Diastereocontrol in Cyclic systems 2

Question 1

Describe difference between cyclobutane and cyclobutene structures

Answer 1

1. Cyclobutane is slightly puckered to relieve torsional strain
2. Cyclobutene is planar

Question 2

Describe nucleophilic addition to cyclobutanones

Answer 2

1. 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
2. Akin to intrinsic preference for axial attack in cyclohexanones (small nucs)
3. Less hindered than in the 6-ring case

Question 3

Describe reaction of 4-membered ring cyclic enolates

Answer 3

1. Strong preference for electrophile attack on the face opposite to a large substituent
2. Electrophile opposite direction in product

Question 4

What are the two low-energy conformations for cyclopentane

Answer 4

1. Envelope and half chair
2. Envelope is slightly favoured
3. 5 atoms not equivalent unlike a cyclohexane chair - Rapid ring-flipping interconverts them

Question 5

How does cyclopentane accomodate for substituents

Answer 5

1. A single substituent prefers pseudoequatorial position of the envelope flap
2. 1,3 cis more stable than 1,3 trans

Question 6

How does cyclopentane accommodate for exocylclic double bonds

Answer 6

1. Carbonyl or exo C=C prefers flat position on half-chair
2. Tend to model as planar

Question 7

How does cyclopentane accomodate for endocyclic double bonds

Answer 7

1. Can only be accommodated at the end of the envelope- where all the atoms can be coplanar
2. Alkenes, enolates and esters
3. Esters have C-O in planar bit of envelope as C-O had partial double bond character

Question 8

Describe selectivity of nucleophilic additions ot cyclopentanones

Answer 8

1. Less predictable than cyclohexanones dues to lack of well-defined conformation
2. Still tendency for small hydride donors to give axial reduction = equatorial alcohol and large to give equatorial = axial alcohol

Question 9

Are cyclopentanones or cyclohexanones more reactive in carbonyl additions

Answer 9

1. Cyclohexanones
2. Cyclopentanones experience an increase in torsional strain during sp2-sp3 rehybridization
3. Hexanones experience a decrease
4. So if cyclohexanone and pentanone are attached nucleophile will attack hexanone

Question 10

Describe selectivity in 4-substituted cyclopentenes electrophilic additions and why

Answer 10

1. Occurs on opposite face to substituent
2. Not to do with sterics as pseudo equatorial groups don’t present an effective steric blockade to either C=C face
3. 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

Question 11

Describe selectivity in 3-substituted cyclopentenes electrophilic additions and why

Answer 11

1. Tend to add to same face as substituent
2. Torsional steering again
   3 Unless C3 group is very bulky then steric hindrance drives reaction to opposite face

Question 12

What is self regeneration of stereocentres strategy

Answer 12

1. Relies on temporary stereogenic centre allowing the original stereo centre to be destroyed and then reset diastereoselectivity
2. Produces good selectivity where would be very hard otherwise

Question 13

What are substrate directed reactions

Answer 13

1. In some reactions reagents preassociate with polar functional groups in the vicinity of the reaction centre
2. Such reactions which are attractive rather than repulsive frequently provide a stereochemical outcome which is opposite to that predicted on steric effects alone

Question 14

What does pre-association often involve

Answer 14

1. Hydrogen bonding
2. Covalent
3. Lewis acid-base interactions
4. Maintained in the TS for the reaction

Question 15

What is a classic example of a substrate-directed reaction

Answer 15

1. hydroxyl-directed cyclopropanation
2. hydroxyl-directed epoxidation

Question 16

Describe hydroxyl-directed cyclopropanation

Answer 16

1. A zinc carbenoid species reacts initially at the hydroxyl group of an allylic alcohol
2. Followed by intramolecular carbene delivery
3. Results in product where alcohol and carbon triangle thing are on same side

Question 17

Describe hydroxyl-directed epoxidation

Answer 17

1. Epoxidation of cyclic allylic alcohols by peracids
2. hydroxyl group delivers the oxidant to the syn face of the alkene via hydrogen bonding

Question 18

What is most reactive conformer of an allylic alcohol

Answer 18

1. One with pseudoequatorial hydroxyl group
2. When OH is axial, the anomeric interaction in the pseudoaxial isomer renders the C=C bond less reactive
3. It stabilises the molecule but loses energy of Pi-bond so makes it less reactive to electrophiles

Question 19

When might epoxidation occur mainly on the anti face

Answer 19

1. For O-protected substrates
2. Under steric control
3. Selectivity can be moderate

Question 20

What other molecules apart from allylic alcohols can undergo substrate-directed reactions by hydrogen-bonding

Answer 20

1. Cyclic allylic amines undergo hydrogen bond-directed epoxidation
2. First need to be protonated on nitrogen to give corresponding ammonium salt
3. This also suppresses competing N-oxidation

Question 21

How can hydrogenation of alkenes be substrate-directed

Answer 21

1. Homogenous hydrogenations of alkenes can be substrate-directed by using cationic irdium (or rhodium) catalysts
2. These associate with a wide range of polar functionality by Lewis acid-base interactions
3. Hydrogens added syn to each other and to DG?

Question 22

What directing groups does the substrate directed Homogenous hydrogenations of alkenes using cationic irdium (or rhodium) catalysts work for

Answer 22

1. Methoxy
2. free esters
3. Alcohol
4. amides
5. All give v good selectivity

Question 23

What are the different substrate directed reactiosn

Answer 23

1. Hydroxyl-directed cyclopropanation of allylic alcohols
2. hydroxyl-directed epoxidation of allylic alcohols
3. Epoxidation of cyclic allylic amines by H-bonding
4. Hydrogenation of alkenes by Lewis-base interactions - Rh or Ir catalyst

Question 24

What are the different types of bicyclic ring systems

Answer 24

1. Spiro bicycle
2. Fused bicycle
3. Bridged bicylce

Question 25

Describe spirocycles

Answer 25

1. Very common in natural products and drugs
2. Not flat
3. The spiro atom introduces a twist into the structure due to the tetrahedral bonding around carbon

Question 26

What are spiroketals

Answer 26

1. Subset of spirocycles
2. Intrinsically chiral structures

Question 27

Which conformation of spiroketals is the most stable

Answer 27

1. When the O groups are both axial to the other ring
2. 2 Anomeric effects

Question 28

Describe ring flipping in trans-fused bicycles

Answer 28

1. It is impossible
2. Too strained
3. Rigid structure

Question 29

Are trans or cis-decalins favoured

Answer 29

1. Trans-decalins are more stable than cis-decalins
2. If reaction has choice it will form trans-decalin

Question 30

Describe stereoselectivity of additions of trans-decalin enolates

Answer 30

1. 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
2. Enolate alkylations have early TSs so if axial substituent is methyl steric interactions drive the alkylation to the opposite face

Question 31

Describe reactions on cis-fused bicyclic systems

Answer 31

1. Undergo highly face-selective reactions
2. Controlled simply by attack on the less-hindered face

Question 32

What are the terms for faces in cis-fused bicyclic systems

Answer 32

1. Convex - accessible
2. Concave - hindered

Question 33

Describe reactions for fused systems containing C=C at the fusion

Answer 33

1. Similar for cis-fused bicyclic
2. Convex faces are accessible

Question 34

Describe reactions for bridged bicyclic systems

Answer 34

1. Steric restrained imposed by bridged bicyclic systems can lead to highly stereoselective transformations
2. with additions generally occurring from the less-hindered face- shortest bridge side unless there are substituents on the short bridge

Question 35

What does the endo and exo face in bridged systems mean

Answer 35

1. Endo= substituent syn to longest bridge e.g 3 carbon over 2 carbon bridge
2. Exo= substituent anti to longest bridge

Question 36

What is another explanation for why bridged bicyclic systems like norbornene or bridged ketone undergo highly selective exo attack

Answer 36

1. Better explanation is torsional control
2. Developing torsional interactions in the TS are minimised

Question 37

How can cyclic compounds be used to solve other problems

Answer 37

1. Stereoselectivity in cyclic compounds is well understood - used to solve problems in acyclic systems
2. Make stereochemically complex acyclic molecules to use a cyclic template to set all the stereocentres
3. Then cleave open the ring at the last minute to reveal the acyclic compound
4. Used in antibiotic erythronolide B