Development of Stereoselective Vinylogous Mukaiyama Aldol Reaction … · 2019-07-19 ·...
35
Development of Stereoselective Vinylogous Mukaiyama Aldol Reaction and Application to Natural Product Synthesis September 9, 2011 1 st Scotish-Japanese Symposium of Organic Chemistry Susumu Kobayashi Tokyo University of Science (RIKADAI)
Transcript of Development of Stereoselective Vinylogous Mukaiyama Aldol Reaction … · 2019-07-19 ·...
Development of Stereoselective Vinylogous Mukaiyama Aldol Reaction
and Application to Natural Product Synthesis
September 9, 2011 1st Scotish-Japanese Symposium
of Organic Chemistry�
Susumu Kobayashi Tokyo University of Science (RIKADAI)
NH
OO
Me
HOOMe Me CO2Me
Me
Epolactaene
N
O
HO
Me
O
O
H
Madindoline A
O
Me
HO
Me
OH
Me
Me
CHO
Citreoviral
Khafrefungin
OHO
O
O
Me
O
MeMe
CH3(CH2)9
Me
OH
Me Me
OH
OH
HO
NH
O
XHO
X = OHX = Cl
Convolutamydine EConvolutamydine B
Br
Br
H
H
NaOSO3
OSO3Na
Akaterpin
HO
OH
H
H
O
OH
O OH
C6H13
Australifungin
O
O
O
O
P
O
NaO
H H
N
S
OMe
Curacin A
PHYLPA
O
O
O
OH
Pseudodeflectusin
NH
HN
NH
O
O
Neoechinulin A
HO
CO2Me
OH
(CH2)15CH3
Plakevulin A
NN
MeH
Flustramine BDebromoflustramine B
O
O
HO
O
O
O
OHOMe
OH
OHOH
Me
OH
OHMeMeMe Me MeMe Me Me
OOH
O
OH
HO
CO2H
O OHOHO
OHHO
O
Me
H
H
O
HMe
NO O
Me
O
Me
MeDiversifolin
TMC-151CFomitellic Acid B Norzoanthamine
NC
Axisonitrile-3X
X = BrX = H
Total Synthesis of Natural Products Accomplished in these 10 Years
Me
N
O
O
O
R
OH
Me
N
TBSO
O
O
+TiCl4
R-CHO
Vinylogous Mukaiyama Aldol reaction (VMAR)
Me
Me Me Me Me Me
OH
Me Me
OH
Me Me
O
O
OH
OH
OH
OH
OH
O
O
HO
HO
HOOH
O
O
Me
O
MeMe
C10H21
Me
OH
Me Me
HOOH
CO2H
OH
NH
O
Br
Br
OH
OH
NH
O
Br
Br
OH
Cl
Convolutamydine E
Convolutamydine B
Khafrefungin
TMC-151C
Application of VMAR to Natural Product Synthesis
Org. Lett. (2006) �
J. Am. Chem. Soc. (2004) �
Org. Lett. (2007) �
Angew. Chem. (2011) �
Stereocontrol of Quaternary Chiral Center by Regio- and Stereoselective Alkylation of Unsaturated Imide
Madindoline A �
R
O
N O
O
MeBnO
R
Me
O
N O
O
THF, -10°C
65%
Me
ONa
N O
O
R
NaHMDS
N
O
HO
O
O
H
R = C4H9
BOMCl
*
*
11 : 1
N
O
HO
O
O
H
*
Madindoline B�
Tetrahedron Letters, 41, 6429, 6435 (2000). �
Stereocontrol of Quaternary Chiral Center Regio- and Stereoselective Alkylation of Unsaturated Imide
O
N O
O
MeEtO2CMe
O
N O
O
THF, -78°CMe
ONa
N O
O
NaHMDS
76%, 30 : 1
THF, -10°C
O
N O
O
MeBnO
67%, 10 : 1
ICH2CO2Et
O
N O
O
Me
61%, 27 : 1
THF, -78 ~ 0°C
CH2=CH-CH2I
BOMCl
Tetrahedron Letters, 44, 9303 (2003). �
Determination of the Geometry of Dienolate Anion Plausible Transition State
N O
OO
N O
OO
Me
NaHMDS, TBDMSCl
THF, -78°C
TBS
H
NOE
NOE
90%single isomer
N
O
OMe
O
Na
H
E+
N O
OO
MeRO
Remote Asymmetric Induction in VMAR
R
OH
N O
O O
N O
TBSO O
+ R CHO
Lewis Acid
*
VMAR
Me
O
N O
O
BnO
Bu
MeAlCl2(2 equiv)
toluene, -78°CO
N O
O
MeBnO
＊
50% (>50 : 1)
O
N O
O
MeBnO
＊
27% (~5 : 1)
+
CH2BnO
Me
O
N O
O
Bu
Tetrahedron Letters, 46, 3245 (2005). �
entry Lewis acid equiv. temp. yield (%) d.s.
Lewis Acid
CH2Cl2
C5H11
OH
N O
O O
N O
TBSO O
BF3OEt2
Et2AlCl
SnCl4
TiCl2(O-i-Pr)2
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
1.0
1.0
1.0
1.0
0.3
0.5
0.7
1.0
2.0
!78 ~ 10°C
!78 ~ 0°C
!78 ~ 0°C
!78°C
!78 ~ 0°C
!78°C
!78°C
!78°C
!78°C
54
multi
25
24
50
68
85
97
85
1 : 2
2 : 1
1.5 : 1
9 : 1
22 : 1
12 : 1
29 : 1
1 : 1
1
2
3
4
5
6
7
8
9
N O
OOOH
1) O3
2) NaBH4
MeOH
3) Ac2O, Et3N
DMAP, CH2Cl2OAc
OAc ["]D24-7.8 (c1.6, CHCl3)
lit. ["]D24+15.2 (c1.7, CHCl3)
for S-isomer
R
*+ C5H11-CHO
*
Effect of Lewis Acid in VMAR
Entry Electrophile Yield (%) d.s.
97%
78%
32% (70%)
29 : 1
18 : 1
9 : 1
1
2
3
NH
O
O
4
5
6
37% (65%)
94%
96%
4 : 1
18 : 1
28 : 1
N O
OTBSO
RR'C=O (2.0 eq.)
CH2Cl2, !78 °C
N O
OO
R
OH*
CHO
CHO
CHO
CHO
CHO
7
*1
Entry Electrophile Yield (%) d.s.
TiCl4 (1.0 eq.)
VMAR with Various Electrophile
R-CHO (2.0 eq.)
TiCl4 (1.0 eq.)
CH2Cl2
N O
Me
O O
N OMe
OTBSO
R
OH
Me
Me
CHO
CHO
CHO
CHO
1
2
3
4
!78°C
!78°C
!78 ~ !40°C
!78 ~ !30°C
87
99
91
56
>50 : 1
>50 : 1
12 : 1
>50 : 1
Entry Aldehyde Temp. Yield (%) d.s.
*
*
*
1,6,7-Remote Asymmetric Induction
J. Am. Chem. Soc., 126, 13604 (2004). �
α,γ-Dimethyl-δ-Hydroxy-α,β-Unsaturated Carbonyl Unit
aldol reaction �
Wittig reaction �
crotylation cross metathesis
N O
Me
O O
R
OH
Me
R-CHOTiCl4
**
N OMe
OTBSO
Me
OMe
Me
O
R
OH
Me
**
O
R
OH
Me
**
X
X = SR etc
O
R
OH
Me
**
H
R
OH
Me
**
Application to Nautral Product Synthesis by Other Groups (1)
Trichostatin D (Tatsuta; 2005)�Actinopyrone A (Tatsuta; 2006)�
Lagunamycin (Tatsuta; 2006)�
Piericidin A1 (Lipshutz; 2009) �
MeMeMe
Me
Me
OH
O OMe
MeMe
O
NH
O
MeMe
Me2N
O
O
OH
HOHO
HO
O
NH
O
O
N
O
O
NMe
Me
Me
Me Me
MeMeMe
Me
Me
OH
N OMe
OMeMe
OH
Palmerolide A (revised) (De Brabander; 2007)
(Nicolaou; 2007)
Application to Nautral Product Synthesis by Other Groups (2)
Oxidation-Reduction (Nicolaou)
Mitsunobu Reaction
(De Brabander) �
OH
MeMe
OH
MeMe
OOO
OH
OH
HN
MeMeO
Me
Me
Me
O
H2N
anti� syn�
Me
N
O
O
O
R
OH
Me
N
TBSO
O
O
+TiCl4
R-CHO
Isolation : Gliocladium catenulatum Gilman & Abbott TC 1280 Tetrahedron, 55, 7771 (1999). Activity : cytotoxicity against several tumor cell lines
TMC-151C
Me
Me Me Me Me Me
OH
Me Me
OH
Me Me
O
O
OH
OH
OH
OH
OH
O
O
HO
HO
HOOH
Unsuccessful Straightforward Linear Approach
Me
OTES
MeMe Me
Me
Me
O
Me
N
O
O
OOH
MeMe MeMe
OH
Me
Me Me
Me
OTES
MeMe MeMe
OTES
Me
Me Me
O
Me
N
O
O
OOH
MeMeMe
OH
Me MeMe
OH
Me
Me Me
O
MeMe
Me
Me
TiCl4,
97%
> 20 : 1
N
TBSO
O
O
Me
N
O
O
OOH
MeMe Me
Me
Me1) TESOTf 2,6-lutidine (quant.)
2) LiBH4 (98%)3) MnO2 (99%)
VMAR
VMAR
51%
13 : 1
VMAR
1) TESOTf 2,6-lutidine (93%)
2) LiBH4 (94%)3) MnO2 (quant)
VMAR
CH2Cl2, -78 to -40°C
CH2Cl2, -78 to -20°C
Convergent Approach to TMC-151C Using Cross Metathesis
Me
Me Me Me Me Me
OH
Me Me
OH
Me Me
O
O
OH
OH
OH
OH
OH
O
O
HO
HO
HOOH
O
Me MeMe
OTES
Me
Me Me
Me
Me Me Me Me Me
OP
Me
O
O
PO
PO
POOP
Me
OP
Me Me
O
O
OP
OP
OP
OP
OP
H
O
Me
H
O
Me
Me
Me Me
H
Cross Metathesis �
VMAR�
VMAR�
Crotylation �
+�
O
Me
H
Me
N
O
O
OOH
MeMe
N
TBSO
O
O
+TiCl4
2.0 equiv.
4.0 equiv.
4.0 eqiov.
CH2Cl2CH2Cl2toluene
23% ( > 20 : 1)
57% ( > 20 : 1)
76% ( > 20 : 1)
methacrolein solvent yield (d.r.)
1) TESOTf
2,6-lutidine
(79%)
2) (MeO)2CO
NaOMe (91%)
Me
CO2Me
OTES
MeMe
Preparation of Substrates for Cross Metathesis
Me
OTES
MeMe Me
Me
Me
O
OTES
MeMe MeMe
OTES
Me
Me Me
O
MeMe
Me
Me
CH2Cl2
97% > 20 : 1
Me
N
O
O
OOH
MeMe Me
Me
Me1) TESOTf 2,6-lutidine (quant.)
2) LiBH4 (98%)3) MnO2 (99%)
H
H
B
O
O CO2-i-Pr
CO2-i-Pr
N
TBSO
O
O
1)
(quant. d.r. 7.9 : 1)
2) TESOTf 2,6-lutidine (87%)
TiCl4
OH O
N O
OOTBDPS
CHO
OTBDPSN O
TBSO OO
N O
O
+ +
TiCl4(1.0 eq)
toluene(0.5 M)!50°C(2.0 eq)
dr >20 : 1
entryadditive(mol%)
time(h)
yield(%)
1
2
3
4
!
H2O (5)
H2O (10)
H2O (20)
77
57
40
26
77
76
74
69
20 mol% � 10 mol% � 5 mol% � none�
Vinylogous Mukaiyama Aldol Reaction (VMAR) Effect of H2O (2)
Tetrahedron Lett. (2010) �
OTES
MeMe MeMe
OTES
Me
Me Me
Me
N
O
O
OOR
MeMe
OTES
MeMe MeMe
OTES
Me
Me Me
Me
CO2Me
OR
MeMe
catalyst (0.2eq.)additive (0.3eq.)solvent, reflux
+
(4.0 equiv)
1
2
3
4
5
6
7
8
TES
TES
H
H
H
H
H
H
Grubbs' 2nd
Grubbs' 2nd
Grubbs' 2nd
Grubbs' 2nd
Grubbs' 2nd
Grubbs' 2nd
Hoveyda-Grubbs' 2nd
Hoveyda-Grubbs' 2nd
entry R catalyst additive solvent
none
none
none
p-benzoquinone
none
p-benzoquinone
p-benzoquinone
p-benzoquinone
CH2Cl2toluene
CH2Cl2CH2Cl2toluene
toluene
CH2Cl2ClCH2CH2Cl
Unsuccessful Cross Metathesis
Silicon-Tethered Approach : Ring Closing Metathesis (RCM)
OH
MeMe MeMe
OTES
Me
Me Me Me
CO2Me
OH
MeMe
+
(1.5 equiv)Et2NPh2SiCl
Et3N, DMAP
86% (brsm 98%)
O
MeMe MeMe
OTES
Me
Me Me Me
CO2Me
O
MeMe
Si
Ph Ph
O
MeMe MeMe
OTES
Me
Me Me Me
CO2Me
O
MeMe
Si
Ph Ph
Hoveyda-Grubbs' 2nd cat. (0.2 equiv.)
p-benzoquinone (1.5equiv.)
xylene (0.009M), reflux
90% E : Z >20 : 1
Me
CO2Me
OH
MeMeMe
OH
Me MeMe
OH
Me
Me Me
TBAF
82%
Me
Me Me Me Me Me
OH
Me Me
OH
Me Me
O
O
OH
OH
OH
OH
OH
O
O
HO
HO
HOOH
TMC-151C
Structure Determination and Synthesis of Polyketide Moiety
O
MeMe MeMe
OTES
Me
Me Me Me
CO2Me
O
MeMe
Si
Ph Ph
11.0 ppm
H
12.9 ppm13.0 ppm
cf. ca. 25 ppm for Z-allylic Me
NOE
Strategy for the Total Synthesis of TMC-151C
TMC-151C
Me
Me Me Me Me Me
OH
Me Me
OH
Me Me
O
O
OH
OH
OH
OH
OH
O
O
HO
HO
HOOH
Me
Me Me Me Me Me
O
Me Me
O
Me Me
O
O
OTES
OTES
OTES
OTES
OTES
O
O
TESO
TESO
TESOOTES
Me
Me Me Me Me Me
OH
Me Me
OH
Me Me
O
O
OTES
OTES
OTES
OTES
OTES
O
O
TESO
TESO
TESOOTES
Si
Ph Ph
+
Preparation of the Left-Half Segment
Me
Me Me Me Me Me
OH
Me
OO
TESOTESO
TESO OTES
Me
N
O
O
OOH
MeMe Me
Me
Me
Me
Me Me Me Me Me
OH
OO
HOHO
HO OH
SPh
O
BnOO
O OPh
CF3
OO
BnOO
O OPh Ar
NSPh
O
N N
Bu-t
Bu-tt-Bu
Tf2O
MS4A
CH2Cl2, !60°C
82%
1) LiBH4
2) Na, liq. NH3
Me
N
O
O
O
MeMe Me
Me
Me
73%
O
B
O
CO2-i-Pr
CO2-i-Pr
1) TESOTf, 2,6-lutidine (quant)
2) AcOH-H2O (47%, brsm 89%)
3) MnO2 (97%)
4) MS4A
(89%, d.r. 4.7 : 1) *D. Crich et al. (2008) �
*�
β : α = >20 : 1 �
Preparation of the Right-Half Segment
Me
OH
Me Me
O
O
OTES
OTES
OTES
OTES
OTES
Me
N
O
O
OOH
MeMe
Me
OPMB
Me Me
O
O
OTES
OTES
OTES
OTES
OTES
Me
OH
OOPMB
MeMe
Me
OPiv
OOPMB
MeMe
1) Cl3C(=NH)OPMB cat. CSA
2) LiOOH
56%
Piv2O, Et3N
HO
OTES
OTES
OTES
OTES
OTES
toluene
60% (2 steps)
DDQ
pH 7.5 buffer
93%
Total Synthesis of TMC-151C
TMC-151C �
Me
Me Me Me Me Me
OH
Me Me
OH
Me Me
O
O
OH
OH
OH
OH
OH
OO
HOHO
HO OH
Me
Me Me Me Me Me
O
Me Me
O
Me Me
O
O
OTES
OTES
OTES
OTES
OTES
OO
TESOTESO
TESO OTES
Me
Me Me Me Me Me
OH
Me Me
OH
Me Me
O
O
OTES
OTES
OTES
OTES
OTES
OO
TESOTESO
TESO OTES
Si
Ph Ph
+
1) (Et2N)Ph2SiCl, Et3N, DMAP (54% & 81% brsm)
2) Hoveyda-Grubbs 2nd cat., p-benzoquinone
xylene, reflux 87% E : Z = >20 : 1
HF-pyridine, pyridine then aq. HF 54%
Angew. Chem. Int. Ed., (2011) �
Silicon-Tethered Approach : Ring Closing Metathesis (RCM)
OH
MeMe MeMe
OTES
MeMe Me Me
CO2MeOH
MeMe
+
(1.5 equiv)Et2NPh2SiClEt3N, DMAP
86% (brsm 98%)
O
MeMe MeMe
OTES
MeMe Me Me
CO2MeO
MeMe
SiPh Ph
O
MeMe MeMe
OTES
MeMe Me Me
CO2MeO
MeMe
SiPh Ph
Hoveyda-Grubbs' 2nd cat. (0.2 equiv.)p-benzoquinone (1.5equiv.)xylene (0.009M), reflux
90% E : Z >20 : 1
E-Olefin Forming 8-Membered Ring Closing Metathesis
J. Prunet (2000)
34% � 46% �
only one example !! �
O O
O
O O
O
O O
O
+Grubbs’ 1st cat. �
Silicon-Tethered 8-Membered Ring Closing Metathesis Examples of 8-Membered Ring Closing Metathesis
OSi O
OTIPS
OPMBO
I
OSi O
OTIPS
OPMBO
I
OSiO
FmocHN
SBn
O
OSiO
FmocHN
SBn
O
L. G. Verdine (2001) J. Eustache (2002)�
Schrock cat.� Grubbs’ 2nd cat. �
O
MeMe MeMe
OTES
Me
Me Me Me
CO2Me
O
MeMe
Si
Ph Ph
C7H15
O
Me Me
CO2Me
O
MeMe
Si
Ph Ph
C7H15
O
Me Me
CO2Me
O
MeMe
Si
Ph Ph
C7H15
O
Me
CO2Me
O
MeMe
Si
Ph Ph
C7H15
O
Me
Me
O
MeMe
Si
Ph Ph
C7H15
O
Me
Me
O
MeMe
Si
Ph Ph
C7H15
O
Me
Me
O
Me
Si
Ph Ph
Silicon- Tethered RCM : Other Examples
E�
Z�
Angew. Chem. Int. Ed., (2010) �
Presumed Conformation of RCM Products
OSi
OMe
H
H
Me
C7H15
H
Ph
Ph
H
RE
O SiO
Me
H H
RH
C7H15
Ph
Ph
Z
H Me
O
O
Si
Ph
Ph
Me
R
H
H
C7H15
H
H
HZ
C7H15
O
Me
R
O
Me
Si
Ph Ph
O Si O
Ph Ph
C7H15
MeMe
R
O Si O
Ph Ph
C7H15
Me
R
crown-like� boat-like� chair-like�
R = OMe
O
X-Ray Structure : Crown-like Conformation
O
Me
R
O
Me
Si
Ph Ph
Br
O
Me
R
O
Me
Si
PhPh
Br
R = OMe
O
Possible Explanation for E-Selective RCM
crown-like� boat-like� chair-like�
C7H15
O
Me
O
Me
Si
Ph Ph
Me
Me
OSi
O
Ph Ph
C7H15
MeMe
Me
Me
O
SiO
Me
H
Me
C7H15
H
Ph
Ph
H
R
[Rh]
O Si
O
Me
H H
RH
C7H15
Ph
Ph
H Me
[Rh]
O
O
Si
Ph
Ph
Me
R
HH
C7H15
H
H
H[Rh]
unfavored �favored �
E-Olefin or Z-Olefin ?
C7H15
O
Me
O
MeMe
SiPh Ph
C7H15
O
Me
O
Me
SiPh Ph
Me
O Si O
Ph Ph
C7H15
MeMeMe
RCM+
OSi
OMe
H
Me
C7H15
H
Ph
Ph
H[Rh]
Me
O
O
Si
Ph
Ph
Me
H
H
C7H15
H
H
Me[Rh]
Me
trace� 83%�
favorable� more favorable�
Me
N
O
O
O
R
OH
Me
N
TBSO
O
O
+TiCl4
R-CHO
Vinylogous Mukaiyama Aldol reaction (VMAR)
Me
Me Me Me Me Me
OH
Me Me
OH
Me Me
O
O
OH
OH
OH
OH
OH
O
O
HO
HO
HOOH
O
O
Me
O
MeMe
C10H21
Me
OH
Me Me
HOOH
CO2H
OH
NH
O
Br
Br
OH
OH
NH
O
Br
Br
OH
Cl
Convolutamydine E
Convolutamydine B
Khafrefungin
TMC-151C
Application of VMAR to Natural Product Synthesis
Org. Lett. (2006) �
J. Am. Chem. Soc. (2004) �
Org. Lett. (2007) �
Angew. Chem. (2011) �
Acknowledgement
Dr. Seijiro Hosokawa (Assoc. Prof. at Waseda Univ.) Dr. Atsuo Nakazaki (Assoc. Prof. at Nagoya Univ.) Dr. Ken-ichi Takao (Assoc. Prof. at Keio Univ.) Dr. Takahiro Suzuki
Dr. Ryosuke Matsui (Chugai Pharm.) Ms. Yuna Sato (Nippon Shinyaku) Mr. Kentaro Seto (Chugai Pharm.) Mr. Kazuhiro Fujita
