Shi Asymmetric Epoxidationtminehan.com/531pdfs2/Oxidation2.pdf · Sharpless Asymmetric...
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Shi Asymmetric Epoxidation Chiral dioxirane strategy: R 3 R 1 • catalyst (10-20 mol%) is prepared from D-fructose, and its enantiomer from L-sorbose • oxone, the stoichiometric oxidant, is a 2:1:1 mixture of KHSO 5 , KHSO 4 , and K 2 SO 4 • H 2 O 2 / CH 3 CN may also be used as stoichiometic oxidant. • a pH of 10.5 is an optimum balance between oxone decomposition and Baeyer-Villiger rearrangement of dioxirane intermediate O O O O O O 1 + Oxone, pH 10.5, K 2 CO 3 , H 2 O, CH 3 CN R 3 R 1 O O O O O O O O formed in situ O O O O O R 1 R 2 R 3 O O spiro TS electronically favored O O O O O O O planar TS R 2 R 1 R 3 n=>!* Higher ee's observed with smaller R 1 and larger R 3 substituents
Transcript of Shi Asymmetric Epoxidationtminehan.com/531pdfs2/Oxidation2.pdf · Sharpless Asymmetric...
Shi Asymmetric Epoxidation
Chiral dioxirane strategy:
R3
R1
• catalyst (10-20 mol%) is prepared from D-fructose, and its enantiomer from L-sorbose
• oxone, the stoichiometric oxidant, is a 2:1:1 mixture of KHSO5, KHSO4, and K2SO4
• H2O2 / CH3CN may also be used as stoichiometic oxidant.
• a pH of 10.5 is an optimum balance between oxone decomposition and Baeyer-Villiger
rearrangement of dioxirane intermediate
O
O
OO
O
O1
+Oxone, pH 10.5,
K2CO3, H2O, CH3CN
R3
R1
O
OO
O
O
OO
O
formed in situ
O
O
O
OO
R1 R2
R3
O O
spiro TS
electronically favored
O
O
O
OO
O O
planar TS
R2
R1
R3
n=>!*
Higher ee's observed with smaller R1 and larger R3 substituents
Shi Asymmetric EpoxidationEffect: smaller R1 beneficial
R1
R2
R3
26% ee
CH3
79% ee
CH3
81%ee
Ph
98%ee
Effect: larger R3 beneficialCH3
H3C
Ph
CH3
H3C
C10H21
CH3
H3C
91% ee86% ee76% ee
Compare:
CH3
H3C
Ph
76% ee
CH3
Ph
CH3
97% ee
Note that the substituent size preferences reflect interactions in the spiro TS.
Proposed Catalytic Cycle: R3
R1
O
O
OO
O
O
HSO5-
O
OH
OO
O
O O O
SO3-
O
O-
OO
O
O O O
SO3-
OO
O
O
OO
O
R3
R1
O
SO42-
Shi Asymmetric Epoxidation
Substrate Product Yield ee
Ph
Ph
Ph
PhO
73% 95%
Ph Ph
O
Cl Cl61% 93%
Ph O
O
Ph O
OO
91% 93%
C10H21 C10H21
O
94% 89%
JACS, 1996, 9806JACS, 1997, 11224
OTBS
Monoepoxidation of dienes occurs at the more e-rich or less sterically hindered olefin
25mol% 1, Oxone
K2CO3, CH3CNOTBS
O
81% yield96% ee
OCH3
25mol% 1, Oxone
K2CO3, CH3CNOCH3
O 65% yeild89% ee
Shi Asymmetric Epoxidation
Trisubstituted olefins are selectively epoxidized because they are more e-rich
SiMe3
Ph
25mol% 1, Oxone
K2CO3, CH3CNPh
O
CH3
TMS
CH3
SiMe3
77%, 92% ee
Epoxidation of enynes occurs selectively at the C-C double bond:
Ph
CH3
SiMe3
25mol% 1, Oxone
K2CO3, CH3CN
Ph
CH3
SiMe3
O
64%, 94%ee
1,1-disubstituted epoxides can be prepared from trisubstituted vinyl silanes by epoxidation and desilylation:
CH3
25mol% 1, Oxone
K2CO3, CH3CN
SiMe3
CH3
OTBAF
CH3
O
JOC, 1999, 7675
TL, 1998, 4425JOC, 1999, 7646
JOC, 1998, 2948
94%ee74%, 94% ee
82%
Shi Asymmetric Epoxidation
A modified catalyst is used for epoxidation of cis-disubstituted olefins and styrenes
ONBoc
O
O
O
O
O
Ph CH3 Oxone, K2CO3, DME
2
Ph CH3
O
82%, 91%ee
JACS, 2000, 11551
Oxone, K2CO3, DME
2
O
100%, 81%ee
Org. Lett. 2001, 1929JOC, 2002, 2435
!-substituent prefers to be proximal to the spiro oxazolidinone:
O
O
O
NBocO
R1
R!
O O
O
Shi Asymmetric EpoxidationKinetic Resolution of racemic 1,3- and 1,6-disubstituted cyclohexenes provides optically enriched allylicSilyl ethers
OTMS
Ph 35 mol% 1
49% conv.
OTMS
Ph
96% ee
OTMS
Ph
O
95% ee
+
OTBS
Ph 35 mol% 1
70% conv.
OTBS
99% ee
OTBS
O
81%ee
+
PhPh
The original Shi catalyst decomposes faster than it reacts with electron-deficient unsaturated esters. A second-generation catalyst,incorporating electron-withdrawing acetate groups, slows the decomposition:
OO
O
O
OO
O
Baeyer-Villiger
reactionO
O O
O
O-O
O
O
O O
O
OO
O
Ph
CO2Et
Ph
CO2Et
O
OO
O
AcO
OAc
O
73% yield, 96% ee
JACS, 2002, 8792
JACS, 1999, 7718
Upjohn Dihydroxylation
Sharpless Asymmetric Dihydroxylation Reaction
Catalytic Cycle:
OsO
O
O
O
L
OsO
O
O
O
L
L
OsO
O
O
O
L
2 H2O, 2HO-
H4OsO62- + HO
HO
+ L
VIII
VI
2 Fe(CN)64- 2 Fe(CN)6
3-
Addition is likely a 3+2 cycloadditionrather than a 2+2 cycloaddition/rearrangement:
OsO
O
O
O
L
OsO
O
O
O
L
turnover is achieved with stoichiometric
oxidants: K3Fe(CN)6, NMO
NMO is found to be deleterious to
the enantioselective process
Original UpJohn Procedure:
R1
R2Cat. OsO4, 1eq. NMO
8:1 acetone : water
N
O
-O CH3
NMO=
R1
R2HO
OH
TL, 1976, 1973
JOC, 1990, 766
TL, 1996, 4899JACS, 1997, 9907
[3+2]
Sharpless Asymmetric Dihydroxylation ReactionLigands: C2-symmetric, pseudo-enantiomeric
NN
OO
N
N
OMe
Et
N
Et
N
MeO
(DHQD)2-PHAL
ligand for AD-mix-!
NN
OO
N
N
OMe
N
N
MeO
EtEt
(DHQ)2-PHAL
Ligand for AD-mix-"
slightly less enantioselective
AD-mix reagents are commercially available:
1.4 g Ad-mix-! will oxidize 1mmol olefin
0.98 g K3Fe(CN)6 (3 mmol)
0.41g K2CO3 (3 mmol)
0.0078 g (DHQD)2-PHAL (0.01 mmol)
0.00074 g K2OsO2(OH)4(0.002 mmol)
ˆJOC, 1992, 2768
Corey Proposes a U- shape binding pocket:
N
NN
OO
MeO
N
Os
OO
O
O
N
MeO
N
H
TL, 1995, 3481
Sharpless Asymmetric Dihydroxylation Reaction: Ligand Accelerated Catalysis
4 of 6 olefin classes are successfully dihydroxylated:
tetra tri trans-di gem-di monocis-di
Mnemonic:
RL
RS RM
H
(DHQD)2-PHAL
(DHQ)2-PHAL
!
"
Application of Mnemonic:
H3C
CH3
CH3
CH3
CH3
H3C
CH3
CH3
H3C OH
OH
AD-mix-!
C5H11
CO2EtC5H11
EtO2C
AD-mix-!
C5H11
EtO2C
OH
OH
S R
R
CH3
AD-mix-!CH2OH
CH3
OH
R
C8H17
AD-mix-!
C8H17 CH2OH
OH
R
very hindered
slightly hindered
attractive area:good foraromatic and alkyl substituents
Generality of Sharpless Asymmetric Dihydroxylation
(DHQD)2-PHAL (DHQ)2-PHAL
H3C
CH3
CH3
C5H11
CO2Et
CH3
C8H17
% ee, config % ee, config
AD-mix-! AD-mix-"
98, R 95, S
99, R, R 97, S, S
99, 2S, 3R 96, 2R, 3S
>99.5, R,R >99.5, S,S
94, R93, S
84, R80, S
97, R 97, S
JOC, 1992, 2768
Generality of Sharpless Asymmetric Dihydroxylation
Cis-Disubstituted Olefins are poor substrates; with a modified catalyst, DHQD-IND, good ee’s can be obtained:
CH3
ee at 0°C
72 (1R, 2S)
CO2iPr80 (2S, 3R)
N
Et
N
O
H
OMe
O
N
DHQD-IND
JACS, 1992, 7568
(DHQD)2AQN is often a superior ligand:
O
ODHQD
ODHQD
Cl
(DHQD)2AQN
90% ee vs. 63% ee with (DHQD)2PHAL
O
O
Ph88%ee vs. 77% ee with (DHQD)2PHAL
78% ee vs. 44% ee with (DHQD)2PHAL
O
ACIEE, 1996, 448.
Generality of Sharpless Asymmetric DihydroxylationGood substrates Allylic 4-methoxybenzoates
O
O
OCH3H3CO
AD-mix-!
(DHQ)2PHAL
O
O
OCH3H3CO
OH
HO
>99%e, 93% yield
But:
OH
OCH3H3CO
18%ee
OTIPS
OCH3H3CO
13%ee
OMe OMe
O
O
MeO
O
O
MeO
O
MeO
AD, (DHQD)2PYDZ
>99% yield, 98%ee
98% yield, 97% ee
96%, 91% ee
PYDZ =N N
OO
JACS, 1995, 10805
Generality of Sharpless Asymmetric Dihydroxylation
Regioselectivity of AD with dienes: in general, AD is selective for more electron-rich doible bonds
OH
OH
Substrate Product % yield, % ee
78, 93
CO2Et
OH
OH
CO2Et 78, 92
OHOH
73, 98
OHOH
70,98
JACS, 1992, 7570
Use of AD with Chiral Olefins
O
O
OMe
CH3
O
O
O
O
OMe
CH3
O
O
OH
HO
"anti"
+
O
O
OMe
CH3
O
O
OH
HO
"syn"
conditions
OsO4, NMO
anti:syn
88% yield (mixture) 1.9:1
(DHQ)2PHAL 86% yield (anti) 54:1
(DHQD)2PYDZ 86% yield (syn) 1:35
matched
mismatched
TL, 1997, 5941
Oxidative Kinetic Resolution
R1
OH
R2
OKR
chiral catalyst [O]
R1
O
R2
racemic
+
R1
OH
R2
non-racemic
It was found that combination of a palladium source, (-) sparteine as a chiral ligand, and O2 could effect Efficient oxidative kinetic resolution under defined conditions
R1
OH
R2
Pd(nbd)Cl2,
MS 3Å, PhCH3O2, 80°C
R1
O
R2
racemic
+
R1
OH
R2
non-racemic
(-)-sparteine5 mol%
20 mol%
Ph
OH
enriched alcohol isolated yield ee ROH
40 93.1
OH
30 93.4
OH
31 99.8
CH3
CH3Ph
OH
29 91.8
JACS,2001, 7725.
OKR Mechanism: a Dual Role for (-)-Sparteine
N N
Pd
Cl Cl
Ph
OH
MeN N
Pd
Cl
Ph
O
Me
H:B
N N
Pd
Cl
Ph
O
Me
+ B–H+ Cl-
Only one enantiomer binds the chiral catalyst efficiently!
!-Hydride Elimination
Ph
O
Me
+ N N
Pd
Cl H
N N
Pd0
:B
O2, Cl-
remaining enantiomer:
Ph
OH
Me
An excess of sparteine is beneficial for the reaction, and it is believed that sparteine not only functions as the chiralLigand, but also as an exogenous base for the deprotonation step, making beta-hydride elimination rate-limiting
Rate-limiting
JACS, 2002, 8202.
