Organic and Transition Metal Catalysts for the Control of Stereochemistry in CarbonCarbon Bond Formi

1
Organic and Transition Metal Catalysts for the
Control of Stereochemistry in Carbon-Carbon Bond
Forming Reactions
Tomislav Rovis
2
Natures Molecular Complexity
Communesin (a.k.a. nomofungin)
prymnesin-1
aburatubolactam
3
Challenges in Controlling Contiguous Stereocenters
eupomatilone-6
pyrrocidine-A
oxokadsuranol
4
Synthetic Utility of Metal-mediated Anhydride
Activation
Uncatalyzed anhydride desymmetrization
unselective
Activation of Anhydrides by Late Transition
Metals
Catalyzed Anhydride Desymmetrization
5
Why do we need a Metal-catalyzed Process?
Grignards present problems
Tetrahedron 1985, 41, 3695
Asymmetric Desymmetrization Heteroatom
Nucleophiles
JACS 2000, 122, 9542 see also ACIE
2001, 40, 3131
6
Accessing the Oxametalacyclopentane Intermediate
Anhydride insertion/CO extrusion
Insertion/Extrusion are established
Tetrahedron Lett. 1990, 31, 4783
observed by crystallography
J. Organomet. Chem. 1993, 447, 131
7
Catalyzed Direct Addition
PPh3
92
78
lt5
PCy3
pyphos
90
20
lt5
Uncatalyzed process
8
Olefin Promotes Reductive Elimination
Knochels Observation
20 mol 0 mol
1 h 15 h
74 20
Knochel, P. J. Org. Chem. 1999, 64, 3544.
Our Results
20 mol 0 mol
94 10-20
9
Reaction Scope - No Epimerization
92
95
95
10
Reaction Scope - Bicyclic Substrates
88
98
98
85
91
83
11
Reaction Scope - Succinic Anhydrides
93
88
64
61
65
12
Reaction Scope - Glutaric Anhydrides
81
88
54
85
85
90
13
Alkyl Zinc Nucleophile Scope
R2Zn
88
86
RZnBr
67
53
Bercot, E. A. Rovis, T. J. Am. Chem. Soc. 2002,
124, 174.
14
Air Stable Catalyst Precursors
97
85
66
15

Asymmetric Desymmetrization
Yield ()
ee ()
Ligand
10
88

85
79
NR
-
16
Asymmetric Desymmetrization Scope
78 yield, 73 ee
70 yield, 80 ee
56 yield, 53 ee
17
Asymmetric Desymmetrization Scope 2
85 yield, 79 ee
74 yield, 71 ee
0 yield, -- ee
18
Palladium Complexes Catalyze Anhydride Alkylation
55 yield
Gooben, L. J. Ghosh, K. Angew. Chem. Int. Edit.
2001, 40, 3458.
86 yield
Kakino, R. Narahashi, H. Shimizu, I. Yamamoto,
A. Chem. Lett. 2001,1242.
19
Searching for a New Catalyst
Initial Investigations
NR
20
Palladium Catalyzed Asymmetric Desymmetrization
Yield ()
Mol BINAP
ee ()
6 12
60 55
83 85
21
Pd-Catalyzed Asymmetric Desymmetrization
61 yield 85 ee
39 yield 96 ee
22
Dibenzocyclooctadiene Lignans and Related Targets
eupomatilone 6
interiotherin A
gomisin G
Malachi 45-6
oxokadsuranol
schiarisanrin C
23
Comparison of nickel and palladium Catalysis
82 yield 5 ee
72 yield 96 ee
24
Total Synthesis of the Eupomatilones
74 (gt955)
58 (4 steps)
eupomatilone 6
Does not match reported data
25
Monosubstituted 1,4-dicarbonyl Compounds
26
Nucleophilic Catalysis - the Mechanism
27
The Stetter Reaction in Synthesis
67 yield
Trost J. Am. Chem. Soc. 1979, 101, 1284
77 yield
Tius J. Am. Chem. Soc. 2001, 123, 8509
28
The Asymmetric Stetter Reaction - Literature
Precedent
70 yield 63 ee
Enders Helv. Chim. Acta 1995, 79, 1899
29
Other Chiral Carbenes and Precursors
Hartwig
Herrmann
Enders
RajanBabu
Lopez-Calahorra
Yamashita
Rawal
Leeper
Leeper
30
Chiral Triazolium Salt Synthesis
X-ray
Overall Yields 32-65
Analogously
Norman, B. H. J. Org. Chem. 1996, 61,
4990 Leeper, F. J. J. Chem. Soc., Perkin Trans 1
1998, 1891.
Overall Yields 50-63
31
Nucleophilic Catalysis - the Stetter
base
yield ()
solvent
ee ()
MeOH THF THF THF
95 N.R. 94 95
2 - 82 84
K2CO3 K2CO3 Et3N KHMDS
ç 16 h
ç 1 h
32
Catalyst Substituent Screen
R
yield ()
ee ()
Bn 95 91 Ph 41
86 i-Pr 45 86 t-Bu NR
-
33
Substrate Scope
95, 90 ee
95, 80 ee
30, 98 ee
95, 90 ee
95, 80 ee
NR
34
The Impact of the N-Substituent
R yield () ee ()
Me 80 32 Ph 85 91 Cy 10 40 t-Bu
0 -
Cat
35
A Better Catalyst
95, 95 ee (1st gen 95, 90 ee)
63, 96 ee (1st gen 60, 98 ee with 50 mol
cat)
95, 87 ee (1st gen 95, 80 ee)
89, 97 ee (1st gen 95, 90 ee)
36
Aza and Carba-Tethered Substrates
64, 82 ee
90, 92 ee
37
Scope of the Stetter - 5-membered Ring
75, 0 ee
Time (h) Conversion () ee () 1 10
80 3 30 50 12
75 0
Kerr, M. S. Read de Alaniz, J. Rovis, T. J. Am.
Chem. Soc. 2002, 124, 10298.
38
Aliphatic Aldehydes
95, gt98 ee
97, 82 ee
39
Epimerization Revisited
Time (h) Conversion () ee () 1 10
80 12 75 0
40
Tertiary Ether Stereocenter Synthesis
85, 99 ee
20 KHMDS
96, 97 ee
20 Et3N
95, 92 ee
41
Quaternary Stereocenter Synthesis
95, 99 ee
55, 99 ee
42
Quaternary Stereocenter Synthesis
80, 96 ee
85, 84 ee
48, 99 ee
80, 96 ee
43
Stereochemical Model
X-Ray
44
Kinetic Resolution
92 ee
11 (58 yield)
98 ee
45
Mechanism Revisited
46
Mechanistic Insights
47
Controlling a-Stereocenters via Conjugate
Additions
Ideal Approach - as yet unknown
48
Setting Contiguous Stereocenters
31 de (95 yield)
49
Acknowledgements
Graduate Students
Postdocs
Eric A. Bercot Jeffrey Frein Mark S. Kerr Qin
Liu Jennifer Moore Chris Nasveschuk Javier Read
de Alaniz Nathan T. Reynolds Robert Yu Rebecca
Zapf Erin M. OBrien Andrew D. Higginbotham
Dr. Yongda Zhang Dr. Mark Sundermeier Dr. Kavita
Manju Dr. Cristobal de los Rios Salgado
Undergraduate Students
Joseph Messer Jacqueline Gogolski Drew
Henschen Kelly Fritzler David Kindrachuk Virginie
Gorteau Julien Descabannes Amanda Schmisseur
(NSF-REU)
Funding
NIH - NIGMS (RO1) NSF CAREER Petroleum Research
Fund (ACS) Colorado State University VP for
Research (Faculty Research Grant - CSU) Merck
Research Laboratories Glaxo SmithKline Solvias
50
Catalyst Electronics
Ar
Shift (ppm)
6.21
6.22
Diagnostic proton in 1H NMR
6.24
6.26
6.44
51

Impact of Olefin in Asymmetric Reaction
ee ()
Ligand
44
lt5

62
56
44
52

Mechanistic Rationale

P
ent-P
53
Consumption of H vs D
54
Diastereoselective Reduction
Super Hydride THF, - 78 C
PhMe2SiH TFA/CH2Cl2 (13), 0 C
41 75 71 52 51 11
19 75 17 52 1gt20 84 1gt20 80
55
An Improved Ligand Synthesis and Scale-up
10 g
24 g
Overall Yield 85
56
Catalyst Loading Profile
5 mol -------
10 mol -------
20 mol -------
57
Total Synthesis of Eupomatilone-6 and Gomisin G
74 (gt955)
58 (4 steps)
eupomatilone 6
4 steps
gomisin G
64
58
Towards Gomisin G
64 (gt955)
81
gomisin G
57
59
Improved Catalyst Loading
92, 92 ee
60
A New Catalyst
BINAP
60 yield 85 ee
49 yield 75 ee
61
Total Synthesis of Eupomatilone-6 and Gomisin G
74 (gt955)
58 (4 steps)
eupomatilone 6
62
Approaches to Pyrrocidine
oxokadsuranol
pyrrocidine-A
eupomatilone-6
63
Controlling Stereochemistry in a Cross-Coupling
Reaction
kalkitoxin (voltage sensitive Na channel
blocker)
64
State of the Art - sp3-sp3 Cross-coupling
72
Kambe et al JACS 2002, 124, 4222
64
Knochel et al ACIE 1998, 37, 2387
81
Fu et al JACS 2001, 123, 10099
65
Setting Stereochemistry in Cross-coupling
95, 68 ee
Hayashi, Kumada et al JACS 1982, 104, 180
Phenethyl Grignard is uniquely competent in
this chemistry
49, 22 ee
Oshima Angew. Chem. Int. Edit. 2002, 41, 4137
Reaction proceeds via radicals
66
Pd-Catalyzed Asymmetric Desymmetrization
61 yield 85 ee
39 yield 96 ee
68 yield 92 ee
72 yield 96 ee
67
Problems with Traditional Approaches
Overall inversionretention 61
Netherton and Fu Angew. Chem. Int. Edit. 2002,
41, 3910
Recent cross-coupling of secondary alkyl
halides Fu, JACS. 2003, 125, 14726.
68
Stable Csp3-Metal Complexes
Z. Anorg. Allg. Chem. 1998, 624, 1329
Organometallics. 1990, 9, 2197
69
Cross-coupling with an sp3(electrophile)
Activation of Anhydrides by Late Transition
Metals 2 Possible Pathways
Catalyzed Anhydride Desymmetrization
70
Development of sp3(electrophile)-sp2
Cross-coupling
A
B
Yield ()
Ligand
AB
lt5
dppb
lt5gt95
65
pyphos
6931
90
bipy
3763
90
phenanthroline
3862
53
neocuproine
gt95lt5
71
Development of sp3(electrophile)-sp2
Cross-coupling
50
25
25
1 equiv
1 equiv
72
Scope of sp3(electrophile)-sp2 Cross-coupling
77
50
78
56
51
73
Scope of sp3(electrophile)-sp2 Cross-coupling
60
85
77
74
Isomerizations in the Cross-coupling
56
74
75
Searching for a New Catalyst
Initial Investigations
NR