Myers

Reviews: Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1-300.

Sharpless Asymmetric Epoxidation Reaction

Chem 215

Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, Ojima, I., Ed.; VCH: New York, 1993, pp. 103-158. Johnson, R. A.; Sharpless, K. B. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 7, pp. 389-436. Pfenninger, A. Synthesis 1986, 89-116.

OH

OH OH

OH

OH OH

OH

Z-disubstituted olefins are least reactive and selective. Asymmetric Epoxidation of Allylic Alcohols: R3 R2 R1 OH R3 OH Examples of Sharpless Epoxidation: product O OH (+)-DET = EtO2C CO2Et OH O O C7H15 Ph R2 R1 HO H3 C D-()-DET "O" Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-5976. Application of Mnemonic: CH3 O OH AE-()-DET CH3 OH AE-(+)-DET O CH3 OH Ph Ph From: Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780 and Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, Ojima, I., Ed.; VCH: New York, 1993; pp. 103-158. M. Movassaghi CH3 O R3 O CH3 OH CH3 OH 100 BnO O CH3 CH3 OH 120 ()-DET (150) 20 5 90 94 OH 5 (+)-DET (7.4) 20 0.75 95 91 (+)-DET (142) 20 14 80 80 5 (+)-DIPT (7.5) 35 2 79 >98 Pr OH OH 10 (+)-DET (14) 10 29 74 86 4.7 (+)-DET (5.9) 12 11 88 95 Ph O OH 5 (+)-DIPT (7.5) 20 3 89 >98 OH Ti(%) 5 tartarate (%) (+)-DIPT (6.0) C 0 h 2 yield (%) ee (%) 65 90 OH

Ti(Oi-Pr)4,(+)-DET t-BuOOH, 3-MS CH2Cl2, 20 C

R2

O R1

5-10 mol% catalyst in the presence of 3 or 4 -MS. 10-20 mol% excess tartarate vs. Ti(OiPr)4 required. (+)- and ()-DET are readily available and inexpensive.

(+)- and ()-DIPT, diisopropyl tartarate, are also available and sometimes lead to higher selectivity. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780. Mnemonic for selectivity: L-(+)-DET "O"

97%, 86% ee

97%, 86% ee

Chiral Substrate: CH3 H3 C O O OH O syn Ratio (syn : anti)

Kinetic Resolution: CH3 H3C O O OH O anti (+)-DET "O" (+)-DET "O" +

CH3

H 3C

Products are diastereomeric. Using the Sharpless mnemonic, contact between the C1 substituent (R) and the catalyst predicts slow reacting isomer.

OH

Reagent

m-CPBA VO(acac)2-TBHP Ti(OiPr)4-TBHP Ti(OiPr)4-()-DIPT-TBHP Ti(OiPr)4-(+)-DIPT-TBHP 1 : 1.4 1 : 1.8 1 : 2.3 1 : 90 22 : 1 MATCHED MISMATCHED krel = kfast/kslow slow

fast

Products are diastereomeric. Sense of induction is dominated by the catalyst. The C4 center reinforces and erodes this in "MATCHED" and "MISMATCHED" cases, respectively, as shown.

With the exception of Z-disubstituted allylic alcohols, krel > 25. When krel = 25, the ee of unreacted alcohol is essentially 100% at 60% conversion. Allylic tertiary alcohols are not successfuly epoxidized under Sharpless conditions. Factors may combine for high selectivity:

Ko, S. Y.; Lee, A. W. M.; Masamune, S; Reed, L. A., III; Sharpless, K. B.; Walker, F. J. Tetrahedron 1990, 46, 245-264. OH H 3C ()

()-DIPT 40% conversion H 3C

OH

Homoallylic, bishomoallylic and trishomoallylic:

Rates of epoxidation are usually slower. Enantiofacial selectivity of the catalyst is reversed for all three. Enantiofacial selectivity is generally lower.

70% yield >95% ee

Disubstituted olefin is more reactive than monosubstituted olefin (krel ~100). kfast/kslow for chiral E-propenylcarbinols is ~100. H3C O OH Excercise: Apply the Sharpless mnemonic to predict the stereochemistry of this product. Sharpless, K. B.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Martin, V. S.; Takatani, M.; Viti, S. M.; Walker, F. J.; Woodard, S. S. Pure Appl. Chem. 1983, 55, 589. Allylic 1,2-diols do not follow the Sharpless mnemonic: OH H OH O H CH3 OH (+)-DIPT OH 71% 90% ee

H3C TBHP, 20 C 1-4 d 50%, 41% ee

OH

Ti(Oi-Pr)4 (1.0 equiv) (+)-DET (1.2 equiv)

Rossiter, B. E.; Sharpless, K. B. J. Org. Chem. 1984, 49, 3707-3711.

CH3 TBHP, 0 C 48 h 22%, 29% ee

Ti(Oi-Pr)4 (1.0 equiv) (+)-DET (1.2 equiv)

OH

O +

OH

O OH 10% 90%ee Excercise: What isomer would you have predicted using the Sharpless mnemonic? Takano, S.; Iwabuchi, Y.; Ogasawara J. Am. Chem. Soc. 1991, 113, 2786-2787. M. Movassaghi

OH

Hosokawa, T.; Kono, T.; Shinohara, T.; Murahashi, S.-I. J. Organometal. Chem. 1989, 370, C13-C16. For other examples see: Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis, Ojima, I., Ed.; VCH: New York, 1993, pp. 103-158 and Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1-300.

C2-Symmetric Substrates: Venustatriol:

Any minor diastereomer that is produced is rapidly removed by bis-epoxidation.

Excercise: Why?

CH3 H3C CH3 H3 C OH H3 C O

H3C CH3 OH H3 C CH3

H3 C

CH3 O OH

OH O
(+)-DIPT

O OH O OBn H 3C O
Ti(Oi-Pr)4, ()-DET TrOOH, 3-MS 0 A 23 C, 15 h

OH O OBn CH3

OBn

meso

OBn

Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J. Am. Chem. Soc. 1987, 109, 1525-1529. Schreiber, S. L.; Goulet, M. T.; Schulte, G. J. Am. Chem. Soc. 1987, 109, 4718-4720.

H3C HO H H3C CH3

CN H

H3C H3C H3 C CH3 HO

O H

CN H

Applications in Synthesis:

L-Hexoses:

RO OH
PhSH, NaOH H2O/t-BuOH, 6 71% TBHP 20 C

Ti(Oi-Pr)4, (+)-DIPT

OH

RO

O
92%, >95% ee

Ti(Oi-Pr)4, ()-DET

H3C CH3 CH3

H3C O HO

HO

CH3 CH3

R = CHPh2

RO OH SPh OH Br H

OAc

SPh

1. 2,2-dimethoxypropane, cat. POCl3 RO

H3 C H3C H 3C O H3 C H O

O H

CHO H
Li +

92% H3C H O O O H CH3 CH3

O H 3C CH3

2. m-CPBA, 78 C 3. Ac2O, NaOAc, 6

93%, 3-steps

K2CO3 CH3OH 25 C

91%

DIBAL-H CH2Cl2 78 C

100%

RO O H

RO

H 3C H3 C H 3 C O H3 C H Br H O

O H

H OH H3C H O H OH

HWE-olefination, reduction, and AE provides an iterative route to the synthesis of polyols.

CH3 CH3 OH

H 3C

O CH3

H3C

O CH3

Venustatriol

syn

anti

Corey, E. J.; Ha, D.-C. Tetrahedron Lett. 1988, 29, 3171-3174.

Ko, S. Y.; Lee, A. W. M.; Masamune, S; Reed, L. A., III; Sharpless, K. B.; Walker, F. J. Tetrahedron 1990, 46, 245-264. M. Movassaghi

Ferensimycin B: (+)-Neocarzinostatin Chromophore: H 3C HO TDSO HO O H CH3 HO H O CH3 N H H (+)-DIPT, Ti(OiPr)4 TBHP, 20 C, CH2Cl2, 4-MS CH3 HO H 3C HO Et Et OH H 70%, 95% de A further example of anomalous stereochemistry in AE of an allylic diol (no reaction with ()-DIPT). TBS CH3 N H HO OH O CH3 Et H O CH3 OH H O O CH3 Et Et OH O H 3C O H O H O O OCH3 O O H O O CH3 N CH3 2. ()-DET, Ti(OiPr)4 TBHP, 20 C, CH2Cl2 TBS 4-MS 1. TDSCl, Et3N, DMAP CH2Cl2, 0 C

H3C EtLi Et2O CH3 Et H

H3CO

CH3

H 3C O Li O H 3C N

N O CH3 H CH3 Et N TBS

94%, 95% de

CH3 N CH3 Et Et Et Et O O Mg Br O OH

Et

Et

(+)-DIPT, Ti(OiPr)4

EtMgBr

OH

TBHP

1. Et2NLi (1.5 equiv) THF 2. NaHSO4, H2O

H 3C

76% of TY, 90% ee H 3C CH3 OH O

H3C

HO2C

O H O O OH CH3 OH CH3 CH3 Et H CH3

Ferensimycin B

Evans, D. A.; Polniaszek, R. P.; DeVries, K. M.; Guinn, D. E.; Mathre, D. J. J. Am. Chem. Soc. 1991, 113, 7613-7630.

(+)-Neocarzinostatin Chromophore

()-7-Deacetoxyalcyonin Acetate: H 3C

H 3C

H 3C H H3 C CH2Cl2 OH TMS 2. Red-Al, THF 15 C; H2O 79% (two steps)

CH3 H

1. (+)-DET, Ti(OiPr)4 TBHP, 20 C

Myers, A. G.; Hammond, M.; Wu, Y.; Xiang, J.-N.; Harrington, P. M.; Kuo, E. Y. J. Am. Chem. Soc. 1996, 118, 10006-10007. Myers, A. G.; Liang, J.; Hammond, M.; Harrington, P. M.; Yusheng, W.; Kuo, E. Y. J. Am. Chem. Soc. 1998, 120, 5319-5320.

CH3 H 3C H H H3 C O O H H

OH

TMS

H 3C H 3C

CH3 H H

H 3C H H 3C H HO OH

CH3 H 3C H H H 3C O HO H H

AcO H ()-7-Deacetoxyalcyonin Acetate

MacMillan, D. W. C.; Overman, L, E. J. Am. Chem. Soc. 1995, 117, 10391-10392. M. Movassaghi