Steroid moiety synthesis

Microwave-assisted Heck reactions have also been carried out with triflates as coupling partners, involving some very complex molecules. Winterfeld and coworkers have reported a multigram synthesis of a complex non-symmetrical bis-steroidal diene by microwave-promoted coupling of the corresponding alkene and triflate steroidal moieties (Scheme 6.8) [27]. 

Encouraged by the success of MUMBIs to synthesize biaryl ether macrocycles, we endeavored to combine this methodology with experience in steroid synthesis to obtain very large macrocycles with both peptide and steroid moieties (Fig. 21). These molecules bear no direct resemblance to any known natural products, but they do display a high degree of structural... 

Most cationic lipids are composed of either two lipophilic tails or a steroid moiety, typically based on cholesterol. The classic method for steroidyl incorporation involves the reaction of a steroidyloxycarbonyl halide (e.g. cholesteryloxycar-bonyl chloride (2)) with primary amines from the linking moiety, a method used for the synthesis of most cholesterol-based cationic lipids including DC-Chol (3) [68, 72] (Fig. 2b) and BGTC (7) [73] (Fig. 3a). 

Bomah and co-workers [99] developed an efficient procedure for the synthesis of ring-A fused [3,2-h]pyrimidines 53 in a steroidal moiety. The novel steroidal pyrimidines were prepared via a solid phase three-component reaction of a 2-hydro-xymethylene-3-keto steroid, an arylaldehyde and ammonium acetate under micro-wave irradiation. This protocol has been applied successfully to the cyclization of bicyclic, monocyclic and acyclic 2-hydroxymethylene ketones with diversely substituted aromatic aldehydes (Scheme 39). 

A novel and versatile synthesis of dialkyl steroid phosphates employs the steroidal alkoxyl radical (545), generated by photolysis of the corresponding nitrite. In the presence of a trialkyl phosphite, the radical attacks at phosphorus to give a phosphoranyl radical (546), which loses one of its four alkyl groups to give the desired phosphate (547). The preference for expulsion of one of the small alkyl groups, rather than the steroidal moiety, is thought to be determined by... 

The synthesis of the steroidal moiety of batrachotoxin (459) has been attempted. In a first pilot-reaction sequence, 5/ 0,19N-[ep(oxyethano-N-methylimino)]-androstan-17-ol (461) was prepared from 17)5,19-diacetoxyandrost-4-en-3-one (460) by a multi-step sequence. The technique developed in this model synthesis was then applied to build the C(14)-C(18) ring of 3)5,20( -diacetoxy-14)50,18AT-[ep(oxyethano-N-methylimino)]-5a,17a-pregnane (463) from the pregnane intermediate (462). This experience was used in the synthesis of 3-0-methyl-17a,20( -tetrahydrobatrachotoxinin A (472) (see Schemes 37 and 38). ... 

The synthetic procedure developed for the preparation of active fonns of vitamin D analogues was applied to the synthesis of various natural steroids by the reaction of steroid moieties with phenyl sulfone derivatives described here. 

From the point of view of a synthetic polymer chemist, there could be four viable routes available for preparing polymeric drugs. They have been described elsewhere. We planned to make use of one particular strategy which requires the synthesis of the steroid based monomers first and finally to polymerize this monomer under appropriate conditions. In this case, each repeat unit of the polymer will carry the steroid moiety. The retrosynthetic analysis is shown in Scheme 1. 

Intermolecular [4C+2S] cycloaddition reactions where the diene moiety is contained in the carbene complex are less frequent than the [4S+2C] cycloadditions summarised in the previous section. However, 2-butadienylcarbene complexes, generated by a [2+2]/cyclobutene ring opening sequence, undergo Diels-Alder reactions with typical dienophiles [34,35] (Scheme 59). Also, Wulff et al. have described the application of pyranylidene complexes, obtained by a [3+3] cycloaddition reaction (see Sect. 2.8.1), in the inverse-electron-demand Diels-Alder reaction with enol ethers and enamines [87a]. Later, this strategy was applied to the synthesis of steroid-like ring skeletons [87b] (Scheme 59). 

The forerunner in the Co-catalyzed [2+2+2] cycloaddition domino processes was that identified by Vollhardt and colleagues [273], with their excellent synthesis of steroids. Reaction of 6/4-1 with [CpCo(CO)2] gave compound 6/4-3 with an aromatic ring B via the intermediate 6/4-2. In this process, trimerization of the three alkyne moieties first takes place, and this is followed by an electrocyclic ring opening of the formed cyclobutene to give o-quinodimethane. This then undergoes a Diels-Alder reaction to provide the steroid 6/4-3 (Scheme 6/4.1). 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

In 2000, Szarka and coworkers reported some preliminary results on the facile synthesis of steroidal hydroxamic acid derivatives via the palladium-catalyzed function-ahzation of skeletons (138-141) possessing iodoaikene moieties (Scheme 65). 

Polyene cyclization in terpene and steroid synthesis is critically dependent on the terminator in order to generate useful functionalities for further modification of the products. Allyl- and propargylsilanes have proven their value in facilitation of the cyclization and generation of an exocyclic methylene and allene, respectively. Thus, a concise approach to albicanyl acetate [126] and the rapid construction of a tetracyclic precursor of steroids [127] are sufficient to demonstrate the concept. Again, a comparison of the substrates with a silyl group with those having a simple alkyl moiety is very enlightening. 

Lehn synthesised guanidinium-based cationic steroids incorporating an acylhy-drazone linker using the approach shown in Fig. 9 [141]. The synthesis was developed from a polyamine scaffold by guanidination of the primary amino groups and alkylation of the secondary amine with methyl chloroacetate to introduce the ester moiety required to form a hydrazide group by reaction with hydrazine monohydrate. Cationic steroid hydrazones were then prepared via an acetic acid catalysed reaction with cholestanones, which demonstrated high transfection efficiency and low toxicity in a variety of cell lines [141]. 

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