Epoxidation & Opening PDF

Epoxidations of Alkenes: The Reagents
R1 R2 R3 R4 [O] R1 R3
R2 O R4
vElectrophilic reagent - electron rich double bonds react faster.

vNucleophilic reagent conjugate carbonyl derivatives

A. m-Chloroperoxybenzoic acid (MCPBA)

O O H O
Mechanism: In the case of an allylic alcohol, an additional hydrogen bond is present (directing effect):
O O H O O H O Cl
Cl
Cl
Electrophilic reagent
Nucleophilic substrate
O H

B. Dioxirane

Dimethyldioxirane (DMDO) or triuoromethylmethyldioxirane (TFDO)
R1 O H3C CX3 Oxone O O H3C CX3 O H3C R2
R3 R4 R1 R3
R2 O R4
X = H or F
CX3
vCan be isolated as a solution in the corresponding ketone or produced in-situ

vCould be directed by hydrogen bonding with allylic alcohols, but more sensitive to steric hindrance than other reagents.

Potentially explosive!
Always be careful when exposing acetone to strong oxidant

Adam Acc. Chem. Res. 1989, 22, 205-211.

Murray Chem. Rev. 1989, 89, 1187-1201.
Adam Eur. J. Org. Chem. 1998, 349-354.
Adam J. Org. Chem. 1996, 61, 3506-3510.


C. Metal-Catalyzed Epoxidations: Peroxide-Based Catalysts

VO(acac)2 or Ti(i-PrO)4 R O M R O M
+
t-BuOOH
O M-OR
+
O O M
R = H, alkyl, etc.
R O O M
Capable of being directed by hydroxy groups.


C. Metal-Catalyzed Epoxidations: Oxo- Based Catalysts

R R N M R N M = Fe, Mn, Ru, Cr R O O R N
N R N M
O [O] M Y M Y [O] = NaOCl, Oxone, H2O2, ROOH, RC(O)OOH....
Efcient for the epoxidation of unfunctionalized olens

Model on Cytochrome P-450.


D. Nucleophilic Epoxidations

HO HOO O or ROO
O O O O
O Me Me H AcO H H AcO Me H2O2 NaOH H H Me H Me
O Me O
Chemoselectivity is inverse to the one of electrophilic reagents.

Epoxidations of Alkenes: Chemoselectivity

H m-CPBA HO DCM O HO 75% H O O m-CPBA DCM
m-CPBA favoured reactions with the most electron donating double bond.

O
H O 71% O
Epoxidations of Alkenes: Chemoselectivity

m-CPBA VO(acac)2 t-BuOOH 1.00 HO O
1.00
H m-CPBA
OH 0.55 (92:8) >200 (98:2)
DCM O 73% O H
OAc 0.046 (37:63) ---
HO
OH 0.42 (60:40) 10.0 (98:2)
VO(acac)2 TBHP, 80 C
OH DMDO Acetone, MeOH
OH
No H-bond directing effect with DMDO.

OH
Epoxidations of Alkenes: Diastereoselectivity

Ar OH O R R R H R R O O H O R R OH
OH MCPBA
OH O
but...
OAc MCPBA
OAc O
4:1
10 : 1
% syn
HO
HO O
n n
n 0 1 2 3 4
VO(acac)2 99.2 99.7 99.6 97 91
MCPBA
84 95 61 0.2 0.2
Epoxidations of Alkenes: Diastereoselectivity

OH Me MCPBA OH Me O
>20 : 1
Me MCPBA HO OH HO
1 isomer
Me
OH
O HN HO HO Me MCPBA HO HN
O Me Me MCPBA O HO
1 isomer
Me
OH
O
1 isomer
OH
Carboxamides are better H-bonding directing groups

O'Brien Tetrahedron Lett. 1999, 40, 391-392. A mixture of oxone/triuoroacetone is sometimes better PG PGO PGO PGO O + PGO trans PGO cis PGO O TBS TES Me Bz trans:cis MCPBA Oxone/CF3COCH3 56:44 39:61 75:25 80:20 98:2 98:2 94:6 81:19
9

Epoxidations of Alkenes: Diastereoselectivity with Acycli Olens

O
+
O OH
anti syn Vo(acac)2
OH
OH
Entry
Substrate
MCPBA VO(acac)2, t-BuOOH MCPBA ~120 OH H2 R R1 R4 R3 H OH R2 R1

1 : 1.5
Me
1 4:1
~50 R4
OH Me
2
Me OH
19 : 1
1:1
R3
Me
Me OH
4:1
1 : 1.5
Me Me OH Me Me OH
1 : 2.4
1 : 19
Rgem Rtrans(H) H R OH
A(1,2) strain
Rgem Rtrans(H) H O R OH
Me
1:5
1 : 19
H Rtrans(H) Rcis R OH
H
A(1,3) strain
Rtrans(H)
R O Rcis OH
10

Epoxidations of Alkenes: Diastereoselectivity with Acyclic Olens

Cl MeO
Me NH
OH Me Me OTBS
Ti(Oi-Pr)4, TBHP Synthesis of maysine
Cl MeO
Me NH
OH O Me
Me OTBS
Me
OMe OMe OMe
Me
OMe OMe OMe
Diastereoselection: >20:1
11

Epoxidation of Homoallylic Alcohols TBHP, VO(acac)2

OH Me Me
OH
O Me
OH Me Me
OH
O
4.6 : 1
2:1
Me
OH Me
Me Me
OH
Me Me
OH Me Me Me
8:1
OH Me O Me
Me
Me
O Me Me
8:1
Me H
Me Me H
H O VL2OOt-Bu H Me
12

Catalytic Asymmetric Sharpless Epoxidation

Proposed transition state model:
R3 R1 R2
1.0 eq
OH
Ti(OiPr)4 (0.05 eq) (+)-DET or DIPT (0.06 eq) t-BuOOH (2 eq) 4A mol sieves -20 C, CH2Cl2
R1
O R2
R3 OH OR RO O O Ti
RO2C O O CO2R O
R3 R2 O Ti CO2R O O R1
ee usually 80-94% yield: 63 - 99% Z-substituent: lower ee's
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.

Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
Johnson, R. A.; Sharpless, K. B. Catalytic Asymmetric Synthesis. Ojima Ed. p. 103.
Katsuki, T.; Martin,V. S. Organic Reactions 1996, 48, 1-299

t-Bu RO
Mnemonic model: MISMATCHED PAIR (-)-(S,S)-D-tartrate (-)-(S,S)-D-tartrate MATCHED PAIR (-)-(S,S)-D-tartrate
R2 R3
R1 OH R3
R2 R H
R1 OH R3
R2 H R
R1 OH
(+)-(R,R)-L-tartrate
(+)-(R,R)-L-tartrate MATCHED PAIR
(+)-(R,R)-L-tartrate MISMATCHED PAIR

13

Catalytic Asymmetric Sharpless Epoxidation: Substrate Scope

O
94% ee
Pr
OH
C7H15
O
96% ee
OH
C8H17
O
94% ee
OH
Ar
O
>98% ee
OH
Me
O
91% ee
OH
O R
R = C7H15
86% ee >80% ee 85% ee
OH
R = C8H17 R = PhCH2OCH2
Ph
Me OH O
93% ee
O OH
95% ee
OH
>98% ee
O OH
Ph OH Ph
Me OH
94% ee
95% ee 90% ee
R OH
R = C3H7 R = C14H29
95% ee 96% ee
14

Catalytic Asymmetric Sharpless Epoxidation: Kinetic Resolution

OH Me
(+)-DIPT fast 98
OH O Me
+
OH O
2
Me
OH OH Me
(+)-DIPT
OH Me Bu
>98% ee 53% conversion
OH O
slow 62
OH Me
+
O
38
Me Me
OH n-C6H13
OH
Me
n-C5H11 O OH
Ti(Oi-Pr)4, (+)-DIPT TBHP (0.6 equiv), -21 C >98% ee, 53% conversion
O Me n-C5H11 O OH
+
HO
O n-C5H11 Me H
O Me O
n-C5H11
OH
15

Synthesis of (+)-Trehazolin

Ledford, B. E.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 11811-11812.
OH OH HO HO O HO HO HO OH HO HO OH N NH O OH HO
+
HO HO
NH2 OH
H OH
H2N
O OH OH
OH O
OH
1. NaH, CpLi, THF, 60% 2. NaH, Cl3CCN, THF, 95%
HO H NH O CCl3
I(sym-collidine)2ClO4 NaHCO3, aq. CH3CN
Cl
O N CCl3
16


HO O N
1. TIPSOTf 2,6-lutidine 2. Li2NiBr4, THF 80%
CCl3
TIPSO HO O N CH2Cl
1. BF3OEt2 2. Bu3SnH, Et3B, NaBH4
TIPSO
Br O
O O
TIPSO
Br O N H CCl3
N H
CCl3
1. PPTS, CH3CN aq. 2. Ac2O, DMAP, 77%
TIPSO AcO OAc NH CH2Cl

1. Chx2BH 2. H2O2 3. Swern 4. PhMgBr LiBr, THF 5. Swern
TIPSO AcO OAc NH
O Ph
1. h 2. OsO4, NMO
TIPSO AcO
OH OH
OAc CH2Cl
NH CH2Cl
17


OH O OH O
1. BnCl 2. Bu4NNCS, BF3OEt2
SCN O BnO BnO OBn OH
OH
OH TIPSO AcO OAc O NH CCl3 SCN

2.
OH OH
OBn
1. 4N HCl
O HO O OH OBn HO HO OH OH H N NH S
OBn OBn
BnO BnO
1. HgO, Et2O/Me2CO 2. PdOH/C, H2 (1 atm), MeOH, 40%
OH
DMAP, MeOH
OH O HO HO OH HO
18

OH OH
OH H N
NH O
Epoxy Alcohols: Synthetic Applications

NUC O
OH O
a,b d
NUC HO OH
OH NUC OH
OH HO NUC
19


Reactions of Type a:

OH HO O
Mitsunobu ROH
OR O
MsCl or TsCl or Tf2O RLi or R2CuLi
H O O
OMs (OTs, OTf)
R O
OH
1. TsCl 2. (n-C9H19)2CuLi, ether
Disparlure
100% ee (55% yield after recrystallization of dinitrobenzoate) 1. TsCl, pyr 2. NaI 3.
TBDPSO
Me O O Me OH
OLi
TBDPSO Ot-Bu
Me O O Me
CO2t-Bu
20


1. MsCl, Et3N 2. NaBr 3. (i-PrO)2Si(Me)CH2MgCl 4. H2O2
Me Me
Me O OH
Me Me
Me O
OH
DIBAL-H
OTs
CH2Cl2, 0 C
R
98%
Me OH
21


Me O I
Zn, AcOH
Me
Chem. Comm. 1990, 843.
OH
O O O OH OPMB
Cp2TiCl
OH O O OPMB
22


1. t-BuCOCl, Et3N 2. TBDPSCl, imidazole
BnO OH
OH
BnO
3. DIBAL 4. (-)-DET, TBHP
OH O OTBDPS
1. Swern 2. Ph3P=CHCO2Me
BnO TBDPSO OTBDMS

1. Sharpless 2. Red-Al 3. F-
OH
1. DIBAL 2. t-BuCOCl, pyr 3. TBDMSCl, imidazole 4. DIBAL
BnO
O OTBDPS
COOMe
BnO OH OH OH
OH
23


R O NPh O O OMe
Pd(0), PhNCO
O R
O
Pd(0), CO2
R OMe O O O
O OMe
OH R
O OMe
Pd(0) HCO2H
O R
O OMe SmI2
DIBAL-H
OH R OH
OH R
O OMe
Me O R OH
LiCuMe2 R
Me OH
68% (+13% of diastereomer)
OH Me
24


R O O R' SmI2
or NaBH4-(PhSe)2
R OH O
R'
O O
OH
1. i-BuOCOCl 2. CH2N2 3. h, EtOH
R OH
CO2Et
Kishi, Tetrahedron 1981, 3873.
O BnO Me OH
LiCuMe2 BnO
OH OH Me Me
Me O R OH
LiCuMe2 R
Me OH
68% (+13% of diastereomer)
OH Me
25


Synthesis 1988, 854.
OPG OH O O OH O TsO OPG
Me O
H OH
OH
endo-brevicomin
OTs
Me O
OH O O OH O
OH OPG TsO
OH
exo-brevicomin
OPG
26

Epoxy Alcohols: Payne and Pummerer Rearrangement

OH OH R O OH R OH Nuc
Nucleophiles: OH-, BH4-, TsNH-, CN-, N3-, R2NH
O R
Nuc
1. PhS 2. Me2C(OMe)2, H+
OPG R OPG SPh
1. MCPBA 2. Ac2O 3. DIBAL
OPG O R OPG H
With K2CO3, MeOH: epimerization
27

Chemoselective Ring-Opening

Nuc O R OPG
Nuc
OH OPG
+
R OH
R Nuc
OPG
O R
O O
Nuc O
Nuc
R OH
Nuc = H, N3, PhS, Me
OH O R OH
Nuc
NEt2 OH
+
R NEt2
R OH
OH
Et2NH, reux: Et2NH, Ti(OiPr)4, reux:
3.7 : 1 < 1 : 10
O R OH R
O O R2HN O
NaH R
OH O HN O
28


R OH
OH
DIBAL-H
O R OH
Red-Al THF
OH R
90%
OH
29


HO X
5,6-endo-tet are disfavored
OH
HO X
HO X H
OH Ph O O BnO OH O OH
Ph
O O BnO
OH O
OH
Vinyl-directing group:
OH X X
O X
OH
Applications: Brevetoxin's synthesis Nicolaou J. Am. Chem. Soc. 1995, 117, 10227.
H BnO BnO
Me O OH Me CO2Et
PPTS, CH2Cl2 97%
H BnO BnO
Me
OH Me H CO2Et
30

Oxidation of Suldes, Selenides and Amines

Me
C6H4Me
Ti(OiPr)4, DET CHP
Me
C6H4Me O
93% ee (90%)
OH Ph N
Ti(OiPr)4, (+)-DIPT CHP Ph
OH N + Ph
OH N O
31

Catalytic Epoxidation of Alkenes: Mn-Salen

References: Jacobsen, E. N. In Comprehensive Organometallic Chemistry II, Vol. 12, Chapter 11.1. Jacobsen, E. N. In Catalytic Asymmetric Synthesis, Ojima Ed. 1993, Chap. 4.2 Recent mechanistic paper: J. Am. Chem. Soc. 1998, 120, 948.
Catalyst:
H N Mn t-Bu O Cl t-Bu O N
t-Bu
t-Bu
Reaction:
R1 H
R2
+
Catalyst (0.5-10 mol%)
R1
R2
+
R1
NaOCl H O H
H O R2
32

Epoxidation of Unfunctionalized Olens: The Jacobsen Catalyst - Ligand Design

(a)
D Ph Ph N Mn B O t-Bu C
(b)
Ph
A
(favored)
N O t-Bu
Me
Ph H
Me H
90% ee

84% ee

D (favored)
H A t-Bu N Mn O t-Bu Ph N Mn O Cl O Ph N O N
B t-Bu
t-Bu C
<10% ee

Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L.! J. Am. Chem. Soc. 1991, 113, 7063-7064.

33

Jacobsen Catalytic Epoxidation of Unfunctionalized Alkenes

B (favored)
C (disfavored)
D (disfavored)
Proposed transition structures for the epoxidation of cis--mehtylstyrene. (A) epoxidation with catalyst 13 and (B-D) epoxidation with catalyst 14. [Structures created with the program Chem 3D based on the coordinates - 6 salt). frm the X-ray crystal structure of 13 (PF
Jacobsen, E. N.; Wei, Z.; Loebach, J. L.; Wilson, S. R. J. Am. Chem. Soc. 1990, 112, 2801-2803.

34

Jacobsen Catalytic Epoxidation of Unfunctionalized Alkenes: Substrate Scope

NaOCl + R N O t-Bu
H N Mn O Cl t-Bu O N
(4 mol%) t-Bu Ar R O X
>95% ee n
90-98% ee
t-Bu
Ph
CO2i-Pr
O
NaOCl (S,S)-catalyst
96% ee 87-94% ee
R1 R2
90-98% ee (trans epoxide)
O O R
Higher ee if:! -R is bulky! -Allylic oxygen

94% ee
O
NaOCl (R,R)-catalyst 93% ee
Ph
86% ee
R R R
88-95% ee
Ph
80-86% ee
Ar
<40% ee
Ar
35

Jacobsen Catalytic Epoxidation of Unfunctionalized Alkenes: Substrate Scope

H N Mn t-Bu O Cl t-Bu R1 R2 + NaOCl OMe N Ph OH N 25 mol% O N
(4 mol%) t-Bu R2 O
t-Bu R1
Cl / PhCl
Ph
Ph O
Ar
CO2i-Pr O
t-Bu
Et O
27 : 1, trans:cis 90% ee
Chang, S. B.; Galvin, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 1994, 116, 6937-6938.

36

Jacobsen Catalytic Epoxidation of Unfunctionalized Alkenes: Synthetic Applications

C2F5 O
O C2F5
O OH
Bell, D.; Davies, M. R.; Finney, F. J. L.; Geen, G. R.; Kincey, P. M.; Mann, I. S. Tetrahedron Letters 1996, 37, 3895-3898. ! ! Buckle, D. R.; Eggleston, D. S.; Pinto, I. L.; Smith, D. G.; Tedder, J. M. Bioorg. Med. Chem. Lett. 1992, 2, 1161-1164.

94% ee, 75% y.
O
BRL 55834
CH3CN H2SO4 / SO3
N OH
>99% ee after NH2 recrystallisation
OH N
Ph H N O
OH
O
~85% ee
Hexanes
N O
NHt-Bu
Indinavir
Jacobsen, E. N.; wLarrow, J. F.; Jacobsen, E. N. Org. Synth., 1998, 75, 1-11.! Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; Mcdaniel, S. L.; Darke, P. L.; Zugay, J.; Quintero, J. C.; Blahy, O. M.; Roth, E.; Sardana, V. V.; Schlabach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I. W.; Vastag, K.; Ostovic, D.; Anderson, P. S.; Emini, E. A.; Huff, J. R. Proc. Nat.l Acad. Sci. USA 1994, 91, 4096-4100.

37

Jacobsen Catalytic Epoxidation of Unfunctionalized Alkenes: Synthetic Applications

OMe O N Ph CDP840
Lynch, J. E.; Choi, W. B.; Churchill, H. R. O.; Volante, R. P.; Reamer, R. A.; Ball, R. G.! J. Org. Chem. 1997, 62, 9223-9228.

OMe O N
O Ph
89% ee, 58% y.
O NBoc
MeO2C HN O N O N H
Duocarmycin SA
OMe OMe OMe
93% ee OBn 70% y.
Boger, D. L.; McKie, J. A.; Boyce, C. W. Synlett 1997, 515.

38

Catalytic Asymmetric Epoxide Ring-Opening Chemistry

OH
NuH Chiral catalyst
Desymmetrization

R R
R Nu
Kinetic Resolution

R
O R
NuH Chiral catalyst
O R
OH
+
Nu
Nielsen, L. P. C.; Jacobsen, E. N. in Aziridines and Epoxides in Organic Synthesis, Yudin Ed, 2006, Chap. 7, p. 229.

39

Desymmetrization of meso-Epoxides: Nitrogen-Centered Nucleophiles

H N Cr t-Bu O Cl O t-Bu N
t-Bu 2 mol% X N3 OH
t-Bu
1. TMSN3 (1.05 equiv) / ether, rt 18-36h 2. CSA / MeOH
OH N3
80% y., 88% ee
OH FmocN N3
85% y., 92% ee (-10 C)
OH O N3
80% y., 95% ee
OH O N3
80% y., 98% ee
OH N3
80% y., 94% ee
OH N3
80% y., 94% ee
Seminal work: Nugent, W. A. J. Am. Chem. Soc. 1992, 114, 2768-2769.! Martinez, L. E.; Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J. Am. Chem. Soc. 1995, 117, 5897-5898.! Hansen, K. B.; Leighton, J. L.; Jacobsen, E. N. J. Am. Chem. Soc. 1996, 118, 10924-10925.! Thiol as nucleophile: Wu, M. H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 5252-5254.

40

Desymmetrization of meso-Epoxides: Oxygen-Centered Nucleophiles

H N Co t-Bu O t-Bu O OAc N
H O t-Bu
1-2 mol%
OH
HO HO
96% y. 98% ee
t-Bu
OH O OH
Wu, M. H.; Hansen, K. B.; Jacobsen, E. N.! Angew. Chem. Int. Ed. 1999, 38, 2012-2014.

HO
86% y. 95% ee
OH O OH
OH HO 45% y. 99% ee O
OMe O HO HO OH
81% 96% ee
OH Me O
TsOH 60% (2 steps)
O O O
41

Desymmetrization of meso-Epoxides: Oxygen-Centered Nucleophiles

O H N Co t-Bu O t-Bu O OAc t-Bu t-Bu
1-2 mol%
H N
O O
Meng, Z. Y.; Danishefsky, S. J.! Angew. Chem., Int. Edit. 2005, 44, 1511-1513.! Yun, H. D.; Meng, Z. Y.; Danishefsky, S. J.! Heterocycles 2005, 66, 711-725.

HO O O
Merrilactone A
CO2Me DMDO / CH2Cl2 CH2OH CH2OH O
CO2Me (R,R)-(salen)CoOAc CH2OH THF, -78 C, then -25 C CH2OH HO O
CO2Me 86% y., 86% ee CH2OH
OTBS O O MeO2C O Br OTBS O Merrilactone A O O MeO2C H MeO
CO2H CO2Me
42

Hydrolytic Kinetic Reaction of Terminal Epoxides

H R t-Bu
1-2 mol%
O R
H2O
Chiral catalyst (0.2-2.0 mol%)
O R
OH
+
OH
t-Bu
Aliphatic Epoxides
R
CH3 (CH2)3CH3 (CH2)11CH3 (CH2)2CH=CH2 CH2Ph c-C6H11 t-C4H9
epox % yield 46 43 42 43 46 44 41
epox % ee >99 >99 >99 >99 >99 >99 >99
diol % yield 45 44 40 44 40 41 40
diol % ee 99 99 99 99 95 99 95
Epoxides bearing ether and carbonyl functionality
epox % yield 48 47 47 38 42 36 46 44 36 43 40 41
epox % ee >99 >99 >99 >99 >99 >99 >99 >99 >99 >99 >99 >99
diol % yield 40 42 41 42 42 36 45 41 36 37 40 33
diol % ee 95 98 95 97 95 96 43 95 78 97 97 96
Halogenated Epoxides
epox % yield 43 41 42 42
epox % ee >99 43 >99 >99
diol % yield 40 90 38 42
diol % ee 95 96 97 >99
CH2Cl CH2Br (dynamic) CH2F CF3
CH2OBn CH2OTBS CH2OPh CH2O(1-naphtyl) CH2CH2OBn oxiranyl CH2OCOn-Pr CH2CO2Et CH2NHBoc CO2CH3 COCH3 COCH2CH3
43

Hydrolytic Kinetic Reaction of Terminal Epoxides

H R t-Bu
1-2 mol%
O R
H2O
Chiral catalyst (0.2-2.0 mol%)
O R
OH
+
OH
t-Bu
Jacobsen, E. N.; Tokunaga, M.; Larrow, J. F.; Kakiuchi, F. Science 1997, 277, 936-938.! ! Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421-431.! ! Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307-1315.

Aryl, vinyl and alkynyl epoxides
R
Ph 4-ClC6H4 3-ClC6H4 3-MeOC6H4 3-NO2C6H4 2-ClC6H4 CH=CH2 CCTBS
epox % yield 44 38 40 41 38 38 36 41
epox % ee >99 >99 >99 >99 >99 >99 >99 >99
diol % yield 42 37 44 41 44 42 38 41
diol % ee 98 94 91 95 99 94 97 99
44

Enantioselective Epoxidation with Dioxiranes

O R R1 R2 Catalytic
HSO5[Oxone] 1 equiv
Shi,Y., Acc. Chem. Res. 2004, 37, 488-496.

Wong, O. A.; Shi,Y., Chem. Rev. 2008, 108, 3958-3987.

R R
R1 R2
O O
HSO4O
180
R R
O O
R R
Spiro Transition State Favored
Planar Transition State Unfavored
O
180
O
180
O L(S) S(L)
O S(L)
L(S)
45

Shis Enantioselective Catalytic Epoxidation: Catalytic Cycle

R1 O R3 R2 O R1 R2 O O O O O O O O O O O O O O OH O O SO3B.V. + O O R3 O O O O O O O O O HSO5-
O O O O O R1 O
Spiro (A) Favored
O O
O O R2
O R3 SO42Epoxidation Cycle O O
OHO OO O SO3
O O
Competing pathway
46

Shis Enantioselective Catalytic Epoxidation: Scope

Wang, Z. X.; Miller, S. M.; Anderson, O. P.; Shi,Y. J. Org. Chem. 1999, 64, 6443-6458.

O O R = Ph Ph R R = Me R = CH2Cl C6H13 R = OEt R = Ph R R = Me R = i-Pr Ph Ph Ph C8H17 O 43% (61%ee) O
47

O O
O O O ----
CH2OAc O O
O O O
CMe2OH O O
85% (98%ee) 94% (96%ee) 49% (96%ee) 89% (95%ee)
91% (96%ee) 94% (80%ee) 95% (84%ee) --
C6H13
51% (42%ee)
O Ph
-----
-80% (94%ee) ---
35% (89%ee) 85% (96%ee) 75% (82%ee) 70% (89%ee)
Ph
54% (97% ee)
--
95% (92%ee)
90% (24%ee) 92% (17%ee)
---
79% (69%ee) 85% (15%ee)
--
93% (21%ee)

Warren, J. D.; Shi,Y. J. Org. Chem. 1999, 64, 7675-7677.

O O O R1 R2 SiMe3
O O R1 TBAF R2 R1 O
Oxone H2O-Solvent
R2
SiMe3 O
84-94% ee
48


Shi,Y.; and Coworkers, J. Org. Chem. 1998, 63, 2948.

O R2 Oxone H2O-Solvent O R1 R2 + O R1 R2 O O O O O
R1
Entry 1 2 3
Dienes Ph Ph CO2Et OTBS O
Epoxides O Ph CO2Et OTBS O Ph O O O Ph
Conv (%) 94 69 100
Ratio 22:1 7:1 4.6:1
Yield (%) 77 41 68
ee (%) 97 96 96
Ph
CO2Et OTBS
O O
OMe CO2Et O
OMe CO2Et O Ph
100
65
89
88 SiMe3
82
95
Ph
SiMe3 SiMe3 Ph
O Ph O Ph
SiMe3 SiMe3
92
14:1
77
94
100
81
95
49


Wang, Z. X.; Cao, G. A.; Shi,Y. J. Org. Chem. 1999, 64, 7646-7650.

R2 R1 Oxone H2O-Solvent O R1 R2 O O O O O O
Entry
Enynes
Yield (%)
ee (%)
Entry
Enynes SiMe3
Yield (%) 71
ee (%) 89
R 1 2 3 4 5 Ph SiMe3 6 Ph 64 94 78 88 86 71 59 93 90 94 93
R=H R = CH3 R = SiMe3 R = CO2Et SiMe3
SiMe3 8 84 95
R 96
9 10
R=H R = SiMe3
60 83
93 97
50

Chiral Alkynyloxiranes as Useful Synthons

OH R1 R2 Nu PdCl2 SnCl2 PR3, CO (R3=H) O O R1 Nu R2
R3
Nu R1
O R2
R3 R4Cu SN2' R1
R2
R3 R4
OH Ag+ R2
Mo(CO)6 R3=H
O R1 Nu R2
R1
R4 R3
Marshall, JOC 1993, 7180
Norton JACS 1981, 7520
McDonald JACS 1996, 6648
51

Shis Epoxidation of Allylic Alcohols and Trisubstituted Olens

Shi,Y.; and Coworkers J. Org. Chem. 1998, 63, 3099.

R2 R1 OH R2 Oxone H2O-Solvent R1 O OH O

O O
O O
Entry
Olens
Yield (%) OH OH OH 85 43 68
ee (%) 94 92 91
Entry
Olens
Yield (%) OH 85 75 82 90
ee (%) 92 74 90 91
1 2 3
Ph Ph
6 7 8 9 Ph
OH OH OH
Ph 4 Ph 5 OH OH 93 94 87 94
Ph
10 11 OH
OH Ph
83 87
91 91
52

Epoxidation of Enol Ethers and Esters

O O OR R1 R2 O R1 Oxone H2O-Solvent Product O Ph OH OTBS 2 O OH 70 83 5 6 7 n=5 n=7 n=8 OBz OR OR O 8 OBz O 92 88 79 87 82 80 91 95 80 90 n n R2 R = R'CO Yield ee (%) (%) O O O OR O R = SiR'3 R1 R2 Entry O OSiR'3 or R1 R2 Substrate Product OBz OBz O Yield (%) ee (%) O OH
Shi,Y.; and Cowokers Tetrahedron Lett., 1998, 39, 7819.

Entry Substrate
OTBS 1 Ph
3 4
R = Ac R = Bz
59 82
74 93
OAc 9 Ph Ph
OAc O
66
91
53


O R1 OBz R R2 Entry OBz S R2 1 (R) OBz O 2 (R) p-TsOH silica gel YbCl3 AlMe3 Ph 3 O 97 97 97 97 97 (R) 97 (S) 96 (S) 69 (S) 68 87 79 90 Epoxide OBz O Acid Epoxide ee (%) 93 92 92 91 Product ee (%) 90 (R) 91 (S) 88 (S) 87 (S) Yield (%) 89 83 73 85
Shi,Y.; and Coworkers J. Am. Chem. Soc. 1999, 121, 4080.

OBz O R
1 R2
O R1
p-TsOH silica gel YbCl3 AlMe3
AcO (S) CH3 OBz O
p-TsOH AlMe3
94 94
94 (R) 90 (R)
72 71
(R)
p-TsOH silica gel YbCl3 AlMe3
99 99 99 99
99 (R) 38 (R) 57 (R) 93 (R)
79 45 87 81
54


Shi,Y.; and Coworkers J. Am. Chem. Soc. 1999, 121, 4080.

O pathway a O R R1 R2 O O LA+ R R1 R2 O pathway b R1 O + R2 O O + OLA [TsOH] or when R1 = Ar O R1 + R2 R OLA -LA+ retention R1
O OCOR R2
R O O -LA+ inversion R1 R2 OCOR
AL
55


Feng, X. M.; Shu, L. H.; Shi,Y. J. Am. Chem. Soc. 1999, 121, 11002-11003.

OBz O 10 mol% O OBz O
OH OH Ti(OiPr)4 5 mol% OBz O + O OBz O 99% ee O 99%ee
51% conversion [(R)-BINOL]2-Ti(OiPr)4
O Racemic 10% TsOH CH 77% 2Cl2, 0 C 5 - 20 min
Not efcient for styrene oxides and acyclic epoxides O OBz O 97%ee
56

Synthesis of Polyepoxides

Vilotijevic, I.; Jamison, T.F. Science 2007, 317, 1189-1192

57



58



59



60

Dihydroxylation of Olens: Introduction

R1 H H R2 OsO4 Co-oxidant L* HO R1 H OH R2 H syn addition of two OH groups
Co-oxidant: NMO or K3Fe(CN)6/K2CO3 General mechanism: R R
OsO4L Ligand (L)
R O O Os O OL ORGANIC LAYER AQUEOUS LAYER 2 K2CO3 4 H2O HO HO O Os O OH OH R R HO 2O O R OH 2OH OH
OsO4
O Os O
2 K2CO3 2 H2O
3 K3Fe(CN)6 2 K2CO3
2 K4Fe(CN)6 2 KHCO3
61

Dihydroxylation of Olens: Introduction

2] 3+ [ ed m ert anis c n h Co Mec
O Os O O L
O O Os O O Ligand R
O O O Os L O
Ste Mepwis ch e [2 an +2 ism ]
O O
O Os L
62

Diastereoselective Dihydroxylation of Olens

OsO4 OH OH NMO HO HO OH
Generally, the reaction is under steric control

OH only product OsO4 NMO HO OH >50 : 1 OH Me >20 : 1 Me OH OH
OsO4 OH OH NMO
HO
Exceptions:

O S OH Me Me Me Ph NMe OsO4 NMO Me Me O S OH Me OH OH OH Me OH Me OH OH cat. OsO4, NMO : OsO4, TMEDA: 91%, 88%, dr = 1 : 4 dr = >25 : 1
63

Ph NMe OH + Me OH OH

Kishi Tetrahedron Lett. 1983, 24, 3943, 3947.
O Me
OsO4
OH Me OH
3.7 : 1
OBn BnO Me
OsO4 BnO
OBn OH Me OH
7:1
Me
OsO4
OH Me OH
7.6 : 1
OBn BnO
Me
OsO4 BnO
OBn OH Me OH
9:1
Me Me OH CO2Et
OsO4 NMO Me
Me OH CO2Et OH OH
HO Me Et
OH
O O only isomer
Me Me OH CO2Et
OsO4 NMO Me
Me OH CO2Et OH OH
HO Me Et O
OH O
only isomer
64


Evans, D. A. J. Org. Chem. 1990, 55, 1698-1700.
t-Bu t-Bu Si O O OBn Me Me HO
t-Bu t-Bu Si O O OBn HO Me Me

diastereoselection 60:1
Level of diastereoselection varies with slight modications:

t-Bu t-Bu Si O O OBn Me Me

60 : 1
H C6H4OMe C O O HO HO Me Me
61 : 1
OH
OH OBn
OAc OAc OBn Me Me

16 : 1
OBn Me Me
35 : 1
OBn Me Me
17 : 1
OBn Me Me
5.1 : 1
Me
65


H H R2 R1
Vedejs Model Based on the steric hindrance of the osmium reagent
OX C R1 C H R2 R2
R1 C XO
Kishi Model Based on ground-state conformational effects and an implied stereoelectronic pfacial bias imposed by the allylic oxygen.
C OX
H R2

R2
H C
H R2
Houk Model "inside alkoxy effect"
References: Houk, K. N. Science 1986, 231, 1108. J. Am. Chem. Soc. 1986, 108, 2754. Vedejs, E. J. Am. Chem. Soc. 1986, 108, 1094. J. Am. Chem. Soc. 1989, 111, 6861.
Kishi, Y. Tetrahedron Lett. 1983, 24, 3943. Tetrahedron 1984, 40, 2247.
66

Dihydroxylation with Chiral Catalysts/Ligands

R R
OsO4L Ligand (L)
R O O Os O R R HO
ORGANIC LAYER AQUEOUS LAYER 22-
OsO4 R OH
O L
2 K2CO3 4 H2O
O HO HO Os O OH OH
O O O Os O OH OH
2 K2CO3 2 H2O
3 K3Fe(CN)6 2 K2CO3
2 K4Fe(CN)6 2 KHCO3
67

Ligand-accelerated Dihydroxylation: Basic Principle

Three important points:
- Level of enantioselection (Ligand design).
- Catalytic turnovers (OsO4 is very expensive).
- OsO4 Ligand must be regenerated.

Monodentate Ligands: + L*
Bidentate Ligands: L
OsO4
16 e-
OsO4 L 18 e-
O O Os O OL 16 e-
OsO4
16 e-
OsO4 L 18 eL
L L
O Os O
O O
18 e-
OK
hydrolysis / reoxidation
X
hydrolysis / reoxidation
68

Sharplesss Dihydroxylation: Chiral Ligands

Dihydroquinidine derivatives

Cl
Et N O O N
DHQD-CLB
Et N H OMe N DHQD-PHN O H OMe N
Et N O O N DHQD-IND H OMe
Et N H MeO N O N Ph Ph
Et N O N N H OMe MeO H
Et N O
Et N N O N H OMe
(DHQD)2-PYR
(DHQD)2-PHAL Ligand used in AD-mix-
Reviews:
Sharpless, K. B. et al. Chem. Rev. 1994, 94, 2483-2547. Sharpless, K. B. In Catalytic asymmetric synthesis, Ojima Ed. p. 227.
69

Sharplesss Dihydroxylation: Chiral Ligands

Dihydroquinidine derivatives Dihydroquinine derivatives
Et N N O N DHQD-IND O H OMe MeO
Et N H O O N DHQ-IND N
Et N H MeO N O
Et N N O N H OMe N MeO N N Et H N O N N O N H OMe Et
(DHQD)2-PHAL Ligand used in AD-mix-
(DHQ)2-PHAL Ligand used in AD-mix-
70

Sharplesss Dihydroxylation: Scope & Model

Me Me (DHQD)2-PHAL 98% ee (DHQ)2-PHAL 95% ee Bu Ph (DHQD)2-PHAL 99% ee (DHQ)2-PHAL 97% ee Me Ph (DHQD)2-PHAL 94% ee (DHQ)2-PHAL 93% ee n-C8H17 (DHQD)2-PHAL 84% ee (DHQ)2-PHAL 80% ee RS

Bu
Bu
(DHQD)2-PHAL 97% ee (DHQ)2-PHAL 93% ee
DHQD ligands () - attack
n-C5H11
COOEt
RM H
RL
Me Ph CO2i-Pr DHQD-IND 80% ee DHQ-IND 72% ee DHQD-IND 56% ee DHQ-IND 44% ee
Bu
n-C5H11 OMe
DHQ ligands () - attack
71

Sharplesss Dihydroxylation: Scope

n-C5H11
COOEt
Ph
COOEt
Ph
Ph Ph
Me Ph (DHQD)2-PHAL 97% ee
(DHQD)2-PHAL 99% ee
(DHQD)2-PHAL 97% ee
(DHQD)2-PHAL >99.5% ee
(DHQD)2-PHAL 94% ee
Me n-C5H11 (DHQD)2-PHAL 78% ee n-C8H17 (DHQD)2-PHAL 84% ee (DHQD)2-PYR 89% ee COOBn (DHQD)2-PHAL 77% ee Ph Me
Bu
n-C5H11
DHQD-IND 72% ee
OMe (DHQD)2-PHAL 95% ee
Me Ph CO2i-Pr DHQD-IND 56% ee (DHQD)2-PHAL 88% ee (DHQD)2-PYR 96% ee
t-Bu (DHQD)2-PHAL 64% ee (DHQD)2-PYR 92% ee
DHQD-IND 80% ee
72

Sharplesss Dihydroxylation: Scope

OH Ph Ph (DHQD)2-PHAL Ph OH 84% (>99% ee) O OEt OH (DHQD)2-PHAL OH O OEt 93% (95% ee) Ph
(DHQD)2-PHAL
OH + OH 13 : 1 56% (94% ee) OH OH
OH Ph Ph OH (DHQD)2-PHAL DHQD-PHN 73% ee 53% ee

73

Sharplesss Dihydroxylation: Catalyst

Structure of the Bis OsO4 complex of (DHQD)2PHAL based on molecular mechanics calculations and NOE experiments.
74

Sharplesss Dihydroxylation: Catalyst

Its presence has a small effect on the rates; however, it increases the binding The nature of R has a very large effect on the rates, but only a small influence on the binding Oxygenation is essential to allow binding to OsO4 - a carbon substituent is too bulky
Dihydroquinine Derivatives
N R O
9
The configuration is important: only erythro allows high rates and binding
"HO
OH" -face
NW OMe
Increases binding to OsO4 as well as rates
NE
N
The presence of a flat, aromatic ring system increases binding and rates; the nitrogen has no influence Relationship between ligand structure and Keq and ceiling rate constants. The alkaloid core is ideally set up to ensure high rates, binding, and solubility. The rates are influenced considerably by the nature of the O9 substituent, while the binding to OsO4 is almost independent of that substituent.
attractive area
SW -face "HO OH"
SE
Dihydroquinine Derivatives
Mechanistic Discussion:
Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 11038-11053.
Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319-329.
Corey, E. J.; Guzmanperez, A.; Noe, M. C. J. Am. Chem. Soc. 1995, 117, 10805-10816.
Delmonte, A. J.; Haller, J.; Houk, K. N.; Sharpless, K. B.; Singleton, D. A.; Strassner, T.; Thomas, A. A.
J. Am. Chem. Soc. 1997, 119, 9907-9908.

75

Sharplesss Dihydroxylation: Synthetic Applications

Reading: Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483-2547.
Differentiation of the hydroxyl groups of a Diol: tosylation
OH R1 OH
Primary vs secondary: unsually not a problem
R2
Unselective tosylation leads to racemization!
O O
OH OH
1. p-TsCl, pyr 2. NaOMe 85%
O O O
OH R1
O OR2
1. TsCl, pyr 2. K2CO3 MeOH
O R1 COOR2
OH
48-91%
76


Differentiation of the hydroxyl groups of a Diol: Cyclic Sulfates
OH R1 OH R2 1. SOCl2 R1
R2 O O S O When R1 = R2: C2 symmetric compound 2. NaIO4, RuCl3 R1
R2 O O SO2
CO2Me O O O O 1. LiN3 2. H2SO4, H2O O O O O MeCuCNLi2 BF3OEt2 O O S O SN2' (anti)
CO2Me Me Me OH
Me
S O2
N3
OH
R2 R1 OAc
NaOEt EtOH
R1
Double displacement of cyclic sulfates: R2 R1 OH O O S O2 R2 MeO2C CO2Me R1 R2
O 5-endo tet O S O O
NaH, DME
MeO2C CO2Me
77


Double displacement from 1,2-diols: halohydrin and epoxides formation
Br OH R1 OH R1 Br R2 OH R2 R1 O R2 R1 OH R1 R2 O R2
OH R1 OH R2
1. MeC(OMe)3, PPTS (cat.) 2. CH3COBr or TMSX 3. K2CO3, MeOH
R1 O
R2
Taxol side-chain: (JOC 94, 5014) OH Ph OH O 1. MeC(OMe)3, PPTS (cat.) 2. CH3COBr or TMSX OMe 3.NaN 3 4. H2, Pd Ph OH NHAc O OMe
78

Sharplesss Asymmetric Aminohydroxylation

R R Chloramine T TsNClNa (3.5 equiv.) NHTs Ph CO2Me Me NHTs CO2Et Ph NHMs CO2Me Me K2OsO2(OH)4 cat., XNCl-M+ (DHQD)2-PHAL or (DHQ)2-PHAL R HO R NHX
Chloramine M MsNClNa (3 equiv.) NHMs CO2t-Bu
OH (DHQ)2-PHAL 66% y. 81% ee NHTs Ph
OH (DHQ)2-PHAL 52% y. 74% ee
OH (DHQ)2-PHAL 63% y. 80% ee NHMs
Ph
Ph
Ph
Higher yields and enantioselectivities with sterically less demanding nitrogen nucleophiles Products are solid, ee can be increased by recrystallisation Drawback: Removing the sulfonyl group.
79


R R
K2OsO2(OH)4 cat., XNCl-M+ (DHQD)2-PHAL or (DHQ)2-PHAL
R HO
R NHX
O
CbzNClNa (3 equiv) BOCNClNa (3 equiv.)
TMS
NHCBz Ph CO2Me OH
(DHQ)2-PHAL 65% y. 94% ee
NHCBz Me CO2t-Bu OH
TeoCNClNa (3 equiv.)
NClNa
NHBOC MeO OH
(DHQ)2-PHAL 60% y. 97% ee 3:1 regioselectivity
NHTeoC Ph CO2i-Pr OH
MeO
BzCHN
CO2Me OH NHBOC MeO BnO NHCBz MeO OH

(DHQD)2-PHAL 68% y. 94% ee 3:1 regioselectivity
(DHQ)2-PHAL 89% y. 84% ee (DHQD)2-PHAL 89% y. 87% ee
OH
(DHQ)2-PHAL 65% y. 99% ee 3:1 regioselectivity
NHBOC MeO BnO OH

(DHQ)2-PHAL 70% y. 99% ee 3.5:1 regioselectivity
MeO
80


R R
K2OsO2(OH)4 cat., RCONBrLi (1 equiv) (DHQD)2-PHAL or (DHQ)2-PHAL
R HO
R NHAc
O AcNBrLi Cl NHBr
O NHBr NHC(O)n-Pr Ph CO2i-Pr OH

NHAc Ph CO2i-Pr OH
NHAc Ph Ph OH
NHC(O)CH2Cl Ph CO2i-Pr OH
NHC(O)CH2Cl Ph OH
AcHN
CO2Me OH Ph
NHC(O)CH2Cl OH
(DHQD)2-PHAL 46 y. 90 ee
81

Sharplesss Dihydroxylation: Synthetic Targets

(+)-Aspicilin (JOC 1994, 59, 949)
OH OH O Me O OH OH Me EtOOC
OH OH OH
OH OH OH HO OH OH OH HO EtOOC
OH OH OH
OH OH OH HO OH OH
82

Sharplesss Dihydroxylation: Synthetic Targets

O O 1. AD-mix- (2 equiv) 2. (CH3O)2CMe2, H+ O O 1. AD-mix- 2. TBDMSCl (1 equiv) 3. MEMCl (1 equiv) 4. TBAF 5. DMS/NCS 6. Horner-Emmons 1. AcOH, H2O (cleave 1 acetonide) 2. (EtO)3CMe, TMSBr (bromoester) 3. AIBN, Bu3SnH (reduction C-Br) 4. LiOH (saponication) 5. Yamaguchi 6. HSCH2CH2SH, BF3 O O O O EtO2C OMEM
OH OH O Me O OH
83

Sharplesss Dihydroxylation: Camptothecin Synthesis

Comins J. Am. Chem. Soc. 1992, 114, 10971. / Fang J. Org. Chem. 1994, 59, 6142. N O HO Heck N N O Alkylation 1. KOt-Bu HN +bromide 2. Pd(OAc)2 O O HN Dihydroxylation I 1. t-BuLi OHC 2. MeN(CHO)CH2CH2NMe2 MeO N 3. BuLi 4. I2 MeO N HO Me O MeO Pd(OAc)2 K2CO3 Bu4NCl, DMF OH O HN O 94% ee OMe O Me 1. I2, CaCO3 2. HCl N OH OH O SAD N OMe O + N OMe O Me Me N O I Et3SiH, TFA O MeO N O HO O Br Me Heck Br
Me
(Ph3P)3RhCl
84

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Epoxidations of Alkenes: The Reagents

vElectrophilic reagent - electron rich double bonds react faster.

A. m-Chloroperoxybenzoic acid (MCPBA)

Epoxidations of Alkenes: The Reagents

Dimethyldioxirane (DMDO) or triuoromethylmethyldioxirane (TFDO)

R1 O H3C CX3 Oxone O O H3C CX3 O H3C R2

vCan be isolated as a solution in the corresponding ketone or produced in-situ

Adam Acc. Chem. Res. 1989, 22, 205-211.

Epoxidations of Alkenes: The Reagents

Capable of being directed by hydroxy groups.

Epoxidations of Alkenes: The Reagents

O [O] M Y M Y [O] = NaOCl, Oxone, H2O2, ROOH, RC(O)OOH....

Efcient for the epoxidation of unfunctionalized olens

Epoxidations of Alkenes: The Reagents

O Me Me H AcO H H AcO Me H2O2 NaOH H H Me H Me

Chemoselectivity is inverse to the one of electrophilic reagents.

Epoxidations of Alkenes: Chemoselectivity

H m-CPBA HO DCM O HO 75% H O O m-CPBA DCM

Epoxidations of Alkenes: Chemoselectivity

OH 0.55 (92:8) >200 (98:2)

OAc 0.046 (37:63) ---

OH 0.42 (60:40) 10.0 (98:2)

OH DMDO Acetone, MeOH

No H-bond directing effect with DMDO.

Epoxidations of Alkenes: Diastereoselectivity

VO(acac)2 99.2 99.7 99.6 97 91

Epoxidations of Alkenes: Diastereoselectivity

Carboxamides are better H-bonding directing groups

Epoxidations of Alkenes: Diastereoselectivity with Acycli Olens

MCPBA VO(acac)2, t-BuOOH MCPBA ~120 OH H2 R R1 R4 R3 H OH R2 R1

Epoxidations of Alkenes: Diastereoselectivity with Acyclic Olens

OMe OMe OMe

OMe OMe OMe

Epoxidation of Homoallylic Alcohols TBHP, VO(acac)2

Catalytic Asymmetric Sharpless Epoxidation

ee usually 80-94% yield: 63 - 99% Z-substituent: lower ee's

Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.

Mnemonic model: MISMATCHED PAIR (-)-(S,S)-D-tartrate (-)-(S,S)-D-tartrate MATCHED PAIR (-)-(S,S)-D-tartrate

(+)-(R,R)-L-tartrate MATCHED PAIR

(+)-(R,R)-L-tartrate MISMATCHED PAIR

Catalytic Asymmetric Sharpless Epoxidation: Substrate Scope

86% ee >80% ee 85% ee

Catalytic Asymmetric Sharpless Epoxidation: Kinetic Resolution

>98% ee 54% conversion

>98% ee 63% conversion

>98% ee 66% conversion

1. NaH, CpLi, THF, 60% 2. NaH, Cl3CCN, THF, 95%

1. BF3OEt2 2. Bu3SnH, Et3B, NaBH4

1. PPTS, CH3CN aq. 2. Ac2O, DMAP, 77%

TIPSO AcO OAc NH CH2Cl

TIPSO AcO OAc NH

SCN O BnO BnO OBn OH

OH TIPSO AcO OAc O NH CCl3 SCN

1. HgO, Et2O/Me2CO 2. PdOH/C, H2 (1 atm), MeOH, 40%

Epoxy Alcohols: Synthetic Applications

Epoxy Alcohols: Synthetic Applications

MsCl or TsCl or Tf2O RLi or R2CuLi

OMs (OTs, OTf)

1. TsCl 2. (n-C9H19)2CuLi, ether

100% ee (55% yield after recrystallization of dinitrobenzoate) 1. TsCl, pyr 2. NaI 3.

Epoxy Alcohols: Synthetic Applications

Epoxy Alcohols: Synthetic Applications