Seminar

Non-Enzymatic Enantioselective Polyene Cyclizations Adam Hill Chem 535 May, 2nd 2013

Enantioselective Polyene Cyclization

(?) General Method to Rapidly Build Molecular Complexity

(+) Exquisite Stereo- and Regio- Control (-) Single Substrate

Methods for Polyene Cyclization Squalene Cyclase Mechanism:

Chiral Bronsted Acid Catalysis:

Transition Metal Catalysis:

Organocatalysis:

Squalene Cyclization

2,3-Oxidosqualene Cyclization Mechanism

Stork-Eschenmoser Hypothesis Stork Studies:

Eschenmoser Studies:

Cyclization occurs by stereospecific and concerted anti-addition Gamboni, G.; Schinz, H.; Eschenmoser, A. Helv. Chima. Acta 1954, 37, 964

Concerted A-Ring Formation

Relative Rates of Cyclization:

15

2.4

1

Epoxide protonation and A-ring closure occurs by a concerted anti-addition

Corey, E.J.; Cheng, H.; Baker, C.H.; Matsuda, S.P.T.; Li, D.; Song, X. J. Am. Chem. Soc. 1997, 119, 1277-1288

B- and C-Ring Cyclization

Cyclization of Truncated Oxidosqualene Analogs:

C-ring closure gives a 6-6-5 system which rearranges to the 6-6-6 system in lanosterol

Corey, E.J.; Virgil, S.C.; Cheng, H.; Baker, C.H.; Matsuda, S.P.T.; Singh, V.; Sarshar, S. J. Am. Chem. Soc. 1995, 117, 11819-11820

C-Ring Expansion and Elimination to Lanosterol


Squalene Cyclization Mechanism


Conformational Restriction of Squalene

2-azasqualene bound to oxidoqualene cyclase Reinert, D.J.; Balliano, G.; Schulz G.E. Chem. Biol. 2004, 11, 121-126

Cation-Stabilization by Squalene Cyclase Mutagenesis Studies

Hopene overlaid on SHC active site

E.J. Corey; Cheng, H.; Baker, H.; Matsuda, S.P.T.; Li, D.; Song, X. J. Am. Chem. Soc. 1997, 119, 1289 Wendt, K.U.; Schulz, G.E.; Corey, E.J.; Liu, D.R. Angew. Chem. Int. Ed. 2000, 39, 2812-2833










Organocatalysis:

Three Roles of Cyclase: •

Enantioselective A ring formation

•

Stabilization of the developing positive charge

•

Conformation control of the linear precursor




Organocatalysis:

Lewis Acid-Assisted Chiral Bronsted Acid (LBA) First example of an enantioselective biomimetic cyclization:

Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 4906-4907

Lewis Acid-Assisted Chiral Bronsted Acid (LBA) Enantioselective Cyclization via Formal [1,3]-rearrangement:

Mechanism of the Formal [1,3]-rearrangement:

Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 4906-4907

Mechanism of LBA catalysis

Entry

Bronsted Acid R1 = R2 =

Yield

ee

1

-

-

89%

racemic

2

R1 = OMe

R2 = Me

83%

racemic

3

R1 = OMe

R2 = OMe

65%

racemic

4

R1 = OH

R2 = Me

83%

46%

5

R1 = OH

R2 = Bz

98%

79%

SnCl4 Catalyzed Cyclization LBA Catalyzed Cyclization

Hydroxyl group is required for asymmetric cyclization

Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8131-8140

Mechanism of LBA catalysis

= 1 equiv LBA = 0.2 equiv LBA

Product inhibition lowers ee when R-BINOL-Bz is used catalytically Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8131-8140

Calculated Transition Structure for LBA with 2-methyl-2-butene

Major Enantiomer Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2000, 122, 8131-8140

Minor Enantiomer

Natural Product Synthesis Using LBA Total Synthesis of (-)-Chromazonarol:

Total Synthesis of (-)-11’-Deoxytanodiol methyl ether:

Ishibashi, H.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 11122-11123

LBA Using Antimony Lewis Acids

4 examples 70% - 80% yield, 87% - 92% ee

4 examples 70% - 78% yield, 84% - 90% ee Surendra, K.; Corey, E.J. J. Am. Chem. Soc. 2012, 134, 11992-11994

pre-transition state assembly:



(+) Enantioselective cyclizationOrganocatalysis: of the first ring


(-) No stabilization of developing cationic charge

(-) Requires low temperatures and long reaction times to control substrate conformation




Organocatalysis:

Platinum Catalyzed Cyclization

Proposed Catalytic Cycle:

Single turnover observed without trityl cation

Catalyst resting state shows a single agostic complex

Mullen, C.A.; Gagne, M.R. J. Am. Chem. Soc. 2007, 129, 11880-11881

Pt Catalyzed Polyene Cyclization

Chiral Ligand Screen:

Large aryl groups in a non-BINAP derived bisphosphine ligands gave the highest enantioselectivity

Mullen, C.A.; Campbell, A.N.; Gagne, M.R. Angew. Chemie. Int. Ed. 2008, 47, 6011-6014

Scope

Mullen, C.A.; Campbell, A.N.; Gagne, M.R. Angew. Chemie. Int. Ed. 2008, 47, 6011-6014

C3-Functionalization Post Catalytic Cycle

Proposed Catalytic Cycle: Scope: 10 examples: 55% - 65% yield and 70%-80% ee

• Possible method to install fluorine into steroid-like frameworks • Other Pt-C bond functionalization may be possible

Cochrane, N.A.; Nguyen, H.; Gagne, M.R. J. Am. Chem. Soc. 2013, 135, 628-631

Alkyne Activation via Gold Catalysis

Chiral Ligand Screen:

Solvent Screen: Entry

Solvent

Yield

ee

1

CH2Cl2

71%

46%

2

benzene

76%

83%

3

toluene

77%

85%

4

m-xylene

76%

87%

*Using (R)-MeO-DTB-BIPHEP

Sethofer, S.G.; Mayer, T.; Toste, D.E. J. Am. Chem. Soc. 2010, 132, 8276-8277

Alkyne Activation via Gold Catalysis

Substrate Scope:

Sethofer, S.G.; Mayer, T.; Toste, D.E. J. Am. Chem. Soc. 2010, 132, 8276-8277

Ir-Catalyzed Activation of Allylic Alcohols

Reaction Optimization: Entry Promoter

Solvent

Yield

ee

1

P(O)(OBu)2OH

DCE

42%

89%

2

TfOH

DCE

12%

81%

3

Sc(OTf)3

DCE

91%

80%

4

Zn(OTf)2

DCE

90%

>99.5%

5

Zn(OTf)2

dioxane

8%

>99.5%

6

Zn(OTf)2

DMF

n.r.

-

Schafroth, M.A.; Sarlah, D.; Krautwald, S.; Carreira, E.M. J. Am. Chem. Soc. 2012, 134, 20276-20278

Scope of Ir-Catalyzed Cyclization

Heteroaryl Terminating Groups:

Successful heteroaryl termination of cation-olefin cyclization


Ir-Catalyzed Tricyclization





Organocatalysis:

(+) Increased enantioselectivities over chiral Bronsted acid catalysis (-) No mechanism by which to prevent early termination




Organocatalysis:

Phosphoramidite Catalyzed Halocyclization

Racemic Cyclization:

Sakakura, A.; Ukai, A.; Ishihara, K. Nature, 2007, 445, 900-903

Entry

Nucleophile

Yield (%)

1

-

3

2

DMAP

0

3

PPh3

67

4

PBu3

99

Phosphoramidite Catalyzed Halocyclization

Chiral Phosphoramidite Screen:

Scope: 4 examples: 50%-60% yield, 90 -95% ee Sakakura, A.; Ukai, A.; Ishihara, K. Nature, 2007, 445, 900-903

Organo-SOMO Catalysis

Rendler, S.; MacMillan, D.W.C. J. Am. Chem. Soc. 2010, 132, 5027-5029

Organo-SOMO Catalysis

Entry

Catalyst

Additive

Solvent

Yield (%)

ee (%)

1

Ar = Ph

-

MeCN

11

34

2

Ar = Ph

TFA

MeCN

16

35

3*

Ar = Ph

TFA

MeCN

42

42

4*

Ar = 1-Np

TFA

MeCN

56

74

5*

Ar = 1-Np

TFA

i-PrCN/DME

54

87

*with slow addition of Cu(OTf)2


Scope


Thiourea Catalysis

Catalyst Optimization:

Knowles, R.R.; Lin, S.; Jacobsen, E.N. J. Am. Chem. Soc. 2010, 132, 5030-5032

Thiourea Catalysis

Reaction Scope:


Eyring Analysis

Catalyst Structures:





Organocatalysis:

(+) Aryl groups may provide a mechanism to prevent early termination (-) Requires contrived substrates or exotic activating groups




Organocatalysis:

Future Directions Chiral Anion Catalysis:

Cavitand Based Catalysts:

Chiral Anion Catalysis: Hamilton, G.L.; Kang, E.J.; Toste, F.D. Science, 2007, 317, 496 Cavitands in epoxide opening cascades: Pinacho Crisostomo, F.R.; Lledo, A.; Shenoy, S.R.; Iwasawa, T.; Rebek, J. J. Am. Chem. Soc. 2009, 131, 7402-7410

Acknowledgements CHEM 535 Class Professor Zimmerman Burke Group Professor Burke