Organocatalysis with N-Heterocyclic Carbenes

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1 rganocatalysis with -eterocyclic Carbenes Frontiers of Chemistry obert B. Lettan II March 28 th, 2009 Key eferences: Enders, D.; iemeier,.; enseler, A. Chem. ev. 2007, 107, Marion,.; Díez-González,.; olan,. P. Angew. Chem. Int. Ed. 2007, 46, Johnson, J.. Curr. pinion Drug. Discov. Develop. 2007, 10, ob Wipf Group Page 1 of 34 3/30/2009

Thiamine-Dependent Enzymes 2 Thiamine: = TPP: = P 2 6 3 Thiamine diphosphate (TPP) is required by a number of enzymes that catalyze the cleavage and formation of bonds to the carbon atom of a

2 Thiamine-Dependent Enzymes 2 Thiamine: = TPP: = P Thiamine diphosphate (TPP) is required by a number of enzymes that catalyze the cleavage and formation of bonds to the carbon atom of a carbonyl group. chanism of pyruvate decarboxylase (PDC) 2 All 3 nitrogens on aminopyridine ring involved in hydrogen binding to enzyme. carbene ylide pyruvate C 2 Jordan, F. at. Prod. ep. 2003, 20, ob Wipf Group Page 2 of 34 3/30/2009

3 Thiamine-Dependent Enzymes ob Wipf Group Page 3 of 34 3/30/2009

Thiamine-Dependent Enzymes chanism of pyruvate dehydrogenase (E1) 2 carbene ylide pyruvate C 2 E1 E2 lipoamide E2 FAD 2 E3 AD CoA E2 E2 FAD AD cellular respiration Krebs cycle CoA

4 Thiamine-Dependent Enzymes chanism of pyruvate dehydrogenase (E1) 2 carbene ylide pyruvate C 2 E1 E2 lipoamide E2 FAD 2 E3 AD CoA E2 E2 FAD AD cellular respiration Krebs cycle CoA Acetyl-CoA ow can nature s Umpolung method of bond-formation be applied to synthesis? Leeper, F. J. et al. Biochem. oc. Trans. 2005, 33, 772. ob Wipf Group Page 4 of 34 3/30/2009

5 Persistent Carbene A "stable" carbene that is a reactive intermediate. 1943: Ugai ecognized that thiamine can be used as a catalyst for the benzoin condensation. 1957: Breslow Br D 2, 28 C t 1/2 ~ 20 min Br D 1960: Wanzlick 1964: Lemal C C C 3 Lemal ruled out dimerization through cross-over exp. X 1970: Wanzlick 4 tbuk C increased stabilization X X Ugai, T. et al. J. arm. oc. Jpn. 1943, 63, 296. Breslow,. J. Am. Chem. oc. 1957, 79, Wanzlick,. W. Angew. Chem. Int. Ed. Engl. 1962, 1, 75. Lemal, D. M. et al. J. Am. Chem. oc. 1964, 86, Wanzlick,. W. et al. Liebigs Ann. Chem. 1970, 731, 176. ob Wipf Group Page 5 of 34 3/30/2009

6 Isolated Carbenes 1991: Arduengo a, TF, cat. DM, T isolated crystal structure 4 5 Bond angles: 1 -C 2-3 = (imid = 109 ). In agreement with theoretical studies on singlet ( 1 A') carbenes bearing!"donor substituents. Change in!-delocalization supported by upfield shift of imidazole ring protons ( ). 13 C M of C 2 : # = 211 ppm o dimerization. ome other isolated -heterocyclic carbenes by Arduengo 1992! C = 214 ppm -C- angle = 102 Less hindered tetramethyl-imidazol-2-ylidene o dimerization suggests this is due to electronic stabilization. 1995! C = 245 ppm -C- angle = 105 cyclic diamino carbene dimesityl i-pr i-pr 1997! C = 220 ppm -C- angle = 102 Air table 1997! C = 254 ppm -C- angle = 104 thiazolium carbene also stable Arduengo, A. J., et al. J. Am. Chem. oc. 1991, 113, 361. ob Wipf Group Page 6 of 34 3/30/2009

7 Carbene tability ca. 87 kcal/mol Carbene tability! inglet Character! Electron Donation into Vacant p-rbital of Carbene ca. 6 kcal/mol ca. 20 kcal/mol Electron donating groups promote more stable singlet carbene Further stabilized by aromatization. Does not dimerize. a, DM Electron lone pairs in close proximity. epulsive electrostatic interactions would have a significant destabilzing effect. errmann, W. A.; Kocher, C. Angew. Chem. Ind. Ed., Engl. 1997, 36, ob Wipf Group Page 7 of 34 3/30/2009

8 Preparation of table Carbenes Deprotonation W X Y Z a 2 C 3 C 4 Y Z X W Base Y Z X W b c 2 C 2 C 4 C 3 d 2 C 2 C 2 e 2 C 2 C 2 4 C formation caveats: pka = 24 (DM) strongly basic react with oxygen their imidazole precursor's are susceptible to nucleophilic attack sometimes difficult to isolate free carbene from metal ions used to prepare i-pr i-pr Bases: tal hydrides: Work, but often sluggish due to relative insolubilitiy in suitable solvents (TF) Catalysts (DM, t-bu) improve solubility and reactivity, but ineffective for non-imidazolium adducts due to nucleophilicity. Must avoid hydroxide, especially with non-aromatic salts. Kt-Bu: as been shown to be effective. Alkyllithiums: Unreliable. n-buli and Li can act as nucelophiles, t-buli can act as a hydride donor. Lithium Amides: LDA and LiTMP work well, if not too much Li in n-buli during preparation. tal hexamethyldisilazides: Works very well for the most part. Alder,. W., et al. J. Chem. oc., Chem. Commun., 1995, ob Wipf Group Page 8 of 34 3/30/2009

9 ome ther thods Preparation of table Carbenes Ag Ag C X C X = C 6 F 5, CF 3, C 3 80 C, 0.1 mbar; toluene,! quant. X =, C 2 ; ' = alkyl K, TF,! olan,. P. -eterocyclic Carbenes in ynthesis, Wiley -VC & Co., ob Wipf Group Page 9 of 34 3/30/2009

10 C/Umpolung eactivity aldol ormal Polarity Michael Inverted Polarity (+ catalyst) (+ catalyst) benzoin tetter C Catalyzed Umpolung eactions benzoin condensation tetter reaction hydroacylations acylation of aryl flourides nucleophilic substitution homoenolate reactivity - cross condensations - Diels-Alder reaction - eck-type cyclizations Additional C Catalyzed eactions transesterification - oxidation - polymerization ring-opening reactions 1,2-additions eebach, D. Angew. Chem. Int. Ed., Engl. 1979, 18, 239. Johnson, J.. Curr. pin. Drug Disc. Dev. 2007, 10, 691. ob Wipf Group Page 10 of 34 3/30/2009

11 Benzoin Condensation Breslow chanism 2 thiamine base thiamine carbene benzoin Ugai, T. et al. J. arm. oc. Jpn. 1943, 63, 296. Breslow,. J. Am. Chem. oc. 1957, 79, ob Wipf Group Page 11 of 34 3/30/2009

12 Asymmetric Benzoin Enders BF 4 ArC (10 mol%) Kt-Bu, TF 0 or 18 C Ar Ar 8-83% yield 80-95% ee J. You 2 C 1 mol% A or B Kt-Bu, TF, 23 C A: 27%, 88% ee B: 95%, 95% ee A B DFT calculations show B has a larger conjugation interaction over mono-triazolyldine A. Enders, D.; Kallfass, U. Ang. Chem. Int. Ed. 2002, 41, You, J. et al. Adv. ynth. Catal. 2008, 350, ob Wipf Group Page 12 of 34 3/30/2009

13 Inoue Et Crossed Benzoin (10 mol%) % selectivity =, Et, n-pr, i-pr, Cy,, 2-furyl Müller: enzymatic Ar 1 Ar 2 BAL, ThDP, Mg 2+, KPi buffer, DM, 30 C Ar 1 BAL = benzaldehyde lyase ThDP = thiamine diphosphate Ar 2 Ar 2 must be a better electron acceptor that Ar 1. conversion, selectivity, ee up to > 99% Johnson: metallophosphite catalyzed iet 3 C 5 mol% A, n-buli (20 mol%) TF, 30 min iet 3 87% yield 91% ee Ar = 2-F A Ar Ar Ar P Ar via a Brook rearrangement pathway Inoue,. et al. J. rg. Chem. 1985, 50, 603. Müller, M. et al. J. Am. Chem. oc. 2002, 124, Johnson, J.. et al. J. Am. Chem. oc. 2004, 126, ob Wipf Group Page 13 of 34 3/30/2009

14 Azabenzoin Murray/Frantz & Miller Ts 2 3 catalyst, conditions 2 3 A Bn I B Bn Boc Murray/Frantz: 10 mol% A, Et 3, DCM, C, h Miller: 15 mol% B, PEMP, DCM, 23 C, 2 h 58-98% yield % yield 75-87% ee cheidt iz 3 2 P 30 mol% I DBU, C 3, i-pr iz 3 Breslow Intermediate 2 P 51-94% yield Murray, J. A.; Frantz, D. E. et al. J. Am. Chem. oc. 2001, 123, Miller,. J. et al. J. Am. Chem. oc. 2005, 127, Mattson, A. E.; cheidt, K. A. rg. Lett. 2004, 6, ob Wipf Group Page 14 of 34 3/30/2009

15 Intramolecular Crossed Benzoin Complex Anthraquinone Precursors 20 mol% Br Et C 2 Et C DBU, t-bu, 40 C, 0.5 h Et 2 C 79% yield dr = 20:1 Enantioselective ynthesis of the Eucomol Core C 15 mol% ovis' catalyst Et 3, TF, rt, 25h ()-eucomol BF 4 ovis' Catalyst uzuki, K. et al. Adv. ynth. Catal. 2004, 346, uzuki, K. et al. Angew. Chem. Int. Ed. 2006, 45, ovis, T. et al. J. rg. Chem. 2005, 70, ob Wipf Group Page 15 of 34 3/30/2009

16 tetter, 1976 tetter eaction X n-pr 10 mol% A Et 3, Et, 78 C n-pr 95% yield A: = Bn, X = B: = Et, X = Br A for aliphatic B for aromatic n-pr n-pr Breslow Intermediate A Et 3 n-pr n-pr n-pr tetter,. Angew. Chem. Int. Ed., Engl. 1976, 15, 639. Yates, B. F.; awkes, K. J. Eur. J. rg. Chem. 2008, ob Wipf Group Page 16 of 34 3/30/2009

17 Asymmetric Intramolecular tetter eaction Ciganek was the first to report and intramolecular tetter reaction (1995). Enders was the first to report an asymmetric intramolecular tetter reaction (1996, 41-74% ee). ignificant progress has been more recently acheived by ovis (2004-present). ovis air and water stable, crystalline solid X EWG 20 mol% A or B, base toluene or xylenes 24 h, 25 C X EWG BF 4 Ar X =,,, C 2 =, alkyl, aryl 82-99% ee if = : catalyst A, Ar = 4- base = 20 mol% KMD if = alkyl/aryl: catalyst B, Ar = C 6 F 5 base = 2 equiv. Et 3 Desymmetrization ' C 10 mol% A, 10 mol% KMD, toluene, 23 C ' 60-94% yield 82-99% ee >95:5 dr Ciganek, E. ynthesis 1995, Ender, D. et al. elv. Chim. Acta. 1996, 79, ovis, T. et al. J. Am. Chem. oc. 2004, 126, Liu, Q.; ovis, T. J. Am. Chem. oc. 2006, 128, ob Wipf Group Page 17 of 34 3/30/2009

Asymmetric Intermolecular tetter eaction Enders BF 4 Bn C TB (10 mol%) 10 mol% Cs 2 C 3, TF, 0 C, 6 h 65% yield, 66% ee ovis Et C 2 t-bu C 2 t-bu BF 4 F F F (20 mol%) i-pr 2 Et, C 4, Mg 4, 10 C, 12

18 Asymmetric Intermolecular tetter eaction Enders BF 4 Bn C TB (10 mol%) 10 mol% Cs 2 C 3, TF, 0 C, 6 h 65% yield, 66% ee ovis Et C 2 t-bu C 2 t-bu BF 4 F F F (20 mol%) i-pr 2 Et, C 4, Mg 4, 10 C, 12 h, 84% yield, 90% ee F F Et C 2 t-bu C 2 t-bu 1. uper-hydride TF, 100 C 95%, 8:1 dr 2. C 2, 23 C quant. Et C 2 Enders, D.; an, J. ynthesis 2008, ovis T. et al. J. Am. Chem. oc. 2008, 130, ob Wipf Group Page 18 of 34 3/30/2009

19 pecial Intermolecular tetter eactions ne-pot ynthesis of Pyrrols and Furans (tetter-paal-knorr) Müller 2 Br cheidt i ( 3 P) 2 Pd 2, CuI, Et 3,! 2. C, 20 mol% A 20 mol% B, DBU, i-pr, TF, 70 C 2 3 2, Ts, 4Å ieves,! Ac,! X A: =, X = I B: = Et, X = Br 53-82% yield 42-84% yield Polymer-upported tetter eactions n Can easily recover polymer and use up to 4 times without loss of reactivity. 2 4 I DMF, Et 3, 80 C % yield 66->95% purity Müller, T. J. J. et al. rg. Lett. 2001, 3, Bharadwaj, A..; cheidt, K. A. rg. Lett. 2004, 6, Barrett, A. G. M. et al. rg. Lett. 2004, 6, ob Wipf Group Page 19 of 34 3/30/2009

20 Tius Bz atural Product ynthesis using the tetter eaction 8 steps from 5-hexenal icolaou Bn 8 steps from dihydroresorcinol ovis (30 mol %) 6-hexenal Et 3, dioxane, 70 C, 18 h, 60% Br PMB 4 steps from -PMB maleimide Bz BF 4 C 6 F 5 Et 3, C 2 2, 45 C, 64% BF 4 (20 mol%) C 6 F 5 20 mol% KMD, 0 C, toluene 88% yield, 99% ee 4 Br single diastereoisomer 1. Grubbs catalyst 2. 2, Pd/C 3. ( 4 ) 2 C 3, propionic acid, 140 C PMB 2 C (±)-roseophilin arrington, P. E.; Tius, M. A. rg. Lett. 1999, 1, 649. icolaou, K. C. et al. Chem. Commun. 2007, rellana, A., ovis, T. Chem. Commun. 2008, 730. (±)-platensimycin FD-838 ob Wipf Group Page 20 of 34 3/30/2009 PMB

21 C 2 omoenolates 5 mol% Kt-Bu/TF or DBU/t-Bu/TF Can also access γ-lactams if imines are used as the electrophile % yield cis/trans! 4:1 C s s s s 2 s 2 s Burstein, C.; Glorius, F. Angew. Chem. Int. Ed. 2004, 43, Bode, J. W. et al. J. Am. Chem. oc. 2004, 126, ohn,..; Bode, J. W. rg. Lett. 2005, 7, ob Wipf Group Page 21 of 34 3/30/2009

22 β-lactones C CF 3 5 mol% Et 3, toluene, 60 C F 3 C 48% yield 3:2 dr C s s s s s s s s 3 2 Glorius, F. et al. ynthesis 2006, ob Wipf Group Page 22 of 34 3/30/2009

23 Azadiene Diels-Alder eaction Et 2 C C Ar 2 10 mol% DIPEA, 23 h 0.05 M toluene/tf (10:1) BF 4 s Ar 2 C 2 Et 90% yield >99% ee Et 2 C C Et 2 C s Et 2 C s s Et 2 C s C 2 Et Ar 2 C 2 Et Ar 2 s Ar 2 Bode, J. W. et al. J. Am. Chem. oc. 2006, 128, ob Wipf Group Page 23 of 34 3/30/2009

24 1,3,4-Trisubstituted Cyclopentenes C C mol% 12 mol% DBU, TF, rt, 8h 2 3 s s s s % yield 2 s s C C s s 4- C 43% 2 Bode, J. W. et al. J. Am. Chem. oc. 2006, 128, ob Wipf Group Page 24 of 34 3/30/2009

25 Enantioselective Cyclopentane ynthesis 99% ee C 2 Et 10 mol% DBU, toluene, rt, 15 h s C Et 2 C 4 10 mol% s DBU, toluene, rt, 15 h 99% ee C 2 Et Kaeobamrung, J.; Bode, J. W. rg. Lett. 2009, 11, 677. ob Wipf Group Page 25 of 34 3/30/2009

26 Annulation with Aryl itroso Compounds C 20 mol% 20 mol% DBU, TF, 5 C Ar 45-81% yield C i-pr i-pr Ar' Ar i-pr i-pr Ar Bamberger-Type earrangement Ar Ar Zhong, G. J. rg. Chem. 2009, 74, ob Wipf Group Page 26 of 34 3/30/2009

27 ovis C-Catalyzed edox Processes Br C 20 mol% Et 3, Bn, toluene, 25 C, 4 h Br Bn 80% yield Bode C 10 mol% Bn i-pr 2 Et, Et, C 2 2, 30 C, 15 h Et 89% yield, 13:1 dr cheidt I Zeitler s C 5 mol% DBU, Bn,, toluene, 100 C, 2 h 82% yield Bn C 5 mol% s DMAP, Et, toluene, 60 C, 2h 65% yield Et ovis, T. et al. J. Am. Chem. oc. 2004, 126, Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. oc. 2004, 126, Chan, A.; cheidt, K. A. rg. Lett. 2005, 7, Zeitler, K. rg. Lett., 2006, 8, 637. ob Wipf Group Page 27 of 34 3/30/2009

28 C-Catalyzed Azidation of Epoxy-Aldehydes C 20 mol% 16 mol% Et 3, TM 3 /a 3, (Et) toluene, 25 C, 4 h TM 3 TM 3 /a 3 (2.5:1) or TM 3 /a 3 /Et (1:1:1) C Et creates equilibrium, which leads to intramolecular oxazolidinone formation. 3 w/ Et 3 Curtius earrangement C u TM u ovis, T. et al. J. rg. Chem. 2008, 73, ob Wipf Group Page 28 of 34 3/30/2009

29 - to C-Acyl Transfer 2 C 2 Ar 1 mol% BF4 0.9 mol% KMD, TF, rt, 5 min 2 C 2 Ar 67-84% yield 2 C 2 2 C 2 Ar Ar 2 C 2 Ar Crossover experiment supports mechanism: 2 different starting materials (1/2 and 1'/2') give 4 different products. ovis, T. et al. J. rg. Chem. 2008, 73, ob Wipf Group Page 29 of 34 3/30/2009

30 olan Movassaghi 2 = alkyl, aryl 2 = 1 alkyl 3 = alkyl, aryl 2 =, vinyl 3 = 1 and 2 alkyl 3 Trans-Esterification mol% Cy 4Å M, TF, < 3 h mol% s 4Å M, TF, < 3 h Cy s 2 2 Competitive experiment with 2 Bn gives only the desired product. 3 or 90-99% yield Equilibrium process that favors product under reaction conditions % yield 2 Alcohol is necessary. s s! + s 2 s 2 s s s! + product (after acyl transfer) s 2 Theoretical studies by u support this mechanism. olan,. P. et al. rg. Lett. 2002, 4, edrick, J. L. et al. rg. Lett. 2002, 4, Movassaghi, M.; chmidt, M. A. rg. Lett. 2005, 7, u, C.-. Tetrahedron Lett. 2005, 46, ob Wipf Group Page 30 of 34 3/30/2009

31 TM = aromatic, aliphatic, branched aliphatic uc i 1 uc C-Catalyzed 1,2-Additions uc mol% TMCF 3 /DMF or TMC/TF = adamantyl, s TMuc C i 3 uc TM i 3 uc Maruoka TM CF 3 or 79-99% yield or or C TM C Ts (1 mol%) TMC/TF Ts C 99% 92% Lewis-base mechanism more plausible. ong, J. J. et al. rg. Lett. 2005, 7, uzuki, Y.; ato, M. et al. Tetrahedron, 2006, 62, Maruoka, K. et al. Tetrahedron Lett. 2006, 47, ob Wipf Group Page 31 of 34 3/30/2009

32 Aziridine ing-opening Chen 2 3 Ts 20 mol% s s K 2 C 3, 18-crown-6 50 C, air, 24 h 2 3 Ts 40-95% Wu 2 Ts 5 mol% s s TMX, TF, 23 C, h X = 3,, I 2 Ts 90-99% yield X Lewis base-catalyzed pathway proposed. Ts 2 1 s 3 i s ate: I > >> 3 = alkyl, aryl, 2 = alkyl, aryl Chen, Y.-C. et al. rg. Lett. 2006, 8, Wu, J. et al. Tetrahedron Lett. 2006, 47, ob Wipf Group Page 32 of 34 3/30/2009

33 ong Et cheidt i 2 C C-Catalysis/Initiation of ilyl Enol Ethers n-bu i 3 LB What is the Lewis base? 5 mol% n-buli TF, 0 C 0.5 mol% Ad Ad TF, 23 C, 3 h; then can be isolated i 2 Et n-bu 5 mol% i-pr i-pr i-pr C, 78 C 83% yield i-pr Et C 2 n-bu 80% 20:1 Z:E ong, J. J. et al. rg. Lett. 2007, 9, cheidt, K. A. et al. rg. Lett. 2007, 9, ob Wipf Group Page 33 of 34 3/30/2009

In Conclusion -eterocyclic carbenes are powerful reagents for the synthesis that have seen a remarkable growth in application over recent years.

34 In Conclusion -eterocyclic carbenes are powerful reagents for the synthesis that have seen a remarkable growth in application over recent years. C organocatalysis has given chemists the ability to access unusual reactivity patterns (Umpolung) along with other reactions (1,2-additions, redox, opening of small rings). ew synthetic opportunities are just beginning to be explored, along with improvements in enantioselective C catalysis. Although not covered in this discussion, it is worth mentioning that C's have also proven as valuable compounds for ring-opening polymerizations and have been utilized effectively as ligands in metal catalysis. ob Wipf Group Page 34 of 34 3/30/2009

Organocatalysis Enabled by N-Heterocyclic Carbenes

Organocatalysis Enabled by N-Heterocyclic Carbenes rganocatalysis Enabled by -eterocyclic Carbenes Acyl Anions X Y omoenolates Acylazolium Azolium enolate Base Catalysis Jiaming Li 2018/04/27 tability of -heterocyclic Carbenes 2p x,y,z p π 2p x,y,z p π