Myers Sharpless Asymmetric Dihydroxylation Reaction Chem 115

Reviews:
Et C2-symmetric, pseudo-enantiomeric
Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547. N
N ligands:
Noe, M. C.; Letavic, M. A.; Snow, S. L.; McCombie, S. W. Org. React. 2005, 66, 109–626. H N N Et
O O
Ligands such as pyridine accelerate the osmylation of olefins (Criegee, R.; Marchand, B.; H
H
Wannowius, H. Liebigs Ann. Chem. 1942, 550, 99-133.) H3CO OCH3
Et Et
Catalytic Cycle: N N N N N N
(DHQD)2-PHAL H
ligand for AD-mix-" O O
H
O H
O H3CO OCH3
O Os 2 H2O, 2 OH–
O
L N N
VI (DHQ)2-PHAL
O L O
O O ligand for AD-mix-!
Os O Os H4OsO62- + HO + L (slightly less
O O O enantioselective)
L VI OH AD-mix reagents are commercially available:
VIII
re-oxidation
1.4 g AD-mix-" will oxidize 1 mmol olefin, contains:
0.98 g K3Fe(CN)6 (3 mmol)
0.41 g K2CO3 (3 mmol) Conditions: t-BuOH, H2O (1:1), 0 °C, 6-24 h
2 Fe(CN)64– 2 Fe(CN)63– 0.0078 g (DHQD)2-PHAL (0.01 mmol) Typical work-up: Na2SO3 then extraction
0.00074 g K2OsO2(OH)4 (0.002 mmol)

Turnover is achieved by reoxidation with stoichiometric oxidants:

Sharpless, K. B., et al. J. Org. Chem. 1992, 57, 2768–2771.

O Corey proposes a U-shaped binding pocket:

NMO = N CH3 UpJohn Process: VanRheenen, V.; Kelly, R. C.; Cha, D. Y.
O Tetrahedron Lett. 1976, 1973–1976.
OMe MeO
MeO OMe
K3Fe(CN)6 Minato, M.; Yamamoto, K.; Tsuji, J. J. Org. Chem. 1990, 55, 766–768.
O O Oa
N N
O Os H Os O
e H
In the original Sharpless procedure using NMO, reoxidation was believed to compete with O N N O N N
NO H N
hydrolysis, leading to a ligand-less "second cycle" olefin dihydroxylation that was non- N N O N
enantioselective: O O N

H
Ogino, Y.; Chen, H.; Kwong, H.-L.; Sharpless, K. B. Tetrahedron Lett. 1991, 32, 3965-3968.
H

Balance of evidence favors 3+2 cycloaddition (vs. 2+2/rearrangement) mechanism between

osmium and olefin. Corey, E. J.; Guzman-Perez, A.; Noe, M. C. Tetrahedron Lett. 1995, 36, 3481–3484.

See, e.g., Corey, E. J.; Noe, M. C.; Grogan, M. J. Tetrahedron Lett. 1996, 37, 4899-4902.
For ligand modifications and improvements based on binding model, see:

DelMonte, A. J.; Haller, J.; Houk, K. N.; Sharpless, K. B.; Singleton, D. A.; Strassner, T.; Corey, E. J.; Noe, M. C.; Grogan, M. J. Tetrahedron Lett. 1994, 35, 6427–6430.
Thomas, A. A. J. Am. Chem. Soc. 1997, 119,!9907–9908. Huang, J.; Corey, E. J. Org. Lett. 2003, 5, 3455–3458.

1
Myers Sharpless Asymmetric Dihydroxylation Reaction Chem 115
4 of 6 Olefin substitution classes are successfully dihydroxylated:
AD-mix-! AD-mix-"
[(DHQD)2-PHAL] [(DHQ)2-PHAL]
% ee, config. % ee, config.

H3C CH3 *
98, R 95, S
tetra tri trans-di gem-di mono cis-di CH3

!
[(DHQD)2-PHAL]
* 99, R, R 97, S, S
Mnemonic:

RS
RM
n-Bu * 97, R, R 93, S, S
RL n-Bu
H
3
CO2Et * 99, 2S, 3R 96, 2R, 3S
n-C5H11
2

[(DHQ)2-PHAL] 3
CO2Et
" * 97, 2S, 3R 95, 2R, 3S
2
Application of Mnemonic:

H3C CH3 CH3 AD-mix-! CH3 Ph

H3C * >99.5, R, R >99.5, S, S
CH3 H3C CH3 R CH3
HO
OH

CH3
AD-mix-! OH 78, R 76, S
CO2Et n-C5H11 S R n-C H H3C
5 11
n-C5H11 EtO2C EtO2C
OH
CH3
94, R 93, S
CH3 AD-mix-! CH3
R
CH2OH
OH
n-C8H17 84, R 80, S

AD-mix-! OH 97, R 97, S

R
n-C8H17 n-C8H17 CH2OH * addition of CH3SO2NH2 (a phase-transfer and
general acid catalyst) leads to faster reactions for
non-terminal olefins
Sharpless, K. B., et al. J. Org. Chem. 1992, 57, 2768–2771.

2
Myers Sharpless Asymmetric Dihydroxylation Reaction Chem 115
Cis-disubstituted olefins are generally poor substrates. With a modified catalyst, DHQD-IND, A few tetra-substituted olefins work well:
fair to good enantioselectivities can be obtained: Sharpless, K. B., et al. J. Am. Chem. Soc. 1993, 115, 8463-8464

OTBS O
ee at 0 °C
Ph AD-mix-! Ph
1 2 N
OH
CH3 72, (1R, 2S) Et
N O H
H 93% ee, 94% yield
O OCH3
3 2

CO2i-Pr 80, (2R, 3S) N a best case; ee's and yields are not generally high
DHQD-IND
Allylic 4-methoxybenzoates are particularly good substrates:
1 2

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

O O

1 O O
asymmetric dihydroxylation (AD)
2
HO OH
16, (1R, 2S)
(DHQ)2PHAL
>99% ee, 93% yield
H3CO OCH3 H3CO OCH3

Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7568–7570.

whereas:
OH OTIPS
(DHQD)2AQN is often a superior ligand: O ODHQD
18% ee 13% ee

Cl H3CO OCH3
90% ee vs. 63% ee, (DHQD)2PHAL O ODHQD H3CO OCH3

(DHQD)2AQN
AD, (DHQD)2PYDZ
O
Ph O
88% ee vs. 77% ee, (DHQD)2PHAL
O >99% yield, 98% ee (DHQD)2PYDZ =
O
H3CO
O
DHQDO ODHQD
CH3
78% ee vs. 44% ee, (DHQD)2PHAL O 98% yield, 97% ee N N

H3CO

O
96% yield, 91% ee
Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 448–451.
H3CO

Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1995, 117, 10805–10816.

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Myers Sharpless Asymmetric Dihydroxylation Reaction Chem 115
Regioselectivity of AD with diene substrates ((DHQD)2PHAL as ligand): Use of AD with chiral olefins:

CH3 OH CH3 OH CH3

Substrate Product % yield, % ee
H3C CH3 H3C CH3 H3C CH3
OH CH3 CH3 CH3
H CH3 H OH CH3 H OH CH3
CH3 CH3 78, 93 CH3 H CH3 H
H3C H3C CH3 H HO HO
OH H H H H
H H
HO HO
O OH O H H H
78, 92
H3C OEt H3C OEt
OH OsO4 alone 1 : 1.6

O OH O (DHQD)2-PHAL 10 : 1
93, 95
H3C OEt H3C OEt
OH
Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547, and refs.
CH3 therein.
CH3
H3C H3C 73, 98
HO O
OH HO
O
CH3 CH3 CH3
O
H3C 70, 98 OH OCH3
H3C HO
OH H3C O
O
H3C anti
CH3
in general, AD is selective for the more electron-rich double bond O
O
OCH3
Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7570-7571. +
O
H3C O
HO
H3C O
CH3
O
O OH OCH3
OH
O H3C O syn
O
H3C
AD H3C OH OCH3 CH3
O
(DHQD)2PYDZ A 56% yield, >99% ee
H3C OCH3

O Conditions anti : syn

HO
O
with ligand (as shown): A:B = ~6:1 OsO4, NMO 88% yield (mixture) 1.9 : 1
without ligand, only OsO4/NMO: A:B !1:10 H3C OCH3
OH
(DHQ)2PHAL (matched) 86% yield (anti) 54 : 1
B 10% yield, >96% ee
(DHQD)2PYDZ (mismatched) 86% yield (syn) 1 : 35

Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1995, 117, 10805–10816. Guzman-Perez, A.; Corey, E. J. Tetrahedron Lett. 1997, 38, 5941–5944.

4
Myers Sharpless Asymmetric Dihydroxylation Reaction Chem 115
Regioselective AD of terminal olefin of oligoprenyl derivatives: Examples in Syntheses of Natural Products:

CH3 CH3 CH3 H3C CH3 CH3 CH3 Cbz Cbz

AD, L* N N
H3C OAc HO OAc 1. MeC(OMe)3, PPTS
OH 2. AcBr
AD-mix-", MeSO2NH2 HO 3. K2CO3, MeOH
OH
Et 64%, 96% ee oC
N t-BuOH, H2O, 0
L* = N 120:1 position selectivity
N N Et >96:4 dr, 88%
H
O O N N
H
n-Pr H
O O n-Pr

n-Pr n-Pr Cbz

N N N

H
OCH3
Examples in Industry
H N O

OH 81%
OH N
K2OsO2(OH)4 (0.7 mol%) N
OH quinine
(DHQ)2PHAL (7.7 mol%)
Oi-Pr
aq. NMO, t-BuOH, H2O, 20 oC Oi-Pr
OCH3 Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 706–707.
OCH3
For conversion of diol to epoxide, see Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48,
2.5 kg, 13 mol
2.5 kg (94% pure) 10515–10530.
90% ee

• Olefin was added over a period of 6.5 h to the reaction mixture to prevent "second cycle" oxidation.
1. K2OsO2(OH)4 (2 mol%)
Ahrgren, L.; Sutin, L. Org. Process Res. Dev. 1997, 1, 425–427. (DHQD)2PHAL (5 mol%)
TESO K3Fe(CN)6, K2CO3
H CH3 MeSO2NH2
OTBS
MEMO t-BuOH, H2O, 0 oC
K2OsO2(OH)4 (0.2 mol%) 2. Ac2O, DMAP, Et3N
(DHQ)2PHAL (1 mol%) OH CH2Cl2, 23 ºC, 51% (2 steps)
O K3Fe(CN)6 (3.5 mol%) O OH
K2CO3, t-BuOH
OH OAc
HO
H2O (460 L), 0!5 ºC
15.38 kg, 105.2 mol 16.2 kg (98.4% pure) Me TESO
H3C O
in 5% MTBE/t-BuOH 99.4% ee N N AcO H CH3
CH3 H OTBS
MEMO
cortistatin A
Prasad, J. S; Vu, T.; Totleben, M. J.; Crispino, G. A.; Kacsur, D. J.; Swaminathan, S.; Thornton, J. E.;
Fritz, A.; Singh, A. K. Org. Process Res. Dev. 2003, 7, 821–827. Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc. 2008, 130, 16864–16866.
Adam Kamlet

5
Myers Sharpless Asymmetric Dihydroxylation Reaction Chem 115
• In the example below, use of the triisopropylsilyl protecting group was crucial to achieve regioselectivity:

OH OH O N2
Et AD-mix-! OH
MeSO2NH2 Et OH
MTBE, t-BuOH OH
OTIPS H2O, –12 oC Et
OTIPS OH O
62%, 91% ee O

(–)-monomeric lomaiviticin aglycon

Woo, C. M.; Gholap, S. L.; Lu, L.; Kaneko, M; Li, Z.; Ravikumar, P. C.; Herzon, S. B. J. Am. Chem. Soc.
2012, 134, 17262–17273.

• In the example below, a 4-phenylbenzyl ester was incorporated to serve as an expedient for
purification and enantioenrichment by re-crystallization:

1. K2OsO4•2H2O (0.25 mol%)

O (DHQ)2AQN (0.5 mol%) OH O
K3Fe(CN)6, K2CO3
H3C O H3C O
t-BuOH, H2O, 0 " 23 oC OH
Ph Ph
2. recrystallization
>20-g scale 81%, >95% ee

CH3
OAc
O

CH3O CH3
OH

methyl trioxacarcinoside A

Smaltz, D. J.; Myers, A. G. J. Org. Chem. 2011, 76, 8554–8559.

Smaltz, D. J.; Svenda, J.; Myers, A. G.; Org. Lett. 2012, 14, 1812–1815.
Adam Kamlet, Fan Liu