CHEM 263 Notes Nov 1, 2016

Androstanes Androsterone was first isolated by Adolf Butenandt in 1931 from the extraction of 15,000 liters of urine. Approximately 15 milligrams of material was isolated and characterized as the below structure. The structure has two methyl groups at the 10 and 13 positions, a ketone functionality at the 17 position and an alpha (α) hydroxyl group at the 3 position. This type of structure is characteristic of an androstane skeleton, which has two beta (β) methyl groups at the 10 and 13 positions. Another example of this type of skeleton is testosterone. Testosterone differs from androsterone by a double bond between positions 4 and 5, a ketone at position 3 and an alcohol at position 17. Male steroidal hormones have the androstane skeleton.

OH O H H H H H H O HO Androsterone Androstane skeleton Testosterone 3!-hydroxyandrostan-17-one 17"-hydroxyandrost-4-en-3-one

Estranes Estradiol was first isolated in 1929 from the extraction of 4 tons of hog ovaries. Approximately 12 milligrams of material was isolated and characterized as the below structure. The structure consists of an aromatized A ring, alcohol functionalities at positions 3 and 17 and a methyl group at position 13. This is characteristic of an estrane skeleton, which has a beta (β) methyl group at the 13 position. Female steroidal hormones have the estrane skeleton. Another example of this type of skeleton is estrone, in which the alcohol at position 17 is oxidized to a ketone.

OH O

H H

H H H H HO HO

Estradiol Estrane skeleton Estrone Estra-1,3,5-trien-3,17β-diol

Pregnanes Progesterone is a hormone whose levels are elevated during pregnancy in females. Its structure has the pregnane skeleton, which has two methyl groups at positions 10 and 13 and a two carbon chain at position 17. Progesterone differs from testosterone by having the side chain of two carbons at position 17.

O 20 18 21 19 H

H H O

Progesterone Pregnane skeleton

Cortisone is a hormone of the adrenal glands that is used medically to relieve inflammation. Cortisone is a highly oxidized steroid, containing a variety of functional groups including ketones, double bonds and alcohols.

OH O

O OH H

H H O Cortisone

Cholestanes Cholesterol is a major steroid found in membranes of animals, and is a precursor to a variety of other steroid structures. Cholesterol has an alcohol at the 3 position and double bond between the 4 and 5 positions and a functionalized side chain as shown below.

H

H H HO

Cholestane skeleton Cholesterol

Preparation of Ketones and Aldehydes from Alkenes

Ozonolysis

1. O3 O O 2. Zn acetone 1. O3 O O 2. Zn acetaldehyde acetone (ethanal)

Mechanism:

H3C CH3 H3C CH3 + - C C H3C H O O + H H3C H O H3C O O O O- O O O O- O+ Concerted reaction ozonide (explosive)

Zn O O O O O O O O O O ZnO O

ozonide (explosive)

Examples:

O O3 O Zn 1-methylcyclopentene 5-oxohexanal

H H

O O

1) O3 H O O 2) Zn H O O

Preparation of Ketones and Aldehydes from Alkynes

Addition of water to acetylenes (Markovnikov)

H O H3C H H C H 2 3 H3C C C H C C C C H

H2SO4 HO H O H Propyne Acetone

Mechanism:

H C H H2O 3 H3C H H3C C C H C C C C H SO 2 4 H H O H H O H H H

tautomerization H C H 3 H3C H C C H C C H O H H O H H keto enol

The keto form (e.g. acetone above) is generally more stable than the enol form Note that for phenol, the enol form is much preferred to the keto form:

OH O

Addition of water to acetylenes (via boranes – overall anti-Markovnikov)

Enol form H C H H C H H3C H 3 NaOH 3 H3C C C H C C C C H C C H B H2O2 H O H H O "Keto" form H H B O H O organoborane H H

propyne propanal Preparation of Ketones and Aldehydes from Alcohols

Oxidation of Alcohols

[O] C OH O H carbon must have at least 1 H

R R O E elimination reaction H

[O] = oxidation; removal of electrons [H] = reduction; addition of electrons

There are many reagents that can be used for this reaction. Only three are given in this course:

1) Pyridinium chlorochromate (PCC) - forms ketones and aldehydes 2) Chromic acid (Jones reagent) – H2CrO4 - forms ketones only; aldehydes are further oxidized to carboxylic acids 3) Swern oxidation – oxalyl chloride, dimethyl sulfoxide (DMSO), triethylamine - forms ketones and aldehydes

1. PCC

O PCC CrO3 RCH2OH R CH Cl N O H PCC R CHOH R C R'

Pyridinium chlorochromate R'

PCC needs an H to work (i.e., 1° or 2° alcohol but not 3° alcohols).

Examples:

PCC OH PCC no rxn OH no rxn

(no H) tert(no-butyl H) alcohol 2-methyl-2-propanol PCC OH PCC O OH O isopropyl alcohol 2-propanone 2-propanol acetone isopropanol rubbing alcohol

O OH PCC H benzyl alcohol benzaldehyde

2. H2CrO4 , same as chromic acid, Jones reagent

This reagent is orange, and as it reacts it becomes green. It turns secondary alcohols into ketones, and primary alcohols into carboxylic acids. Primary alcohols first form aldehydes, but the reagent quickly reacts with the aldehyde to from the carboxylic acid. Tertiary alcohols are inert.

Secondary Alcohol: O H2CrO4 R CHOH R C R'

R'

Primary Alcohol: O O H2CrO4 H2CrO4 RCH2OH R C H R C OH

Example: H CrO O O 2 4 H2CrO4 CH3CH2OH H C H 3 H3C OH orange + green chromates

H2O

OH H H3C OH

Another secondary alcohol:

OH O

H H H2CrO4 H H H H HO HO estradiol estrone R. B. Woodward

3. Swern Oxidation Swern reagents:

O O Organic Base H C CH 3 S+ 3 eg Triethylamine Cl C C Cl Et3N O- oxalyl chloride DMSO N dimethyl sulfoxide

The Swern Oxidation is fairly mild and will oxidize primary alcohols to aldehydes and secondary alcohols to ketones.

O Swern

RCH2OH R C H

O Swern R CHOH R C R'

R' O

C OH Swern H

Benzyl alcohol Benzaldehyde

If benzyl alcohol were treated with Jones reagent, the result would be benzoic acid.

OH ClCOCOCl O

DMSO, Et N 3

Preparation of Aldehydes from Acid Halides

O ? O + HCl R C Cl R C H

acid chloride aldehyde aka acyl chloride

Needed: H Actual Reagents: H2/Pd H2 H

Examples:

O H2 O + HCl

H3C C Cl Pd H3C C H

acetyl chloride acetylaldehyde