Kinetic Resolutions - The Stoltz Group

N
Me
N
Kinetic Resolutions
Episode III: Non-Enzymatic Alcohol, Alkene, and Epoxide Resolutions
O
O P NMe 2
N N
M
R O O
R
t-Bu
t-Bu
H
N
OH 2-naphthyl
H
N
(±)-S Cat.
Me 2 N
Ph
Ph
Ph
Ph
Ph
Presented by David Ebner
Stoltz Group Literature Seminar
Wednesday, June 4, 9 am (Before Group Meeting)
N
(+)-S + P
Outline: Non-Enzymatic Kinetic Resolutions
I. Quick KR Review
II. Alcohols
A. Acylation
B. S N2
III. Allylic Alcohols
A. Epoxidation
B. Reduction
IV. Alkenes
A. Epoxidation
B. Dihydroxylation
V. Epoxides
A. Nucleophilic Opening
B. Hydrolytic Opening
VI. Other KR
Reviews:
Fe
N
N
N
N
H
Boc
Keith, Larrow, and Jacobsen, Adv. Synth. Catal, 2001, 343, 5
Spivey and Maddaford, Org. Prep. Proced. Int. 2000, 32(4), 331
Somfai, Peter, Angew. Chem. Int. Ed. Engl. 1997, 36, 2731
Pfenninger, A. Synthesis, 1986, 89
Cook, Gregory R., Current Organic Chemistry, 2000, 4, 869
Kagan and Fiaud. Topics in Stereochemistry, Wiley, New York, 1988, Vol 18, 249-331
O
H
O
P
N
H
O
Ph 2
P
Ph 2
H
O
N
P
Ru
O
H
OMe
Ar
O
O
O
Bn
1

Requirements
- Enantioselective reaction (some chiral influence)
- Significant difference in reaction rate
- Incomplete conversion to product
Preferable
Quick Review of KR
Kinetic Resolution - "A process in which one of the enantiomer constituents of a racemic mixture is more readily
transformed into a product than is the other." (Fiaud and Kagan, 251)
- Enantioenriched product and starting materials are easily separable
- Conversion near 50% returns high ee's for both starting material and product
(Or, even better, all is converted to a single enantiomer --> Dynamic KR)
- Inexpensive and stable reagents (Catalytic process)
R 1
R 1
R 1
R 1
OH
+
OH
OH
+
O
R 2
R 2
Oxidation to
Ketone
(McFadden)
Reduction of
Allylic Alcohol
R
R
s = k fast / k slow = ln((1-C)(1-ee)) / ln((1-C)(1+ee))
C is conversion to product
ee is enantiomeric excess of starting material
Alcohol Resolution Approaches
(±)-
R 1
Esterification
R 1
R 1
O
OH
OH
+
O
R 2
R 2
R 2
R
Epoxidation of
Allylic Alcohol
R 1
R 1
S N 2 Displacement /
Mitsunobu
R 1
R 1
OH
+
OH
O
OH
+
Nu
R 2
R 2
R
R
2

(±)-
Evans - Oxazolidinone Acylating Agent
R 1
OH
10 eq
R 2
OH
(±)-
Ar Me
O
O
O
N Ph
t-Bu
1.1 eq MeMgBr
CH2Cl2 R 1
R 2
+
OH
+
Vedejs - Chiral DMAP Acylating Agent
Wegler
(±)-
Horner
(±)-
2 eq
OH
1 eq
Cl 3 C
O
NMe 2
N
Chiral Acylating Agent
O
OMe
Cl -
t-Bu
2 eq ZnBr 2, 3 eq Et 3N
OH
Ar Me
Ph
O
R 1
O
R 2
Cl 3C
Ester ee's:
R 1 =Ph, R 2 =Me, ee=95%
R 1 =Ph, R 2 =i-Pr, ee=65%
R 1 =c-C 6H 11, R 2 =Me, ee=5%
Evans, et. al., Tet. Lett. 1993, 34, 5563
+
Carbonate:
Nucleophilic Activators for Acylation
0.25 eq (-)-brucine
0.53 eq Ac 2 O
CCl 4 , 77 o C, 3h
s ~ 3.5
Also used other tertiary amines and acylating agents
OH
OH
0.5 eq amine
OH
0.5 eq AcCl
CH 2 Cl 2 , 12h
-78 o C to r.t.
Screened a variety of temperatures, amines,
solvents, and acylating agents
Vedejs unable to reproduce this result
+
+
O
O
O
Ar Me
Ar = Ph, 25% conv, 93% ee, s = 38
Ar = 1-Naphthyl, 28% conv, 94% ee, s = 44
Ar = 2-Naphthyl, 24% conv, 94% ee, s = 45
Vedejs, et. al, J. Am. Chem. Soc., 1996, 118, 1809
OAc
OAc
68% ee
??% conv.
MeO
MeO
N
N
H
H
O
(-)-brucine
Wegler, Liebigs. Ann. Chem. 1932, 498, 62
Liebigs. Ann. Chem., 1933, 506, 77
Liebigs. Ann. Chem., 1934, 510, 72
NMe 2
Horner, et. al. Liebigs Ann. Chem., 1989, 533
H
H
O
3

(±)-
R 1
OH
n
n
R 1
R 2
OCOR
OH
NHR
OH
5 mol% Catalyst 1
(i-PrCO) 2O, r.t.
OH
OH
OCOR
R = i-Pr, t-Bu, Ph, p-NMe 2C 6H 4CO-
NHR
R = p-NMe 2C 6H 4CO-
R 1
Only anti- acyclic substrates were selective
Acylation with DMAP Derivatives - Fuji
OH
R 1
R 2
OCOR
OH
NHR
OH
+
R 1
2-5 hours
R 1
~70% conv.
54-99% ee
R 2
s = 2.4 to > 10.1
9-44 hours
58-73% conv.
89-99% ee
s = 10 to > 18
OCOi-Pr
H H
N
Me 2N
H
OH
R
N
R
OH 2-naphthyl
H
Catalyst 1
N
NH
O
N
OH
O
Cl -
Fuji, et. al. J. Am. Chem. Soc., 1997, 119, 3169
Chem. Comm., 2001, 2700
4

Cl
(±)-
R 1
R 1 = Ar
OH
R 2
R 2 = Alkyl, CH 2 Cl
DMAP Derivatives as Catalysts for Acylation - Fu
OH
Me
1 mol% Catalyst 2
Ac 2 O
Et 3 N
t-amyl alcohol
0 o C
Acetate can also be recovered in high ee
R 1
OH
MeO
R 2
+
50-55% conversion
96-99% ee (alcohol)
s = 32 - 95
Catalyst is air/moisture stable and easily recoverable/reusable
Resolution can be performed on large (2 g) scale
Propargylic alcohols could be resolved, though generally with lower selectivities (s = 8 - 20)
R 1
OAc
Me
R 2
OH
Me
O
Et
Me 2 N
Ph
Ph
N
Fe
Ph
Catalyst 2
Allylic alcohols, especially cinnamyl alcohols, generally worked (s = 5.4 - 80), and were used to synthesize
enantioenriched intermediates in several natural products:
40% yield, 99.4% ee
s = 37
(-)-baclofen
47% yield, 98.0% ee
s = 107
Ph
Ph
epothilone A
Fu, et. al., J. Org. Chem., 1998, 63, 2794
J. Am. Chem. Soc., 1999, 121, 5091
Chem. Comm., 2000, 1009
5

OH
(±)-
Nucleophilic Catalysts for Acylation - Oriyama
R 1
OH
R 2
N
Me
OH
0.3 mol%
Diamine Catalyst 3 or 4
BzCl, Et 3N, CH 2Cl 2
MS4A, -78 o C, 3 hr
Me
N
Catalysts:
Bn
N
R 1
R
n = 1, 2, 4
s = 4 R = H, s = 9
R = Ph, CO2Et, CO2i-Pr, Br
R = Me, s = 20
n s = 27 (esters) to 170
R
OH
R 2
3
Me
4
N
+
Ph
O
R 1
O
R 2
OH
Oriyama, et. al., Chem. Lett. 1999, 265
6

(±)-
(±)-
Et 3N
Me
(±)-
Ph
Ph
OH
n
N
H
OH
OH
OH
Proposed Oriyama Diamine Mechanism
Et 3NHCl
Cl -
N R1
R 2
OH
R
R 1
OBz
n
R 2
N
Me
R 1
N
R 2
R 1
OH
R 2
Me
Phosphines as Catalysts - Vedejs
5-8 mol% Catalyst 5
Ph
Ph
(R'CO) 2 O
CH 2 Cl 2 , r.t.
OH
OAc
OCOR'
OH
n = 1, s = 3.2
n = 2, s = 4.3-5.1
R' = CH 3, s = 1.2
R' = Ph, s = 5.5
OH
R
+
N
Ph
O
BzCl
Cl -
N R1
R 2
Oriyama, et. al. Synthesis, 1999, 1141
OCOR'
R
R = CH 3 , R' = CH 3 , s = 2.7
R = CH 3 , R' = m-Cl-Ph, s = 2.8
R = t-Bu, R' = CH 3, s = 3.8
R = t-Bu, R' = m-Cl-Ph, s = 12-15
(10 days at room temp)
Me
P Ph
Me
Catalyst 5
Vedejs, J. Org. Chem. 1996, 61, 430
7

(±)-
R 1
OH
R 2
An Improved Phosphine Catalyst - Vedejs
5 mol% Catalyst 6
(RCO) 2 O
-40 o C
PhCH 3 / heptane
R 1 = Ar, R 2 = Alkyl, R = Ph, i-Pr
1-24 hours, s = 6.9 - 390
Catalyst %ee important
R 1
OH
R 2
R 1
OCOR
r.t. to -40 o C decreases rate only 8-fold, but enantioselectivity is much higher
Ph anhydride faster but less selective
Catalyst Ar - Ph, 3,5-tBu 2Ph, 2,4,6-Me 3Ph : generally increasing selectivity
heptane generally faster reactions - believed to be because of tighter ion pairing of carboxylate and
carbonylated catalyst
Allylic alcohols also worked (s = 4-82), but only when there was significant steric direction
Resolutions based purely on sterics of R 1 and R 2 gave no selectivity
+
R 2
H
P
H
Catalyst 6
Vedejs, et. al., Synlett, 2001, 10, 1499
J. Am. Chem. Soc., 2003, 125, 4166
Ar
8

BocHN
(±)-
N
N
Tripeptides for Acylative KR - Miller
O
O
OH
NHAc
Other examples had much lower selectivities
N
N
H
H
Catalyst 7
N
O
0.5 mol% Catalyst 7
0.1 eq Ac 2O
PhCH 3, 0 o C
Ac 2O
BocHN
s = 12.6
N
O
N
O
OAc
NHAc
N
N
H
H
N
O
Miller, et. al., J. Am. Chem. Soc., 1998, 120, 1629
O
9

(±)-
NHAc
Miller Peptide Catalyst - Round 2
OH
NHAc
N
N
2 mol% Catalyst 8
4.8 eq Ac 2 O
PhCH 3 , 0 o C
N
Boc
OH OH
N
H
NHAc
O
O
N
H
O
Catalyst 8
H
N
OMe
O
Bn
OAc
NHAc
OH
NHAc
s = 28
Miller has extended this hairpin turn structure to an octapeptide, which shows improved selectivities for
this class of substrates:
s = 51 s = 15 s = 27
Miller, et. al., J. Am. Chem. Soc., 1999, 121, 11638
10

CO2R PPh3 N N
RO2C
RO2C
CO2R HN NH
Mitsunobu-type KR of ROH
Ph3P CO2R R
N N
RO2C
2 CO2H Step 1 Step 2
Ph3PO R 2 CO 2R 3
Chiral recognition can be introduced at steps 3 and 4
Step 4
Ph 3 PO-R
R 2 -
CO2 Ph 3 P
RO 2C
RO2C
CO2R N NH
R 3 OH
Step 3
CO2R HN NH
Chiral Phosphine, azodicarboxylate, or acid are possible means to induce chiral influence
Kellogg
Tang
(±)-
(±)-
Ar
Ar
OH
OH
1-2 eq Catalyst 9
O
R +
NH
Catalyst 9
1-2 eq ArCO 2H
DIAD, PhH
1 eq 1 eq
Chiral Phosphines for Mitsunobu KR
O
O
O P NMe 2
Ar
OH
+
1) 1 eq Catalyst 9
DEAD, THF
Reflux
2) NH 2 NH 2
DIAD, PhH
Ar
Ar
OCOAr
OH
40-50%
R
13-30% ee
R 2 -
CO2 Chandrasekhar, Tet. Asym. 2002, 13, 615
Ar = Ph, 2-Naphthyl
14-73% conv.
11-39% ee
+
Ar
NH 2
55-62%
R
26-45% ee
Me2N O
P
O
O
N N
CO 2i-Pr
Oi-Pr
Kellogg, et. al., J. Chem. Soc., Perkin Trans. 1, 1995, 2961
Tang, et. al., Tet. Asym., 2002, 13, 145
11

(±)-ROH +
O
EtO 2 C
O
N
H
HO 2C O
O
PPh 3
N
CO 2 Et
ROH
More Mitsunobu KR - Chandrasekhar
PPh 3 , DEAD
CH 2 Cl 2 , -23 o C
O
O
RO
O
PPh3
(-)-ROH +
KOH
EtOH
(-)-ROH +
RO2C O
ROH = Arylalkylalcohol, (-)-ROH from Mitsunobu: ~40% yield, 70-90% ee
(-)-ROH after saponification: ~80% yield, ~80% ee
M
O
L
H
O
O
O
PPh 3
HO 2C O
RO 2 C
Chandrasekhar, Kulkarni, Tet. Asym., 2002, 13, 615
O
12

Nishiyama, Sekar (our very own!)
n
Kinetic Resolution through S N2 Displacement
OH
R
0.3-0.9 eq BINAP
n = 2; R = Ph, 4-CH 3OPh, 2-CH 3Ph, 3-CH 3Ph, 4-CH 3Ph, 1-Naphthyl, 2-Naphthyl, Cyclohexyl
n = 4; R = Ph
0.9-1.0 eq NCS
THF
48-63% conversion, 69-99% ee, s = 13-118
-10 o C overnight or 10 min at r.t.
BINAP-bisoxide could be reduced back to (S)-BINAP
H
(±) -
OH
OH
H
(±) -
OH
Ph
0.3 eq BINAP
1 eq NCS
THF, 12 h
-74 o C to r.t.
OH
R
+
Cl
R
OH
Ph
+
s = 253
Cl
Ph
(S)-(-)-BINAP
PPh 2
PPh 2
Nishiyama, Sekar, J. Am. Chem. Soc., 2001, 123, 3603
Epoxidation of Allylic Alcohols - Sharpless!!!
Made kinetic resolution a practical technique for synthesis
Most widely used kinetic resolution technique
Bulkier tartrate esters work better
1.2 : 1 tartrate to titanium ratio is best
Can use catalytic amount of tartrate,
though reactions are much slower
(S)-fast
(R)-slow
Ti(Oi-Pr) 4, TBHP
L-(+)-DIPT
CH 2Cl 2, -20 o C
O
H
O
H
H
H
OH
H
OH
H
+
O
H
erythro : threo
98 : 2
+
O
H
R 3
erythro : threo
62 : 38
R 2
H
H
H
OH
H
OH
R 1
OH
D-(-)-(S,S)-Dialkyltartrate
L-(+)-(R,R)-Dialkyltartrate
HO CO 2i-Pr
HO
CO 2i-Pr
(+)-(R,R)-L-Diisopropyltartrate
Sharpless, et. al., J. Am. Chem. Soc., 1981, 103, 6237
13

Worked well (typically ~60% conv., > 80% ee, s > 15)
Me 3 Si
OH
R
OH
OH
OH
Ph
Sharpless Epoxidations - Examples
OH
OH
OH
R
OH
SiMe3
OH
OH
R
OH OH
Ph OH Ph OH t-Bu
Sometimes selectivities up to "700" were observed (determined by measuring k fast and k slow separately)
Did not work so well:
H
•
H
OH
OH
OH
OH
Sharpless, et. al., J. Am. Chem. Soc., 1981, 103, 6237
J. Am. Chem. Soc., 1987, 109, 5565
J. Am. Chem. Soc., 1988, 110, 2978
14

t-Bu
R 3
OH
R 1
R 1
R 1
(±)- + +
R 2
N N
Mn
MeO O Cl O
OMe
t-Bu
Epoxidation of Allylic Alcohols - Salen too! (Adam)
(R,R)-10
10 mol% Catalyst 10 or 11
t-Bu
20 mol% PPNO
60 mol% PhIO
CH 2Cl 2, r.t.
Enantiomer of alcohol depends on catalyst used (10 and 11 give opposite enantioenrichment)
Epoxide ee's 50-80%, Alcohol ee's < 50% (10 -50% conv.), s = 1.5-12.9
Oxidation of alcohol to ketone over epoxidation often problematic
R 3
OH
R 2
N N
Mn
O
R 3
OH
R 2
t-Bu O Cl O
t-Bu
t-Bu
(S,S)-11
t-Bu
R 3
O
R 2
PPNO
R 1
N O
Adam, et. al., J. Org. Chem., 2001, 66, 5796
Selectivity in Salen Epoxidations of Allylic Alcohols
O
t-Bu
N
O
Mn
2
N
HO
O
t-Bu
Ph
3
1 - A 1,3 Interaction
1
2 - Hydrogen Bonding
3 - Katsuki Trajectory
H
Me
t-Bu
Me
Ph
H
OH
Katsuki Trajectory
O
Mn
O
R L is forced away from the bulky salen tert-butyl groups, especially when R L is aromatic
1, 2, and 3 require that the (S)-enantiomer be the more reactive (when the catalyst is derived from the (S,S)-salen
ligand, as shown)
N
R S
R L
Adam, et. al., J. Org. Chem., 2001, 66, 5796
Katsuki, et. al., J. Mol. Cat. A, 1996, 113, 87
15

(±)-
R
R 1
OH
R 2
OH
KR Through Hydrogenation of Allylic Alcohols - Noyori
R 3
MeO
0.05-0.5 mol% 12
H2 (1-100 atm)
O
MeOH
Typically done in 1-3 hours at 25 o C
OH
R 1
OH
(R)-12 also used to yield other enantiomer of allylic alcohol
R = H, s = 62
R = Me, s = 76
R 2
OH
R 3
+
R 1
OH
R 2
R 3
OH
OH
Ph 2
P
O
Ru
P
Ph2O
(S)-12
s = 16 s = 11 s = 1.7 s = 20 s = 11
Increasing the H 2 pressure tends to decrease selectivity
Lowering the temperature slightly improves the selectivity
(±)-
Jacobsen
(±)-
Katsuki
R
O R
R = i-Bu, i-Pr, n-Hexyl, prenyl
R = Me, i-Pr, s = 2.6-7.5
Epoxidation of Alkenes and Allenes - Salen
4 mol% Catalyst 13a
MCPBA, NMO
CH 2Cl 2, -78 o C
< 10 min
2 mol% 13b or 14
NaOCl, PPNO
CH 2Cl 2, -20 o C
< 10 min
cis and trans epoxides recovered in >80% ee
R
O
O R
s = 4.5-9.3
R
R
O
O
O
OH
Noyori, et. al., J. Org. Chem., 1988, 53, 708
N N
Mn
R O Cl O
R
t-Bu
N N
Mn
O O
Ph Ph
- OAc
t-Bu
(S,S)-13
a: R = OTIPS
b: R = t-Bu
Velde, Jacobsen, J. Org. Chem., 1995, 60, 5380
14
Katsuki, et. al., Tet. Lett., 1996, 37(26), 4533
O
16

(±)-
Gardiner
(±)-
(±)-
MeO 2C
Ph
Ph
Ph
Ph
CO 2Me
Other Epoxidation Examples with Salen
Catalyst 15
MCPBA, NMO
CH 2Cl 2, -78 o C
Ph
CO 2Me
Ph
H
Ph
O
41% conv., 38% ee, s = 5.2
Anti- compound also in reaction, but no epoxidation of it was observed
(±)-
Matched
(R,R)-15
4 mol% (S,S)- or (R,R)-15
MCPBA, NMO
CH 2Cl 2, -78 o C
Mismatched Matched
(S,S)-15
OR
Ph
O
O
O
Ph
O
O O
O
OR
Mismatched
OR
Ph
Ph
s = 6.3-9.1
CO 2 Me
N N
Mn
t-Bu O Cl O
t-Bu
t-Bu
Ph
O
t-Bu
Catalyst (R,R)-15
Gardiner, et. al., Tet. Lett., 1996, 37(46), 8447
+
CO 2 Me
Linker, Toth, Bringmann, Chem. Eur. J., 1998, 4 (10), 1944
An Alternate Method to Epoxidation KR - Shi
25-75 mol% Catalyst 16
2.3 eq Oxone
9.5 eq K 2CO 3
CH 3CN / DMM
Na 2B 4O 7 in EDTA (aq)
-10 or 0 o C
R = TMS Me COMe CO 2 Et
s = >100 16 39 70
vs.
O
O
OR
O
Ph
O
Ph
O
O O
Favored enantiomer Disfavored enantiomer
+
O
OR
O
O O
Shi, et. al., J. Am. Chem. Soc., 1999, 121, 7718
O
Catalyst 16
O
O
17

(±)-
(±)-
R S
RL
O
R 1
O
R 2
O
R 2
O
25-75 mol% Catalyst 16
O O
O
2.3 eq Oxone
9.5 eq K 2 CO 3
CH 3CN / DMM
Na 2 B 4 O 7 in EDTA (aq)
-20 to 0 o C
R 1
More Shi Epoxidation
R
TMS
1 = Alkyl, OMe, OTBS, OTMS
R 2 = Ph, OPiv,
s = 11-61
vs.
O
R 1
O
O
R 2
O
R 2
O O
Favored enantiomer Disfavored enantiomer
R M
H
R L
RS
H
R S
R L
RM
R M
R S
H R L
OH OH
H
R M
O
+
R 1
R 1
O
R 2
O
O O
Shi, et. al., J. Am. Chem. Soc., 1999, 121, 7718
Alkenes and Allenes - Sharpless Dihydroxylation
Top (!)- attack
Bottom (")- attack
AD-mix
AD-mix contains:
Cinchona alkaloid PHAL ligand
K 2 OsO 2 (OH) 4
K 3 Fe(CN) 6
K 2 CO 3
+
N N
O
O
Catalyst 16
Et
Et
N
N N N
H
O
O
H
MeO OMe
Et
MeO
H
N
N
O
(DHQD) 2PHAL
(In AD-mix-!)
N
N
O
(DHQ) 2 PHAL
(In AD-mix-")
N
N
H
Et
O
OMe
Sharpless, et. al., J. Org. Chem., 1992, 57, 2768
18

Sharpless
Et
t-Bu
Proposed Asymmetric Dihydroxylation Mechanisms
O
O
Os
O
O
L*
O O
O Os
O
N
N
R
O
R = Ph, s = 9.7
R = CO 2Et, s = 32
R
R
N
[2+2]
N
O
N
Et
Sharpless, J. Am. Chem. Soc., 1993, 115, 7864
OAc
R 1
R = Me, 80% conv., 95% ee
N
R = Ph, 70% conv., >98% ee
Alkene: 47% Yield
Ph Ph
>99% ee
Diol: 40% conv.
>95% ee
s = 51.1
O
O
Os
O
O
L*
[3+2]
R 2
OAc
Ph
Corey
N
Et
O
O
Os
O
O
L*
OMe
R
O
H Os O
O N
N
O
O
Resolution of Alkenes Via AD
(unreactive)
Gardiner, et. al., Chem. Comm., 1996, 2709
R = Me, 90% conv., >98% ee
R = Ph, 90% conv., 33% ee
MeO
R
H
N
O
N
Corey, et. al., J. Am. Chem. Soc., 1995, 117, 10827
Sharpless, et. al., J. Am. Chem. Soc., 1996, 118, 35
C 8 H 17
OAc
O R
O
R = Me, s = 3.1
R = Ph, s = 1.6
O
O O
With modified chiral ligand
N
Ph
(anthryl instead of quinuclidine)
R = Me, s = 20
R = Ph, s = 79
25-30% Yield
95-98% ee
Corey, et. al., J. Am. Chem. Soc., 1995, 117, 10827
Ph
Jefford, et. al., Tet. Lett., 1994, 35, 6275
90% conv., >98% ee
Lohray, et. al., Tet. Asym., 1992, 3(11), 1317
19

N3
O
O
O
Epoxide Kinetic Resolution
While asymmetric epoxidation is much more practical for many compounds, some cannot be accessed in high ee
through current methods
In particular, terminal epoxides are difficult to get enantiopure, although the racemic epoxides are often
commercially available.
H2N
O
(±)-
Yamamoto
(±)-
O
15% recovered
27% ee
OTMS
R
R
1. CSA, MeOH
2. 10% Pd/C
MeOH, H 2
OH
R
(R,R)-18
TMSN 3
4.4 mol% 19
ArOH
TBME, 12-18 hr
-30 to 25 o C
O
Catalyst 17
CH 2Cl 2
-30 o C, 5 h
Ph
O
21% recovered
52% ee
R
ArO
PhO
R
OH
R
OH
O
O
O
20% epoxide recovered
>95% ee
TMSN 3
R
OTMS
+
O
O
(R)-(+)-17
Epoxide Kinetic Resolution - Jacobsen
+
(S,S)-18
R = alkyl, Bn, CH 2 Cl, c-C 6 H 11 , CH 2 OR,
CH(OEt) 2 , CH 2 CN, (CH 2 ) 2 CH=CH 2
2 mol% 18, 18-50 hr, 0 o C
Yields > 80% (based on 1 eq TMSN 3 )
ee > 90% (most > 97% ee)
s = 48 - 280
O
O
OBu
Al
Cl
Li +
Yamamoto, et. al., Tetrahedron, 1988, 44 (15), 4747
N 3
Wide range of Ar and R tolerated
Yields usually > 95%
(based on 1 eq ArOH)
Typically > 90% ee
Epibromohydrin (R = CH 2 Br) racemizes in presence of LiBr
Dynamic Kinetic Resolution was possible!
(±)-
Br
4 mol% 19
PhOH
4 mol% LiBr
CH 3 CN, MS3A
Br
74% yield
> 99% ee
N N
Cr
t-Bu O O
t-Bu
t-Bu
N 3
N N
Co
t-Bu
t-Bu O O
t-Bu
t-Bu
(R,R)-18
Jacobsen, et. al., J. Am. Chem. Soc., 1996, 118, 7420
(R,R)-19
t-Bu
- OC(CF3 ) 3 + H 2 O
Jacobsen, et. al., J. Am. Chem. Soc., 1999, 121, 6086
20

R
(CH2)3CH3
CH 3
(CH2)11CH3
(CH 2 ) 2 CH=CH 2
CH 2Ph
c-C 6H 11
t-Bu
CH2Cl
CH 2 F
CF 3
CH 2OBn
CH 2OTBS
CH2OPh
CH 2 O(1-naphthyl)
Resolution Through Epoxide Hydrolysis - Jacobsen
(±)-
R
Epoxide
% Yield
(>99% ee)
43
46
43
43
46
44
41
43
43
43
48
47
47
38
O
R
oxiranyl
0.2-0.85 mol% 20
0.55 eq H 2 O
5-68 hr, r.t.
CH 2 OCO(CH 2 ) 2 CH 3
CH2CO2Et
CO 2 Me
COMe
COEt
CH=CH 2
Ph
(p-Cl)C 6 H 4
(m-Cl)C 6 H 4
(o-Cl)C6H4
(m-OMe)C 6 H 4
(m-NO2)C6H4
TBS
R
Epoxide
% Yield
(>99% ee)
Other Kinetic Resolutions
36
46
43
43
40
41
36
44
39
40
38
41
37
41
O
+
R
OH
OH
N N
Co
t-Bu O O
t-Bu
t-Bu
(R,R)-20
t-Bu
- OAc + H2 O
Jacobsen, et. al., Science, 1997, 277, 936
Beta-hydroxy amine resolution through N-oxide formation: Sharpless, J. Org. Chem., 1983, 48, 3608
Epoxide to Allylic Alcohol Resolution: Andersson, Org. Lett., 2002, 4, 3777 and J. Am. Chem. Soc., 2000, 122, 6610
Also, Feringa, Org. Lett., 2000, 2, 933
Alpha-amino acid N-carboxyanhydrides to alpha-aryl amino acids: Deng, Org. Lett., 2002, 4, 3321
Alpha-hydroxy epoxide resolution through semipinacol rearrangement: Tu, Tet. Asym., 2002, 13, 395
Meso-diol desymmetrization through Dioxane acetal ring cleavage: Harada, J. Org. Chem., 2002, 67, 7080
Dynamic Kinetic Resolution of alpha-halo acids to beta-amino alcohols: Durst, J. Org. Chem., 1998, 63, 3117
Oxidative Sulfoxide: Uemura, J. Org. Chem., 1993, 58, 4529
Baeyer-Villiger: (review) Bolm, Beckmann, Comprehensive Asymmetric Catalysis Vol II , Springer, NY, 1999, Ch. 22
Carboxylic Acid Acylation: Najera, Tet. Asym., 1992, 3(11), 1455
!-Allyl Pd - Many examples: Reetz, J. Organomet. Chem., 2000, 603, 105; Trost, JACS, 1999, 121, 3543
Also, Gais, J. Am. Chem. Soc., 2003, 125 6066; Osborn, ACIEE, 1998, 37, 3118
Metal-Mediated Cross-Coupling (Heck, MgR Coupling, etc.): Lloyd-Jones, Tetrahedron, 1998, 54, 901
Also, Hayashi, J. Am. Chem. Soc., 1995, 117, 9101; Shibasaki, Tet. Lett., 1999, 40, 311
Aziridine Carbonylation: Alper, J. Am. Chem. Soc., 1989, 111, 931
Diazocyclization: Doyle, Russ. Chem. Bull., 1995, 44, 1729
Anhydride Opening: Deng, J. Am. Chem. Soc., 2001, 123, 11302
Ring-Closing Metathesis: Grubbs (of course!), J. Am. Chem. Soc., 1996, 118, 2499, and J. Org. Chem., 1998, 63, 824
Also, Hoveyda and Schrock, J. Am. Chem. Soc., 1998, 120, 4041
Cyclic Allylic Ether Resolution through Zr catalyzed MgR addition: Hoveyda, J. Org. Chem., 1999, 64, 9690
Horner-Emmons-Wadsworth: Rein, Angew. Chem., Int. Ed. Engl., 1994, 33, 556
Imine Resolution: Buchwald, J. Org. Chem., 2000, 65, 767
Intramolecular Rh-catalyzed alkynyl ketone cyclization KR: Fu, J. Am. Chem. Soc., 2002, 124, 10296
21