Transcript Slide 1

Applications of a Novel Nickel-Catalyzed Reductive
Coupling Reaction Towards the Total Synthesis of
Amphidinolide T1
Me
Me
CH2
HO
O
Me
O
O
O
Me
Julie Farand
April 1st, 2004
Jamison et al, J. Am. Chem. Soc., 2004, 126, 998
Jamison, T.F. et al, Org. Lett., 2000, 26, 4221
1
Introduction
Me
• Methods of generating allylic alcohols
• Nickel-catalyzed coupling between
• alkynes and aldehydes
• alkynes and epoxides
• alkynes and imines
Me
CH2
HO
O
Me
O
O
• Jamison’s methodology applied towards
the total synthesis of amphidinolide T1
O
Me
2
Preparation of Allylic Alcohols
• Reductions, organomagnesium and organolithium reagents
OH
O
O
Li
RMgBr
R
H
R
H
NaBH4
O
R
• Reactive allylic sulfoxides via a [2,3]-sigmatropic rearrangement
Ph
Ph
S
R
R
P(OMe)3
S
S
O
O
Ph
P(OMe)3
O
OH
MeOH
R
R
3
Preparation of Allylic and Homoallylic Alcohols
• Allylic oxidation with selenium dioxide
O
Se
O
HO
Se
O
H
O
Se
[2+4]
R
OH
OH
[2,3]
R
R
R
• Homoallylic alcohols via chiral or achiral crotyl and allyl metals
OH
O
H
R2
R1
M
M = B, Al, Sn, Si ... + auxiliaries
R1
(L.A.)
R2
4
Preparation of Allylic Alcohols : The Nozaki-Hiyama-Kishi Reaction
+
R1
R2CHO
CrCl2, catalytic NiCl2
R
DMF, 25 °C
OTf
R2
1
OH
Entry
Alkenyl triflate
Aldehyde
Product
Yield
O
O
1
Bu
OTf
OHC
7
87%
Bu
OctCHO
2
Oct
OTf
3
Ph
92%
Ph
(from trans)
PhCHO
Ph
OTf
HO
5
83%
OH
Ph
OTf
4
7
OH
Ph
PhCHO
46%
(from cis)
Ph
85%
Ph
OTf
HO
Nozaki et al, J. Am. Chem. Soc., 1986, 108, 6048
5
Nozaki-Hiyama-Kishi Mechanism
The success of this reaction heavily depended on the
nature of the CrCl2!
• In 1983, anhydrous CrCl2 from ROC/RIC Corp (New Jersey) proved to
contain ca. 0.5 mol% of Ni on the basis of Cr
• Aldrich Co. (90% purity) and Rare Metallic Co. (99.99% purity) offers
anhydrous CrCl2 free from Ni salts
Cr(III)
X
NiX
Cr(III)
X = I, Br, OTf
RCHO
Ni(0)
Ni(II)
2 Cr(III)
2 Cr(II)
R
Hiyama, T.; Nozaki, H. et al, Tetrahedron Letters, 1983, 24, 5281
Kishi Y. et al, J. Am. Chem. Soc, 1986, 108, 5644
Nozaki, H. et al, J. Am. Chem. Soc, 1986, 108, 6048
OH
6
Synthesis of Enantioselective (E)-Allylic Alcohols
O
1) HB
R
2
1
R1
H
Et
R2
Zn
2) Et2Zn
Me2N
HO
(+)DAIB
Me2
N
Et
Zn
C=O Re-face attack
H
O
NH4Cl (aq)
O
R2
R1
R2
R1
OH
Zn
Et
L
67-94%
(79-98% ee)
Oppolzer, W.; Radinov, N. J. Am. Chem. Soc., 1993, 115, 1593
7
Synthesis of Macrocyclic (E)-Allylic Alcohols
O
HO
Me2N
HO
HO
(+)-DAIB
1) (c-hexyl)2BH
2) Dilute rxn (0.05M)
+
A
B
3) (+)-DAIB/Et2Zn
4) NH4Cl (aq)
n
n
Entry
n
ring size
1
1
2
n
Yield (%)
A
B
ee (%)
of A
13
20
9
90
2
14
35
7
91
3
3
15
60
3
88
4
6
18
61
7
91
5
9
21
43
8
88
Limitation: -Disubstituted allylic alcohols only!
-Procedure is not effective with internal alkynes
Oppolzer et al, J. Org. Chem., 2001, 66, 4766
8
Addition to RCHO by Zirconocene-Zinc Transmetallation
R1
Cp2ZrHCl
R
CH2Cl2, 22°C
Me2Zn
ZrCp2Cl
1
toluene, -65°C
R1
ZnMe
Not catalytic!
R2CHO,
NMe2
SH
Limitation....intermolecular rxn only!
RCHO hydrozirconation is faster than alkyne hydrozirconation
Zr
R1
H
O
O
n
n
H
*
R2
OH
63-99% ee
H
H
Zr
Wipf, P.; Ribe, S. J. Org. Chem., 1998, 63, 6454
EWG on aromatic R2CHO
increase ee
9
Intramolecular Ni-Catalyzed Alkylative Cyclizations
R2
R1
O
X
Ni(COD)2
ZnR22
HO
R1
H
X
Alkylative Cyclization
Terminal and internal alkynes .... tri- and tetrasubstituted allylic alcohols
O
H
Entry
X
1
R1
CH2
2
X
CH2
R1
Ni(COD)2 : PBu3
H
ZnR22
H
R2
CH3
Yield(%) H
HO
70
Ph
72
62
X
3
CH2
H
n-Bu
4
CH2
CH3
Ph
5
CH2
CH3
n-Bu
R1
64Cyclization
Reductive
76
Terminal and internal alkynes .... di- and trisubstituted allylic alcohols
CH3
72
6
NCOPh
H
with PBu3!
Terminal
and internal alkynes .... tri- and tetrasubstituted allylic alcohols
20 mol% Ni(COD) is required to avoid 1,2-addition of the organozinc to RCHO
2
Montgomery, J.; Oblinger, E. J. Am. Chem. Soc., 1997, 119, 9065
10
Nickel-Catalyzed Alkylative and Reductive Coupling
L
O
0
+
R3
O
L
1
H R
L
L
NiII
R3
O
ZnEt2
EtZnO
L
Ni
R1
1
H
R3
Ni
R1
H
R
R2
Ni
L
Et
R3
R2
Large
Substituent
Oxidative
Cyclization
Small
Substituent
(or tether chain)
L = (n-Bu)3P
EtZnO
Ni H
R1
R3
H
R2
L
H
R2
R2
L = THF
OH
R1
Et
OH
R3
R2
Alkylative Coupling
R1
H
R3
R2
Reductive Coupling
Montgomery, J.; Oblinger, E.; J. Am. Chem. Soc, 1997, 119, 9065
11
Choice of Ligand
R
Phosphine Ligands with EDG
• Soft neutral 2e-donor ligand
R
P
M
• σ-donor ability :
(t-Bu)3P > Cy3P > (n-Bu)3P > Et3P > Ph3P
R
CO
R3 P
Ni
CO
CO
PR3
 , cm-1
CO
(t-Bu)3P
2056.1
Cy3P
2056.4
(n-Bu)3P
2060.3
Et3P
2061.7
Ph3P
2068.9
Tolman, C. Chem. Rev. 1977, 77, 313
-donor
ability
12
Reductive vs β-Hydride Elimination : Additive Effect?
L
O
Ni0
EtZnO L
+
R1
R3
H
R
Et
L = (n-Bu)3P
EtZnO L
Ni H
R1
H
2
Ni
3
R
R
R1
R3
H
R2
2
Intramolecular Rxn
Only!
L = THF
OH
R1
Et
OH
R3
R2
Alkylative Coupling
R1
H
R3
R2
Reductive Coupling
• Direct reductive elimination is
• π-acidic ligands (aldehyde) accelerate
accompanied by a 2e- reduction
reductive elimination
• In the absence of (n-Bu)3P, unreacted RCHO of Ni
• Process disfavored by the
can coordinate to Ni
coordination of good σ-donor (n-Bu)3P
13
Catalytic Intermolecular Reductive Coupling
of Alkynes and Aldehydes
Ni(COD)2 (10 mol%)
phosphine (20 mol%)
Et3B (200 mol%)
O
Ph
CH3
+
Ph
Solvent, 23 °C, 18 h
H
R
100 mol%
100 mol%
OH
CH3
1a R = Ph
1b R = n-Pr
Entry
Aldehyde
Phosphine
R
2a-2b
Solvent
Product
Yield
Regioselectivity
Cy3P
THF
2a
76%
77:23
2
Et3P
THF
46%
91:9
3
(n-Bu)3P
THF
77%
92:8
(n-Bu)3P
THF
86%
90:10
5
(n-Bu)3P
Toluene
85%
92:8
6
(n-Bu)3P
Toluene (40 °C)
88%
92:8
1
4
1a
1b
2b
Jamison, T.F. et al, Org. Lett., 2000, 26, 4221
14
Proposed Mechanism via an Oxametallacyle
L
O
+
R2
Ni0(COD)2
R3
Ni
(n-Bu)3P
R1
H
O
L
1
H
L
R3
O
Et2BO Et
Et3B
R1
1
H

R2 3
SiMe
Oxidative
Cyclization
Small
Substituent
L
L
NiII
R
R
R3
Ph
Stabilized
Large
cation
Substituent
R2
OH
L
R3
H
R2
Ni
-H Elimination
Et2BO
H
R1
Ni
L
R3
H
R2
H
Reductive
Elimination
R1
R3
R2
15
Choosing the Reducing Agent
O
OZnR
H
R
1
ZnR2
+
R2
20 mol% Ni
R3
L
H
R3
O
H
L
H
Ni
R1
R
L
II
L
L
NiII
Et3Si
Et3SiH
1,2-addition onto the aldehyde
in complex systems
R1
O
R
Et3SiO
H
Ni
R1
R1
2
intermolecular
R3
R3
H
R2
H
L
R2
L
Et2BO Et
Ni
L
-H Elimination
Et3B
R1
R3
H
R2
Et2BO
H
R1
Ni
L
OH
Reductive
Elimination
R3
H
R1
R3
H
R2
Montgomery, J.; Tang, X-Q. J. Am. Chem. Soc., 1999, 121, 6098
Jamison, T.F. et al, Org. Lett., 2000, 26, 4221
R2
16
Catalytic Intermolecular Reductive Coupling
of Alkynes and Aldehydes
Ni(COD)2 (10 mol%)
(n-Bu)3P (20 mol%)
Et3B (200 mol%)
O
R1
R2
+
R3
H
Entry
Aldehyde
OH
R1
R3
Solvent, 18 h
Product
Solvent, T °C
R2
Yield
Regioselectivity
THF, RT
77%
92:8
THF, RT
76%
96:4
Toluene, RT
89%
>98:2
Toluene, RT
58%
>98:2
Toluene, RT
83%
93:7
OH
1
PhCHO
Ph
Ph
CH3
OH
2
PhCHO
n-Hex
Ph
OH
3
n-HeptCHO
Ph
n-Hept
SiMe3
OH
4
n-HeptCHO
n-Bu
n-Hept
SiMe3
OH
5
o-TolCHO
Ph
CH3
CH3
17
Asymmetric Reductive Coupling with NMDPP
Ni(COD)2 (10 mol%)
(+)-NMDPP (20 mol%)
O
+
R2
CH3
H
H3C
R3
Et3B (200 mol%)
EtOAc:DMI (1:1)
R1
H
OH
R1
R3
R2
CH3 PPh2
(+)-(neomenthyl)
diphenylphophine
Entry
R1
R2
R3
1
i-Pr
Me
Ph
95 (>95:5)
90
2
i-Pr
Me
(p-Cl)Ph
75 (>95:5)
83
3
i-Pr
CH2OTBS
Ph
59 (>95:5)
85
4
i-Pr
CH2NHBoc
Ph
60 (>95:5)
96
5
n-Pr
SiMe3
Ph
43 (>95:5)
92
Yield (%)
Regioselectively
Jamison, T.F. J. Am. Chem. Soc., 2003, 125, 3442
ee (%)
18
Ph
Proposed Steric and Electronic Control
Me
Ni
R
H
R
H
Ph
Me
H
H
O
Ni
Me
Me
Sterically Disfavored,
electronically favored
Ph
R
H
Me
R
Me
C
Me
Me
B
Sterically and
electronically disfavored
D
Sterically and
electronically favored
Ph
H
P
Me
Me

 Me
Ni
O
O
Me
H
H
R
P
Me
Me
A

O
Ni
P
Ph
PR3
Sterically favored,
electronically disfavored
Ni
O
Me
P
Me
Me
19
Proposed Mechanism for Asymetric Reductive Coupling

Ph
H
H
Me
R
Ph
Ni
O
Me
P
Me
Et3B
Me
Ni
D
Me
R
Sterically and
electronically favored
PR3
O
L
L
Ni
Et OBEt2
Ph
R
Me
Hydride
Elimination
L
Ni
H
Ph
OBEt2
R
Me
H
Reductive
Elimination
OH
Ph
R
Me
20
Catalytic Three-Component Coupling Reaction:
Allylic Amines
R
Me
4
Et
Me
HN
H
HN
N
Ni(COD)2 (5 mol%)
RBX2
+ R
1
R
2
+
H
X = OH, R
R1 = aryl, alkyl
R2 = alkyl, H
R3
R3 = aryl, alkyl
Cyp3P (5 mol%)
Ph
Ph
+
Ph
Ph
Me
Me
1a
Alkylative Coupling
2a
Reductive coupling
Yield : 65-98%
1a:2a >90:10
Regioselectivity >90:10
-Organoborane reagents are used for
alkylative coupling
-Exclusive cis addition across alkyne
( ³ 97:3)
-Compatible with ketones, esters, and
protic solvents
21
Boronic Acids in Catalytic Three-Component Couplings
Me
Ph
HN
B(OH)2
Ph
Me
Me
Ni(COD)2 (5 mol%)
(c-C5H9)3P (5 mol%)
N
Ph
Me
+
H
Ph
Ph
72% (92:8 regioselectivity)
MeOH/MeOAc
50 °C
Ph
Me
HN
B(OH)2
Ph
Ph
Me
68% (92:8 regioselectivity)
22
Enantioselectivities for Alkylative and Reductive
Coupling Using (S)-(+)-NMDPP
Me
Me
N
Ph
Me
Ni(COD)2 (10 mol%)
Et
Me
HN
H
HN
(S)-NMDPP (20 mol%)
+
H
Ar
+
Et3B (300 mol%)
MeOAc/MeOH
0 °C, 20 h
Ph
CH3
H3C
CH3 PPh2
(+)-(neomenthyl)
diphenylphophine
Ph
Ph
Ph
Me
Me
1
Alkylative Coupling
+
minor regioisomer
2
Reductive coupling
+
minor regioisomer
Same ratio!
Entry
Ar
ee 1(%)
ee 2 (%)
1
Ph
41
42
2
p-ClC6H4
33
33
3
(p-CF3)C6H4
40
39
23
Proposed Mechanism for the Ni-catalyzed Coupling Reaction
Between Alkynes and Imines
Isolated in identical ee
Me
PR3
Alkylative Coupling
Me
Et
N
BEt2
Reductive Coupling
N
+
Ni
L
Ar
H
BEt2
Me
N
Reductive
Elimination
BEt2
Me
Ar
H
H
Me
PR3
BEt2
Ni
N
Ar
N
Ar
Ni
Et
H
PR3
Reductive
Elimination
Me
PR3
Me
OH
BEt2
Ni
N
Me
Ar
Me
PR3
BEt2
Ni
N
Ar
-H Elimination
MeOH
Ar
• Enantioselectivity and regioselectivity are determined in the same step
and before the azametallacyclopentene
• Highly selective for alkylative coupling in MeOH
24
Intermolecular Reductive Coupling of Alkynes and Epoxides
R1
R2
R
+
Ni(COD)2 (10 mol%)
Bu3P (20 mol%)
3
100 mol%
R
Et3B (200 mol%)
Solvent, 23 °C, 24 h
O
200 mol%
R3
1
R2
OH
Entry
R1
R2
R3
Additive
Solvent
1
Ph
Me
Me
Bu3P
Ether
36
>95:5
>95:5
2
"
"
"
Bu3P
Toluene
25
"
"
3
"
"
"
Bu3P
EtOAc
34
"
"
4
Ph
Me
Me
Bu3P
Neat
71
>95:5
>95:5
5
n-Pr
n-Pr
Et
Bu3P
Neat
35
na
>95:5
Yield (%)
Regioselectivity
alkyne
epoxide
Jamison, T.F.; Molinaro, C. J. Am. Chem. Soc, 2003, 125, 8076
25
Reductive Cyclization via a Proposed Nickella(II)oxetane
R
R
H
O
Ni(COD)2
Bu3P
PBu3
Bu3P
Ni
PBu3
Ni
O
O
R
exo-dig
cyclization
Et3B
PBu3
H
H
OH
R
Et
Ni PBu3
OBEt2
OBEt2
R
Ni PBu3
R
26
Summary of Nickel-Catalyzed Reaction
• Racemic and enantioselective allylic alcohols
OH
O
R1
R2
Ni(COD)2 , (n-Bu)3P
+
R3
H
R1
R3
Et3B
R2
OH
Ni(COD)2 , (+)-NMDPP
Et3B
R1
R3
R2
• Allylic amines via three-component coupling
R4
R4
N
1
R
2
R
R
Ni(COD)2, PR'3
+
H
R3
R3B / RB(OH)2
MeOH
R1
R2
R3
+
O
Ni(COD)2), Bu3P
Et3B
R3
R2
• Homoallylic alcohols
R1
HN
R
R3
1
R2
OH
27
Synthesis of Amphidinolide T1
Me
• The amphidinolides are a family of macrolides
produced by marine dinoflagellates of the genus
Amphidinium
Me
CH2
HO
• The marine algae live in symbiosis with the Okinawan
flatworm
O
Me
O
O
• Amphidinolide T1, a 19-membered macrolide, is
cytotoxic against human epidermoid carcinoma KB
and murine lymphoma L1210 cell lines
O
Me
Total Synthesis of Amphidinolide T1
• Ghosh (2003)
• Fürstner (2003)
• Jamison (2004)
Amphidinium
carterae
Amphidinium
lactum
Kobayashi, J. et al, J. Org. Chem., 2001, 66, 134
28
Ghosh’s Enantioselective Synthesis of Amphidinolide T1
via Macrolactonization
Br
Br
Cl
Me
O
Cl
Me
O
OH
Me
Me
O
OH
Cl
Cl
O
O
Me
O
i-Pr2NEt, then DMAP
Toluene
O
O
Me
71%
O
O
Me
Me
Me
Me
CH2
HO
O
Zn, NH4Cl, EtOH, 80 °C
61%
Me
O
O
O
(+)-Amphidinolide T1
30 steps
Me
Ghosh, A.K.; Liu, C. J. Am. Chem. Soc., 2003, 125, 2374
29
Fürstner’s Synthesis of Amphidinolide T1
via RCM Macrocyclization
Me
Me
N
Mes
O
Me
N
Mes
Me
Cl
Ru
MOMO
Cl
O
Me
TBDPSO
O
MOMO
Ph
PCy3
CH2Cl2, reflux
86%
O
O
Me
TBDPSO
O
O
O
Me
Me
Me
E/Z = 6:1
Me
CH2
HO
O
H2 , Pd/C
Me
O
O
O
(+)-Amphidinolide T1
30 steps
Me
Fürstner, A. et al, J. Am. Chem. Soc., 2003, 125, 15512
30
Jamison’s Approach to Amphidinolide T1
Me
Me
Ph
Ph
CH2
Me
Me
HO
O
O
O
OH
Ph
Me
O
Me
O
O
Ph
O
O
Me
Me
Jamison’s Approach : Ni-catalyzed reductive rxn
• alkyne-epoxide
• alkyne-aldehyde
Jamison et al, J. Am. Chem. Soc., 2004, 126, 998
31
Me CH2
HO
Synthesis of Amphidinolide T1
Me
O
Me
O
O
O
Me
O
O
O
Me
O
N
1) LDA, THF
2) PhC
CCH2Br
O
O
1) LiAlH4, THF
2) TBSCl, imid, DMF
N
70% over 3 steps
Me
i-Pr
Ph
i-Pr
Me
O
>99% ee
TBSO
Me
Ph
Ni(COD)2 (10 mol%)
Bu3P (20 mol%)
Et3B
Me
TBSO
Me
OH
Ph
81%, >99% dr
32
Me CH2
HO
Mechanism Revisited
Me
O
Me
O
O
O
Me
Me
Me
O
R
R
Ni(COD)2
Bu3P
+
Me
O
Ni
TBSO
Me
Ph
Ph
Ph
O
PBu3
Ni
Bu3P
PBu3
Et3B
R
Me
R
Me
R
Me
L
L
Ph
H
OBEt2
OBEt2
OH
Ph
Ni
H
Ph
Ni
Et
L
33
Me CH2
HO
Enantioselective Brown (Z)-Crotyl Addition
Me
O
Me
O
O
O
Me
O
OH
(+)-Ipc2B
H
CH3
OTBS
OTBS
93% ee
CH3
H3C
CH3
H
B
RCHO
R
H
CH3
B
O
CH3
CH3
2
L
S
M
H
Both methyl groups of the
campheyl moiety are on the
opposite side of the allyl group
H3C
RB
R
O
S
B
M
2
L
CH3
Brown, H.C.; Bhat, K. J. Am. Chem. Soc.,1986, 108, 5919
34
Me CH2
HO
Synthesis of Amphidinolide T1
Me
O
Me
O
O
O
Me
OH
BH3.THF;
H2O2, NaOH
OH
HO
OTBS
OTBS
Me
Me
HO
O
(CH2)4OTBS
TPAP, NMO
O
Me
DIBAL-H
HO
O
O
(CH2)4OTBS
Me
(CH2)4OTBS
31% over 4 steps
Me
35
Me CH2
HO
Synthesis of Amphidinolide T1
Me
O
Me
O
O
O
Me
Me3Si
HO
O
(CH2)4OTBS
O
Et2O.BF3, CH2Cl2
-78 °C; then warm to
23 °C (-TBS)
Me
(CH2)4OH
Ph
Ph
Me
40% overall
>95:5 dr
1) LDA, LiCl,
O
(CH2)4I
Me
Ph
Me
Me
O
N
OH
Ph
I2, PPh3, imid
O
Me
Me
2) NaOH, t-BuOH, CH3OH
CO2H
Ph
Me
>95:5 dr
65% over 3 steps
36
Me CH2
HO
N
Synthesis of Amphidinolide T1
Me
Me
O
O
O
O
N
4-PPY
Me
Me
1) TBSO
Me
Me
Ph
O
OH
DCC, 4-PPY
CO2H
Ph
2) TBAF
3) Dess-Martin
Me
59% over 3 steps
Me
Ph
Me
O
H
Me
*
O
O
O
Me
Ph
Ni(COD)2 (20 mol%)
Bu3P (40 mol%)
*
Ph
Me
HO
*
*
Et3B, toluene, 60 °C
X = 0.05 M
Ph
Me
O
Me
O
O
Me
44%, >10:1 dr
37
Me CH2
HO
Synthesis of Amphidinolide T1
Me
O
Me
O
O
O
Me
Me
Me
Ph
Me
Me
HO
O
TBSO
O
O
1) TBSOTf, 2,6-lutidine
Me
O
Ph
Me
O
2) O3; Me2S
O
O
O
Me
Me
Me
Me
CH2
HO
O
1) CH2I2, Zn, ZrCl4, PbCl2
Me
2) HF.py
O
O
25% over 4 steps
O
Me
38
Conclusion
Me
• Two nickel-catalyzed carbon-carbon bond
forming reactions were utilized during the
synthesis of Amphidinolide T1:
Me
CH2
HO
• catalytic intermolecular alkyne-epoxide
reductive coupling
• catalytic intramolecular alkyne-aldehyde
reductive coupling
O
Me
O
O
O
• This is the most direct synthesis of
Amphidinolide T1 with 20 synthetic operations.
Me
39
Aknowledgements
Prof Louis Barriault
Irina Denissova
Steve Arns
Effie Sauer
Jeff Warrington
Roxanne Clément
Patrick Ang
Louis Morency
Rachel Beingessner
Gerardo Ulibarri
Danny Gauvreau*
Ross MacLean*
Jermaine Thomas*
Roch Lavigne
Nathalie Goulet
Christiane Grisé
Financial Support
University of Ottawa
NSERC
OGS
Canada Foundation for Innovation
Ontario Innovation Trust
Premier’s Research Excellence Award
Merck Frosst Canada
Astra Zeneca
Bristol Myers Squibb
Boerhinger Ingelheim
40