MEDC 527 Fall 20081 Heterocycles Nomenclature Hetero-atom is to be counted as 1 or as low as possible When there is more than one hetero-atom, preference.

MEDC 527 Fall 2008 1

Heterocycles

Nomenclature

Hetero-atom is to be counted as 1 or as low as possible When there is more than one hetero-atom, preference is given to O, then S, then N,

then C. Also N-H presides over –N=. Mnemonic: Old Soldiers Never Cry When there is more than one hetero-atom, numbering should be as direct as possible

from one to the other Substituents are numbered as low as possible Acceptable prefixes include O=Oxa; S=Thia; N=Aza Common suffixes for N- and non-N-heterocycles For partially unsaturated systems, H

is(are) are used to indicate the location of saturation Hantzsch-Widman System of systematic name of heterocyclic compounds


Heterocycles

Hantzsch – Widman Nomenclature (adopted by IUPAC)

Ring Size

Saturated

Partly Saturated Unsaturated

3 -irane - -irene

4 -etane (dihydro) -ete

5 -olane (dihydro) -ole

6 -inane (di or tetrahydro) -ine

7 -epane (di or tetrahydro) -epine

8 -ocane (di, tetra, or hexahydro)

-ocine

OCommon name : ethylene oxideSystematic name : Oxa + irane …. Oxirane

OCommon name : furanSystematic name : Oxa + ole …. Oxole


Heterocycles


NH Common name : pyrroleSystematic name : H at 1 position + Aza + ole …. 1H-Azole

HN

Common name : piperidineSystematic name : Aza + inane …. 1H-Azinane

N

N Common name : pyrimidineSystematic name : two aza at 1, 3 positions + ine …. [1,3]-diazine


Heterocycles

HN

Azocane

NH

O

[1,3]-Oxazocane

S

NH

O

[1,3,7]-Oxathiazocane

S

N

O

4,5-dihydro-2H,8H-[1,3,7]-oxathiazocine

6-Methyl-2-phenyl-2H,8H-[1,3,7]-oxathiazocine

6-Methyl-2-phenyl-2H,3H,8H-oxocine

S

N

O

CH3

Ph

O

CH3

Ph



Oxygen Containing Heterocycles

3-Membered Ring :: Ethylene Oxide or oxirane

O

H

H

H

H

Oxirane formation in our body

Structure? Form at room temperature? Reactivity? Usage? Toxicity?

R

H

H

H

R

H

H

H

O

Oxidizing Enzymes



O

O

O

CH3CH3

CH3

CH3

3

Vitam in K epoxide

O

Squalene Epoxide

Epoxides in our system

Role of Vitamin K epoxide?

Role of Squalene epoxide?



Reactions of Epoxides

Acid Opening of Epoxides

O HR

H H

O HR

H H

OHH

HH

ROH

HR

H H

OHHClH+

+

H2O



Reactions of Epoxides

Enzymatic opening of epoxides

O HR

H H

O HR

H H

OHHR

H H

OHEpoxideHydrase

H+

H2O

Opening of epoxides with amines (lysine mimics) and alcohols (serine mimics)

R’ÖH

O

H

H

R

HO

H

H

R

H

H+

OH

H

R

OR'

R'O

H

R

OHH++

R’NH2

O

H

H

R

HO

H

H

R

H

R'H2N

H

R

O

O

H

R

NH2R'+

R'HN

H

R

OH

OH

H

R

NHR'+

+ -

-+



Higher Oxides

O

O

O O

O

Oxetane oxolane oxane 1,4-dioxane

Structure? Reactivity? Usage? Toxicity?

MEDC 527 Fall 2008 10


Higher Oxides

Stability of these oxides change drastically on -substitution

O O OHCOOHH+, H2O

O OO OO O

OO H -, H 2 O

_ _

O OH OH OHH2O

O OMe OH OHH3O

+

Lactones anhydrides

Hemi-acetals acetals

MEDC 527 Fall 2008 11


Examples of Acetals or Hemi-Acetals in Nature

CH2OH

OHH

OHH

OHH

CHO

O

H

OH

H

OH

HOH2C

HOH

Same side = Opposite side =

ribose hemiacetal

MEDC 527 Fall 2008 12


Interconversion of - and -forms of sugars The phenomenon of mutarotation

O HH

HOH

O HH

C H O

C H 2 O H

O HH

O HH

HOH

O HH

C H 2 O H

OH

O HH

O HH

HOH

O HH

C H 2 O H

OH

HOH

HOH

HOH

O HH

C H O

C H 2 O H

O HH

glucose -g lucose g lucose -g lucose

OH

H

H

H

HOH

H

O

OHOH

O

H

H

H

HOH

H

OH

OHOH

O

H

H

H

HOH

H

OH

OHOH

H

H

H

H

OHOH

H

O

OHOH

D -glucose -glucose D -glucose -glucose

CH 2OH CH 2OH CH 2OH CH 2OH

OH

H

H

H

HOH

H

O

OHOH

O

H

H

H

HOH

H

OH

OHOH

O

H

H

H

HOH

H

OH

OHOH

H

H

H

H

OHOH

H

O

OHOH

D -glucose -glucose D -glucose -glucose

CH 2OH CH 2OH CH 2OH CH 2OH

MEDC 527 Fall 2008 13


Examples of sugars in natural systems Deoxynucleic Acids and Ribonucleic Acids

O

H

OH

H

O

OH2C

H

Base

H

H = DNA= RNA

O

H

OH

H

O

OH2C

H

Base

H

H = DNA= RNA

N

NN

N

NH2

Sugar

N

NNH

NSugar

O

NH2

N

N

NH2

O

Sugar

NH

N

O

O

Sugar

CH3

Adenine Guanine Cytidine Thymidine

Live link: http://www.bmrb.wisc.edu/referenc/nomenclature/

MEDC 527 Fall 2008 14


Sugars and Diabetes

OHH

HOH

OHH

CH2OH

OHH

HO

NH2

OHH

HOH

OHH

CH2OH

OHH

HOH

NHR

OHH

HOH

OHH

CH2OH

OHH

H

NR

..

Glycated Hemoglobin (HbA1c or GHb)Also called glycosylated hemoglobin. The saccharide equilibrium is the reason for the formation of

glycated hemoglobin in diabetic patients. Excess free plasma sugar, and therefore the open-chain aldehyde, reacts with the N-terminal NH2 group of hemoglobin (or lysine side chains) to form glycated

adducts, which are detected to confirm and monitor diabetes. The upper limit for a normal individual is 7% HbA1c.

MEDC 527 Fall 2008 15


Sugars Monosaccharides

CH2OH

OHH

CHO

HOH

CHO

CH2OH

OHH

OHH

CHO

CH2OH

OHH

HOH

CHO

HOH

CH2OH

OHH

OHH

CHO

HOH

CH2OH

OHH

OHH

CHO

OHH

CH2OH

OHH

HOH

CHO

OHH

CH2OH

OHH

OHH

CHO

HOH

HOH

OHH

CH2OH

HOH

CHO

HOH

HOH

OHH

CH2OH

OHH

CHO

OHH

HOH

OHH

CH2OH

HOH

CHO

OHH

HOH

OHH

CH2OH

OHH

CHO

OHH

OHH

OHH

CH2OH

HOH

CHO

OHH

OHH

OHH

CH2OH

OHH

CHO

HOH

OHH

OHH

CH2OH

HOH

CHO

HOH

OHH

OHH

CH2OH

D-Glyceraldehye

D-Threose D-Erythrose

D-Lyxose D-RiboseD-Xylose D-Arabinose

D-Galactose D-AlloseD-Gulose D-GlucoseD-Talose D-AltroseD-Idose D-Mannose

MEDC 527 Fall 2008 16


Reducing and Non-reducing Sugars

OHH

CHO

HOH

OHH

OHH

CH2OH

HOH

CHO

HOH

OHH

OHH

CH2OH

D-Glucose D-Mannose

OHH

CH2OH

HOH

OHH

OHH

CH2OH

HOH

CH2OH

HOH

OHH

OHH

CH2OH

D-Sorbitol D-Mannitol

Sorbitol is 66% as sweet as glucose. It is poorly absorbed and hence does not lead to high sugar levels in blood. It is not as calorific (~70% as calories as glucose) … used as sugar-free sweetner.

Mannitol is a good osmotic diuretic …. Intravenous drip …. Rapidly filtered by kidneys but not reabsorbed resulting in an osmotic effect of water/Na+ excretion

MEDC 527 Fall 2008 17


Derivatized Forms of Monosaccharides

OHH

CHO

HOH

OHH

OHH

CH2OH

HOH

CHO

OHH

HOH

OHH

CH2OH

D-Glucose D-Idose

OHH

HOH

OHH

OHH

CH2OH

COOH

HOH

OHH

HOH

OHH

CH2OH

COOH

D-Gluconic Acid D-Idonic Acid

OHH

HOH

OHH

OHH

CHO

COOH

HOH

OHH

HOH

OHH

CHO

COOHD-Glucuronic Acid D-Iduronic Acid

H

H

H

OHH

O

OHOH

H

OH

COOH

-D-Glucuronic Acid

OH

OH

OH

HH

O

HH

H

OH

COOH

-D-Iduronic Acid

NH2H

CHO

HOH

OHH

OHH

CH2OH

D-Glucosamine

H

H

H

OHH

O

OHNH2

H

OH

CH2OH

-D-Glucosamine

O

O

CH2OSO3

NHSO3

OH

O

OH

OH

O

COO

O

O

CH2OSO3

NHSO3

OH

O

OSO3

OH

O

COOO

O

CH2OH

NHSO3

OH

O

OSO3

OH

O

COO

_

__

__

__ __ _

MEDC 527 Fall 2008 18


Fructose

OHH

HOH

OHH

CHO

CH2OH

OHH

OH

HOH

OHH

CH2OH

OH

OHH

HOH

OHH

CH2OH

CH2OH

OHH

O O OH

CH2OHOH

H

H

OH

HOH2C

H

D-glucose ene-diol fructose (open-chain form) fructose (furanose form)

O

OH

H

H

O H

H O H 2 C

O

H

C H 2 O H

H

H

H

OHH

O

OHO H

C H 2 O H

H

-D -g lu co se -D -fru c to se

Sucrose

MEDC 527 Fall 2008 19


Polysaccharides – Cellulose and Starch

H

HH

HO

H

OH

OC H 2 O H

O HH

H

H

OH

O

OHO H

C H 2 O H

O

H

* *n

1 4

14

C ellu lose (1 4 - -D -g lucose po lym er)

O

H

H

H

OH

O

OHOH

CH2OH

H

H

H

H

OH

O

OHOH

CH2OH

*H

*n

Amylose (14--D-glucose polymer)80% constituent of starch; 20% is amylopectin

MEDC 527 Fall 2008 20

Nitrogen Containing Heterocycles

3-Membered Ring

MEDC 527 Fall 2008 21

Nitrogen Containing Heterocycles

3-Membered Ring in our system?

NClCH3

Cl

Mechlorethamine NH

NH2

CH3

OCONH2

O

O

OMe

Mitomycin C

O

PN N

N

TEPA

How do these work?

MEDC 527 Fall 2008 22

Higher Heterocycles Containing Nitrogen

Basic Ring Systems

NH N

HNH

NH

NH

O

NH

azetidine pyrrolidine piperidine piperazine morpholine(azolidine) (perhydroazine) (perhydro-1,4-diazine) (perhydro-1,4-oxazine)

Acid – Base Properties

Ist pKA ?IInd pKA ?

Stability to Water, Acid and Base Without substituents ?

With substituents ?

H2+

NH

NH

NH

N

N

N

H2+

H2+

pKA 9.6 pKA 9.9

MEDC 527 Fall 2008 23


NHO

N

S

O

CH3

CH3

NH

O

R

COOH

N

S

O

RCONH

R'

COOH

NO

S NH2

CH3

CH3

OH

COOHNH

NO

S

CH3

CH3

OH

COOH

O

NCH3CH3

penicillin-lactam

cephalosporin

meropenem thienamycin

Examples of Drugs … 4-membered ring

Hydrolysis of -lactams …… acid/base and enzymatic conditions

NHO

RR'

NH3+

O

RR'

O

MEDC 527 Fall 2008 24


Importance of -lactam ring in activity …… generation of resistance!!

Clavulinic Acid …… antidote to antibiotic resistance

N

O OH

OCOOH

NH

O OH

OCOOH

H

Nu-Enz-Ser-O

NH

OH OH

OCOOH

Ser-O

O

OSer

Enz Nu

NH

OH OH

COOH

Nu-Enz-Ser-OH

Enz- Nu

.. ..

....

..

Clavulinic acid-lactamase

N

O OH

OCOOH

NH

O OH

OCOOH

H

Nu-Enz-Ser-O

NH

OH OH

OCOOH

Ser-O

O

OSer

Enz Nu

NH

OH OH

COOH

Nu-Enz-Ser-OH

Enz- Nu

.. ..

....

..

Clavulinic acid-lactamase

MEDC 527 Fall 2008 25


Examples of Drugs … 5-membered ring

atorvastatintryptophanpyrrole

NHNH

N

F

OH

OH

CH3CH3

O OOC

NH

NH2

COOH

clem astinen ico tine

pyrro lid ine

N H

N

O

C H 3

C lC H 3

NCH 3

(anti-hyperlipidemic agent)

(anti-histaminic)

MEDC 527 Fall 2008 26

Five-membered Rings Containing Nitrogen and Another Heteroatom

Nitrogen and Oxygen

NON

O

NO NHO

Oxazole(1,3-oxazole)

Isoxazole(1,2-oxazole)

Oxazoline(1,3-oxazoline)

Oxazolidine(1,3-oxazolidine)

NNHN

NH

NNH NHNH

Imidazole(1,3-diazole)

Pyrazole(1,2-diazole)

Imidazoline(1,3-diazoline)

Imidazolidine(1,3-diazolidine)


Ist pKA ?IInd pKA ?Why is imidazole not strongly basic ?pKA with greater substitution ?

MEDC 527 Fall 2008 27

Higher Heterocycles Containing Nitrogen and Another Heteroatom

Stability to Water, Acid and Base Without substituents ?

With substituents ?

O

NH

OH

NH3+H3O

+

+ HCHO

NH

NH

NH3+

NH3+H3O

+

+ HCHO

O

N

OH

NH3+

NH

N

NH3+

NH3+

O

NH+

O

NH

OH2+H3O

+

+ HCHO

H3O+

+ HCHO

O

N

NH

N

H3O+

H3O+

no degradation

no degradation

MEDC 527 Fall 2008 28

5-Membered Aromatic Heterocycles

Metabolism of Aromatic Rings Containing One Heteroatom 5-Membered heterocycles generally react well with electrophiles; better

than benzene Stability to metabolic enzymes is generally lower than their carbocyclic

analogs EAS occurs at the 2-position of 5-membered heterocycles

N

H

N

HSO3H

S S Br

O O OH

sulfation

bromination

metabolic enzyme

MEDC 527 Fall 2008 29

O

N

NH

N

O

N

OH

NH

N

OH

O

NH

O

NH

NH

O

OH

NH2

NH2

NH2

O

NH2

H

Oxidativemetabolism

Oxidativemetabolism

5-Membered Heterocycles

Metabolism of Aromatic Rings Containing Two Heteroatoms

MEDC 527 Fall 2008 30

NO

CH3CH3

NH

S

NH2

OO

Sulfisoxazole

NN

CH3

OH

O2N

Metronidazole

CH3

NN

SO2NH2

CF3

Celecoxib

Examples of such heterocycles in Drugs

Higher Heterocycles Containing Nitrogen and Another Heteroatom

(anti-biotic agent) (anti-biotic agent) (pain medication)

MEDC 527 Fall 2008 31

Heterocycles Containing Sulfur

Basic Ring Systems

NSS

S

T e t r a h y d r o t h io p h e n e( t h io la n e )

T h io p h e n e( T h io le )

1 , 3 - t h ia z o le

S

N NN

CH3

CH3

S

N NN

CH3

CH3

methapyrilene

N

S

N

NH

O

NH2

OMe

S

O

COOH

ceftizoxime

S

N

NH2SO O

NH2

thiazolsulfone

Examples in Drugs

(Antihistamine) (Antibiotic) (Antimalarial)

MEDC 527 Fall 2008 32

Complex Heterocycles

Examples in Drugs

(Antibiotic) (Antihypertensive)

NH2 SNH NN

S CH3

OO

sulfamethizole

NN

S

NO N

H

OH

CH3 CH3

CH3

timolol

N

O

N O

NHAc

F

O

linezolid

NH

NH O

O

phenytoin

FF

OH

N NN

NNN

fuconazole

N

N

OH

Cl

CH3

N

NHN

N

losartan(for pneumonia) (Antihypertensive)

(Anti-infectious) (Anti-seizure)

MEDC 527 Fall 2008 33

6 Membered Rings Containing One Nitrogen

Examples in Drugs

N N

C H 3

O

S

NHO

O

R o s i g l i t a z o n e( p y r i d i n e + t h i a z o l i d i n e 2 , 4 - d i o n e )

A n t i - d i a b e t i c

N

O

C H 3

O E t

M e p e r id in e(p ip e r id in e )

re lie v e s p a in , n a rc o tic a n a lg e s ic

NH

C l

C H O C H 2 C H 2 N H 2CH 3

C O O E tM e O O C

A m lo d ip in e( d ih y d r o p y r id in e )

C a 2 + c h a n n e l b lo c k e r , A n t ih y p e r t e n s i v e , a n t ia n g i n a l

NH

NH

O

O O

C2H5

Phenobarbital(pyrimidine)

controls epilepsy, seizures,as a sedative to relieve anxiety

NN

NH

O

F C O O H

C i p r o f l o x a c i n( p i p e r a z i n e )A n t i b a c t e r i a l

( a n t h r a x )

NH

O

C H 3

P h e n m e tra z in e(m o rp h o lin e )

A p p e tite s u p p re s a n tC N S s tim u la n t

A m p h e ta m in e -lik e

MEDC 527 Fall 2008 34

6 Membered Rings Containing Two Nitrogens

Diazines

NN

N

N

N

N1,2-diazine 1,3-diazine 1,4-diazine(pyridazine) (pyrimidine) (pyrazine)


Ist pKA ?IInd pKA ?Why are these dibasic compounds not strongly basic ?

MEDC 527 Fall 2008 35


Pyrimidines

N

N

O

O

H

H

Three derivatives are important for RNA/DNA

N

N

O

O

H

H CH3 N

NO

H

NH2

Uracil Thymine Cytosine

Forms of Pyrimidines

N

N

O

O

H

HN

N

O

O

H

H

N

N

OH

OH

Urea Imide or Keto form Enol form(neutral) (acidic) (acidic)

MEDC 527 Fall 2008 36

NH

NH

O

O O

C2H5

Phenobarbital(pyrimidine)

controls epilepsy, seizures,as a sedative to relieve anxiety

N

N OO

H

H

O

Me

Ph

N

N OO

H

H

O

H

HN

N OO

H

H

H

H

NH

NH

O O

Ph

Ph

Phenytoin(anti-psychotic)

N

N OHOH

H

H

OH

H

pKA = ~4

(Enol form)

(Keto form)


Special Pyrimidines … Barbituric Acid

MEDC 527 Fall 2008 37

Heterocycles

More Complex Unsaturated Ring Systems

6-membered and higher heterocycles

N NN

N

NN

NPyridine pyridazine pyrimidine pyrazine

N

NO O

N

N

N

N

N

N

Q u i n o l i n e I s o q u i n o l i n e C o u m a r i n Q u i n a z o l i n e P t e r i d i n ep r e s e n t i n … … C h l o r o q u i n e P r a z i q u a n t e l W a r f a r i n P r a z o s i n T r i a m t e r e n e( a n t i m a l a r i a l ) ( a n t i - w o r m ) ( a n t i c o a g u l a n t ) ( a n t i h y p e r t e n s i v e ) ( a n t i h y p e r t e n s i v e

NH

N HNH

N

O

N

S

N

I n d o l e I s o i n d o l e B e n z i m i d a z o l e B e n z o x a z o l e B e n z t h i a z o l ep r e s e n t i n … . .T r y p t o p h a n L S D O m e p r a z o l e C h l o r o z o x a z o n e E t h o x z o l a m i d e( c o m m o n A A ) ( h y p n o t i c ) ( a n t i - u l c e r ) ( r e l i e v e s p a i n ) ( d i u r e t i c )

MEDC 527 Fall 2008 38

Heterocycles

More Complex Unsaturated Ring Systems

6-membered and higher heterocycles

N

NS

OON

N

NH

N

O

NH

S

N

NH

1 , 2 , 4 - b e n z o t h i a 3 H - 1 , 4 - B e n z o 1 , 3 - D i h y d r o - 2 H - 1 , 4 - P h e n o t h i a z i n e A c r i d i n e 5 H - d i b e n zd i a z i n - 1 , 1 , - d i o x i d e d i a z e p i n e b e n z o d i a z e p i n - 2 - o n e [ b , f ] a z e p i n ep r e s e n t i n … . .C h l o r o t h i a z i d e C h l o r d i a z e p o x i d e D i a z e p a m C h l o r o p r o m a z i n e Q u i n o c r i n e I m i p r a m i n e( a n t i h y p e r t e n s i v e ) ( s e d a t i v e , h y p n o t i c ) ( s e d a t i v e , a n x i o l y t i c ) ( a n x i o l y t i c ) ( a n t i b i o t i c ) ( a n t i - d e p r e s s a n t s )

NH

NH

N

O

N

Azepine diazepine oxazepine

MEDC 527 Fall 2008 39

7 and 8 Membered Nitrogen Containing Heterocycles

NNH

O

SOO

C H 3

T o l a z a m i d e( h e x a h y d r o a z e p i n e )O r a l h y p o g l y c e m i c

CH 3

C H 3

NC H 3

C H 3

OH

P e n ta z o c in e( o c ta h y d r o a z e p in e )

P a in r e l ie v e r

MEDC 527 Fall 2008 40

Six Membered Aromatic Heterocycles

Metabolism of Pyridines Pyridines are less reactive toward electrophiles than benzene Stability to metabolic enzymes is generally higher than their carbocyclic

analogs EAS occurs at the 3-position of 6-membered heterocycles

N N

NO2

N N

OH

nitration

metabolic enzyme

MEDC 527 Fall 20081 Heterocycles Nomenclature Hetero-atom is to be counted as 1 or as low as possible When there is more than one hetero-atom, preference.

Documents

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