Stereoselective synthesis

How can enantiomers be separated? (4)

• Covalent attachment of an enantiomerically pure functional group to create diastereomers

• Form salts with an enantiomerically pure reagent to create diastereomers

• Use chiral chromatography

• Resolution with enzymes

Limitations of enzymatic resolution (4)

• Limited solubility of enzymes in organic solvents

• Enzymes only exist as one enantiomer

• Can be too substrate specific

• lose half of the product (applies to all separations)

Limitations of using a natural chiral pool (2)

• Chiral pool molecules generally available as only one enantiomer.

• Many steps may be required to convert it into the target.

Chemoselectivity

The selective transformation of one of several potentially reactive functional groups within a molecule.

Regioselectivity

The favored formation of one constitutional isomer in preference to another.

Stereoselectivity

one stereoisomer of product is formed predominantly

Optically inactive starting materials can give optically active products only if…(2)

they are treated with an optically active reagent

OR

the reaction is catalyzed by an optically active substance

enantiotopic faces of a carbonyl

What do a) enantiomeric and b) diastereomeric transition states lead to?

a) racemic product

b) diastereomeric excess

chiral auxiliary

a small chiral molecule which is covalently attached to a prochiral starting material to make diastereoselective reactions possible.

formula for calculating enantiomeric excess

Δ[S] & [R]/ [S]+[R]

reactions result from the interaction between…

Hint: orbitals

LUMO of electrophile and HOMO of nucleophile

Rationalization behind Bürgi-Dunitz angle

looking at the orientations of the LUMO of a carbonyl, the greatest overlap between the nucleophile and electrophile orbitals occurs when the Nu approaches at a >90^o angle

From what direction(s) can nucleophiles attack the pictured molecule and why? (2)

LARGE Nu: equatorial to avoid steric hindrance

SMALL Nu: axial because the transition state is more favoured, and are too small to be limited by steric interactions

How to determine the most reactive conformation at a diastereotopic carbonyl?

Felkin-Anh model: In a Newman projection with the largest group perpendicular to the C=O bond and the smallest group close to R, nucleophile will attack from direction of smallest group

What causes changes in the Felkin-Anh model’s stipulated preferred conformation? (2)

electronegative atoms at α-chiral center; prefer to be perpendicular to C=O

chelation control: will coordinate eclipsed conformation between heteroatom, metal and C=O — 4-6 membered cyclic transition state

What is required for chelation control to occur? (2)

• A heteroatom with lone pairs available for coordination to a metal.

• A metal ion that prefers to coordinate to >1 heteroatom at once; typically M²⁺ or higher

TRUE OR FALSE: Chelation increases the rate of the addition reaction

TRUE

TRUE OR FALSE: Alkenes are nucleophilic

TRUE, BUT can also be electrophilic

Epoxidation reaction

What determines the stereospecificity of epoxidation? (2)

• substituents will remain in same relative cis/trans configuration

• mCPBA attacks less hindered face→ anti epoxide

• hydroxyl (OH) groups can direct epoxidation to give syn epoxides

What is an exception to the general mechanism/stereoselectivity of epoxidation with mCBPA?

hydroxyl (OH) groups can direct epoxidation to give syn epoxides

What is the preferred/lowest energy conformation of an alkene?

with smallest group eclipsing/in the same plane as double bond

Epoxide ring opening gives what stereoselectivity of product?

OH from epoxide, retaining stereochemistry of epoxide, anti to nucleophile adding at less hindered position

Hydroboration

In unsymmetrical alkenes, the boron adds to the less-substituted carbon

Oxidation of organoboranes: R₂B-CR₂-CHR₂ —(a)→ (b)

a) H₂O₂, NaOH

b) HO-CR₂-CHR₂

Bromination of alkenes

anti addition of Br2 across the double bond

Iodolactonization

Syn addition of I⁺ followed by trans ring-opening generates the anti product

Simmons-Smith reaction

converting an alkene into a cyclopropane

What result does presence of an OH group have on Simmons-Smith reaction?

• cyclopropanate over 100 times faster

• new CH₂ group also adds to the same face of the double bond as the hydroxyl group

R₂CO + LDA → ?

Enolate stereochemistry assignment (E/Z, Re/Si)

Stereoelectronic effects controlling enolate formation

Hint: deprotonation

Deprotonation is favoured when the C-H bond is perpendicular to the C=O bond

Formation of which stereochemistry enolate is normally favoured for ketone in a) acyclic and b) cyclic systems?

a) Z-isomer

b) E-isomer; only one they can give

Reactive conformation of acyclic enolates (with stereocentre β to the carbonyl)

has C-H bond of the stereocenter co-planar with the plane of the enolate to minimise 1,3-allylic strain.

generic structure of Evans’ oxazolidinone chiral auxiliaries

synthesis of Evans’ oxazolidinone chiral auxiliaries from amino acids

Mechanism of Evans’ oxazolidinone chiral auxiliaries in synthesis (5 steps)

1. deprotonate auxiliary: H-NR₂ —^n-BuLi→ ^-NR₂

2. attach carbonyl (acid chloride): ^-NR₂ + RCOCl → RCO-NR₂

3. deprotonate at α-C to form Z enolate

4. LDA/ alkali metal coordination; M⁺

5. Reaction with electrophile (activated alkyl halides) on opposite face to bulky group

Davis oxaziridine

electrophilic source of oxygen

Davis oxaziridine + Evans’ oxazolidinone system→ ?

asymmetric synthesis of C-O^- bonds

Evans’ oxazolidinone chiral auxiliaries removal (4)

• H^- (NaBH₄/ LiAlH₄) → HOCH₂R

• H₂O₂, LiOH → HO₂CR

• LiSEt → RCOSEt

• LiOBn → RCO₂Bn

RCO-NR₂ + NaBH₄ or LiAlH₄ → ?

RCH₂OH

RCO-NR₂ + M(:X)R →

where M= alkaline earth metal (M⁺)

and :X= group 16 element

RCO-:XR

RCO-NR₂ + H₂O₂, LiOH →

RCOOH

TRUE OR FALSE: stoichiometric quantities of the Evans’ auxiliary are needed

TRUE, BUT can be recovered/ recycled after cleavage

Do the following conditions promote E1 or E2 elimination?: greater a) base concentration, b) base strength, c) carbocation stability

a) E2

b) E2

c) E1

acid catalysed aldol reaction

Elimination is easier under (acidic/basic) conditions and occurs via (E1/E2) mechanism

Elimination is easier under acidic conditions and occurs via E1 mechanism

What does an aldol (1,3- hydroxycarbonyl) turn into once it is subject to a) elimination, b) oxidation, c) reduction?

a) enone R(C=O)-C=C

b) dicarbonyl

c) diol

What requirements have to be satisfied for a chemoselective aldol reaction? (2)

• Only one enolate possible/ specific enol equivalent used

• The other partner is significantly more electrophilic

Lithium enolate formation

structure of LDA

formation of aldol from lithium enolate intermediate

through Zimmerman-Traxler transition state

R₂CO—(a; 2)→ (boron enolate; b)

R₂CO—^{R₂B-Cl, NEt₃}→ R₂CO-BR₂

formation of aldol from boron enolate intermediate

R₂CO—(a; 2)→ (silyl enol ether; b)

R₂CO—^{R₃Si-Cl, NEt₃}→ R₂CO-SiR₃

formation of aldol from silyl enolate intermediate

With substituted enolates, the aldol reaction forms (…) new stereocentres

2

What stereochemistry aldol products do a) cis and b) trans enolates give?

favoured Zimmerman-Traxler transition state for trans enolate

favoured Zimmerman-Traxler transition state for cis enolate

What will be the result of this reaction if R= a) sterically demanding, b) small substituent?

a) cis lithium enolate

b) trans lithium enolate

How can of Enolate/enol equivalent Geometry be made to favour cis or trans?

Boron enolates from BR₂Cl

where R₂ is sterically demanding to favour trans

and less so to favour cis

How can Evans’ auxiliary be exploited in aldol reactions?

serve as a large R group for [RCOC^-R ] to favour cis enolate

Benefits of organocatalysts (6)

• Simple to work with

• No expensive metals or reagents

• Catalytic in a cheap chiral source

• High yields

• High enantioselectivities

• Green solvent

in acyclic systems hydroxyl groups need what characteristic to behave as a directing group?

allylic to C=C; RC=C-COH

The presence of OH groups will result in what product with the reagents:

VO(acac)₂, t-BuOOH

epoxide added across double bond from same face as OH

Sharpless epoxidation reagents (4)

• DET

• Ti(OⁱPr)₄

• allylic alcohols (R₂C=CR-COH)

• tBuOOH

a) What is the structure of (+)-DET and b) what face of the alkene does it attack?

a) image

b) Re for trans, Si for cis (to OH)

a) What is the structure of (-)-DET and b) what face of the alkene does it attack?

a) image

b) Si for trans, Re for cis (to OH)

What side of the double bond do the enantiomers of DET add OH?

in the conformation with OH bottom right, (+)-DET adds below and (-)-DET adds above

Ring opening of an epoxide (acidic conditions) gives what stereochemical outcome?

anti diol

how are syn diols formed?

OsO4

In Sharpless dihydroxylation, what is the relationship between the two reagents?

pseudo-enantiomers; enantiomeric at all but one stereocenter as both enantiomers of quinine and quinidine are not readily available

AD-mix-α contains …

(DHQ)₂PHAL

AD-mix-β contains …

(DHQD)₂PHAL

For Sharpless dihydroxlation, the largest group can be placed front right with alkene along y-axis, as for the OH group in Sharpless epoxidation; what faces will DHQ/DHQD add to?

Corey-Bakshi-Shibata transition state rationalizing stereoselectivity

Corey–Bakshi–Shibata a) reaction b) reagents and c) product

a) enantioselective reduction of a ketone to an alcohol

b) CBS catalyst (image), BH₃, R₂CO

c) R₂CHOH

RNH₂ + R₂CO—(a)→ (b)

a) needs acid catalyst

b) RHC=NR

HNR₂ + R₂CO→ ?

What is the electro/nucleophilicity of a) iminiums, b) enamines?

a) electrophilic

b) nucleophilic

enamine catalysis transition state/ enantioselectivity

least sterically clashing configuration made

What determines the preferred a) enamine and b) aldol formed in enamine catalysis?

a & b) occurs at the least hindered ketone (fewest R groups on α-Carbon)

Mannich reaction

imine (less hindered carbonyl) + enol (enolizable reagent)

If the Mannich reaction is conducted under enamine catalysis, the enamine will act as the (electrophile/nucleophile)

If the Mannich reaction is conducted under enamine catalysis, the enamine will act as the nucleophile; opposite reactivity to imine

What feature of imines allows them to react enantioselectively?

convert between trans/cis very fast and heavily favour trans

Key design considerations for iminium catalysis (2)

• Enamine formation must be avoided

• iminium geometry needs to be controlled

Kinetic resolution, for example, in Sharpless Epoxidation

if the rate of two reactions of a racemic mixture is significantly different, stopping the reaction at 50% completion can give just one stereoisomer of product ie. only pink product in image

imine formation

enamine formation

same as imine, but if there is a C–H protons next to the C=N the pictures conversion occurs