Reactivity Umpolung-1 Ready

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1 eactivity Umpolung-1 eady eactivity Umpolung: reversal of normal polarity electrophiles become nucleophiles nucleophiles become electrophiles complimentary disconnections ormal reactivity: x = heteroatom d = donor (u - ) a = acceptor ( ) d a d a d 1 3 or c b a bond normal umpolung a MgBr Me 2 Br 5 Li 1 b Li t Br Cu Br ow to make: 1 2 or 1 4 c 2 CuLi t Br Li Li utline: 1. electrophilic heteroatoms 2. acyl anions 3. homoenolates 4. the cyclopropane trick 5. sulfone chemistry General eview: ACI, 1979, 239 Carey and undburg, sec 13.2

2 eactivity Umpolung-2 eady lectrophilic eteroatoms General form: Y Y,Y = heteroatoms mcpba 'ubottom []' TM 1. mcpba 2. F 60% TM ubottom, TL, 1974, 4319 lectrophile xamples 2 1. LDA; 2 Me 2 2. a % Me 2 Me 2 DMD P P' P" P" 1. TBTf, t 3 2. DMD 69% P P' Falck, JC, 1995, 3385 P" TB P" C 2 t " 81% C 2 t Wasserman and Lipshutz TL, 1975, 1731 xaziridines 1. LiMD 2. Mo Py P(Me 2 ) 3 MoP LDA; MoP 87% Vedejs, JC, 1978, % ee Davis, Chem. ev. 1992, 919 not a general asymmetric method. For racemic, most commonly used is 'Davis xaziridine' Ts

3 eactivity Umpolung-3 eady Aminations (eview: yn Lett, 1997, 741) eteroatom exchange: Most commonly with Br, lectrophile Bn C 2 Me xamples 1. LDA 2. BC BC Bn C 2 Me Boc Boc cat P 3 3 Br 2 Br can you name this rxn? 2 α-halo carbonyls are excellent electrophiles (recall 2 rxn accelerated by either electron withdrawing or electron releasing groups) 1. 2 Pd/C (-Bn) 2. TFA (-Boc) 3. ai, 2 C 2 Me Br u vancomycin 2 70%; de > 98% C- synthesized from enolate (or equiv) and electrophilic halogen: omewhat realated; rarely used; unusual mechanism: eber rearrangement JAC, 2005, 5970 Ts 2 Ts, Bu 4 Br uene/k (aq) Include stoltz use of neber in dragmacidin, 2 2 azirine Maruoka, JAC, 2002, 7640 TM Li C, B, 2 2 Ts, Br 2, 2, Cu 2 Lead references: Brummond, TL, 1999, 2231; enantioselective chlorination: Jorgensen, ACI, 2004, 5507

4 eactivity Umpolung-4 eady Acyl anions are the most sought umpolung reagents trecker amino acid synthesis: ne of the oldest and most effective ways to make amino acids ac 4 2 C 2 C 2 Cyanide: uper nucleophile (small, non-basic), can be converted into amine, aldehyde, acid, ketone. ecently has become hot topic for asymmetric catalysis. eview: Chem ev. 2003, 2795 DM ac C Jacobsen JAC 2002, KC DM C 70% Bn 1 mol% 3 Bn C Piv Bn C C DIBAL MgBr With keto-imines Bn Bn ipr tbu npent %ee LiAl 4 2 C ee's for 3- or 4-substituted

5 eactivity Umpolung-5 eady trecker xn with quinolines (eissert xn) Me 2 P Al P TMC Me C ydrocyanation of aldehydes and ketones P Al P TMC 0.4 equiv Bu 3 P hibasaki, JAC, 1999, 2641 TM C 0.1 equiv yields > 85% (C 2 ) 2 exyl ee C C Me C P 97 91%, 85%ee 72%, 89%ee 99%, 91%ee Ti TM C Propose: Me 3 i P ' TM C TMC ' 70-90% yield TM C TM C Al =, 92% ee, 92% ee 91% ee hibasaki, JAC, 2000, % ee

6 eactivity Umpolung-6 eady Increasing the acidity of the formyl proton ature uses carbenes: KC Benzoin condensation K C Cyanomethyl ethers C C WG t C WG 1. LDA 2. ' 3. a tork, JAC, 1971, 5286 =Me; ' = n-hex (85%) ipr (80%); allyl (76%) t Ts C P ' 1. LDA 2. K P ' ' 2 PP Base Vitamin B1 (thiamine) Coenzyme: thiamine pyrophosphate 2 PP enamine intermediate 'C α-keto acid or 2.. Ketose substrate 2 -C PP PP elated Chemistry: 2 C eview: Chem. oc. ev 2000, ' PP ' ketose product

7 eactivity Umpolung-7 eady In the lab: eview: rg. xn. 1991, 407; ACI 2004, 1326 Benzoin reaction enantioselective version: tbu (10 mol%) K t Bu (10 mol%) 80-95% ee nders, ACI, 2002, 1743 Problem: crossed benzoin gives mixture of homo and hetero dimers. oln: Acyl silanes Catalytic homoenolate generation Bode, JAC, 2004, DBU (8 mol %) TF/tBu 1 2 d.r. ~4:1 1 it 3 C KC (30 mol%) 18-C-6 (10 mol%) - it 3 C Brook it 3 it 3 it 3 C - C Johnson, ACI, 2003,

8 eactivity Umpolung-7a eady catalytic ila-tetter eaction chiedt, JAC, 2004, 2314 ime 2 = Me or ' '' 30 mol% C 3 DBU, ipr Br - C 3 ' '' ovis, JAC, 2002, C C 2 t DBU BF 4 C 3 C 2 t ' ' '' '' ime 2 i 3 - quaternary stereocenters with activated catalyst: ovis, JAC, 2004, 8876 BF 4 F F C C 3 C2 t LiMD F F F 94% ee 94% y C 2 t C 3 99% ee 95% y ' '' ime 2 i 3 ime 2 C C 3 LiMD BF 4 F F F F F opposite enantiomers! 99% ee 63% y C 3 o xn o xn

9 eactivity Umpolung-7b eady Isonitriles Versitile C1 synthons; often act as acyl anion Passerini xn: Ugi Four-component coupling (U4CC) C ' '' ''' 2 ''' C ' '' ' ' ' ' acyl migration 2 C'' ''' acyl migration '' ' ' protected amino acid ''' 2 C'' ' ' ''C 2 ' ''' ' an enantioselective version has appeared tbu C i 4 Cat. ' ' C'' ' tbu as been applied extensively for library synthesis: Y C C 3 cat = Propose silyl cation lewis acid: P * 2 i tol naphthyl 2-furyl c-hex JAC, 2003, 7825 ee Fe, Ac Y 2 Y 3 1 2

10 eactivity Umpolung-7c eady U4CC in synthesis: MM Bn 3 C 2 I Boc TBDP C 3 C 3 C 2 C 3 C C 3 C Isonitriles as linchpins (first as, then as u - ) Bn 3 C C 3 C 1. 2 mi Bn 3 C MM TBDP 3 C I Bn C 3 3 C MM TBDP 90% 3 C PMP Boc I Bn C 3 Bn 2 mi 2 (Barbier reaction) Bn m 2 C C 3 C Ac 3 C C 3 C 3 C 3 Bn 3 m 2 cteinascidin 743 Antiproliferative (IC 50 = nm) Fukuyama, JAC, 2002, 6552 Bn Ito, JC, 1993, 1458

11 eactivity Umpolung-8 eady BuLi Dithiane anions Li sample products: Bn TB Corey, eebach, JC, 1975, % % yield Me n-pent t-i ipr-i ipr-i C TB TB 65% Vinyl thioether anions P 77 An extension: dithianes as linchpins 1. tbuli TB 2. TB Li Li 3. MPA, ' table until addn of MPA mith,iii, JAC, 2003, ' TB TB 1. t sbuli t 2. g II, 2 TF/MPA ' ' Li ' sample products: n-c 8 17 n-c 8 17 t ow? Br Br Li 52% Yamamoto, JAC, 1973, 2694

12 eactivity Umpolung-9 eady omoenolate equivalents conjugate addn. " M " C 2 t MgBr Br MgBr hydrolysis C CuBr-DM C 2 t C 58% available from aldrich TL, 2003, 737 examples: C 1. MgBr 2. oush, JAC, 1978, 3599 γ α Many examples. Few work well. electivity (α vs. γ) usually poor M Me 1. s-buli 2. Me nc 3 7 MgBr 77% nc 3 7 C 6 13 n 79% Me 72% Me 2 Pd/C 90% vans, JAC, 1974, 5560 Bosch, JC, 2003, 1919 nc 3 7

13 eactivity Umpolung-10 eady homoenolates, cont. T till, JAC, 1974, s-buli 2. T Yield (%) Me t Allyl eebach: 1. 2 BuLi TMDA MeI = n-alkyl Br tc C c-pentanone eview: Tet, 1983, 205 Me yields = α:γ = 1:3-1:4 Boc 1. sbuli 2. Boc % yield % ee Me Allyl eview: ACI, 1997, 2282

14 eactivity Umpolung-11 eady The Cyclopropane Trick cyclopropanes convert even to odd, odd to even: 2 C 2 Me C 2 Me Base C 2 Me normal reactivity mode - Y examples u C 2 Me C 2 Me C 2 Me C 2 Me Y a DM 84% with cyclopropane Y - C 2 Me C 2 Me C 2 Me C 2 Me u Y Danishefsky JAC, 1974, 1256 TM t t 2 Ti 4 Me 1. Acid 2. Base t C 2 Wenkert, JC, 1978, 1267 Ti IV (a homoenolate equivalent) Kuwajima, JAC, 1977, 7360

15 eactivity Umpolung-12 eady Me Br ulfones Me Li Me ote: leaving group β to lithium, but no cyclopropene formed from eilimination Ms; sulfones display amphoteric reactivity pattern: they can be either electrophilic or nucleophilic 2 2 Base, TB 2 [] LDA, then 1 Corey, TL, 1975, 3685 TB Tf (85% yield) Bn 1 TB Bn TB LDA, MoP 40% yield =, 2 = Masamune, TL, 1988, 451

16 eactivity Umpolung-13 eady piroketal synthesis TB P' P 2 nbuli; epoxide; BF 3 t 2 Me TIP 2 nbuli; -78 o C 2 C- 2 is nucleophilic then electrophilic rt TB P' P 2 75%, 4:1 Me TIP 76% CA Ley, TL, 1986, 5277 Perkin, 1991, 25 trategies &Tactics in rganic ynthesis, 1991, nbuli; C 2 I 2 -iprmgbr 2. s 4, Pyr 3. ai 4, p7 TB P' P 69% Me P Me P' 2 1. BuLi 2. wern [] 77% Me P P 2 P Al-g, 90% chreiber, JAC, 1993, 7906 TIP mith, III, TL, 1989, 6963 Me P