Brønsted Acids in Asymmetric Catalysis

Transcription

1 Brønsted Acids in Asymmetric Catalysis Literature eminar Jenn tockdill, toltz esearch Group 15 ovember 2004 F 3 C 2 P Tf 2 Ar Ar 2 Ar Ar

2 utline I. Introduction - Benefits of rganic Catalysts - Early Developments -- acemic Catalysts II. Catalysts in Asymmetric eactions - C Addition to Aldehydes - The trecker eaction - The Mannich eaction - The Aza-Friedel-Crafts eaction - ydrophosphination of Imines - The Acyl-Pictet-pengler eaction - The Aza-enry eaction - Michael eaction of Malonates to itroolefins - The Baylis-illman eaction - The Diels-Alder eaction P III. ummary eviews: - Pihko, P. M. Activation of Carbonyl Compounds by Double ydrogen Bonding: An Emerging Tool in Asymmetric Catalysis. Angew. Chem. Int. Ed. 2004, 43, chreiner, P.. tal-free organocatalysis through explicit hydrogen bonding interactions. Chem. oc. ev. 2003, 32, Dalko, P. I. and Moisan, L. Enantioselective rganocatalysis. Angew. Chem. Int. Ed. 2001, 40,

3

4 Double -Bonding -- on-enantioselective Catalysts X ine biphenylene diol catalyst (epoxide opening) J. rg. Chem. 1985, 50, J. rg. Chem. 1987, 52, Jorgenson model for 2 - catalyzed Diels-Alder eactions and Claisen earrangements C 8 17 C 8 17 Curran urea and thiourea catalysts (sulfoxide allylation &Claisen rearrangents) J. rg. Chem. 1994, 59, Tet. Lett. 1995, 36, J. Am. Chem. oc. 1991, 113, J. Am. Chem. oc. 1992, 114, F 3 C Kelly biphenylene diol catalyst (Diels-Alder) Tet. Lett. 1990, 31, X chreiner thiourea catalyst (Diels-Alder) Chem. oc. ev. 2003, 32, Etter Urea Catalyst (co-crystallizes) J. Am. Chem. oc. 1988, 110, Binding model for catalysis by ureas and thioureas B 4 Göbel aminopyridinium catalyst (diastereoselective Diels-Alder) J. rg. Chem. 2000, 65,

5 Asymmetric C Addition to Aldehydes C (1 eq),, 35 ºC ~2 mol% catalyst C un Time (h) % Conv % ee Inoue, et al. J. Chem. oc. Chem. Comm. 1981, C (2 eq),, -20 ºC C ~2 mol% catalyst = alkyl: 2.5-8h, 44-96% yield, 18-71% ee EDG EWG ' 8-10h 45-97% conv % ee 2.5-8h % conv. 4-53% ee ' = : 1.5h, 61% conv., 91% ee ' = : 6h, 88% conv., 73% ee 8h 60% conv. 42% ee 0.5h 73% conv. 54% ee J. rg. Chem. 1990,55,

6 ' The trecker Amino Acid ynthesis ' C ' 2 mol % catalyst C C ' solvent yield, % ee,% p-bn 97 >99 3,4,5-() 3 C 2 98 >98 2 C 95 >99 t-buc i-pr ' C 3 + ' 2 C, ' ' 6 Cl, 60 C, 6h C ' needs to be benzhydryl Lipton, et al. J. Am. Chem. oc. 1996, 118, mol % catalyst C T, ºC yield, % ee,% >99 p-cl >99 p m-cl >99 m m <10 3-pyridyl <10 2-furyl i-pr <10 t-bu

7 The trecker Amino Acid ynthesis C,, -40 C 10 mol % catalyst C C C = Aryl, 10 examples, 80-99% yield, (50) 76-88% ee = Aliphatic, 3 examples, ~95% yield, 63-84% ee C C C C Pre-transition-state assembly for aryl benzhydryl aldimines Corey, et al. rg. Lett. 1999, 1, Pre-transition-state assembly for alkyl benzhydryl aldimines

8 The trecker Amino Acid ynthesis Catalyst Identification via Parallel Library ynthesis Library 1-12 Compounds 5 M 2 2 M one Ti Mn Fe u Co Cu Zn Gd d Yb Eu % ee % conv Library 2-48 Compounds 5 Amino Acids Leu, D-Leu, is g (phenylglycine) 1 * Diamines alicylaldehydes 3 4 t-bu t-bu t-bu Br t-bu 2 t-bu t-bu Br 2 Key esults AA derived from Leu (,)-diamines matched case: L-Leu (32% ee) mismatched: D-Leu (5% ee) 3 = t-bu Jacobsen, et al. J. Am. Chem. oc. 1998, 120,

9 The trecker Amino Acid ynthesis Catalyst Identification via Parallel Library ynthesis Library Compounds Amino Acids 1 Leu, Ile, t, e, Tyr (t-bu), Val, Thr (t-bu), or (orleucine), g, Chg (Cyclohexylglycine), t-leu Diamines 2 2 alicylaldehydes t-bu,, Br, Key esults AA = t-leu Diamine = cyclohexyl alicylaldehyde = ptimized Catalyst 1) C,, -78 C 2 mol % catalyst 2) TFAA F 3 C C yield, % ee,% p p-br naphthyl t-butyl cyclohexyl Jacobsen, et al. J. Am. Chem. oc. 1998, 120,

10 The trecker Amino Acid ynthesis A General Catalyst for Aldimines 1 1) C,, -70 C 2 mol % catalyst, 20h 2) TFAA F 3 C 1 C % yield % ee C 6 5 allyl t-butyl allyl (91) p- allyl m- allyl o- allyl p- allyl m- allyl o- allyl p-br allyl m-br allyl o-br, 36h allyl p-t-bu allyl cyclooctyl allyl cyclohexyl allyl cyclohexyl benzyl t-butyl benzyl (93) 1-cyclohexenyl benzyl (87) neopentyl benzyl (87) pentyl benzyl i-propyl benzyl cyclopropyl benzyl C t-bu t-bu Preparative reactions using resin-bound catalyst 1) 4 mol % catalyst C,, -78 C, 15h 2) Ac 2, C t-bu 10 cycles of catalyst, yield 96-98% each time, 92-93% ee each time C >99%ee (recrystallized) 1) 65% (w/v) C, 20h, 99% t-bu 2) Cl (conc.), 70 C, 12h 3) 2, Pd/C,, quant. C 2 Cl >99% ee 84% overall yield Jacobsen, et al. Angew. Chem. Int. Ed. 2000, 39,

11 The trecker Amino Acid ynthesis Also a General Catalyst for Ketoimines mol % catalyst C, -75 C 1 2 C 1 2 time, h % yield % ee Et naphthyl C 2 C mol % catalyst C, -75 C C time, h % yield % ee p p-br 80 quant 93 (76) (>99.9) p quant 93 (79) (>99.9) p p- 65 quant 95 (75) (>99.9) m-br o-br t-butyl C =, 90% ee =Br, >99.9% ee conc. Cl 105 C 2 Cl C, Ac 2 C 2 =, 97% yield =Br, 98% yield C =, 97% yield =Br, 98% yield 2, Pd/C aq. /Cl quant. =, 92% overall yield, 90-91% ee =Br, 93% overall yield, >99.9% ee Jacobsen, et al. rg. Lett. 2000, 2,

12

13 1 The trecker Amino Acid ynthesis Mode of Action for Jacobsen Catalyst Can face selectivity be altered by amino acid bulk? Previous problem substrates Previous good substrates 1) 1 mol % catalyst C,, -78 C F 3 C 2) TFAA C 2 3 X % ee 80.0 Bn Bn 93.5 Bn Bn ) 1 mol % catalyst C,, -78 C F 3 C catalyst = original % ee 80 i-pr n-pent 79 t-bu 70 p-br 92 t-bu C = new % ee X Jacobsen, et al. J. Am. Chem. oc. 2002, 124,

14 TM Boc The Mannich eaction 10 mol% catalyst Boc, 23 C 1 X X time, h % conv % ee C(t-Bu) C(t-Bu) i-pr TB Boc 1) 5 mol% catalyst X=, 1 =, 2 =t-bu, 23 C i-pr 2) TFA, 2 min Boc Et TB 1 Boc 2 1) 5 mol% catalyst X=,, 23 C 2) TFA, 2 min temp, C time, h Boc % conv % ee C(t-Bu) C(t-Bu) i-pr C(t-Bu) i-pr C(t-Bu) t-bu C(t-Bu) o- temp, C time, h % yield % ee m p p p-f m-br p-br 1-naphthyl 2-naphthyl 2-furyl 2-thienyl 3-quinolinyl 3-pyridyl Jacobsen, et al. J. Am. Chem. oc. 2002, 124,

15 The Mannich eaction chanism of tereoinduction for Jacobsen Catalyst -- ame as trecker eaction? Aldimines for trecker and Mannich reactions differ electronically and sterically. ucleophiles are also sterically and electronically different. TB C i-pr eference eactions for tructure-activity tudies: Modifications tested: - Amide bond and urea functionalities - Amino acid - alicylaldimine - Diamine linker trecker eaction: C Mannich eaction: 1) 1 mol% catalyst, -65 C, 20h 2) TFAA F 3 C C 98% ee 100% conv. Boc TB i-pr 1) 5 mol% catalyst, -40 C, 48h 2) TFA, 2 min Boc i-pr 97% ee 96% conv. Jacobsen, et al. ynlett 2003,

16 The Mannich eaction chanism of tereoinduction -- Amide Bond, Urea, and Amino Acid Influence trecker Mannich 1 2 X Y % ee % ee Bn Bn Bn Bn Bn Bn Bn i-bu i-bu Cy Bn Thiourea enhances enantioselectivity for both reactions; effect is more dramatic for Mannich reaction. - Tertiary amides provided better selectivity than secondary amides, again, more dramatic for Mannich. - Esters are not acceptable replacements for amides. - For the trecker reaction, the sterically smaller,-dimethyl amide catalyst was better than the sterically larger,-diisobutyl amide. The opposite was true for the Mannich reaction. 1 2 X Y trecker Mannich % ee % ee i-pr (L-Val) (L-Ala) (L-g) C 2 (D-2-amino-3-methyl -3-phenylbutyric acid) For the Mannich reaction, the amino acid identity is integral to the efficacy of the catalyst. Bulky amino acids are essential, but increasing the bulk too much also lowers the enantioselectivity somewhat. - The trecker reaction is not significantly altered by the amino acid size. Jacobsen, et al. ynlett 2003,

17 The Mannich eaction chanism of tereoinduction -- alicylaldimine and Diamine Influences trecker Mannich % ee % ee t-bu t-bu i-pr t-bu t-bu t-bu t-bu hydroxy-2-naphthyl (98) in TF The trecker reactionwas largely insensitive to changes in 2, but altering 3 resulted in significant drops in ee. (ecall the original catalyst gave an ee of 98% where 2 = t-bu and 3 = Ct-Bu). - The identity of the 2 group was inconsequential for the Mannich reaction, as was the 3 group (original catalyst gave an ee of 97%). trecker Mannich 1 2 configuration % ee % ee (,) t-bu t-bu (,) -(C 2 ) 4 - (,) 27() The trecker reaction tolerates substitution of the (,)-cyclohexyl unit with an (,) diphenylethylene, but it does not tolerate further increase in steric bulk or the mismatched (,) cyclohexyl unit. - The Mannich reaction suffers from replacement of the cyclohexyl unit by the diphenylethylene and is also unreactive with the bulky diamine. owever, reversing the configuration of the diamine is well-tolerated and, interestingly, provides the same sense of stereoinduction in high ee. Jacobsen, et al. ynlett 2003,

18 The Mannich eaction implified Catalysts Based on tructure-chanism tudies Boc TB 1) 5 mol% catalyst, -40 C, 48h Boc i-pr 2) TFA, 2 min i-pr 97% ee 96% conv. t-bu t-bu t-bu t-bu 37% ee 42% conv. 90% ee 90% conv. 94% ee 100% conv. (in TF) - chiff base and diamine linker are unnecessary for the efficient catalysis of the Mannich reaction. - The C 2 -symmetric catalyst is ineffective, perhaps due to the significant increase in bulk in the right half of the compound. - eturning to a C 1 -symmetric compound revives catalytic activity. - Further modification of the cyclohexyl ring to a phenyl ring brings the ee nearly to the original catalyst ee, accompanied by an increase in conversion. Jacobsen, et al. ynlett 2003,

19 The Mannich eaction TM 30 mol% catalyst, -78 C time, h % yield % ee ,4, C 2 P 2 P Ar 1 2 Akiyama, et al. Angew. Chem. Int. Ed. 2004, 43, TM 30 mol% catalyst, -78 C 1 C % yield syn/anti % ee syn a Et :13 96 p- a Et :8 88 p-f a Et :9 84 p-cl a Et :14 83 p- a Et : thienyl a Et 81 94:6 88 styrenyl a Et 91 95:5 90 Bn a Et :7 91 p- Bn Et 92 93:7 87 styrenyl Bn a Et 65 95: i b :0 91 C 2 a E/Z=87:13 b E/Z=91:9

20 The Mannich eaction Boc 2 mol% catalyst 1.1 eq acac, C 2 Cl 2 T, 1h Boc Ac % yield % ee a biphenyl (β-naph) Ac P a opposite enantiomer Boc 2 mol% catalyst 1.1 eq acac, C 2 Cl 2 T, 1h Boc Ac Ac % yield % ee syn p p p-br p-f o naphthyl P Terada, et al. J. Am. Chem. oc. 2004, 126,

21 Aza-Friedel-Crafts Alkylation of Furan Boc Boc 2 mol% catalyst solvent, 20h olvent, = temp, C % yield % ee TF i-pr Cl CCl C 2 Cl (CCl 2 ) (C 2 Cl) (C 2 Cl) (C 2 Cl) P (DCE, -35 C, 24h) % yield % ee p o m p o-br m-br p-br p-cl p-f naphthyl naphthyl furyl Boc B, ac 3 Et 2 / 2, 0 C 30 min, 90% 97% ee Aza-Achmatowicz CeCl 3 7 2, ab 4, -78 C --> T 5h, 95% Boc Boc Terada, et al. J. Am. Chem. oc. 2004, 126, syn/anti = 85:15 96% ee syn

22 1 P ydrophosphonylation of Imines time, h 1 % conv 100 % ee 77 3-pentyl * C * 3-pentyl * 2-cyanoethyl pentyl chloroethyl pentyl methoxyethyl pentyl p-nitrobenzyl pentyl o-nitrobenzyl pentyl Jacobsen, et al. J. Am. Chem. oc. 2004, 126, mol% catalyst, 23 C 1 P 1 Bn 2 10 mol% catalyst B P B P 2 B B Et 2 Bn temp, C time, h % yield % ee pentyl i-pr Cy t-bu C=C (64) 82 (99) p p-c o o-cl m-cl p-cl naphthyl pyridyl furyl thienyl pyrrolyl B P B Bn 2 = (98% ee) = 3-pentyl (96% ee) = 2 C=C- (99% ee) p 2 (1 atm) Pd/C (20 mol%), 24-72h 23 C P 2 2 = (87% yield, 97% ee) = 3-pentyl (89% yield, 96% ee) = i-bu [()-Leu P ] (93% yield, 98% ee)

23 The Acyl-Pictet-pengler eaction - Pictet-pengler imine substrates are fairly unreactive; normally strong Brønsted acids, naked Lewis acids or high temperatures are required to promote the reaction. - All compounds initially tested were unreactive unless at high temps. - o ee was observed due to the temps required. - Activate the substrate? --> Acyl-Pictet pengler Catalyst ptimization eaction: AcCl, 2,6-lutidine 10 mol% catalyst Et 2, -78 C --> -30 C Ac 65% yield, 59% ee 2 1) 1 C (1.05 eq) 3Å M or a 2 4 2) AcCl, 2,6-lutidine a 5 - b 10 mol% catalyst Et 2, -78 C --> T C C(C 2 C 3 ) 2 T, C -30 % yield 65 a % ee 93 C(C 3 ) b 85 n-pentyl b 95 C 2 C(C 3 ) b 93 C 2 C 2 TB b C(C 2 C 3 ) a C(C 2 C 3 ) b 86 1 Jacobsen, et al. J. Am. Chem. oc. 2004, 126, Ac 45% yield, 61% ee t-bu 1 2 = 1 = 2 = : 65% yield, 77% ee =, 1 = 2 = : 55% yield, 71% ee = 1 =, 2 = : 70% yield, 93% ee = i-bu, 1 =, 2 = : 70% yield, 93% ee

24 1 The Aza-enry eaction Boc Boc 2 10 mol% catalyst -20 C % yield dr % ee p m Tf 69 14:1 59 p :1 81 p-cl 59 17:1 82 m :1 89 o :1 82 p :1 84 p :1 90 Johnston, et al. J. Am. Chem. oc. 2004, 126, F 3 C Takemoto, et al. rg. Lett. 2004, 6, P mol% catalyst C 2 Cl 2, T 1 P % yield 87 dr -- % ee 67 p p-cl naphthyl furyl pyridyl thienyl cinnamyl :

25 The Michael eaction of Malonates to itroolefins 2 10 mol% catalyst, T Et 2 C C 2 Et 2 F 3 C Et 2 C C 2 Et (2 equiv) F 3 C Ac F 3 C Ar 24h, 86% yield, 93% ee +TEA: 24h, 57% yield, 0% ee 24h, 14%yield, 35% ee 1 2 Ar = 3,5-( ) 2, 1 = 2 = o-(c 2 ) 2 48h, 29% yield, 91% ee Ar = 3,5-( ) 2, 1 =, 2 = i-pr 48h, 76% yield, 87% ee Ar =, 1 = 2 = 48h, 58% yield, 80% ee Ar = 2-, 1 = 2 = 48h, 40% yield, 52% ee mol% catalyst, T 2 C C C C 2 2 (2 equiv) time, h % yield % ee Et () 2,6 - () 2 Et () p-f 1-naphthyl Et Et () 92 (-) 2-thienyl Et (-) pentyl Et () i-bu Et () () Takemoto, et al. J. Am. Chem. oc. 2003, 125,

26 The Michael eaction of Malonates to itroolefins 10 mol% Q or QD TF, -20 C 2 Et 2 C C 2 Et (3 equiv) Et 2 C * C 2 Et 2 Q QD time, h (QD) % yield (QD) % ee (QD) p-f p-cl p-br 36 (36) 36 (36) 36 (36) 36 (36) 97 (99) 97 (97) 97 (97) 99 (98) 96 (93) 97 (94) 97 (94) 96 (94) p- 36 (44) 97 (97) 98 (94) p-(i-pr) 36 (39) 95 (96) 97 (93) p- 44 (47) 90 (94) 97 (95) m- 36 (36) 97 (99) 98 (96) o- 36 (36) 95 (97) 98 (96) o-f o- 2 1-naphthyl 36 (36) 69 (72) 36 (36) 97 (94) 90 (88) 99 (99) 97 (95) 97 (92) 98 (92) 2-thienyl 36 (44) 99 (96) 98 (95) 2-furyl 36 (36) 97 (95) 98 (96) 3-pyridinyl 36 (36) 98 (99) 96 (92) pentyl 72 (72) 86 (84) 94 (92) i-bu 72 (72) 86 (84) cyclohexyl 108 (108) 71 (80) 94 (92) 94 (91) Deng, et al. J. Am. Chem. oc. 2004, 126,

27 The Baylis-illman eaction F 3 C - Achiral reaction experiences a 60-fold increase in rate upon addition of the achiral thiourea catalyst. - M experiments indicate that the catalyst interacts with both the enone and the aldehyde. - Asymmetric catalyst was designed based on idea for one catalyst to bind to both reaction partners at once, allowing for further rate increase by proximity effects. F 3 C 3 40 mol% catalyst cyclohexenone (2 eq) 40 mol% base F 3 C F 3 C Proposed Transition tate Base temp, C time, h % yield % ee DMAP Imid -5 T o- m- DMAP DMAP p- DMAP Imid (C 2 ) 2 DMAP hexyl DMAP i-pr DMAP cyclopentyl DMAP cyclohexyl DMAP Base screen indicated that DMAP provides the best yields and imidazole provided the highest ee. - Aromatic aldehydes -- low ee, generally higher yields - Aliphatic aldehydes -- higher ee, generally lower yields agasawa et al. Tet. Lett. 2004, 45,

28 The Morita-Baylis-illman eaction Catalyst creen: 1 = C 2 C 2, 2 mol% catalyst, PEt 3, TF, 0 C Br % yield 0% ee 43% yield 3% ee 15% yield 3% ee Br 1 10 mol% catalyst PEt 3, TF, -10 C % yield % ee Bn C =, 73% yield, 48% ee = Br, 73% yield, 79% ee =, 69% yield, 86% ee = 70% yield, 88% ee cyclohexyl i-propyl C C = = C phenyl % yield, 31% ee 84% yield, 86% ee chaus, et al. J. Am. Chem. oc. 2003, 125, C

29 The Diels-Alder eaction Key ources of Inspiration: - Double -bonding in urea catalysts (as already discussed) - uccess of BIL catalysts (already discussed) - Diels-Alder catalysis acheived by Göbel et. al. (rg. Lett. 2000, 2, ) - olvent-acccelerated hetero-diels-alder reactions. (J. Am. Chem. oc. 2002, 124, ) Göbel (Best esult): awal's solvent-acccelerated hetero-diels-alder reactions: TB 2 (1 equiv), C 2 Cl 2, -27 C d-solvent, T TB 94% yield, 3.2:1 dr 43% ee major, -50% ee minor Ar olvent dielectric constant TF-d benzene-d AC-d CDCl t-butyl alcohol-d i-propyl alcohol-d relative rate awal, et al. Proc. at. Acad. ci. 2004, 101, ature, 2003, 424, 146.

30 TB The Diels-Alder eaction 20 mol% TADDL catalyst Ar = 1-napthyl, -78 or -40 C TB AcCl C 2 Cl 2 / -78 C, 15 min Ar Ar Ar Ar - First highly enantioselective -bond catalyzed cycloadditon - Yields 52-97%, aliphatic 83% ee, aromatic 95% ee TB 1 20 mol% TADDL catalyst TB C 1 1) LA, Et 2-78 C --> T, 2h 2) F/AC 0 C --> T, 0.5h 1 Ar time temp, C % yield % ee phenyl 2 d naphthyl 2 d naphthyl 2 d naphthyl 15 min naphthyl 6 h naphthyl 1 d naphthyl 1 d naphthyl 2 d naphthyl 2 d naphthyl 2 d Et 1-naphthyl 2 d i-pr 1-naphthyl 2 d Bn 1-naphthyl 2 d C 2 C 2 TB 1-naphthyl 2 d awal, et al. Proc. at. Acad. ci. 2004, 101, and ature, 2003, 424,

31 ummary - By utilizing double hydrogen-bonding, chiral organic catalysts can accomplish rotational control and organized transition states. - Brønsted acids are unique as catalysts because of their ability to readily dissociate from the product, allowing catalyst turnover without any parallel catalyst pathways. - Because there is no need to coordinate to a metal center, only to the compound itself, the scope of novel catalysts that could be developed is expansive, and catalysts can be more readily optimized for a specific reaction, if the need arises. - With no metal center, the chiral framework also has the opportunity to be closer to the reacting center than with Lewis acid catalysts. - A variety of well-known reactions have been cayalyzed asymmetrically using Brønsted acid catalysts that serve as hydrogen-bond donors. They include C addition to aldehydes, the trecker reaction, the Mannich reaction, the Aza-Friedel-Crafts reaction, hydrophosphination of imines, the acyl-pictet-pengler reaction, the Aza-enry reaction, Michael eaction of malonates to nitroolefins, the Baylis-illman reaction and its Morita modification, and hetero- and all-carbon Diels-Alder reactions. "ydrogen bonding by a simple chiral alcohol to a carbonyl group can accomplish what has previously been considered to be in the domain of enzymes, catalytic antibodies and chiral metal-based Lewis acids. These studies indicate the broad potential for hydrogen-bond catalysis in asymmetric synthesis." ~ V.. awal

32

33

34