Myers

Review:

Sharpless Asymmetric Dihydroxylation Reaction

Chem 215

Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994 , 9 4, 2483-2547. Ligands such as pyridine accelerate the osmylation of olefins (Criegee, R.; Marchand, B.; Wannowius, H. Liebigs Ann. Chem. 1 9 4 2, 550 , 99-133.)

Et N H H O N N Et O H N
(DHQD)2-PHAL Ligand for AD-mix-

N H

C2 -symmetric, pseudo-enantiomeric ligands:

Catalytic Cycle:

CH3O N

OCH3

O O O Os O L VI O Os O O O
L

Et N H CH3O H O N N O H N
(DHQ)2-PHAL Ligand for AD-mix-, (slightly less enantioselective)

Et N H OCH3

2 H2 O, 2 OH

O O O Os O L

H4 OsO6 2 - + HO VI
HO

VIII

2 Fe(CN)64

2 Fe(CN)63 AD-mix reagents are commercially available:

Turnover is achieved by re-oxidation with stoichiometric oxidants:

O
+N CH 3 O

UpJohn Process: VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976 , 1973-1976.

1.4 g AD-mix- will oxidize 1 mmol olefin, contains: 0.98 g K3Fe(CN)6 (3 mmol) Conditions: t-BuOH, H2O (1:1), 0 C, 6-24 0.41 g K2CO3 (3 mmol) h 0.0078 g (DHQD)2-PHAL (0.01 mmol) 0.00074 g K2OsO2(OH)4 (0.002 mmol) Sharpless, K. B., et al. J. Org. Chem. 1992 , 5 7, 2768-2771.

K3 Fe( CN) 6

Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1 9 9 0, 5 5, 766-768. Corey proposes a U-shaped binding pocket:

In the original Sharpless procedure, using NMO, reoxidation was believed to compete with hydrolysis, leading to a competing 2nd-cycle oxidation that was less enantioselective: Ogino, Y.; Chen, H.; Kwong, H.-L.; Sharpless, K. B. Tetrahedron Lett. 1 9 9 1, 3 2, 3965-3968.

MeO O O Os O O N N N N N O O H

OMe N H N H

OMe

OMe

Balance of evidence appears to favor 3 + 2 Mechanism (vs. 2 + 2 pathway). See, e.g., Corey, E.J.; Noe, M. C.; Grogan, M. J. Tetrahedron Lett. 1996 , 3 7, 4899-4902. DelMonte, A. J.; Haller, J.; Houk, K. N.; Sharpless, K. B.; Singleton, D. A.; Strassner, T.; Thomas, A. A. J. Am. Chem. Soc. 1 9 9 7, 119 , 9907-9908.

O O N a H Os H Oe N ON N ON O

Corey, E. J.; Guzman-Perez, A.; Noe, M. C. Tetrahedron Lett. 1995 , 3 6, 3481-3484.

4 of 6 Olefin substitution classes are successfully dihydroxylated:

AD-mix- [(DHQD)2-PHAL] % ee, config.

AD-mix- [(DHQ) 2-PHAL] % ee, config. 95, S

H3C
tetra tri trans-di gem-di mono cis-di

CH3 * CH3

98, R

99, R, R

97, S, S

Mnemonic:

(DHQD)2-PHAL

n-Bu RS RL RM H n-C5H11

n-Bu

97, R, R

93, S, S

CO2Et *

99, 2S, 3R

96, 2R, 3S

(DHQ)2-PHAL

CO2Et *

97, 2S, 3R

95, 2R, 3S

Application of Mnemonic:

CH3 H3C CH3 CH3 H3C CH3

AD-mix-

CH3 H3C HO
R OH

>99.5, R, R

>99.5, S, S

CH3 CH3 H3C

78, R 76, S

n-C5H11

CO2Et

EtO2C

n-C5H11

AD-mix-

HO S R n-C5H11 EtO2C OH CH3 R CH2OH OH

CH3
94, R 93, S

CH3

AD-mix-

n-C8H17

84, R

80, S

97, R AD-mix-

97, S

n-C8H17

n-C8H17

OH R CH2OH

* addition of CH3 SO2NH2 leads to faster reaction from: Sharpless, K. B., et al. J. Org. Chem. 1 9 9 2, 57 , 2768-2771.

Cis-Disubstituted Olefins are generally poor substrates. With a modified catalyst, DHQD-IND, fair to good enantioselectivities can be obtained: ee at 0 C

a few tetra-substituted olefins work well, see: Sharpless, K. B., et al. J. Am. Chem. Soc. 1993, 115, 8463-8464.

N N O Et O H N H OCH3

TBSO

O
AD-mix- R

CH3

72 (1R, 2 S)

OH
a best case, ee's and yields are not yet generally high

93% ee, 94% yield

CO2i-Pr

80, (2S, 3R)

DHQD-IND

Allylic 4-methoxybenzoates are particularly good substrates:

OCH3 CH3
56, (1R, 2 S), 44% ee of enantiomer with DHQ-IND

OCH3 O

O O
AD (DHQ)2 PHAL >99% ee, 93% yield

O HO OH

16, (1R, 2S)

CH3O OCH3
Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7568-7570. whereas:

CH3O OCH3 OTIPS

18% ee 13% ee

OH

O
(DHQD)2AQN is often a superior ligand:

ODHQD

CH3O OCH3

CH3O OCH3
AD, (DHQD)2 PYDZ

Cl

O
90% ee vs. 63% ee, (DHQD)2 PHAL

ODHQD

O O CH3O
>99% yield, 98% ee

PYDZ =

O N N

(DHQD) 2 AQN
Ph O O
88% ee vs. 77% ee, (DHQD)2 PHAL

O O CH3O CH3
98% yield, 97% ee

78% ee vs. 44% ee, (DHQD)2 PHAL

O
96% yield, 91%ee Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996 , 3 5, 448-451.

CH3O
Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1 9 9 5, 1 1 7, 10805-10816.

Regioselectivity of AD with Diene Substrates ((DHQD)2 -PHAL as Ligand): Substrate Use of AD with Chiral Olefins: Product % yield, % ee

HO
78, 93

OH OH H O OEt OH
78, 92

OH H OH H HO H HO H O H

H OH HO H H HO H O
1 : 1.6 10 : 1

O OEt

HO

H H H O OEt
93, 95

O
OsO4 alone (DHQD)2 -PHAL

O OEt

HO OH

73, 98

HO

Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994 , 94 , 2483-2547, and refs. therein.

OH O HO
70, 98

O OH O
anti +

HO

OH O O

O O H3C H 3C OCH3 O CH3

98% ee

OCH3

in general, AD is selective for more electron-rich double bond Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114 , 7570-7571.

CH3

OH O O O H 3C OCH3
AD

H 3C H3C

O HO O O OH O CH3
syn anti : syn

OCH3

H3C

OH
56% yield, >99%ee

OCH3
Conditions

H3C H 3C

(DHQ)2 PHAL

6:1 ratio

O HO H3C O OH OCH3

OsO4 , NMO
(DHQ)2 PHAL (matched)

88% yield (mixture)

1.9 : 1

86% yield (anti)

54 : 1

with OsO4, NMO ratio is 1:10 10% yield, 96%ee Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1 9 9 5, 117 , 10805-10816.

(DHQD)2PYDZ (mismatched)

86% yield (syn)

1 : 35

Guzman-Perez, A.; Corey, E. J. Tetrahedron Lett. 1997, 38 , 5941-5944.