2 Ph B(OH) (3 mol%) 2 B(OH) dioxane/ H O ( 10 : 1) 2 2 dioxane/ H O ( 10 : 1) 100°C, 5h Ph C5H13 2 100°C, 5h C5H13 93%, 97% ee 64%, 96% ee
PPh2 • Initial report closely followed by asymmetric variant
PPh2 • Uses Rh-Binap catalyst • Both aryl and alkenyl boronic acids can be used with generally high ee • Remains the benchmark for other metal ligand systems (S)-BINAP Miyaura, Hayashi et al. JACS 1998, 120, 5579
Esters and amides
O Rh -BINAP O (3 mol%) X Ar B(OH)2 X •High ee’s for cyclic lactone/lactams dioxane/ H2O ( 10 : 1) •Comparable ee’s for acyclic systems under Ar 100°C, 5h same conditions X = O, 97-98% ee X = NBn, 97-98% ee
Esters: Hayashi et al. Tetrahedron: Asymmetry 1999, 10, 4047 Amides: Hayashi et al. JOC 2001, 66, 6852 For review, see: Chem. Rev. 2003, 103, 2829 Rh-mediated 1,4-addition of Boronic Acids
Addition of organotrifluoroborates
O O O O [Rh(cod)2][PF6] / (R)-BINAP [Rh(cod)2][PF6] / (R)-BINAP (3 mol%) BF3K (3 mol%) BF K 3 S toluene/ H2O ( 10 : 1) toluene/ H2O ( 10 : 1) 105-110 °C C6H13 105-110 °C C6H13 S 99%, 92% ee 84%, 90% ee
• Extended to include organotrifluoroborates (easier to handle, greater stability) • Addition of vinyl group - not possible with vinyl boronic acid
Genet et al. TL 2002, 43, 6155; EJOC 2002, 3552
Tandem 1,4-additon - alkylation/aldol reaction O
BuLi, allylBr BBN O O Rh(OMe)(cod)2 / (S)-BINAP Ph (3 mol%) 98% ee Ph B(OH)2 toluene 80°C, 1h Ph O OH PrCHO H Pr
Ph Reaction performed under aprotic conditons using B-Ar-9-BBN 98% ee Intermediate Rh-enolate transmetallates back to 9-BBN-enolate Followed by direct aldol addition Or further transmetallation with BuLi enables alkylation Hayashi et al. JOC 2003, 68, 1901
For review, see: Chem. Rev. 2003, 103, 2829 Organocatalytic 1,4-additions of Boronic Esters
Asymmetric Alkynylation: Chong 2005 C H 6 13 I (S)-3,3-I -BINOL O iPrO 2 O 20 mol% OH B C6H13 Ph R iPrO DCM Ph R OH
R = Ph, 94%, 86% ee I R = Me, 89%, 94% ee (S)-3,3-I2-BINOL • Asymmetric addition of alkynylboronic ester to enones • Enone must contain aryl group to achieve high ee • Chong proposes complete ligand exchange with catalyst- see Schaus allylation for alternative view Wu & Chong JACS 2005, 127, 3244
Asymmetric Alkenylation: Chong 2007
C H QuickTime™ and a 6 13 decompressor (R)-3,3-I -BINOL are needed to see this picture. O MeO 2 O R = Ph, 93%, 97% ee 20 mol% B R = Me, 95%, 96% ee Ph R Ph R R = CO Me, 84%, 97% ee MeO C6H13 DCM 2
R (R)-3,3-I -BINOL O MeO 2 O 20 mol% R = CH2OBn, 83%, 97% ee B R = Ph, 97%, 98% ee Ph Ph MeO R DCM Ph Ph QuickTime™ and a decompressor are needed to see this picture. • Analogous alkenylation also proceeds with high ee • Trisubstituted alkenylboronic esters can also be used
•Possible TS’s shown for (R)-3,3-I2-BINOL Wu & Chong JACS 2007, 129, 4908 Organocatalytic 1,4-additions of Boronic Acids
Takemoto 2009
CF3 R2 S O OH 10 mol% thiourea* O B 1 OH 2 OH F3C N N R R OH PhMe, rt 1 H H R N
R1 = aryl R2 = aryl 91-98% ee thiourea* HO OMe
• Combination of hydrogen bonding to isothiourea and formation of ate complex between substrate, boronic ester and catalyst prior to intramolecular transfer
Derivitisation of products OMe OMe
MeO H 1. NBS DIAD, PPh3, O O 2. tBuOK o-NsNH2 Ph O OH Ph Ph O H
Takemoto et al. OL 2009, 11, 2425 MacMillan’s α-vinylation of aldehydes
O O O 20 mol% 1•TFA R NMe H KF3B H R 2.5 eq CAN, H O N C6H15 2 C6H15 DME or Acetone, -50°C Ph H •TFA R = aryl, alkyl 89-95% ee 1•TFA • Organo-SOMO catalysis - • Applicable to range of aliphatic aldehydes with high selectivity
O O O O NMe NMe NMe -H2O H N N Bn H - N X Ph - 1e Ph X
X KF3B KF B R 3 R - 1e- O X H H2O O O NMe NMe Bn Bn N N R X X
KF3B R R
• Single electron oxidation of intermediate enamine • Radical cation then undergoes reaction with alkene • Further single electron oxidation of intermediate radical • Dicationic species then undergoes Peterson-like trans-elimination of boron trifluoride Kim & MacMillan JACS, 2008, 130, 398 Aggarwal’s Homologation of Boranes and Boronic Esters
OLi O O O LiCHCl2 O OtBu B B B B O O O O Cl Cl Cl OtBu O • Matteson reported the homologation of boronic esters in 1980 using LiCHCl2 • Use of chiral pinane diol ester enabled asymmetric version - though applications limited
Matteson et al. JACS, 1980, 102, 7588 & 7590 • Alternative would be to use chiral deprotonation - Aggarwal 2007 R2 BBN R2 s-BuLi or 2 Li O BL2 R R2 (-)-sparteine R2 Bpin MgBr2 H2O2 R R R ROCb i R O N Pr2 OCb BL2 OH H H H H R2 = Et, Ph R = alkyl 90-96% ee transmetallation with retention Li O R3 O NiPr H 2
HO HO HO HO R R2 R R2 H H2O2 H Ph Ph Ph Ph R3 R3 BL OH H 2 H >90% ds, >96% ee • Utilises Hoppe’s chiral deprotonation to give stabilized lithiated carbamates • Reaction with alkyl/aryl boranes or boronates proceeds with retention • Migration of alkyl/aryl group from B to C - • Further iterations possible by sequential addition of lithiated carbamates/migration process • Either enantiomer of lithiated carbamate available by use of appropriate sparteine/ sparteine surrogate
Aggarwal et al. ACIEE 2007, 46, 7491 Aggarwal’s Homologation of Boranes and Boronic Esters
R2 BBN R2 s-BuLi or 2 Li BL2 R R2 (-)-sparteine R2 Bpin MgBr2 H2O2 R R R R ROCb OCb OCb BL2 OH H H H H R2 = Et, Ph R = alkyl 90-96% ee sp3 - C-Li transmetallation with retention
• For R = alkyl: transmetallation occurs with retention- C-Li sp3 hybridised
Et Et Bpin Bpin heat Et H O Et 2 2 HO Me Me Me Me retention OCb Bpin OH Ar Ar Ar Ar Et Me Li s-BuLi 98% ee Me Ar OCb OCb Ar
Me Me Me Me OH Et BEt2 OCb heat Bpin H2O2 OH Ar Ar Ar Ar Et inversion Bpin Et Et Et 98% ee
R • With substituted benzylic-type carbamates - lithiated O carbamate has more sp2 character, resulting in flatter RO B anion - interaction with Ar group Et Li O Li O Me Me • For boronic ester- interaction with Li and OR group of O NiPr O NiPr Ar 2 Ar 2 boronic ester delivers on same face as metal -retention
Et BEt • For borane- no complexation and significant electron 2 denisty on opposite face - inversion Aggarwal et al. Nature 2008, 456, 778 Extras β-alkoxy aldehydes
For E-enolates - effect of β-oxygen is moderate, Felkin adduct predominates BL2 O O OR O OH OR O OH OR
H
L = cHex R major minor
centres reinforcing TBS 99 1 PMB 93 7
BL2 O O OR O OH OR O OH OR
H
L = cHex R major minor
centres non-reinforcing TBS 94 6 PMB 74 26 Evans JACS 1995, 117, 9073 For methyl ketones - effect of β-oxygen is not so predictable
BL2 O BL2 O OR O OH OR O O OPMB O OH OPMB Bn H H Bn BL2 = 9-BBN R = PMB, 77% ds BL = 9-BBN 69% ds 2 R = TBS, 48% ds BL2 O O OPMB O OH OPMB BL H 2 O O OTBDPS O OH OTBDPS
BL2 = 9-BBN 77% ds H β-OPMB dominates - 1,3-anti addition L = cHex 89% ds Chiral Auxiliaries: Oppolzer’s Sultam
nBu2BOTf iPr NEt O 2 O O OH N N L Me O N S B L R O2 S H R O H O Me 2 SO2 H R > 97% ds crystalline
Complimentary Sn-aldol
BuLi H O OH Bu SnCl Me O 3 O N N N R R Me O S O S H O2 SO2 H R O O Sn Bu Bu Bu 64-87% ds crystalline
Oppolzer et al. JACS 1990,112, 2767 Substrate Control: α-amino ethyl ketones
α-amino ethyl ketones
OBBu2 Bu2BOTf O cHex2BCl OB(cHex)2 iPr NEt Me2NEt Bn2N 2 Bn2N Bn2N
(Z)-enolate (E)-enolate
Me H R R O O L H L Me O O B B H H NBn H L 2 L H Me Me NBn2 Control: Opposing dipoles Control: Sterics
iPrCHO iPrCHO
O OH O OH
Bn2N Bn2N
SA: 86% ds AS: 85% ds
Paterson and Mackay: TL 2001, 42, 9269 Substrate Control - β-oxygenated methyl ketones
Origin of 1,5-anti induction PO O
Comparison of Expt’l and Calculated dr R Goodman and Paton OL, 2006, 8, 4299 L2BX, R3N; R'CHO
R H
H R PO O OH PO O OH PO L L OP O O R R' H B B H R R'
O L L O R' R' 1,5-Anti 1,5-Syn Favoured
methyl ketone major adduct exp. dr model system major adduct pred. dr
B(c-Hex)2 BMe2 PMBO OMe O PMBO OMe O OH OMe O OMe O OH i) i-PrCHO 75:258 MeCHO 80:20
OTBS OTBS
B(c-Hex)2 BMe2 PMBO O PMBO O OH OBn O OBn O OH 5 ii) Ph(CH2)2CHO 94:06 MeCHO 97:03 (CH2)2Ph
PMP PMP Ph Ph BBu 2 BMe2 O O O O O O OH O O O O O O OH iii) Ph(CH2)2CHO 93:075 MeCHO 100:00 (CH2)2Ph
B(c-Hex)2 BMe2 TBSO O TBSO O OH TMSO O TMSO O OH iv) i-PrCHO 58:423 MeCHO 66:34 Substrate Control: Merging 1,4- and 1,5-induction
combine effects to increase selectivity
TBSO
PMBO O PMP PMP H cHex2BCl, OTBS O O O O O O OH (-)-Ipc2BCl Et3N Et3N O MeCHO
TBSO OTBS >95% ds PMBO O OH Dias et al. OL 2002, 4, 4325 83%, 95% ds Mulzer & Burger TL 1998, 39, 803
Paterson discodermolide synthesis
cHex2BCl, Et N OHC 3 5 1 MeO2C MeO2C R 4
PO O PO OBL2 PO O OH P = TBS, PMB 1,4-syn 1,5-anti (major) P = TBS: ACIEE, 2000, 39, 377; TL 2000, 41, P = TBS (62%, 54% ds) 6935; JACS 2001, 123, 9535 P = PMB (73%, 95% ds) P = PMB: Florence & Paterson, unpublished
24 O 7 L2BCl, Et3N MeO C 2 H O O O TBSO O 24 TBS OTBS NH2 L Yield ds MeO 1 7S cHex 67 16 87 84 O O O OH O O O (+)-Ipc TBS TBS Use chiral reagent in combination to overturn aldehyde facial selectivity OTBS NH2 Asymmetric Allylboration: Brown’s Ipc-Reagent Diversity
Methallylation
OH BOMe BuLi, TMEDA B RCHO 2 2 R BF3•OEt2 • acetone aldol equivalent
(-)-Ipc2BOMe 90-96% ee TL 1984, 25, 5111; JOC 1986, 51, 432 Isoprenylation
OH BH B RCHO 2 2 R
(-)-Ipc2BH 89-96% ee TL 1984, 25, 1215; JOC 1986, 51, 432
K BOMe B RCHO OH 2 2 R BF3•OEt2
(-)-Ipc2BOMe 90-96% ee TL 1990, 31, 455
methoxyallylation chloroallylation OMe Cl OH OH s-BuLi B RCHO LDA B RCHO (-)-Ipc BOMe 2 (-)-Ipc BOMe 2 2 R 2 R BF3•OEt2 OMe BF3•OEt2 Cl OMe Cl 95-96% ee 90-99% ee
JACS 1988, 110, 1535 Hu, Jayaraman & Oehlschlager JOC 1996, 61, 7513 Asymmetric Allylboration: Soderquist’s 10-TMS-9-BBD Reagents
R1 Anti-allenylation R1 R1
TMS TMS H TMS TMS EtO B B LiAlH3(OEt) B B TMSCl R1 Li EtO BF •OEt 10R-TMS 3 2
10R-TMSBBD-H O
R2 H 1 R R1 1 2 R = nC5H11, R = Pr, 73%, 98% ee 2 H O R 2 2 O TMS 1 2 NaOH R = (CH2)4Cl, R = Ph, 78%, 99% ee B
OH R2
• Sequential alkyne hydroboration-insertion-allylation to give 1,2-anti-3-allenes • Tolerates wide-range of terminal alkynes • High levels of selectivity • Syn variant is also comparable syn-allenylation
TMS H EtO O B TMS TMS MgBr B B Ph H Li Ph
BF3•OEt2 then H2O2 OH NaOH 10S-TMSBBD-H 71%, 96% dr, 99% ee
Soderquist et al. JACS 2009, 131, 9924