Semi Synthesis of Corticosteroids

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The medicinal use of corticosteroids was stimulated by reports of the dramatic effects of cortisone on patients suffering from rheumatoid arthritis in the late 1940s and early 1950s. The cortisone employed was isolated from the adrenal glands of cattle, and later was produced semi-synthetically by a laborious process from deoxycholic acid (see page 260) isolated from ox bile and necessitating over 30 chemical steps. Increased demand for cortisone and hydrocortisone (cortisol) (it had been shown that cortisone was reduced in the liver to hydrocortisone as the active agent) led to exploitation of alternative raw materials, particularly plant sterols and saponins. A major difficulty in any semi-synthetic conversion was the need to provide the 11^-hydroxyl group which was essential for glucocorticoid activity.

Sarmentogenin (Figure 5.115) had been identified as a natural 11-hydroxy cardenolide in Stro-phanthus sarmentosus but it was soon appreciated that the amounts present in the seeds, and the limited quantity of plant material available, would not allow commercial exploitation of this compound. As an alternative to using a natural

11-oxygenated substrate, compounds containing a

12-oxygen substituent might be used instead, in that this group activates position 11 and allows chemical modification at the adjacent site. Indeed, this was a feature of the semi-synthesis of cortisone from deoxycholic acid, which contains a 12a-hydroxyl. Hecogenin (Figure 5.115) from sisal (Agave sisalana; Agavaceae) (see page 240), a steroidal sapogenin with a 12-keto function, made possible the economic production of cortisone on a commercial scale. This material is still used in the semi-synthesis of steroidal drugs, and the critical

Agave Sisalana Sapogenins Steroids

sarmentogenin

sarmentogenin

Sarmentogenin Structure

hecogenin

Figure 5.115

hecogenin

Figure 5.115

modifications in ring C are shown in Figure 5.116. Bromination a to the 12-keto function generates the 11a-bromo derivative, which on treatment with base gives the 12-hydroxy-11-ketone by a base-catalysed keto-enol tautomerism mechanism. The 12-hydroxyl is then removed by hydride displacement of the acetate using calcium in liquid ammonia. The new 11-keto sapogenin is subjected to the side-chain degradation used with other sapogenins, e.g. diosgenin (see Figure 5.119), to the 11-ketopregnane (Figure 5.117) which can then be used for conversion into cortisone, hydrocortisone, and other steroid drugs.

Of much greater importance was the discovery in the mid-1950s that hydroxylation at C-11 could be achieved via a microbial fermentation. Progesterone was transformed by Rhizopus arrhizus into 11a-hydroxyprogesterone (Figure 5.118) in yields of up to 85%. More recently, Rhizopus nigricans has been employed, giving even higher yields. 11a-Hydroxyprogesterone is then converted into hydrocortisone by chemical means, the 11^ configuration being introduced via oxidation to the 11-keto and then a stereospecific reduction step. Progesterone could be obtained in good yields (about 50%) from diosgenin extracted from Mexican yams (Dioscorea species; Dioscore-aceae) (see page 239) or stigmasterol from soya beans (Glycine max; Leguminosae/Fabaceae) (see page 256). Steroidal sapogenins such as diosgenin may be degraded by the Marker degradation

bromination a SN2 displacement

bromination a SN2 displacement

SN2 displacement;

Figure 5.116

Ac2O

Ac2O

keto-enol-keto tautomerism; the 11-keto form is preferred, probably because in the 12-keto form, the carbonyl is X adjacent to the five-membered D-ring

Figure 5.116

Marker degradation (see Figure 5.119)

Figure 5.117

side-chain degradation

Marker degradation (see Figure 5.119)

side-chain degradation

3ß-hydroxypregnan-11,18-dione hydrocortisone (Cortisol)

3ß-hydroxypregnan-11,18-dione

Figure 5.117

Hydrocortisone Oxidized Cortisol
Figure 5.118

(Figure 5.119), which removes the spiroketal portion, leaving carbons C-20 and C-21 still attached to contribute to the pregnane system. Initial treatment with acetic anhydride produces the diacetate, by opening the ketal, dehydrating in ring E, and acetylating the remaining hydroxyls. The double bond in ring E is then selectively oxidized to give a product, which now contains the unwanted side-chain carbons as an ester function, easily removed by hydrolysis. Under the conditions used, the product is the ^-unsaturated ketone. Hydrogenation of the double bond is achieved in a regioselective and stereoselective manner, addition of hydrogen being from the less-hindered a-face to give pregnenolone acetate. Progesterone is obtained by hydrolysis of the ester function and Oppenauer oxidation to give the preferred a,ß-unsaturated ketone (see page 241). It is immediately obvious from Figure 5.119 that, since the objective is to remove the unwanted ring F part of the sapogenin, features like the stereochemistry at C-25 are irrelevant, and the same general degradation procedure can be used for other sapogenins. It is equally applicable to the nitrogen-containing analogues of

Marker Degradation of Diosgenin

diosgenin

AcO-Ac

AcO-Ac involves opening of spiroketal and acetylation of 26-hydroxyl followed by loss of proton; 3-hydroxyl is also esterified

H AcO

Spiroketal Steroid Diosgenin

diosgenin involves opening of spiroketal and acetylation of 26-hydroxyl followed by loss of proton; 3-hydroxyl is also esterified

H AcO

AcO,

selective oxidation of 20,22 double bond

dehydropregnenolone acetate ester hydrolysis; resultant O alcohol dehydrates to form conjugated system

dehydropregnenolone acetate selective catalytic hydrogenation of 16,17 double bond occurs from less-hindered a face

pregnenolone acetate

pregnenolone acetate

ester hydrolysis; resultant O alcohol dehydrates to form conjugated system

pregnenolone

Figure 5.119

pregnenolone

Figure 5.119

Oppenauer oxidation of 3-hydroxyl to ketone, with tautomerism to give conjugated system

Oppenauer oxidation of 3-hydroxyl to ketone, with tautomerism to give conjugated system

progesterone progesterone

sapogenins, e.g. solasodine (Figure 5.88). In such compounds, the stereochemistry at C-22 is also quite immaterial.

Degradation of the sterol stigmasterol to progesterone is achieved by the sequence shown in Figure 5.120. The double bond in the side-chain allows cleavage by ozonolysis, and the resultant aldehyde is chain shortened via formation of an enamine with piperidine. This can be selectively oxidized to progesterone. In this sequence, the ring A transformations are carried out as the first reaction. A similar route can be used for the fungal sterol ergosterol, though an additional step is required for reduction of the A7 double bond.

An alternative sequence from diosgenin to hydrocortisone has been devised, making use of another microbiological hydroxylation, this time a direct 11^-hydroxylation of the steroid ring system (Figure 5.121). The fungus Curvu-laria lunata is able to 11^-hydroxylate cortex-olone to hydrocortisone in yields of about 60%.

stigmasterol

Oppenauer oxidation of 3-hydroxyl to ketone, with tautomerism to give conjugated system ozonolysis to cleave side-chain double bond

Oppenauer oxidation of 3-hydroxyl to ketone, with tautomerism to give conjugated system ozonolysis to cleave side-chain double bond

Chemical Formation Progesterone
O

enamine formation: Schiff base (minium) formed first, followed by base-catalysed

Figure 5.120

enamine formation: Schiff base (minium) formed first, followed by base-catalysed iminium-enamine tautomerism

CrO3

"O

progesterone ... , selective oxidation of side-chain double bond

Figure 5.120

diosgenin

Marker degradation (Figure 5.119)

diosgenin

Marker degradation (Figure 5.119)

Chemical Formation Progesterone

dehydropregnenolone acetate chemically dehydropregnenolone acetate cortexolone

O OH

chemically

Cortexolone Propionate

cortexolone

Figure 5.121

Curvularia lunata

Curvularia lunata

Cortexolone

hydrocortisone (cortisol)

hydrocortisone (cortisol)

Figure 5.121

Although a natural corticosteroid, cortexolone may be obtained in large amounts by chemical transformation from 16-dehydropregnenolone acetate, an intermediate in the Marker degradation of diosgenin (Figure 5.119).

Some steroid drugs are produced by total synthesis, but, in general, the ability of microorganisms to biotransform steroid substrates has proved invaluable in exploiting inexpensive natural steroids as sources of drug materials. It is now possible via microbial fermentation to hydroxylate the steroid nucleus at virtually any position and with defined stereochemistry. These processes are in general more expensive than chemical transformations, and are only used commercially when some significant advantage is achieved, e.g. replacement of several chemical steps. The therapeutic properties of cortisone and hydrocortisone can be further improved by the microbial introduction of a 1,2-double bond, giving prednisone and prednisolone respectively (Figure 5.122). These agents surpass the parent hormones in antirheumatic and antiallergic activity with fewer side effects. As with cortisone, pred-nisone is converted in the body into the active agent, in this case prednisolone.

R1R2 = O, cortisone

R'R2 = O, prednisone

Figure 5.122

R1R2 = O, cortisone

R'R2 = O, prednisone

Figure 5.122

Corticosteroid Drugs

Glucocorticoids are primarily used for their antirheumatic and anti-inflammatory activities. They give valuable relief to sufferers of rheumatoid arthritis and osteoarthritis, and find considerable use for the treatment of inflammatory conditions by suppressing the characteristic development of swelling, redness, heat, and tenderness. They exert their action by interfering with prostaglandin biosynthesis, via production of a peptide that inhibits the phospholipase enzyme responsible for release of arachidonic acid from phospholipids (see page 55). However, these agents merely suppress symptoms and they do not provide a cure for the disease. Long term usage may result in serious side-effects, including adrenal suppression, osteoporosis, ulcers, fluid retention, and increased susceptibility to infections. Because of these problems, steroid drugs are rarely the first choice for inflammatory treatment, and other therapies are usually tried first. Nevertheless corticosteroids are widely used for inflammatory conditions affecting the ears, eyes, and skin, and in the treatment of burns. Some have valuable antiallergic properties helping in reducing the effects of hay fever and asthma. In some disease states, e.g. Addison's disease, the adrenal cortex is no longer able to produce these hormones, and replacement therapy becomes necessary. The most common genetic deficiency is lack of the 21-hydroxylase enzyme in the biosynthetic pathway, necessary for both hydrocortisone and aldosterone biosynthesis (Figure 5.114). This can then lead to increased synthesis of androgens (see Figure 5.133).

Mineralocorticoids are primarily of value in maintaining electrolyte balance where there is adrenal insufficiency.

Natural corticosteroid drugs cortisone (as cortisone acetate) and hydrocortisone (Cortisol) (Figure 5.112) are valuable in replacement therapies, and hydrocortisone is one of the most widely used agents for topical application in the treatment of inflammatory skin conditions. The early use of natural corticosteroids for anti-inflammatory activity tended to show up some serious side-effects on water, mineral, carbohydrate, protein, and fat metabolism. In particular, the mineralocorticoid activity is usually considered an undesirable effect. In an effort to optimize anti-inflammatory activity, many thousands of chemical modifications to the basic structure were tried. Introduction of a A1 double bond modifies the shape of ring A and was found to increase glucocorticoid over mineralocorticoid activity, e.g. prednisone and prednisolone (Figure 5.122). A 9a-fluoro substituent increased all activities, whereas 16a- or 16^-methyl groups reduced the mineralocorticoid activity without affecting esterification with tosyl chloride to generate good leaving group

TsCl

TsCl

Sn2 displacement does not occur

AcO AcO

base-catalysed E1 elimination

base-catalysed E1 elimination

less-hindered a face

base-catalysed intramolecular SN2 gives epoxide

Figure 5.123

acid-catalysed opening of epoxide (favouring trans-fused ring system)

Figure 5.123

the glucocorticoid activity. The discovery that 9a-fluoro analogues had increased activity arose indirectly from attempts to epimerize 11a-hydroxy compounds into the active 11^-hydroxy derivatives (Figure 5.123). Thus, when an 11a-tosylate ester was treated with acetate, a base-catalysed elimination was observed rather than the hoped-for substitution, which is hindered by the methyl groups (Figure 5.123). This syn elimination suggests an E1 mechanism is involved. The same A9(11)-ene can also be obtained by dehydration of the 11^-alcohol by using thionyl chloride. Addition of HOBr to the 9(11)-double bond proceeds via electrophilic attack from the less-hindered a-face, giving the cyclic bromonium ion, and then ring opening by ^-attack of hydroxide at C-11. Attack at C-9 is sterically hindered by the methyl at C-10. 9a-Bromocortisol 21-acetate produced in this way was less active as an anti-inflammatory than cortisol 21-acetate by a factor of three, and 9a-iodocortisol acetate was also less active by a factor of ten. Fluorine must be introduced indirectly by the ^-epoxide formed by base treatment of the 9a-bromo-10p-hydroxy analogue (Figure 5.123). The resultant 9a-fluorocortisol 21-acetate (fluorohydrocortisone acetate; fludrocortisone acetate) (Figure 5.124) was found to be about 11 times more active than cortisol acetate. However, its mineralocorticoid activity was

,OAc

O OH

,OAc

Fludrocortisone Non Esterifi

fludrocortisone acetate (9a-fluorocortisol acetate)

fludrocortisone acetate (9a-fluorocortisol acetate)

dexamethasone

Syntetic Methylprednisolon

betamethasone methylprednisolone

methylprednisolone

betamethasone 17-valerate

dexamethasone

.OCOEt O

-OCOEt betamethasone fh2csk betamethasone 17-valerate

X = F, betamethasone 17,21-dipropionate X = Cl, beclometasone (beclomethasone) 17,21-dipropionate

Cl fh2csk

Total Synthesis Fluticasone

-OCOEt

fluticasone propionate

-OCOEt

fluticasone propionate

X = F, betamethasone 17,21-dipropionate X = Cl, beclometasone (beclomethasone) 17,21-dipropionate

Synthesis Beclometasone Propionate

fluorometholone clobetasol 17-propionate clobetasone 17-butyrate

Figure 5.124

rimexolone fluorometholone clobetasol 17-propionate clobetasone 17-butyrate

Figure 5.124

rimexolone

also increased some 300-fold, so its anti-inflammatory activity has no clinical relevance, and it is only employed for its mineralocorticoid activity. The introduction of a 9a-fluoro substituent into prednisolone causes powerful Na+ retention. These effects can be reduced (though usually not eliminated entirely) by introducing a substituent at C-16, either a 16a-hydroxy or a 16a/16^-methyl. The 16a-hydroxyl can be introduced microbiologically, e.g. as in the conversion of 9a-fluoroprednisolone into triamcinolone (Figure 5.125). The ketal formed from triamcinolone and acetone, triamcinolone acetonide (Figure 5.125) provides a satisfactory means of administering this anti-inflammatory by topical application in the treatment of skin disorders such as psoriasis. Methylprednisolone (Figure 5.124) is a 6a-methyl derivative of prednisolone showing a modest increase in activity over the parent compound. A 6-methyl group can be supplied by reaction of the Grignard reagent MeMgBr with a suitable 5,6-epoxide derivative. Dexamethasone and betamethasone (Figure 5.124) exemplify respectively 16a- and 16^-methyl derivatives in drugs with little, if any, mineralocorticoid activity. The 16-methyl group is easily introduced by a similar Grignard reaction with an appropriate a,p-unsaturated A16-20-ketone. Betamethasone, for topical application, is typically formulated as a C-17 ester with valeric acid (betamethasone 17-valerate), or as

Synthesis Betamethasone

9a-fluoroprednisolone triamcinolone triamcinolone acetonide

Figure 5.125

9a-fluoroprednisolone triamcinolone triamcinolone acetonide

Figure 5.125

the 17,21-diester with propionic acid (betamethasone 17,21-dipropionate) (Figure 5.124). The 9a-chloro compound beclometasone 17,21-dipropionate (beclomethasone 17,21-dipropionate) is also an important topical agent for eczema and psoriasis, and as an inhalant for the control of asthma. Fluticasone propionate (Figure 5.124) is also used in asthma treatment, and is representative of compounds where the 17-side-chain has been modified to a carbothiate (sulphur ester).

Although the anti-inflammatory activity of hydrocortisone is lost if the 21-hydroxyl group is not present, considerable activity is restored when a 9a-fluoro substituent is introduced. Fluorometholone (Figure 5.124) is a corticosteroid that exploits this relationship and is of value in eye conditions. Other agents are derived by replacing the 21-hydroxyl with a halogen, e.g. clobetasol 17-propionate and clobetasone 17-butyrate (Figure 5.124), which are effective topical drugs for severe skin disorders. In rixemolone, a recently introduced anti-inflammatory for ophthalmic use, neither a 21-hydroxy nor a 9a-fluoro substituent is present, but instead there are 17a-and 16a-methyl substituents. Rimexolone has significant advantages in eye conditions over drugs such as dexamethasone, in that it does not significantly raise intraocular pressure.

Many other corticosteroids are currently available for drug use. Structures of some of these are given in Figure 5.126, grouped according to the most characteristic structural features, namely 16-methyl, 16-hydroxy, and 21-chloro derivatives. The recently introduced deflazacort (Figure 5.127) is a drug with high glucocorticoid activity, but does not conveniently fit into any of these groups in that it contains an oxazole ring spanning C-16 and C-17.

Trilostane (Figure 5.127) is an adrenocortical suppressant, which inhibits synthesis of glucocorticoids and mineralocorticoids and has value in treating Cushing's syndrome, characterized by a moon-shaped face and caused by excessive glucocorticoids. This drug is an inhibitor of the dehydrogenase-isomerase that transforms pregnenolone into progesterone (Figures 5.92 and 5.114).

Spironolactone (Figure 5.127) is an antagonist of the endogenous mineralocorticoid aldosterone and inhibits the sodium-retaining action of aldosterone whilst also decreasing the potassium-secreting effect. Classified as a potassium-sparing diuretic, it is employed in combination with other diuretic drugs to prevent excessive potassium loss. Progesterone (page 273) is also an aldosterone antagonist; the spironolactone structure differs from progesterone in its 7a-thioester substituent, and replacement of the 17^ side-chain with a 17a-spirolactone.

alclometasone

desoximetasone

alclometasone desoximetasone

(used as 17,21-dipropionate) (desoxymethasone)

diflucortolone flumetasone (flumethasone)

(used as 21-valerate) [used as pivalate (trimethylacetate)]

fluocortolone (used as 21-hexanoate)

fluocortolone (used as 21-hexanoate)

budesonide

fluocinolone acetonide

fluocinonide

fluocinolone acetonide

fluocinonide

OH O

OH O

budesonide fludroxycortide (flurandrenolone)

fludroxycortide (flurandrenolone)

halcinonide

OH O

OH O

flunisolide

halcinonide

flunisolide

Cl sO

mometasone (used as 17-furoate)

mometasone (used as 17-furoate)

Figure 5.126

deflazacort

trilostane

Figure 5.127

deflazacort

trilostane r-f

Nature Review Trilostane Synthesis

spironolactone

spironolactone

Figure 5.127

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  • saare
    How can synthesis prednisone from diosgenin?
    8 years ago

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