Mechanism Problem. 1. NaH allyl bromide, THF N H

Transcription

1 Mechanism Problem 1. a allyl bromide, TF 2. 9-BB (1.2 equiv), TF, rt; ame (1.2 equiv); t-buli (2.4 equiv), TMEDA (2.4 equiv) 30 to rt; allyl bromide; 30% 2 2, aq. a, 0 C (58% yield)

2 Mechanism Problem 9-BB Me B 2 t-bu Me B 2 Li Me B 2 Br B 2 B 2 alkyl migration B 2 2 B B Terashima, TL 1992, 33,

3 Enantioselection by C 1 -Symmetric Ligands Design and Applications in Asymmetric Catalysis Boram ong Stoltz Group January 10, 2011

4 Privileged Ligand Structures Prevalence of C 2 -symmetry P P BIL ( = ) BIAP ( = P 2 ) Duos BX TADDL Me Et Et Me SALE Cinchona alkaloid Diverse applications: Diels-Alder, hydrogenation, Mukaiyama aldol, conjugate additions, cyclopropanation, epoxidation Jacbosen, Science 2003, 299,

5 First C 2 -symmetric ligands DIP & DIPAMP Kagan's DIP Ligand conformations must have maximum rigidity Ligands must stay firmly bonded to the metal Avoid competing, diastereomeric transition states via C 2 -symmetry 2 P P 2 DIP CMe [h(cyclooctene) 2 ] 2 C DIP, 2 Et/ CMe C (95% yield) 72% ee Knowles' DIPAMP Me Me C h(i) DIPAMP Me * C P P Ac Ac 2 Ac Ac Me 95% ee DIPAMP Kagan, J. Am. Chem. Soc. 1972, 94, Knowles, Adv. Synth. Catal. 2003, 345, 3-13.

6 ational Design of C 1 -symmetric Bisphosphine Ligand Electronic and Steric Asymmetry Mechanism of asymmetric hydrogenation of dehydroamino acids reported by alpern xidative addition of 2 is rate-determining step Important interactions: occupied d yz of h and σ* of hydrogen d-π* back-donation from h to olefin P cis 1 * h 2 C P trans P cis : steric control (enantioselection) P trans : electronic control Distinct roles; need to optimize each phosphine group individually Achiwa, Synlett 1992,

7 Electronic Desymmetrization Controlling egioselectivity Faller studied nucleophilic addition reactions on unsaturated ligands bound to Mo Mo C Mo C endo isomer exo isomer preferred Mo C Mo C 95% regioselectivity Mo C Mo C Mo C not observed Faller, J. Am. Chem. Soc. 1984, 3,

8 ational Design of C 1 -Symmetric Bisphosphine Ligand Electronic and Steric Asymmetry 2 P Cy 2 P C 2 t-bu P 2 BPPM (2S, 4S)--butoxycarbonyl-4-diphenylphosphino-2- diphenylphosphinomethylpyrrolidine P 2 C 2 t-bu BCPM CMe C h(i), BPPM Et 3, 2 Et * CMe C 91% ee t-bu 2 C 2 P P 2 h C C h(i), BCPM * C C Et 3, 2 Me C 92% ee Achiwa, J. Am. Chem. Soc. 1976, 98, Achiwa, Synlett 1992,

9 ational Design of C 1 -Symmetric Bisphosphine Ligand Electronic and Steric Asymmetry Cy 2 P CMe C h(i), BCPM 2 Et CMe P 2 * C C 2 t-bu 37% ee BCPM CMe C h(i), MD-BPPM 2 Et * CMe C 99% ee Ar 2 P cis (enantioselecting function) steric effect of m-methyl groups Me PAr 2 C 2 t-bu MD-BPPM Ar= Me trans (rate-acceleration) electron-donating effect Me Achiwa, Synlett 1992,

10 ational Design of C 1 -Symmetric Bisphosphine Ligand Development of Modified DIP ligand 2 P P 2 DIP 2 P PCy 2 DICP h(i), DIP 2 TF * 52% ee activity and enantioselectivity of catalyst enhanced by desymmetrization of DIP h(i), DICP 2 TF * 75% ee Achiwa, Synlett 1992,

11 From C 2 -Symmetric to onsymmetrical Ligands C BX to PX Semicorrins BX Ac Me 2 C C 2 Me [(C 3 5 )] 2 (1 mol%) L* (2.5 mol%) * Ligand Conditions % yield % ee ac(c 2 Me) 2, TF, 50 C C 2 (C 2 Me) 2, BSA, KAc C 2 2, 23 C " " = SiMe 2 t-bu Pfaltz, Acc. Chem. es. 1993, 26,

12 From C 2 -Symmetric to onsymmetrical Ligands BX to PX u u = benzyl u - u u steric repulsion between allylic phenyl group and benzyl substituent nucleophile attacks the longer, more strained C bond: strain release Pfaltz, Acc. Chem. es. 1993, 26,

13 Controlling egioselectivity via Electronic Differentiation PX BX 2 P PX Desymmetrize,-ligand to mixed donor P,-ligand "soft" P-ligand (π acceptor) and "hard" -ligand (σ donor) exploit trans influence of P atom Ac Me 2 C C 2 Me [(C 3 5 )] 2 (1 mol%) L* (2.5 mol%) ac(c 2 Me) 2 * 98.5% ee Ac Me 2 C C 2 Me [(C 3 5 )] 2 (1 mol%) L* (2.5 mol%) ac(c 2 Me) 2 * 94% ee Pfaltz, Proc. atl. Acad. Sci. 2004, 101, Pfaltz, Acc. Chem. es. 2000, 33,

14 Controlling egioselectivity via Electronic Differentiation PX exo P 9 : 1 P endo u - high exo/endo selectivity through sterics enantioselectivity controlled by electronics (trans influence guides regioselectivity) P E E E E Pfaltz, Acc. Chem. es. 2000, 33,

15 Controlling egioselectivity via Electronic Differentiation Cyclic substrates PX u - P C C Mn C 3 CC CC 3 95% ee onsymmetrical substrates A B A B P X X P X X u - Ac u - [L*] u - = ac(c 2 Me) 2 u * : : : 16 2 u L = t-bu 94% ee ( = phenyl) 98% ee ( = 1-naphthyl) Ts P Ts Usually complexes favor linear products More cationic and bulky phosphine favors branched products Pfaltz, Acc. Chem. es. 2000, 33,

16 C 2 -Symmetric,-ligands Sulfoximines Br Br 5 equiv S Me 2 dba 3 (4 mol%) rac-biap (8 mol%) at-bu, toluene 135 C, 10 h Me S Me S (70% yield) (S,S)-1 BiSX Et (S,S)-1 (5 mol%) Cu(Tf) 2 (5 mol%) MS 4 Å, C 2 2 C 2 Et 98% ee endo:exo 99:1 (81% yield) Et Et (S,S)-1 (5 mol%) Cu(Tf) 2 (5 mol%) MS 4 Å, C C C 2 Et C 2 Et 98% ee (92% yield) Bolm, J. Am. Chem. Soc. 2001, 123,

17 From C 2 - to C 1 -Symmetric Sulfoximines Spectroscopic investigations of BiSX Cu(II) complexes revealed distorted, nonsymmetric square pyramidal geometry Two coordinating sulfoximine nitrogens occupy non-equivalent positions 2 dba 3 (5 mol%) rac-biap (10 mol%) 1 S 2 Br 3 Cs 2 C 3, toluene 110 C, 20 h 1 S 2 3 Et Ligand Cu(Tf) 2 C 2 2, rt C 2 Et entry ligand % yield %ee endo:exo :1 98:2 Me S Me S Me S Me 3* 2 65 *with Cu( 4 ) 2, 10 C 96 99:1 (S,S)-1 BiSX ()-2 Bolm, J. Am. Chem. Soc. 2003, 125, Bolm, Chem. Commun. 2003,

18 From C 2 - to C 1 -Symmetric Sulfoximines Mechanistic Model S Me Cu vs S Me Cu A favored Enantioselectivity of the reaction is determined by the coordination mode of substrate B Me S t-bu S Me 75% ee 0% ee Bolm, Chem. Commun. 2003,

19 C 1 -Symmetric P,-ligand in Enyne Cyclization E [(MeC) 4 ](BF 4 ) 2 (5 mol%) Ligand (10 mol%) E X C (1 equiv) DMS, 80 C X X = C(C 2 Et) 2, E = CMe 2 ligand time % yield % ee 1 3 >99 6 config. S PAr 2 PAr 2 P 2 t-bu S >99 86 S P 2 t-bu P C 1 symmetry yields better enantioselectivities than C 2 symmetry Sense of chirality does does not matter Mikami, Eur. J. rg. Chem. 2003,

20 C 1 -Symmetric P,-ligand in Enyne Cyclization X-ray analyses reveals: ational Design of ptimized Ligand IV * I less hindered little difference P X X P 2 III II hindered 5 E [(MeC) 4 ](BF 4 ) 2 (5 mol%) Ligand 5 (10 mol%) E X C (1 equiv) DMS, 80 C X X = C(C 2 Et) 2, E = CMe 2 (>99% yield) 95% ee previous best 86% ee (with t-bu ligand) Mikami, Eur. J. rg. Chem. 2003,

21 C 1 -Symmetric P,-ligand in Enyne Cyclization Transition State Analysis IV I IV I Me 2 P * X P * X III II III II Me 2 A B favored Steric factors: A: steric repulsion between terminal Me groups of substrate and dimethyl substituents of oxazoline B: terminal akenyl Me groups cannot fully differentitate the two groups Electronic factor: π-coordination of olefin trans to P is favored (trans influence) Mikami, Eur. J. rg. Chem. 2003,

22 Asymmetric Cyclopropanation of lefins with Diazoacetates PyBX u 2 / 2 2 C 2 2 then C 2 4 u PyBX-ip-(S,S) 2 CC 2 u(pybox-ip) 2 cat. C 2 2 C 2 C 2 up to 98:2 trans:cis up to 97% ee ishiyama, J. Am. Chem. Soc. 1994, 116,

23 Asymmetric Cyclopropanation of lefins with Diazoacetates Single-Chiral PyBX Analysis of transition states reveals C 2 -symmetry may not be necessary u C Ester Ester A favored Ester B = t-bu ishiyama, Tetrahedron: Asymmetry 1998, 9,

24 Asymmetric Cyclopropanation of lefins with Diazoacetates Single-Chiral PyBX 2 CC 2 [u 2 (p-cymene) 2 ] 2 Ligand C 2 2 C 2 C 2 trans cis entry Pybox 2 CC 2, = % yield trans:cis % ee (trans) % ee (cis) 1 1 Me 88 83: Me 82 89: Et 93 89: i-pr 80 92: l-menthyl 84 99: t-bu u Ester = 2 C t-bu Me C Ester nly one isomer detected by M analysis ishiyama, Tetrahedron: Asymmetry 1998, 9,

25 Asymmetric 1,4-Additions of rganoboron eagents C 2 -Symmetric Dienes B() 2 [h(c2 4 ) 2 ] 2 (3 mol%) K (50 mol%) dioxane/ 2 (10/1) 30 C (94% yield) 95% ee h h = benzyl h ayashi, J. Am. Chem. Soc. 2003, 125,

26 Asymmetric 1,4-Additions of rganoboron eagents ayashi's ligand synthesis Ligand Synthesis 1. Si 3 [(C 3 5 )] 2 ()-Me-MP, 0 C 2. Me, Et , KF 2 TF/Me 1. Me 2 S, (C) 2 Et 3, C C 2 C 2 Ts 1. LDA, TF then Comins reagent 2. C 2 MgBr/Et 2 2 (dppf) (1 mol%) 1. /TF 2. LDA, TF then Tf 2 py-2 3. C 2 MgBr/Et 2 2 (dppf) (1 mol%) Carreira's ligand synthesis Me Me 1. BS Me 2. t-buk t-bu 1. LDA, Tf 2 2. ArZn, cat ayashi, J. Am. Chem. Soc. 2003, 125, Carreira, J. Am. Chem. Soc. 2004, 126,

27 Asymmetric 1,4-Additions of rganoboron eagents ationale Behind Application of C 1 -Symmetric Diene Me C 2 Me [Ir(CE) 2 ] 2 L* C 2 Me L* = (0.5 equiv) C 2 2, rt 93% ee h h Assume coordination of unsaturated substrate to rhodium occurs after transmetalation of the organoborane Aryl group would block one of the substituents Therefore, only one substituent would be sufficient for chiral recognition of enantiotopic faces Carreira, J. Am. Chem. Soc. 2004, 126, Darses, Angew. Chem. Int. Ed. 2008, 47,

28 Asymmetric 1,4-Additions of rganoboron eagents Application of C 1 -Symmetric Diene C 1 diene B() 2 [h(c2 4 ) 2 ] 2 (3 mol%) K (2.2 mol%) C 2 2 /Me (10/1) 30 C * C 1 diene = Me Me Me 95% ee 98% ee 95% ee C 1 diene B() 2 [h(c2 4 ) 2 ] 2 (3 mol%) K (2.2 mol%) C 2 2 /Me (10/1) 30 C * 90% ee ( = 4-MeC 6 4 ) 90% ee ( = 2,4,6-(Me) 3 C 6 2 high ee's (up to 98% ee) with a wide range of boronic acids (electron-rich, -deficient) Darses, Angew. Chem. Int. Ed. 2008, 47,

29 xidative Kinetic esolution of Secondary Alcohols Sparteine, a C 1 -Symmetric Ligand C 1 IV III I II ( )-sparteine C 2 IV III I II ( )-α-isosparteine C 2 IV III I II (+)-β-isosparteine Stoltz J. Am. Chem. Soc. 2008, 130,

30 xidative Kinetic esolution of Secondary Alcohols egioselectivity by Sparteine + SbF 6 + SbF 6 AgSbF 6 (1 equiv) C 2 2, 23 C Mes (1 equiv) Ag A B + SbF 6 + SbF 6 C D nly A observed with bulk of substrate oriented toward vacant quadrant IV Stoltz J. Am. Chem. Soc. 2008, 130,

31 A Proposed Model for the bserved Stereochemistry Sparteine and C 1 -Symmetry S L L (±) L S + (sp) 2 S IV III L I II S S - β- elimination S L L L S L S + + L S resolved alcohol Stoltz J. Am. Chem. Soc. 2008, 130,

32 Summary C 2 -symmetry is still a dominant structural motif Advantage of C 2 -symmetry: reduced number of possible, competing diastereomeric structures Careful consideration of transition states showed that C 2 -symmetry is not always necessary C 1 -symmetric ligands allow the application of steric and electronic differentiation C 1 -symmetric ligands also offer the possibility of creating a single site of reactivity via desymmetrization of transition states With the continuous discovery of new "privileged" frameworks, C 1 -symmetric ligands are likely to play an increasing role in the development of asymmetric catalysis

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