Steroidal dienes, cycloaddition

In Situ Preparation of 5H-1,2,4-THazole-3,5(4//)-diones and Their Cycloaddition to Steroidal Dienes General Procedure101 ... 

The hetero-Diels-Alder reaction of steroidal dienes (156) with nitroso-aromatics are regioselective with two stereoisomers (157) and (158) produced in a 2 1 ratio (Scheme 60) The regio-, stereo-, and enantio-selectivity of 4 -I- 2-cycloadditions of nitrosoalkenes to alkenes have been extensively reviewed.The intramolecular acylnitroso Diels-Alder cycloaddition of (159) produced the bicyclic adducts (160) in high yields (Scheme 61). ... 

The photochemical addition of simple olefins to a,j -unsaturated ketones is a reaction of great current interest. The steroidal A -20-ketone system is especially prone to cycloaddition under mild conditions. Sunder-Plassmann et irradiated 3j5-acetoxypregna-5,16-dien-20-one (67) in the presence... 

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). 

Dihydro-1-vinylnaphthalene (67) as well as 3,4-dihydro-2-vinylnaphtha-lene (68) are more reactive than the corresponding aromatic dienes. Therefore they may also undergo cycloaddition reactions with low reactive dienophiles, thus showing a wider range of applications in organic synthesis. The cycloadditions of dienes 67 and 68 and of the 6-methoxy-2,4-dihydro-1-vinylnaphthalene 69 have been used extensively in the synthesis of steroids, heterocyclic compounds and polycyclic aromatic compounds. Some of the reactions of dienes 67-69 are summarized in Schemes 2.24, 2.25 and 2.26. In order to synthesize indeno[c]phenanthrenones, the cycloaddition of diene 67 with 3-bromoindan-l-one, which is a precursor of inden-l-one, was studied. Bromoindanone was prepared by treating commercially available indanone with NBS [64]. 

Synthesis of 16,16,16-trifluororetinal requires the constmction of a quaternary center bearing a CF3 group. For this, a Diels-Alder cycloaddition (cf. trifluoromethyl steroids) between a trifluoromethacrylate and a functionahzed diene has been conducted. The obtained adduct has been transformed further into the trifluoromethyl analogue of jS-cyclocitral (Figure 4.26). ... 

Photo-[4+2] reactions of the dienone steroid 105 illustrates interesting regio-, stereo-, and site selectivities (Sch. 24) [75-78]. Reaction with 1-acetoxy-1,3-diene 106 gives trans adduct 107 in good yield, epimeric at the acetate. The trans cycloaddition was attributed to a triplet pathway rather than a twisted enone intermediate [75]. Reaction with 2,3-dimethyl-1,3-butadiene 108 leads to four [4+2] adducts, with reaction at both alkenes groups of the dienone. Note that the products of reaction at the y,5-alkene are both cis. 

The fused pyrrole ring system (204) has been obtained by the reaction of 17/3-hydroxy-17-methylandrosta-l,4-dien-3-one with tosylmethyl isocyanide in the presence of sodium hydride in DMSO,92 and 17/3-hydroxy-17-methyl-7-oxa-5o -androstano-[3,2-c]- (205) or -[2,3-d]-isoxazoles (206 X = O) have been prepared by treating 7-oxa-2-(hydroxymethylene)-17/3 -hydroxy-17-methyl-5 a -androstan-3-one with hydroxylamine hydrochloride.93 In the presence of pyridine, the isox-azole (206 X = O) is formed, but when the reaction is catalysed by sodium acetate in acetic acid the isomeric steroid (205) results. Cycloaddition of hydrazine hydrate to the same 2-hydroxymethylene-7-oxa-steroid results in the [3,2-c]pyrazole (206 X = NH). A similar addition is encountered in the reactions between 3/3-hydroxy-16-(hydroxymethylene)-5a-androstan-17-one and the substituted hydrazines RNHNH2 (R = H, o-COC6H4NH2, or p-COQHUNH ,) when the corresponding [17,16-c]pyrazoles (207) are formed after cyclization of the intermediate hydrazones.94... 

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]. 

Steroid-type molecules, e.g., 48, were generated from (l-alkynyl)carbene complex 11 by [4+2] cycloaddition of a TBSO butadiene to the C2-C3 triple bond of lk and subsequent two-alkyne annulation to the M = C bond (Scheme 17).75 Other polycyclic compounds have been obtained similarly by insertion of several alkyne units tethered by a carbon chain.76,77 It should be noted that an annulation of an aromatic ring instead of a 1,4-cycIohexa-diene is achieved if the diene component contains a potential leaving group, as shown in Schemes 16 and 17. 

Cycloaddition to steroid 2,4- and -5,7-dienes 26 and 28, as well as to levopimarie acid (24) takes place exclusively oil the a-face. 

Trienes are produced by treatment of the adducts with boron trifluoride85 87. However, the cycloaddition of 4-phenyl-3//-l,2,4-triazole-3,5(4//)-diones has been principally applied to protect steroidal 5,7-dienes allowing manipulation of other groups. The diene group is then... 

The Lewis acid-promoted Diels-Alder reaction has been employed in the assembly of steroid skeletons [108]. The cycloaddition reaction between a substituted bicyclic diene and 2,6-dimethylbenzoquinone produces two stereoisomers in a 1 5 ratio with a yield of 83 % when SnCU is used in acetonitrile. TiCU results in slightly higher selectivity (1 8) but a lower yield (70 %) (Eq. 70). 

Photochemical cycloadditions of homodienes are extremely rare. An unusual photocycloaddition of the 3-OXO-4,6-diene steroid 28 to 2,3-dimethylbutadiene has been reported.The reaction has been described as a [(27H- 27t) -t- (2n + 2a)] cycloaddition, but can also be explained as a sequence of two independent processes, a [(2n + 2n) + (2n + 2a)] and a [27c- -27t] addition (both photochemically allowed). 

Reactions with Alkenes,—Further examples have been reported of the cycloaddition of 1,3-dienes to chlorophosphines. - Certain of these reactions show a high overall stereoselectivity when hydrogen sulphide is used to quench the initial complex. Thus the sulphide (11) is formed as one isomer only. 15-Phospha-steroids and 17-phospha-steroids have been prepared by this type of reaction. In general, both possible isomers (at phosphorus) are formed, as with the oxides (12). ... 

The diene precursor 78 is readily accessed in a few steps from the Wieland-Miescher ketone 79, which also provides the A- and B-rings of the steroid skeleton. Furthermore, the presence of an axial methyl group at C(19) (steroid numbering) allows the possibility of controlling the absolute stereochemical outcome of the key cycloaddition used to... 

Protection of a diene system by cycloaddition with suitable dienophiles is an attractive method for specific structural modifications. The use of TADs is advantageous for their high reactivity and their stability as adducts under various reaction conditions. The range of dienes that can be protected is somewhat limited to compounds having substituents compatible with the reaction conditions. The reactivity of double bonds situated in a urazole-moiety-containing molecule toward electrophiles may be entirely suppressed or retarded depending on their distance from the electron-withdrawing urazole moiety [78H(11)359], This effect can be exploited for selective suppression of electrophilic attack, e.g., in steroid chemistry. 

Cycloaddition.The cycloaddition between dienes and unactivated 7t-systems often proceeds at room temperature in the presence of transition metal catalysts. The catalytic system [Nifacacjj and EtjAlOEt] for such a stereoselective process can be replaced by Ni(cod)j, as applied to a synthesis of a precursor to A-aromatic steroids. 

Another important group of dienophiles of the a,p-unsaturated carbonyl class are quinones. 1,4-Benzoquinone reacts readily with butadiene at room temperature to give a high yield of the mono-adduct, tetrahydronaphthaquinone (3.8) under more vigorous conditions a bis-adduct is obtained which can be converted into anthraquinone by oxidation of an alkaline solution with atmospheric oxygen. As with other dienophiles, alkyl substitution on the double bond leads to a decrease in activity and cycloaddition of monoalkyl 1,4-benzoquinones with dienes occurs preferentially at the unsubstituted double bond. In addition to steric effects, electronic effects can play a part, such that cycloaddition occurs at the more electron-deficient double bond of the benzoquinone. The first step in an approach to the steroid ring system makes use of such selectivity (3.9). ... 

Under enyne cross-metathesis conditions, the intermolecular reaction of the a,(D-dienes 153, derived from the MBH reaction, with different terminal alkynes 154 afforded triene intermediates that cyclized spontaneously under the reaction conditions to give substituted cis-hexahydro-l/f-indenes 155 (Scheme 4.45), which can be further transformed into steroid analogues via TBS deprotection and oxidation. However, metathesis reactions starting with 156 only furnished trienes 157 [as EfZ) mixtures] and no spontaneous intramolecular cycloaddition occurred. Even at elevated reaction temperatures, trienes 157 cyclized only slowly to give octahydronaphthalene diastereomers. With deprotection of the TBS and subsequent Dess-Martin oxidation, trienes 157 could be converted exclusively into cw-fused 7-substituted 6,7-dehy-drodealone-l-one-lO-carboxylic esters 158 in 50-60% yields. Moreover, c ross-metathesis of TBS-unprotected MBH adduct 159 with alkynes 154 along with treatment with Dess-Martin periodinane (DMP) in one pot could conveniently produce the corresponding bicyclic ketones 160 in moderate yields. ... 

D were cis-fused. In point of fact, the Dane diene 4 and cyclopentenone 5 (R = Me or Et) on reaction are expected to lead to rac-3. Since this [4+21-cycloaddition would comfortably construct the steroid skeleton, one might accept additional effort required to correct the configuration at C(14). 

The cobalt-catalyzed [2+2+2] cycloaddition of 4-hydroxy-substituted enediynes [152] that has been implemented in the synthesis of 2-hydroxy substituted decahydrophenanthrenes [153] has shown that the hydroxy group in the propargyl position tolerates the chosen reaction conditions. So, this approach could be an appropriate route to hydrogenated trans-phenanthrenes, which are the ABC cores of ergosterin and lumisterin steroids. This was a reason to consider the diastereoselective synthesis of (3S)-hydroxyandrosta-5,7-diene-17-ones 2.307, the precursors of vitamin D, via a D ABCD approach. 

The Lewis acid-promoted Diels-Alder reaction has been employed in the assembly of steroid skeletons. The cycloaddition reaction between a substituted bicyclic diene and 2,6-dimethylbenzoquinone produces two stereoisomers in a 1 5... 

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