Reactivity Umpolung-1 Ready complimentary disconnections Reactivity Umpolung: reversal of normal polarity electrophiles become nucleophiles O nucleophiles become electrophiles

R Normal reactivity: X c ba 3 d X a bond normal umpolung x = heteroatom a 1 d = donor (Nu-) d d X + or O Br a = acceptor (E ) a MgBr + R X R + SS NMe2 5 Li

OLi + O 1 b X OEt R Br R Cu + Br O

How to make: O X RBr OEt + SLi 4 c R2 CuLi + X Li 1 or 1 2 X X

Outline:

1. electrophilic heteroatoms General Review: ACIEE, 1979, 239 2. acyl anions Carey and Sundburg, sec 13.2 3. homoenolates 4. the cyclopropane trick 5. sulfone chemistry Reactivity Umpolung-2 Ready

Electrophilic Heteroatoms mCPBA 'Rubottom [O]' OTMS 1. mCPBA OTMS O General form: 2. HF Ph Ph Ph 60% O OH X X Y+ X,Y = heteroatoms Y Rubottom, TL, 1974, 4319

Electrophile Examples O O O O2 O O 1. LDA; O2 O 1. TBSOTf, Et3N DMDO PO PO OTBS NMe2 2. Na2S2O3 HO 2. DMDO NMe2 84% P'O OP" 69% P'O OP" OP" O OP" HO O NMe2 Falck, JOC, 1995, 3385 Oxaziridines 1. LiHMDS 2. " HO

Ph CO2Et Ph CO2Et 81% O O N OH O S O Wasserman and Lipshutz O TL, 1975, 1731

O 95% ee O O Mo O O Davis, Chem. Rev. 1992, 919 O O OH Py O LDA; MoOPH not a general asymmetric method. For racemic, most 87% commonly used is 'Davis Oxaziridine' P(NMe2)3 O MoOPH Ph Vedejs, JOC, 1978, 188 TsN Reactivity Umpolung-3 Ready Aminations (Review: Syn Lett, 1997, 741) Heteroatom exchange: Most commonly with Br, Cl

Electrophile Examples O O cat PCl3 O NH3 R R R OH E OH OH Br2 OH N 1. LDA NH CO2Me Br 2 N 2. OH E BOC NN CO2Me can you name this rxn? BnO BOC Cl NHBoc α-halo carbonyls are excellent electrophiles (recall SN2 rxn accelerated by BnO NHBoc either electron withdrawing or electron releasing groups) Cl

1. H2 Pd/C (-Bn) - 2. TFA (-Boc) N3 3. RaNi, H2 O O PhO- Br Nu OH CO2Me RSH

vancomycin NH2 HO CN- Cl 70%; de > 98% synthesized from enolate (or equiv) and electrophilic halogen:

Somewhat realated; rarely used; unusual mechanism: TMS O NeberInclude rearrangement stoltz use of neber in dragmacidin, NCS, NBS, SO2Cl2 OTs O 1. H2N-OHJACS, 2005, 5970N O 2 TsCl, Bu NBr Cl Ph 4 Ph Cl Ph Toluene/KOH(aq) Ph Cl O Li O O TsCl, Cl Cl Cl Cl O H2O N Ph Ph OH Ph Ph Br2, Cl2, CuCl2 NH2 azirine Lead references: Brummond, TL, 1999, 2231; Maruoka, JACS, 2002, 7640 enantioselective chlorination: Jorgensen, ACIEE, 2004, 5507 Reactivity Umpolung-4 Ready

Acyl anions are the most sought umpolung reagents Strecker amino acid synthesis: One of the oldest and most effective ways to make amino acids O O NH2 R NH2 + NaCN + NH4Cl R R CN R CO2H

Cyanide: Super nucleophile (small, non-basic), can be converted into amine, aldehyde, acid, ketone. Recently has become hot topic for asymmetric catalysis. Review: Chem Rev. 2003, 2795

DMSO Jacobsen JACS 2002, 10012 Cl +NaCN CN

70% O Cl N DMSO CN Bn N N + KCN H H O N

1 mol% HO

O OPiv + H O NBn 3 NHBn OH R HCN R CN

DIBAL R%ee O Ph 99 CN iPr 97 RMgBr O With keto-imines tBu 99 R NBn NBn nPent 96 NH R Ar LiAlH4 2 CN ee's 88-95 for 3- or 4-substituted Ar Reactivity Umpolung-5 Ready

Strecker Rxn with quinolines (Reissert Rxn) Hydrocyanation of aldehydes and ketones O O Tol P Tol P Tol Tol O O Cl Al Cl Al O O Tol Tol O P TMSO CN P Tol Tol O 0.1 equiv R H O R H R N O R N CN TMSCN yields > 85% O TMSCN O 0.4 equiv Bu3PO ee Cl R O Ph 96 Ph(CH2)2 97 MeO Shibasaki, JACS, 1999, 2641 Me2N Hexyl 98

MeO N CN N CN N CN S 97 O N O O O Ph P O O O O Ph 91% , 85%ee 72%, 89%ee 99%, 91%ee O O RO Ti O RO O TMSO CN R R' TMSCN R R' 70-90% yield Propose: O TMSO CN TMSO CN P TMSO CN Me3Si X N X= H, 92% ee 91% ee 85% ee N Cl, 92% ee O Cl Al O Shibasaki, JACS, 2000, 7412 Reactivity Umpolung-6 Ready

Increasing the acidity of the formyl proton Nature uses carbenes:

O RO EWG RO EWG NH2 NH2 R H R H R + .. N N Base S N N S Benzoin condensation N OPP O N OPP KCN OH O KOH OH Ph H NC Vitamin B1 (thiamine) + NC Ph Ph OH Ph Coenzyme: thiamine pyrophosphate O Ph Ph OH O OH Ph H HO OH R OH Cyanomethyl ethers 1. LDA O O or 2. R'X α-keto acid Ketose substrate O O O OEt 3. NaOH O R H HCN R CN R R' HO R HO HO Stork, JACS, 1971, 5286 R=Me; R' = n-hex (85%) NH NH iPr (80%); allyl (76%) 2 OH 2 OH -RCHO + OEt N N S N N S O O 1. LDA N OPP N OPP R' 2. KOH R' NC enamine intermediate

TsO R PO R OP R'CHO

Related Chemistry: R' OH NR2 Review: Chem. Soc. Rev HO NH2 OH R CN 2000, 359 OH R' OH N N S O N OPP ketose product Reactivity Umpolung-7 Ready In the lab: Review: Org. Rxn. 1991, 407; ACIEE 2004, 1326 Catalytic homoenolate generation Bode, JACS, 2004, 14370 Benzoin reaction H Cl- Mes Mes enantioselective version: O N N O O + N Ph N + + 2 O O Ar DBU (8 mol %) 1 N H Ar1 THF/tBuOH Ar Ar2 (10 mol%) O tBu O d.r. ~4:1 KOtBu (10 mol%) Ar Ar Ar OH O O 80-95% ee Enders, ACIEE, O Mes N N Mes 2002, 1743 Ar1 Ar1 Problem: crossed benzoin gives mixture of homo and Ar2 hetero dimers. Soln: Acyl silanes

1 KCN (30 mol%) Ar O Mes OH Mes O - 18-C-6 (10 mol%) O Ar2 N+ N + RCHO Ar SiEt3 Ar SiEt3 CN OH N 1 N Mes Ar Mes +

Brook

O OSiEt 3 OSiEt R R 3 Ar Ar CN - Ar 1 O OH Mes OSiEt3 O CN Ar OH Mes Ar2 N + N Johnson, ACIEE, 2003, 2534 N OH N Ar1 Mes Mes Reactivity Umpolung-7a Ready

catalytic Sila-Stetter Reaction 30 mol% - Rovis, JACS, 2002, 10298 Schiedt, JACS, 2004, 2314 Br O BF S 4 CH HO N 3 N + N O O R' O N + CH 3 Ar O CO2Et Ar SiMe2R R' R'' R'' CHO DBU, iPrOH OCH3 R = Me or Ph O O CO Et DBU 2 O R' O 94% ee O 94% y Ar R'' Ar SiMe2R O S N quaternary stereocenters with activated catalyst: Rovis, JACS, 2004, 8876 O BF4 N F N + N F SN SiR3 Ar OH N+ O CHO F F O Ar - CO2Et O CH3 S LiHMDS F R' R'' CO2Et CH3

99% ee 95% y

O opposite enantiomers! O BF4 R' R'' N F N OH OSiR N F Ph 3 Ph N N O Ar Ar CHO F F S S CH3 O LiHMDS F CH3 O O O 99% ee 63% y Ar SiMe2R Ar SiMe2R

No Rxn No Rxn Reactivity Umpolung-7b Ready

Isonitriles Ugi Four-component coupling (U4CC) R Versitile C1 synthons; often act as acyl anion + O O H NR''' N + + + R'''NH2 C Passerini Rxn: R' R'' OH R

R H+ OH OH N O O + + O2CR'' O C R' R' NHR''' NHR''' R' R'' OH R''' R''CO H N N acyl migration 2 + R' R'' N O2CR'' R' R' R' NHR' N R' N + R' R' O acyl migration protected amino acid

OCOR'' NHR' Has been applied extensively for library synthesis: R' an enantioselective version has appeared O X CO H R1 Ar R3 tBu 2 + Cat. OH + O + NC 2 N + RCHO + SiCl4 NHtBu R O NH3Cl R' Y NO2 O

O R ee N cat = P N O R3 N tol 99 O R3 naphthyl 99 R1 R2 NH R1 R2 NH O 2 2-furyl 92 O c-hex 64 X Fe, AcOH X N N Ar

* Y NO2 Y N O JACS, O Ar Propose silyl cation + O Si Cl 2003, 7825 lewis acid: Cl Cl Reactivity Umpolung-7c Ready

U4CC in synthesis: Isonitriles as linchpins (first as E+, then as Nu-) OCH3 OCH 1. 2 SmI OMOM 3 2 BnO CH O H C 3 3 2. + OH NH 2 I NC + O BnO Cl + H3C CH3 3. H O BocHN 3 BnO O CH CHO N OTBDPS 3 O C CO2H

PMP OMOM O OMOM O NH H C H3C 3 NH NHBoc 2 SmI2 N N BnO Cl BnO SmX2 O O (Barbier reaction) O O I O O I TBDPSO TBDPSO Ar Ar H C N N H3C OBn 3 OBn OCH C C OCH3 90% 3

O Ar OH N HO BnO NH OCH3 R SmX2 N HO CH3 Ar H3CO O S AcO O H H3C H O+ N CH3 3 N O O OH OH

Ecteinascidin 743 BnO Ito, JOC, 1993, 1458 Antiproliferative (IC50 = 0.2 - 1 nM) O Fukuyama, JACS, 2002, 6552 Reactivity Umpolung-8 Ready

Dithiane anions sample products: R BuLi R Li + R E E R E SS SS SS OTBS SS OH O BnO O O

Corey, Seebach, JOC, 1975, 231 74% R E % yield 85 H Et-I O OTBS SS OH OTBS O Me iPr-I 83 OP 97 Ph iPr-I 65% H PhCHO 99 n-pent O 95 Vinyl thioether anions 1. E+ 77 H R SEt R SEt 2. HgII, H O O sBuLi 2 O THF/HMPA R R' R' Li E R' An extension: dithianes as linchpins sample products: 1. tBuLi TBS O O 2. O TBS OLi O Li OTBS Ph SS R SS Ph R SS n-C8H17 n-C H O R 8 17 3. HMPA, OH R' Stable until addn of HMPA O SEt How? HO OTBS + Br Br Li Smith,III, JACS, 2003, 14435 SS R' R 52% Yamamoto, JACS, 1973, 2694 Reactivity Umpolung-9 Ready

Homoenolate equivalents conjugate addn.

""M O O O CO2Et O MgBr O Tol Tol CN CuBr-DMS 1. E+ CO2Et O O 2. hydrolysis O NC O O Br MgBr E 58% available from aldrich TL, 2003, 737

OH examples: X O O CHO O γ α M 1. MgBr Roush, JACS, 1978, 3599 Many examples. Few work well. 2. HCl Selectivity (α vs. γ) usually poor

1. s-BuLi OMe E OMe 2. E+

OO Ph HO Ph C6H13n OMe OMe O O OH N nC3H7 MgBr 79% N nC3H7 72% 77% O

Evans, JACS, 1974, 5560 H2 Pd/C 90% Bosch, JOC, 2003, 1919

N nC3H7 Reactivity Umpolung-10 Ready homoenolates, cont. Seebach: 1. 2 BuLi OTES 1. s-BuLi + E OTES TMEDA 2. E SH 2. E+ SMe E Yield (%) 3. MeI E

Me 95 Et 83 E+ = n-alkyl Br yields = 65-95 Allyl EtCHO 68 PhCHO α:γ = 1:3 - 1:4 Still, JACS, 1974, 5561 c-pentanone

Review: Tet, 1983, 205

1. H N Boc N Boc Ph N H Ph N Ar sBuLi Ar 2. E+ E

E+ % yield % ee

Me 73 95

Allyl 72 94 O 77 98

Review: ACIEE, 1997, 2282 Reactivity Umpolung-11 Ready

CO Me The Cyclopropane Trick 2 CO2Me CO2Me Base NH N cyclopropanes convert even to odd, odd to even: 2 O normal reactivity mode with cyclopropane

1. Acid Y Y 2. Base + + X O X XY XY OMe O Wenkert, JOC, 1978, 1267 O- O O O- E E OEt IV O TMSO TiCl4 O Ti O O O (a homoenolate equivalent) Nu EtO Nu O O2N H examples CHO CO Me CO2Me 2 CO Me CO Me 2 NaH 2 Danishefsky O DMSO CO Me NO 2 JACS, 1974, 1256 O 2 O CO2Me CO2Me CO2Me EtO 84% OH

Kuwajima, JACS, 1977, 7360 Reactivity Umpolung-12 Ready

OMe Br Sulfones

MeO sulfones display amphoteric reactivity pattern: they can be either electrophilic or nucleophilic O OMe HO Li + SO2Ph Base, E+ SO2Ph [O] R R E R E Note: leaving group β to lithium, but no MsCl; cyclopropene formed from eilimination HO SH PhO2S LDA, then 1 OOOTBS O

OS Corey, TL, 1975, 3685 OTBS OTf (85% yield)

OBn OO OO 1

OTBS

OBn OO OOX OOOTBS O

X = H, SO2Ph LDA, MoOPH 40% yield X = O Masamune, TL, 1988, 451 Reactivity Umpolung-13 Ready

Spiroketal synthesis

OTBS OP' OP SO2Ph nBuLi; epoxide; BF3 Et2O o nBuLi; -78 C PhO2S O OH OTIPS O PhO2S O O MeO O O O

C-SO2Ar is nucleophilic rt then electrophilic

O OH O CSA O O OTBS OP' OP PhO S OH O 2 O OH OMe OH 76% OTIPS Ley, TL, 1986, 5277 75%, 4:1 Perkin, 1991, 25 Strategies &Tactics in Organic Synthesis, 1991, 237

1. nBuLi; CH2I2-iPrMgBr PO 2. OsO4, Pyr 69% PO 3. NaIO , pH7 MeO 1. BuLi 4 2. Swern [O] SO2Ph + SO2Ph MeO 77% S S O O OP S OP' S OTBS OP' OP O OH Al-Hg, ∆ OMe 90% PO

OTIPS Smith, III, TL, 1989, 6963 MeO S Schreiber, JACS, 1993, 7906 O OP S