Organocatalysis with N-Heterocyclic Carbenes Frontiers of Chemistry Robert B. Lettan II March 28th, 2009 Key References: Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606-5655. Marion, N.; Díez-González, S.; Nolan, S. P. Angew. Chem. Int. Ed. 2007, 46, 2988-3000. Johnson, J. S. Curr. Opinion Drug. Discov. Develop. 2007, 10, 691-703. Rob Lettan @ Wipf Group Page 1 of 34 3/30/2009 Thiamine-Dependent Enzymes NH 2 Me N OR Thiamine: R = H N 3— TPP: R = P2O6 S Me N H 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. Mechanism of pyruvate decarboxylase (PDC) Me Me N Me N OR HO N N pyruvate Me S —CO2 Me NH2 S Me H O O N N HO S H S Me N Me Me carbene Me H N OR ylide N N O H S NH H Me S Me H All 3 nitrogens on aminopyridine ring OH involved in hydrogen binding to enzyme. Jordan, F. Nat. Prod. Rep. 2003, 20, 184-201. Rob Lettan @ Wipf Group Page 2 of 34 3/30/2009 Thiamine-Dependent Enzymes Rob Lettan @ Wipf Group Page 3 of 34 3/30/2009 Thiamine-Dependent Enzymes Mechanism of pyruvate dehydrogenase (E1) Me Me N Me pyruvate N N N HO —CO2 S NH2 S E1 Me carbene ylide S S H N E2 O SH H O FADH2 NAD N lipoamide Me S E2 O E3 SH H FAD NADH CoASH N E2 HS E2 O O Krebs cycle How can nature’s Umpolung method cellular Me SCoA of bond-formation be applied to synthesis? respiration Acetyl-CoA Leeper, F. J. et al. Biochem. Soc. Trans. 2005, 33, 772. Rob Lettan @ Wipf Group Page 4 of 34 3/30/2009 Persistent Carbene A "stable" carbene that is a reactive intermediate. 1943: Ugai Recognized that thiamine can be used as a catalyst for the benzoin condensation. 1957: Breslow Br H Br D D2O, 28 °C Me Me Me N S N S N S t1/2 ~ 20 min Me Me Me Me Me Me 1960: Wanzlick 1964: Lemal Lemal ruled out dimerization H CCl through cross-over exp. Ph Ph 3 150 °C N N HCl Ph Ph Ph Ph N N N N X N N —HCCl3 Ph Ph H X Ph Ph X H HCl N N Ph Ph N N 1970: Wanzlick N N Ph Ph H Ph Ph ClO4 N N NPh Ph Ph tBuOK PhNCS N N N N S Ugai, T. et al. J. Pharm. Soc. Jpn. 1943, 63, 296. Ph Ph Breslow, R. J. Am. Chem. Soc. 1957, 79, 1762. Wanzlick, H. W. Angew. Chem. Int. Ed. Engl. 1962, 1, 75. increased Lemal, D. M. et al. J. Am. Chem. Soc. 1964, 86, 2518. stabilization Wanzlick, H. W. et al. Liebigs Ann. Chem. 1970, 731, 176. Rob Lettan @ Wipf Group Page 5 of 34 3/30/2009 Isolated Carbenes 1991: Arduengo H NaH, THF, cat. DMSO, RT N N 2 isolated crystal structure 3N N1 4 5 Cl Bond angles: N1-C2-N3 = 102.2 ° (imid = 109 °). In agreement with theoretical studies on singlet (1A') carbenes bearing !"donor substituents. Change in !-delocalization supported by upfield shift of imidazole ring protons (7.92 6.91). 13 C NMR of C2: # = 211 ppm No dimerization. Some other isolated N-heterocyclic carbenes by Arduengo Me Me Me Me Me Me 1997 N N Me Me Me Me N N !C = 220 ppm N N Me Me N-C-N angle = 102 ° Cl Cl Me Me Air Stable Me Me 1992 1995 !C = 214 ppm !C = 245 ppm i-Pr N-C-N angle = 102 ° N-C-N angle = 105 ° 1997 ! = 254 ppm Less hindered cyclic diamino carbene N S C tetramethyl-imidazol-2-ylidene dimesityl N-C-N angle = 104 ° i-Pr Me Me thiazolium carbene No dimerization suggests this is also stable due to electronic stabilization. Arduengo, A. J., et al. J. Am. Chem. Soc. 1991, 113, 361. Rob Lettan @ Wipf Group Page 6 of 34 3/30/2009 Carbene Stability Carbene Stability ! Singlet Character ! Electron Donation into ca. –87 kcal/mol Vacant p-Orbital of Carbene H H R R ca. –6 kcal/mol N N R R ca. –20 kcal/mol R R N N Electron donating groups promote more stable singlet carbene R R Ph Ph N N N N N Ph Further stabilized by aromatization. Does not dimerize. NaH, N H N DMSO N N Electron lone pairs in close proximity. Repulsive electrostatic interactions would have a N H N N N significant destabilzing effect. Herrmann, W. A.; Kocher, C. Angew. Chem. Ind. Ed., Engl. 1997, 36, 2162. Rob Lettan @ Wipf Group Page 7 of 34 3/30/2009 Preparation of Stable Carbenes Deprotonation W X Y Z a R2 N CR3 CR4 H Base b — S CR2 CR4 R1 W R1 W N X N X c R2 N N CR3 Y Z Y Z 2 d R N CH2 CH2 2 e R N CH2 C2H4 H NHC formation caveats: pKa = 24 (DMSO) i-Pr i-Pr — strongly basic N N — react with oxygen — their imidazole precursor's are susceptible to nucleophilic attack — sometimes difficult to isolate free carbene from metal ions used to prepare Me Me Bases: Metal hydrides: Work, but often sluggish due to relative insolubilitiy in suitable solvents (THF) Catalysts (DMSO, t-BuOH) improve solubility and reactivity, but ineffective for non-imidazolium adducts due to nucleophilicity. Must avoid hydroxide, especially with non-aromatic salts. KOt-Bu: Has been shown to be effective. Alkyllithiums: Unreliable. n-BuLi and PhLi can act as nucelophiles, t-BuLi can act as a hydride donor. Lithium Amides: LDA and LiTMP work well, if not too much LiOH in n-BuLi during preparation. Metal hexamethyldisilazides: Works very well for the most part. Alder, R. W., et al. J. Chem. Soc., Chem. Commun., 1995, 1267. Rob Lettan @ Wipf Group Page 8 of 34 3/30/2009 Preparation of Stable Carbenes Some Other Methods AgCl2 R R N N 40 - 100 °C R N Ag N R N N R R H X R 40 - 100 °C R N N N R N R X = C6F5, CF3, CCl3 H 80 °C, 0.1 mbar; Ph OMe Ph N toluene, ! N N Ph N Ph Ph N quant. Ph N X = N, CH2; R' = alkyl Me Me N K, THF, Me ! N S N Me N Me Me Me Me Nolan, S. P. N-Heterocyclic Carbenes in Synthesis, Wiley -VCH & Co., 2006. Rob Lettan @ Wipf Group Page 9 of 34 3/30/2009 NHC/Umpolung Reactivity O OH O OH O O aldol Me Me Me Me Me H Me Normal Polarity O O O O O O Michael Me Me Me Me Me Me O O OH O O Me benzoin Me Me Me Me H H Me (+ catalyst) Inverted OH Polarity O O O O O Me Stetter Me Me Me Me H Me O (+ catalyst) NHC Catalyzed Umpolung Reactions Additional NHC Catalyzed Reactions benzoin condensation Stetter reaction transesterification hydroacylations - oxidation acylation of aryl flourides - polymerization nucleophilic substitution ring-opening reactions homoenolate reactivity 1,2-additions - cross condensations - Diels-Alder reaction Seebach, D. Angew. Chem. Int. Ed., Engl. 1979, 18, 239. - Heck-type cyclizations Johnson, J. S. Curr. Opin. Drug Disc. Dev. 2007, 10, 691. Rob Lettan @ Wipf Group Page 10 of 34 3/30/2009 Benzoin Condensation Breslow Mechanism O Me N Me Ph H Me base N N N Me S NH S 2 H OH N thiamine carbene H thiamine S O Ph HO Ph Me Ph Me O HO N benzoin N S Ph HO O S Ph Me Ph O N O Ph S Ph H HO Ph Ugai, T. et al. J. Pharm. Soc. Jpn. 1943, 63, 296. Breslow, R. J. Am. Chem. Soc. 1957, 79, 1762. Rob Lettan @ Wipf Group Page 11 of 34 3/30/2009 Asymmetric Benzoin Enders BF4 N N N O Me Me Me O (10 mol%) Ar ArCHO Ar KOt-Bu, THF OH 0 or 18 °C 8-83% yield 80-95% ee J. You O 1 mol% A or B Ph A: 27%, 88% ee 2 PhCHO Ph KOt-Bu, B: 95%, 95% ee THF, 23 °C OH Cl Cl N N N N N N O N O N N O DFT calculations show B has a larger conjugation interaction over mono-triazolyldine A. A Enders, D.; Kallfass, U. Ang. Chem. Int. Ed. 2002, 41, 1743. B You, J. et al. Adv. Synth. Catal. 2008, 350, 2645. Rob Lettan @ Wipf Group Page 12 of 34 3/30/2009 Crossed Benzoin Et Inoue N S O O O (10 mol%) OH 64-100% selectivity R R H H H R = Me, Et, n-Pr, i-Pr, Cy, Ph, 2-furyl Müller: enzymatic BAL, ThDP, Mg2+, KPi buffer, O O O 2 1 DMSO, 30 °C Ar must be a better electron acceptor that Ar . Ar2 1 conversion, selectivity, ee up to > 99% Ar1 H Ar2 H Ar OH BAL = benzaldehyde lyase ThDP = thiamine diphosphate Johnson: metallophosphite catalyzed Ar = 2-FPh Ar Ar CHO OMe O O O 5 mol% A, O Me O n-BuLi (20 mol%) P 87% yield Me H Ph SiEt Ph 91% ee O O 3 THF, 30 min Ar Ar OSiEt3 A OMe via a Brook rearrangement pathway Inoue, S. et al. J. Org. Chem. 1985, 50, 603. Müller, M. et al. J. Am. Chem. Soc.