Enantioselective Lithiation

H H RLi/L* H Li•L* E H E

X Y X Y X Y

Spencer Jones MacMillan Group Meeting March 19, 2008

Key Articles: Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552. Beak, P.; Johnson, T. A.; Kim, D. D.; Lim, S. H. Top. Organomet. Chem. 2003, 5, 139. Hoppe, D.; Hense, T. Angew. Chem. Int. Ed. Engl. 1997, 36, 2282 Overview ! Introduction to Enantioselective Lithiation - Complexation induced proximity effects - Use of (!)-sparteine as a ligand for enantioinduction ! Mechanism of Lithiation - Kinetics studies - Pathways for enantioinduction - Substitution phenomena ! Ligands Other Than (!)-Sparteine - Initial attempt at finding a sparteine surrogate - O'Brien's Ligand ! Catalytic Asymmetric Lithiation ! Synthetically Useful Examples Complexation Induced Proximity Effects

! Enables Reactivity at sites that are otherwise nonreactive or not thermodynamically favored

BuLi

OLi O !78 °C O O

Ph Ph Ph BuLi Ph Li

Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356

Me2N NMe2 TMEDA

O Li O Me O s-BuLi/TMEDA CH3I

Ph N(iPr)2 Ph N(iPr)2 Ph N(iPr)2 !78 °C Me Me Me

Lutz, G. P.; Wallin, A. P.; Kerrick, S. T.; Beak, P. J. Org. Chem. 1991, 56, 4938. Use of (!)-Sparteine as a Ligand for Enantioinduction

! (!)-Sparteine is a readily available alkaloid that can serve as a ligand for various metals

H N N " N N N N H (-) sparteine = sp* $116, 100 g

! Metalation in the presence of (!)-sparteine

Me Me Li/sp* Me * n-BuLi/sp*

50 °C, Hexane Li (o-, m-, p-)

21 : 79

Nozaki, H.; Toraya, T.; Noyori, R. Tetrahedron, 1971, 27, 905 Use of (!)-Sparteine as a Ligand for Enantioinduction

! (!)-Sparteine is a readily available alkaloid that can serve as a ligand for various metals

H N N " N N N N H (-) sparteine = sp* $116, 100 g

! Metalation in the presence of (!)-sparteine

Me Me Li/sp* Me CO2H * n-BuLi/sp* CO2

50 °C, Hexane

21 30% ee

Nozaki, H.; Toraya, T.; Noyori, R. Tetrahedron, 1971, 27, 905 First Highly Enantioselective Lithiation Using Sparteine

! Chelation directed lithiation provides a configurationally stable, dipole stablized carbanion capable of reacting with several electrophiles. ! The bulky carbamate serves to prevent nucleophilic addition into the carbamate

N N O H H O Li O E H s-BuLi/sp* H E N O R N O R N O R O Et2O, 5 h O O Me !78 °C Me Me Me Me Me 52 ! 81% yields R = CH3, (CH2)5CH3, CH(CH3)2 " 95% ee

E = Me3SnCl, CO2, CH3I

Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem. Int. Ed. Engl. 1990, 12, 1422. Mechanism of Enantioselective Lithiation

! Boc-pyrrolidine is asymmetrically lithiated with s-BuLi/sp* and reacts selectively with a variety of electrophiles

s-BuLi/sp* E Li/sp* E N N N !78 °C, Et2O Boc Boc Boc

Electrophile Yield ee (%) TMS-Cl 87 96 PhCOPh 75 90

CO2 55 88

(CH3)2SO4 88 94

Sn(Bu)3Cl 83 96

Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994, 116, 3231 Mechanism of Enantioselective Lithiation

! BuLi/sparteine is present in solution as an organolithium dimer ! If the lithiation were to occur in a single step with the dimer, the reaction order in s-BuLi should be 1, whereas if the reaction occurs via monomer the order should be 0.5

N N N Li N Li/sp* s-Bu s-Bu t-BuO O Li t-BuO O

(Et2O)n

Reaction Order in Organolithium dimer? ! Kinetics experiments revealed the lithiation is zeroth order in organolithium dimer

Gallagher, D. J.; Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1992, 114, 5872 Gallagher, D. J.; Beak, P. J. Org. Chem. 1995, 60, 7092 Mechanism of Enantioselective Lithiation

! The fact that the lithiation is zeroth order in organolithium dimer under pseudo first order conditions suggests the presence of a prelithiation complex, C, with a large equilibrium constant, Kc

N N Kc k2 N Li N N Li/sp* s-Bu s-Bu Li/sp* t-BuO O Li t-BuO O t-BuO O

(Et2O)n C ! The RDS was determined to be the deprotonation step due to the high kinetic isotope effect (kH/kD)

D D Me N 1. s-BuLi/sp* N D N D kH/kD >30

2. (CH3)2SO4 t-BuO O t-BuO O t-BuO O 1 : 1

Gallagher, D. J.; Beak, P. J. Org. Chem. 1995, 60, 7092 Origin of Stereoselectivity in Lithiation

■ Calculations of the four possible low energy conformers leads to two prelithiation complexes leading to abstraction of pro-S and pro-R hydrogens

A B pro-S pro-R main pathway minor pathway

Wilberg, K. B.; Bailey, W. F. J. Am. Chem. Soc. 2001, 123, 8231 Origin of Stereoselectivity in Lithiation

■ Calculations reveal that abstraction of the pro-S hydrogen is favored due to greater nonbonded interactions in transition state leading to abstraction of the pro-R hydrogen.

A B pro-S pro-R main pathway minor pathway

ΔΔG (B3P86/6-31G*) 0.0 kcal/mol 3.2 kcal/mol

Wilberg, K. B.; Bailey, W. F. J. Am. Chem. Soc. 2001, 123, 8231 Mechanism of Proton Transfer

! Tunneling may be operative for deprotonations

O Me Me H H Me O H D 1. s-BuLi/sp* Me N O Me O N O Me 2. MeOD O Me Me Me Me >99% D

TMEDA/Li D TMS D TMS-Cl >96% ee 98.7% D Me O H D CbO Me CbO Me Me s-BuLi/ TMEDA N O Me O Me H Li/TMEDA H TMS Me TMS-Cl >99% D CbO Me CbO Me

98.7 H k /k = = 76 H D 1.3 D

Hoppe, D.; Paetow, M.; Hintze, F. Angew. Chem. Int. Ed. Engl. 1993, 32, 394 Pathways for Enantioinduction

! Configurational stability of lithiated intermediate cannot be assumed. ! The two limiting pathways for enantioinduction are asymmetric deprotonation, and asymmetric substitution Asymmetric Deprotonation

H H RLi/L* H Li•L* E H E

X Y X Y X Y

Asymmetric Substitution

H Li•L* E H E

X Y X Y

H H RLi/L* H Li•L* Dynamic E Thermodynamic X Y X Y Resolution Dynamic Kinetic Resolution

H Li•L* E H E

X Y X Y Establishing the Asymmetric Deprotonation Pathway

! If the enantiodetermining step is postdeprotonative, the ligand should resolve the diastereomeric complexes

s-BuLi 1. sp* R Li TMS N N 2. TMS-Cl N Boc Boc Boc

R = H or SnBu3 racemic ! In addition, the enantioenriched lithiated species should remain enantioenriched in the absence of a chiral ligand

s-BuLi 1. sp* SnBu Li TMS N 3 or s-BuLi/ N 2. TMS-Cl N Boc TMEDA Boc Boc 96% ee 93% ee, s-BuLi 74% ee, s-BuLi/TMEDA

Kerrick, S. T.; Beak, P J. Am. Chem. Soc. 1991, 113, 9708 Dynamic Thermodynamic Resolution Asymmetric Substitution

! In a dynamic thermodynamic resolution, the enantioselectivity is controlled by !G

!G (S)-RLi/sp* !G !!GG (R)-RLi/sp* (S)-R-E (R)-R-E

! Lithiation of o-ethylaniline gives a slowly equilibrating benzyl lithium. The asymmetric deprotonation pathway is immediately ruled out PivNH PivNLi Li PivNH TMS s-BuLi 1. sp* Me Me Me "25°C 2. TMS-Cl

12"98% ee

Basu, A.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996, 61, 5718. Dynamic Thermodynamic Resolution Asymmetric Substitution

! Proving a dynamic thermodynamic resolution

PivNH PivNLi Li PivNH TMS s-BuLi 1. sp* Me Me Me !25°C 2. TMS-Cl

DTR exposure of A to sp* prior to addition TMS-Cl entry of TMS-Cl (equiv.) %ee

1 "78°C, 15 min 2.3 12 2 "78°C, 15 min 0.10 82 3 "25°C, 45 min then "78°C, 30 min 2.1 84 !G 4 "25°C, 45 min then "78°C, 30 min 0.1 98 (S)-RLi/sp* !G 5 "25°C, 45 min then "78°C, 30 min 0.50 96 !!GG (R)-RLi/sp* 6 "25°C, 45 min then "78°C, 30 min 0.45 (S)-R-E (R)-R-E "25°C, 45 min then "78°C, 30 min 0.45 94

Basu, A.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996, 61, 5718. Dynamic Thermodynamic Resolution Asymmetric Substitution

! Proving a dynamic thermodynamic resolution

PivNH PivNLi Li PivNH TMS s-BuLi 1. sp* Me Me Me !25°C 2. TMS-Cl

DTR exposure of A to sp* prior to addition TMS-Cl entry of TMS-Cl (equiv.) %ee

Basu, A.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996, 61, 5718. Dynamic Thermodynamic Resolution Asymmetric Substitution

! Proving a dynamic thermodynamic resolution

PivNH PivNLi Li PivNH TMS s-BuLi 1. sp* Me Me Me !25°C 2. TMS-Cl

DTR exposure of A to sp* prior to addition TMS-Cl entry of TMS-Cl (equiv.) %ee

Basu, A.; Gallagher, D. J.; Beak, P. J. Org. Chem. 1996, 61, 5718. Dynamic Kinetic Resolution Asymmetric Substitution

! In a dynamic kinetic resolution, the enantioselectivity is controlled by !!G

!!G

(S)-RLi/sp* (R)-RLi/sp* (S)-R-E (R)-R-E ! Lithiation of o-ethylbenzamide gives rapidly equilibrating benzyl lithium

(i-Pr)2N O (i-Pr)2N O (i-Pr)2N O Li/sp* s-BuLi/sp* Cl Me Me Me "78°C

89%, 92% ee

Thayumanavan, S.; Lee, S.; Liu, C.; Beak, P. J. Am. Chem. Soc. 1994, 116, 9755 Dynamic Kinetic Resolution Asymmetric Substitution

! Proving that the reaction proceeds under asymmetric substitution

(i-Pr)2N O (i-Pr)2N O (i-Pr)2N O R Li s-BuLi ligand Me Me Me !78°C Cl

A, R = H C B, R = SnBu3

reactant (ee) Ligand %ee of C A or B (0%) sp* 87 B (87%) none 5 B (87%) TMEDA 1

Thayumanavan, S.; Lee, S.; Liu, C.; Beak, P. J. Am. Chem. Soc. 1994, 116, 9755 Dynamic Kinetic Resolution Asymmetric Substitution ■ Proving dynamic kinetic resolution over dynamic thermodynamic resolution

(i-Pr)2N O (i-Pr)2N O Li/sp* O Me N(Bn)2

MeO N(Bn)2 Me N Me −78°C Me Me O

1.0 equiv. or dr 1:1.6 0.1 equiv. 1:1.6 ■ The results suggest a dynamic kinetic resolution, but do not explicitly rule out a dynamic thermodynamic resolution where ΔG are the same. DTR DKR

ΔΔG

ΔGS (S)-RLi/sp* ΔGR

(R)-RLi/sp* (S)-RLi/sp* (R)-RLi/sp* (S)-R-E (R)-R-E (S)-R-E (R)-R-E

Thayumanavan, S.; Lee, S.; Liu, C.; Beak, P. J. Am. Chem. Soc. 1994, 116, 9755 Invertive or Retentive SE2 ! The stereochemistry in the substituted product may or may not correspond to the stereochemistry of the lithium complex. ! For most non-resonance stabilized carbanions, retentive substitution is usually the observed SE2 pathway

s-BuLi/ O H SnMe H Li/TMEDA Me Me 3 TMEDA

N = Cb CbO Me CbO Me O Me3SnCl

Me 1. CO2 Me 2.CH2N2

H H H Li/sp* H CO Me s-BuLi/sp* 1. CO2 2

CbO Me CbO Me 2.CH2N2 CbO Me

Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem. Int. Ed. Engl. 1990, 29, 1422 Invertive or Retentive SE2 ! Resonance stabilized carbanions may undergo invertive or retentive substitution depending on the electrophile

(i-Pr)2N O (i-Pr)2N O (i-Pr)2N O (i-Pr)2N O Me Li/sp* E E s-BuLi/sp* E Me Me Me !78°C

A B

enantiomeric ratio Electrophile A B

H2C=CHCH2OTs 6 : 94

H2C=CHCH2Cl 96 : 4 n-BuOTs 2 : 98 n-BuCl 90 : 10 n-BuBr 87 : 13 n-BuI 64 : 36

Thayumanavan, S.; Lee, S.; Liu, C.; Beak, P. J. Am. Chem. Soc. 1994, 116, 9755 Invertive or Retentive SE2 ! Retention or inversion can be a function of the reactivity of the electrophile

Me2N NMe2 Me O Li E Me Me E s-BuLi/ Me Boc E Boc Boc N Ph TMEDA tBuO N Ph N Ph N Ph Ar Ar Ar Ar Ar = p-MeOC6H4 Retention Inversion

Inverting Electrophiles Retaining Electrophiles Non Selective Electrophiles a CO2 98% ee MeOD 94% ee allyl bromide 33% ee a allyl triflate 96% ee ClCO2Me 90% ee allyl iodide 6% ee a favoring inversion

! Beak et al. suggest that for resonance stabilized carbanions, highly reactive and/or non-lithium coordinating electrophiles proceed with inversion, while less reactive and/or lithium coordinating electrophiles proceed with retention

Fabish, N. C.; Park, Y. S.; Lee. S.; Beak, P. J. Am. Chem. Soc. 1997, 119, 11561 Using Invertive or Retentive SE2 to Access Either Enantiomer ! Because (!)-sparteine is only readily available as one enantiomer the preference for inversion or retention can allow access to either enantiomer

SnMe3 CO2H Boc 1. n-BuLi/sp* Boc N Ph N Ph 2. CO Ar 2 Ar 77%, 90% ee 1. n-BuLi/sp*

2. Me3SnCl CO2H Boc 1. n-BuLi/sp* Boc N Ph N Ph Ar 2. CO2 Ar

Ar= pMeOC6H4 95%, 92% ee

1. n-BuLi/sp* 1. CH2N2 2. ClCO2CH3 2. CAN

CO CH CO2CH3 CO2CH3 2 3 CAN Boc N Ph HN Ph HN Ph Ar Boc Boc 55%, 88% ee 71%, 92% ee Park, Y. S.; Beak, P. J. Org. Chem. 1997, 62, 1574 Using Invertive or Retentive SE2 to Access Either Enantiomer ! Because (!)-sparteine is only readily available as one enantiomer the preference for inversion or retention can allow access to either enantiomer

O CO2Me TfO Me O Boc N Ph Ar 25%, 86% ee O Li/sp* Boc N Ph n-BuLi/sp* t-BuO N Ph Ar Ar Ar = p-MeOC6H4 O CO2Me Br Me O Boc N Ph Ar 32%, 84% ee

Park, Y. S.; Beak, P. J. Org. Chem. 1997, 62, 1574 Ligands Other Than (!)-Sparteine ! For carbanions that only undergo retentive substitution, a (+)-sparteine surrogate is required to enter the opposite enantiomeric series ! Deprotonation/trimethylsilylation of Boc-pyrrolidine used as a benchmark

1. s-BuLi/ligand TMS N N N 2. TMS-Cl N Boc Boc (!)-sparteine 87%, 96% ee

Me OH Me OH OH Me N N O O N N N N N Me Me Me Me 51%, 84% ee 18%, !41% ee 89%, !30% ee !64% ee

Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc., 1994, 116, 3231 Gallagher, D. J.; Wu, S.; Nikolic, N. A.; Beak, P. J. Org. Chem. 1995, 60, 8148 Ligands Other Than (!)-Sparteine ! For carbanions that only undergo retentive substitution, a (+)-sparteine surrogate is required to enter the opposite enantiomeric series ! Deprotonation/trimethylsilylation of Boc-pyrrolidine used as a benchmark

1. s-BuLi/ligand TMS N N N 2. TMS-Cl N Boc Boc (!)-sparteine 87%, 96% ee

NMe2 NMe 2 N N

Me2N NMe2 (!)-isosparteine <10%, 0% ee 90%, 0% ee <10%, 60% ee

Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc., 1994, 116, 3231 Gallagher, D. J.; Wu, S.; Nikolic, N. A.; Beak, P. J. Org. Chem. 1995, 60, 8148 Reason Why Cyclohexanediamine is a Poor Ligand ! Transition state models for removal of the pro-R and pro-S hydrogens are approximately isosteric

s-BuLi/TMCDA Li/TMCDA N N N Li/TMCDA Boc t-BuO O t-BuO O racemic

Me2N NMe2 TMCDA

pro-R hydrogen pro-S hydrogen

Wilberg, K. B.; Bailey, W. F.; J. Am. Chem. Soc. 2001, 123, 8231 Reason Why (-) Isosparteine is a Poor Ligand ! Space filling models for complexes of TMEDA, (!)-sparteine and (!)-isosparteine with lithium show that (!)-isosparteine significantly encapsulates lithium

Me Me Me N N Me N N N N Li Li Li

TMEDA (!)-sparteine (!)-isosparteine ! The rate of lithiation follows the degree of encapsulation.

ligand lithiation time s-BuLi/ligand Li/ligand TMEDA 30 min N N !78 °C sparteine 4 h Boc t-BuO O isosparteine <10%, 4 h

Gallagher, D. J.; Wu, S.; Nikolic, N. A.; Beak, P. J. Org. Chem. 1995, 60, 8148 Finding a (+)-Sparteine Surrogate ! O'Brien wanted to test structural analogues of sparteine to determine which components of the molecule are responsible for the enantioinduction

remove the bridge?

remove remove this ring? this ring? N N

(+)-sparteine

N N N N Me Me H

N MeN ! N N Me

Dearden, M. J.; Firkin, C. R.; Hermet, J. R.; O'Brien, P.; J. Am. Chem. Soc. 2002, 124, 11870 Hermet, J. R.; Porter, D. W.; Dearden, M. J.; Harrison, J. R.; Koplin, T.; O'Brien, P.; Parmene, J.; Tyurin, V.; Whitwood, A. C.; Gilday, J.; Smith, N. M. Org. Biomol. Chem. 2003, 1, 3977 Finding a (+)-Sparteine Surrogate ! O'Brien wanted to test structural analogues of sparteine to determine which components of the molecule are responsible for the enantioinduction

1. s-BuLi/ligand TMS N N N 2. TMS-Cl N Boc Boc (!)-sparteine 87%, 90% ee

N N N N Me Me A (90% ee) B (98% ee) 37%, racemic 31%, 21% ee

1. s-BuLi/ligand TMS N N N 2. TMS-Cl N Boc Boc (!)-sparteine 87%, 90% ee

N N N N N N Me Me Me A (90% ee) B (98% ee) C (>90% ee) 37%, racemic 31%, 21% ee 84%, 90% ee

Dearden, M. J.; Firkin, C. R.; Hermet, J. R.; O'Brien, P.; J. Am. Chem. Soc. 2002, 124, 11870 Hermet, J. R.; Porter, D. W.; Dearden, M. J.; Harrison, J. R.; Koplin, T.; O'Brien, P.; Parmene, J.; Tyurin, V.; Whitwood, A. C.; Gilday, J.; Smith, N. M. Org. Biomol. Chem. 2003, 1, 3977 Synthesis of O'Brien's (+)-Sparteine Surrogate ! (!)-Cytisine has a structure closely related to O'Brien's (+)-sparteine surrogate

MeO2C Me H HN N 1. PtO2/H2 N Et3N, ClCO2Me EtOH N N CH2Cl2 2. LAH, THF N 92% 86%

(!)-cytisine O O " 250 mg, $850

N seeds $70/Kg N Me (!)-cytisine (+)-sparteine from Vilmorin, 18 g/Kg seeds surrogate France

Laburnum anagyroides

Dearden, M. J.; Firkin, C. R.; Hermet, J. R.; O'Brien, P. J. Am. Chem. Soc. 2002, 124, 11870 Dixon, A. J.; McGrath, M. J.; O'Brien, P. Org. Syn. 2005, 83, 141 Comparison of (!)-Sparteine to O'Brien's Ligand

! O'Brien's (+)-sparteine surrogate demonstrates approximately equal levels of enantioinduction as that achieved with (!)-sparteine

1. s-BuLi/sp* 1. s-BuLi/(+)sp*

Et2O, !78 °C, 5h Et2O, !78 °C, 5h R O NiPr2 N N N N 2. Bu3SnCl 2. Bu3SnCl O Me R = PhCH CH (!)-sparteine 2 2 (+)-sparteine surrogate (+)sp*

R O NiPr2 R O NiPr2

SnBu3 O SnBu3 O 68%, 98% ee 84%, 92% ee

Dearden, M. J.; Firkin, C. R.; Hermet, J. R.; O'Brien, P. J. Am. Chem. Soc. 2002, 124, 11870 Catalytic Asymmetric Lithiation ! Using a substoichiometric amount of (!)-sparteine affords low yields and selectivities in the deprotonation/substitution sequence

1. 1.3 eq s-BuLi 0.2 eq sp* 34% 75:25 er TMS N N stoichiometric sp* 2. TMS-Cl 87%, 95:5 er Boc Boc

1. 1.4 eq s-BuLi SnBu O O 0.2 eq sp* 3 17% 85:15 er Ph O NiPr2 stoichiometric sp* Ph O NiPr2 2. Bu3SnCl 73%, 99:1 er ! The diamine does not dissociate from the lithiated complex

N N Li X = O or NR H O X

McGrath, M. J.; O'Brien, P. J. Am. Chem. Soc. 2005, 127, 16378 Catalytic Asymmetric Lithiation ! In order to achieve ligand turnover, O'Brien et al proposed the use of an achiral stoichiometric diamine to displace the chiral diamine

(-) sparteine

s-BuLi N Boc

H 0.2 eq N N Li N N N Li t-BuO O s-Bu Ligand exchange

H 1.2 eq E R2N s-BuLi E N R2N NR2 N Li R2N NR2 Li Boc R2N t-BuO O s-Bu

McGrath, M. J.; O'Brien, P. J. Am. Chem. Soc. 2005, 127, 16378 Catalytic Asymmetric Lithiation ! Several criteria must be met in order to achieve enantioselective lithiation/ subsitution

1. Ligand exchange must occur 2. Organolithium must be configurationally stable during and after ligand exchange 3. Deprotonation with s-BuLi/sp* must be faster than with the achiral complex ! Using information gained from their studies into designing a (+)-sparteine surrogate, the designed a ligand that should not facilitate deprotonation

Me Me H Me N Me N

N N Me

McGrath, M. J.; O'Brien, P. J. Am. Chem. Soc. 2005, 127, 16378 Catalytic Asymmetric Lithiation ! Several criteria must be met in order to achieve enantioselective lithiation/ subsitution

Me Me H Me N Me N

N N Me Me Me i-PrNH Me N Me 2 O Wolff-Kishner paraformaldehyde 38% N O N Me Me AcOH/MeOH 69% Me McGrath, M. J.; O'Brien, P. J. Am. Chem. Soc. 2005, 127, 16378 Catalytic Asymmetric Lithiation ! Catalytic enantioselective lithiation/substitution works efficiently using the achiral bispidine ligand

Me 1. 1.3 eq s-BuLi 0.2 eq ligand Me N 1.2 eq bispidine TMS N N N Me 2. TMS-Cl Boc Boc bispidine Me

ligand product yield er sp* S-TMS 76 90:10 N N N N (+)-sp* R-TMS 66 6:94 Me (!)-sparteine, sp* (+)-sparteine surrogate (+)-sp*

McGrath, M. J.; O'Brien, P. J. Am. Chem. Soc. 2005, 127, 16378 Catalytic Asymmetric Lithiation ! Catalytic enantioselective lithiation/substitution works efficiently using the achiral bispidine ligand

Me 1. 1.3 eq s-BuLi X eq ligand Me N O SnBu3 O 1.2 eq bispidine N Me R O Ni-Pr2 R O NiPr2 2. Bu3SnCl R = PhCH CH 2 2 bispidine Me

ligand eq product yield er

sp* 0.2 S-SnR3 77 92:8 N N N N (+)-sp* 0.2 R-SnR3 72 6:94 Me sp* 0.1 S-SnR3 54 81:19 (!)-sparteine, sp* (+)-sparteine (+)-sp* 0.06 R-SnR3 63 15:85 surrogate (+)-sp*

McGrath, M. J.; O'Brien, P. J. Am. Chem. Soc. 2005, 127, 16378 Synthetic Utility of Asymmetric Lithiation ! Anti-homoaldol reaction of allylic N-Boc amines proceeds with high levels of selectivity

R R R AlEt2 n-BuLi/sp* Et2AlCl sp*/Li NBocAr NBocAr inversion of NBocAr configuration Ar = p-MeOC6H4 O R R' Yield (%) ee (%) E:Z R' H Ph Ph 85 94 90:10 Ph Me 66 84 95:5 Ph i-Pr 61 90 98:2 OH Boc H NBocAr Ph Cy 66 96 95:5 AlEt2 N R O Cy Ph 82 88 90:10 R' Ar R' H Cy Me 72 86 97:3 R Cy i-Pr 81 88 98:2 Cy Cy 84 90 98:2

Whisler, M. C.; Vaillancourt, L.; Beak, P. Org. Lett. 2000, 2, 2655 Synthetic Utility of Asymmetric Lithiation

! Changing the lewis acid from Et2AlCl to Ti(Oi-Pr)3Cl results in an inversion in the enantiomeric series of the product due to a differing transition state

R R R Ti(Oi-Pr) n-BuLi/sp* Ti(Oi-Pr)3Cl 3 sp*/Li NBocAr NBocAr inversion of NBocAr configuration Ar = p-MeOC6H4 O

R' H R R' Yield (%) ee (%) Z:E

Ph Ph 64 98 98:2 H OH Cy Ph 38 88 98:2 R' O Ti(Oi-Pr)3 R R' H R N NBocAr Ar Boc

Whisler, M. C.; Vaillancourt, L.; Beak, P. Org. Lett. 2000, 2, 2655 Synthetic Utility of Asymmetric Lithiation ! Transmetalation of lithiated Boc-pyrrolidine to zinc enables Negishi coupling with a range of aryl halides Pd(OAc)2 s-BuLi/sp* ZnCl2 t-Bu3P-HBF4 Li/sp* N ZnRn Ar N MTBE, !78 °C N Ar-X N Boc t-BuO O Boc RT 12 h Boc

entry Ar-X eq ZnCl2 % yield er 1 Ph-Br 1.0 82 96:4 2 Ph-Br 0.6 80 96:4 3 Ph-Br 0.3 79 96:4 4 Ph-Cl 1.0 48 96:4 5 Ph-OTf 1.0 <5 96:4 6 p-F-PhBr 1.0 75 96:4

7 p-NH2-PhBr 1.0 70 96:4 8 o-MeO-PhBr 1.0 72 96:4 9 5-Br-NBoc-indole 1.0 81 96:4 10 4-Br-indole 1.0 77 96:4 11 3-Br-pyridine 1.0 60 96:4a a 4 mol% Pd(OAc)2, 5 mol% t-Bu3P-HBF4. coupling performed at 60 °C.

Campos, K. R.: Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen, C. J. Am. Chem. Soc. 2006, 128, 3538 Synthetic Utility of Asymmetric Lithiation ! Transmetalation of lithiated Boc-pyrrolidine to zinc enables Negishi coupling with a range of aryl halides Pd(OAc)2 s-BuLi/sp* ZnCl2 t-Bu3P-HBF4 Li/sp* N ZnRn Ar N MTBE, !78 °C N Ar-X N Boc t-BuO O Boc RT 12 h Boc

entry Ar-X eq ZnCl2 % yield er 1 Ph-Br 1.0 82 96:4 2 Ph-Br 0.6 80 96:4 3 Ph-Br 0.3 79 96:4 4 Ph-Cl 1.0 48 96:4 5 Ph-OTf 1.0 <5 96:4 6 p-F-PhBr 1.0 75 96:4

Campos, K. R.: Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen, C. J. Am. Chem. Soc. 2006, 128, 3538 Synthetic Utility of Asymmetric Lithiation ! Hoppe demonstrated that O-alkylcarbamates can be deprotonated and trapped with boronic esters to yield precursors to 1,2 metalate rearrangement products O sp*/Li O s-BuLi/sp* 1. B(Oi -Pr)3 BPin O

R O Ni-Pr2 R O Ni-Pr2 Et2O, !78 °C 2. pinacol, pTsOH R O Ni-Pr2 R = PhCH2CH2 MgSO4, CH2Cl2 1,2-metalate rearrangement R'MgX H2O2 Me Et2O R OH NaOH R Bpin 25 C R' O ° B Me !78 °C O Me R' THF R' R OCb Me

Grignard reagent, R' % yield ee (%) PrMgCl 50 >95 CyMgBr 70 >95 i-PrMgCl 56 >95 t-BuMgCl 64 >95

Beckmann, E.; Desai, V.; Hoppe, D. Synlett, 2004, 13, 2275 Synthetic Utility of Asymmetric Lithiation ! Kocienski et al. recently applied this methodology toward the synthesis of (S)-(!)-N-Acetylcolchinol

OMe MeO MeO MeO

MeO MeO oxidative OH biaryl coupling NHAc

HO SN2 substitution OTBS (S)-(!)-N-Acetylcolchinol

Besong, G.; Jarowicki, K.; Kocienski, P. J.; Sliwinski, E.; Boyl, F. T. Org. Biomol. Chem. 2006, 4, 2193 Synthetic Utility of Asymmetric Lithiation ! Kocienski et al. recently applied this methodology toward the synthesis of (S)-(!)-N-Acetylcolchinol

OTBS MgBr 1. s-BuLi/sp* BPin R H R OCb 2. PinBOi-Pr R OCb B OCb 70% OTBS R = ArCH2CH2 O O Cb = CONi-Pr 2 Me Me OMe Me Me MeO

H2O2/H2O BPin 1,2-metalate K CO MeO 2 3 OTBS rearrangement R OH RT RT, 12 h 73%, 88% ee

OTBS

Besong, G.; Jarowicki, K.; Kocienski, P. J.; Sliwinski, E.; Boyl, F. T. Org. Biomol. Chem. 2006, 4, 2193 Catalytic Asymmetric Variant of Hoppe's Methodology ! Using his bispidine exchange ligand, O'Brien was able to a achieve a metalation, electrophile trapping, 1,2-metalate rearrangement under catalytic conditions

Me 1. 1.3 eq s-BuLi 0.2 eq sp* BPin 1.2 eq bispidine Me N Ph OCb Ph OCb Et2O, !78 °C, 5 h N Me Cb = CONi-Pr2 2. B(Oi-Pr)3 3. HCl bispidine Me 4. Pinacol, pTSA

Me Me Me Me 1. PhMgBr OH !78 °C to RT O O 2. H2O2, NaOH Ph B Ph Ph 60%, 87:13 er Ph OCb

McGrath, M. J.; O'Brien, P. Synthesis, 2006, 13, 2233 Conclusions

! Enantioselective Lithiation/Substitution Generally Proceeds Through Two Limiting Pathways:

- Asymmetric deprotonation

- Asymmetric substitution

Dynamic thermodynamic resolution

Dynamic kinetic resolution

! Work By O'Brien has Produced a (+)-Sparteine Surrogate as Well as the First Catalytic Asymmetric Lithiation/Substitution Reaction

! Lithiated Intermediates Can Be Precursors to Various Transmetallative Processes Such as Homo-Aldol Reactions, Negishi Couplings and 1,2-Metallate Rearrangements