User:Benjah-bmm27/degree/4/CLW

Revision of previously encountered selective reactions

Chemoselectivity

• As an example of chemoselectivity (selectivity between different functional groups), consider reduction of carbonyl compounds with metal hydrides
• NaBH₄ is very mild and reduces ketones in the presence of esters
• LiAlH₄ reduces both ketones and esters
• In a keto-ester: (i) protect the ketone with ethylene glycol and H⁺, (ii) reduce the ester with LiAlH₄, then (iii) deprotect with H⁺/H₂O
• It's preferable to avoid protecting groups wherever possible

Regioselectivity

• As an example of regioselectivity (selectivity between parts of the same functional group), consider addition of carbon nucleophiles to enones
• Hard nucleophiles like MeLi undergo direct addition (1,2-addition) to the carbonyl carbon, forming an alcohol
• Soft nucleophiles like Me₂CuLi undergo conjugate addition (1,4-addition, Michael reaction) to the β carbon, forming ketone

Stereoselectivity

• As an example of stereoselectivity (control over stereochemistry), consider epoxidation of a chiral cyclic allylic alcohol with mCPBA
• Option 1: Don't protect the OH group
  • the OH group forms a hydrogen bond to mCPBA – chelation control
  • mCPBA delivers an oxygen atom to the top (hydroxy) face of the unprotected allylic alcohol
• Option 2: Protect the OH group with Ac₂O/py to get a chiral allylic acetate
  • mCPBA delivers an oxygen atom to the bottom (unblocked) face of the allylic acetate

Selective reductions with boron and aluminium reagents

DIBALH

Selective reduction of esters to aldehydes

• Diisobutylaluminium hydride (DIBALH) is less flammable and easier to use than LiAlH₄
• It selectively reduces esters to aldehydes, if the reaction is conducted at −70 °C
• An ester oxygen coordinates to Al, then hydride migrates from Al to C
• The tetrahedral intermediate is stable at low temperature, and can be worked up with H⁺/H₂O to the aldehyde
• Yields well over 90% when done properly

Reduction of nitriles to aldehydes

• Same conditions as above, proceeds via the imine which is then hydrolysed

Borane

• Used in Et₂O or THF solution or as the Me₂S complex

Asymmetric (CBS) reduction

• Corey-Bakshi-Shibata reduction (see APD Level 3 Asymmetric synthesis)
• Uses the CBS catalyst
• Hydride attack from the Si face
• E.e. around 97%
• Chair transition state, large group occupying an equatorial position determines the stereoselectivity
• E. J. Corey, R. K. Bakshi, S. Shibata, J. Am. Chem. Soc. (1987) 109, 5551–5553

L-selectride

• Stereoselective reduction of cyclohexanones with the bulky reagent L-selectride, Li[HB(sBu)₃]
• Small nucleophiles like LiAlH₄ prefer axial attack (OH group ends up equatorial rather than axial – the thermodynamic product)
• Bulky nucleophiles likes Li[HB(sBu)₃] prefer equatorial attack to avoid steric clash with 1,3-hydrogens (OH group ends up axial – the kinetic product)

Rearrangements

Pericyclic rearrangements

• Claisen rearrangement: forms aldehydes
  • Johnson-Claisen rearrangement:forms esters
  • Ireland-Claisen rearrangement: forms acids
  • Eschenmoser-Claisen rearrangement: forms amides

To be added

• Evans–Saksena reduction
• Yamaguchi esterification
• Still-Gennari reaction
• Pinnick oxidation
• Dess-Martin periodinane