Diastereoselective Construction of Remote Stereocenters:
The use of Chiral Allylstannes & Claisen Rearrangements
Y
X
R'
R
Scott Peterson
Evans' Group Friday Seminar
May 24, 2002
01-Title 5/24/02 11:03 AM
Synthetic Strategies for the Construction of Remote
Stereogenic Centers Across a Double Bond
Coupling of Chiral Fragments
Asymmetric Induction by Reagent Control
Useful references:
Warren, S. Perkin I. 1999, 1899
Asymmetric Induction by Substrate Control
Chirality Transfer Methodology
02-Overview 5/23/02 5:47 PM
Thomas, E.J. Chemtracts. 1994, 7, 207
Synthetic Strategies for the Construction of Remote
Stereogenic Centers Across a Double Bond
S
Me
N
OAc
Me
Coupling of Chiral Fragments
OMe
MeO
Me
OP'
OP
Asymmetric Induction by Reagent Control
Me
I
i) 9-BBN
ii) PdCl2(dppf)2,
Cs2CO3, Ph3As
Asymmetric Induction by Substrate Control
Chirality Transfer Methodology
S
Me
N
Me
OAc
OMe
OMe
Epothilone A
OP'
OP
Me
Danishefsky, S.J. ACIEE 1996, 35, 2801
03-Overview-Coupling-1 5/23/02 5:47 PM
Synthetic Strategies for the Construction of Remote
Stereogenic Centers Across a Double Bond
O
O
Coupling of Chiral Fragments
Asymmetric Induction by Reagent Control
THPO
O
Asymmetric Induction by Substrate Control
H
Chirality Transfer Methodology
N
Ph
Ph
O
BH3•THF
B
CH3
O
O
THPO
OH
9:1
Corey, E.J. J. Am. Chem Soc. 1987, 109, 7925
04-Overview-Reagent-1 5/23/02 5:47 PM
Synthetic Strategies for the Construction of Remote
Stereogenic Centers Across a Double Bond
Coupling of Chiral Fragments
OTBS Me
O
13
9 H
OTBS Me
O
13
9 H
OPMB
OPMB
Asymmetric Induction by Reagent Control
O
O
O
N
Asymmetric Induction by Substrate Control
Me
O
Me
Bn
Chirality Transfer Methodology
Cy2BCl, EtNMe2
-78 °C
OTBS Me
OH
O
OTBS Me
O
OH
O
O
Xp
Xp
OPMB
Me
Me
diastereoselection 55:45
OPMB
Me
Me
diastereoselection 92:8
Evans, D.A. J. Am. Chem. Soc. 2002, 124, 5654
05-Overview-Substrate-1 5/23/02 5:49 PM
Synthetic Strategies for the Construction of Remote
Stereogenic Centers Across a Double Bond
OTBDPS
Coupling of Chiral Fragments
CH3
Asymmetric Induction by Reagent Control
Asymmetric Induction by Substrate Control
MeO2CCHO
SnCl4, -78 oC
Chirality Transfer Methodology
MeO2C
H
OH
TBDPSO H H
H
O
CH3
CH3
O
MeO
OTBDPS
1,5 syn:anti 94:6
76% yield
SnCl4
Mikami, K. J. Org. Chem. 1992, 57, 6105
06-Overview-Substrate-2 5/23/02 5:57 PM
Synthetic Strategies for the Construction of Remote
Stereogenic Centers Across a Double Bond
Coupling of Chiral Fragments
Bu3Sn
OBn
Asymmetric Induction by Reagent Control
Asymmetric Induction by Substrate Control
i.) SnCl4, 5 min, -78 oC
ii.) PhCHO, 1 hour
Chirality Transfer Methodology
OH
Ph
OBn
1,5 syn:anti >98:2
Z olefin formed exclusively
90% yield
Thomas, E.J. Tetrahedron Lett. 1990, 31, 6239
07-Overview-Substrate-3 5/23/02 6:01 PM
SnCl4 Catalyzed Allylstannane Reactions
OH
OH
SnCl4, -78 oC
Bu3Sn
R
CH3
RCHO
R
CH3
CH3
E and Z
R and S
syn and anti
Bu3Sn
CH3
Cl3Sn
SnCl4
CH3
RCHO
RCHO
OH
OH
R
R
CH3
CH3
H
CH3
RCHO
OH
H 3C
Cl3Sn
R
CH3
H
SnBu3
O
O
R
08-SnCl4 Cat allylstannane 5/23/02 6:06 PM
CH3
SnCl3
R
Keck, G.E. Tetrahedron Lett. 1984, 25, 3927
Keck, G.E. J. Am. Chem. Soc. 1989, 111, 8136
Denmark, S.E. J. Am. Chem Soc. 1988, 110, 984
1,5-Asymmetric Induction Using 4-Alkoxy-allylstannanes
OH
i.) SnCl4, 5min, -78 oC
Bu3Sn
OBn
R
ii.) RCHO, 1 hour
OBn
1,5 syn favored
Aldehydes
PhCHO
p-ClC6H4CHO
p-NO2C6H4CHO
p-MeOC6H4CHO
furfural
CH3CH2CH2CHO
(CH3)2CHCHO
(CH2)5CHCHO
PhCH=CHCHO
MeO2CCHO
Yield
90
77
77
77
72
84
84
78
64
68
1,5 syn : anti
98 : 2
94 : 6
95 : 5
97 : 3
95 : 5
95 : 5
93 : 7
92 : 8
95 : 5
95 : 5
Thomas, E.J. Tetrahedron Lett. 1990, 31, 6239
Thomas, E.J. Chemtracts 1994, 7, 207
09-initial allylstannane 1,5 5/23/02 6:08 PM
Mechanism for 1,5 Induction with 4-Alkoxy-allylstannanes
CH3
Bu3Sn
i.) SnCl4, -78 oC
OH
ii.) RCHO
OBn
CH3
R
OBn
syn : anti >95:5
Bu3Sn
CH3
CH3
SnCl4
OH
RCHO
CH3
R
OBn
Cl3Sn
OBn
OBn
RCHO
H
Cl
R
O
H 2O
Cl
Sn
H
H
Cl
Cl
R
O
OBn
H
CH3
Cl
Sn
H
Cl
OBn
H
CH3
Thomas, E.J. Tetrahedron Lett. 1990, 31, 6239
10-1,5 mechanism 1 5/23/02 6:09 PM
Mechanism for 1,5 Induction with 4-Alkoxy-allylstannanes
CH3
Bu3Sn
CH3
SnCl4
OBn
H 3C
ii) PhLi
iii.) N N
OBn
H
O
H
H 3C
CH3
Ph3SnLi
H 3C
Ph3Sn
CH3
H
O
Ph3Sn
H 3C
CH3
SnPh3
H
CH3
H 3C
Ph3Sn
CH3
SnPh3
NaH, BnBr
OH
OH
Ph3SnLi
OBn
H
OH
CH3
CH3
H 3C
OBn
H
H 3C
OBn
Ph3Sn
i) SnCl4, -78 oC, 5 min
CH3
Ph3Sn
Cl3Sn
NaH, BnBr
H 3C
CH3
OH
Thomas, E.J. Chem. Commun. 1998, 8, 899
11-1,5 mecanism allyltintric 5/23/02 6:11 PM
Mechanism for 1,5 Induction with 4-Alkoxy-allylstannanes
CH3
Bu3Sn
OBn
CH3
SnCl4
Cl3Sn
OBn
Cl
Cl
Cl3Sn
Bu3Sn
OBn
H
H
Cl3Sn
CH3
OBn
Cl
Favored: A1,3 minimized
H
Bu3Sn
H 3C
H
A1,3
Cl
Disfavored
Thomas, E.J. Chem. Commun. 1998, 8, 899
12-1,5 mecanism form allyltin 5/23/02 6:13 PM
Mechanism for 1,5 Induction with 4-Alkoxy-allylstannanes
H
CH3
Cl3Sn
RCHO
Cl
R
O
OBn
Cl
Sn
H
CH3
R
OBn
H
OCH3
HO
OCH3
OBn
CH3
CH2O
Cl3Sn
OH
Cl
HO
OCH3
favored
Cl
Cl
H
2.222 Sn
H
O
2.370
Cl
H 2.380
OCH3
∆E = 1.9 kcal•mol-1
2.182
H
Cl
Cl
H
O
Sn
Cl
3.297
OCH3
2.374
H
∆E = 12.0 kcal•mol-1
(GAUSSIAN94 Calculation, split valence basis)
Thomas, E.J. Chem. Commun. 1998, 8, 899
13-1,5 mecanism calculations 5/23/02 6:15 PM
1,5-Asymmetric Induction Using 5-Alkoxy-allylstannanes
Bu3Sn
OBn
CH3
OH
i.) SnCl4, 5min, -78 oC
OBn
R
ii.) RCHO, 1 hour
CH3
1,5 anti
Aldehydes
PhCHO
p-ClC6H4CHO
p-MeOC6H4CHO
CH3CH2CHO
(CH3)2CHCHO
Yield
1,5-anti : 1,5 syn
86
67
65
70
81
96 : 4
96 : 4
96 : 4
95 : 5
95 : 5
Thomas, E.J. Synlett 1992, 585
14-init 5-o-allylstannane 1,5 5/23/02 8:06 PM
1,5-Asymmetric Induction Using 5-Alkoxy-allylstannanes
OH
o
Bu3Sn
i.) SnCl4, 5min, -78 C
OBn
CH3
OBn
R
ii.) RCHO, 1 hour
CH3
1,5 anti
Bu3Sn
OBn
Cl3Sn
SnCl4
OBn
OH
RCHO
R
CH3
OBn
CH3
CH3
RCHO
Cl
Cl
H
Cl
Sn
BnO
H 3C
H 2O
Cl
Cl
R
O
H
H
Cl
Sn
BnO
H 3C
R
O
H
Thomas, E.J. Synlett 1992, 585
15-mech 5-o-allylstan 1,5 5/23/02 8:07 PM
1,5-Asymmetric Induction Using 5-Alkoxy-allylstannanes
OH
i.) Lewis Acid, -78 oC
Bu3Sn
OBn
CH3
OBn
Ph
ii.) PhCHO, -78 oC
CH3
1,5 anti
Lewis Acids
Yield
SnCl4
BuSnCl3
SnBr4
Bu2SnCl2
TiCl4
BF3•OEt2
AlCl3•i-PrOH
86
40
75
low
low
low
low
1,5-anti : 1,5 syn
96 : 4
95 : 5
99 : 1
-----
Thomas, E.J. Synlett 1992, 585
16-LA Screen 5-o-allylstan 1,5 5/23/02 8:07 PM
1,5-Asymmetric Induction Using 5-Alkoxy-allylstannanes
Bu3Sn
OR
CH3
OH
i.) SnCl4, -78 oC
ii.) PhCHO, -78 oC
OR
Ph
CH3
1,5 anti
R
p-MeOC6H4CH2
MOM
SEM
SiMe2tBu
SiPh2tBu
Yield
80
66
71
60
61
1,5-anti : 1,5 syn
95 : 5
93 : 7
80 : 20
81 : 19
80 : 20
Thomas, E.J. Tetrahedron Lett. 1993, 34, 3933
17-OP - 5-o-allylstan 1,5-cor 5/24/02 8:45 AM
1,5-Asymmetric Induction Using 5-Alkoxy-allylstannanes
E or Z
Bu3Sn
OP
CH3
OH CH3
i.) SnCl4, -78 oC
CH3
P=MOM, H, Bn
OP
R
ii.) RCHO, -78 oC
CH3
1,5 anti : syn >99:1
yield >70%
R=Ph, Aliphatic
Cl3Sn OBn
Cl3Sn OBn
H 3C
H 3C
Bu3Sn
H
CH3
H
CH3
Bu3Sn
E-isomer
Z-isomer
Thomas, E.J. Perkin Trans. I ,1993, 2863
18-2 sub 5-o-allylstan 1,5 5/24/02 8:42 AM
1,5-Asymmetric Induction with Imines
HN
i.) SnCl4, -78 oC
Bu3Sn
ii.)
OBn
N
OBn
BuO2C
X
1,5 anti, E olefin
BuO2C
X
Yield
CHPh2
79
75
67
72
73
CMe2Ph
OBn
(1)
ent - (1)
X
anti : syn
90 : 10
90 : 10
90 : 10
90 : 10 Mismatched
96 : 4
Matched
Me
N
BuO2C
Ph
(1)
19-initial 1,5 4-O imine 5/23/02 8:15 PM
Thomas, E.J. Chem. Commun. 1995, 6, 657
Thomas, E.J. Tetrahedron. Assym. 1995, 4, 2575
1,5-Asymmetric Induction with Imines
HN
i.) SnCl4, -78 oC
Bu3Sn
OBn
ii.)
N
R
OBn
BuO2C
Rr
1,5 anti, E olefin
BuO2C
CH3
H
Ph
H 3C
H
N
Cl3Sn
H
CO2Bu
Cl3Sn
CH3
CH3
H
OBn
N
BuO2C
OBn
BuO2C
Me
OBn
Ph
SnCl3
N
H
CH3
Ph
Thomas, E.J. Chem .Commun. 1995, 6, 657
20-mech 1,5 4-O imine 5/23/02 8:15 PM
Limitations of the Allylstannane Chemistry
CH3
Bu3Sn
OH
i.) SnCl4, -78 oC
Ph
ii.) PhCHO
OTBS
HO
CH3
OTBS
CH3
Ph
OTBS
1: 2 product ratio
CH3
Bu3Sn
CH3
SnCl4
OH
RCHO
CH3
R
OTBS
Cl3Sn
OTBS
OTBS
SnCl4
H
OTBS
H
RCHO
Ph
CH3
Cl3Sn
OTBS
HO
SnCl3
O
CH3
Ph
OTBS
CH3
H
Thomas, E.J. Tet rahedron Assym. 1995, 6, 2579
21-1,5 limitations, TBS-1 5/23/02 8:17 PM
Limitations of the Allylstannane Chemistry
CH3
Bu3Sn
i.) SnCl4, -78 oC
ii.)
OR
N
X
NHX
OR
NHX
CH3
BuO2C
Stannane (R)
Imine (X)
Bn
Bn
Bn
CHPh2
TBS
TBS
TBS
CH3
BuO2C
1,5-anti
BuO2C
OR
1,5-syn
Yield
1,5-anti : 1,5 syn
(S)-CHMePh
(R)-CHMePh
79
73
72
90 : 10
96 : 4
90 : 10
CHPh2
(S)-CHMePh
(R)-CHMePh
74
76
93
25 : 75
25 : 75
33 : 67
Thomas, E.J. Tet rahedron Assym. 1995, 6, 2579
22-1,5 limitations, TBS-2 5/23/02 8:19 PM
Limitations of the Allylstannane Chemistry
Bu3Sn
OR
CH3
i.) SnCl4, -78 oC
ii.)
N
X
NHX
OR
NHX
CH3
BuO2C
CH3
BuO2C
1,5-syn
OR
1,5-anti
BuO2C
Stannane (R)
Imine (X)
Bn
Bn
Bn
SiMe2tBu
SiMe2tBu
SiMe2tBu
CHPh2
(S)-CHMePh
(R)-CHMePh
CHPh2
(S)-CHMePh
(R)-CHMePh
Yield
78
82
73
77
80
74
1,5 syn : 1,5-anti
95 : 5
98 : 2
90 : 10
80 : 20
67 : 33
75 : 25
Thomas, E.J. Tetrahedron Assym. 1995, 6, 2579
23-1,5 limitations, TBS-3 5/23/02 8:24 PM
1,5-Asymmetric Induction with 4/5-Alkoxy-allylstannanes
OH
i.) Lewis Acid, -78 oC
Bu3Sn
R
o
ii.) RCHO, -78 C
OP
OP
1,5 syn selective, Z olefin
OH
o
R'
i.) Lewis Acid, -78 C
Bu3Sn
OP
R'
CH3
ii.) RCHO, -78 oC
OP
R
CH3
1,5 anti selective, Z olefin
SnCl4 or SnBr4
Chelating protecting group on oxygen is necessary
Other heteroatoms are also effective (N, S)
2-Substitution on the olefin is acceptable
SM olefin geometry is not important
High selectivities for a range of aldehydes and imines
Generally >95:5 diastereoselctivity
24-general 1,5 aldehyde 4,5-O 5/24/02 8:43 AM
1,6-Asymmetric Induction Using 5-Alkoxy-allylstannanes
OR
Bu3Sn
CH3
(3:2 E:Z)
Bu3Sn
Br3Sn
OH
OH
RCHO
CH3
CH3
CH3
1,6 syn >90:10
yields >70%
R'=aromatic, aliphatic
SnBr4
OR
R'
ii.) R'CHO, 1 hour
R=Me, H
OH
OH
i.) SnBr4, 10 min, -78 oC
OR
R'
CH3
RCHO
H
Br3Sn
CH3
O
H
R
Cl
O
H 2O
H
Cl
Cl
Cl
Sn
O
HH
H 3C
H
R
O
Cl
Cl
Sn
O
H
H 3C
H
H
Thomas, E.J. Tet rahedron Lett. 1993, 24, 3935
25-init 5-o-allylstannane 1,6 5/23/02 8:27 PM
1,7-Asymmetric Induction Using 6-Alkoxy-allylstannanes
OH
i.) SnBr4, 10 min, -78 oC
Bu3Sn
ii.) RCHO, 1 hour
OH
OH
1,7 syn >90:10
yield >50%
R=aromatic, aliphatic
CH3
Bu3Sn
Br3Sn
O
H
CH3
CH3
R
OH
H
Br
Br
Br
HO Sn O
R
H
O
OH
RCHO
SnBr4
OH
Br3Sn
CH3
R
CH3
H 3C
H
Br
Br
Br
HO Sn O
R
H 3C
Thomas, E.J. Chem. Commun. 1994, 3, 283
26-mech 6-o-allylstan 1,7 5/23/02 8:28 PM
Synthetic Strategies for the Construction of Remote
Stereogenic Centers Across a Double Bond
O
OP
O
Coupling of Chiral Fragments
Ph
OBn
Asymmetric Induction by Reagent Control
i) LiHMDS, TMSCl
ii) TMSCHN2, MeOH
Asymmetric Induction by Substrate Control
O
Chirality Transfer Methodology
Ph
OCH3
OBn
OP
I
OP
OP
OP
OP
C1 - C16 - Amphidinol 3
27-Overview-Transfer 5/23/02 8:30 PM
OP
2-Step 1,8-Asymmetric Induction via Chirality Transfer
(Ireland-Claisen Rearrangement)
O
BnO
OH
O
CH3
CH3
OSEM
O
[3,3]
CH3
CH3O
OSEM
OSEM
OBn
1,5 syn : anti 96:4
1,8 anti
H
TMSO
CH3
BnO
O
H
OSEM
Thomas, E.J. Tetrahedron Lett. 1999, 40, 471
28-initial 1,8 5/23/02 8:37 PM
2-Step 1,8-Asymmetric Induction
Synthesis of (±)-Patulolide
H 3C
O
OH
O
O
OH
CH3
OSEM
BnO
BnOCH2COCl
CH3
Et3N, DMAP
84%
OSEM
CH3O
H
i)
80%
H
N
O
N
CH3
CH3O
CH3
OTBDPS
ii) TMSCl, -78 to RT
iii)TMSCHN2
OSEM
1,5 syn : anti 96:4
77% from (±)-stannane
O
i) LiHMDS, -78 oC
O
ii) H2 / Pd
iii) TBDPSCl, imid
71%
OSEM
OBn
1,8 anti : syn
86:14
Thomas, E.J. Tetrahedron Lett. 1999, 40, 471
29-1,8-claisen-pat-1 5/24/02 8:47 AM
2-Step 1,8-Asymmetric Induction
Synthesis of (±)-Patulolide
H 3C
O
OH
O
O
OSEM
CH3O
OSEM
i) DIBAl-H
CH3
ii) Swern
iii) PH3P=CHCO2Me
OTBDPS
1,8 syn:anti
86:14
MeO2C
CH3
OTBDPS
72%
i) MgBr2, BuSH, K2CO3
ii) LiOH, MeOH-H2O
Cl
O
81%
Cl
H 3C
i)
O
Cl
Cl
HO2C
OH
O
(±)-Patulolide
OH
, Et3N
ii) DMAP, ∆ (separate isomers)
iii) TBAF, THF
CH3
OTBDPS
27%
15 steps from stannane
Thomas, E.J. Tetrahedron Lett. 1999, 40, 471
30-1,8-claisen-pat-2 5/24/02 8:49 AM
2-Step 1,8-Asymmetric Induction via Chirality Transfer
(2,3 Wittig Rearrangement)
OH
CH3
OSEM
1,5 syn : anti 96:4
NaH,
cinnamyl-Br
O
n-BuLi
Ph
CH3
Bu4NI
OSEM
70%
CH3
Ph
-78 oC
OH
OSEM
74%
1,8 syn : anti
90:10
O
Ph
H
H
CH3
OSEM
Thomas, E.J. Tet rahedron Lett. 1999, 40, 475
31-1,8-wittig-1 5/23/02 8:40 PM
2-Step 1,8-Asymmetric Induction
Synthesis of (±)-Epipatulolide
Ph
CH3
OH
OSEM
1,8 syn : anti
90 : 10
OSEM
t
i) VO(acac)2, BuOOH
Ph
O
ii) TBDPSCl, imid
iii)
N
H
CH3
OTBDPS
N
H
i) SmI2
ii) O3, DMS
iii) PH3P=CHCO2Me
34%
H 3C
OSEM
5 steps
O
MeO2C
OH
O
22 %
CH3
OTBDPS
(±)-Epipatulolide
14 steps from stannane
Thomas, E.J. Tet rahedron Lett. 1999, 40, 475
32-1,8-wittig-2 5/23/02 8:42 PM
2-Step 1,8-Asymmetric Induction
Syntheses of Epothilones B and D
CH3
n
I
O
O
CH3
O
CH3
i) Amberlyst
DMPU, BuLi
O
ii) TBDMSCl, imid
iii) Bu3SnH
SO2Ph
PhSO2
SnBu3
TBSO
OH
1:1 E:Z
53 %
86 %
i) SnBr4
ii) O
H
iii) TBAF
O
CH3
O
OPMB
CH3
O
MeO
OMe
Me
i)
OH
CH3
O
ii)
OPMB
HO
O
CH3
DIC, DMAP
1,6 anti 85:15
60% of desired
HO
OH
66 %
Thomas, E.J. Tetrahedron Lett. 2001, 42, 8373
33-Epothilone-1 5/23/02 8:42 PM
2-Step 1,8-Asymmetric Induction
Syntheses of Epothilones B and D
O
Me
OPMB
O
Me
Me
i) LiHMDS, TMSCl
CO2Me
Me
ii) TMSCHN2
O
78 %
O
OPMB
O
O
i) MCPBA
ii) H2/PtO2
iii)KSeCN
68 %
Me
Me
i) DDQ
ii) LiAlH4
iii) NaIO4, NaBH4
Me
O
OH
O
46 %
Me
O
O
OPMB
CO2Me
Me
S
Me
Me
N
OH
Me
O
Me
O
34-Epothilone-2 5/23/02 8:45 PM
OH
O
Thomas, E.J. Tet rahedron Lett. 2001, 42, 8373
1,9-Relationship Constructed by 1,7 Induction
Followed by a Claisen Rearrangement
i.) SnBr4, 10min, -78 oC
OH
Bu3Sn
CH3
OH
Ph
ii.) PhCHO, 1 hour
CH3
OH
60% ee
1,7 syn 90:10
yield 64%
i) TBDPSCl, imid
ii) NaH, PMBCl
iii) TBAF
iiii) Ac2O, NEt3
49 %
O
CH3
Ph
O
i) LDA, TBSCl
OCH3
O
Ph
CH3
CH3
ii) CH2N2
OPMB
OPMB
1,9 anti:syn 90:10
60% ee
73 %
Thomas, E.J. Tetrahedron. 1999, 55, 3723
35-initial 1,9 5/23/02 8:56 PM
Fe(CO)3 Complexes as Chiral Transfer Groups
HO
OH
O
O
R
OC
Fe
CO
CO
R'
[1,3]
[R]
HO
base
R
OC
Fe
CO
CO
HO
H
R'
OC
R
R'
Fe
CO
CO
[O]
OH
Fe(CO)3 moiety shifts to the electron deficient olefin
Hydride is delivered from opposite face of Fe complex
R'
R
OH
1,8 anti diol
Takemoto, Y. Chem. Commun. 2000, 15, 1445
36-FeCO3 1,3 shift initial 5/23/02 8:57 PM
Fe(CO)3 Complexes as Chiral Transfer Groups:
Formal Synthesis of Epipatulolide
TBSO
O
HWE
TBSO
i) KHMDS
O
H 3C
OC
Fe
CO
CO
H
H 3C
54%
OC
Fe
CO
CO
OPMB
TBSO
ii) NaBH4
51%
86% ee
OH
H 3C
H
OC
Fe
CO
CO
OPMB
i) H2O2, NaOH
ii) H2, Pt
89%
OH
CO2Me
H 3C
OTBDPS
OTBS
i) TBDPSCl, imid
ii) DDQ
iii) Swern
iv) Ph3P=CHCO2Me
v) AcOH, THF, H2O
H 3C
OPMB
OH
>98:2 dr
86%ee
24 %
H 3C
O
OH
O
37-FeCO3 1,3 shift epipat 5/23/02 9:01 PM
Epipatulolide C
15 steps from aldehyde
Takemoto, Y. Chem. Commun. 2000, 15, 1445
Thomas, E.J. Tetrahedron Lett. 1999, 40, 475
Fe(CO)3 Complexes as Chiral Transfer Groups
O
Fe(CO)3
O
O
R
R
O
H
Fe2(CO)9
CH3
O
CH3
O
O
Fe(CO)3
X2AlR''
O
R
H
Fe(CO)3
O
H
CH3
Ba(OH)2,
MeOH
endo : exo 4:1
X2AlR'' =
Me3Al
Et3Al
Bu3Al
Fe(CO)3
R
Bu
Bu
R''
CH3
dr >99:1
yield >70%
O
R
OH
AlMe2
OH
R''
CH3
AlMe2
Ley, S.V. Perkin Trans. I 1997, 3299
38-Ley-1,5 5/23/02 9:02 PM
Possibility for 1,10-Asymmetric
Combining the Work of Ley and Takemoto
O
Fe(CO)3
O
R
Fe2(CO)9
O
CH3
O
PO
R
O
OP
CH3
Ba(OH)2, MeOH
PO
OP
R
OH
R
OC
Fe
CO
CO
O
CH3
39-Ley-1,5-PROP 5/23/02 9:04 PM
Possibility for 1,10-Asymmetric Induction Using Fe(CO)3 Complexes
O
TBSO
KHMDS
C5H11
OC
Fe
CO
O
CO
TBSO
OC
70 %
Fe
CO
CH3
CO
C5H11
CH3
NaBH4
72 %
OH
TBSO
(S)
C5H11
H
CH3
OH
i) H2O2, NaOH
ii) H2, Pt
TBSO
OC
Fe
CO
CO
CH3
C5H11
89 %
Stereochemistry determined by
Mosher Ester Analysis
Takemoto, Y. Chem. Commun. 2000, 15, 1445
40-1,10-proposal-1 5/23/02 9:04 PM
Synthetic Strategies for the Construction of Remote
Stereogenic Centers Across a Double Bond
Coupling of Chiral Fragments
Asymmetric Induction by Reagent Control
Asymmetric Induction by Substrate Control
Chirality Transfer Methodology
OR
Bu3Sn
n
CH3
HO
R
OC
Fe
CO
41-Summary 5/23/02 9:05 PM
CO
OH
i.) SnCl4, 5min, -78 oC
ii.) RCHO, 1 hour
O
i.) B-
R'
ii) [R]
iii.) [O]
R
OR
n
1,5 to 1,9
Induction
CH3
OH
R'
R
OH
1,8 & 1,10
Induction