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
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