lecture six

and now, the end is near; and so I face my final curtain.

.
OH
2 3

Aldol-like reactions
NH2 R1 1 R2

1,3-aminoalcohols

the reaction
NC R1 Me
pKa of the alpha hydrogens of acetonitrile is about 25 (the same as alpha to an ester)

i. base ii. O Me

Me Me HO R1

N reduce

Me Me NH2 HO R1

The reductioon can be achieved with LiAlH4 or TM-catalysed hydrogenation

MeO N Me Me

HO

venlafaxine antidepressant

Buena Vista 2005

MeO

Remember: when we are performing the synthesis of this compound that alkylation of the amine with methyl iodide is probably not the best reaction. Instead we should do a reductive amination (in reality they used methanal and formic acid; see if you can work out the mechanism for this reaction).

retrosynthesis
MeO NH2 N Me Me CN HO amine

HO

FGI reduction MeO CN O 1,3-N,O HO (ish) MeO CN

Aldol-like reactions
O R1
1 2

R3

N
3

R3 R2

1,3-amino ketones

retrosynthesis
R1 O R2 NR32 CC Mannich O R2 R1 H O H R3 H N

R3

MMIII-MMVIII - William H. Baird

HO NMe O O

atropine deadly nightshade

retrosynthesis
HO NMe O O Ph CO NMe ester OH reduction FGI decarbonylation CO2H CHO MeNH2 CHO CO2H O 2 x Mannich CO2H 2 x 1,3-NO NMe O CO2H FGI NMe O

synthesis
CO2H CHO MeNH2 CHO CO2H O OH amine condensation CO2H N Me OH CO2H Mannich reaction Me N Me N CO2H OH CO2H HO CO2H CO2H O

Me

N CO2H O

Me N

HO2C

Mannich reaction

1,3-dicarbonyl compounds
O R1
1 2

O
3

R2

Claisen-type condensations

the reaction
O R1 Me X O R2 R1 O X O R2 R1 O O R2

Ph N

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Buena Vista 2005

retrosynthesis
O Ph several N steps O O Ph O Ph 1,3-diCO

synthesis
O O N H enamine formation Ph Cl N

The chemistry of enamines is quite fascinating. The last few years have seen an explosion in the use of proline derivatives for the temporary formation of chiral enamines.

Ph

O O hydrolysis

Ph

O N

1,5-dicarbonyl compounds
O R1
1 2 3 4

O
5

R2

Michael addition

the reaction
O 1,5-diCO O HO2C HO2C

the reaction
O 1,5-diCO O HO2C HO2C Why do malonates prefer 1,4 addition? Might be time to learn about Hard-Soft Acid-Base theory (or when reactions are controlled by electrostatics and when they are controlled by orbital overlap!!) Then again, perhaps not... O EtO2C EtO2C O EtO2C CO2Et CO2H i. KOH ii. H+, heat O

O NH N Et O

rogletimide sedative

retrosynthesis
Me O CN NH N O imide
The real synthesis uses acrylamide instead of ethyl acrylate; this allows a simple final cyclisation step.

Me

CO2Et CO2Et

N 1,5-diCO Me

Me

Br CC CO2Et

CO2Et N

CO2Et

1 Me R

Me

O steroid skeleton
www.sporting-heroes.net

retrosynthesis
Me O C=C Me O 1,5-diCO O O Me O Me O O Me O

The Robinson annelation

O Me O base O Me O base Me O O O Me O Me O base Me O O Me O

The Robinson annelation

O Me O base O base Me O Me O base O Me O Me O

OH

OH

alkene disconnection
R1 R3 C C R2 R4

H H O Br Br

valuable intermediate
OH OH HO HO H OH

Aldol condensation
O R1 R2 C=C R1 O R2

reagents
O R1 Me O R2 R1 O R2

Wittig reaction
R1 R4 R2 R3 C=C R1 R4 R2 R3

I guess it could be argued that the synthons should be a double +ve and a double ve but this looks confusing

R1 PPh3 R4 O

!
R2 R3

Wittig reaction
simplification!

H Br R1 R4 PPh3

base H PPh3 R1 R4 R1

PPh3 R4

O PPh3 R2 R3 R1 R4 R2

O PPh3 R1 R3 R4 R2

O R3 R1

PPh3 R4

Cl Me Me OH Me OH phenaglycol tranquilliser

retrosynthesis I
Cl Me Me OH Me FGI dihydroxylation PPh3 Me Me O Me Me Cl C=C OH

Cl

Cl Me O C=C Me Ph3P Me Me Me

retrosynthesis II
Cl Me Me OH Me OH FGI dihydroxylation Cl Me Me Me OH Me 3 possible Grignards Cl Me Me Me 3 possible Grignards Cl Me Me OH

retrosynthesis III
Cl Me Me OH Me OH Me OH FGI CN Cl O Me Me OH CC CC Cl O OEt

Cl N

umpolung
O R !+ R O !

reverse polarity

example
!+ ! R Br Mg umpolung ! !+ R MgBr O C N Ph OH R C N Ph
This is not a true example of umpolung but is just meant to aid us understanding the concept of polarity reversal

dithianes
O R H HS H SH S electrophile S

Curiously, the 5-membered dithioacetal ring (dithiolane) cannot be used in this reaction and fragments on treatment with strong base

BuLi

R H

R nucleophile

Some interesting uses of this kind of chemistry have been reported by the group of Amos B Smith III

OH Me Me O Me OH O O O Me

Me

Me OH

OMe O Me OH O

Me

(+)-tedanolide anti-carcinogen

retrosynthesis
split molecule Me Me remove reactive functionality O Me OH O OH O umpolung O O Me OMe O Me OH Me Me OH Me

J. Am. Chem. Soc. 2007, 129, 10957

synthesis
OP PO OMe O Me Me Me OP O OP Me O Me S S Me Me OP Me

the only way to improve is practice