Sharpless Epoxidation in Organic Synthesis

Dr. Mukund Ghavre

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Katsuki ˆ

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Why do need selective reactions ?

All kinds of selectivities enrich the art of organic synthesis.

Especially, chemo-selectivity provides an excellent tool to organic chemist for the synthesis of molecules containing a number of functional groups.

O O

O

mCPBA

O

mCPBAO

O

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It is the first method for asymmetric epoxidation of allylic alcohols, published on 1st August 1980 in JACS.

Prof. Sharpless says that ‘it was Katsuki’s (then his postdoc) idea to use DET for chiral induction’.

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Works on a wide spectrum of substrates

offering > 80 % ee and 70-90 % yield.

5-10 mol% catalyst is required in presence of 3 or 4 Å molecular sieves.

Demands 10-20 mol% excess tartrate wrt Ti catalyst.

The stereochemistry of epoxide depends on the enantiomer of tartrate used in reaction.

Ti-Complex

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TS proposed by Corey

Ti

HOR

OR

ORO

OROO

RO

O

RO

Ti

OR

OO

OO tBu

R1 R2

CO2R

O

H

RO

Johnson, R. A.; Sharpless. K. B.; Catalytic Asymmetric Epoxidation of Allylic Alcohols. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I. Ed.; Wiley-VCH: New York, 2000; 231–280; Corey, E. J. J. Org. Chem. 1990, 55, 1693–1694.

X

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O

Ti

O

O

Ti

O

CO2Et

CO2Et

OiPr

OiPr

OiPriPrO

OEtO

OEtO

tBuOOH

iPrOH

O

Ti

O

O

Ti

O

CO2Et

CO2Et

O

OiPr

OiPriPrO

OEtO

OEtO

OtBu

iPrOH

HO R

O

Ti

O

O

Ti

O

EtO2C

CO2Et

CO2Et

O

O

OiPriPrO

OEtO

tBu

O

R

O

Ti

O

O

Ti

O

EtO2C

CO2Et

CO2Et

OtBu

OiPriPrO

OEtO

O

R

O

tBuOH

2 iPrOH

HO R +

O

O O

C O

145 kJ/mol

360 kJ/mol

C C 230 kJ/mol(Pi bond)

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Choice of tartrate:

R2 R1

R3

OH

Want epoxide on the side of kNuckles ?then use Negative, (-)-DET

Want epoxide on the side of Palm ?then use Positive, (+)-DET

R2 R1

R3

OHO

R2 R1

R3

OHO

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Johnson, R. A.; Sharpless. K. B.; Catalytic Asymmetric Epoxidation of Allylic Alcohols. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I. Ed.; Wiley-VCH: New York, 2000; 231–280; Keith, J. M.; Larrow, J. F.; Jacobsen, E. N. Adv. Synth. Catal. 2001, 343, 5–26,

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Substrate Scope:

Sharpless, K. B.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Marin, S.; Takatani, M.; Viti, S. M.; Walker, F. J.; Woodard S. S. Pure & Appl. Chem. 1983, 55, 589–604. Schweitzer, M. J.; Sharpless, K. B. Tetrahedron Lett. 1985 26, 2543–2546. Gao, Y. Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780. Erickson, T. J. J. Org. Chem. 1986, 51, 934–935.

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Choice of Metal:

• When allyl alcohol was subjected to SKAE using various metal catalysts, following results were obtained.

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Modifications:

(A) Molecular Sieves:

– Economy

– Less catalyst required

– Somewhat milder conditions

– Ease of isolation

– Increased yields

– Possible in-situ derivatization

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(B) Polymer support:Metal catalyst is mounted on a polymer

which makes it (usually) heterogeneous– Lab scale: facilitate workup and isolation– Industry: continuous process– Minimizes catalyst loss during workup– Polymer support vital with water-soluble

substrates Possible Polymers:– alkaloid polymers– polystyrene

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Early work with polystyrene had low % ee

A Scottish group used linear chiral poly (tartrate esters)

Combining benefits of polymer support with the active functionality built in

Reaction gives good yields and % ee Branched poly(tartrate esters) were found to be even more selective and had higher yields

COOH

H OH

HO H

COOH

OH

HO

n

CO2HO

HO CO2 (CH2)n

x

Kinetic Resolution:

08/04/2023 15Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237–6240.

In kinetic resolution, two enantiomers react with different reaction rates in a chemical reaction with a chiral catalyst or reagent, resulting in an enantioriched sample of the less reactive enantiomer.

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

krel = kfast/kslow

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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

successfully epoxidized under

Sharpless conditions.

Disubstituted olefin is more reactive

than monosubstituted olefin (krel

~100).

08/04/2023 18Roush J. Org. Chem. 1982, 47, 1371.

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Payne Rearrangement

Payne J. Org. Chem. 1962, 27, 3819.

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1. In general, the more substituted epoxide is favoured as the reaction product.

2. However, steric factors and relative alcohol acidities (1° > 2° > 3°) are additional factors which determine the ultimate composition of the equilibrium mixture.

3. The more reactive epoxide can be trapped by strong nucleophiles (e.g., PhSH).

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Homoallylic epoxidation:

Makita, N.; Hoshino, Y.; Yamamoto, H. Angew. Chem. Int. Ed. 2003, 42, 941–9434.; Blanc, A.; Toste, F. D. Angew. Chem. Int. Ed. 2006, 45, 2096–2099.

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Applications in Total SynthesisVenustatriol

Marine-derived natural product discovered initially

in 1986, found in red alga Laurencia venusta.

Derived in vivo from squalene, made as a triterpene.

Shown to have antiviral and anti-inflammatory properties.

Structure contains repeated polyether moieties.

Key problems: multiple stereocenters and polyether moieties.

Corey proposed a “simple and straightforward” disconnection.

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Venustatriol – Retro-synthetic Analysis

O

O

OO OH

Br

OH

H

H

OH

H

H

HH

H

O

O

O CHO

Br

H

HH

H

O OH

H

H

OH

Br+

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Fragment A

O

O

O CHO

Br

H

HH

H

Fragment A

OH

E,E - Farnesol

SAE OH

O

1. CrO3.Py (Jones Ox.)2. Ph3P=CHCO2CH3 (Wittig)3. H2, Rh-Al2O3 (Hydrogenation)4. DIBAL-H, PhCH3 (Reduction)

O

CHO

NaCN (SN2)

Ring Closure

O CN

HO

O CN

HO

O

SAE

1. MsOH (Ring Closure)2. TBCD/CH3NO2 (Bromination)3. DIBAL-H (Reduction)

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Fragment BHO

Geraniol

HOSAE O

O OH

BnO

H OH

H

OOHC

H O

H 1. NaH2. MOMCl (Methyl ether)3. Swern oxidation

O

1. Ph3P=CH2 (Wittig)2. 9-BBN/H2O2 (Alcohol)3. CBr4 (Bromination)

O

H O

H

O

Br

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Final step to Venustatriol

O

O

OO OH

Br

OH

H

H

OH

H

H

HH

H

O

O

O CHO

Br

H

HH

H

+O

H O

H

O

Br

1. tBuLi

2. (CH3)2BBr

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

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Amphoteronolide - B

Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K.; Ogawa, Y.; J. Am. Chem. Soc., 1988, 110, 4696 – 4705

O

O OH OH

OH

OH OH

OH

O

OH

OH

O

OH

HO

Horner-Wadsworth-Emmons Reaction

Esterification

Fragment 17

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OBn

HO SAEOBn

HO

O

1. Swern Ox.2. Wittig

OBn

O

H3CO2C

1. Reduction

2. tBuCOCl, Py

3. TIPS, Imidazole

4. Reduction

OBn

OTIPS

HOSAE

OBn

OTIPS

HO

O

1. Red-Al2. Protection

OBn

O

PgO

O

1. H2/Pd2. TIPS, Imidazole3. DIBAL-H

OTIPS

O

HO

O

1. BnBr, KH2. TBAF3. Parikh–Doering oxidation

O

O

BnO

O

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(-)-Laulimalide Epoxidation at final stage

discriminates between two allylic alcohols to give desired product.

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Other Methods for

Enantioselective

Epoxidation

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Chiral Peroxides:

• Simplest approach towards asymmetric

epoxidation – generally not spectacular.

H-J Hamann et al., Chirality, 1993, 5, 338.A. Lattanzi et al., Chem Comm. 2003, 1440.

OH

O

AcO

OAc

OOH

Ti(OiPr)4

OH

O

33 % ee

OH

Ti(OiPr)4

OH

O

46 % ee

OOH

O

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Modified Johnson–Corey– Chaykovsky Reaction

• Not applicable to broad substrate scopes. Reaction conditions generally clumsy (days or weeks).

32

N. Furukawa et al. J. Org. Chem., 1989, 54, 4222 P. Metzner et al. J. Org. Chem., 2005, 70, 4166 V.K. Aggarwal and J. Richardson. Chem Comm., 2003, 2644.

OH

SMe

SEt Et O

H

O

Br OOH-, Chiral Sulphide

+Ph Ph

S

47 % ee

92 % ee93 % ee

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Jacobsen Epoxidation• Applicable to most cis-olefins. A small

number of conjugated trisubstituted and tetrasubstituted olefins also work (not general).

• Also works for electron deficient olefins (enones) but requires higher catalyst loading and longer reaction times.

E.N. Jacobsen et al. JACS, 1991, 113, 7063.

R2

R1 R3

R4

O

R2 R4

R3R1

O

Mn

N

O

N

tBu

tBu tBu

tBu

Cl

NaOCl, DCM

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Shi Epoxidation:• Useful for epoxidation of trans-disubstituted

olefins (ketone 1), trisubstituted olefins (ketone 1), conjugated cis-disubstituted olefins (ketone 2, see p. 3), and styrenes (ketone 2, see p. 3).

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Enders Method:• Pros: Oxygen as stoichiometric oxidant.• Cons: Not very broad substrate scope (R2

must be Ph or other large group for good enantioselectivity).

D. Enders et al. Angew. Chem. Int. Ed. Eng., 1996, 35, 1725.

R1 R2

O

R1 R2

O

O

Et2Zn, O2, ROH

OZn

N

Ph

OO

Et

80-90 % ee

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Shibasaki Method:• Pros: Catalytic in L-M complex (5 mole %),

Broader substrate scope than Enders method.• Cons: Expensive catalyst; mechanism poorly

understood (active catalyst is presumed to be oligomeric).

M. Shibasaki et al. JACS, 1997, 119, 2329.

R1 R2

O

R1 R2

O

O

80-95 % ee

ROOH, 4 A, MS, THF

O

La OiPr

O

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Corey Method:• Pros: Catalytic in ligand (0.1 eq.),

consistently high e.e. values.• Cons: R2 must be aryl. Ligand is not

particularly cheap or easy to come by. Reaction conditions are annoying.

E.J. Corey and F-Y Zhang. Org. Lett., 1999, 1(8), 1287 E.J. Corey et al. Tet. Lett., 1996, 37(11), 1735.

R1 R2

O

R1 R2

O

91-99 % ee

KOCl, Toluene, -40oC

O

N

OBn

N

Br

Summary: Recommended Methods

Allylic or Terminal Olefins

Sharpless Jacobsen HKR

Di- or Tri-substituted Olefins

Jacobson Shi Shi & Jacobsen

Electron Deficient

Shibasaki Shibasaki & Jacobsen

OR1 R3

R2

HO

O

R

O

R1 R2

O

R1

R2O

R2

R3R1

OR1

EWG

O

R1 EWG

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How to convert epoxide into olefin ?

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"Scott Tips Very Crappy Money; Felipe Counts Nicaraguan Cucumbers."

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THANK YOU !

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Questions ?