Vicky Paddock Monday Meeting Problem Questions – 12/09

The Biosynthesis of Alkaloids.

Introduction

Alkaloids are non-peptidic, non-nucleosidic compounds containing nitrogen, abundant in

higher (flowering) plants, insects, amphibians and fungi. They are mainly produced from α-

amino acids including ornithine, lysine, tyrosine, phenylalanine and tryptophan.

Part 1 – Alkaloids from ornithine and lysine

These two amino acids are mainly involved in the biogenesis of aliphatic alkaloids, for

example cocaine (Figure 1).

MeNCO2Me

OCO.Ph

Figure 1: Cocaine

The early stages of the biosynthetic pathways of ornithine and lysine are shown below

(Scheme 1).

NH2HO2C NH2

( )n

1a Ornithine, n=11b Lysine, n=2

PLP

NH

OPN

Enzyme

H

OPLP =

NH2

( )n

2a, n=12b, n=2

H2N

?

NH2

( )n

3a, n=13b, n=2

MeHN

( )n

4a, n=14b, n=2

MeHN OPLP

( )n

N

Me

5a, n=15b, n=2

Scheme 1: Early stages of ornithine and lysine biosynthetic pathways.

Qu 1: The first step in the biosynthesis is a pyridoxal phosphate (PLP) dependant

decarboxylation; suggest the mechanism for this step.

Qu 2: Suggest a suitable co-substrate for the methylation of 2 to give 3.

Qu 3: Suggest the mechanism of the oxidative deamination of 3 to 4.

Qu 4: How would you synthesise compounds 5 from readily available starting materials

synthetically, giving suitable reagents.

Feeding studies have shown that symmetrical diamines 2 and iminium salts 5 can be

incorporated by the plant Erythroxylum coca to synthesise cocaine. The biosynthesis of

cocaine is shown below (Scheme 2).

Vicky Paddock Monday Meeting Problem Questions – 12/09

N Me

5a

2 x acetyl-SCoANMe

6O

O

SCoA

Hydroxylase

?

7

NMe O

O

SCoA

8

NMe O

O

OMe

9

Cocaine

Scheme 2: Biosynthesis of cocaine.

Qu 5: Suggest a retro-synthesis and forward synthesis of cocaine, different from the

biosynthesis.

Qu 6: Give the mechanism of the formation of 6 from iminium salt 5.

Qu 7: What is the structure of intermediate 7?

Qu 8: Give the mechanism for the transformation of 7 to 8.

Part 2 – Alkaloids from phenylalanine and tyrosine.

These two amino acids make up alkaloids with ArC2N units. The major classes include

monocyclic alkaloids, benzylisoquinolines alkaloids and amaryllidaceae alkaloids.

Morphine is member of the benzylisoquinoline class of alkaloids (Figure 2), biosynthetically

derived from two molecules of tyrosine.

O

HO

HO

NMeHH

Figure 2: Morphine

Qu 9: Assign each stereocentre in morphine as R or S.

Qu 10: Suggest a retro-synthesis and forward synthesis of morphine, not related to the

biosynthesis.

Vicky Paddock Monday Meeting Problem Questions – 12/09

The biosynthesis of morphine has been shown below (Scheme 3).

CO2

NH3HO

Tyrosine

PLP

?

CO2

NH3HO

10

11

[O]

?

CO2

HO

12

NH2HO

13

HO HO

[O]

O

?

14

EnzymaticPictet-Spengler

MECHANISM?

PLPdecarboxylation

?

153 x SAM

MeO

HONMe

HHO

MeO

16

2 x 1e- oxidation

followed by phenolic

coulping

MECHANISM?

17

MeO

MeO

NMeH

HO

O

?

18

NADPH

NADP+

-H2O

Oxidative demethylationP450

19

MeO

NMeH

O

O

H

?

Codeine

MeO

NMeH

HO

O

H

Morphine

HO

NMeH

HO

O

H

HO

Scheme 3: Biosynthesis of morphine.

Qu 11: Work through scheme 3, filling in missing structures, coenzymes and suggest

mechanisms for the highlighted steps.