chiral aldols: examining chiral auxiliaries as the …...zimmerman-traxler six-membered transition...

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Chiral Aldols: Examining Chiral Auxiliaries as the

Superior Method

Spencer Knight, Dave McLeod, Sam Kalirai Marlena Whinton

The reason for using chiral auxilaries is to obtain not just a specific Diastereomer, but a specific enantiomer.

Mechanistic View of the Aldol

Mahrwald, R. Aldol Reactions, Springer-Science: (2009), New York, pp. 27.

Evans Syn

Chiral Auxilaries outweigh any effects produced by α-induction

Polar Felkin-Ahn Vs. Cornforth Model

PFA Model

Cornforth Model

PFA Model is based on transition-state stabilization. This occurs through hyperconjugation of the Homo of the forming bond with the best viscinal acceptor.

α-Heteroatom Induction

Evans, D. A., Angew. Chem. Int. Ed. 2003, 42, pp. 1761.

Cornforth model is based on dipole minimization between the C-X bond and that of the carbonyl.

Zimmerman-Traxler Six-Membered Transition States

Dis-favoured

Favoured

Mahrwald, R. Aldol Reactions, Springer-Science: (2009), New York, pp. 3.

Chair Vs. Twist BoatChair vs. Twist Boat Transition States

The chair transition states come from the Z-enolate while the twist boat is derived from the E-enolate.

Reference

Open vs. Chelating Transition States

The chair transition states come from the Z-enolate while the twist boat is derived from the E-enolate.

Mahrwald, R. Aldol Reactions, Springer-Science: (2009), New York, pp. 7.

Effect of Metal and Conditions on Aldol Products

Mahrwald, R. Aldol Reactions, Springer-Science: (2009), New York, pp. 4.

Conditions Solvent Configuration (Z:E)

1:2 Yield [%]

9-BBNOTf, DIPEA EtO2 95:05 94:06 82

(c-Hex)2BCl, TEA EtO2 07:93 04:96 79

Curtin-Hammett: If two transition states are inter-convertible, the ratio between them is solely based on the stability of the two products, not the equilibrium between them.

Kinetic vs. Thermodynamic Control

Evans, D. A., Angew. Chem. Int. Ed. 2003, 42, pp. 1761.

Esters produce mainly E-enolates while aldehydes and ketones produce mainyl Z-enolates. HMPT is used to form the opposite enolate.

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Variations of Chiral Aldol Processes

Aldol: Evans Oxazolidinone Auxiliary

Absolute Stereo Control

Relative Stereo Control

Evans Syn

Non-Evans Syn Non-Evans Anti

Evans Anti

Masamune Norephedrine Aldol Mukaiyama Aldol

Syn

Anti

There are innumerous variations. For the sake of time, we will look at those variations that give us absolute stereocontrol within the framework of Evans Oxazolidinone Chiral Auxiliaries

Reaction Conditions and Reagents

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Variations of Chiral Aldol Processes – Boron Enolates

Although Boron Enolates generally direct to the (Z) stereoisomers (favouring syn), the effect of the ligands can drive the enolate intermediate to (E) stereochemistry (favouring anti enantiope)

Mahrwald, R. Aldol Reactions, Springer-Science: (2009), New York, pp. 130-133.

Evans, D. A., J. Am. Chem. Soc. 1981, 103(11), pp. 3099-3111.

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Variations of Chiral Aldol Processes - Syn

Crimmins, M.T., J. Am. Chem. Soc. 1997, 119, 7883-4

Titanium Enolates of N-Acyloxazolidithiones: variations of amine base and lewis acid stoichiometry

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Variations of Chiral Aldol Processes - Syn

Titanium Enolates of Acyloxazolidinethiones: proposed mechanism: Zimmerman-Traxler TS Model

Crimmins, M.T., J. Am. Chem. Soc. 1997, 119, 7883-4Crimmins, M.T., Org. Lett. 2007, 9(1), 149-152

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Variations of Chiral Aldol Processes - Anti

Relative Stereocontrol via chelation control

Restricted to Non-enolizable aldehydes (McNulty & Nair broke that notion)Evans, D.A., J. Am. Chem. Soc. 2002, 184(3), pp. 392-393Evans, D.A., Org. Lett. 2002 4(7), pp. 1127-1131

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Variations of Chiral Aldol Processes - Anti

Auxiliary Chelation Leads to Non-Evans Anti

Restricted to Non-enolizable aldehydes (McNulty & Nair broke that notion)Evans, D.A., J. Am. Chem. Soc. 2002, 184(3), pp. 392-393Evans, D.A., Org. Lett. 2002 4(7), pp. 1127-1131

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Variations of Chiral Aldol Processes - Aside

McNulty, J, Nair, J.J., Eur. J. Org. Chem. 2007, 5669-5673

• natural product precursor to erythromycin antibiotic•requires syn selective and distereoselective synthesis•Evans aldol has excellent syn distereoselectivity with high enantiomeric excess

1) 6-Deoxyerythronolide

Problems Solved Using Chiral Auxiliaries

Nature Chemistry. Volume 1. 549. 2009

• Syn control achieved through the use of a chiral oxazolidinone and boron enolate

O

Evans Syn

Employing Syn Selectivity

Nature Chemistry. Volume 1. 549. 2009

•Another Evans reaction was performed to

•The chirality on the auxiliary is changed to

obtain the other enantiomer (Non-Evans Syn)

Non-Evans Syn

Nature Chemistry. Volume 1. 549. 2009

A B

•Previous compound under went a Myers’ alkylation-reduction-oxidation sequence to obtain compound A

•Compound A undergoes another Evans aldol reaction using a titanium reagent to obtain Evans Syns distereoselectivity

Distereoselectively Building the Backbone

Nature Chemistry. Volume 1. 549. 2009

• Steric difference between enolate and aldehyde afford high syn selectivity with high diastereomeric excess

• The Evans method can produce both diastereomer syn products by changing the reagents or by altering the chirality of the oxazolidinone auxiliary

• Easy removal and change of the oxazolidinone auxiliary to obtain either Evans Syn or Non-Evans syn product

Why Evans Auxiliary was the Smart Choice

2) Premonensin

Need Syn Selectivity

Examining Another Problem

•Intermediate compound for monensin•monensin is an antiobiotic

Reference: Evans, DiMare. J Am. Chem. Soc. 1986. 108, 9, 2476

This requires syn selectivity

The Disconnection

Reference: Evans, DiMare. J Am. Chem. Soc. 1986. 108, 9, 2476

Sn(OTf)2; N-ethylpiperidine; CH2Cl2; -78ºC

•Chiral auxiliary and Tin reagent allow for distereoselectivity•37:1 ratio of distereomers and 94% yield

Reference: Evans, DiMare. J Am. Chem. Soc. 1986. 108, 9, 2476

1. “The Mukaiyama Aldol Reaction”

2. Organocatalysis

3. Biological Catalysis

Competing Reactions

4. Inorganic catalysis

• Lack of steric difference between enolate and aldehyde make stereo control more difficult

• Requires isolation and separate synthesis of activated silyl enolate

• Low yields (50%-80%) when compared to using oxazolidinone auxiliary

• 3:1 Syn:Anti Ratio (not as selective)

• Selectivity highly dependent on the enolate and the type of lewis acid used

The Mukaiyama Aldol Reaction

+1) TiCl4

CH2Cl2

2) H2O

C h e m . S o c . R e v . , 2 0 0 4 , 3 3 , 6 5 – 7 5

•Enzyme - Biological catalyst • Doesn’t work on a wide range of substrates• Low yields• Expensive

Proline Catalysis

Aldolase Catalysis

•Organocatalysis •Large amounts of proline required•aromatic aldehydes has low enantioselecitivity •preferentially anti selective

C h e m . S o c . R e v . , 2 0 0 4 , 3 3 , 6 5 – 7 5

• Metal complex catalysts (i.e. zirconium catalyst)

• Direct aldol approach

• limited carbonyl donors (methyl ketones) need to be used in excess

• aromatic and unbranched aldehydes have the lowest efficiency for the reaction

• only moderate yields and selectivity

Inorganic Catalysis

C h e m . S o c . R e v . , 2 0 0 4 , 3 3 , 6 5 – 7 5

Applications in Total Synthesis

Countless applications in organic synthesis

Chiral aldol = stereogenically controlled diols, triols, ethers etc.

Stereogenic control can produce biologically active molecules with antifungal and/or cytotoxic applications.

Control of the stereoselectivity of these reactions is essential for producing the biological activity of the molecule.

Chiral aldol reactions can produce both syn- and anti- reaction products according to what is required for biological activity.

Opens the door for the synthesis of many incredibly useful and biologically active natural products.

Synthetic Example

Microsclerodermins: antitumor and antifungal cyclic peptide family-Microscleroderma (Deep Sea Marine Sponge)-Cytotoxicity to human carcinoma cell line HCT-116-Antifungal activity against Candida albicans-No sufficient extraction methods from Sponge, natural product synthesis is necessary

Microsclerodermins:

Burnett, C.M. and Williams, R.M. Tet. Letters 50. 2009, 5449-5451

Retrosynthesis of Biologically Active Centre

Burnett, C.M. and Williams, R.M. Tet. Letters 50. 2009, 5449-5451

1 2

3

4

TARGET

Synthesis of Chiral Target 4 Analogue (Evans syn-)

Burnett, C.M. and Williams, R.M. Tet. Letters 50. 2009, 5449-5451

Substrate

Chiral Auxiliary

Synthesis of Chiral Target 4 Analogue (Non-Evans syn-)

Burnett, C.M. and Williams, R.M. Tet. Letters 50. 2009, 5449-5451

Andrus’ modified Masamune norephedrine

Synthesis of Chiral Target 4 Analogue (Evans syn-)

Burnett, C.M. and Williams, R.M. Tet. Letters 50. 2009, 5449-5451

Synthesis of Chiral Target 2 Analogue (Evans syn-)

Burnett, C.M. and Williams, R.M. Tet. Letters 50. 2009, 5449-5451

Synthesis of Chiral Target 3 Analogue (Evans syn-)

Burnett, C.M. and Williams, R.M. Tet. Letters 50. 2009, 5449-5451

Completed Synthesis of Chiral Target 1

Burnett, C.M. and Williams, R.M. Tet. Letters 50. 2009, 5449-5451