Manganese Triacetate-Promoted Cyclizations

1
Manganese Triacetate-Promoted Cyclizations
Annulations
Leading References Melikyan, G. G.
Aldrichimica Acta 1998, 31, 50 Snider, B. B.
Chem. Rev. 1996, 96, 339 Melikyan, G. G.
Synthesis, 1993, 833.
Daniel Beaudoin Literature Meeting September
25, 2006 Under the supervision of Prof. André B.
Charette
2
Oxidative Radical ReactionsTransition Metal
Oxidants
Oxidative vs Reductive Radical Reactions
Transition Metal One Electron Oxidants1
1 Review on transition metal-promoted radical
reactions Iqbal, J. et al. Chem. Rev. 1994, 94,
519.
3
Mn(OAc)3An Underappreciated Oxidant
Preparation1
Electronic and Redox Properties
Distorted Octahedron (High Spin)
Outer-Sphere Electron Transfer
Inner-Sphere Electron Transfer
1 Heiba, E. I. et al. J. Am. Chem. Soc. 1969, 91,
138.
4
Mn(OAc)3Solid State Structure
Mn(OAc)3.2H2O Mn2O(OAc)4.2AcOH.3H2O1
Bond Distance (A)
Mn1-O16 1.848
Mn2-O16 1.858
Mn3-O16 2.108
Anhydrous Mn(OAc)3 Mn3O(OAc)7.AcOH2
Bond Distance (A)
Mn-O1 1.898
Mn-O2 2.176
Mn-O3 1.936
1 Hessel, C. et al. Recl. Trav. Chim. Pays-Bas
1969, 88, 545. 2 Christou, G. et al. Polyhedron
2003, 22, 133.
5
Mn(OAc)3Solution Structure (AcOH)

• Polynuclear solution structure proposed
• Mn3O(OAc)7 and Mn(OAc)3.2H2O are
  indistinguishable in solution
• Mn3O(OAc)7 is slightly more reactive than
  Mn(OAc)3.2H2O (1.7x)
• Metathesis with other acids occurs readily

6
Mn(OAc)3Initiation
Most Common Substrates
Classical Carbonyls Compounds (High T Required)
Activated Methylenes (Low T Required)
Enolization Precedes Inner-Sphere Electron
Transfer
1 eV 23.1 kCal/mol
Fristad, W. E. et al. J. Org. Chem. 1985, 50, 10.
7
Mn(OAc)3Initiation
Oxidation of Alkenes
Alkene I.P. (eV) Alkene Electron Transfer () Alkene Electron Transfer () Alkene Electron Transfer ()
Alkene I.P. (eV) Acetic acid (IP 10.65 eV) Acetic anhydride (IP 10.00 eV) Dimethyl Malonate (IP 9.2)
1-Hexene 9.65 0 - 0
Cyclohexene 8.95 0 - 0
p-Methylstyrene 8.20 6 - 0
b-Methystyrene 8.17 22 - 0
Indene 8.14 54 22 0
trans-Stillbene 8.00 96 75 0
Anethole 7.68 100 - 0
1,2-Diacetate Formation
Fristad, W. E. et al. Tetrahedron 1986, 42, 3429.
8
Mn(OAc)3Seminal Works
First Reported Reactions
Annulation to g-Lactone1,2
Annulation to 2,3-dihydrofuran3
Proposed Mechanism1,3
1 Bush, J. B. et al. J. Am. Chem. Soc. 1968, 90,
5903. 2 Heiba, E. I. et al. J. Am. Chem. Soc.
1968, 90, 5905. 3 Heiba, E. I. et al. J. Org.
Chem. 1974, 39, 3456.
9
Lactone AnnulationRate-Determining Step
Enolization Proposed as the Rate-Determining Step
R pKA (ester) Relative Rate
H 25 1.0
Cl 22 1.1 x 101
SO2Ph 14 3.8 x 103
CO2Me 13 1.1 x 104
CO2H 13 1.4 x 104
CN 9 4.0 x 105
Added Base Accelerates Lactone Formation
KOAc MnIII (equiv) Reaction Time Yield
0.005 2.5 23 h 67
0.010 2.5 gt12 h 78
0.500 2.0 7.5 h 85
3.050 2.0 1.3 h 81
Fristad, W. E. et al. J. Org. Chem. 1985, 50, 10.
10
Lactone AnnulationRate-Determining Step
Enolization of Carboxylic Acids
Acetic acid enol content negligible1
Mn(II) and Mn(III) have no effect on deuterium
incorporation2
Enolization of a Complexed Acetate
Conclusion
Enolization must occur irreversibly at a
complexed acetate2
1 Guthrie, J. P. et al. Can. J. Chem. 1995, 73,
1395. 2 Fristad, W. E. et al. Tetrahedron 1986,
42, 3429.
11
Lactone AnnulationRate-Determining Step
Rate-Determining Step is Substrate-Dependant
R R2 pKA Deuterium Incorporation
Me H 10.7 100 after 2 h _at_ 25C
Et Me 12.5 50 after 10 h _at_ 40C
R R2 IP Oxidation Time
Me H 9.2 56 h, 6-8 h (excess alkene)
Et Me 8.8 6-8 h, 6-8h (excess alkene)
Concerted Oxidation-Addition Proposed
Snider, B. B. et al. J. Org. Chem. 1988, 53, 2137.
12
Lactone AnnulationTermination
Secondary Carbocation Not a Predominant
Intermediate1,2
Fristad Radical Cyclization1
Snider MnIV Intermediate3
1 Fristad, W. E. et al. J. Org. Chem. 1985, 50,
10. 2 Davies, D. I. et al. J. Chem. Soc. Perkin
Trans. 1 1978, 227. 3 Snider, B. B. Chem. Rev.
1996, 96, 339.
Carbocations are generated from tertiary, alylic
and benzylic radicals.
13
Lactone Annulation Scope and Selectivity
g-Lactone Annulation Isnt Stereospecific
Reaction Scope
1 Fristad, W. E. et al. J. Org. Chem. 1985, 50,
10. 2 Fristad, W. E. et al. J. Org. Chem. 1985,
50, 3143.
14
Lactone Annulation Scope and Selectivity
g-Lactone Annulation Isnt Stereospecific
Reaction Scope
1 Fristad, W. E. et al. J. Org. Chem. 1985, 50,
10. 2 Fristad, W. E. et al. J. Org. Chem. 1985,
50, 3143.
15
Lactone AnnulationRadical Addition Selectivity
Relative Rate of Addition (Competition Study)1
Relevant Examples2,3
1 Heiba, E. I. et al. J. Am. Chem. Soc. 1968, 90,
5905. 2 Corey, E. J. et al. J. Am. Chem. Soc.
1993, 115, 8871. 3 Garda, C. Synth. Coomm. 1984,
14, 1191.
16
2,3-Dihydrofuran AnnulationReaction Scope
1 Heiba, E. I. et al. J. Org. Chem. 1974, 39,
3456. 2 Shi, M. et al. J. Org. Chem. 2005, 70,
3859. 3 Corey, E. J. et al. Chem. Lett. 1987,
223. 4 Mellor, J. M. et al. Tetrahedron 1993, 49,
7557. 5 Mellor, J. M. et al. Tetrahedron Lett.
1991, 7107.
Reaction yield depends mostly on the ease of
carbocation formation
17
2,3-Dihydrofuran AnnulationSynthetic Studies
Podophyllotoxin
Fristad, W. E. et al. Tetrahedron Lett. 1987, 28,
1493.
18
2,3-Dihydrofuran AnnulationChiral Auxiliaries
Oxazolidinone Auxiliaries
Scope Cleavage
Brun, F. et al. Tetrahedron Lett. 2000, 41, 9803.
19
TerminationGeneral Scheme
20
TerminationHydrogen Abstraction
Hydrogen Abstraction
Hydrogen abstraction predominates when primary or
secondary radicals are involved
Solvent HAA Rate
Acetic Acid 2 x 102 s-1M-1
Acetonitrile 3 x 102 s-1M-1
Ethanol 5.9 x 102 s-1M-1
Snider, B. B. et al. J. Org. Chem. 1991, 56,
5544. Snider, B. B. et al. J. Org. Chem. 1993,
58, 6217.
21
TerminationCupric Salts
Radical Oxidation by Cupric Salts1
Rate of Oxidation of Secondary Radicals2
Mn Relative Rate
MnIII 1
CeIV 12
CuII 350
1 Kochi, J. K. et al. J. Am. Chem. Soc. 1968, 90,
4616. 2 Heiba, E. I. et al. J. Am. Chem. Soc.
1971, 93, 524.
Rate of reaction between CuII and secondary
radicals 106 s-1M-1
22
TerminationCupric Salts
Oxidative Substitution
SN1-Like Substitution1
Applications in Lactone Annulation2
1 Kochi, J. K. et al. J. Am. Chem. Soc. 1968, 90,
4616. 2 Burton, J. W. et al. Chem. Comm. 2005,
4687.
23
TerminationCupric Salts
Oxidative Elimination
Concerted Elimination1
Follows Hofmann Rule, Stereoselective for
trans-Alkene2
1 Kochi, J. K. et al. J. Am. Chem. Soc. 1968, 90,
4616. 2 Snider, B. B. et al. J. Org. Chem. 1990,
55, 1965.
24
TerminationNitriles Carbon Monoxide
Nitriles1
Carbon Monoxide2
1 Snider, B. B. et al. J. Org. Chem. 1992, 57,
322. 2 Alper H. et al. J. Am. Chem. Soc.
1993,115, 1543.
25
CyclizationRadical Aromatic Substitution
Mechanism
Monocyclization Scope
Citterio, A. et al. J. Org. Chem. 1989, 54, 2713.
26
Radical Aromatic SubstitutionModel Studies
Tronocarpine
Synthesis of Tetrahydroindolizines
Synthesis of the Tronocarpine Skeleton
Kerr, M. A. et al. Org. Lett. 2006, ASAP.
27
CyclizationExo vs Endo Cyclization Mode
Diastereoselectivity (Beckwith-Houk Model)
5-exo 6-exo Cyclizations
Reversibility of Cyclization
Representative rates
k5-exo 2 x 105 s-1 k6-endo 4 x 103
s-1 k6-exo 5 x 103 s-1 k7-endo 7 x 102
s-1
kopen 1 x 104 s-1 kterm 3 x 106 s-1M-1
(Bu3SnH)
28
CyclizationExo vs Endo Cyclization Mode
Reversible Cyclization
Rate of Iodine Abstraction gt Rate of Ring Opening1
kI 2 x 109 s-1M-1
Rate of Hydrogen Abstraction lt Rate of Ring
Opening2
kopen 1 x 104 s-1
Rate of Oxidation gt Rate of Ring Opening3
kOx 1 x 106 s-1M-1
1 Halpern, J. Acc. Chem. Res. 1971, 4, 386. 2
Curran, D. P. et al. J. Org. Chem. 1989, 54,
3140. 3 Snider, B. B. J. Am. Chem. Soc. 1991,
113, 6609.
29
Hexenyl Radical Cyclization5-exo vs 6-endo
Cyclization Mode
Substrate Substrate Substrate Conditions Products Products Products Ref
R1 R2 R3 5-exo 6-endo X
H H H 4 Mn(OAc)3 Cu(OAc)2 - 94 - Peterson, J. R. et al. Tetrahedron Lett. 1987, 6109.
Me Me H 4 Mn(OAc)3 Cu(OAc)2 - 91 - Snider, B. B. et al. J. Org. Chem. 1989, 54, 38.
H H Me 2 Mn(OAc)3 Cu(OAc)2 21 5 Snider, B. B. et al. J. Org. Chem. 1985, 50, 3661.
H H Ph 2 Mn(OAc)3 70 - Peterson, J. R. et al. Tetrahedron Lett. 1987, 6109.
Baldwin Rules for sp2-sp2 cyclization
30
Hexenyl Radical Cyclization5-exo vs 6-endo
Cyclization Mode
Presence of heteroatoms favors 5-exo cyclization
mode
Snider, B. B. et al. Tetrahedron 1993, 49, 9447.
31
Hexenyl Radical CyclizationFormal Synthesis
Gibberelic Acid
Snider, B. B. et al. J. Org. Chem. 1987, 52,
5487. Snider, B. B. et al. J. Org. Chem. 1991,
55, 5544.
32
Hexenyl Radical Cyclization Model Studies
Nemorosone
Kraus, G. A. et al. Tetrahedron Lett. 2003, 44,
659. Kraus, G. A. et al. Tetrahedron 2003, 59,
8975.
33
Hexenyl Radical Cyclization Model Studies
Bilobalide
Corey, E. J. et al. J. Am. Chem. Soc. 1984, 106,
5384.
34
Hexenyl Radical Cyclization Synthesis
Podocarpic Acid
Snider, B. B. et al. J. Org. Chem. 1985, 50, 3659.
35
Todays Question(Beer Break)
Predict Diastereoselectivity of this Cyclization
(32 possible diastereoisomers!)
36
Hexenyl Radical Cyclization Synthesis
Isosteviol
Snider, B. B. et al. J. Org. Chem. 1998, 63, 7945.
37
Hexenyl Radical Cyclization Chiral Auxiliaries
Substrate Substrate Products Yield dr
- - -
- - -
- - -
B 28 96 4
B 28 96 4
A 44 100 0
A 44 100 0
B 90 93 7
B 90 93 7
A B 45 -
A B 45 -
Snider, B. B. et al. J. Org. Chem. 1991, 56, 328
J. Org. Chem. 1993, 58, 7640
38
Hexenyl Radical CyclizationChiral Auxiliaries
ß-Ketosulfoxide Auxiliary
Snider, B. B. et al. J. Org. Chem. 1991, 56, 328.
39
Hexenyl Radical CyclizationChiral Auxiliaries
Phenylmethyl and Pyrrolidine Auxiliaries
Selectivity difficult to rationalize with
tertiary radicals.
Porter, N, A, et al. J. Am. Chem. Soc. 1991, 113,
7002.
40
Hexenyl Radical CyclizationChiral Auxiliaries
Phenylmenthyl and Sultam-Based Auxiliaries
Similar example
Snider, B. B. et al. J. Org. Chem. 1993, 58,
7640. Zoretic, P. A. et al. Tetrahedron Lett.
1992, 33, 2637. Curran Porter Geise In
Stereochemistry of Radical Reactions,VCH
Weinheim, 1996, 198.
41
Heptenyl Radical Cyclization 6-exo vs 7-Endo
Cyclization Mode
Substrate Substrate Substrate Products Products Ref Ref
R R1 R2 6-exo 7-endo Ref Ref
Et H H 12 32 Snider Tetrahedron Lett. 1988, 29, 5209.
Me H Me - 68 Snider Tetrahedron 1991, 47, 8663.
Me Me Me 67 - - Snider J. Org. Chem. 1987, 52, 5487.
42
Heptenyl Radical Cyclization Synthesis Upial
epi-Upial
Snider Formal Synthesis1,2
Paquette 14-epi-Upial3
Snider, B. B. et al. Tetrahedron 1995, 51,
12983. Taschner, M. J. et al. J. Am. Chem. Soc.
1985, 107, 5570. Paquette, L. A. et al.
Tetrahedron 1987, 43, 5567.
43
Heptenyl Radical Cyclization Synthesis
Dihydropallescensin D
White, J. D. et al. Tetrahedron Lett. 1990, 31,
59.
44
Heptenyl Radical CyclizationSynthesis
Gymnomitrol
Application to the acetylene zipper reaction
Brown, C. A. et al. J. Am. Chem. Soc. 1975, 97,
891.
Snider, B. B. et al. J. Org. Chem. 1997, 62, 1970.
45
Oxidative Ring OpeningSynthesis Silphiperfolene
Snider, B. B. et al. J. Org. Chem. 1994, 59, 5419.
46
Summary

• Mn(OAc)3 is a unique one electron oxidant.
• There are no reliable equivalent to the one-step
  Mn(OAc)3-
• mediated lactone and dihydrofuran annulations.
• Cyclizations often exhibits very high
  selectivity.
• Selectivity observed with chiral auxiliaries
  arent well understood.
• Low yields and large amounts of by-products are
  common.