recent developments and applications in enantioselective desymmetrisation
DESCRIPTION
Recent Developments and Applications in Enantioselective Desymmetrisation. Xin Linghu Department of Chemistry University of North Carolina, Chapel Hill. Outline. Introduction Enantioselective Desymmetrisation of Different Functional Groups Cyclic anhydrides Epoxides - PowerPoint PPT PresentationTRANSCRIPT
Recent Developments and Applications in Enantioselective Desymmetrisation
Xin Linghu
Department of ChemistryUniversity of North Carolina, Chapel Hill
Outline
Introduction
Enantioselective Desymmetrisation of Different Functional Groups
Cyclic anhydrides Epoxides Aldehydes and Ketones Alkenes Diols
Summary
Acknowledgement
Introduction to Enantioselective Desymmetrisation
achiral molecule (meso)
mirror plane
inversion center
chiral reagent or catalyst
chiral molecule
Enantioselective Desymmetrisation in Total Synthesis
1987, Schreiber:
1992, Harada:
Me Me Me MeMe Me
OTBS OBnOH OHOH OH
d-menthone enol TMS etherTfOH, THF, -40 ¡ãC, 2 h
61%
O O O O O OOH OH
Me Me Me Me t-BuOOHTi(OiPr)4
L-(+)-DIPT
81%
O O O OOH OH
Me Me Me Me
O
Me Me Me Me
OBnOH OOH O
Me Me Me Me
OBnO OHO OH+
4.5:1
Enantioselective Desymmetrisation of Cyclic Anhydride: Previous Work
OO O
10 mol% cinchonine4 equiv MeOH
toluene, RT, 4 d>95%, 70% ee
MeO2C CO2H
O
O
O
110 mol% quinidine3 equiv MeOH
toluene/CCl4, -55 ¡ãC, 60 h98%, 99% ee CO2H
CO2Me
O
O
O
120 mol%TADDOL A:Ti(OiPr)4 (1:1)
THF, -30 ¡ãC, 5 d91%, 98% ee CO2iPr
CO2H
O
O
O
120 mol%TADDOL B:Ti(OiPr)4 (1:1)
THF, -34 ¡ãC, 24 d74%, 96% ee CO2iPr
CO2H
1985, Oda:
1999, Bolm:
1995, Seebach:
N
H
OH
N
R
98
R C-8 C-9
H R S cinchonine
H S R cinchonidine
OMe S R quinine
OMe R S quinidine
configuration
O
O OH
OH
Ar Ar
Ar Ar
TADDOL A: Ar=PhTADDOL B: Ar=2-Nap
Formation of C-X Bond via Anhydrides
O
O
O
+ MeOH
catalyst (5-30 mol%)toluene, -20 or -40 ¡ãC CO2H
CO2Me
H
H
H
H
R
R
R
RN
H
O
N
OMe
DHQD (dihydroquinidyl)
O
O
O
O
N
OMe
N
OMe
N
N
H
H
(DHQD)2AQN
CO2H
CO2Me
CO2H
CO2Me
H
H
H
H
CO2H
CO2Me
H
H
CO2H
CO2Me
CO2H
CO2Me
CO2H
CO2Me
OCO2H
CO2Me
CO2HCO2Me
CO2H
CO2Me
99% 95% ee 95% 98% ee 97% 97% ee
93% 98% ee 70% 91% ee 72% 92% ee
88% 96% ee 74% 92% ee 82% 95% ee
Chen, Y.; Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542-9543.
Formation of C-C Bond via Anhydrides
O
O
O
H
H
+ Et2Zn
20 mol% Ni(COD)2,22 mol% ligand CO2H
H
HA (0.4 equiv)
THF, 12 h, 0 to 25 ¡ãC
Et
O
N PPh2
F3C
pyphos
A
ligand yields (%)
pyphos 80bipy 92PPh3 (2 equiv) <5dppe 20dppb 78
R
R
O
O
O
H
H
+ Et2Zn
10 mol% Ni(COD)2,12 mol% bipy or pyphos
R
R CO2HH
H
61-96% yields Et
O
chiral ligand
BINAP, DIOP, DuPHOS
PPh2 N
O
i-Pr
no reactionor low yields
85% yield79% ee
O
O
O
H
H
+ Et2Zn
10 mol% Ni(COD)2,12 mol% chiral ligand CO2H
H
H
A (0.2 equiv)THF, 3 h, 0 ¡ãC
Et
O
Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 174-175.
Formation of C-C Bond via Anhydrides
OO O
Ph
+ PhMgCl1.0 equiv of ligand
toluene, -78 ¡ãC, 9 h Ph
O Ph
OH
O
*1.0 equiv
Me Ph
Me2N OH
MeO
Ph
OMe
Ph
N
NH
H
HH
N
O
N
O
Me Me
Ph Ph
N
H
OH
N
OMe
(+)-1(+)-2
(+)-3
(-)-4 (-)-5
entry ligand % ee yield (%)
1 (+)-1 1 76
2 (+)-2 12 76
3 (+)-3 32 66
4 (-)-4 39 77
5 (-)-5 88 63
Shintani, R.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 1057-1059.
Formation of C-C Bond via Anhydrides
Shintani, R.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 1057-1059.
OO O
Ph
+ ArMgX
1.3 equiv of (-)-sparteine
toluene, -78 ¡ãC, 24 h Ar
O Ph
OH
O
1.3 equiv
OO O
R
+ PhMgCl
1.3 equiv of (-)-sparteine
toluene, -78¡ãC, 24h Ph
O R
OH
O
1.3 equiv
entry ArMgX % ee yield (%)
1 PhMgCl 92 91
2 p-MeOC6H4MgBr 89 88
3 p-FC6H4MgBr 78 82
4 o-TolMgCl 37 66
Ph
OH
O
PhO
Bn
OH
O
PhO
OH
O
PhO
OH
O
PhO
S
OH
O
PhO
Me
OH
O
PhO
Me
Me
OH
O
PhO
Me
Me
Me
OH
O
PhO
Me MeTBSO
OH
O
PhO
91% 92% ee 87% 92% ee 87% 88% ee
74% 91% ee 74% 90% ee 76% 91% ee
92% 70% ee 84% 91% ee 51% 87% ee
Enantioselective Desymmetrisation of Epoxides: Previous Work
O
R
R
iPrMe2SiN3, TMS-TFA
CH2Cl2, r.t. OHR
R N3
83-93% ee N
Me
Me
Me OH
HO OH
L*H3
1992, Nugent:
1998, Nugent: O
R
R
TMS-N3 (1.25 equiv)
(~20 equiv) OTMSR
R Br
84-95% ee
Br
PhCl, r.t., 48 h
L*Zr ZrL*(OtBu)2
L*Zr ZrL*(OtBu)2
O
R
R
TMS-N3, A (2 mol%)
OHR
R N3
82-98% ee
N N
O OCr
Cl
H H
t-Bu
t-Bu
t-Bu
t-Bu
N N
O OCo
H H
t-Bu
t-Bu
t-Bu
t-Bu
O
R
R
B (2.5-5.0 mol%),
OHR
R OCOPh
55-93% ee
1995, Jacobsen:
1997, Jacobsen:
A
B
PhCO2H, iPr2NEt
Enantioselective Desymmetrisation of Epoxides: Previous Work
O
O
O
OGa
Li
O
R
ROHR
R S-tBu
82-98% ee
1997, Shibasaki:toluene, r.t.
+ tBuSHCat. (10 mol), 4A MS
O
R
R
Cat. (10 mol%), SiCl4
OHR
R Cl
52-87% ee
1998, Denmark:CH2Cl2, -78 ¡ãC
N
N
PO
N
Me
Me
O + PhLiCat., BF3¡¤OBu2
Et2O, -78 ¡ãC
OH
Ph 99%, 47% ee
1996, Tomioka:MeO
Ph Ph
O
Ph
OMe
OCat. (20 mol%),
4 ¡ãC, toluene
TMSCN, Ti(OiPr)4CN
OTMS 80% conv, 86% ee
1996, Hoveyda and Snapper:
MeO
HN
N
O
OOMe
H
MeMeMe
Me MeMe
H
HO
F
Fe
N
R R
RR
R
O
O
Ph Ph
+ SiCl4(-)-catalyst (10 mol%)
(i-Pr)2NEt, CH2Cl2 PhPh
OSiCl3
Cl
A: R = MeB: R = PhC: R = 3,5-Me2C6H3
Enantioselective Ring Opening Catalyzed by
Planar-Chiral Pyridine N-Oxides
Tao, B.; Lo, M. M. C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 353-354.
catalyst temp % ee
A rt 11
B rt 25
B -78°C 60
C rt 68
C -78°C 92
O
R R
+ SiCl4(+)-C (5 mol%)
(i-Pr)2NEt, CH2Cl2, -85 ¡ãC
RR
OSiCl3
Cl
entry R yield (%) % ee
1 Ph 88 94
2 4-FC6H4 97 91
3 4-CH3C6H4 94 93
4 4-CF3C6H4 93 98
5 2-naphthyl 84 94
6 CH2OBn 91 50
Enantioselective Ring Opening Catalyzed by
Chiral Bipyridine N,N’-Dioxide Derivatives
O
R R
+ SiCl4cat. (10 mol%)
(i-Pr)2NEt (1.5 equiv), CH2Cl2, -78 ¡ãC, 6 h
RR
OSiCl3
Cl(2.0 equiv)
entry R yield (%) % ee (confgn)
1 Ph 95 90
2 CH2OCH2Ph 98 74
3 CH2O(CH2)3Ph 95 70
4 -(CH2)4- 83 0
N
N
O
O
Nakajima, M.; Saito, M.; Uemura, M.; Hashimoto, S. Tetrahedron Lett. 2002, 43, 8827-8829.
Asymmetric Ring Opening with TMSCN Catalyzed by (pybox)Yb Complexes
O
R R
YbCl3 (5 mol%)ligand a or b (6 mol%)
TMSCN, CHCl3 RR
TMSO
CN
NO
N N
O
R Ra: R = t-Bub: R = Ph
entry substrate ligand temp (°C) time (d) yield (%)% ee
(confgn)
1 (S,S)-b -45 4 9091
(1S, 2R)
2 (S,S)-a -10 7 8392
(1R, 2S)
3 (S,S)-b -40 7 8090
(2S, 3R)
4 (S,S)-a 0 7 8683
(1R, 3S, 4R)
5 (S,S)-a -10 7 7287
(3R, 4R)
O
O
O
Me Me
O
CO2Et
N
O
COCF3
Schaus, S. E.; Jacobsen, E. N. Org. Lett. 2000, 2, 1001-1004.
Enantioselective Alkylation of Vinyloxiranes
O
ZnEt2/toluene1.5 mol% Cu(OTf)2
3 mol% 1 or 2
-70 ¡ãC to 0 ¡ãC, 3 h
Et
OH*
O
OP N
Me
Me
(S,S,S)-1
O
OP N
Me
Me
(S,R,R)-2
Et
OH
H
H
Et
OH
Et
OH
Et
OH
1 2 1 2 1 1
yield (%) 92 86 80 68 78 90
% ee 66 37 85 76 71 97
SN2’/SN2 >99/1 98/2 87/13 75/25 93/7 98/2
Bertozzi, F.; Crotti, P.; Macchia, F.; Pineschi, M.; Arnold, A.; Feringa, B. L. Org. Lett. 2000, 2, 933-936.
Desymmetrisation by Enantioselective Deprotonation
( )n
O-deprotonation
( )n
O
Li
proton transferand ring opening
( )n
OLi
( )n
OH
O-deprotonation
OH
LiN
RR
OLi
H
H
H
Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996, 52, 14361-14384.
Enantioselective -Deprotonation of Epoxides: Previous Work
1996, Hodgson:
O
O
O
Et2O, -98 ¡ãC
H H
H H
H H
OH
OH
OH
PriLi andN
NH
H
HH
(-)-sparteine
86%, 84% ee
77%, 83% ee
97%, 77% ee
1996, Hodgson:
Li
O O
Et2O, 0 ¡ãC to rt Ph NLi
Ph
BusLi andpentane, -78 ¡ãC to rt
OH
OH
73%, 49% ee
73%, 52% eeN
NH
H
HH
(-)-sparteine
Enantioselective -Deprotonation of Epoxides: Previous Work
O Ph NLi
Ph
THF, reflux OH65%, 36% op
BnO O
C6H6/THF,-78 ¡ãC to rt BnO
OH
98%, 80% eeLiHN OLi
Me Ph
O
THF/DBU (10 mol%)0 ¡ãC, 24 h OH
91%, 96% eeNLi
N
1980, Whitesell and
Felman:
1993, Milne and
Murphy:
1998, Andersson:
Enantioselective Alkylative Double Ring Opening of Epoxides
O
N N
O
N
NH
H1 2
OO
n( )
iPrLi or nBuLi/1 or 2
Et2O or cumene-78 ¡ãC (5h) to rt (16h)
n( )
HOOH
Bu/iPr
HO
Bu
OH
Bu
OH
Bu
OH
iPr
OH
OH OH OH
MeO
MeO
O
O
iPr
OHOH
iPr
OH
OH
iPr
OH
OH
iPr
OH
OH
TBSO TBSO
46%, 34% ee 57%, 27% ee 50%, 51% ee 44%, 74% ee
42%, 56% ee 44%, 85% ee 46%, 69% ee 54%, 84% ee
Hodgson, D. M.; Maxwell, C. R.; Miles, T. J.; Paruch, E.; Stent, M. A. H.; Matthews, I. R.;
Wilson, F. X.; Witherington, J. Angew. Chem. Int. Ed. 2002, 41, 4313-4316.
X ORLi
X O XRLi
R
Li
OLiHX
R
OHLi
Enantioselective Alkylative Double Ring Opening of Epoxides
Hodgson, D. M.; Maxwell, C. R.; Miles, T. J.; Paruch, E.; Stent, M. A. H.; Matthews, I. R.;
Wilson, F. X.; Witherington, J. Angew. Chem. Int. Ed. 2002, 41, 4313-4316.
XN
On( )
iPrLi or nBuLi/1 or 2
Et2O-78 ¡ãC (5h) to rt (16h)
n( )
XHNOH
Bu/iPr
BusHN
Bu
OH
iPr
OH
iPr
OH
NHBus
NHBoc
CH2TMS
OH
NHBoc
iPr
OH
NHBoc
Bu
OH
NHBoc
TBSO
TBSO
79%, 45% ee 25%, 45% ee 42%, 64% ee
78%, 87% ee 44%, 71% ee
61%, 57% ee
59%, 65% ee
68%, 79% ee
BocHN
Bu
OH
iPr
OH
NHBoc
iPr
OH
NHBoc
85%, 71% ee
MeOTBSO
-Deprotonated Epoxides as Nucleophiles
entry E yield (%) % ee
1 TMS 72 74
2 SnBu3 60 79
3 PhCH(OH) 80 76
4 PhCO 68 77
5 Et2C(OH) 75 77
6 EtCH(OH) 74 76
7 EtCO 67 78
8 EtOCO 58 81
Hodgson, D. M.; Gras, E. Angew. Chem. Int. Ed. 2002, 41, 2376-2378.
OsBuLi/chiral amine
Et2O -78 ¡ãCO
LiE
O
E
N
NH
H
OHH
H
First Desymmetrisation of Centrosymmetric Diepoxide in Natural Product Synthesis
O
O OH H Me
H OH
HHH
CHOHO Me
AB C
D
Hemibrevetoxin B
O
O
O Me
MeH
H
OO
A B
O
O
O
O
Me
MeH
H
O
O
MeO
OMe
Me
MeH
H
85% yield
O O
H H
MeO OMe
O O
O
O
O
O
5 mol% [(Cy3P)2RuCHPh]
CH2Cl2, 92%
m-CPBA,
98%
PPTS,
MeOH,
E:Z 2:1
Holland, J. M.; Lewis, M.; Nelson, A. Angew. Chem. Int. Ed. 2001, 40, 4082-4084.
N N
O OCo
H H
t-Bu
t-Bu
t-Bu
t-Bu
OAc
Holland, J. M.; Lewis, M.; Nelson, A. Angew. Chem. Int. Ed. 2001, 40, 4082-4084.
First Desymmetrisation of Centrosymmetric Diepoxide in Natural Product Synthesis
O
O
Me
MeH
H
¡¤¡¤
O
O
OHC
CHO
Me
MeH
HTMS
Me3SiOTf, 92%
O
O
MeO
OMe
Me
MeH
HO3, then
Me2S
98%
d.r. >99:1
O
O
O
O
Me
MeH
HO
O
O Me
MeH
H
OHOH
20 mol% cat.,1.1 equiv H2O
MeCN/CH2Cl2>98% yield, >95% ee
(MeO)2CMe2,PPTS/CH2Cl2,
98%
Me3S(O)I,NaH, DMSO,75%
d.r. >20:1
O
O
O Me
MeH
H
OO
Enantioselective Desymmetrisation of Ketones and Aldehydes: Previous Work
NP
NMe
Me
O
Ph+
1. BuLi, -78 ¡ãC2. AcOH
PhO
tBu tBu
91%, >99:1 er
O
tBu
(EtO)2POEt
O O+
1. cat. (20 mol%), PhH, RbOH, rt, 191h
2. HCl/EtOH
O
OEt
tBu
69%, 57% ee
N
H
OH
N
OMe
Br
OHC CHO
Fe(CO)3
OHC
Fe(CO)3toluene:hexane4:1
R2Zn
N
Me OH
PhPh
R
OHH
R = Et, >98% eeR = Me, 86% ee
OHC CHO
Fe(CO)3
OHC
Fe(CO)3-78 ¡ãC, toluene
OHH
O
B O
CO2iPr
CO2iPr
>98% ee
1990, Roush:
1998, Takemoto:
1998, Arai and
Shioiri:
1984, Hanessian:
Enantioselective Desymmetrisation of Ketones and Aldehydes: Previous Work
O
Me
Ipc2BCl (2 equiv)sparteine (1 equiv)
pentane, -131 ¡ãC
OB(Ipc)2
Me
N
NH
H
HH
(-)-sparteine
BCl
Ipc2BCl2
O
tBu
Me Me
OH N3
1. BF3¡¤OEt2
2. NaHCO3
N
OOH
Me Me
But
1. PCC2. NaH
NH
O
But
Ph
O
tBuCHO, O2
cat. * (1 mol%)O
O
OO
O
Ph O2N O
ON NO2O
ON
Cu
cat. *:
1997, Bolm:
1995, Aubé:
1998, Ward:
Enantioselective Baeyer-Villiger Oxidations by Transition Metal Catalysis
N N
O OCr
IF
F
F
F
N N
O OZr
Y
PhPh
YY = PhO
R
O OO
R
A
B
*
B (5 mol%), UHP
CH2Cl2, r.t.
R
O OO
R *
A (5 mol%), H2O2
EtOH, 0 ¡ãC
R = Ph, 96%, 79% ee (4S)R = 4-ClC6H4, 82%, 75% ee (4S)R = 4-MeC6H4, 99%, 75% ee (4S)R = Me(CH2)7, 89%, 69% ee (4S)
R = 4-ClC6H4, 63%, 82% ee (4R)R = 4-MeC6H4, 43%, 84% ee (4R)R = Me(CH2)7, 63%, 81% ee (4R)
Uchida, T.; Katsuki, T.; Ito, K.; Akashi, S.; Ishii, A.; Kuroda, T. Helv. Chim. Acta 2002, 85, 3078-3089.
Watanabe, A.; Uchida, T.; Ito, K.; Katsuki, T. Tetrahedron Lett. 2002, 43, 4481-4485.
Enantioselective Baeyer-Villiger Oxidations by Organocatalysis
R
O OO
R *
cat. (10 mol%), H2O2-30 ¡ãC, 6 d
AcONa (cat.),CF3CH2OH/MeOH/H2O
H
N
N
NN
NOMe
O
Et
H
NN
NO
OMe
Et
2ClO4
NN
EtN
O
NMe
O
OOH
N
O H
entry R yield (%) % ee
1 4-MeOC6H4 67 61(+)
2 4-MeC6H4 53 62(+)
3 Ph 67 63(S)
4 4-BrC6H4 28 68(+)
5 4-ClC6H4 34 66(S)
6 4-FC6H4 55 65(+)
Murahashi, S.-I.; Ono, S.; Imada, Y. Angew. Chem. Int. Ed. 2002, 41, 2366-2368.
Rhodium-Catalyzed Desymmetrisation of 4-Alkynals
M
M
O
H
M
O
H
H
O
M: metal complex
trans addition of M-Hto an alkyne
O
HH
O O
R
OMe
R
10 mol%[Rh((R)-Tol-BINAP)]BF4
CH2Cl2, 10 ¡ãC
R
OMe
R
entry R yield (%) % ee
1 n-C5H11 95 92
2 Cy 94 95
3 (CH2)3Cl 91 91
4 CH2OMe 93 82
Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 10296-10297.
P(Tol)2
P(Tol)2
(R)-Tol-BINAP
Enantioselective Reduction of 2-Alkyl-1,3-diketones
R R
O O
R'
cat, (5 mol%)NaBH4, EtOH, THFA
CHCl3, 0 ¡ãC, 10hR R
OH O
R'N N
O OCo
O
Me Me
O
OH O OH OOH O
anti-selectivity: 99%,yield: 93%, ee: 99%
anti-selectivity: 99%,yield: 97%, ee: 99%
anti-selectivity: 99%,yield: 73%, ee: 99%
OH O
Br Br
anti-selectivity: 99%,yield: 68%, ee: 99%
OH O OH O
MeO OMe
anti-selectivity: 99%,yield: 96%, ee: 97%
anti-selectivity: 99%,yield: 88%, ee: 99%
OH O OH O OH O
Ph
anti-selectivity: 99%,yield: 45%, ee: 91%
anti-selectivity: 98%,yield: 88%, ee: 97%
anti-selectivity: 99%,yield: 96%, ee: 98%
Ohtsuka, Y.; Koyasu, K.; Ikeno, T.; Yamada, T. Org. Lett. 2001, 3, 2543-2546.
Synthesis of a Potential Intermediate for Pseudomonic Acid B
BnO OBn
OTBS
BnO OBn
O
O O
BA
BnO OBn
OTMS
O O
Ph NLi
Ph
Me Me
TMSClTHF, -78 ¡ãC
C
BnO OBn
O O
HO2C OH
1. O3, MeOH/CH2Cl22. PPh3
3. NaBH4, MeOH
D92% yield from B
O
OBnO
O
MeO2C
O
OBnO
O
MeO2C
+
1. MeI, K2CO3, DMF
2. NaHMDS, THF
E
F
O
OBnHO
OH
MeO2C
O
OBnO
OH
O
p-TsOH, MeOHG
H
67% yield
24% yield
+
O
HO
OH
OHRO2C
OOH
R = (CH2)8CO2H
Psedomonic acid B
Honda, T.; Kimura, N. Org. Lett. 2002, 4, 4567-4570.
1987, Schreiber:
1996, Landais:
1990, Ito:
MeMe
OH
OMe
OH
Me
(-)-DIPT, Ti(OiPr)4
tBuOOH
after 1.5 h, 99.3% ee, 99% de
SiMe2OH SiMe2OH
OH
OH
K2OsO2(OH)4, K2CO3K3Fe(CN)6, tBuOH/H2O
(DHQ)2PYR, 0 ¡ãC
80%, 65% ee, >98% de
Me Me
OSi
H
R R
[RhCl(C2H4)2]2 (2 mol%)
ClCH2CH2Cl30 ¡ãC, 11 d
Me Me
O SiR2O O
Me Me
Ph2P PPh2
ligand (3 mol%) Me
OH OH
MeH2O2, KF
93% ee, 99% de66% yield from diene
(-)-DIPT
OH
OHO
O
OiPriPrO
N N
Ph
Ph
DHQQHD
(DHQ)2PYR
Enantioselective Desymmetrisation of Alkenes: Previous Work
PhO
O
O
H
H
H
+ SnCl4
CH2Cl2,-78 ¡ãC to -30 ¡ãC
H
HH
OOR*
HHO
81% yieldsingle isomer
1985, Whitesell:
Me Me
OTBScat. (10 mol%)
CH2Cl20 ¡ãC
99% ee, >99% synMeO
O
O
H
+
Me
OTBS
OH
O
OMe
O
OTiCl2
ON2
Ocat. (1.0 mol%)
CH2Cl2reflux
OO
OO
HHH
H
endo exo
75% yield, 20:1 endo:exo, 94% ee (endo)
Rh Rh
NO
H
CO2Me1994, Martin:
1992, Mikami:
Enantioselective Desymmetrisation of Alkenes: Previous Work
Enantioselective Desymmetrisation of Alkenes: Previous Work
Enantioselective Desymmetrisation of Alkenes: Previous Work
Mo
N Me
PhMe
RR
OO
Me
Me
MeMe
MeMe
MeMeMe
Me
a: R = iPrb: R = Me
Me Me
O
Me Me
O
Me Me
O
O
Me Me
n-octyl
Ph
O
Me
HMe
O
Me
HMe
O
Me
n-octylMe
O
Me
Ph
Me
Substrate Catalyst(5 mol%)
a
b
b
b
Product % Yield % ee
86
83
28
91
93
99
50
82
1998, Schrock and Hoveyda:
Preparation of Cyclic Amines Through Mo-Catalyzed Asymmetric RCM
NAr
cat. (5 mol%)
C6H6, 22 ¡ãC NAr
Me
Me
H
Mo
N Me
PhMe
OO
Me
Me
MeMe
MeMe
MeMeMe
Me
iPr iPr
a
Mo
N Me
PhMe
iPr
OO
Mes
Mes
iPr
b Mes = 2,4,6-Me3C6H2
entry Ar cat. yield (%) % ee
1 Ph a 78 98
2 p-OMePh a 81 97
3 p-BrPh a 81 98
4 o-OMePh b 77 84
5 o-BrPh b 90 82
Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 2002, 124, 6991-6997.
Enantioselective Ru-Catalyzed RCM
N N
Ph Ph
RuPh
Cl
ClPCy3
R
R
a: o-methylb: o-isopropyl
Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225-3228.
Me Me
O
Me Me
O
Me Me
O
Me
HMe
O
Me
HMe
Me
substrate catalyst(5 mol%)
a
product convn (%) % ee
95961820
9182
23233839
8590
bab
+ NaI+ NaI
Me Me
O
O
Me
HMe 78
901735
entry
1234
ab
+ NaI+ NaI
ab
+ NaI+ NaI
56
78
Me
N N
Ph Ph
Ru
X
iPr
iPr
X
O
H R
N N
Ph Ph
Ru
X
iPrX
O
R H
iPr
R =
S
O
Me
HMe
Me S Observed as Major Isomer
R
Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225-3228.
Enantioselective Ru-Catalyzed RCM
Mo
N Me
PhMe
RR
O
O
Me
Me
MeMe
MeMe
MeMeMe
Me
a: R = iPrb: R = Me
O O
=MLn
=MLn
ROM O O
LnM
O O
LnM
=MLn
O O
O
O
RCM
RCM
OO
MLn
=MLn
O O
Weatherhead, G. S.; Ford, J. G.; Alexanian, E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 1828-1829.
Tandem Catalytic Asymmetric ROM/RCM
O
Substrate Catalyst
a
a
Product % Yield % ee
10
69
>98
92
O O
H H
O
H
H
O O
Me Me
OO
Me
Me
OO
H H
OO
Me Me
OO
H
H
OO
Me
Me
Convn. ofbicycle %
a
b
76 98
84 >98
73
_
20
10
Weatherhead, G. S.; Ford, J. G.; Alexanian, E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 1828-1829.
Tandem Catalytic Asymmetric ROM/RCM
Desymmetrisation of Meso Bicyclic Hydrazines by Enantioselective Hydroboration
NN R
RN
N RR
HO
+
RN=NR
CH2Cl2, 0 ¡ãC quantitative
CatBH (2 equiv), DME1 mol% [Rh(COD)Cl]2
2 mol% ligand*-50 ¡ãC, 30 min
entry R yield (%) % ee
1 CO2Et 49 83
2 CO2Bn 90 84
3 CO2Bu 58 80
4 -CONPhCO- 78 60
P P
(S,S)-DBPP
Luna, A. P.; Ceschi, M. A.; Bonin, M.; Micouin, L.; Husson, H. P.; Gougeon, S.; Estenne-Bouhtou,
G.; Marabout, B.; Sevrin, M.; George, P. J. Org. Chem. 2002, 67, 3522-3524.
OH
NN CO2Bn
CO2Bn
HOPhH2CON NCOPh
OH
H H
NN CO2Bn
CO2Bn
HO
NN CO2Bn
CO2Bn NN CO2Bn
CO2Bn
PhH2CON NCOPh
OAc
H H
O
OAcN
N CO2BnCO2Bn
1. H2, CH3CO2H, Pt
2. PhCOCl, Py74%, 84% ee92% ee after one recryn.
oxalyl chloride
DMSO/Et3N, 84%
BH3¡¤THF, 76%
1. H2, CH3CO2H, Pt
2. PhCOCl, Py, 78%
Ac2O,Py/DMAP,82%
Luna, A. P.; Ceschi, M. A.; Bonin, M.; Micouin, L.; Husson, H. P.; Gougeon, S.; Estenne-Bouhtou,
G.; Marabout, B.; Sevrin, M.; George, P. J. Org. Chem. 2002, 67, 3522-3524.
Desymmetrisation of Meso Bicyclic Hydrazines by Enantioselective Hydroboration
Asymmetric Synthesis of Polyhydroxylated Celastraceae Sesquiterpene Cores
O
AcOAcO
H
OAcO
OAc
OAcO
O
N
OOH
OOH
O
O
hypoglaunine B
O
HOHO
H
OHOH
X1
OH
X2
X4
X3 OH
RORO
OROR
OR
O OH
RORO
OROR
OR
epoxidativeenantioselective
desymmetrisationeuonyminol: X1, X2, X3, X4 = OH
4-hydroxyalatol: X1, X3 = OH, X2, X4 = H
14-deoxyalatol: X1, X2, X3, X4 = H
Spivey, A. C.; Woodhead, S. J.; Weston, M.; Andrews, B. I. Angew. Chem. Int. Ed. 2001, 40, 769-771.
Enantioselective Desymmetrisation of Meso-Decalin Diallylic Alcohols by Zr-Based SAE
O
OH
CN
OH
CN
O O
Et2AlCN,CH2Cl2,
rt (98%)
VO(acac)2,tBuOOH,
CH2Cl2, 70 ¡ãC(87%)
OBn
CN
O O
BnBr, NaHnBu4NI, NMP
50 ¡ãC (83%)
1. Ph3PBr2, rt,CH2Cl2 (87%)
2. TBSOTf,2,6-lutidine, rt,CH2Cl2 (98%)
3. DBU
50 ¡ãC (83%)
OBn
CN
TBSO OTBSOBn
CN
TBSO OTBS
OO O
O
1. OsO4, NMO (79%)
2. Me2C(OMe)2, TSOH/CH2Cl2 (95%)
3. K2OsO2(OH)4, K3Fe(CN)6, Base (74%)
4. Me2C(OMe)2, TSOH/CH2Cl2 (98%)
1. Na/NH3,THF, then,TBAF/THF (91%)
OH
CNO
O OO
2. MsCl, EtN3, CH2Cl2 (99%)
3. DBN, C7H8 (67%)
OH
CNO
O OO
O
enantioselectivedesymmetrisation
Ti(OiPr)4¡¤iPrOH/(L)-DIPT:
Zr(OiPr)4¡¤iPrOH/(L)-DIPT:
Zr(OiPr)4¡¤iPrOH/(D)-DIPT: 44% (55%), >95% ee
59% (74%), >95% ee
40%, 14% ee
(+) PDT
(-) PDT
Spivey, A. C.; Woodhead, S. J.; Weston, M.; Andrews, B. I. Angew. Chem. Int. Ed. 2001, 40, 769-771.
R
OH
OH
R
cat. (0.5 mol%)BzCl, Et3N,
CH2Cl2, -78 ¡ãC
R
OBz
OH
RN
Me
N
Me
Bn73-85% yield60-96% ee
Me Me
MeMe
OH OH
Me Me
MeMe
OH OAccat. (1 mol%)Ac2O, Et3N,
t-amyl alcohol, 0 ¡ãC
FeN
Ph Ph
PhPh
Ph
Me2N
91% yield99.7% ee
OBz
OBz
ligand (0.75 mol%)[C3H5PdCl]2 (0.25 mol%)
TMS-N3, THF, 0 ¡ãC
OBz
N3
88% yield>95% ee
NH HNO O
PPh2 Ph2P
1998, Oriyama:
1998, Fu:
1996, Trost:
Enantioselective Desymmetrisation of Diols: Previous Work
R
OH
OH
R
Me
CHO
PPTS
Me
O O
H
R R
NBS, MeOHcollidine
Me
OO
MeO
RR
Br
1. Zn, MgBr2¡¤Et2O
2.BnBr, NaH
Me
MeO
R R
O
H
H
OBn
PPTS R
OBn
OH
R
59-64% yield>99% ee
+
1997, Fujioka:
Me
OH
OH
Me
PhC¦®CCH(OEt)2O O
Me Me
Ph
NH
BOO
Bn
Ph
(1.2 equiv)
O
StBu
TMS(1.5 equiv)
CH2Cl2, -78 ¡ãC
Me
O OH
Me
COStBu
Ph
97%, 96% ee
1. MEMCl
2. LDA
Me
OH
OMEM
Me
1997, Harada:
Enantioselective Desymmetrisation of Diols: Previous Work
Pd-Catalyzed Enantioselective Oxidation
OH
R1R R1R
OH
R1R
O+
5 mol% Pd(II), DCE, O2
20 mol% (-)-sparteine N
NH
H
HH
(-)-sparteine66-99% ee, krel =7.6-23.6
Ph Ph
OHOH10 mol% Pd(MeCN)2Cl2, DCE, O2
20 mol% (-)-sparteine, 60 ¡ãC
69% yield, 82% eePh Ph
OOH
Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001, 123, 7475-7476.
Asymmetric Oxidation of Meso-Diols under Photo-Irradiation
OH
OH(CH2)n (CH2)n O
Ocat. (2.0 mol%)
h, rt, CHCl3
PDA
CH2Cl2(CH2)n O
OH
N N
O O
Ru
Cl
Me MeNO
Ph Ph
R
R
a: n = 2b: n = 3c: n = 5
OHOH
d:
entry substrate yield (%) % ee confign
1 a 49 59 1R, 4S
2 b 57 65 1R, 5S
3 c 64 63 -
4 d 66 66 1R, 6S
Shimizu, H.; Nakata, K.; Katsuki, T. Chem. Lett. 2002, 1080-1081.
Enantioselective Desymmetrisation of Meso Cyclic Allylic Bisdiethylphosphate
O OP(OEt)2
O
(EtO)2P
O
OP(OEt)2
O
O(EtO)2P
O
+
1. (CuOTf)2¡¤C6H6 (10 mol%)
ligand (10 mol%)toluene/THF (95:5) rt
2. Et2Zn (1.1 equiv) -78 ¡ãC a b
N
R1
SO O
NHR2
R3 OH
entry R1 R2 R3 a/b yield (%)
1 iBu CHPh2 3-Ph 94:6 54
2 iBu CHPh2 3,5-Cl2 94:6 47
3 iBu CHPh2 3,5-tBu2 87:13 42
4 Me CHPh2 3,5-Cl2 86:14 62
5 iBu CHPh2 H 84:16 54
6 iBu CHPh2 5,6-(CH)4- 83:17 49
7 Me CHPh2 H 31:69 13
8 iPr CHPh2 H 30:70 12
9 tBu (R)-CH(Me)Cy H 24:76 26
Piarulli, U.; Daubos, P.; Claverie, C; Roux, M; Gennari, C. Angew. Chem. Int. Ed. 2003, 42, 234-236.
Pd-Catalyzed Enantioselective Ring Opening with Dialkylzinc
OPd(CH3CN)2Cl2 (5 mol%), L*
R2Zn (1.5 equiv), CH2Cl2, rt
R1
R1
R2
R2
R1
R1
R2
R2
OH
R
R = Et, L* = (R)-Tol-BINAPR = Me, L* = (S)-i-Pr-POX
entry R R1 R2 yield (%)
% ee
1 Me H F 87 90
2 Me Me Br 67 90
3 Me Me H 76 89
4 Me H O(CH2)O 85 91
5 Et H F 89 92
6 Et H O(CH2)O 91 92Pd
R1
R1
R2
R2
O
P
P*
Pd
R1
R1
R2
R2
P
P*O
Zn
Lautens, M.; Renaud, J.-L.; Hiebert, S. J. Am. Chem. Soc. 2000, 122, 1804-1805.
P(Tol)2
P(Tol)2
(R)-Tol-BINAP
PPh2 N
O
(S)-i-Pr-POX
Rh-Catalyzed Enantioselective Ring Opening with Organoboronic Acids
OO
O
OH
O
OX
B(OH)2
X(1.2 equiv)
[Rh(COD)Cl]2 (2.5 mol%),(R)-(S)-PPF-P(t-Bu)2 (5 mol%),
Cs2CO3 in H2O (0.5 equiv), THF, rt
Fe
Ph2P
(t-Bu)2P
(R)-(S)-PPF-P(t-Bu)2
entry X yield (%) % ee
1 4-Me 88 95
2 None 91 95
3 2-Me n.r. -
4 4-Cl 95 95
5 3-Cl 73 99
6 2-Cl n.r. -
7 3-I 85 95
8 4-Ac 71 94
9 4-OMe 87 96
10 3-OMe 91 95
Rh
P
P
Ar O* +
O
Rh ArPP
*
O
Ar
RhP
P*
Lautens, M.; Dockendorff, C.; Fagnou, K.; Malicki, A. Org. Lett. 2002, 4, 1311-1314.
Desymmetrisation of Diols with a Dinuclear Zinc Asymmetric Catalyst
ROH
OH O Ph
O
+OCOPh
OHR
H
5-10 mol% ligand10-20 mol% Et2Zn
toluene, -15 ¡ãC
OCOPh
OH
HOCOPh
OH
H OCOPh
OH
H OCOPh
OH
H
OCOPh
OH
H OCOPh
OH
HOCOPh
OH
H OCOPh
OH
H
OCOPh
OH
H
Me
S
S
OCOPh
OHMe
H OCOPh
OH
94%, 91% ee 98%, 91% ee 99%, 93% ee 89%, 90% ee
88%, 74% ee97%, 93% ee99%, 59% ee83%, 86% ee
78%, 70% ee 89%, 82% ee 93%, 91% ee
MeO Cl
Ph
Trost, B. M.; Mino, T. J. Am. Chem. Soc. ASAP
OHNN
OH HO
PhPh
Ph Ph
ONN
O O
ArAr
Ar ArZnZn
OOHOH
R H
Summary
Previous works on the enantioselective desymmetrisation have been introduced briefly according to different functional groups
Recent developments in the enantioselective desymmetrisation have been surveyed based on different functional groups
Recent applications of enantioselective desymmetrisation in natural products synthesis have been shown
Acknowledgement
Dr. Jeffrey Johnson
Johnson group