Steroidal phosphonates

The steroidal phosphonic acid derivatives 366 and 367 have been synthesised and studied as potential drugs/probes for therapies in the treatment of infections due to various parasitic protists, including the AIDS associated Pneumocystis... 

Although other mechanisms are conceivable, the most likely scheme involves direct nucleophilic displacement by phosphite on carbon to furnish a trialkoxy phosphonium halide intermediate as in the Michaehs-Arbuzov reaction. Recently, we have developed an improved method for the preparation of Mannich bases of steroids and carried ouf reactions with their methiodides and trialkyl phosphite to obtain the first steroidal phosphonates to be reported (132). 

Newly diagnosed, asymptomatic patients may be observed without treatment. This asymptomatic period may last for months to a couple years. All patients with multiple myeloma will become symptomatic, and once this occurs, treatment is required. First-line treatment may be one of several therapies, including VAD, thalidomide plus steroids, and autologous transplant. Nearly all patients will progress at some point, and second-line therapy usually will include bortezomib. All patients who have bone lesions should receive monthly bis-phosphonates, with the hope of reducing pain and fractures. 

Further examples of the use of the hDA reaction in dihydropyran synthesis include the formation of the fused pyrans 18 from vinylallenes 17 and aldehydes (Scheme 8) <00TL6781> and a trans-fused dihydropyran containing a phosphonate group 19 . A total synthesis of the 11-oxa steroid system is based on an intramolecular Diels-Alder reaction involving an orthoquinodimethane derived from a benzocyclobutene (Scheme 9) <00TL1767>. 

More recent developments in the field of the Pirkle-type CSPs are the mixed r-donor/ r-acceptor phases such as the Whelk-Of and the Whelk-02 phases.The Whelk-Of is useful for the separation of underiva-tized enantiomers from a number of families, including amides, epoxides, esters, ureas, carbamates, ethers, aziridines, phosphonates, aldehydes, ketones, carboxylic acids, alcohols and non-steroidal anti-inflammatory drugs.It has been used for the separation of warfarin, aryl-amides,aryl-epoxides and aryl-sulphoxides. The phase has broader applicability than the original Pirkle phases. The broad versatility observed on this phase compares with the polysaccharide-derived CSPs... 

Bromo- and 2,4-dibromo-3-oxo-steroids are dehydrobrominated smoothly, and without rearrangement, by suitable phosphate and phosphonate salts [e.g. (Me0)2P02"NMe or Me0(Me)P02 NMe+] in DMF or acetonitrile. ... 

The phosphonic acid analog of NSAID (Non-Steroidal Anti-Inflammatory Drug) diclofenac was successfully synthesized in the laboratory of B. Mugrage using a novel acid catalyzed Arbuzov reaction as the key step followed by a TMSBr promoted dealkylation. It needs to be pointed out that the nucleophilic attack takes place on the ortho-quinonoid intermediate in a non-SN2 process. 

Methylthiotrimethylsilane converts aldehydes and ketones into bis(methyl-thio)acetals under very mild conditions, without the need for an acidic catalyst. 5a-Androstane-3,17-dione reacted selectively at C-3.The reaction appears to depend upon the high affinity of silicon for oxygen.2-Methylenepropane-l,3-diol protects ketones as acetals from which the ketones can be regenerated without resort to acidic treatment, if required.Hypophosphorous acid adds on to 3-oxo-steroids to give 3-yl phosphonous acids. 5a-Cholestan-3-one gives the 3-hydroxy-derivative (177), but a 4-en-3-one gives the 3,5-dien-3-yl phosphonous acid (178). ... 

The second section deals with the dynamics of organic primary ammonium salts of carboxylic acids, sulfonic acids, and phosphonic acids. Inspired by the steroidal crystals described above, our research has been extended to the supramolecular properties of organic salts. We focus on the latest research on solid-state fluorescence emission and pseudo-cubic hydrogen bonding clusters. It is noteworthy that the salts have practical advantages, including the relatively simple preparation oftheir crystals,... 

The year s reviews cover phosphorylated indoles, phosphorus-selenium compounds, phosphoryl carbenes, phosphorus-sulphur compounds, and steroid phosphates, as well as the synthesis of phosphorus esters via oxyphosphoranes. A review on phosphonates contains many interesting applications of some of the well-tried syntheses of these as analogues of natural phosphates. ... 

Hirai, S., Harvey, R.G., and Jensen, E.V., Phosphonic acids. Part 21. Steroidal 21a-phosphonate esters. Tetrahedron, 22, 1625, 1966. 

Zhang, J., and Xu, X., Total synthesis of 6-ep/-sarsolilide A, Tetrahedron Lett., 41, 941, 2000. Boehm, H.M.. I landa, S., Pattenden, G., Roberts. L.. Blake, A.J., and Li, W.-S., Cascade radical cyclizations leading lo steroid ring constructions. Regio- and stereo-chemical studies using ester- and fluoroalkene substituted polyene acyl radical intermediates.,/. Chem. Soc., Perkin Trans. 1, 3522, 2000. Hampton, A.. Sasaki, T, and Paul, B., Synthesis of 6 -cyano-6 -deoxyhomoadenosine-6 -phosphonic acid and its phosphoryl and pyrophosphoryl anhydrides and studies of their interactions with adenine nucleotide utilizing enzymes, J. Am. Chem. Soc.. 95. 4404, 1973. 

Conklin JJ, Alderson PO, Zizic TM et al (1983) Comparison of bone scan and radiograph sensitivity in the detection of steroid-induced ischemic necrosis of bones. Radiology 147 221-226 Council of Europe (2005) Technetium " Tc medronate injection. In European Pharmacopeia 5.0, monograph no 641. Council of Europe, Maisonneuve, Sainte-Ruffine, p 1219 Davis MA, Jones AG (1976) Comparison of " Tc-labeled phosphate and phosphonate agents for skeletal imaging. Semin Nucl Med 6 19-31... 

Among interesting olefin syntheses with ester phosphonates are those with the allenic aldehydes (141) and with the steroidal epoxy-aldehyde (142). The yield of allenic carboxylic esters has been increased to... 

Steroids possessing one or two isolated or conjugated double bonds are converted into their dihydrogen phosphates when brought into contact with (l-phenyl-l,2-dibromoethyl)phosphonic acid in the presence of ethyldiisopropyl-amine. The reactions presumably involve monomeric metaphosphate ion as the effective phosphorylating agent. ... 

The steroidal a-(isocyanomethyl)phosphonates (130) and (133) have been synthesized by methylation of the carbanions (129) and (132), respectively.66 Compounds (130) and (133) behave as N,P-ketals in that they can be hydrolysed to the corresponding ketones (131) and (134) (Scheme 10). A range of a-substituted a-aminophosphonic acids (136) have been prepared in moderate to excellent yield by the alkylation of the protected a-aminophosphonate (135) with alkyl and aryl halides and Michael acceptors under phase transfer catalysis (Scheme 11).67 The reactions of the lithium carbanion of diethyl prop-2-enyIphosphonate (137) with a,P-unsaturated ketones and esters have been investigated.6S Attack can be at the a- or y-positions in the phosphonate although in all cases Michael addition to the a, p-unsaturated carbonyl is preferred to attack at carbonyl carbon. In some examples simple adducts (138) are formed, but in more complex cases addition is followed by cyclisation to give (139) (Scheme 12). The bisphosphonate (141), which is a potent inhibitor of myo-inositol monophosphatase, has been prepared with the phosphonylation of the carbanion of (140) as a key step.6 9... 

Due to the common occurrence of steroids in Nature, there is not much need to synthesize the steroid skeleton from simple substrates. Therefore, the use of phosphonates in syntheses involving this class of compounds, concerns mostly modifications of the steroid pool, like in the case of the conversion of 17-oxo-steroids to 20-ketosteroids and progesterone as well as construction of the South steroid subunit of cephalostatin 1 from hecogenin acetate. 

Reaction of dimethyl phosphonate (74) with the steroidal dienyl triflate 73 gave the dimethyl alkenylphosphonate 75 [23]. Dimethyl alkynylphosphonate (77) was produced in one step by the reaction of 1,1-dibromo-l-alkenes 76 with dimethyl phosphonate (74) in DMF using Pd(OAc)2-DPPF as a catalyst and propylene oxide as a scavenger of HBr. The expected monocoupling product, bromovinylphos-phonate, was not obtained [24]. Phosphonates 78 can be converted to arylphos-phines 79 by reaction with aryl Grignard reagents, followed by reduction with HSiCls [25]. 

Provide a mechanistic interpretation of this transformation. See Henrick, C. A. Boehme, E. Edwards, J. A. Fried, J. H. Reaction of phospho-ranes and phosphonate anions with enol lactones. A new method for the preparation of cyclic a,)8-unsaturated ketones J. Am. Chem. Soc. 1968, 90, 5926-5927 for more information. (Steroids-4)... 

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