π-trimethylenemethane cyclization Provide a mechanism for the following transformation.

Transcription

1 M.C. White, Chem 153 π-allyl chemistry Week of ecember 9, 2002 π-trimethylenemethane cyclization Provide a mechanism for the following transformation. + Ac Si 3 ( 3 P) 4 Pd toluene, mixture of stereoisomers Si 3 L n Pd (0) Si3 Ac Pd (II) L n Ac L n Pd (II) L n Pd (II) Pd (0) Pd (0) L n Pd (II) L n Trost JACS 1980 (102) 6359, JACS 1983 (105) 2326.

2 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 Fischer Carbenes (formally derived from a singlet carbene) The presence of strong π-acceptor ligands on the metal renders π-backbonding into the empty carbene p orbital weak. π-donation from the carbene substituents competes w/ π-donation from the metal singlet carbene X = heteroatoms ' X δ - δ + C M C ' L n M=C 2 sp 2 tal Carbenes Schrock Carbenes (formally derived from a triplet carbene) triplet carbene alkyl (or ) ' X M C δ + δ - ' sp 2 L n M=C 2 ' ' X M p z sp 2 p z C extreme π-backbonding: where the 2e- in the M(dπ) orbital are transfered to the C(p z ) orbital. alkyl (or ) Low oxidation state, late metals π-acceptor ligands on the metal π-donar substituents on the carbene C likened to a carbonyl: δ - δ - (C) 5 Cr 0 18 e- δ + δ + note: that the formal charge for the carbene unit is zero, the # of electrons donated is 2. p z electrophilic carbenes σ-donation is stronger than π-backbonding resulting in a partial positive charge on the carbene carbon (C) 5 Cr II igh oxidation state, early metals on-π acceptor ligands on the metal (often π-donor ligands such as Cp or ) alkyl (or ) substituents on the carbene. The first characterized Schrock carbene: likened to a phosphorus ylide: -2 charge/ 4 electron donor δ + Ta V δ and moisture 10 e- sensitive δ + 3 P nucleophilic carbenes The metal-carbon bonds are more covalent in nature and highly polarized towards C resulting in a partial negative charge on the carbene C. δ - pentane/ 2 (C 2 ) 3 Ta V highly oxophilic, early metal Cr 0 (C) 6 + Fischer Chem. Ber (105) C (C) 5 Cr II (C 2 ) 3 Ta V + 85% Schrock JACS 1974 (96) 6796, 1976 (98) (C 2 ) 3 Ta V

3 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 The first isolated and characterized Schrock carbenes The first characterized Schrock carbene: α-agostic interaction provides the metal w/extra electron density (C 2 ) 2 ()Ta V 10 e- complex C 4 2 eq C 2 Li (C 2 ) 2 ()Ta V (C 2 ) 2 Ta V Li steric conjestion induces direct α-proton abstraction by one of the neopentane ligands resulting in the metal alkylidene. Li (C 2 ) 3 Ta V Schrock JACS 1974 (96) 6796, Acc. Chem. es (12) 98. The first isolated Schrock carbene: 2.246Å Ta V C() 3 BF 4 C Ta V 2 BF 4 base Ta V C 2 18 e- C() 3 16 e- 18 e Å Schrock JACS 1975 (97) 6577, ~ 10 % shorter Ta-C bond is suggestive of a significant amount of db character

4 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 Carbonyl methylenation: Tebbe s reagent Tebbe's reagent: Tebbe JACS 1978 (100) Al 2 stoichiometric C Al 3 toluene rt Al 2 toluene, -15 o C 65% 16 e- In situ prep: Grubbs JC 1985 (50) C 4, Al 2 16 e- Tebbe's reagent 0.5M soln 100 ml/$363 (Aldrich 2001) Al 2 16 e- Synthetic applications: TBS Bn TBS Et 2 C TBS Bn TBS Schreiber JACS 1990 (112) Cp 2 TiC 2 Al 2 tol-tf-py, -78 o C to -15 o C 82% Et 2 C TBS TBS Bn Bn TBS TBS key intermediate in the total synthesis of ikizimycin Cp 2 TiC 2 Al 2 TF, rt, 1h 85% icolaou ACIEE 1994 (33), 2184, 2187, 2190 key intermediate in the total synthesis of Zaragozic acid

5 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 Tebbe s reagent Tebbe's reagent reacts with olefins to give metallocyclobutanes: Al 2 + Al 2 16 e- 1 Grubbs M 1982 (1) Titanium metallocyclobutane 1 reacts with acid chlorides to form Ti enolates. tol, -20 o C to 0 o C TiCp 2 C 69% Grubbs JACS 1983 (105) 1665.

6 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 lefin metathesis: Tebbe s reagent Tebbe's reagent reacts with olefins to give titanacyclobutanes: Al 2 + Al 2 16 e- 1 Titanacyclobutanes are effective catalysts for α-olefin metathesis. First application of olefin metathesis to synthesis: + t-b u 1, cat + t-b u Cp 2 TiC 2 Al 2 MAP, benzene 25 o C 90 o C TiCp 2 t-b u t-b u t-b u Cp 2 Ti() p-ts TiCp 2 t-b u t-b u t-b u 81% overall yield (±)-Capnellene Grubbs JACS 1982 (104) Grubbs JACS 1986 (108) 855.

7 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, C 8 Carbonyl methylenation: Petasis reagent ifficulties with the Tebbe and Grubbs' Ti-mediated olefinations include the high cost of Ti reagent, long preparation times, short shelf life, and the need for special techniques due to sensitivity to air and water. Many of these difficulties are overcome with Petasis' procedure which uses dimethyltitanocene. Petasis JACS aldehydes Cp 2 Ti 2 3 eq. toluene o C 3 C 8 62 % ketones Cp 2 Ti 2 3 eq. toluene o C 83 % esters chemoselectivity for ketones in the presence of esters Cp 2 Ti 2 3 eq. toluene o C 80 % C 3 Cp 2 Ti 2 1 eq. toluene o C C 3 60 % Petasis JACS Based on deuterium labelling studies, Petasis originally proposed a mechanism involving initial carbonyl complexation to Cp 2 Ti 2 followed by methyl transfer and subsequent loss of methane and titanocene oxide. 3 C 3 C 11 Cp 2 Ti(C 3 ) 2 TiCp 2 Petasis JACS TiCp 2 C 3 3 C C 3 3 C 11? Cp 2 Ti C 3 C 2 3 C C C C ~50% 11 "significant amount of deuterium detected at C-3." TiCp 2 C 2 ughes finds that in the reaction with C-13 labelled ethyl acetate shown below, scrambling of the label only occurs if trifluoroacetic acid is present and proposes that this scrambling is due to an acid-catalyzed, degenerate [1,3]-hydrogen shift. e proposes that the scrambling observed by Petasis was likely due to adventitious acid present on all acid-washed glassware. To support this argument, ughes repeated the deuterium labelling experiments reported by Petasis using glassware that was not acid washed and, contrary to Petasis, observed no scrambling of the label C 3 C TiCp C Et TiCp 2 TiCp C 3 C <1% incorporation of 13 C label into methylene position ughes uses these experiments in conjunction with detailed kinetic studies to provide strong support for a mechanism involving a titanium carbene. ughes M TiCp 2 TiCp 2 C 2

8 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 lefin metathesis The first reports of olefin cross metathesis (heterogeneous cat) by Banks: The first report of MP (ring opening metathesis polymerzation): 2 Mo(C) 6 supported on Al 150 o C, 30 atm. Banks Ind. and Eng. Chem. (Product es. and evelopment) 1964 (3) 170. aines Chem. Soc. ev (4) 155. Well-defined W VI and Mo VI olefin cross metathesis and MP catalysts: + MX n + Al(Et) 3 MXn = Ti 4, Zr 4, Mo 5, W 6 atta Makromol. Chem (69) 163. atta ACIEE 1964 (3) 723. n F 3 C 3 C F 3 C W VI F 3 C F 3 C C 3 Wittig-type chemistry with aldehydes> ketones>> and esters (slow rates). F 3 C 3 C Mo VI F 3 C 12 e- 12 e- Schrock JACS 1986 (108) F 3 C F 3 C C 3 Wittig-type chemistry with aldehydes>>ketones (slow rates). Schrock JACS 1990 (112) 3875, 8378; 1991 (113) lefin cross metathesis: M n MP (ing opening metathesis polymerization) M n M M n initiation M n M n M n M n M n M n termination C m m + M n = propagation M n ften called a "living polymerization" because termination only occurs upon addition of a capping unit (often aldehyde). Grubbs Science 1989 (243) 907.

9 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 Mo-mediated ring closing metathesis (CM) of acyclic diene ethers Grubbs recognized the potential for applying olefin metathesis towards a productive synthetic pathway: CM (ing osing tathesis) 5-membered ring formation: dihydrofurans 1, 5 mol% 1, 5 mol% benzene, rt F benzene, rt 3 C CF 3 15 min 3 h 92 % yield Mo 6-membered ring formation: dihydropyrans VI 7-membered heterocycles F 1, 5 mol% 3 C CF 3 1, 5 mol% benzene, rt 15 min 92 % yield 1 Tri-and tetrasubstituted olefins: benzene, rt 4 h 93 % yield 75 % yield Grubbs JACS 1992 (114) Et General mechanism: X X L n Mo VI X X Evaporative loss of the low molecular weight acyclic olefin generated and the entropic gain of generating 2 molecules from 1 are thought to be two factors favoring the CM pathway. X L n Mo VI X VI MoL n L n Mo VI L n Mo VI An early synthetic application of CM: Grubbs JC 1994 (59) Bn Bn Bn 1, 12 mol% Bn 2, Pd-C 85 % 95 % Sophora compound I

10 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 Mo-mediated CM of acyclic diene amines and amides 5-membered rings Bn 6-membered rings Bn Grubbs JACS Bn 1, 4 mol% 1, 4 mol% benzene, rt F 3 C CF 3 benzene, rt 3 h 15 min 1, 4 mol% benzene, rt 1 h 93 % yield Bn 86 % yield F 3 C CF 3 Mo VI 1 Mo stable chelate 1 F 3 C 7-membered ring - lactam formation Bn 1, 4 mol% benzene, rt 1.5 h F 3 C Bn 83 % yield 90 % yield Formation of 5- and 6-membered lactams via CM of acyclic diene-amides is hindered by formation of stable chelate intermediates. This may be due to the Lewis acidic properties of the formally 12 e- Mo alkylidene. 12e- 1 Mo stable chelate This problem can be averted by directing the catalytic cycle with appropriate olefin substitution patterns. Because metathesis of monosubstituted olefins by 1 is faster than that of disubstituted olefins, the initial Mo alkylidene preferentially forms at the less substituted olefin where intramolecular chelate formation with the amide carbonyl is not favored. Bn 1, 10 mol% benzene 50 o C 1.5 h Bn Mo Grubbs JACS 1992 (114) 7324, see also Schrock M 1989 (8) Bn 74 % yield Bn Et 1, 10 mol% benzene 50 o C 1.5 h Bn Mo Et Bn 80 % yield

11 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 Application of CM-mediated macrolactam formation in TS TBS F 3 C CF 3 Mo VI F 3 C CF 3 25 mol % TBS 2 TF (0.01M) 60 o C; silica column oveyda JACS Bn C 2 F 3 C CF 3 Mo VI F 3 C CF 3 benzene, 50 o C 4 h 63 % yield 5 mol % Bn 60 % yield >98% Z The high levels of stereoselectivity in these examples is an exception. Attaining reliable E/Z selectivity is still an unsolved problem with this chemistry. C 2 Fluvirucin B 1 (Sch 38516) Manzamine A Martin TL :

12 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 Synthesis of cycloalkenes via olefin metathesis/carbonyl olefination [M] 3 F 3 C CF 3 Mo VI F 3 C CF 3 benzene, 20 o C 30 min 1 eq. 86 % yield Effecting this process requires an alkylidene which metathesizes olefins more rapidly than it olefinates ketones. It had been demonstrated previously that this Mo-alkylidene efficiently metathesizes acyclic mono- and disubstituted alkenes at rt, but requires elevated temperatures to olefinate ketones. 3 Schrock JACS 1990 (112) [M] olefin metathesis carbonyl olefination [M] 3 [M] 3 [M] 3 six-membered rings seven-membered rings as above 84 % yield Bn as above 86 % yield Bn Grubbs JACS 1993 (115) 3800.

13 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 Grubbs JACS 1988 (110) 960, [u II ( 2 ) 6 ] 2+ (Tos) n u II u alkylidenes A 2+ (Tos)2 " " u IV proposed catalytically active species note: u 3 2 is also effective. Since identical olefin resonances are observed by M during the reaction as those for u II /olefin complex A (u III does not form stable olefin complexes), Grubbs speculates that u III becomes reduced in situ to u II. m u II coordination complexes may form u IV alkylidenes with strained cyclic olefins: Grubbs JACS 1992 (114) P 3 u II P 3 P 3 P 3 + Efficient u catalyst for acyclic olefin metathesis. stronger σ-donor ligands C 2 2 /C o C, 11h u IV u IV 1 Stable to 2 igh activity for low-strain cyclic olefins and for acyclic olefins. Generation 2 catalyst: P 3 u II P 3 P 3 P C 2. PCy3 u IV P 3 u IV P 3 Stable to 2 (but insoluble pure 2 ), alcohols, and acids Unstable to 2 propagating species: u ethylidene and u propylidene observed by M u IV Advantages of 2 vs. 1: More facile synthesis due to greater availability of diazoalkanes relative to cyclopropenes. u catalyst 2 is significantly more reactive than 1 because of more facile initiation. o Wittig-like activity observed even with aldehydes Poor activity for low-strain cyclic olefins and no activity for acyclic olefins. + m Grubbs JACS 1993 (115) Grubbs ACIEE 1995 (34) 2039.

14 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 u vs. Mo alkylidene catalysis of CM u IV u IV vs. F 3 C CF 3 F 3 C CF 3 Mo VI 1 (16e-, d 4 ) 2 (16e-, d 4 ) u alkylidene complexes 1/2 are effective CM catalyst in the presence of atmospheric 2, water and trace solvent impurities. eagent grade solvents may be used directly for the reactions. Alternatively, Mo alkylidene complex 3 is highly sensitive to atmospheric 2, moisture and solvent impurities. Boc 1 (2 mol%) solvent, air Boc 88-93% solvents: reagent-grade (undistilled): benzene, C 2 2, TF, u alkylidenes 1/2 are highly functional group tolerant. Unlike Mo complex 3 which is known to react with acids, alcohols, aldehydes (and ketones intramolecularly), complexes 1/2 are stable to these functionalities. X 1 (2 mol%) C 6 6, rt, 1h X X = C 2, 87% C 2, 88% C, 82% CM of acyclic diene-amides in 5- and 6-membered lactam formation is not complicated by the formation of stable chelated species as observed with 3. This may be due in part to the less oxophilic character of u vs. Mo. Moreover, the 16 e-, d 4 u complex is less electrophilic than the 12e- d 0 Mo complex. n 1 (3 mol%) C 6 6, rt, 1h n 3 (12e-, d 0 ) Free amines are not tolerated by u catalysts and must be masked as the corresponding salts: 1. 1 (4 mol%) C 2 2, rt 36 h 2. a 79% (note: CM of this amine with 3 took 40 min and proceeded in 89% yield; JACS 1992 (114) 5426) CM of substituted olefins is problematic with 1 and 2. ienes w/sterically demanding and/or electron withdrawing substituents can be cyclized more effectively w/ Mo catalyst 3. 2 C C 2 2 C = Et, 2 93%; 3 >99%, 2 ; 3 96%, 2 25%, 3 97% C 2, 2 5%, 3 89% C 2 2 C C 2 2 C C 2 Grubbs JACS 1993 (115) n= 0, 78% 1, 93% Grubbs JC 1997 (62) , 3 93%

15 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 Grubbs third generation u alkylidene catalyst u IV s u IV s F 3 C CF 3 F 3 C CF 3 Mo VI s u IV s 1 (16e-, d 4 ) 2 (16e-, d 4 ) 3 (12e-, d 0 ) 4 (16e-, d 4 ) Increased reactivity of 2 makes it comparable to 3 in many cases: 2 C C 2 2 (5 mol%) 45 o C, 60 min >99% recall: 1 gave P tetrasubstituted olefins 2 C C 2 not entirely general: 2 (5 mol%) 45 o C, 90 min 90% 1 gave P 2 C C 2 t-b u 2 C C 2 C 2 C 2 Improved E/Z ratios for macrocyclization (1 mol%) 40 o C, C 2 2, 40 min >99% E/Z ratio increases over time with catalyst 2: Most likely due to a secondary "metathetical" isomerization ring closing metathesis: L n u IV L n u IV L n u IV 1, E/Z (4.5:1) 2, E/Z (11.5:1) via ring opening metathesis/ 2 C C 2 2 (5 mol%) 45 o C, 24h 31% 1 gave P 3, 93% espite increased reactivity 2 has retained it's functional group tolerance (as well as air and 2 stability). Grubbs L 1999 (1) (5 mol%) 45 o C, 10 min >99% 1, P; 3, P Grubbs L 2000 (2) Cross metathesis of terminal olefins with α-carbonyl functionalized olefins: TBS 7 C 2 C 3 3 eq. slow addition 0.5 eq. 4 (5 mol%) 40 o C, C % TBS 7 E/Z (>20:1) The ester-carbene complex is L n u IV unstable and is not thought to be C 2 C 3 effective in olefin metathesis. Grubbs JACS 2000 (122) C 2 C 3

16 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 chanism of Grubbs third generation u alkylidene catalyst stable diaminocarbene u IV s u IV s C M Fisher-type carbene, strong σ-donor The strongly σ-donating -heterocyclic carbene ligand of 2 is thought to significantly improve the binding selectivity of 14 e- intermediate A for relatively π-acidic olefins vs. σ-donating phosphines. 1 (16e-, d 4 ) 2 (16e-, d 4 ) Arduengo JACS 1995 (117) Proposed mechanism: s L = or s Catalyst 2, whose propagation rates significantly exceed those of 1, exchanges phosphine 2 orders of magnitude slower than 1. The reaction is thought to proceed via a dissociative mechanism to form the active 14e- catalytic species. Excess phosphine inhibits the rxn. (or after 1st cycle) L osphine dissociation L - k 1 u IV u IV + k -1 PCy 14 e- 3 L A u IV k -2 The ratio of k -1 /k 2 determines if the 14e- intermediate binds olefin to initiate metathesis or binds phosphine to return to its resting state. This ratio is 4 orders of magnitude greater for 1 than for 2 (1 =15300, 2 = 1.25). While 1 is faster to initiate by loosing phosphine, the rebinding of phosphine is competitive with olefin binding. Alternatively, 2 dissociates phosphine more slowly but binds the olefin with such high affinity that it may cycle through many times before binding phosphine and returning to its resting state. k 2 L u IV L u IV Grubbs JACS 2001 (123) 749.

17 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 ienyne metathesis SiEt 3 u IV SiEt SiEt mol% + unsymmetrical dienyne 1:1 SiEt 3 u IV SiEt 3 SiEt 3 SiEt 3 SiEt 3 SiEt 3 ul n ul n Cycle A SiEt 3 SiEt 3 Cycle B SiEt 3 u L n ul n SiEt 3 SiEt 3 u L n ul n L n u ul n Sterically differentiating the two olefins biases the intial site of metallocyclobutane formation and results in selectivity for one cycle vs. the other. SiEt 3 SiEt 3 SiEt 3 SiEt 3 L n u SiEt 3 SiEt 3 Et L n u Et ul n Grubbs JACS 1994 (116) ul n 83% 78%

18 M.C. White, M.S. Taylor Chem 153 tal alkylidenes Week of ecember 9, 2002 Macrocyclization via ene-yne metathesis ( ) - Longithorone A TBS TBS TBS TBS TBS TBS TBS u [u] TBS TBS PCy 3 u PCy 3 (0.5 equiv.) Ethylene (1 atm) C 2 2 TBS TBS >20:1 favoring atropisomer shown [u] TBS TBS TBS TBS TBS TBS TBS [u] TBS PCy 3 u (0.5 equiv.) Ethylene (1 atm) C 2 2 [u] TBS TBS TBS TBS TBS TBS the protected benzylic hydroxyl was used to gear the atropisomerism of the aromatic rings during ene-yne metathesis [u] TBS TBS [u] TBS TBS TBS Shair JACS 2002 (124) 773.

19 M.C. White, Chem 153 tal alkylidynes Week of ecember 9, 2002 iyne metathesis Schrock Carbynes (formally derived from a triplet carbene) ing-closing diyne metathesis: Furstner ACIEE 1998 (37) M C M C trianionic ligand (-3), 6 electron donor Early example of catalytic alkyne metathesis by W VI -alkylidyne note: catalyst is incompatible with terminal alkynes. W VI () 3 C () 3 C C() mol% C 6 5, Ar, 80 o C Functional group tolerance demonstrated for esters, amides, and sulfones. 73% Lindlar hydrogenation stereoselectively generates Z-alkenes (still an unsolved problem for CM of alkenes). ovel Mo alkyne metathesis catalyst: Et W VI PEt 3 Tol, rt 5 mol% Et Et + Et Mo IV WL n Et WL n Et WL n It is unclear how the halide Mo catalyts initiates the catalytic cycle. This catalyst demonstrates increased functional group tolerance (relative to the W catalyst) for basic amines, thioethers, and ketones. Schrock JACS 1981 (103) Furstner JACS 1999 (121) 9453.

20 M.C. White/Q. Chen Chem 153 tal alkylidynes Week of ecember 9, 2002 ing-closing alkyne metathesis in TS C 3 Mo 10 mol% C 2 2 /toluene, 80 C C 3 2 (1 atm) Lindlar catalyst quinoline C 2 2, rt C 3 known to generate a mixture of L n Mo- and L n Mo C, both known to initiate diyne metathesis. 78% yield 3 C = PMB (note that this Mo-based catalyst requires protection of the hydroxyl groups. Corresponding CM of a related substrate with terminal olefins gave 3:1 olefin ratio favoring the undesired trans isomer. C 3 Q C 2 2 / (18:1) rt, 8 h C 3 global deprotection Sophorolipid lactone quantitative conversion 93 % yield Fürstner JC 2000 (65) 8758.

21 M.C. White, Chem 153 tal alkylidenes Week of ecember 9, 2002 Asymmetric ring-closing metathesis with chiral molybdenum alkylidene complexes Kinetic resolution in ring-closing metathesis k 1 k -1 k 2 (a) [Mo] k 2 (b) [Mo] Ac F 3 C CF 3 F3 C Mo VI CF 3 benzene, 25 o C, 20 min 90 % conversion Ac + Ac 10 % recovered from reaction mix 84% ee, k rel = 2.02 Grubbs and coworkers reasoned that the second (ring-closing) step would be suitable for asymmetric induction, because this step involves diastereomeric cyclic transition states which differ in energy. iene substrates were chosen which contained a trisubstituted olefin to slow the cyclization step (and thus presumably increase the selectivity) and to control the site of the first metathesis. Grubbs JACS 1996 (118) Enantioselective synthesis of dihydrofurans by Mo-catalyzed desymmetrization. Enantioselective synthesis of quaternary carbon centers oveyda/schrock JACS 1999 (121) Mo VI benzene, rt, 6 h 5 mol % = Mo * 86% yield, 93% ee Mo * toluene -25 o C, 18h Mo * toluene -25 o C, 18h 84% yield, 73% ee 91% yield, 82% ee

22 M.C. White, Chem 153 lefin xidation Week of ecember 9, 2002 (TBP) V Sharpless Aldrichimica Acta 1979 (12), 63. V IV V V irected epoxidations Bystander oxo ligands are present in many early d 0 metals capable of oxidation. They occupy potentially useful binding sites for appending chiral ligands. V Stereoelectronic factors lead to a highly ordered TS. Perfect for asymmetric induction... M M LUM M planar orientation: the plane defined by the lone pair of the oxygen of the η 2 -peroxo is perpendicular to the plane defined by the olefin π-orbital. This orientation avoids unfavorable lone pair-π interactions M M LUM spiro orientation favored: the plane defined by the lone pair of the oxygen of the η 2 -peroxo is parallel to the plane defined by the olefin π-orbital. This orientation aligns the lone pair-π* orbitals thereby facillitating C- bond formation. Formation of covalent, intramolecular allyloxide intermediates leads to large rate accelerations in the V catalyzed epoxidation of allylic alcohols. thyl ethers undergo epoxidation 1000 times slower than the corresponding alcohols. V 1000 x faster Sharpless Chem. Br (22) 38. vs. V F 3 C 2 open coordination sites required for effective catalysis. Appending a chiral ligand occupies these sites and results V in ligand-decelerated catalysis. 1 mol% TBP (2 eq) tol, -20 o C, 4 days 3 mol% optimal substrate 90%, 80% ee

23 M.C. White, Chem 153 lefin oxidation Week of ecember 9, 2002 The Sharpless epoxidation For all metals capable of effecting catalytic epoxidation of allylic alcohols with TBP, only Ti displayed ligand accelerated catalysis. All other systems were strongly inhibited or entirely deactivated with added tartrate ligand. note: no bystander oxo ligand M n+ () n cat. TBP Sharpless ACIEE 2002 (41) "For years, right up until January of 1980, when the asymmetric epoxidation was discovered, every expert in asymmetric synthesis and catalysis advised me that what we sought- a catalyst that was both selective and versatile- was simply impossible." K.B. Sharpless Chem. Br (22) 38. Unsymmetrical disubstituted (+)-ET or (+)-IPT TBP, 3 Å MS, C 2 2, -20 o C ' ' ' = Et : (+)-ET : (+)-IPT Uniformly >90% ee, 60-70% yields C 2 -symmetric ligand Sharpless JACS 1987 (109) Sharpless In Asymmetric Synthesis, Morrison, Ed.; Academic Press: ew York, 1986 (5) C 7 C % ee 88% yield cis-disubstituted Tetrasubstituted 86% ee 74% yield Trisubstituted >98% ee 79% yield 94% ee 90% yield All olefin substitution patterns result in high ee's and good yields, with the exception of cis-disubstituted olefins that generally react slowly and give moderate ee's (80's)

24 M.C. White, Chem 153 lefin xidation Week of ecember 9, 2002 chanism note: no bystander oxo ligand Ti IV (+)-ET or (+)-IPT TBP, 3 Å MS, C 2 2, -20 o C Uniformly >90% ee, 60-70% yields ' ' C 2 -symmetric ligand The catalyst self-assembles under the reaction conditions to give predominantly a dimeric species that epoxidizes allylic alcohols with high levels of ee. The dimeric species is significantly more active than Ti tetraalkoxide alone or Ti-tartrates of other than 1:1 stoichiometry which lead to zero or low ee products (respectively). ' = Et : (+)-ET : (+)-IPT ' () 3 C()' ' '()C C()' ' Major species in solution and kinetically most active. Leads to high ee products. 0 ee rel. rate: 0.38 rel. rate: 0.28 low ee's ' '()C C()' proposed intermediate C 2 rel. rate: 1.0 Sharpless JACS 1991 (113) 106, 113. high ee's

25 M.C. White, Chem 153 lefin xidation Week of ecember 9, 2002 on-directed epoxidations: transferable metal oxo P-450 catalyzed epoxidations Stereoelectronically favored side-on approach: Chiral P-450 mimics M LUM I Fe III 85% yield 84% ee Fe V catalyst Collman JACS 1993 (115) Fe III 1 e- 2 C Fe II S-Cys C 2 Fe III 2 C 2 C S-Cys Fe V S-Cys C 2 C C C Fe IV S-Cys Fe III S-Cys C 2 C 2 2 C 2 C S-Cys 1 e- Fe III S-Cys C 2 C 2

26 M.C. White, Chem 153 lefin xidation Week of ecember 9, 2002 The first report of epoxidation activity: PF 6 Mn III I (1 eq), C 3 C 2 eq limiting reagent 4 mol% Jacobsen epoxidation Bleach as a terminal oxidant: a i II cat a (p 13)/C 2 2 Bu 3 Bz + Br - 84% I PF 6 Mn V 56% based on iodosylbenzene (I) i IV i III Kochi JACS 1986 (108) The Jacobsen epoxidation Burrows JACS 1988 (110) Cis-disubstituted adical intermediate envoke to account for exclusive formation of the E-epoxide from the Z. Trisubstituted cis-disubstituted substrates give optimal yields and ee's Jacobsen JACS 1990 (112) Jacobsen JACS 1991 (113) Jacobsen JC 1991 (56) Jacobsen TL 1996 (37) Mn III mol% a, C 2 2, pyridine -xide (20 mol%) 84% yield cis: trans (11.5:1) 92% ee 88% ee 90% yield Jacobsen TL 1995 (36) % ee 69% yield Tetrasubstituted Cis-enynes give trans-epoxides : TMS Br Cy TMS 96% ee 84% yield Jacobsen JACS 1991 (113) Cy

27 M.C. White, Chem 153 lefin xidation Week of ecember 9, 2002 chanism Proposed mechanism: Mn III cis-disubstituted substrates give optimal yields and ee's t-b u mol% a, C 2 2, pyridine -xide (20 mol%) + 84% yield cis: trans (11.5:1) 92% ee Mn V L Mn IV L Mn IV L ationale for enantioselection: All trajectories to Mn oxo are sterically blocked except the one over the chiral diimine backbone. Mn V Jacobsen JC 1991 (56) 6497.

28 M.C. White, Chem 153 lefin xidation Week of ecember 9, 2002 Sharpless dihydroxylation Commercially available as a mix: A-mix-α uses the ligand (Q) 2 -PAL A-mix-β uses the ligand (Q) 2 -PAL Sharpless JC 1992 (57) s VI 2- +K 2 s VI 0.2 mol% (Q) 2 -PAL (1 mol%) K 3 Fe(C) 6 (3 eq) K 2 C 3 (3 eq) : 2 (1:1) General mechanism: Sharpless Chem. ev (94) K 2 2 K 3 Fe(C) % ee >90% yield Works well for all olefin substitution patterns with the exception of cis-disubstituted and tetrasubstituted. 2 K 4 Fe(C) s VIII 2- +K 2 pseudoenantiomeric Et (Q) 2 -PAL (Q) 2 -PAL Et s VI L L s [3+2] s VIII L s VIII Evidence favors the [3+2] mechanism vs. [2+2]: Corey TL 1996 (28) ouk, Sharpless, Singleton JACS 1997 (119) ligand accelarated catalysis: The enzyme-like binding cleft is especially well suited for π-stacking with although s 4 is capable of aromatic substrates. Large rate accelarations are observed for aromatic dihydroxylating olefins, the ligand substrates with the phalazine class of ligands. bound complex does so at a much greater rate. Corey JACS 1993 (115) 2861, Sharpless JACS 1994 (116) 1278.