The Staunton-Weinreb Annulation. SED Group meeting Guanqun Zhang
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1 The Staunton-Weinreb Annulation SED Group meeting Guanqun Zhang
2 Steven M. Weinreb Brooklyn, Y May 10, 1941 (Age 73) Cornell University, A.B University of Rochester, Ph.D Advisor: Marshall Gates I Postdoc Fellow Columbia; Gilbert Stork: MIT: George Buchi: Fordham University 1970 Associate professor Penn State University 1978 Professor of chemistry 1980 Russell and Mildred Marker Professor of atural Products Chemistry 1987 Weinreb, S. M. Acc. Chem. Res. 1985, 18, 16. Weinreb, S. M. Acc. Chem. Res. 2002, 36, 59. Short, P. C&E 2005, 83, 65. Weinreb, S. M. eterocycles 2006, 70, 5.
3 Early synthetic targets papuamine (1994) pancracine (1997) Me cephalotaxine (1972) olivin ("1984") Me Me 2 streptonigrin (1982) Me 2 Me Me C 2 Me Steve Weinreb 2 C C 2 C 2 methoxatin (1981) Me Me Me Me tri--methylolivin (1984) Me Me tylophorine (1979) Franck, R. eterocycles 2006, 70, 1.
4 Tri--methylolivin Initial plan: Me Me Me Me Me Me Me Me tri--methylolivin Me C C Me linear synthesis: too many steps Me Cl Convergent synthesis: let s take the naphthalene apart... Me Me Me Me Me Me Me Me TP Me Me Me C 2 atch, R. P.; Shringarpure, J.; Weinreb, S. M. JC 1978, 43, Todd, J..; Starrett, J. E.; Weinreb, S. M. JACS 1984, 106, 1811.
5 Weinreb was inspired by four other people: SPh LDA, TF methyl acrylate -78 o C 68% C 2 Me C LDA (3.3 equiv) MVK (3 equiv) TF, -78 o C 85% auser, 1978 Kraus, 1978 Dodd, J..; Weinreb, S. M. Tetrahedron 1979, 20, auser, F. M.; Rhee, R. P. JC 1978, 43, 178. Kraus, G. A.; Sugimoto,. TL 1978, 19, 2263.
6 a (2-3 equiv) Ts Ph Ph 1,2-dimethoxyethane -78 o C 78% Ph Ph van Leusen, 1978 Parker, 1979 Me Et 2 C Me C (1) a, -56 o C (2) K, Et, 2 (3) TFA, TFAA (2:3) (4) C 2 C 2, Ts, C(Et) 3 47% over 4 steps Me Me C Dodd, J..; Weinreb, S. M. Tetrahedron 1979, 20, Wildeman, J.; Borgen, P. C.; Pluim,.; Rouwette, P..F.M.; van Leusen, A. M. TL 1978, 19, Parker, K. A.; Kallmerten, J. L. TL 1979, 20, 1197.
7 Me Me Me Me Me FS 3 LDA, TF -78 o C 35% Me Me Me Me Et (1) LDA, TF, -78 o C Me Me Me (2) 2 C 2 48% over two steps Jim Staunton And this brings us to the Staunton-Weinreb annulation Dodd, J..; Weinreb, S. M. Tetrahedron 1979, 20, Evans, G. E.; Leeper, F. J.; Murphy, J. A.;Staunton, J. JCS Chem. Comm. 1979, 205 and 406.
8 Staunton-Weinreb annulation general scheme R 1 R 2 Y LDA TF R 1 Y Me X -78 o C rt R 1 = R 2 = alkyl, Bn, MM, MEM X = usually or Me Y = C 2 or o-toluate is preformed with base o-toluate anion is bright yellow electrophile is added later Michael acceptor can be acyclic or cyclic, esters or ketones It s a stepwise sequence involving Michael addition followed by Dieckmann condensation and subsequent aromatization
9 Staunton-Weinreb annulation general mechanism Me Me LDA TF R 1 Me Me Me -78 o C rt LDA -78 o C - Me Me Me Me Me Me Me Me Me Me Me Me can be isolated if quenched at 0 o C can be isolated if quenched at -78 o C Evans, G. E.; Leeper, F. J.; Murphy, J. A.;Staunton, J. JCS Chem. Comm. 1979, 205 and 406.
10 Staunton-Weinreb annulation general mechanism Me Me LDA TF Me Me Me -78 o C rt Me if a leaving substituent is absent, tetralones will be isolated Me Me Me R Me LDA TF -78 o C rt Me R Me if the alpha position is saturated, decarboxylation can be done to aromatize Evans, G. E.; Leeper, F. J.; Murphy, J. A.;Staunton, J. JCS Chem. Comm. 1979, 406. Mahidol, C.; Tarnchopoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. TL 1989, 30, 3861.
11 The reaction works great with... variety of o-toluates α,β-unsaturated esters/ketones Br Me Bn C 2 Ph Boc C 2 Ph Me Boc C 2 Ph Me 2 Et 2 C Et Boc C 2 Ph C 2 Et Me C 2 Ph Boc C 2 Ph C 2 Et S Me Me Me SPh 8 Me TBS Me TMS Donnor, C. D. Tetrahedron 2013, 69, 3747.
12 Essentials in the nucleophile Me C 2 Me LDA, TF Me S S 34% -78 o C 67% without Ph 2 S 2 Me Me Me Me LDA, TF C 2 Et S S C 2 Me -78 o C SPh 87% Me Li Me A methyl ether ortho to the ester group is necessary to stabilize the anion auser, F. M.; Rhee, R. P.; Prasanna, S.; Weinreb, S. M.; Dodd, J.. Synthesis 1980, 72, 74.
13 Aryl Substituent effects R C 2 Me LDA (2 equiv) -65 o C, TF C 2 Me R Me TBS 6 steps from aspartic acid slow warm to rt 30 min R TBS Me C 2 Me 0% Me C 2 Me 46% Me C 2 Me <5% Piv Me Me C 2 Me C 2 Me MEM C 2 Me 0% 0% 0% Me Me Me Me C 2 Me MEM C 2 Me TBS C 2 Me 41% 49% 0% Br Me C 2 Me 20% Me Me C 2 Me "10%" It s a three-way balance between steric interactions, electron density on the toluate and the stabilization offered by chelation Tan,. P..; Donner, C. D. TL 2008, 49, 4160.
14 Skipping the preformed enolate (1) E (2) LDA, MPA Me 2 E = C 2 Ph o C 76% Bn TBS Bn TBS Br C 2 Ph (1) E (2) n-buli o C 81% Me 2 Bn TBS Br C 2 Ph Me (1) E (2) n-buli o C 75% Me Me 2 Bn TBS Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siegel, D. R.; Myers, A. G. Science 2005, 308, 395.
15 Two additional enolate generation methods...sn Me C 2 Et (1) LDA, TF, -78 o C Me C 2 Et (1) n-buli, -78 o C Me (2) Bu 3 SnCl SnBu 3 (2) E, o C (75%) 60% 75% Me TMS 71% Me TMS 51% 74% 83% Me TMS 62% Me SPh 47% ill, B.; Rodrigo, R. L 2005, 7, 5223.
16 Two additional enolate generation methods...si C 2 Me TMS C 2 Me R CsF, MPA 60 o C, 3 h C 2 Me R C 2 Me R C 2 Me C 2 Me C 2 Me C 2 Me C 2 Me C 2 Me 17% 14% 41% C 2 Me C 2 Me C 2 Me C 2 Me C 2 Me C 2 Me 21% C 2 Me 43% C 2 Me 15% C C 2 Me 2 Me C 2 Me Me 2 C C 2 Me C 2 Me 33% 28% C 2 Me C 2 Me C 2 Me 0% C 2 Me Me 2 C C 2 Me Ph C 2 Me C 2 Me Ph 0% 0% C 2 Me 70% C 2 Me C 2 Me Ph C 2 Me 26% 41% Aono, M.; Terao, Y.; Achiwa, K. Chem. Lett. 1985, 339.
17 Two additional enolate generation methods...si C 2 Me TMS Me 2 C C 2 Bn one step C 2 Bn C 2 Me C 2 Me TMS Me 2 C C 2 Bn CsF, MPA 60 o C C 2 Me C 2 Bn C 2 Me (1) 2, Pd/C (2) 150 o C C 2 Me 60% ame, Me, TF C 2 Me C 2 Me 96% over two steps quant. Xiang, J.-.; ambi, P.; hlstein, E..; Elliott, J. D. Bioorg. Med. Chem. 1998, 6, 695.
18 Characteristics of electrophiles Acyclic Michael acceptor are hit/miss and generally don t work well Me C 2 Me Me Me R Me LDA, TF -78 o C Me Me R Me R = Me 50% R = Me 0% R 1 Me C 2 Me R 2 Me (1) LDA, TF, o C (2) Cl, Me, reflux R 1 Me R 2 R 1 = R 2 = 41% R 1 =, R 2 = Me 40% R 1 = Me, R 2 = 52% R 1 = R 2 = Me 51% Yields aren t so great Dodd, J..; Garigipati, R. S.; Weinreb, S. M. JC 1982, 47, Tarnchopoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. Synthesis 1986, 785.
19 A cyclic Michael acceptor Me 2 C C 2 Me 2 eq. Me C 2 Me LDA (2 equiv) TF, -78 o C Me Me Me C 2 Me C 2 Me Me (1) a (aq.), Me, dioxane (2) (Me) 3 C, Ts, Me LDA, -78 o C 74% rt Me Me (3) DDQ, Ph (4) BCl 3, DCM 57% over 4 steps C 2 Me 500 o C, 0.01 torr Me Me 92% Me Me C 2 Me (1) a, Et, TF (2) Me 2 S 4, K 2 C 3 48% over two steps Me 2 C C 2 Me Me C 2 Me LDA, -78 o C rt 80% Me C 2 Me C 2 Me DDQ, dioxane reflux 60% Me C 2 Me C 2 Me Mahidol, C.; Tarnchopoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. TL 1989, 30, 3861.
20 Applications of this annulation in natural product synthesis C Me 2 Me semiviriditoxin Me (R)-atrochrysone FtsZ inhibitor; broad spectrum antibiotic activity against gram-positive pathogens A family of anthranoids, which has displayed antibacterial, anti-malarial, and insect antifeedant activities neojusticidin B Interesting skeleton for organic synthesis
21 Synthesis of semiviriditoxin 2 C 2 (1) a 2, 2 S 4, KBr, 2, 0 o C, 4 h (91%) (2) B 3 -Me 2 S, TF, -30 o C to rt, 18 h (97%) C 2 (3) K 2 C 3, DCM, 72 h (96%) (4) TBSCl, imidazole, DCM, 4 h (98%) TBS methyl propiolate n-buli, BF 3 -Et 2 TF, -78 o C, 30 min (72%) C 2 Me TBS LDA, TF, -60 o C, 30 min (36%) Me Me Me Me TBS ame, Me, 16 h (80%) Me Me TBS (1) TF, 10% Cl, 16 h (2) PhI(Ac) 2, TEMP, DCM, 20 h (3) acl 2, tbu, 2, a 2 P 4, 3 h (4) Me, conc'd 2 S 4, 16 h (5) BCl 3, DCM, 6 h 44% over 5 steps Me C 2 Me Donner, C. D.; Tan,. P.. Tetrahedron 2009, 65, 4007.
22 Synthesis of atrochrysone pig liver esterase TBDMS-Tf, lutidine TBDMS Me 2 C C 2 Me p 8, 92 % Me 2 C C 2 DCM, 0 o C to rt 86% Me 2 C C 2 TBDMS Me TBDMS (1) K 2 C 3, Me (2) Tf 2, DMAP, DCM Me 40-80% over two steps TBDMS C 2 TBDMS Tebbe reagent, TF -78 o C, 30 min, then rt, 1 h 61-85% Me Me Me (1) LDA, TF, -78 o C (25%) (2) F, MeC (78%) Me Muller, M.; Lamottke, K.; Low, E.; Magor-Veenstra, E.; Steglich, W. JCS Perkin Trans , 2483.
23 Synthesis of neojusticidin B C 2 Et (1) LDA, TF, -78 o C (2) p-cymene, 10% Pd/C, reflux C 2 Et not attempted Kobayashi, K.; Maeda, K.; Uneda, T.; Morikawa,.; Konishi,. JCS Perkin Trans , 443.
24 The molecule in hand... TMSE 2 C 2 equiv LiMDS, TF, -78 o C C 2 Me TMSE 2 C Ts Cl -Cl C 2 Me TMSE 2 C TMSE 2 C C 2 Me Ts C 2 Me TMSE 2 C Ts C 2 Me alstilobanine A C 2 Me Feng, Y.; Majireck, M. M.; Weinreb, S. M. ACIE 2012, 51,
25 Staunton-Weinreb Annulation Discovered Independently by Staunton and Weinreb in 1979 for synthesizing linear polycycles Me Me Me Me Me Me Me Me Me C 2 Et Tandam Michael addition, Dieckmann condensation followed by optional aromatization ortho-toluates Me Me Me Me Me Me C 2 Et Me Me Generally requires an ether group ortho to ester for anion stabiliztion Me Me C 2 Et Br...unless the Anion is generated in situ by lithium-halogen exchange cyclic esters and ketones are generally better electrophiles Me 2 C C 2 Me Me C 2 Ph still acyclic
26 What happened to auser, Kraus, van Leusen, and Parker?
27 Supposingly, this should be the beginning of this part of history Me LDA Me (1) Ac 2, py C 2, TF (2) a, 2-78 o C C 2 (3) Ac 2, Cl 4 90% 68% over 3 steps Me ethyl bromoacetate Zn, Ph refulx Me (1) K, Me 2 S 4 (2) 2 Et Me Me 73% Frank auser then on and on for longer polycyclic chains auser, F. M.; Rhee, R. JACS 1977, 99, 4533.
28 (Stabilized) phthalide nucleophiles SPh LDA, TF methyl acrylate -78 o C 68% C 2 Me C 2 (1) PhS, Ph, reflux (2) mcpba, DCM 87% over two steps S 2 Ph LDA, TF methyl acrylate -78 o C 86% C 2 Me Frank auser ne oxidation state higher than the Staunton-Weinreb version C 2 Me S 2 Ph auser, F. M.; Rhee, R. JC 1978, 43, 178.
29 Synthesis of neojusticidin B C 2 Et LDA, TF, -78 o C not attempted LDA, TF, -78 o C I 2, CCl 3 C 2 2, 0 o C Me 50% over two steps Kobayashi, K.; Maeda, K.; Uneda, T.; Morikawa,.; Konishi,. JCS Perkin Trans , 443.
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