Epoxidation, Dihydroxylation, and the Utility of Epoxides and Diols Ready
Outline:
Epoxidation
Condensation approaches
Darzens condensation
Sulfur ylides
With organic peroxides
Peroxy acids
Peroxy iminic acids
Dioxiranes
DMDO
Enantioselective versions
Metal-catalyzed Approaches
V(O)(acac)
2
Sharpless AE
Metal Oxo’s
MTO
Fe, Pt and Mn-based
(Salen)Mn Jacobsen AE
Epoxide Ring Opening
Opening under acid or basic conditions
Organocopper additions
Reactions of epoxy alcohols
Dihydroxylation
General considerations
Sharpless AD
Conditions and scope
Mechanism
Applications

Ready Darzens Condensation
Ph
O
Condensations: general scheme
R
O
M LG
+
R
(carbene equiv)
Darzens condensation
O
+
Cl
CO
2
R
R
OM
LG
R
LG = leaving group
Base
O
+
Cl
O
OEt
KOtBu
90%
+
Cl
O
OEt
KOtBu
62%
1:1 dr
O
CO
2
R
Et
O
R
Ph
O
O
CO
2
Et
CO
2
Et
Br
PhCHO +
Ph
Cl
OHC
+
CO
2
Me
O
OEt
KOtBu
75%
O
LDA
70%
O
Ph
O
Ph
CO
2
Et
Ar
O dr = 3:4
CO
2
Me
Cl SiMe
3
O sBuLi Cl SiMe
3
R
Li
Si stabilizes anions (and cations)
R
SiMe
3
O
High yields
Magnus, JACS, 1977, 4536

Ready Sulfur Ylide Condensations

Ready Sulfur Ylide Condensations: Enantioselective Variants

Ready Epoxidation with Peroxides: general considerations
Most common peroxides:
AcOOH, mCPBA, MMPP, Oxone (KHSO
5
), DMDO

Ready Epoxidation with Peroxides
Payne Oxidation: mechanistically similar to peracids, but under basic conditions.
OH
H
2
CH
3
O
2
CN
KHCO
3
-CH
3
CONH
2
OH
H
3
H
N
C
H
O
O
'peroxy imidic acid' epoxidation driven by cleavage of
OO bond and by formation of amide
O
OEt
OEt
H
2
O
2
PhCN, MeOH
KHCO
3
70%
O
OEt
OEt
Dimethyl Dioxirane : Very strong oxidant; very easy to use
Organic Reactions, 2002, vol 61, p219 - ref includes prep for DMDO and experimental conditions for use.
prep:
O
O
KO S O
O
OH sold as oxone: 2KHSO
5
KHSO
4
K
2
SO
4
O O
Can be prepared in situ or as ~0.1M soln in acetone
Like peracids, reacts via spiro transition state
Most useful for prep of sensitive epoxides b/c byproduct is acetone
BnO
BnO
O
O
OBn
O
99%
20:1 dr
OBz
TBSO
O H
82%
N
Cbz
CO
2
Me
O
H
H
72% note: e- poor; no B.V. oxidation
N
DMDO quant.
BF
3
; DMDO
85%
O
N
N
O
For even more horsepower:
O O
1000x as reactive as DMDO
Prepared in situ (JOC, 1988, 3890; 1995, 3887)
CF
3

Ready Enantioselective Epoxidation with Dioxiranes
Several groups have developed chiral ketones as catalysts for asymmetric epoxidation. The most successful has been the Shi epoxidation. The catalyst is easily prepared from fructose and displays broad generality. Shi, Accts, 2004, 488
Principle drawbacks: requires slow addition of two reagent solutions
Enantiomeric catalyst more difficult to access
But: one of the most effective catalysts for AE.

Ready Sulfur Ylide Condensations: Application
S-trans configuration favored for dienes

Ready Metal-Catalyzed Epoxidation: VO(acac); brief review
Key point: V and Mo show increased reactivity and high selectivity Key points: VO(acac)
2 and stereoselective reliable, chemoselective

Ready Metal-Catalyzed Epoxidation: VO(acac); origin of selectivity
Preferred conformation
R
R gem
R trans
OH R cis
[O]
R
R
OH
O
R erythro
R : R
R
OH
O threo
R
R
For table: R1 = Me Æ threo; R2 = Me Æ erythro
Can use conformational analysis to understand and predict
A
1,3
A
1,2 strain between R strain between R
2 and R gem
Interaction b/w L and R
1
σ
C-R2
Æ π
* favors erythro cis and R
1 favors threo favors erythro favors erythro

Ready Metal-Catalyzed Epoxidation: Ti(OiPr)4
See lecture notes from Synthesis and Catalysis
See handout from Andrew Myers

From Sharpless, Masamune, Science, 1983, vol 220, 949; see also Tet, 1990, 254.

Ready Metal-Catalyzed Epoxidation: inspiration
Much research has gone into mimicking cytochrome P450, natures oxidant. The objectives are generally three-fold: 1) Identify highly reactive catalysts. 2) use H2O2 as the terminal oxidant and 3) induce asymmetry.

Ready Metal-Catalyzed Epoxidation: MTO
Rev on epox with H2O2: Chem Rev 2003, 2457.

Ready Metal-Catalyzed Epoxidation: Epox with H2O2
TMTACN: Trimethyl-triazacyclononane (TACN)
Discovered by group from Unilever (oxidative stain removal)
De Vos, TO, 1998, 3221
TMTACN (0.15%), MnSO
4
(0.1%), Oxalic acid (0.3%)
H
2
O
2
(1.3 equiv) O
N
N N
TMTACN
Expensive ligand (difficult to make)
Mostly GC yields
Minimal Functionality demonstrated
Fe-based system
White, Doyle, Jacobsen, JACS, 2001, 7194
N
N
N
N Fe[SbF
6
]
2
AcOH, H
2
CH
3
CN
O
2 O
Assembles into di-iron core (2 AcO bridges)
Mimic of MMO
Good yields for terminal olefins
Little functionality allowed
Pt-based system
Strukul, JACS, 2007, 7680
Asymmetric version: JACS, 2006, 14006
Ph
2
P OH
2
Pt
P
Ph
2
C
6
H
5
OTf
(2 mol%)
H
2
H
2
O
2
(1 equiv)
O/DCE
O
Propose addition to Pt-coordinated olefin, but details have evolved
Good yields for terminal, unhindered olefins
Very sensitive to sterics and electronics

Ready Metal-Catalyzed Epoxidation: Jacobsen Epoxidation
Background: Collman (review: Science, 1993, 261, 1404) showed metal porphyrin complexes could catalyse epoxidation
Kochi (JACS 1986, 2309) showed that (salen)Mn and (Salen)Cr complexes could catalyze epoxidation
Burrows (JACS, 1988, 4087) showed that (salen)Ni complexes could catalyze epoxidation
Katsuki (TL, 1990, 7345) showed moderate enantioselectivity with (salen)Mn complexes
Ligand synthesis:
O
2
R
OH
+
SAL icylaldehyde deriviative
Ethylene diamine ( derivative
Catalytic epoxidation:
EN )
R
N N
OH HO salen ligand
R t-Bu
N
Mn
O
N
O
Cl t-Bu t-Bu t-Bu
0.1 - 4 mol%
O
C sp2
R
+ NaOCl
(pH 10-13) C sp2
R
Ar R
87-98% ee
JACS, 1991, 7063 n
Warning:
C sp3
C sp3 and
Ar
R
Ar
R R
Ar
R
92-98%ee up to 97%ee
JOC, 1994, 4378
TL, 1995, 5123
R
R
R
R
>90%ee >80%ee trans epoxide!
TL, 1991, 6533
JOC, 1993, 6939 poor substrates (slow, poor ee)
Ar
80's
JACS, 1994, 9333
TL, 1995, 5457
Review: Chem Rev. 2005, 1563

Ready Metal-Catalyzed Epoxidation: Jacobsen Epoxidation: application
+ NaOCl
(salen)MnCl
R
3
N
+
-O
amine oxides in Jacobsen AE:
TL, 1996, 3271
O
+ NaCl
Cat. H
2
CH
3
SO
CN
4
H
2
O
OH + AcOH
NH
2 N
O
CH
3 no byproducts
Known as Ritter reaction
OH
N
OH
OH
H
N
Ph
OH
N
N
O
CONH(iPr)
Indinavir - HIV protease inhibitor
(Merck)
N
Senanayake, Reider, Jacobsen, Org. Syn, 1999, 76.

Ready Metal-Catalyzed Epoxidation: Jacobsen Epoxidation: Mechanism in general, three different mechanisms possible for metal oxo epoxidation:
[2+2]
O
M n
+
O
M
M n-2
+
O concerted
O
M n
O
M n
M n-2
+ electron transfer
O
M n
Experimental data: secondary KIE's
O
M n-1
M n-2
+
O k
H
/k
D
= 0.82
H k
H
/k
D
H
= 0.91
Sp2
H
H
H
Sp2 -> Sp3
O
Mn
H k
H
/k
D
= 1.00
Recall enynes and dienes
R
R
(salen)MnO
R k
H
/k
D
H
= 0.90
R
R R cis O
Mn iv
Ph
R
Radical traps
R
2
R
1
Ph
(salen)MnCl
R
1
R
1
NaOCl
R
2
O Ph R
2
O Ph
Ph
Mn Mn
Norby, Akermark, ACIEE, 1997, 1723
Note: these authors interpret the data in terms of a [2+2] mechanism
O
M n-1
Ph
R
O trans various ring-opened products
R1 R2 epox ring-opened
H
Me
Me
H
100:0
56:44
O

Ready Epoxide Ring-Opening: Overview
Three common classes of epoxide ring-opening reactions
Nucleophilic addition
Nu
Nu
-
O generally stereospecific
OH
Isomerization
Lewis acid
O generally stereospecific
O
Elimination
H
Base
O
Stereoretentive
OH
General considerations:
O
Nu H
+
/M
+
+
M
O
Nu
OH
Addition to more stable partial cation
Common for solvolysis
Common with strong Lewis or protic acids
Total SN1 = loss of stereochemistry
HO
Nu-
Nu
Addition to less hindered C
Often good reaction for H-, RO-, RS-, CN-, N3-, R2N
Common with weak Lewis acids (esp R2N, CN-
Stereospecific
Generally, bond-breaking more advanced than bondmaking with epoxides.

Ready Epoxide Ring-Opening: Overview

Ready Epoxide Ring-Opening: Diaxial opening
O
Furst-Plattner Rule : experimentally observed that cyclohexene oxides react such that the nucleophile approaches along an axial trajectory.
Nu path a
Nu a
Nu b
O twist-boat-like TS
+ ~5 Kcal/mol
OH disfavored
O =
Nu
Nu
O path b
Furst, Helv Chem Acta, 1949, 275
Barton, " 1954, 4284
H H
O
Chair-like TS
OH favored
Notes: Faster-forming product may be less stable product
Same analysis applies to conjugate additions, additions to halonium ions, additions to cyclic imines.
Also known as 'trans-diaxial rule' for obvious reasons
H
H
2
O, cat. H
2
SO
4
HO
HO H
O
H
LiAlH
4
MeOH
H
+
HO
MeO
HO
H
H
O
H
HO
LiAlH
4
HO
MeOH
H
+
MeO
H
H

Ready Epoxide Ring-Opening: Carbon nucleophiles
Addition of carbon-centered nucleophiles usually involves organocopper chemistry
O + R
2
Cu(CN)Li
2 low temp,
THF or Et
2
O OH
R
Review: Lipshutz, Tet, 1984, 5005.
Generally high yielding, stereospecific
Addition to less substituted C
Often waste 1 equiv R
Problems:
Tetrasubstituted
Hindered trisubstituted
Vinyl epoxides (good Sn2’)

Ready Epoxide Ring-Opening: Additions to epoxy alcohols
OH base
Ph
Nu
OH
O O
Payne rearrangement
(Major from SAE) (Major from SAE - KR)
O
Ph O
OH
0.5N KOH, Et
2
NH slow
OH
OH
Nu
OH
Ph O
0.5N KOH, Et
O
Ph
Lewis-Acid promoted addition:
Sharpless, JOC, 1985, 1557, 1560
Fast
2
NH
O 1.5 equiv Ti(OiPr)
4
+ NuH
OH
O
O
X
X = OH, NHBn
OH
Nu = Et2NH
Nu
O
X
+Ti
-Ti
+
Ph
Ph
O
R
OH
OH
NEt
2
Sharpless
Aldrichimica Acta,
Nu
16 , 1983 , 67
1:20
6:1
O
OH
L n
Ti
Nu O
OH
O OH generally >5:1 regioselectivity
Nu = R
2
NH, ROH, RSH, TMSN
3
KCN, NH
4
X, NH
4
OBz
Ti increases rate and selectivity
,
X e.g. w/Et
2
NH: +Ti 20:1 (90%y)
-Ti 3.7:1 (4%y) origin of selectivity: orbital overlap? Least motion? Charge distribution?
R
O
OH
OH R
[CH
3
OCH
2
CH
2
O]AlH
2
Na OH
R
1
OH
2
OH
Sharpless, JOC, 1982, 1378; Kishi, TL, 1982, 2719
R hex
CH
2
OBn
OBn
1:2
1:1
5:1
40:1

Ready
O
O
BF
3
O
Lewis-acid catalyzed rearrangement of epoxides
M
O
H
O CHO
OTBS cat. MeAl(OAr)
2
88%
OTBS
Yamamoto, JACS, 1989, 6431
Br
O
H
Ph
O
Rearrangement to more stable carbocation
Often high degree of stereospecificity
Ph CHO
10% MeAl(OAr)
2
'Yamamoto's catalyst' tBu
OAr = O Br tBu
OTBS
O
OTBS
Br cat. MeAl(OR)
2
CHO
Chen, JACS, 2009, ASAP
O
OBz
Ph
O
OM
O
Yb(OTf)
3
Ph
O
O
O
TsOH
O
Ph
O
OH
O
OBz
88% ee
Shi, JACS, 1999, 4080
90% ee

Ready Conversion of epoxides to allylic alcohols

Ready Conversion of epoxides to allylic alcohols

Ready Dihydroxylation – general considerations
Stark, OL, 2006, 3433

Ready Dihydroxylation – OsO
4
-NR
3
Best conditions for dihydroxylating olfefin: Upjohn conditions
1 mol% OsO
4
H
2
, 1.05 equiv NMO
O/Acetone
HO
OH
O
NMO:
Catalytic Os
Easy workup ([H-], H+)
R3N may accelerate rxn
N
O
O
O
Os
NR
3
O
Os(VI)
Upjohn Co
TL, 1976 , p1973
N
O
O
O
OH
O
N-methyl-morpholine-N-Oxide
(NMO)
Ph
25%
OH
OH
OH
(from cis olefin)
>95%
OAc
OH
OH
OH
OH
OH
91% 79%
OH
OH
O
78%
O
O
O
Os
NR
3
O
Os(VIII)
OH
O
Os OH
O
NR
3
Os(VI)
OH
OH
65%
O
O
O
Os
NR
3
O
Os(VI)
H
2
O
HO
HO

Ready Sharpless Asymmetric Dihydroxylation: overview
Sharpless asymmetric dihydroxylation
Shapless, Chem Rev 1994, 2483.
General considerations:
Strategy based on observation that tertiary amines accelerate reaction.
Monodentate ligand required for turnover
Ligands based on cinchona alkaloids
Simple experimental protocol
One of the most general enantioselective reactions
R
3
N*/OsO
4 oxidant
(cat)
HO OH
R
3
N
N* = Linkers:
Lig O
N N
O Lig
[linker]O O[linker]
N N
OMe
Dihydroquinidine (OH)
(DHQD)
Pseudo-enantiomers
Lig O
N
MeO
Dihydroquinine (OH)
(DHQ)
N N
Phthalazine
(PHAL) used in AD-Mix; therefore most used
Lig O
O Lig N
Ph
N
O Lig
Pyridazine
(PYDZ)
Ph
Pyrimidine
(PYR)
Lig O
Lig
O
O
Anthraquinone
(AQN)
N N
X X
O
O
Lig
O Lig
Ph Ph
X = N: DPP
X = CH: DP-PHAL

Ready Sharpless Asymmetric Dihydroxylation: details
AD-Mix-
AD-Mix (Lig = DHQ)
AD-Mix (Lig = DHQD)
K
3
Fe(CN)
6
K
2
CO
3
Lig-PHAL
K
2
OsO
2
(OH)
4
0.94 g (3 equiv)
0.41 g (3 equiv)
7.8 mg (1 mol%)
0.74 mg (0.2 mol%)
1.36 g tBuOH:H
2
O (1:1)
1 mmol
R
3
N-OsO
4
R s
R
L
R
M
H
AD-Mix-
AD-Mix-
AD-Mix-
OsO
4
HO
+
L
OH
O
O
Os O
O
NR
3 osmate ester
Proposals to rationalize stereochemistry:
Corey, JACS, 1995, 10805; 1996, 319
Sharpless, JACS, 1994, 8470 org.
aq.
2K
2
2H
4
CO
3
O
HO
HO
O
OH
Os
OH
O
Os(VIII)
HO
HO
OK
OH
Os
OH
OK
Os(VI)
2K
2
4H
4
CO
3
O
HO OH
R s
R
L H
R
M
R s
R
L
H
HO OH
R
M net reaction
HO
2K
4
Fe(CN)
6
2KHCO
3
Fe(II)
2K
3
2K
2
Fe(CN)
CO
3
Fe(III)
6
+ 2H
2
O + 2K
2
CO
3
+ 2K
3
Fe(CN)
6
OH
+ 2KHCO
3
+ 2K
4
Fe(CN)
6

Ready Sharpless Asymmetric Dihydroxylation: scope
Shapless, JOC,
1995, 3940

Ready Sharpless Asymmetric Dihydroxylation: mechanism
A non-linear Eyring plot is taken as evidence for a stepwise mechanism. Sharpless interpreted these data to support a mechanism involving [2+2] cycloaddition (to yield an osmaoxetane) followed by ring expansion.
R'
R
4: R = R' = n-Butyl
5: R = Ph, R' = H
6: R = n-Octyl, R' = H
OsO
4
(1 equiv)
ODHQD
N
(2-20 equiv)
R
OH
OH
R'
P = e.r.
Sharpless, ACIEE, 1993, 1329

Ready Sharpless Asymmetric Dihydroxylation: mechanism
Corey observed enzyme-like kinetics which he interpreted in terms of reversible binding followed by rate-limited [3+2] cycloaddition (aka Criegee mechanism).
4
-1
1
3
4
cat
JACS, 1996, 319

Ready Sharpless Asymmetric Dihydroxylation: mechanism
Houk, Singleton and Sharpless performed natural abundance KIE studies of the dihydroxylation of tBu ethylene. The data are more consistent with a concerted [3+2] addition. JACS, 1997, 9907
0.05
0
-0.05
-0.1
-0.15
-0.2
H2 Hcis Htrans C2 C1
[3+2]
[2+2] expansion

Ready Sharpless Asymmetric Dihydroxylation: applications
‘no other known organic reaction comes close to achieving such enormous scope coupled with such great selectivity.’ – Sharpless in Chem Rev.
OL, 2008, 5007 (95% ee)
OL, 2009, 293. Often AD-Mix is best way to do dihydroxylation regardless of stereochemistry d.r. 4:1 (15 major); [O]/[H-]: 9:1 (14 major); ACIEE, 2008, 3426

Ready Sharpless Asymmetric Dihydroxylation: applications
Diol-to-epoxide is common application of AD. ‘d’ in scheme is
1. TsCl. 2. K
2
CO
3
Furstner, ACIEE,
2006, 5510, From the conclusion:
Synthesis of amphidinolide A: Trost, JACS, 13589.
In scheme 2: d: 11:1 24/25, 90%ee.