Diastereocontrol in Cyclic systems 2 Flashcards
Describe difference between cyclobutane and cyclobutene structures
- Cyclobutane is slightly puckered to relieve torsional strain
- Cyclobutene is planar
Describe nucleophilic addition to cyclobutanones
- Usually selective for attack on the C=O face opposite the C3 substituent, regardless of the nucleophile size - but selectivity higher for small nucs - alcohol on same side as substituent
- Akin to intrinsic preference for axial attack in cyclohexanones (small nucs)
- Less hindered than in the 6-ring case
Describe reaction of 4-membered ring cyclic enolates
- Strong preference for electrophile attack on the face opposite to a large substituent
- Electrophile opposite direction in product
What are the two low-energy conformations for cyclopentane
- Envelope and half chair
- Envelope is slightly favoured
- 5 atoms not equivalent unlike a cyclohexane chair - Rapid ring-flipping interconverts them
How does cyclopentane accomodate for substituents
- A single substituent prefers pseudoequatorial position of the envelope flap
- 1,3 cis more stable than 1,3 trans
How does cyclopentane accommodate for exocylclic double bonds
- Carbonyl or exo C=C prefers flat position on half-chair
- Tend to model as planar
How does cyclopentane accomodate for endocyclic double bonds
- Can only be accommodated at the end of the envelope- where all the atoms can be coplanar
- Alkenes, enolates and esters
- Esters have C-O in planar bit of envelope as C-O had partial double bond character
Describe selectivity of nucleophilic additions ot cyclopentanones
- Less predictable than cyclohexanones dues to lack of well-defined conformation
- Still tendency for small hydride donors to give axial reduction = equatorial alcohol and large to give equatorial = axial alcohol
Are cyclopentanones or cyclohexanones more reactive in carbonyl additions
- Cyclohexanones
- Cyclopentanones experience an increase in torsional strain during sp2-sp3 rehybridization
- Hexanones experience a decrease
- So if cyclohexanone and pentanone are attached nucleophile will attack hexanone
Describe selectivity in 4-substituted cyclopentenes electrophilic additions and why
- Occurs on opposite face to substituent
- Not to do with sterics as pseudo equatorial groups don’t present an effective steric blockade to either C=C face
- Reaction proceeds under torsional control with substituent pseudo equatorial and the electrophile adding to the top face to relieve torsional strain in the TS - Away from eclipse
Describe selectivity in 3-substituted cyclopentenes electrophilic additions and why
- Tend to add to same face as substituent
- Torsional steering again
3 Unless C3 group is very bulky then steric hindrance drives reaction to opposite face
What is self regeneration of stereocentres strategy
- Relies on temporary stereogenic centre allowing the original stereo centre to be destroyed and then reset diastereoselectivity
- Produces good selectivity where would be very hard otherwise
What are substrate directed reactions
- In some reactions reagents preassociate with polar functional groups in the vicinity of the reaction centre
- Such reactions which are attractive rather than repulsive frequently provide a stereochemical outcome which is opposite to that predicted on steric effects alone
What does pre-association often involve
- Hydrogen bonding
- Covalent
- Lewis acid-base interactions
- Maintained in the TS for the reaction
What is a classic example of a substrate-directed reaction
- hydroxyl-directed cyclopropanation
- hydroxyl-directed epoxidation
Describe hydroxyl-directed cyclopropanation
- A zinc carbenoid species reacts initially at the hydroxyl group of an allylic alcohol
- Followed by intramolecular carbene delivery
- Results in product where alcohol and carbon triangle thing are on same side
Describe hydroxyl-directed epoxidation
- Epoxidation of cyclic allylic alcohols by peracids
- hydroxyl group delivers the oxidant to the syn face of the alkene via hydrogen bonding
What is most reactive conformer of an allylic alcohol
- One with pseudoequatorial hydroxyl group
- When OH is axial, the anomeric interaction in the pseudoaxial isomer renders the C=C bond less reactive
- It stabilises the molecule but loses energy of Pi-bond so makes it less reactive to electrophiles
When might epoxidation occur mainly on the anti face
- For O-protected substrates
- Under steric control
- Selectivity can be moderate
What other molecules apart from allylic alcohols can undergo substrate-directed reactions by hydrogen-bonding
- Cyclic allylic amines undergo hydrogen bond-directed epoxidation
- First need to be protonated on nitrogen to give corresponding ammonium salt
- This also suppresses competing N-oxidation
How can hydrogenation of alkenes be substrate-directed
- Homogenous hydrogenations of alkenes can be substrate-directed by using cationic irdium (or rhodium) catalysts
- These associate with a wide range of polar functionality by Lewis acid-base interactions
- Hydrogens added syn to each other and to DG?
What directing groups does the substrate directed Homogenous hydrogenations of alkenes using cationic irdium (or rhodium) catalysts work for
- Methoxy
- free esters
- Alcohol
- amides
- All give v good selectivity
What are the different substrate directed reactiosn
- Hydroxyl-directed cyclopropanation of allylic alcohols
- hydroxyl-directed epoxidation of allylic alcohols
- Epoxidation of cyclic allylic amines by H-bonding
- Hydrogenation of alkenes by Lewis-base interactions - Rh or Ir catalyst
What are the different types of bicyclic ring systems
- Spiro bicycle
- Fused bicycle
- Bridged bicylce
Describe spirocycles
- Very common in natural products and drugs
- Not flat
- The spiro atom introduces a twist into the structure due to the tetrahedral bonding around carbon
What are spiroketals
- Subset of spirocycles
- Intrinsically chiral structures
Which conformation of spiroketals is the most stable
- When the O groups are both axial to the other ring
- 2 Anomeric effects
Describe ring flipping in trans-fused bicycles
- It is impossible
- Too strained
- Rigid structure
Are trans or cis-decalins favoured
- Trans-decalins are more stable than cis-decalins
- If reaction has choice it will form trans-decalin
Describe stereoselectivity of additions of trans-decalin enolates
- If axial substituent on ring fusion is hydrogen then axial attack of the electrophile is kinetically favoured due to slight amount of chair character in TS
- Enolate alkylations have early TSs so if axial substituent is methyl steric interactions drive the alkylation to the opposite face
Describe reactions on cis-fused bicyclic systems
- Undergo highly face-selective reactions
- Controlled simply by attack on the less-hindered face
What are the terms for faces in cis-fused bicyclic systems
- Convex - accessible
- Concave - hindered
Describe reactions for fused systems containing C=C at the fusion
- Similar for cis-fused bicyclic
- Convex faces are accessible
Describe reactions for bridged bicyclic systems
- Steric restrained imposed by bridged bicyclic systems can lead to highly stereoselective transformations
- with additions generally occurring from the less-hindered face- shortest bridge side unless there are substituents on the short bridge
What does the endo and exo face in bridged systems mean
- Endo= substituent syn to longest bridge e.g 3 carbon over 2 carbon bridge
- Exo= substituent anti to longest bridge
What is another explanation for why bridged bicyclic systems like norbornene or bridged ketone undergo highly selective exo attack
- Better explanation is torsional control
- Developing torsional interactions in the TS are minimised
How can cyclic compounds be used to solve other problems
- Stereoselectivity in cyclic compounds is well understood - used to solve problems in acyclic systems
- Make stereochemically complex acyclic molecules to use a cyclic template to set all the stereocentres
- Then cleave open the ring at the last minute to reveal the acyclic compound
- Used in antibiotic erythronolide B
