Shi Asymmetric Epoxidation

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1 Shi Asymmetric Epoxidation Chiral dioxirane strategy: R xone, ph 10.5, K 2 C 3, H 2, C R 3 formed in situ catalyst (10-20 mol%) is prepared from D-fructose, and its enantiomer from L-sorbose oxone, the stoichiometric oxidant, is a 2:1:1 mixture of KHS 5, KHS 4, and K 2 S 4 H 2 2 / C may also be used as stoichiometic oxidant. a ph of 10.5 is an optimum balance between oxone decomposition and Baeyer-Villiger rearrangement of dioxirane intermediate R 3 R2 R 3 R 2 spiro TS electronically favored n=>!* planar TS Higher ee's observed with smaller and larger R 3 substituents

2 Effect: smaller R1 beneficial Shi Asymmetric Epoxidation R 3 R 2 79% ee 81%ee 98%ee 26% ee Effect: larger R3 beneficial Compare: H 3 C H 3 C C 10 H 21 H 3 C H 3 C 76% ee 86% ee 91% ee 76% ee 97% ee ote that the substituent size preferences reflect interactions in the spiro TS. R 3 Proposed Catalytic Cycle: R 3 HS 5 - H S - 3 S S - 3

3 Shi Asymmetric Epoxidation Substrate Product Yield ee 73% 95% Cl Cl 61% 93% 91% 93% C 10 H 21 C 10 H 21 94% 89% JACS, 1996, 9806 JACS, 1997, Monoepoxidation of dienes occurs at the more e - rich or less sterically hindered olefin 25mol% 1, xone TBS K 2 C 3, C TBS 81% yield 96% ee 25mol% 1, xone K 2 C 3, C 65% yeild 89% ee

4 Shi Asymmetric Epoxidation Trisubstituted olefins are selectively epoxidized because they are more e-rich TMS 25mol% 1, xone K 2 C 3, C SiMe 3 JC, 1998, %, 92% ee Epoxidation of enynes occurs selectively at the C-C double bond: SiMe 3 25mol% 1, xone K 2 C 3, C SiMe 3 64%, 94%ee TL, 1998, 4425 JC, 1999, ,1-disubstituted epoxides can be prepared from trisubstituted vinyl silanes by epoxidation and desilylation: SiMe 3 25mol% 1, xone K 2 C 3, C 74%, 94% ee SiMe 3 TBAF 82% 94%ee JC, 1999, 7675

5 Shi Asymmetric Epoxidation A modified catalyst is used for epoxidation of cis-disubstituted olefins and styrenes Boc 2 JACS, 2000, xone, K 2 C 3, DME 82%, 91%ee 2 xone, K 2 C 3, DME 100%, 81%ee rg. Lett. 2001, 1929 JC, 2002, 2435!-substituent prefers to be proximal to the spiro oxazolidinone: Boc R!

6 Shi Asymmetric Epoxidation Kinetic Resolution of racemic 1,3- and 1,6-disubstituted cyclohexenes provides optically enriched allylic Silyl ethers TMS 35 mol% 1 49% conv. TMS + TMS TBS 35 mol% 1 70% conv. 96% ee TBS 99% ee + 95% ee TBS 81%ee The original Shi catalyst decomposes faster than it reacts with electron-deficient unsaturated esters. A second-generation catalyst, incorporating electron-withdrawing acetate groups, slows the decomposition: JACS, 1999, 7718 Baeyer-Villiger reaction - C 2 Et Ac Ac 73% yield, 96% ee C 2 Et JACS, 2002, 8792

7 Upjohn Dihydroxylation

8 riginal UpJohn Procedure: Sharpless Asymmetric Dihydroxylation Reaction R 2 Cat. s 4, 1eq. M 8:1 acetone : water H R 2 H TL, 1976, 1973 M= - Catalytic Cycle: s L 2 H 2, 2H - s L L s L VI H 4 s H H + L VIII turnover is achieved with stoichiometric oxidants: K 3 Fe(C) 6, M M is found to be deleterious to the enantioselective process Addition is likely a 3+2 cycloaddition rather than a 2+2 cycloaddition/rearrangement: 2 Fe(C) Fe(C) 6 3- JC, 1990, 766 [3+2] s L s L TL, 1996, 4899 JACS, 1997, 9907

9 Ligands: C2-symmetric, pseudo-enantiomeric Sharpless Asymmetric Dihydroxylation Reaction Et Et Et Et Me Me Me Me (DHQD) 2 -PHAL ligand for AD-mix-! (DHQ) 2 -PHAL Ligand for AD-mix-" slightly less enantioselective AD-mix reagents are commercially available: 1.4 g Ad-mix-! will oxidize 1mmol olefin 0.98 g K 3 Fe(C) 6 (3 mmol) 0.41g K 2 C 3 (3 mmol) g (DHQD) 2 -PHAL (0.01 mmol) g K 2 s 2 (H) 4 (0.002 mmol) ˆJC, 1992, 2768 Corey Proposes a U- shape binding pocket: Me Me s H TL, 1995, 3481

10 Sharpless Asymmetric Dihydroxylation Reaction: Ligand Accelerated Catalysis 4 of 6 olefin classes are successfully dihydroxylated: tetra tri trans-di gem-di mono cis-di Mnemonic: slightly hindered (DHQD) 2 -PHAL! R S R M Application of Mnemonic: H 3 C C 5 H 11 C 2 Et attractive area: good for aromatic and alkyl substituents H 3 C Et 2 C R L H " (DHQ) 2 -PHAL C 5 H 11 very hindered AD-mix-! R H 3 C H H AD-mix-! H S R C 5 H 11 Et 2 C H R AD-mix-! CH 2 H H C 8 H 17 AD-mix-! C 8 H 17 H R CH 2 H

11 Generality of Sharpless Asymmetric Dihydroxylation AD-mix-! AD-mix-" (DHQD) 2 -PHAL (DHQ) 2 -PHAL % ee, config % ee, config H 3 C 98, R 95, S 99, R, R 97, S, S C 5 H 11 C 2 Et 99, 2S, 3R 96, 2R, 3S >99.5, R,R >99.5, S,S 94, R 93, S C 8 H 17 84, R 80, S 97, R 97, S JC, 1992, 2768

12 Generality of Sharpless Asymmetric Dihydroxylation Cis-Disubstituted lefins are poor substrates; with a modified catalyst, DHQD-ID, good ee s can be obtained: ee at 0 C 72 (1R, 2S) Et JACS, 1992, 7568 H Me C 2 ipr 80 (2S, 3R) DHQD-ID (DHQD) 2 AQ is often a superior ligand: DHQD (DHQD) 2 AQ DHQD Cl 90% ee vs. 63% ee with (DHQD) 2 PHAL 88%ee vs. 77% ee with (DHQD) 2 PHAL ACIEE, 1996, % ee vs. 44% ee with (DHQD) 2 PHAL

13 Good substrates Allylic 4-methoxybenzoates Generality of Sharpless Asymmetric Dihydroxylation Me Me But: H TIPS H 3 C AD-mix-! (DHQ) 2 PHAL >99%e, 93% yield H H 3 C H H 3 C 18%ee H 3 C 13%ee AD, (DHQD) 2 PYDZ >99% yield, 98%ee PYDZ = Me 98% yield, 97% ee JACS, 1995, Me 96%, 91% ee Me

14 Generality of Sharpless Asymmetric Dihydroxylation Regioselectivity of AD with dienes: in general, AD is selective for more electron-rich doible bonds Substrate Product % yield, % ee H 78, 93 C 2 Et H H C 2 Et 78, 92 JACS, 1992, 7570 H 73, 98 H H 70,98 H H

15 Use of AD with Chiral lefins H H Me "anti" Me H + H "syn" Me conditions anti:syn s 4, M 88% yield (mixture) 1.9:1 matched (DHQ) 2 PHAL 86% yield (anti) 54:1 TL, 1997, 5941 mismatched (DHQD) 2 PYDZ 86% yield (syn) 1:35

16 H xidative Kinetic Resolution KR H + R 2 chiral catalyst R 2 R 2 [] racemic non-racemic It was found that combination of a palladium source, (-) sparteine as a chiral ligand, and 2 could effect Efficient oxidative kinetic resolution under defined conditions H Pd(nbd)Cl 2, 5 mol% (-)-sparteine 20 mol% + H racemic R 2 MS 3Å, 2, 80 C R 2 R 2 non-racemic enriched alcohol isolated yield ee RH H H JACS,2001, H H

17 KR Mechanism: a Dual Role for (-)-Sparteine nly one enantiomer binds the chiral catalyst efficiently! H Pd Me Pd Pd Cl Cl Cl H :B Cl + B H + Cl - Me Me 2, Cl - Rate-limiting!-Hydride Elimination JACS, 2002, Pd 0 Me + Pd remaining enantiomer: H Cl H :B Me An excess of sparteine is beneficial for the reaction, and it is believed that sparteine not only functions as the chiral Ligand, but also as an exogenous base for the deprotonation step, making beta-hydride elimination rate-limiting

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