Alkenes steroidal, oxidation

Acetoxy-l,7-octadiene (40) is converted into l,7-octadien-3-one (124) by hydrolysis and oxidation. The most useful application of this enone 124 is bisannulation to form two fused six-membered ketones[113]. The Michael addition of 2-methyl-l,3-cyclopentanedione (125) to 124 and asymmetric aldol condensation using (S)-phenylalanine afford the optically active diketone 126. The terminal alkene is oxidized with PdCh-CuCh-C to give the methyl ketone 127 in 77% yield. Finally, reduction of the double bond and aldol condensation produce the important intermediate 128 of steroid synthesis in optically pure form[114]. 

Longer templates promote chlorination over greater distances. In compound (11 Scheme 17) the biphenyl template promotes chlorination of C-17 with good selectivityDehydrochlorination forms the A - ene (12) in reasonable (66%) yield this has been used in an indirect scheme to remove the side chain of cholesterol and of sitosterol to afford the 17-keto steroid. Under other conditions the 17-chloro steroids can be dehydrochlorinated toward C-20, and the resulting A < >-alkenes directly oxidized to afford the 17-keto steroid. - ... 

Steroids Carbonyl Compounds Cycloaddition Enone and Dienone Rearrangements Alkenes Isomerisation and Rearrangement Alkenes Cycloaddition Alkenes Photo-oxidation Terpenoids Aromatic Compounds Isomerisation and Cycloaddition Practical Photochemistry Scale-up Aromatic Compounds Substitution and Cyclisation Alkaloids Photoinitiated Free-radical Chain Reactions. 

Intramolecular reaction can be used for polycyclization reaction[275]. In the so-called Pd-catalyzed cascade carbopalladation of the polyalkenyne 392, the first step is the oxidative addition to alkenyl iodide. Then the intramolecular alkyne insertion takes place twice, followed by the alkene insertion twice. The last step is the elimination of/3-hydrogen. In this way, the steroid skeleton 393 is constructed from the linear diynetriene 392(276]. 

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-... 

Not unexpectedly, cycloalkene oxides are equally important as alkene oxides in medicinal chemistry and drug metabolism, as illustrated below with a few selected examples. Other compounds of interest that will not be discussed here include epoxytetrahydrocannabinols and endogenous 16,17-ep-oxy steroids. 

Steroids and sterols represent an important class of drugs that are susceptible to oxidative degradation through the possession of alkene moieties. The oxidation of phenothiazines forms the sulfoxide moiety. 

The first observation of the c/x-dihydroxylation reaction with RuO was made by Sharpless et al. in 1976, who noted that E and Z-cyclododecene were oxidised by stoich. RuO /EtOAc/-78 C to the threo and erythro diols [299]. Later RuCyaq. Na(IO )/EtOAc-CH3CN/0 C was used and reaction conditions optimised for many alkenes [300] a useful paper with good practical examples discusses the scope and limitations of the procedure (Table 3.2) [301]. Later oxidations were done with stoich. RuOyaq. acetone/-70 C [302] the same reagent converted A, and A steroids to cw-diols, ketones or acids [303], while RuO /aq. Na(10 )/acetone gave diones and acids [304]. 

An enantioselective synthesis of (+)-estradiol has been accomplished from 1,3-dihy-drobenzo[c]thiophene 2,2-dioxide (306) by successive thermal S02-extrusion and cycloaddition (80HCA1703). Treatment of the optically active iodide (307) with two mole equivalents of the masked quinodimethane (306) in the presence of two mole equivalents of sodium hydride gave (308) as a 1 1 mixture of diastereoisomers. Thermolysis of this alkenic sulfone in 1,2,4-trichlorobenzene furnished the trans-anti-trans steroid (309) in 80% yield. Treatment of (309) with methyllithium gave the methyl ketone, which was subjected to a Baeyer-Villiger oxidation and then silyl ether-acetate cleavage to afford (-l-)-estradiol (310 Scheme 66). 

This section includes oxidations of alkanes and cycloalkanes, alkenes and cycloalkenes, dienes, alkynes, aromatic fluorocarbons, alcohols, phenols, ethers, aldehydes, ketones and carbohydrates, carboxylic acids, nitrogen compounds, and organoelement compounds, such as boron, phosphorus, sulfur, selenium, and iodine compounds, and steroids. 

Owing to their relevance in steroid chemistry Okamoto et al. investigated aerobic allylic hydroxylations of octahydronaphthalene derivatives such as lc in the presence of Fe(III) picolinate complexes Fe(PA)3H20 (Scheme 3.21) [108]. The combination of electrolysis and the Fe(PA)3-02-MeCN system suppressed epoxidation almost completely, leading exclusively to the oxidation products 2c and 3c, albeit with low yields. In contrast, when alkene lc was submitted to chemical oxidation using the... 

As a striking exanqrle, photo-initiated chlorination (Scheme 21) of 3 mM (19) with 1.5 equiv. PhICb led to the 9-chloro derivative (20) in >98% yield with Ag this was converted to the A -alkene. Again the template-directed reaction overcomes the normal reactivity of the substrate, but at 21 mM (19) undirected reactions start to compete and some 6-chloro steroid is also formed. A pyridine A(-oxide template, that can use three-electron bonding to complex a chlorine to the oxygen atom, seems to be almost as effective. Furthermore, an imidazole template in compound (21) directs chlorination at C-9 with similar efficiency to the templates previously examined, and (21) is particularly easily prepared using caibonyldiimidazole. 

Earlier work using lead(IV) azide or persulfate mediated by iion as oxidant has beat reviewed this last procedure, a radical redox one, can work very well (Scheme 47). Dimes can undergo 1,4-ad-ditimi with lead(IV) azide " reactions with steroid alkenes are varied (refs. 152,154 and references cited therein, and Section 3.5.11) but can yield the 1,2-adducts. 

However, the oxidation of other steroid alkenes with Cr02X2 (X Cl, F) is affected by the structure of substrates. For example, cholesteryl acetate (22), when treated at -70 to -30 C, produces 3p-acetoxy-5a-chlorocholestan-6-one (23 12%), a mixture of a> and p-cholesteryl acetate epoxides (24 acetoxy>6p-chlorocholestan-6a-ol (25 9%) and 3p-acetoxy-5a-chlorocholestan-63-ol (25 equation 8). 

More recently, methods based on the use of mild reductants, able to transfer a single electron to the polyhaloalkyl halide, have been described. Various metals or their derivatives have been employed ruthenium, platinum and their complexes in low oxidation state, iron" and its carbonyl complexes, or tetrakis(triphenylphosphane)palladium. Sodium arcncsul-finate, sodium dithionite" and various oxidants have also been used. Other examples of polyhaloalkyl halide additions to simple alkenes are summarized in Table 1. Typical examples are the formation of diiodide 6, chloro iodide 7, and iodo steroid 8. ... 

A functionalization that converts C—H bonds to C— NO bonds occurs when nitrite esters are photo-lyzed (the Barton reaction Scheme 4). Again an alkoxyl radical abstracts a 8-hydrogen, and the resulting carbon radical picks up NO. The product nitroso compounds convert easily to oximes. Particularly valuable examples have bMn studied in the steroid field. If the photolysis is performed in the presence of copperfll) acetate the intermediate carbon radical can be oxidized to an alkene, rather than capture NO. If the alcohol whose nitrite ester is photolyzed is part of a cyanohydrin, then the Heusler-Kalvoda reaction occurs, and the product is a ketone with a migrated cyano group (Scheme 5) ... 

In contrast to lead tetraacetate, simple addition to the double bond does not occur as a side re-action. While allylic rearrangement is common and mixtures of products are frequently obtained, the reaction often proceeds in very high yield and is simple to carry out the alkene is simply heated in an appropriate solvent with mercury(II) acetate until reaction is complete. Mercury(II) acetate has also been us for dehydrogenation, particularly in the steroid field. One interesting example incorporating simultaneous dehydrogenation and allylic oxidative rearrangement is seen in the reaction of abietic acid (37 equation 16). ... 

Heathcock has reported an anomalous case of ozonolysis of a silyl enol ether. Usually these substrates undergo facile oxidative cleavage in the same manner as alkenes. However, in this instance the a-silyloxy ketone (61) was obtained in quantitative yield. The intermediacy of a silyloxy epoxide was suggested. A more recent report has indicated that a similar process is competitive with the simple cleavage reaction, (63a) versus (63b), in the ozonolysis of the steroidal enol ether (62). 

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