1
Applications of a Novel Nickel-Catalyzed Reductive Coupling Reaction Towards the Total Synthesis of
Amphidinolide T1
Julie FarandApril 1st, 2004
O
CH2
Me
O
OMe
Me
HO
O
Me
Jamison et al, J. Am. Chem. Soc., 2004, 126, 998Jamison, T.F. et al, Org. Lett., 2000, 26, 4221
2
Introduction
• Methods of generating allylic alcohols
• Nickel-catalyzed coupling between• alkynes and aldehydes• alkynes and epoxides• alkynes and imines
• Jamison’s methodology applied towards the total synthesis of amphidinolide T1
O
CH2
Me
O
O
Me
Me
HO
O
Me
3
Preparation of Allylic Alcohols
• Reductions, organomagnesium and organolithium reagents
H
O
R
OH
RMgBrLi
R
O
H
R
O
NaBH4
• Reactive allylic sulfoxides via a [2,3]-sigmatropic rearrangement
R
SOPh
R
PhS
O P(OMe)3
R
OS
Ph
P(OMe)3
MeOH
R
OH
4
Preparation of Allylic and Homoallylic Alcohols
• Allylic oxidation with selenium dioxide
• Homoallylic alcohols via chiral or achiral crotyl and allyl metals
H R1
OM
R1
OHR2
R2
M = B, Al, Sn, Si ... + auxiliaries
(L.A.)
R
H
O Se O
R
SeOHO
[2,3]
R
OSe
OH
R
OH
[2+4]
5
Preparation of Allylic Alcohols : The Nozaki-Hiyama-Kishi Reaction
Nozaki et al, J. Am. Chem. Soc., 1986, 108, 6048
R1 OTf+ R2CHO
CrCl2, catalytic NiCl2
DMF, 25 °C R1R2
OH
Entry Alkenyl triflate Aldehyde Product Yield
1
2
3
4
5
Bu OTf
Ph
OTf
Ph OTf
Ph
OTf
OTf
Bu
OH
OH
Oct
Ph
PhHO
Ph
PhHO
OctCHO
PhCHO
PhCHO
87%
83%
92% (from trans)
46% (from cis)
85%
OHC
O
7
O
7
6
Nozaki-Hiyama-Kishi Mechanism
• 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
The success of this reaction heavily depended on thenature of the CrCl2!
Hiyama, T.; Nozaki, H. et al, Tetrahedron Letters, 1983, 24, 5281Kishi Y. et al, J. Am. Chem. Soc, 1986, 108, 5644
Nozaki, H. et al, J. Am. Chem. Soc, 1986, 108, 6048
X
X = I, Br, OTf
NiX Cr(III)
RCHO
R
OH
Cr(III)
Ni(II)
2 Cr(II)2 Cr(III)
Ni(0)
7
Synthesis of Enantioselective (E)-Allylic Alcohols
R1
HB
2
1)
2) Et2Zn
R1
ZnEt
H R2
O
Me2N
HO
(+)DAIB
Me2N
O
Zn
Et
OZn
R1Et
L
R2
HC=O Re-face attack
NH4Cl (aq)
R1 R2
OH
(79-98% ee)
67-94%
Oppolzer, W.; Radinov, N. J. Am. Chem. Soc., 1993, 115, 1593
8Oppolzer et al, J. Org. Chem., 2001, 66, 4766
Synthesis of Macrocyclic (E)-Allylic Alcohols
O
1) (c-hexyl)2BH2) Dilute rxn (0.05M)
3) (+)-DAIB/Et2Zn4) NH4Cl (aq)
HO
n n
HO
n
+
Entry n ring size Yield (%) ee (%) A B of A
13
14
15
18
21
901
2
3
4
5
20
35
60
61
43
91
88
91
88
1
2
3
6
9
9
7
3
7
8
Me2N
HO
(+)-DAIB
Limitation: -Disubstituted allylic alcohols only! -Procedure is not effective with internal alkynes
A B
9
R1 Cp2ZrHCl
R1 R2
OH
63-99% ee
R1ZrCp2Cl
CH2Cl2, 22°C
Me2Zn
toluene, -65°C R1ZnMe
R2CHO, NMe2
SH
*
EWG on aromatic R2CHOincrease ee
Not catalytic!
Limitation....intermolecular rxn only!RCHO hydrozirconation is faster than alkyne hydrozirconation
H
O
n
ZrH
H
O
n
HZr
Addition to RCHO by Zirconocene-Zinc Transmetallation
Wipf, P.; Ribe, S. J. Org. Chem., 1998, 63, 6454
10
Intramolecular Ni-Catalyzed Alkylative Cyclizations
HX
O R1 Ni(COD)2
ZnR22
X
HO
R2
R1
Alkylative Cyclization
Entry X R1 R2 Yield(%)
H
H
H
CH3
CH3
701
2
3
4
5
Ph
n-Bu
Ph
n-Bu
72
62
64
76
CH2
CH2
CH2
CH2
CH2
6 NCOPh H
CH3
CH3 72
Terminal and internal alkynes .... tri- and tetrasubstituted allylic alcohols
Montgomery, J.; Oblinger, E. J. Am. Chem. Soc., 1997, 119, 9065
HX
O R1 Ni(COD)2 : PBu3
ZnR22
X
HO
H
R1
Reductive Cyclization
Terminal and internal alkynes .... tri- and tetrasubstituted allylic alcohols
Terminal and internal alkynes .... di- and trisubstituted allylic alcoholswith PBu3!
20 mol% Ni(COD)2 is required to avoid 1,2-addition of the organozinc to RCHO
11Montgomery, J.; Oblinger, E.; J. Am. Chem. Soc, 1997, 119, 9065
Nickel-Catalyzed Alkylative and Reductive Coupling
R3R2
H R1
ONi0 Ni
LL
R3
R2
R1H
O
Small Substituent
(or tether chain)
Large Substituent
O
NiIIR3
R2R1
H
LL
ZnEt2
R1 R3
EtZnO
R2
Ni
H
L
L
Et
R1 R3
OH
R2
Et
OxidativeCyclization+
L = (n-Bu)3P
R1 R3
EtZnO
R2
Ni
H
L H
L = THF
R1 R3
OH
R2
H
Alkylative Coupling Reductive Coupling
12
Choice of Ligand
Phosphine Ligands with EDG
• Soft neutral 2e-donor ligand
• σ-donor ability : (t-Bu)3P > Cy3P > (n-Bu)3P > Et3P > Ph3P
CO
NiR3P
CO
CO
PR3 , cm-1
(t-Bu)3P
Cy3P
(n-Bu)3P
Et3P
Ph3P
2056.1
2056.4
2060.3
2061.7
2068.9
-donor ability
CO
P M
R
R
R
Tolman, C. Chem. Rev. 1977, 77, 313
13
• π-acidic ligands (aldehyde) accelerate reductive elimination• In the absence of (n-Bu)3P, unreacted RCHO can coordinate to Ni
• Direct reductive elimination is accompanied by a 2e- reduction of Ni• Process disfavored by the coordination of good σ-donor (n-Bu)3P
Reductive vs β-Hydride Elimination : Additive Effect?
R1 R3
EtZnO
R2
Ni
H
L
L
Et
R1 R3
OH
R2
Et
L = (n-Bu)3P
R1 R3
EtZnO
R2
Ni
H
L H
L = THF
R1 R3
OH
R2
H
Alkylative Coupling Reductive Coupling
R3R2
H R1
O
Ni0
+
Intramolecular Rxn Only!
14
Catalytic Intermolecular Reductive Coupling of Alkynes and Aldehydes
Jamison, T.F. et al, Org. Lett., 2000, 26, 4221
CH3Ph +H
O
R
Ni(COD)2 (10 mol%)phosphine (20 mol%)
Et3B (200 mol%)
Solvent, 23 °C, 18 hPh R
OH
CH3
Entry Aldehyde Phosphine Solvent Product Yield Regioselectivity
1a Cy3P
(n-Bu)3P
(n-Bu)3P
(n-Bu)3P
(n-Bu)3P
Et3P
THF
THF
THF
THF
Toluene
Toluene (40 °C)
100 mol% 100 mol%
1a R = Ph1b R = n-Pr
2a-2b
2a
2b
76%
46%
77%
86%
85%
88%
77:23
91:9
92:8
90:10
92:8
92:8
1
2
3
CH3Ph +H
O
R
Ni(COD)2 (10 mol%)phosphine (20 mol%)
Et3B (200 mol%)
Solvent, 23 °C, 18 hPh R
OH
CH3
Entry Aldehyde Phosphine Solvent Product Yield Regioselectivity
1a Cy3P
1b
(n-Bu)3P
(n-Bu)3P
(n-Bu)3P
(n-Bu)3P
Et3P
THF
THF
THF
THF
Toluene
Toluene (40 °C)
100 mol% 100 mol%
1a R = Ph1b R = n-Pr
2a-2b
2a 76%
46%
77%
86%
85%
88%
77:23
91:9
92:8
90:10
92:8
92:8
1
2
3
4
5
6
15
Proposed Mechanism via an Oxametallacyle
R3R2
H R1
ONi0(COD)2 Ni
LL
R1H
O
(n-Bu)3P
O
NiIIR3
R2R1
H
LL
Et3B
R1 R3
Et2BO
R2
Ni
H
Et
L
L
R1 R3
Et2BO
R2
Ni
H
H L
R1 R3
OH
R2
H
OxidativeCyclization
-H Elimination
Reductive Elimination
+R3
R2
Small Substituent
Large SubstituentPh
SiMe3
Stabilized cation
16
Choosing the Reducing Agent
Montgomery, J.; Tang, X-Q. J. Am. Chem. Soc., 1999, 121, 6098
R3R2
H R1
O
+ZnR2
H R1
OZnR
R
1,2-addition onto the aldehydein complex systems20 mol% Ni
O
NiIIR3
R2R1
H
LL
Et3SiH
R1 R3
Et3SiO
R2
Ni
H
H
L
LO
NiIIR3
R2R1
H
LL
Et3Si
H
intermolecular
Et3B
R1 R3
Et2BO
R2
Ni
H
Et
L
L
R1 R3
Et2BO
R2
Ni
H
H L-H Elimination
R1 R3
OH
R2
HReductive Elimination
Jamison, T.F. et al, Org. Lett., 2000, 26, 4221
17
Catalytic Intermolecular Reductive Coupling of Alkynes and Aldehydes
Entry Aldehyde Product Solvent, T °C Yield Regioselectivity
58%
83%
89%
93:7
1
2
3
4
5
PhCHO
PhCHO
n-HeptCHO
n-HeptCHO
o-TolCHO
Ph Ph
OH
CH3
n-Hex Ph
OH
Ph n-Hept
OH
SiMe3
n-Bu n-Hept
OH
SiMe3
Ph
OH
CH3
CH3
77% 92:8
76% 96:4
>98:2
>98:2
THF, RT
THF, RT
Toluene, RT
Toluene, RT
Toluene, RT
R2R1
+H
O
R3
Ni(COD)2 (10 mol%)(n-Bu)3P (20 mol%)
Et3B (200 mol%)
Solvent, 18 hR1 R3
OH
R2
18
Asymmetric Reductive Coupling with NMDPP
R3R2
H R1
O
+
Ni(COD)2 (10 mol%)(+)-NMDPP (20 mol%)
Et3B (200 mol%)EtOAc:DMI (1:1)
R1 R3
OH
R2
H CH3
PPh2
H3C
CH3
(+)-(neomenthyl)diphenylphophine
Jamison, T.F. J. Am. Chem. Soc., 2003, 125, 3442
Entry R1 R2 R3 Yield (%) ee (%)
Regioselectively
i-Pr Ph
i-Pr
i-Pr
i-Pr
n-Pr
Ph
(p-Cl)Ph
Ph
Ph
Me
Me
CH2OTBS
CH2NHBoc
SiMe3
95 (>95:5)
75 (>95:5)
59 (>95:5)
60 (>95:5)
43 (>95:5)
90
83
85
96
92
1
2
3
4
5
19
Proposed Steric and Electronic Control
O
Ni
Ph
Me
R
PR3
Me
Me Me
PNi
H
O
H
R
Me
Me Me
PNi
H
O
H
R
C DSterically favored,electronically disfavored
Sterically andelectronically favored
Me
Ph
Ph
Me
Me
Me Me
PNi
O
RH
H
Me
Me Me
PNi
O
RH
H
A BSterically Disfavored,electronically favored
Sterically andelectronically disfavored
Me
Ph
Ph
Me
20
Proposed Mechanism for Asymetric Reductive Coupling
O
Ni
Ph
Me
R
PR3
Et3B
Ph R
Me
OBEt2NiL
L
Et
Ph R
Me
OBEt2NiL H
Ph R
Me
OHH HydrideElimination
Reductive Elimination
Me
Me Me
PNi
H
O
H
R
D Sterically andelectronically favored
Ph
Me
21
Catalytic Three-Component Coupling Reaction:Allylic Amines
R1 R2
H
N
R3
R4
Ni(COD)2 (5 mol%)
Cyp3P (5 mol%)+RBX2 +
X = OH, R R1 = aryl, alkyl
R2 = alkyl, H
R3 = aryl, alkyl
-Organoborane reagents are used for alkylative coupling-Exclusive cis addition across alkyne ( ³ 97:3) -Compatible with ketones, esters, and protic solvents
Yield : 65-98% 1a:2a >90:10
Regioselectivity >90:10
Ph Ph
HNEt
Me
Me
Ph Ph
HNH
Me
Me
+
1aAlkylative Coupling
2aReductive coupling
22
Boronic Acids in Catalytic Three-Component Couplings
MePh
B(OH)2
B(OH)2
N
H Ph
Me
Ph Ph
Ph HNMe
Me
Ph Ph
HNMe
Me
Ph
+MeOH/MeOAc
50 °C
Ni(COD)2 (5 mol%)(c-C5H9)3P (5 mol%)
72% (92:8 regioselectivity)
68% (92:8 regioselectivity)
23
Enantioselectivities for Alkylative and Reductive Coupling Using (S)-(+)-NMDPP
Ph MeH
N
Ar
MeNi(COD)2 (10 mol%)
(S)-NMDPP (20 mol%)
Ph Ph
HNEt
Me
Me
+ Et3B (300 mol%)
MeOAc/MeOH0 °C, 20 h
Ph Ph
HNH
Me
Me
+
1Alkylative Coupling
2Reductive coupling
Entry Ar ee 1(%) ee 2 (%)
421
2
3
41
33
40
33
39
Ph
p-ClC6H4
(p-CF3)C6H4
CH3
PPh2
H3C
CH3(+)-(neomenthyl)
diphenylphophine
+minor regioisomer
+minor regioisomer
Same ratio!
24
Proposed Mechanism for the Ni-catalyzed Coupling ReactionBetween Alkynes and Imines
• Enantioselectivity and regioselectivity are determined in the same step and before the azametallacyclopentene• Highly selective for alkylative coupling in MeOH
Ar
NiH
NPR3
MeBEt2
Ar
H NMe BEt2
ReductiveElimination
-H Elimination
Reductive Coupling
Ar
NiEt
NOH
MeBEt2
PR3
Me
Ar
Et NMe BEt2
ReductiveElimination
MeOH
Alkylative Coupling
Ni
PR3
L
+N
H Ar
Me
N
Ni
Ar
PR3
BEt2
Me
Me
Ar
Ni
H
NPR3
MeBEt2
Isolated in identical ee
25
Intermolecular Reductive Coupling of Alkynes and Epoxides
Jamison, T.F.; Molinaro, C. J. Am. Chem. Soc, 2003, 125, 8076
R2R1+
Ni(COD)2 (10 mol%)Bu3P (20 mol%)
Et3B (200 mol%)Solvent, 23 °C, 24 h
R1
R2100 mol%
R3
O
R3
OH
Entry R1 R2 R3 Additive Solvent Yield (%) Regioselectivity
alkyne epoxide
Ph Me
Ph Me
Me
Me
>95:51
2
3
4
5 n-Pr n-Pr Et
Bu3P Ether
Bu3P Toluene
Bu3P EtOAc
Bu3P Neat
Bu3P Neat
36
25
34
71
35
>95:5
na
>95:5
>95:5
>95:5
200 mol%
"
"
"
"
"
"
"
"
"
"
26
Reductive Cyclization via a Proposed Nickella(II)oxetane
R
O
H
R
ONi
PBu3
Ni(COD)2
Bu3PO
NiR
Bu3P PBu3
Et3B
R
Ni
OBEt2
Et
PBu3
PBu3
R
Ni
OBEt2
H PBu3
ROH
H
exo-digcyclization
27
Summary of Nickel-Catalyzed Reaction
• Racemic and enantioselective allylic alcohols
R2R1+
H
O
R3
Ni(COD)2 , (n-Bu)3PR1 R3
OH
R2
Ni(COD)2 , (+)-NMDPP
R3R1
OH
R2
Et3B
Et3B
• Allylic amines via three-component coupling
R1 R2
H
N
R3
R4
R1 R3
HNR
R2
R4
+
R3B / RB(OH)2
MeOH
Ni(COD)2, PR'3
• Homoallylic alcohols
+Ni(COD)2), Bu3P
R1
R2
R3
O
R3
OHEt3B
R1 R2
28
Synthesis of Amphidinolide T1
• The amphidinolides are a family of macrolides produced by marine dinoflagellates of the genus Amphidinium
• The marine algae live in symbiosis with the Okinawan flatworm
• Amphidinolide T1, a 19-membered macrolide, is cytotoxic against human epidermoid carcinoma KB and murine lymphoma L1210 cell lines
Amphidiniumcarterae
Amphidiniumlactum
O
CH2
Me
O
O
Me
Me
HO
O
Me
Total Synthesis of Amphidinolide T1
• Ghosh (2003)• Fürstner (2003)• Jamison (2004)
Kobayashi, J. et al, J. Org. Chem., 2001, 66, 134
29
Ghosh’s Enantioselective Synthesis of Amphidinolide T1 via Macrolactonization
Ghosh, A.K.; Liu, C. J. Am. Chem. Soc., 2003, 125, 2374
O
CH2
Me
O
OMe
Me
HO
O
Me
O
OH
OMe
O
Me
O
Me
OHMe
Br
O
Cl
Cl
Cl Cl
i-Pr2NEt, then DMAPToluene
O
O
O
Me
O
Me
O
Br
Me
Me
Zn, NH4Cl, EtOH, 80 °C
(+)-Amphidinolide T130 steps
71%
61%
30
Fürstner’s Synthesis of Amphidinolide T1 via RCM Macrocyclization
Fürstner, A. et al, J. Am. Chem. Soc., 2003, 125, 15512
O
CH2
Me
O
OMe
Me
HO
O
Me
(+)-Amphidinolide T130 steps
O
O
Me
O
OMe
Me
MOMO
TBDPSO
Me
O
O
Me
O
OMe
Me
MOMO
TBDPSO
Me
RuCl
ClPCy3
NN
Ph
MesMes
CH2Cl2, reflux86%
E/Z = 6:1
H2 , Pd/C
31
Jamison’s Approach : Ni-catalyzed reductive rxn• alkyne-epoxide
• alkyne-aldehyde
Ph
Ph
O
Me
O
O
Me
Me
HO
Me
CH2
O
O
Me
O
O
Me
Me
Me
O
Ph
Ph
OH
Jamison’s Approach to Amphidinolide T1
Jamison et al, J. Am. Chem. Soc., 2004, 126, 998
32
O N
O
Me
O
i-Pr
1) LDA, THF2) PhC CCH2Br
O N
O O
i-Pr
Me Ph
1) LiAlH4, THF2) TBSCl, imid, DMF
Me Ph
TBSO
Me
O
Ni(COD)2 (10 mol%)Bu3P (20 mol%)
Et3B
Me
TBSO
Ph
Me
OH
70% over 3 steps
>99% ee
81%, >99% dr
Synthesis of Amphidinolide T1O
CH2Me
O
OMe
Me
HO
O
Me
33
Mechanism Revisited
Ni(COD)2
Bu3P
Et3B
Me
O
TBSO
PhMe
Ni
Ph
R
PBu3
O
Me
NiO
Ph
MeR
Bu3P PBu3
NiOBEt2
Ph
MeR
EtL
L
NiOBEt2
Ph
MeR
H
L
HOH
Ph
MeR
+
O
CH2Me
O
OMe
Me
HO
O
Me
34Brown, H.C.; Bhat, K. J. Am. Chem. Soc.,1986, 108, 5919
Enantioselective Brown (Z)-Crotyl AdditionO
CH2Me
O
OMe
Me
HO
O
Me
CH3
B
CH3
RCHO
2
BO
H
R
CH3
H3C
H
CH3
BO
CH3
R
HS
S
L
L
M
M
RB
H3C
H OTBS
O
CH3(+)-Ipc2BOTBS
OH
CH3
Both methyl groups of thecampheyl moiety are on the
opposite side of the allyl group
2
93% ee
35
Synthesis of Amphidinolide T1O
CH2Me
O
OMe
Me
HO
O
Me
BH3.THF;
H2O2, NaOH
O (CH2)4OTBS
Me
HO
31% over 4 steps
OTBS
OH
Me
DIBAL-H
OTBS
OH
Me
HO
TPAP, NMO O (CH2)4OTBS
Me
O
O (CH2)4OTBS
Me
HO
36
Synthesis of Amphidinolide T1O
CH2Me
O
OMe
Me
HO
O
Me
Me3Si
Ph
Et2O.BF3, CH2Cl2-78 °C; then warm to23 °C (-TBS)
O (CH2)4OH
Me
>95:5 dr
Ph
40% overall
I2, PPh3, imid
1) LDA, LiCl,
PhN
O
Me
MeOH
MeO
Me
Ph
CO2H
Me
2) NaOH, t-BuOH, CH3OH
65% over 3 steps
O (CH2)4OTBS
Me
HO
O (CH2)4I
Me
Ph
>95:5 dr
37
Synthesis of Amphidinolide T1O
CH2Me
O
OMe
Me
HO
O
Me
N
N
4-PPY
Me
TBSO
Ph
Me
OH
1)
DCC, 4-PPY
2) TBAF3) Dess-Martin
O
MePh
Me
O
O
Me
Ph
O
H
Me
59% over 3 steps
O
Me
Ph
CO2H
Me
O
Me
O
OMe
Me
HO
Me
Ph
Ph
44%, >10:1 dr
Ni(COD)2 (20 mol%)Bu3P (40 mol%)
Et3B, toluene, 60 °CX = 0.05 M
* **
*
38
O
Me
O
OMe
Me
HO
Me
Ph
Ph
1) TBSOTf, 2,6-lutidine
O
O
Me
O
OMe
Me
TBSO
O
Me
2) HF.py
O
CH2
Me
O
OMe
Me
HO
O
Me
25% over 4 steps
2) O3; Me2S
1) CH2I2, Zn, ZrCl4, PbCl2
Synthesis of Amphidinolide T1O
CH2Me
O
OMe
Me
HO
O
Me
39
Conclusion
• Two nickel-catalyzed carbon-carbon bond forming reactions were utilized during the synthesis of Amphidinolide T1:
• catalytic intermolecular alkyne-epoxide reductive coupling• catalytic intramolecular alkyne-aldehyde reductive coupling
• This is the most direct synthesis of Amphidinolide T1 with 20 synthetic operations.
O
CH2
Me
O
O
Me
Me
HO
O
Me
40
Aknowledgements
Prof Louis BarriaultIrina DenissovaSteve ArnsEffie SauerJeff WarringtonRoxanne ClémentPatrick AngLouis MorencyRachel BeingessnerGerardo UlibarriDanny Gauvreau*Ross MacLean*Jermaine Thomas*Roch LavigneNathalie GouletChristiane Grisé
Financial SupportUniversity of OttawaNSERCOGS
Canada Foundation for InnovationOntario Innovation TrustPremier’s Research Excellence Award
Merck Frosst CanadaAstra ZenecaBristol Myers SquibbBoerhinger Ingelheim