by Dr. Dorian Didier

Office: F 3.080 [email protected] Lab: F 2.064

Dorian Didier Research Group DidierResearchGroup 1 0 Table of contents by D. Didier (LMU)

1 Introduction, definitions and reminders

2 Preparation of optically active

3 Diastereoselective reactions

4 Enantioselective reactions

2 0 Table of contents by D. Didier (LMU)

1 Introduction, definitions and reminders

2 Preparation of optically active molecules

3 Diastereoselective reactions

4 Enantioselective reactions

3 1 Introduction, definitions and reminders by D. Didier (LMU)

1.1 Frontier Molecular Orbitals

1.2 Isomerism

1.3 Definitions and reminders

1.4

1.5 Absolute configurations

4 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals Steric vs. electronic effects

Nonbonding interactions (Van der Waals repulsion) between Steric effects substituents within a or between reacting molecules

The effect of bond and through-space polarization by Electronic effects heteroatom substituents on reaction rates and selectivities

Example: 1,4-addition

Tet. 2000, 7715 (Yakura) Electronic effect: Steric effect: coordination repulsion

5 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals Stereoelectronic effects

Stereoelectronic Geometrical constraints placed upon ground and transition effects states by orbital overlap considerations

Anomeric effect

s*(C-O)

DG° = +0.6 kcal.mol-1

nO (filled sp3)

DG° = -0.6 kcal.mol-1

6 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals Hybridization

1 x s + 3 x p 1 x s + 2 x p 1 x s + 1 x p

s p p p s p p p s p p p

sp3 sp3 sp3 sp3 sp2 sp2 sp2 p sp sp p p

sp3 p p

sp2 sp2 sp sp sp3 sp2 p sp3 sp3 tetrahedral planar linear

3 2 1 sp sp sp or sp 7 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals Resulting geometry

sp3 sp2 sp

8 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals Orbital orientation

s bonds p bonds

antibonding s* p*

bonding s p

Nat. 2001, 539 (Weinhold)

staggered eclipsed conformation s*C-H conformation LUMO sC-H s*C-H sC-H

HOMO LUMO HOMO 9 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals study case: N2F2

LUMO LUMO HOMO HOMO s*N-F s*N-F nN nN

s*N-F s*N-F Lone pair delocalization HOMO-LUMO appears to override delocalization is stronger electron-electron and in the cis isomer due dipole-dipole repulsion to better orbital overlap in the stabilization of nN nN the cis isomer

the cis isomer is favored by 3 kcal/ mol at 25 °C 10 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals SN2

The Nu–C–X bonding interaction is that of a 3-center, 4-electron bond (3c4e). ∗ The frontier orbitals which are involved are the nonbonding orbital from Nu as well as σC–X and σ C–X

3c4e model Inversion Retention

E LUMO s*C-X

n HOMO N nN s*C-X HOMO LUMO s C-X Overlap from this Constructive overlap geometry results in no between Nu & σ* C–X net bonding interaction11 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals E2

synperiplanar antiperiplanar

s C-H s*C-X s C-H s*C-X HOMO LUMO HOMO LUMO

The interaction between s C-H and s*C-X leads to a conformation with H and X being trans-antiperiplanar 12 1 Introduction, definitions and reminders by D. Didier (LMU) 1.1 Frontier Molecular Orbitals electrophilic trapping

inversion retention

ACIE 2002, 717 (Basu)

ACIE 2018, 5516 (Knochel)

13 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism – reminder

Isomers are structures that possess the same chemical formula

Isomers

same connectivity?

NO YES

Constitutional Stereoisomers isomers

14 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism

Form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms, but differ in the three-dimensional orientations of their atoms in space

Stereoisomers

Through Through bond rotation bond cleavage

Configurational Conformers isomers

15 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Conformers

Natta Sägebock Newman projection projection projection

eclipsed conformation

E (kcal.mol-1) 3

0 j () 0 60 120

staggered conformation 16 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism n-butane E (kcal.mol-1)

4.5

3.6

gauche-conformation

0.9

0 dihedral angle 180° 120° 60° 0° (H3C-C-C-CH3)

anti-conformation 17 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Conformers

chair boat conformation conformation

E (kcal.mol-1) half-chair 11

7 5.5

twisted-boat

0 18 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Relevance

Important to understand Felkin-Anh models eclipsed staggered

Important to understand Zimmermann-Traxler models chair 1 chair 2

19 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism hydrazine N2H4

The nonbonding lone pair orbitals in the gauche isomer should be destabilizing due to electron-electron repulsion. s s N-H s n *N-H *N-H anti- N conformation E

s*N-H Hydrazine can exist in LUMO either gauche or anti conformations (relative to lone pairs)

nN gauche- HOMO conformation s N-H 20 HOMO 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism hydrogen peroxide H2O2

Major stabilizing interaction is the delocalization of O-lone pairs into the C–H antibonding orbitals. There are no such stabilizing interactions in the anti-conformation while there are 2 in the gauche conformation.

anti- E conformation

H2O2 can exist in either s*O-H gauche or anti LUMO conformations (relative s*O-H to H atoms) n nO O HOMO gauche- conformation 21 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Esters – (E) or (Z)?

? (E)-conformation (Z)-conformation

22 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Esters – (E) or (Z)?

? (E)-conformation (Z)-conformation

E (kcal.mol-1)

1 s*C-O 10-12 s*C-R LUMO LUMO

nO HOMO nO HOMO 2-3 1 nO – s*C-O nO – s*C-R overlap overlap

1 σ*C–O is a better acceptor than σ*C-R (where R is a carbon substituent). Therefore the (E) conformation is stabilized by this interaction. 23 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Destabilizing effects

eclipsed staggered repulsive interaction between

πC-C & σC-H πC-C πC-C -1 E (kcal.mol ) σC-H σC-H 2 σC-H σC-H σC-H σC-H

0

JACS 1985, 5035 (Wiberg)

JACS 1987, 6591 (Houk) 24 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Allylic systems 1-butene

E (kcal.mol-1)

1.32

0.49

0 j

25 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Allylic systems 2-propen-1-ol

E (kcal.mol-1)

2

1.18

0.37 0 j

26 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Allylic systems 2-methyl-1-butene

E (kcal.mol-1)

2.68

1.39

0.06 0 j

27 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Allylic systems 2-methyl-2-propen-1-ol

E (kcal.mol-1)

2.01

1.16

0.21 0 j

28 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Allylic systems (Z)-2-pentene

E (kcal.mol-1)

3.88

0.56 0

29 1 Introduction, definitions and reminders by D. Didier (LMU) 1.2 Isomerism Allylic systems (Z)-2-buten-1-ol

E (kcal.mol-1)

1.44

0.86

0

30 1 Introduction, definitions and reminders by D. Didier (LMU) 1.3 Definitions

Asymmetric synthesis Preparation of chiral molecules

Point in a molecule bearing different substituents, such that interchanging any two of them or stereogenic center leads to a stereoisomer

Molecule that possesses a non-superposable Chiral molecule mirror image

31 1 Introduction, definitions and reminders by D. Didier (LMU) 1.3 Definitions

Configurational isomers

are the molecules mirror images?

NO YES

Diasteoisomers

32 1 Introduction, definitions and reminders by D. Didier (LMU) 1.3 Definitions

Mixture containing equal quantities of both enantiomers

Mixture containing different quantities of Enantioenriched mixture two enantiomers

Enantiopure compound Mixture containing only one

33 1 Introduction, definitions and reminders by D. Didier (LMU) 1.3 Definitions

Enantiomeric excess Value representing the excess of one (ee) enantiomer over the second one

n[(R)-A] – n[(S)-A] ee = 100 · 62% ee n[(R)-A] + n[(S)-A]

n[(R)-A] er = er = 81:19 n[(S)-A] enantiomeric ratio Diastereomeric ratio (dr)

dr = 93:7 dr = 95:3:1:1 34 1 Introduction, definitions and reminders by D. Didier (LMU) 1.3 Definitions

A reaction that selectively leads to one or a series Stereoselectivite reaction of stereoisomers, disfavoring the other ones. This can be a result of competitive interactions.

A reaction in which the stereochemical outcome is Stereospecific reaction guided by the mechanism. It requires a particular (specific) arrangement of the atoms (or functional groups) for the reaction to proceed.

Stereospecific does not mean that only one stereoisomer is obtained. If a reaction gives only one diastereoisomer, it is fully diastereoselective. However, the ratio of stereoisomer in the product ! after a stereospecific transformation is identical to the ratio of stereoisomer in the substrate. 35 1 Introduction, definitions and reminders by D. Didier (LMU) 1.4 Chirality

An object or a system is chiral if it is distinguishable from its mirror image, and cannot be superposed onto it.

Two mirror images of a chiral molecule are called enantiomers or optical isomers. Pairs of enantiomers are often designated as "right-", "left-handed“.

If mirror image molecules are superimposable, they are "achiral".

As polarized passes through a chiral molecule, the plane of polarization, when viewed along the axis toward the source, will be rotated clockwise (to the right) or anticlockwise (to the left). A right handed rotation is dextrorotary (d); that to the left is levorotary (l).36 1 Introduction, definitions and reminders by D. Didier (LMU) 1.4 Chirality

Central chirality

C-centered chirality S-centered chirality

P-centered chirality M-centered chirality 37 1 Introduction, definitions and reminders by D. Didier (LMU) 1.4 Chirality

Axial chirality

allene chirality spirocyclic chirality

biaryl chirality helical chirality 38 1 Introduction, definitions and reminders by D. Didier (LMU) 1.4 Chirality

Planar chirality

chirality papacyclophane chirality

constraint chirality (E)-cyclooctene chirality 39 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations CIP rules

Cahn-Ingold-Prelog rules are used to determine the priorities of substituents in order to assign R, S, E and Z configurations

1. The groups directly attached to the stereocenter (first sphere) are sorted following their atomic numbers. The group having the atom of higher atomic number receives higher priority.

2. If one or more atoms identical in the first sphere, look at the second sphere.

3. If one or more atoms identical in the sphere x, look at the sphere x+1.

4. Double bonds (C=X) count as two single C-X bonds. Triple bonds (C X) count as three single C-X bonds.

40 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations CIP rules

1. Atomic number > > > > > > > > >

2. Second sphere > > > > >

3. x+1 sphere > > > >

4. Multiple bonds > > > > > > >

41 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Central chirality

3 1 2 (R) (S) (S) 2 1 2 3 3 1

3 1 2 (S) (R) (R) 1 2 3 2 1 3 42 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Fischer representation

1. The longest chain is placed vertically

2. D-Glucose D The most oxidized Fisher projections group is placed on top

3. Side chains point toward the viewer

L-Fructose L 43 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Fischer representation

2 D-Glucose 2

(R) 1 1 (S)

3 3

2 2

(R) 1 1 (R)

3 3 absolute configuration (2R,3S,4R,5R) 44 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Fischer representation

let the chain fall on the right rotate C4-C5 to align OH

D-Glucose Fischer projection cyclization

a-D-Glucose b-D-Glucose a-D-Glucose b-D-Glucose Chair model Haworth projection 45 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Disubstituted c-hexane

trans- cis- 4-aminocyclohexan-1-ol 4-aminocyclohexan-1-ol

stereoisomers (1R,2R)- (1R,3R)- not enantiomers 2-aminocyclohexan-1-ol 3-aminocyclohexan-1-ol = diastereoisomers mirror images are superimposable ! No stereocenter Achiral 46 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Diast. without C*

trans-cyclohexane cis-cyclohexane series series

trans-cyclobutane cis-cyclobutane series series

trans-alkene cis-alkene series series 47 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations L and D

D L

! The metal is the stereocenter

achiral D L optically active 48 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations L and D used as photocatalyst used in asymmetric catalysis

D L L

Chem. Rev. 2013, 5322 Nat. 2014, 100

(MacMillan) (Meggers) 49 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Allenes

4 1 (S) 2

3

Org. Chem. Front. 2014, 1 3 1210 (Ma)

3 4 (R) 2 1 2 2 4 3 (R) 4 The assignment of absolute configuration follows the CIP rules 1

The front substituents have the priority Nat. 2018, 240 over the substituents in the back (Bach) 50 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Spiranes

4 cases

achiral central chirality axial chirality

51 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Spiranes

mirror images are identical

achiral

52 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Spiranes

The central carbon atom possesses 4 different substituents. It is therefore treated as a classical stereocenter.

here, has the lowest priority

(S) (R) (R)

1 3 1 3 2 3 2 1 2 53 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Spiranes

The central carbon atom possesses 2 different substituents. It is not a stereocenter. The molecule is axially chiral.

In this case, the priority should be given according to CIP rules. The substituent with the highest priority should not be placed in the back (behind the plane).

The substituent in the back is given the lowest priority ( ).

(S) (R) (R)

3 1 1 2 2 2 1 3 3

54 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Spiranes

The substituents on both rings are pointing in different directions. The central carbon is not a stereocenter.

The molecule is axially chiral.

The absolute configuration should be assigned as for an allene, where both rings are assimilated to double bonds.

(R) (S) (S)

3 3 3 simplified 2 1 1 2 1 2 model 4 4 4 55 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Alkylydenecycloalkanes

The molecule is axially chiral. The configuration should be determined as for allenes and spiranes.

axially chiral

assignment of R and S configurations

(S) (R)

3 1 achiral

1 2 3 4 assignment of cis and trans 4 2 or E and Z

56 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Biaryls

The molecule is axially chiral.

CIP rules apply, considering that the substituents in front (on the model) have the priority over the ones in the back.

(R)-VAPOL

(S)-BINAP (S)

1 2 3 4 1 4

4 2 3 2 1 3 JACS 1993, 3814 (Wulff) CEJ 2019, 15694 (Corti) 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Helical chirality

(P) (M) (P)

ACIE 2015, 5470 (Marinetti)

(M)

JOC 2020, 3981 (Mastalerz) 58 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Metallocene chirality

the “old way”

(S) (R) R1 > R2

TL 2015, 1751 (Ogasawara)

(R) (R) (R)

(R)

59 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Metallocene chirality

1. define the atom of highest precedence current way (IUPAC) 2. assign the priorities following CIP rules

5 1 1 4 3 2 (1S) (2R) (4S)

3 2 2 3 3 2 (1S,2R,3R,4S,5S) (S) 1 1 1

Dynamic Stereochemistry of Chiral Compounds (C. Wolf) 2008, RSC Publishing 60 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Chirality in p-complexes

3 2 3 2

(S) (Sp)(Sc) 1 1 TL 2015, 1751 (Ogasawara)

3 2 2 3

(S) (Rp)(Sc) 1 1 61 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Paracyclophane chirality

define the pilot atom (S)

plane of symmetry plane of symmetry plane of symmetry center of symmetry (meso) (meso) (meso) (meso) achiral achiral achiral achiral

homochiral homochiral homochiral 62 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations Paracyclophane chirality

(R)

(S)

(R)

priority pilot atom

Dynamic Stereochemistry of Chiral Compounds (C. Wolf) 2008, RSC Publishing 63 1 Introduction, definitions and reminders by D. Didier (LMU) 1.5 Absolute configurations

(R)

pilot atom

pilot atom (R) priority (R)

64