Literature Talk, Birte Schröder, , AK Gaich Group Seminar

Transcription

1 2002 Literature Talk, Birte Schröder, , AK Gaich Group Seminar 1

2 Detailed Syntheses Key steps (+) Austamide (-) Morphine (+)-brasilenyne ypnophilin - 3 S Cacospongionolide B VM55599 (+) Aspidospermidine Bn thodologies Strychnofoline 1. h-catalyzed Bamford-Stevens/aisen rearrangement (-) Tuberostemonine Furaquinocin E 7-Epicylindrospermopsin Ph Eschenmoser hydrazone h 2 (ac) 4, C 2 C 2 80 C, 75% yield 2. Synthesis of γ-butanolides BF 3 *Et 2, 0 C C 2 2, 30min TMS KF 2, 2, C, 30min α β γ dr = 3:1 up to > 20:1 2

3 M. L. Snapper: Cacospongionolide B Michael Additon Grignard -Alkylation tathesis C 2 Et Mg - Structural Features: - γ-hydroxybutenolide - trans-decalin system with a quaternary stereo center - 6 stereocenters: - 2 quaternary stereocenter - Key step: - three-step coupling sequence J. Am. Chem. Soc. 2002, 124, a, TF, 0 C to rt C 2 C 2 C 2 5, 0 C 84% brsm 2. Li, / 2 (3:1), rt 3. Weinreb amide, 86% 4. vinyl-mg, TF, 83% Uma Tet. Lett. 1984, 25, Et 3, EtAc 2. S(-) Phenylalanine Ac, 120 C, 2h 3. CSA

4 M. L. Snapper: Cacospongionolide B 7 5. Li/ 3, t-bu, -33 C then Et 2, -78 C, 70% 8 6. Ph 3 P=C 2, DMS, 75 C, 60% 7. Cy 3 P(is)() 2 u=cph, C 2 2, rt, 91% 8. [(CD)h] 2, ()-BIAP, 2 (3 atm), C 2 2, 30 C 91%, dr = 3.3: M /TF (1:2) rt, 90% 10. Ph 3 P=C 2, DMS 75 C, 84% 11. 2, rose bengal, DiPEA, 150 W tungsten filament lamp, C 2 2, -78 C, 69% 11 Cacospongionolide B 4

5 (-) Morphine eck coupling D intramolecular bis-cyclization C eck A B B B.M. Trost: 7 (13) steps, 15.4 % A (-) Morphine Cyclization A C - Structural Features: - pentacyclic ring system - bridged piperidine ring - compact array of functionality - 5 contiguous stereocenters: - 1 quaternary stereocenter - Landmark synthesis was in 1952 by Gates (today: at least 18 TS) C D. F. Taber: 23 (27) steps, 0.77 % 5

6 B. M. Trost: (-) Morphine hydroamination D B A C eck C B A C olefination C 6 steps B. M. Trost ACIE 2002, 41, Troc C 2 + J. Am. Chem. Soc. 2002, 124, Troc C {[η 3 -C 3 Pd] 2 } (1%) chiral Ligand (3%) Et 3, C 2 2, rt 72%, 89% ee Tsuji Trost reaction [Trost Ligand] C 2 2. Ts (5 %), C() 3, 3. DIBAL-/toluene, -78 C, 85%

7 B. M. Trost: (-) Morphine 4. Ph 3 P, acetonecyanohydrin, DIAD, Et 2 5. Ts (20 %), TF, 2, 76%, 96% ee C 6. Pd(Ac) 2 (15 %), dppp (15 %), Ag 2 C 3, PhC 3, 107 C, 24 h eck coupling C 7. C 4, Ph 3 P, C 2 2, 91% 8. Pd(PPh 3 ) 4 (5%) nbu 3 Sn, Ph, 88% C Pd(Ac) 2 (15 %), dppp (15 %), Ag 2 C 3, PhC 3, 65% eck coupling C B A C 10. Se 2, dioxane, sand, 75 C, then DMP, rt 11. DiBAL, C 2 2 /Et 2 then 4, 2 then ab 4 B A C LDA, TF, tungsten bulb 13.B 3, C 2 2, 57% (-) Morphine 7

8 E. J. Corey: (+) Austamide C 2 2 C Fmoc (+) Austamide - Structural Features: - indoloazocine tricyclic subunit - diketopiperazine - 2 stereocenters: - 1 heteroatom-based spiro stereocenter - Key steps: - Pd-mediated cyclization - Previous Synthesis: Kishi Group, racemic, 29 steps J. Am. Chem. Soc. 2002, 124, C ab 4 C 2 2. Fmoc > 98% overall 25 2 C Fmoc 3. Pd(Ac) 2 Ac/TF/ 2, 2, 25 C, 36h (29%, 45% brsm) 2 C Fmoc Et 2 ; then Ph, heat, 95% 5. mcpba; a 54% benzoyl peroxide, TF, 2, 72% brsm 7. Ms, Et 3 (+) Austamide 8

9 E. J. Corey: (+) Austamide Studies towards the key step: 1. in absence of acetic acid: no cyclization occurs 2. in absence of water: major product is dihydroindoloazepine xxx (4:1) 3. similiar results are obtained starting from performed chloromercury derivative but the rate is faster! C 2 Ac Pd(Ac) 2 C 2 Ac Ac, no 2 C 2 Ac + C 2 Ac PdX :4 ring enlargement 2 -Ac (2:1) 2 C Ac Additional significant mechanistic details are missing: the methoxycarbonyl of the tryptophan subunit is crucial for the cyclization 9

10 P. Wipf: (-) Tuberostemonine Seleno - lactonization Eschenmoser-aisen rearrangement Keck allylation 1,2 addition CM Bz C 2 CBz I Ph 3 Sn Ph (-) Tuberostemonine - Structural Features: - pentacyclic ring system - azepane ring - γ-butyrolactone - 10 stereocenters: - 6-membered ring with only stereogenic carbon centers - Key steps: - 1,2 addition of a lithiated ortho-ester - CM to form the azepane - Eschenmoser-aisen rearrangement J. Am. Chem. Soc. 2002, 124, Bz C 2 CBz 1. Pd 2 (dba) 3 C 3, Et 3, C, PBn 3, TF, 65 C, 93% 2. TBDMS, imid., DMAP, C 2 2, 97% 3. Et 3 Si, Pd(Ac) 2, Et 3, C 2 2, rt TBDMS C 2 4. cinnamyl bromide, K 2 C 3, K 2 C 3, toluene, 60 C, 96% 5. TBAF, TF, rt, 96% 6. TPAP, M, C 2 2, 88% 7. KMDS, allyl iodide, -90 C, 66% C 2 Ph 10

11 P. Wipf: (-) Tuberostemonine C 2 Ph 8. A, C 2 2, reflux, 92% 9. PhS, Et 3, C (PPh 3 ) 3 h, 2, Et/C 2 2, rt 11. DBU, C 2 2, rt 89% C Ce* 7 2, ab 4, TF/ 13. TBDSM, imid., DMAP C 2 2, rt, 79% TBDMS C ()*, 2 Al C 2 2, rt 15. B, LiDBB, 93% 1,2 addition TBDMS 16. L-Selectride, TF, -78 C 17. Ts,, 70% ,-Dimethylacetamide dimethyl acetal, xylenes, 135 C, 78% Eschenmoser-aisen PhSe, C/ 2, 0 C, 67% Seleno-lactonization PhSe PhSe A: B: s s u Ph PCy 3 11

12 P. Wipf: (-) Tuberostemonine PhSe 20. AIB, allyltriphenyltin (neat), 95 C, 70% 21. LDA, MPA, TF, -78 C; I, 76% brsm 22. A, allyltritylamine, DIEA, 110 C, 85% 23. Ts, C, C22 reflux, ethylene,81% 24. Pd/C, 2 (1 atm),, 97% (-) Tuberostemonine A: C: s s s s u PCy 3 Ph u i-pr 12

13 S. Denmark: (+) asilenyne own allylation intramolecular cross-coupling (ipc) 2 B 2 C C 2 condensation LA-mediated ring opening (+)-brasilenyne TiPS TiPS TMS TMS J. Am. Chem. Soc. 2002, 124, Structural Features: - nine-membered cyclic ether skeleton - 1,3-cis,cis-diene unit - 3 Stereocenters - Key steps: - intramolecular cross-coupling 2 C C 2 1. Propanal, BF 3 *Et 2,Et 2, -30 C to rt, 2h, 85% 2. B 3 *TF, TF, 0 C, 3h, 82% 3. TBS, pyr., C 2 2, rt, 4h, 85% 4a. bis(tms)acetylene, Ti 4 C 2 2, -73 C, 3h b. ptsa (1mol%), Ph, 1h, 86% 5. IS, Ag 3 (10mol%), DMF, rt, 10min, 95% I 6. K 2 C=C 2 K, Ac, TF/i-Pr, rt, 6h, 80% 7. *, Al 3, C 2 2, 0 C to rt, 1h, 93% 8. PMB, Ag 2, C 2 2, rt, 24h, 82% I 47 PMB TBS L-(S)-malic acid 13

14 S. Denmark: (+) asilenyne PMB I 9. DIBAL-, C 2 2, -73 C, 3h, 87% 10. allylb(ipc) 2, Et 2, -100 C, 2h, 89% own Allylation I 11. chlorodimethylvinylsilane, Et 3, C 2 2, 0 C to rt, 30min, 91% 12. Schrock's catalyst (5mol%), Ph, rt, 1h, 92% 50 PMB 51 PMB 52 Si I 13. [allylpd] 2 (7.5 mol%), TBAF, rt, 60h, 61% silicon-assisted intramolecular cross-coupling 14. TBSTf, pyr., DMAP (10%mol), C 2 2, 0 C to rt, 2h., 88% 15. DDQ, C 2 2 / 2 (19/1), rt., 30min, 84% 16. DMP, C 2 2, rt, 2h, 83% TBS 17. 1,3-bis(triisopropylsilyl)propyne, nbuli, TF, -74 C to rt, 8h, 83% (Z/E = 6/1) 18. TBAF, TF, 0 C, 1.5h, 93% 19. C 4, (n-ct) 3 P, toluene, 65 C, 12h, 92% PMB Peterson-lefination (+)-brasilenyne 14

15 B. M. Trost: Furaquinocin E 1,2 addition AAA WE Ph C 2 C 6 π electro - cyclization reductive eck Furaquinocin E I P C 2 - Structural Features: - nine-membered cyclic ether skeleton - 1,3-cis,cis-diene unit - 3 Stereocenters - Key steps: - intramolecular cross-coupling J. Am. Chem. Soc. 2002, 124, C 2 C 1. A, Pd 2 (dba) 3 *C 3 (1 mol%) ligand(,)-b (2.65mol%), C 2 2, rt, 97%, dr 92/8 Triple AAA C I C 2. a) Pd 2 (C 3 C) 2 (10mol%) C, PMP, DMP, 50 C b) Ac 2, TEA, DMAP, C 2 2, rt, 81%, 87% ee eductive eck 57 Ac C A: I B: PPh 2 Ph Ph Ph 2 P 15

16 B. M. Trost: Furaquinocin E Ac C 3. a,, rt, 94% 4. TIPSTf, TEA, C 2 2, 96% 5. BS, TF, rt, 92% C TIPS 6. a) DIBAL-, C 2 2, -78 C b) C, LiMDS, TF, 0 C, 89% TIPS 2 C 7. a) DIBAL-, C 2 2, -78 C b) TBDMS, imid., C 2 2, reflux, 89% 8. a) nbuli, TF, -78 c b) D,TF, -78 C c) oxalic acid, TF/ 2, 50% TBDMS TBDMS TBDMS 59 TIPS 9. a) Ph, 110 C 4 π ring opening TIPS 6 π ring closure TIPS Moore-Liebeskind naphtoquinone synthesis b) air, rt, 64% 10. TBAF, TF, 0 C, 65% C: C 2 D: P 1. a) Li, TF, -100 C b) TFAA, -78 C, c) aniline, -78 C to -15 C Ph 53% Furaquinocin E 16

17 L. A. Paquette: ypnophilin 1,2 addition cascade cyclization Li i-pr ypnophilin 1,2 addition i-pr J. Am. Chem. Soc. 2002, 124, Structural Features: - linear fused triquinane system - uncommon Michael acceptor - 6 stereocenters: - 5 contiguous stereocenters - 1 quaternary stereocenter - Key steps: - cascade cyclization with diisopropyl squarate 1. 2, C 2 2, 0 C 40min; Et 3, 20 C, 3h, 77% 3. t-buli, TF, -78 C 2. Ethylene glycol, Dowex, Ph, reflux 3 days, 80% i-pr brsm Li i-pr 4. Li 66 in TF, -78 C then C 2 =CLi then 4 (degassed) i-pr i-pr 67 17

18 L. A. Paquette: ypnophilin A closer look at the key step: i-pr i-pr Li 66 in TF, -78 C then C 2 =CLi then 4 (degassed) i-pr i-pr 67 i-pr i-pr i-pr i-pr π ring opening dianionic oxy-cope i-pr -ipr 8 π ring closure i-pr i-pr elimination i-pr i-pr 73 transannular Aldol rxn i-pr i-pr 72 18

19 L. A. Paquette: ypnophilin i-pr i-pr 5. 10% 2 S 4, o/n, rt, 24% over two steps 6. Ms, Et 3, DMAP, rt, o/n, 72% i-pr i-pr 7. Li, 3, TF, -78 C, 1.5h, Li benzoate, -78 C, 72% i-pr i-pr 8. LA, TF, -10 C, 5min then 1 M, 76% 9. MM, DiPEA, C 2 2 rt, o/n, quant. yield i-pr MM 10. LDA, MPA, TF, I, rt, o/n, 95% 11. Li, Et 2, 0 C, 2h, then 30% 2 S 4, TF, reflux, 10h, 85% LDA, DMPU, TF, TMS, Pd(Ac) 2, C, rt, o/n, 60% 13. K 2 C 3, 30% 2 2, 2, C 2 2, rt, 3h, 80% brsm ypnophilin 13. KtBu, DME, -78 C to rt, 10% aq Ac 14. mcpba, C 2 2, DBU, Ph, 48% over two steps 15. Ac 2, DMAP, pyr., 98% 16. Li, TF, 30% Coriolin 19

20 7-Epicylindrospermopsin intramolecular nitrone CA - 3 S D intramolecular nitrone CA D A B C 7-Epicylindrospermopsin -sulfinylurea Diels Alder cascade -sulfinylurea Diels Alder cascade J. D. White A S. M. Weinreb - Structural Features: - polycyclic ring skeleton - unusual enolic uracil D-ing - guanidine C-ing - 7 stereocenters 20

21 S. M. Weinreb: 7-Epicylindrospermopsin Mg - 3 S WE Et P Et C 2 Grignard -sulfinylurea Diels Alder 7-Epicylindrospermopsin J. Am. Chem. Soc. 2002, 124, Si Mg Cbz, TF, -20 C 2. Et 2, 94% 81 Si Mg Si 3. amds, TF I, 88% 4. Cbz Mg Cbz CuI, TF Si L-Selectride, TF, 80% 6. a, TF, TBAI, Bn, 95% 7. KF 2, C 3, TFA 8., ac 3, TF, 30% 2 2, 88% Bn 84 21

22 S. M. Weinreb: 7-Epicylindrospermopsin Bn Sia 2 B, TF, 2 2, a, 97% 10. Swern, 84% 11. Li* 2, TF, 80% Et P Et 85 C 2 Bn 12. DiBAL-, BF 3 *Et 2 C 2 2, 83% 13. a, TF, TBAI, Bn PMB, 96% C a, 2, Et 100% PMB 15. a, TF, TBAI, Bn, 65% 16. KC, Ac, pyr, Et 3, 85% Bn Bn 2 PMB 17. S 2, imid., C C - rt Bn Bn S PMB Bn Bn 90 S PMB 18. PhMg, TF/C () 3 P,, 84% [2,3] sigmatropic rearrangement Bn Bn 91 PMB C() 2, 2 C, CSA, 93% 24. DDQ, 2, C 2 2, 78% Bn Bn C DMP 26. a 2, tbu, ipr 2 Et, I, Bn 28. TMSTMS, TF, Bn Et, 82% DMF, 81% Bn Bn C 2

23 S. M. Weinreb: 7-Epicylindrospermopsin Bn Bn C Tf 2, pyr, C 2 2 MM 73% 29. PhC, Et 3, TF Bn 32. TMS, MM, 30. 4, ipr, 65% DIPEA 33. Pd() 2, Et, 2, 100% Bn MM 33. triphosgene, TF MM MM MM MM 4 Ac or a 3, DMF, 86% 3 98 u , 2, TF 35. Tf, 2,6-di-t-butylpyridine then 10% Pd/C, Et, 2 MM MM C M, reflux 37. S 3 *DMF, DMF, pyr, a 2 S 4-3 S 7-Epicylindrospermopsin 23

24 Key steps in Total (+) Aspidospermidine Synthesis JACS 2002 Bn Strychnofoline VM

25 Williams Group: (-)VM55599 intramolecular Diels Alder (S) 2 (S) C 2 (S)-Ile + VM Key step: Intramolecular Diels Alder cycloaddition J. Am. Chem. Soc. 2002, 124, Ac, rt 14 days Ac + Ac intramolecular Diels-Alder reaction + 35% %

26 Marino Group: (+) Apsidospermidine [3,3] sigmatropic rearrangement + Boc - Key step: [3,3]-sigmatropic rearrangement with of chiral vinyl sulfoxid with a ketene J. Am. Chem. Soc. 2002, 124, S ptol Zn(Cu), 3 CC, TF, -45 C, 78% Boc p-tols Boc 2 S ptol S Boc 2 ptol Boc p-tols Boc 2 26

27 Careirra Group: Strychnofoline ing expansion Bn TBDPS + Bn Bn Strychnofoline - Key step: ing expansion reaction J. Am. Chem. Soc. 2002, 124, Proposed pathways: ' A '' Bn Mg 112 I ' '' Bn 115 ' '' 111 Bn B ' Bn '' I Mg I C ' '' Bn I 113 ' 114 '' 27

28 thodology JACS 2002 Ph h 2 (ac) 4, C 2 C 2 80 C, 75% yield α β γ Eschenmoser hydrazone dr = 3:1 up to > 20:1 BF 3 *Et 2, 0 C C 2 2, 30min TMS KF 2, 2, C, 30min 28

29 JACS 2002: thodology 1) xazaborolidines in enantioselective Diels-Alder reactions: - broad substrate scope - high ee values 2) Wender - [5+2+1] Cycloaddition - Aza-[5+2] Cycloaddition B o-tol Ph Ph -78 C, 13h Tf - 96% yield 97% ee C 117 J. Am. Chem. Soc. 2002, 124, [][h(c) 2 ] 2 5mol% dioxane, conc., temp., C 2 5mol% [hc) + 2 ] 2 Ph, 60 C C (pressure), ' [5+2+1] '' C 2 C 2 2 C ) Allenoate-aise earrangement J. Am. Chem. Soc. 2002, 124, addition across > (E) - enamine favored - depending on (E) vs. (Z) in the starting: anti vs. syn X Y LA C 2 X Y 129 [3,3] J. Am. Chem. Soc. 2002, 124, X Y LA LA 128 Y X 29

30 Tandem h-catalyzed Bamford-Stevens/aisen rearrangement sequence Synthesis of α, γ unsatured aldehydes - modification of the aisen rearrangement β - improvement: stereoselective preparation of (Z)-isomer utilization of non-carbonyl stabilized diazo compounds Eschenmoser hydrazone dr = 3:1 up to > 20:1 - works in high dr, good yields and a broad range of substrates ( =, Ar, alkyl, acyclic, cyclic) - etron: Eschenmoser hydrazone J. Am. Chem. Soc. 2002, 124, Ph h 2 (ac) 4, C 2 C 2 80 C, 75% yield α γ Proposed mechanism: ice feature: Ph h 2 (ac) 4, C 2 C 2 80 C, 75% yield Eschenmoser hydrazone dr = 3:1 up to > 20:1 α β γ Ph h 2 (ac) 4, C 2 C 2 80 C, 75% yield 2. 2 Al, -40 C Ph 138 thermal decomposition aisen rerrangement Prins-cyclization/ Alder-en reaction non-carbonyl stabilized diazo-compound 134 allylic enol ether (> 20:1, Z:E) Ph LA h-mediated de-diazotization h 2 (Ac) ,2-hydride migration hl

31 Conversion of terminal epoxides into γ-butanolides - single step: Lewis acid-mediated epoxide opening of 1-morpholino-2-trimethylsilyl acetylene - mild reaction conditions - enantiomerically enriched epoxides can be converted into enantiomer pure γ-butanolides without loss of optical purity 139 BF 3 *Et 2, 0 C C 2 2, 30min TMS KF 2, 2, C, 30min = allyl, -Ph, different alcohols, alkylhalides, esters,. TMS 140 J. Am. Chem. Soc. 2002, 124, 2457 Modification: BS, 0-23 C BF 3 *Et 2, 0 C C 2 2, 30min TMS 141 TMS 140 BS, 0-23 C; Li, Li 2 C 3, DMF DMF, 70 C, 15min

32 Thank you for your kind attention! 32

33 D. F. Taber: (-) Morphine intramolecular bis-cyclization D B C A C A C (-) Morphine D. F. Taber: 23 (27) steps, 0.77 % - Key step: intramolecular bis-cyclization J. Am. Chem. Soc. 2002, 124, S 2 Ph K 2 C 3, TBAB Ph, reflux S 2 Ph S 2Ph 33