On Stereochemistry and Chirality Interacon with plane polarized light

What is the relaonship between R,S and d,l aka (±)?

Nomenclature

There isn’t any! All Isomers (same molecular formula)

Stereoisomers

Idencal Enanomers Diastereomers

Same atom Same atom Same atom connecvity connecvity connecvity

Same spaal Same spaal Different spaal arrangement arrangement arrangement

Superimposable Non-superimposable Non-superimposable

Constuonal (Structural) Isomers

Same molecular formula; different atom connecvity The Limonenes

(-)-limonene (+)-limonene

lemon orange

(S) (R) Meso Compounds

Meso – (middle or intermediate) - the achiral member(s) of a set of diastereoisomers which also includes one or more chiral members.

CO2H CO2H CO2H CO2H HO OH OH HO HO OH HO OH CO2H CO2H CO2H CO2H

meso tartaric acid R,R-(+)-tartaric acid S,S-(-)-tartaric acid “natural” R,S-stereoisomer Meso Tartaric Acid

Why is meso tartaric acid not opcally acve?

CO2H The Fischer projecon is unstable; it is eclipsed and H OH only a mnemonic device to test for a meso compound. H OH CO2H

CO2H H H HO H HO H H OH

H OH HO CO2H HO2C OH CO2H CO2H CO2H

An staggered Gauche staggered Center of symmetry Racemic mixture Enanomers and Diastereomers

enantiomers

CO2H CO2H R H OH HO H S S H Br Br H R

CO2H CO2H diastereomers 1 2 3 4

CO2H CO2H R H OH HO H S R Br H H Br S

CO2H CO2H Other Sources of Chirality

B H B H B B H H

A A A A

(R) "M" (S) "P" (R) "M" (S) "P" trans - cyclooctene atropisomerism

CO H HO C H 2 2 H C C C C C C H HO2C H CO2H

allene dicarboxylic acid

O O O O O O

1,7-dioxaspiro[5.5]undecane (R) "M" (S) "P" Cholesterol – How Many Stereoisomers are Possible?

256 centers of chirality (and 32 stereochemistry) 64 2(S), 4(S), 8(S), 16(R), 32(R), 64(R), 128(S), 256(R) H3C 128 CH3 One double bond stereochemistry; no chirality 256 (Although the double bond has two H3C stereogenic carbons, only two double bond geometries are possible.)

HO 16 512 conceivable stereoisomers of cholesterol 8 4 2 All other double bond isomers – namely, (E) 512 -- are impossible to exist.

2n stereoisomers; 2n-1 pairs of enanomers O OAc O More on Atropisomerism H O CH3O H O CH3O

CH3O

Steganacin

O O O O O O O O O S S S CH O CH3O CH3O 3 CHO CHO CHO

CH O CH O CH3O 3 3 CH O CH O CH3O 3 3

two racemic compounds 3:1 rao The Ambient Temperature Ullmann Reacon and Its Applicaon to the Total Synthesis of (±)-Steganacin; Frederick E. Ziegler*, Irene Chliwner, Kerry W. Fowler, Sheldon J. Kanfer, Stephen J. Kuo, and Nanda D. Sinha; J. Am. Chem. Soc., 1980, 102, 790. Stereogenic Atoms (Stereocenters)

“An atom bearing several groups of such nature that an interchange of two groups will produce a stereoisomer.” Mislow & Siegel - 1984

Stereocenters that are not chiral centers.

OH OH Br H H H C C C C H Br Br Br OH OH

H Br Br C Br C Br H Chiral Atom (Chiral Center)

“An atom holding a set of ligands in a spaal arrangement which is not superimposable on its mirror image.”

CH3 CH3 OH OH OH HO C2 and C4 chirotopic and stereogenic; OH OH C3 stereogenic and achirotopic CH3 CH3 meso stereoisomers

CH 3 CH3 OH OH HO OH C2 and C4 chirotopic and stereogenic; C chirotopic and nonstereogenic HO HO 3 CH 3 CH3 idencal Resoluon - I

B(+) A(+) + A(-) A(+)B(+) + A(-)B(+) enanomers

B(-) diastereomers A(+) + A(-) A(+)B(-) + A(-)B(-)

Assume A(+)B(+) less soluble than A(-)B(+)

A(+)B(+) precipitates from soluon

Cinchonidine Isolate A(+)B(+) water soluble ether soluble

aq. NaOH A(+)B(+) A(+)-(CO2Na) + B(+)

A(+)-(CO2H) aq. HCl Brucine Resoluon - II

B(+) A(+) + A(-) A(+)B(+) + A(-)B(+) enanomers

B(-) diastereomers A(+) + A(-) A(+)B(-) + A(-)B(-)

What if A(-)-(CO2H) is desired? Then use B(-) as the resolving agent. Then A(-)B(-) is less soluble than A(+)B(-). A(-)B(-) precipitates from soluon. Isolate A(-)B(-) water soluble ether soluble aq. NaOH A(-)B(-) A(-)-(CO2Na) + B(-)

A(-)-(CO H) aq. HCl 2 NH NH Resoluon – III (Pasteur 1853)

CO H CO H O 2 2 O H OH HO H

H HO H H OH H3CO

CO2H CO2H N N (+)-Cinchotoxine R,R-(+) S,S-(-) (+)-Quinotoxine

(+/-)-Tartaric Acid

(-)-T/(+)-C n-salt insoluble (-)-T/(+)-Q n-salt soluble

(+)-T/(+)-C p-salt soluble (+)-T/(+)-Q p-salt insoluble

(+)-A/+)-B or (-)-A/(-)-B = p(aired) salt

(-)-A/(+)-B or (+)-A/(-)-B = n(on-paired) salt Resoluon - IV

Na

C2H5OH N N H d,l - coniine

d-tartaric acid 1886 – resoluon of racemic coniine

d-tartaric acid Albert Ladenburg less soluble l-coniine (1842 – 1911) +

d-(S)-coniine d-tartaric acid d-coniine N H Resoluon – V The Method of Pope & Peachey - 1899

d,l - B N H

d,l-Tetrahydroquinaldine [d,l-2-Methyl-1,2,3,4-tetrahydroquinoline]

HO3S

d - A Br O

Dextrorotatory Reychler’s Acid [[(1R)-(endo,an)]-(+)-3-Bromocamphor-8-sulfonic acid]

Sir William Jackson Pope How do you maximize the difference in solubility (1870 – 1939) of the two diastereomers?

How do you minimize the use of resolving agent? Resoluon – VI The Method of Pope & Peachey - 1899

HO3S d-B HCl l-B HCl same solubility

Br N H O

d,l - B d-A,d-B different solubilies d - A Solubility d-A,l-B but close

In soluon mix, conc. sol’n d-A + HCl + 2 d,l-B d-A,l-B + d-A,d-B + d-B HCl + l-B HCl

cool Precipitates d-A,l-B

d-B HCl In soluon Resoluon - VII

Is there a down side to resoluon?

You bet!

The yield will always be less than 50%.

Can not predict which enanomer will be isolated.

Mirror image resolving agents are not always available.

Trial and error may be required. Asymmetric Reacons – A Beer Way

Pd/C CO2H CO2H

H3CO H2 H3CO

racemic naproxen H2 chiral catalyst

Ph O Ph CO2H P O Ru P H3CO Ph O Ph O (S)-Naproxen (97% ee) (S)-BINAP-Ru(OAc)2 The End

F. E. Ziegler 2013, 2016