Are mirror images identical ( symmetric) , or different ( asymmetric - - PowerPoint PPT Presentation

Are mirror images identical (symmetric),

• r different

(asymmetric)?

Left hand mirror

Right hand the left and right hands are nonsuperimposable

A molecular case: the amino acid alanine Symmetric or asymmetric?

Molecules with the same constitution that differ only by the relative positions of their atoms in space:

• stereoisomers!

Molecular stereoisomers that are nonsuperimposable mirror images are called

• enantiomers
• An enantiomer possesses the property of molecular chirality.

Enantiomers

• Usually have 4 different functional groups bonded to an sp3-hybridized atom. That atom is

referred to as a

• Stereogenic center
• Stereocenter
• Chiral center
• Have identical physical properites save for one: they cause exactly opposite rotations of

plane-polarized light and so are said to exhibit optical activity.

• A clockwise rotation is
• (+)
• dextrorotatory
• d
• A counterclockwise rotation is
• (-)
• levorotatory
• l

Light: electromagnetic radiation

Electric

field

Electric

wave

Magnetic

Magnetic wave field

Oscillating orthogonal electric and magnetic fields of a beam of light

Plane-polarized light and its consequences

1st polarizing

2nd polarizing filter filter

• bserver sees

maximum light source plane- polarized light

• bserver sees

no light plane- polarized light

Polarimeter: An instrument to measure optical activity

[ α ]C

D = 100 α

cl % e.e. = [(+)-enantiomer] - [(-)-enantiomer] x 100 [(+)-enantiomer] + [(-)-enantiomer] % e.e. = α x 100 [ α ]C

D

Defining a physical constant: Specific rotation = the observed rotation of plane-polarized light in degrees c = the concentration in g / 100mL l = the pathlength (always 1 dm) Enantiomeric purity (% e.e.): Note: a 50 : 50 mixture of enantiomers has no . It appears to be achiral. Such mixtures are called racemates.

SO WHAT?

Is molecular chiralty important? Consider:

• Gloves
• Smells
• Drug-receptor interactions

Different stereoisomers like enantiomers interact with one another in different ways!

Stereochemical theory of odor

H O H O H H

(S)-(+)-CARVONE (R)-(-)-CARVONE smells like caraway seeds smells like spearmint gum (R)-(+)-LIMONENE (S)-(-)-LIMONENE smells like citrus fruit smells like turpentine

Some drugs that exist as enantiomers and why this matters

(-)-ibuprofen (+)-ibuprofen [α]D

25 = - 20.6 (c 1.00, ethanol)

[α]D

25 = + 58.5 (c 2.00, ethanol)

Advil, Motrin OTC for arthritis, fever; general anti-inflammatory analgesic (+)-enantiomer is the active isomer (-)-enantiomer is inactive the enzyme 2-arylpropionyl-CoA epimerase converts (-)-enantiomer to the (+)-enantiomer

(Zhao, X.; Eur. J. Med. Chem. 2006, 41, 1352-1358; Piccolo, O.; J. Org. Chem. 1985, 50, 3945-3946.)

O OH O O H

Some drugs that exist as enantiomers and why this matters

(-)-thalidomide (+)-thalidomide [α]D

25 = - 64.6 (DMF)

[α]D

25 = + 64 (DMF)

teratogen antiemetic enantiomers are interconvertable (undergo racemization) in vivo racemate is immunomodulator used to treat erythema nodosum leprosum (in combination with dexamethasone) newly diagnosed multiple myeloma actinic prurigo

(Ellis, G.P.; West, G.B. Progress in Medicinal Chemistry, Elsevier: New York, 198, p 170) N O H O N O O N O H O N O O

Some drugs that exist as enantiomers and why this matters

(-)-ketamine (+)-ketamine [α]D

25 = - 91.88 (c 2.00, H2O)

[α]D

25 = + 92.48 (c 2.00, H2O)

analgesic racemate used to induce general anesthesia (+)-enantiomer (Ketanest S) is more potent (-)-enantiomer is more hallucinogenic: may cause nightmares

(Marrietta, M. P.; Way, W.L.; Castagnoli, N. Jr.; Trevor, A.J. J. Pharmacol. Exp. Ther. 1977, 202, 157-165.) N Cl O H N Cl O H

N H N H (+)-methamphetamine (-)-methamphetamine The Alan Baxter story

2002 Salt Lake City Winter Olympics bronze medalist in downhill skiing (slalom) failed IOC routine drug test: + for methamphetamine source of + : Vicks nasal spray U.S. version contains the legal enantiomer of methamphetamine: (decongestant) (crank) IOC test did not differentiate between enantiomers Baxter cleared, but lost his medal – now IOC explicitly bans both enantiomers 2006 Turin Winter Olympics Baxter finishes 16th

How do constituional isomers differ from stereoisomers? What kinds of stereoisomers are there?

What ways are there to draw enantiomers?

• 1. Hatched and wedged line projections (most popular)

are these these enantiomers,

• r just different hatched and wedged line projections of the same molecule?

C H3 H H CH3

H O H O H H

Remember carvone and limonene? Do these have R or S configurations?

What ways are there to draw enantiomers?

• 3. Newman projections

Are these anti-staggered and gauche staggered conformations of the same molecule?

C H3 CH2CH3 H H H CH2CH3 H CH2CH3 CH3 CH3CH2 H H

CH3 C C H2 H3C Br H 1 2 3 4

CH3 C CH2 CH3 Br H

What ways are there to draw enantiomers?

• 4. Fisher projections

\

• a. Orient your point of view so that your

body lines up with the parent chain of the molecule and your line of sight bisects the bond angle formed by the remaining two substituents of the chiral center.

• b. Draw the molecule as it appears to you

using wedged and hatched lines:

• c. The Fisher convention replaces wedged and hatched lines with regular ones.
• The vertical lines of a chiral center are always pointing away from you
• The horizontal lines of a chiral center are always pointing towards you

becomes

Two of these Fisher projections of different conformations of the same configuration. Which two?

CH3 C CH2CH3 Br H

CH3 CH2CH3 Br H CH2CH3 CH2CH2CH2CH3 H O H CH2CH3 H OH CH3CH2CH2CH2 CH2CH3 CH2CH2CH2CH3 OH H

Br OH Br HBr 0 C, dark * Br2 H2O * Sterochemical outcomes of reaction involving 1 stereogenic center: 1.

• ptically inactive starting materials + optically inactive reagents = optically inactive products

(racemic) (racemic) 2.

• ptically active starting materials with spectator stereocenter + optically inactive reagents =
• ptically active products

(S) (S) C H3 H C H3 H H2 Pd /C

3.

• ptically active starting materials with participating stereocenter + optically inactive reagents =
• products of the same configuration: Retention
• products of the opposite configuration: Inversion
• a mixture of retention and inversion products: Racemization

(racemic) why? A symmetrical (achiral) intermediate forms: Cl C H3 H Cl C H3 Br Br2 light * C H3 Cl

A molecule with 2 chiral centers and 4 stereoisomers 2,3-dihydroxybutanoic acid, also called tartaric acid:

• Draw all four R,S isomers of this molecule

Note: the maximum number of nonconformational stereoisomers a moleclue can have is = 2n where n = the number of stereogenic “parts” of the molecule = number of chiral centers + number of E,Z double bonds O OH OH OH * *

CH3 O OH O H H O H H H3C O O H OH H OH H CH3 O OH H O H O H H H3C O O H H OH OH H CH3 H OH H OH CO2H CH3 H O H H O H CO2H CH3 H OH O H H CO2H CH3 H O H OH H CO2H (2R,3R) (2S,3S) (2R,3S) (2S,3R) enantiomers enantiomers diastereomers

A molecule with 2 chiral centers and 4 stereoisomers

OH OH

CH3 CH3 O H H O H H H3C H3C OH H OH H CH3 CH3 H O H O H H H3C H3C H OH OH H CH3 H OH H OH CH3 CH3 H O H H O H CH3 CH3 H OH O H H CH3 CH3 H O H OH H CH3 (2S,3R) = meso (2R,3S) = meso (2S,3S) (2R,3R) the same enantiomers diastereomers diastereomers

A molecule with 2 chiral centers and 3 stereisomers: one isomer is a meso isomer

Consider with 2 chiral centers and (not counting conformational ismoers) 22 = 4 possible stereoisomers, but there are only 3!

C H3 CH3 H H C H3 CH3 Br Br H H CH3 C H3 Br Br H H CH3 CH3 H Br Br H CH3 CH3 Br H H Br Br2 CCl4 + +

Stereochemical outcomes of reactions involving 2 or more stereogenic centers: 1. Anti-addtion of X2 to alkenes: diastereoselective (Z) (2R, 3R) (2S, 2S) threo-2,3-dibromobutane (a racemate)

C H3 H H H CH3 Br Br C H3 H H C H3 Br Br CH3 H CH3 CH3 Br H Br H CH3 Br2 CCl4 +

(E) (2S, 3R) (2R, 2S) the same! erythro-2,3-dibromobutane (meso)

• All anti-additions behave in a similar, diastereoselective manner.

H H H H2 Pt H H H H H2 Pt +

• Syn-addition of H2 to alkenes: diastereoselective

(S) (1S, 2S) 1 enantiomer (Z) (3R, 4S) (3S, 4R) racemate

• All syn-additions behave in a similar diastereoselective manner.