Steroidal acrylates

In the laboratory of D.A. Holt, the synthesis of a new class of steroid 5 -reductase inhibitors was undertaken. They found that unlike the steroidal acrylates, steroidal A ring aryl carboxylic acids exhibit greatly reduced affinity for rat liver steroid 5 -reductase. The tested steroidal A ring carboxylic acids were synthesized from estrone in one example, fluorine was incorporated into the 4-position of estrone via the Balz-Schiemann reaction. 

Bystrom et al. [9] used MIPs generated by the ester methodology for the selective reduction of steroid ketones. The sterol was converted at the 3- or 17-position into the acrylate esters (17-steroid acrylate ester 6 shown in Fig. 4). 

Diene carboxylates can be prepared by the reaction of alkenyl halides with acrylates[34]. For example, pellitorine (30) is prepared by the reaction of I-heptenyl iodide (29) with an acrylate[35]. Enol triflates are reactive pseudo-halides derived from carbonyl compounds, and are utilized extensively for novel transformations. The 3,5-dien-3-ol triflate 31 derived from a 4,5-unsaturated 3-keto steroid is converted into the triene 32 by the reaction of methyl acrylate[36]. 

The protic catalytic conditions are also compatible with trapping of the radicals formed after cyclization with acrylates or acrylonitriles prior to their reduction with Cp2TiCl . In this manner highly substituted alkenes for the potential preparation of modified steroids can be accessed (Scheme 19) [97]. 

Thiemann and coworkers [68] sought novel types of steroids with different biological activity, and in doing so prepared areno-annulated compounds such as 6/1-133 (Scheme 6/1.35). This is achieved with a Heck reaction of 6/1-132 with an acrylate, followed by an electrocydic ring closure of the formed hexatriene. The reaction is then terminated by removal of the nitro group, with formation of the aromatic ring system. 

With the exception of the parent compounds, where the Michael adducts are isolated, acrylic esters [see, e.g. 6,7,31,105,111 ] and nitriles [6,7], and vinyl ketones [26, 113, 115] generally yield the cyclopropanes (Table 7.6) under the standard Makosza conditions with chloroform. Mesityl oxide produces a trichlorocyclopropy-lpropyne in low yield (10%) [7]. When there is no substituent, other than the electron-withdrawing group at the a-position of the alkene, further reaction occurs with the trichloromethyl anion to produce spiro systems (35-48%) (Scheme 7.12) [7, 31]. Under analogous conditions, similar spiro systems are formed with a,p-unsaturated steroidal ketones [39]. Generally, bromoform produces cyclo adducts with all alkenes. Vinyl sulphones are converted into the dichlorocyclopropane derivatives either directly or via the base-catalysed cyclization of intermediate trichloromethyl deriva-... 

Phases of extended length (C30) have been utilized for the separation of larger-size constrained solutes, such as carotenoids and steroids [27-29,93,106,107]. Apractical limit of alkyl chain length of C34 to C36 is imposed by the commonly employed silan-ization chemistry techniques [106]. Immobilization of longer alkyl stationary phases has been achieved through the use of poly(ethylene-co-acrylic acid) materials for use in carotenoid separations [27,28,93]. Rimmer et al. [28] have recently compared the selectivity of both alkyl and poly(ethylene-co-acrylic acid) stationary phases on the basis of separations of carotenoids in food matrices (Figure 5.12), in addition to mixtures of tocopherols and PAHs. 

The number of investigations on the enantioselective dipolar cycloaddition of nitronates is still rather limited. In the case of simple alkyl nitronates, the facial selectivity is controlled solely by the steric environment about the two faces of the chiral unit. For example, the reaction of steroid dipolarophile 270 proceeds with the nitronate approaching the Re face of the alkene (Eq. 2.23) (234). The facial selectivity is controlled by the C(19) methyl group, which blocks the Si face of the dipolarophile. Similarly, exposure of 279 to ethyl acrylate at 40 °C for 24 h, provides a single nitroso acetal (Scheme 2.21) (242). The facial selectivity is presumed to arise from steric shielding by the menthol group, however the full stereostructure has not been established. 

Ene reaction with methyl acrylate.3 Methyl acrylate undergoes an ene reaction with (Z)-ethylidene steroids (1) in the presence of one equiv. of C2H5A1C12 to afford... 

PNIPAM and its copolymers are not the only options for thermoresponsive stationary HPLC phases. Poly(acrylates) and poly(methacrylates) bearing OEG groups in the side chains are known as thermoresponsive polymers that offer some advantages over PNIPAM [40]. Such polymers were recently employed for the modification of silica monoliths, which then served as stationary phase in the HPLC separation of steroids [193], Unsurprisingly, the results were qualitatively similar to those obtained for PNIPAM-based systems, but the separation of relatively hydrophilic steroids was superior. 

Another successful example is the separation of a series of steroids listed in Fig. 6.11 using a monolithic capillary column prepared by redox initiated polymerization of a solution of acrylamide 4, methylene bisacrylamide 5, vinylsulfonic acid 12, and dodecyl acrylate 18 in N-methylformamide/TRIS-boric acid buffer (pH 8.2) to which polyethylene glycol) (MW 10,000) was added (overall composition 5% T, 60% C, 10% vinylsulfonic acid, 15% lauryl acrylate, 3% polyethylene glycol)). The capillary tube was first vinylized and its part beyond the detection window was coated with linear polyacrylamide to avoid band broadening. Since laser induced fluorescence was used to decrease the detection limit of the method to about 100 attomoles for neutral steroids, all of the analytes were first tagged with dansylhydrazine. Fig. 6.12 shows an... 

Separations of complex steroid mixtures were achieved recently by Que et al. [76] using both isocratic and gradient elution. Mass spectrometric detection gave femto-mole detection limits while laser-induced fluorescence of dansylated ketosteroids ranged in attomole levels (Fig. 10.16). Monolithic column packings were used with a 35 cm (25 cm packed bed) x 100 pm i.d. capillary packed with a polymer prepared from 5% T (total monomer concentration), 60% C (total crosslinker concentration), 3% polyethylene glycol, 10% vinylsulfonic acid and 15% lauryl acrylate. Details of the monolithic column preparation can be found in refs. 36,76, and 193. Similar monolithic columns can be used for the separation of bile acids [194],... 

Willson TM, Henke BR, Momtahen TM, Charifson PS, Batchelor KW, Lubahn DB, Moore LB, Oliver BB, Sauls FIR, Triantafillou JA, Wolfe SG, Baer PG (1994) 3-[4-(l,2-Diphenylbut-l-enyl)phenyl]acrylic acid a non-steroidal estrogen with functional selectivity for bone over uterus in rats. J Med Chem 37 1550-1552... 

These examples demonstrate that a selective Heck-Diels-Alder sequence with two different alkenes is only possible either in a stepwise manner, if an alkene reacts much faster in the Heck reaction than in the subsequent cycloaddition so that the 1,3-diene can be isolated, or as a real cascade reaction if one alkene is more reactive and thus selectively reacts as a coupling partner, whereas the other one is a better dienophile. Both concepts have been used by Kollar et al. for the annelation of cyclohexene rings onto the steroidal skeleton 26 (Scheme 4) [28-30]. At 60 °C the cycloaddition was sufficiently suppressed so that the Heck coupling product 29 could be isolated and subsequently subjected to Diels-Alder reactions with different dienophiles. For a domino reaction with both methyl acrylate and dimethyl fumarate (28) present in the reaction mixture, the conditions had to be precisely adjusted so that the mixed products 31 and 32 were formed predominantly along with only small amounts of the products of a twofold reaction of either 27 (R = CC Me) or 28 with 26. These conditions also proved suitable for a cascade reaction of 26 involving allyl alcohol 27 (R = CH2OH) or allyl acetate 27 (R = CH2OAc) and dimethyl fumarate (28). 

Drawn from these examples it is apparent that controlling the chemose-lectivity in inter-intermolecular Heck-Diels-Alder reactions of two different alkenes can be tedious if the alkenes show comparable reactivities. Nevertheless, the stepwise approach was realized in several other cases. In a synthesis of a derivative of cephalostatin 1 containing a central benzene instead of the pyrazine ring, Winterfeldt et al. linked two steroidal systems by a Heck coupling and subsequently performed high pressure Diels-Alder reactions of the conjugated diene with electron-deficient alkynes [34], Another example, reported by Hayashi et al., involves a selective Heck reaction of a bromoglu-cal with ethylene or acrylic acid derivatives followed by cycloadditions with maleic anhydride or N-phenylmaleimide [35]. 

Singlet oxygen can be used to oxidize a range of substrates, such as phenols, acrylics, steroids and terpenes.162... 

Polymer-other species have also been described in the literature. Carriers of vitamin E have been prepared from a-tocopherol methacrylate monomers. These would have potential use as antioxidants to protect against cellular damage. Poly(acrylate)s that release non-steroidal anti-inflammatory drugs (NSAIDs) through hydrolysis of links to the backbone have also been described. ... 

PVP forms molecular adducts with many substances. Insoluble complexes are formed when aqueous solutions of PVP are added to tannic acid, poly(acrylic acid) and methyl vinyl ether-maleic anhydride copolymer. Soluble complexes, called iodophors, are formed with iodine the solubility of iodine is increased from 0.034% in water at 25°C to 0.58% by 1% PVP. The resulting iodophor retains the germicidal properties of iodine. It is thought that the iodine is held in a PVP helix in solution. The influence of two samples of PVP on the solubility of testosterone is shown in Fig. 8.21. The PVP correspondingly increases the rate of solution of the steroid from solid dispersions. 

Regioselective acylations of polyhydroxylated compounds such as carbohydrates, glycerols, steroids, or alkaloids have been carried out with lipases, esterases, and proteases [13, 20]. One example is the Candida antartica lipase (immobilized on acrylic resin) catalyzed monoacylation of the signalling steroid ectysone (1) giving selectively the 2-C)-acetate 2 (eq. (1)). Using vinyl acetate for this transesterification the reaction was irreversibly pushed to the product side, since the liberated enol instantaneously isomerizes to acetaldehyde [21]. The sometimes unfavorable aldehyde is avoided when 1-ethoxyvinyl acetates [22], trichloro- or -fluoroethyl esters [23 a, b], oxime esters [23 c] or thioesters [23 d] are employed for the quasi-irreversible reaction courses. 

Steroids substituted by spiro-a-methylene-7-lactones [e.g. (431)] have been synthesized as possible antitumour agents by Reformatsky reactions between ethyl 0 -(bromomethyl)acrylate and suitable steroid ketones. 

Schubert, G., Schbnecker, B.. Wunderwald, M.. and Ponsold, K.. Synthesis of 17P-configurated acrylic acid derivatives of 19-nor steroids, Pharmazie. 41, 469, 1986. 

A novel class of complexes, Ir-(5 )-26a, with chiral spiro aminophosphine ligands was found to be effective catalyst for the asymmetric hydrogenation of a-substituted acrylic acids (Scheme 11) [62]. Under mild reaction conditions and at ambient pressure, various a-aryl and alkyl propionic acids were produced with extremely high efficiency (TONS up to 10 000 TOFs up to 6000h ) and excellent enantioselectivity (up to 99% ee). This reaction provides a practically useful method for the preparation of a-aryl propionic acids, a popular class of non-steroid anti-inflammtory reagents. 

The classic Diels-Alder reaction continues to be applied to steroidal dienes and has been used to prepare benzene-fused compounds (277) (from 6-methylene testosterone ), and (278) and (279) [from the furano-steroid (217) ] and adducts between A -dienes and methyl acrylate, hexafluorobut-2-yne, dimethylacetylene dicarboxylate, and methyl propiolate have been obtained. In this last reaction the mono-adduct (280) was accompanied by a diadduct, assigned the structure (281), which arises from homo-conjugate Diels-Alder addition and which appears to be the first example of homo-conjugate addition to a substituted bicyclo[2,2,l]heptadiene. The diadduct was also obtained in good yield by treatment of the mono-adduct with more methyl propiolate. 

The q -phenol complex undergoes conjugate addition at C4 with a variety of Michael acceptors (Fig. 7), including those with p substituents [44]. In most cases, the addition reaction is accomplished with an amine base as catalyst (see 25). Less reactive electrophiles, such as methyl acrylate or acrylonitrile, require a Lewis acid co-catalyst (e.g., 24). An example of the versatility of this reaction is shown in Fig. 7, where the aromatic steroid p-estradiol (26) is complexed (27) and subsequently alkylated exclusively at CIO (i.e.,para) at -40 °C. Since the osmium preferentially binds the a face of the steroid in 27, conjugate addition occurs from the p face, yielding the stereochemistry found in testosterone [26]. The overall yield of this transformation after decomplexation of the dienone product 29 is 69%. 

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