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 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

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)

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

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. S. Matteson. et al. Synthesis., 1990, 200. Limitations of the Matteson-type Homologation-Alkylation (2)

Additional steps are required when changing the stereochemistry of boronic ester.

(1) NaOH Cy O Cy O Me Cy OH (1) LiCHCl2 (HOCH ) C-R B Me B 2 3 (2) LiOBn (2) H+ Cy O Cy O OBn Cy OH 17 18 19

Cy Cy + Cy Cy O Me HO OH HO Me O OBn (1) LiCHCl2 ent-19 B B Cy B (2) MeMgBr O Cy O OBn HO OBn

22 21 20

OH OBn

D. S. Matteson. et al. J. Org. Chem., 1996, 61, 6047. Limitations of the Matteson-type Homologation-Alkylation (3) Limited success for the synthesis of quaternary stereocenters.

Cl Cl Li O O Cl O CH3 Cl R B B + B O ZnCl2 R O R O R S

R dr a Et R/S = 8 b Ph S/R = 24 c Bu R/S = 1.04 ・ Variable levels of selectivity were d Cy S/R = 1.5 obtained. e i-Pr ?/? = 40 ・ The sense of asymmetric induction H C f 3 ?/? = 10 was unpredictable. OBn g O O R/S = 1.5

H3C D. S. Matteson. J. Org. Chem., 2013, 78, 10009. Reagent Control: Homologation-Alkylation of Boronic Esters and Boranes using Chiral Carbanions

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. Chiral Carbanions Derived from Sulfur Ylides

BF4 (1) 1.2 eq, LiHMDS S dioxane, THF, 5℃ OH/NH2 + BR3 (2) BF O 3 Ph R (3) H2O2, NaOH or NH2OSO3H 68-73% yield 95-97% ee

H H BEt3 S Ph Ph S BEt Et3B 2

O O Ph Et major product

ΔE = 4.37 kcal/mol

H Ph H Ph BEt3 H S H S BEt Et3B 2

Ph Et O O minor product V. K. Aggarwal. et al. J. Am. Chem. Soc., 2005, 127, 1642. Outcome of the 1,2-Metallate Rearrangement Ate Complexes Resulting from the 9-BBN Derivatives R OH BF4 B (1) LiHMDS, -78℃ OH + + S Ph (2) -100℃ to r.t. H Ph R Ph (3) H2O2, NaOH HO

Entry R Yield Yield

1 Hexyl 56% 41% 2 Allyl 51% 39% 3 Benzyl 51% 35% 4 i-Pr Trace 77% 5 Cyclopropyl 89% Trace 6 Ph Trace 94% 7 1-Hexenyl Trace 21% 8 1-Hexynyl 92% Trace

Ph H S Ph H S R S B R R B H B Ph H H a b c V. K. Aggarwal. et al. J. Am. Chem. Soc., 2007, 129, 14632. Chiral Carbanions of Lithiated Alkyl Chlorides

nBuLi O or R B O Ph Ph 1 R1 R EtMgCl B(neo) 1 M O S Bn p-Tol THF, -78 Bn B(neo) Cl H Cl -78℃ Cl H

M = Li or MgCl R1 = Ph, nBu, Ph(CH2)2, c-hex

O tBuLi (pin)B Bn (2eq) Li Bn Bn B(pin) S Bn O O Ar B Bn Cl Bn Bn Cl a 24 Cl 26 Bn Bn 25 (1) LiCH2Cl (2) a OH (3) H2O2 Bn 27 (R,R) 38% yield 99:1 er, 79:21 dr

(1) a or ent-a Bn Bn Bn Bn Bn Bn (2) LiCH2Cl Bn B(pin) or or (3) a or ent-a OH OH OH (4) H2O2 Bn Bn Bn (R,S) (S,S) (S,R) 97:3 er, 81:19 dr 99:1 er, 76:24 dr 99:1 er, 80:20 dr

P. R. Blakemore. et al. J. Am. Chem. Soc., 2007, 129, 3068. Chiral Carbanions of Lithiated Carbamates (1)

R2 R R H H (1) R B(R ) B(R ) 2 (1) warm 2 sBuLi N N 2 3 2 3 2 R R1 R1 R OCb Et O, -78℃ (2) Lewis Acid 1 B(R ) (2) H O OH 1 2 OCb H 3 2 2 2 H (-)-sparteine Li O H R1 O NiPr H 2

V. K. Aggarwal. et al. Angew Chem Int Ed., 2007, 46, 7491. Chiral Carbanions of Lithiated Carbamates (2)

H H

N N Me N N

H (-)-Sparteine (sp) (+)-Sparteine surrogate (sps)

Ph OCb Ph OCb

sBuLi sBuLi (-)-sparteine (+)-sparteine surrogate

Li-sp Li-sps

Ph OCb Li-sp HO HO Li-sp Ph OCb

OCb OCb EtB(pin) EtB(pin) Ph Ph 82% yield 64% yield B(pin) er > 98:2, dr = 96:4 er > 98:2, dr = 94:6 B(pin) Li-sps Li-sps Ph HO HO Ph (78% yield, er = 98:2) OCb OCb (75% yield, er = 97:3) Ph Ph 63% yield 63% yield er > 98:2, dr = 94:6 er > 98:2, dr = 90:10 Short Summary • Substrate control and reagent control are two routes to homochiral organoboranes involving 1,2-metallate rearrangement.

• Although a powerful transformation, Matteson’s homologation-alkylation sequence (substrate control) suffers from a number of drawbacks (limitation 1-3).

• The reactions between chiral carbanions bearing potential leaving groups with achiral boronic esters (reagent control) is complementary to the Matteson approach. Contents

Secondary boronic Tertiary benzylic boronic 1,2-diols -Amino alcohols Tertiary alkyl boronic esters and derivatives esters and derivatives esters and derivatives OH OH OH NHBn OH OH R OH OH Et i-Pr 1 Et Ph NHBus R R1 R1 R1 R1 1 R R R R Ph R3 2 H 2 H Ar 2 2 Ar OH NHBoc R2 50-94% yield, >95:5 er 60-91% yield, 69-95% yield, 70% yield, 99:1 er, 90% yield, >99:1 er, 80-87% yield, 35-80% yield, >95:5 er >95:5 er >95:5 dr >95:5 dr >99:1 er >97:3 er

Allylic boronic esters and homoallylic alcohols -Hydroxy allylsilanes Acyclic γ-dimethylamino OH OH OH OH OH tertiary boronic esters R Bpin R1 R1 R3 R3 R3 R2 R2 Ph N R2 R1 R2 R2 R1 SiMe3 R1 SiMe3 54-91% yield, >95:5 er, 46-59% yield, 99:1 er, 51-67% yield, >95:5 er, 74-96% yield, >94:6 er, 64-67% yield, >93:7 er, 44-75% yield >99:1 dr >99:1 dr >99:1 dr >25:1 dr >25:1 dr

-Silyl boronic esters Tertiary allylic boronic Tertiary propargylic boronic Contiguous quaternary 1,3-Bis(boronic esters) esters and derivatives esters and derivatives stereocenters and derivatives Bpin Bpin OH OH Ar OH OH Si HO R R 2 R SiMe Ph R2 R3 1 2 R1 R R4 2 R3 R1 68-69% yield, 52-84% yield, R1 43-94% yield, >95:5 dr, >96:4 er >97:3 er R2 R1 Ar t 99:1 er 72-92% yield, Bu 32-85% yield, >95:5 dr, >98:2 er 42-58% yield, >99:1 er >95:5 er Lithiation-Borylation in Total Synthesis

OH NC OH OH OH O O O O H N OTBS OH N Ph NH NMe2

O O H

(-)-Stemaphylline F (+)-Erogorgiaene F Sch725674 Atorvastatin (Lipitor) Derivative Escitalopram

OMe O OH OH OH MeO OMe O O C14H29 ( )5 O O O OH OH HO OH OH H (+)-Giganin OH O O O (-)-Decarestrictine H H OH H O O O Cl C5H11 O O O OH Cl H H OH H Mycolactone Core O Solandelactone E H O O OH OH Br MeO OMe HO OMe O NHMe O (-)-Clavosolide A -1 Hormone (+)-Sertraline (-)-Filiformin Assembly-Line Synthesis Examples

O N OMe Bpin N MeO S Ph (+)-kalkitoxin All-Syn Helical Structure OMe OMe

OH OH OH O OMe HO O MeO R OMe (+)-Faranal MeO OMe Tatanan A OH Baulamycin A (R = CH2CH3) Baulamycin B (R = CH3) C15H31 HO2C OH (+)-Hydroxyphthioceranic Acid Iterative Assembly-Line Synthesis

Li Li Li Li Li H H H H H TIBO TIBO TIBO TIBO TIBO Me Me Me Me Me Bpin Bpin Li Li Li Li Ph H H H H Ph TIBO TIBO TIBO TIBO 99.3:0.7 er Me Me Me Me 58% yield (9 steps) 9-mer:10-mer:11-mer = 1:97:2

Li Li Li Li Li Me Me Me Me Me TIBO TIBO TIBO TIBO TIBO H H H H H Bpin Bpin Li Li Li Li Ph H H H H Ph TIBO TIBO TIBO TIBO 99.3:0.7 er Me Me Me Me 44% yield (9 steps) 9-mer:10-mer:11-mer = 1:94:5

Li Li Li Li Li Me H Me H Me TIBO TIBO TIBO TIBO TIBO H Me H Me H Bpin Bpin Li Li Li Li Me H Me H 98.7:1.3 er TIBO TIBO TIBO TIBO 45% yield (9 steps) H Me H Me 9-mer:10-mer:11-mer = 0:97:3

Li O H R TIBO Me O B H TIBO ・ Ten contiguous, stereochemically defined methyl groups. Me ・ Bpin Total stereocontrol. R ・ Re-entry into Bpin No extra manipulation required. iterative cycle H R Me

V. K. Aggarwal. et al. Nature., 2014, 513, 183. Iterative Assembly Line Synthesis of Polypropionates

OMe OMe OMe OH OH OH [SI] [Ir] [Me] Si [SI] [Ir] [Me] [C] Si Si Bpin m-CPBA Bn Bn Bpin Bn Bpin Bn LEDs LEDs KHF2, DMF

70% yield, >95:5 dr 58% yield, 94:6 dr 66% yield, >95:5 dr

OH OH OH OH OH OH OH OH OH Bn Bn

75% yield, >95:5 dr 52% yield, >95:5 dr 71% yield, >95:5 dr

Li Li [Me] = H [Me]= Me [C]= TIBO TIBO Li Cl Me H ・ Five contiguous stereocenters. OMe OMe ・ Full stereocontrol in an effectively N Li N Li [Si] = [Si] = ‘one-pot’ process. H Cl Si ・ Purification of intermediates is not Si Cl H required.

[Ir] = Photoredox cleavage LEDs V. K. Aggarwal. et al. Nature Chem., 2017, 9, 896. Stereocontrolled Homologation of Lithiated α- chloromethyl silane with boronic esters

OMe OMe OMe OMe

s-BuLi, Et O R-Bpin, Et2O O -78℃ to rt N H 2 N Li R O N R N B Cl -78℃, 1h -78℃ 1h Si Cl Si Cl Si Bpin Si Cl H 60%-92% yield, >85:15 dr

R = alkanes, aromatic substituted alkanes, alkenes, protected alcohols, tert-butyl esters, azides

・ Since the boronate complex is prone to undergo β-elimination rather than the desired 1,2-migration, the oxygen functionality is masked as a silyl group.

・ The silyl group renders an adjacent carbanion configurationally unstable even at low temperature, lithiated benzylsilane bearing a tethered chiral methoxymethyl pyrrolidinomethyl moiety is used.

・ The pronounced tetrahedral nature of organoithium together with its potential to complex with the oxygen atoms of the boronic ester directs the reagent to the same face as the lithium atom, accounts for the origin of the retention of configuration observed.

・ A good leaving group Cl- is used to improve the reactivity of the 1,2-migration instead of

utilizing additives such as Mg(ClO4)2. V. K. Aggarwal. et al. Nature Chem., 2017, 9, 896. Assembly Line Synthesis Protocol for the construction of polypropionates

OMe

Li N Li H Me Si TIBO N Cl [Si] H Me Si 2 No reaction Bn OMe Bpin Bn Bpin 28

61% yield, >95:5 dr OMe

Li N Li OMe OMe H OMe Me Si TIBO Me2Si Cl Si [Si] [Ir] Me2Si H 30 32 Bn Bpin LEDs Bn Bpin Bpin 29 79% yield 31 Bn 33 Li OMe OMe (1) Li Me OH OH TIBO Si Si [Ir] H I2, NaOMe Bn Bpin LEDs (2) Urea-H2O2, KF KHCO3, THF, MeOH 35 Bn 34 92% yield, >95:5 dr 59% yield, >95:5 dr

V. K. Aggarwal. et al. Nature Chem., 2017, 9, 896. Contents

• Several factors should be considered when thinking about 1,2-migraton and stereoselectivity of lithiation-borylation reaction.

• Lithiation-Borylation is a powerful method in assembly-line synthesis. Thank You ! Appendix

Proposed catalytic cycle for photoredox cleavage of aminosilane

V. K. Aggarwal. et al. Nature Chem., 2017, 9, 896.