Steroid acyl chloride

As a catalyst for ester and amide formation from acyl chlorides or anhydrides, 4-(di-methylamino)pyridine has been recommended (DMAP G. Hdfle, 1978). In the presence of this agent highly hindered hydroxyl groups, e.g. of steroids and carbohydrates, are acylated under mild conditions, which is difficult to achieve with other catalysts. 

The usual reagents for acylation of steroid alcohols are acyl chlorides or acid anhydrides, in pyridine as catalyst and solvent, or acid anhydrides with mineral acids as catalyst. All secondary hydroxyl groups (except [12]) can be esterified in pyridine,... 

The full paper concerning the reaction of acyl chlorides (benzoyl and toluene-p-sulphonyl chlorides) with the steroidal nitrone derivative (23) of conanine has been published. Additional information concerning the mechanism of these reactions is given. Thus, it was shown that the formation of the a -benzyloxyimine (24) needs acidic conditions which favour the heterolysis of the N—O bond (Scheme 2). At room temperature, under Schotten-Baumann conditions, the epimeric compounds (25) were obtained from (23) with benzoyl chloride. Compound (25) gave (24) on refluxing in neutral solvent or by treatment with acid, whereas (24) was obtained directly from (23) when treated with a benzene solution of benzoyl chloride in the presence of aqueous sulphuric acid. 

Hydroxy compoimds such as alcohols, carbohydrates, steroids, and phenols are known to play important physiological roles. Although many analytical reagents have been developed for determination of hydroxy compounds, some of them can be also applied to amines as described in the previous section (e.g., isocyanates, sulfonyl chlorides, acyl chlorides, halogenobenzofurazans, acyl amides, and chloroformates). The derivatization conditions for hydroxy compounds are relatively more drastic than those for amines. By using fairly different conditions from those for amino compounds. 

Other, removable cation-stabilizing auxiliaries have been investigated for polyene cyclizations. For example, a sdyl-assisted carbocation cyclization has been used in an efficient total synthesis of lanosterol. The key step, treatment of (257) with methyl aluminum chloride in methylene chloride at —78° C, followed by acylation and chromatographic separation, affords (258) in 55% yield (two steps). When this cyclization was attempted on similar compounds that did not contain the C7P-silicon substituent, no tetracycHc products were observed. Steroid (258) is converted to lanosterol (77) in three additional chemical steps (225). 

The thiocyanatohydrin must be acylated in a second step to provide substrates for thiirane syntheses. The most convenient acylating agent, methane-sulfonyl chloride, has been used to prepare thiiranes at the 1,2 (A-nor)-, " 2,3-, 3,4-, " 5,6-, ll,12-, o 14,15- ° and 16,positions of steroids in high yield, e.g., conversion of (126) to (129). 

The acylation of enamines has been applied to the use of long-chain acid chlorides (388) and particularly to the elongation of fatty acids (389-391) and substituted aliphatic acids (392). The method has been used in the synthesis of the antineoplastic cycloheximide and related compounds (393-395) and in the acylation of steroids (396). Using an optically active chlorocarbonate, an asymmetric synthesis of lupinine could be achieved (397). 

The scheme used to prepare the direct 8-aza-analogue 21 of estrone bears at least formal similarity to the Torgov-Smith steroid total synthesis sequence. Acylation of the phenethylamine 9 with acryloyl chloride gives amide 16. Michael addition of dimethylamine followed by Bischler-Napieralski cyclodehydration gives the dihydroisoquinoline, 17. 

Ethoxycarbonyl chloride is, by virtue of resonance involving the ester function, less reactive than acetyl chloride, and the reagent has found application for selective O-acylation in the steroid field.34 With this reagent, methyl 4,6-O-benzylidene-a-D-glucopyranoside yielded35 2- and 3-esters in the ratio 24 1, and the related benzyl-thiocarbonyl chloride gave the 2-ester in 58% yield.36... 

A chiral recognition was observed in aminolysis of 3-acyl-4(R)-methoxycarbonyl-l,3-thiazolidine-2-thione, a derivative of (R)-cysteine, by racemic amines to give an optically active amide [(S)-excess] and amine [(R)-excess]264). In the reaction of cyclic meso-1,3-diols with chiral N-protected phenylalanyl chlorides, Yamada et al.26S) observed the preferential formation of one of the two possible diastereomeric monoesters, which has been used for the synthesis of optically active steroids 266) and prostaglandins 267). 

Other workers [358] carried out the acylation of estrogens in acetone and reported the following conditions as optimal for the preparation of tris-HFB-estriol 0.1—0.3 jul of acetone per 1 jug of the substrate and 0.05 ml of HFB anhydride at room temperature for 10 min. The use of a larger amount of another solvent (benzene, methylene chloride, dimethyl sulphoxide, diethyl ether, dioxane) was said to result in the formation of a number of by-products. Poole and Morgan [359], however, stated that the HFB derivatives of some steroids are not thermally stable and that only the decomposition product is detected, e.g., cholesta-3,5-diene is produced from cholesterol. This leads to a considerably lower ECD response, so that the detection limit, which under favourable circumstances can be as low as 0.005 ng, is usually not achieved. As steroids that form unstable HFB derivatives they reported cholesterol, lumisterol, ergosterol, estradiol, pregnanetriol and others. 

The Leukart reaction has also been used in the conversion of dehydroepiandro-sterone into 17/3-formylamino-3/3-formyloxyandrost-5-ene, which on reduction with lithium aluminium hydride afforded 3/3-hydroxy-17/3-me thylaminoandrost-5-ene. Acylation with isocaproyl chloride then furnished the N-methyl-N-isocaproyl steroid (197), after selective ester hydrolysis of the initially formed ON-diacyl derivative. The amide (197) was further converted into its 3,5-cyclo-6-ketone via the 3,5-cyclo-6/3-alcohol and thence by reaction with hydrogen bromide into the corresponding 3/3-bromo-5a-6-ketone which upon dehydrobromination furnished a A2-5a-6-ketone and ultimately the 2-monoacetate of the 2/3,3/3-diol (198) after reaction with silver acetate and iodine. Hydrolysis to the 2/3,3/3-diol (198) gave a separable mixture of the 2/3,3/8-dihydroxy-5a- and -5/3-ketones.88... 

Low-valent metal salts have been used to bring about reductive cleavage of oximes. Corey and Rich-man used chromium(II) acetate to convert O-acetyl ketoximes into imines, which were hydrolyzed to ketones. " Aqueous titanium(III) chloride and vanadium(II) salts also reduce oximes again, the imines are usually hydrolyzed in situ, but some hindered imines, such as compound (37), are isolable." A method of preventing hydrolysis is to carry out the reduction in anhydrous conditions in the presence of an acylating agent. The products of such reactions, when applied to oximes of enolizable ketones, are en-amides. For example, these ketoximes are converted into A/-formylenamines when heated in acetonitrile with anhydrous titanium(III) acetate and acetic formic anhydride cyclohexanone oxime gives the en-amide (38 97% Scheme 22)." This type of reduction has been used by Barton and coworkers to prepare enamides from steroidal oximes. They reported that the reaction could be performed by acetic... 

The conditions used by Stille provided an increased rate of conversion in a related synthesis of a steroid precursor (equation 93) however, HMPA was the solvent. Enone (113) was previously synthesized in 40-44% yield by aluminum chloride mediated acylation of ethylene. ... 

Replacement of side chain carbon C21 by thioester sulfur retains corticoid activity and at the same time provides a function that is destroyed by serum enzymes. The synthesis starts with the potent antiallergic agent flumethasone (32-1). Reaction of that steroid with periodic acid cleaves the terminal bond in the hydroxyacetone side chain to give the hydroxyl acid 32-2 (Scheme 7.32). Steric hindrance around the acid invoke the need for extra activation of that function. Reaction of 32-2 with diphenyl chlorophosphate thus provides the mixed anhydride 32-3. This intermediate is not isolated but reacted in situ with AA -thioformamido chloride. The transient new mixed anhydride, 32.4, then undergoes an internal O to S rearrangement to give the acyl thioacid 32-5. Saponification with sodium hydroxide affords the corresponding thioacid. Alkylation of that intermediate with fluoromethyl bromide then yields the fluoromethyl thioester fluticasone (32-6). 

Similar diyne intermediates have been used by Volhardt and coworkers in an acylation/addition manner for steroid ring syntheses. Acetylenic precusors have also found a place in addition/acylation reactions. Propyne with 2,3-dimethylbut-3-en-oyl chloride gave 2,3,5-trimethylphenol and but-3-enoyl chloride with but-2-yne resulted in 2,3-dimethylphenol (ref. 72)..The outcome of using trimethylsilylacetylene in this reaction would be of interest. 

Vapour phase acylation procedures, as described earlier with acetyl chloride [33], have also been successfully used with the similarly volatile and reactive perfluoro-acyl anhydrides on a variety of compounds including several steroids. The 17-hydroxyls reacted very rapidly, but the enol groups of the 3-keto compounds took variably longer times to react completely, and so it may be preferable to convert them to methoximes. 

---