Diels-Alder reaction steroids

A major difficulty with the Diels-Alder reaction is its sensitivity to sterical hindrance. Tri- and tetrasubstituted olefins or dienes with bulky substituents at the terminal carbons react only very slowly. Therefore bicyclic compounds with polar reactions are more suitable for such target molecules, e.g. steroids. There exist, however, several exceptions, e. g. a reaction of a tetrasubstituted alkene with a 1,1-disubstituted diene to produce a cyclohexene intermediate containing three contiguous quaternary carbon atoms (S. Danishefsky, 1979). This reaction was assisted by large polarity differences between the electron rich diene and the electron deficient ene component. 

Two approaches to convergent steroid syntheses are based on the thermal opening of benzocyclobutenes to the o-quinodimethane derivatives (see p. 80 W. Oppolzer, 1978 A) and their stereoselective intramolecular Diels-Alder cyclizations. T, Kametani (1977 B, 1978) obtained (+ )-estradiol in a six-step synthesis. The final Diels-Alder reaction occurred regio- and stereoselectively in almost quantitative yield, presumably because the exo transition state given below is highly favored over the endo state in which rings A and D would stcrically inter-... 

Numerous examples of intramolecular Diels-Alder reactions have been repor-ted especially from application in the synthesis of natural products, where stereoselectivity is of particular importance e.g. syntheses of steroids. " ... 

A highly efficient construction of the steroidal skeleton 166 is reported by Kametani and coworkers111 in the intramolecular Diels-Alder reaction of the a, jS-unsaturated sulfone moiety of 165 (equation 117). Thus, when the sulfone 165 is heated in 1,2-dichlorobenzene for 6h, the steroidal compound 166 can be obtained in 62% yield. The compound 166 produces estrone (167) by elimination of benzenesulfinic acid and subsequent hydrogenation of the formed double bond. The stereoselectivity of the addition reflects a transition state in which the p-tosyl group occupies the exo position to minimize the steric repulsion between methyl and t-butoxy groups and the o-quinodimethane group as shown in equation 117. 

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 selectivity for two-alkyne annulation can be increased by involving an intramolecular tethering of the carbene complex to both alkynes. This was accomplished by the synthesis of aryl-diynecarbene complexes 115 and 116 from the triynylcarbene complexes 113 and 114, respectively, and Danishefsky s diene in a Diels-Alder reaction [70a]. The diene adds chemoselectively to the triple bond next to the electrophilic carbene carbon. The thermally induced two-alkyne annulation of the complexes 115 and 116 was performed in benzene and yielded the steroid ring systems 117 and 118 (Scheme 51). This tandem Diels-Alder/two-alkyne annulation, which could also be applied in a one-pot procedure, offers new strategies for steroid synthesis in the class O—>ABCD. 

Vinylnaphthalenes give Diels-Alder reactions more easily than styrenes and have been used to synthesize steroid-like compounds. 2-Vinylnaphthalene (61) is less reactive than 1-vinylnaphthalene (62) (Figure 2.7) it requires drastic conditions to undergo Diels-Alder reaction and the yields are low. Better results can be obtained by carrying out the reaction under high pressure (Chapter 5). Some Diels-Alder reactions of 1-vinylnaphthalene (62) are summarized in Scheme 2.23. 

Quinkert G., Del Grosso M. Progress in the Diels/Alder Reaction Means Progress in Steroid Synthesis in Stereosel. Synth. 1993 109, Ed. Ottow E., Schoellkopf K. and Schultz B. G., Pb. Springer Berlin... 

A highly efficient construction of the steroidal skeleton 166 is reported by Kametani and coworkers in the intramolecular Diels-Alder reaction of the ot, jS-unsaturated sulfone... 

Synthetic Applications of the Diels-Alder Reaction. Diels-Alder reactions have long played an important role in synthetic organic chemistry.74 The reaction of a substituted benzoquinone and 1,3-butadiene, for example, was the first step in one of the early syntheses of steroids. The angular methyl group was introduced by the methyl group on the quinone and the other functional groups were used for further elaboration. 

The reaction of benzyne with cyclohexadiene has been known for some time 4>, but although a number of steroidal cis-dienes are readily available no reactions with arynes had been reported prior to our beginning such investigations 145>. This was somewhat surprising in view of the number of reports concerning the modification of steroids by means of reactions with carbenes 146 i49) and the known Diels-Alder reactions of steroidal dienes and trienes iso.isi). 

The combination of a Stille and a Diels-Alder reaction has also been used for a derivatization of steroids, for example, in the synthesis of pentacydic compounds such as 6/1-189, as described by Kollar and coworkers [97]. Reaction of 17-iodoan-drosta-16-ene 6/1-187 with vinyltributyltin and various dienophiles such as diethyl... 

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). 

The thermally and Lewis acid-promoted transannular Diels-Alder reactions have proven to be a powerful tool for the synthesis of steroids and other natural products [24]. A research team led by Takamura, Arimoto, and Uemura utilized this reaction to assemble the polycyclic skeleton of nakiterpiosin (1) [25]. Heating macrolide 39 at 160 °C gave 40 and 41 as a mixture of diastereomers in good yields. 

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>. 

The presence of a 5-hexenyl substituent in 28i allowed the o-quinodimethane 229b to be captured in an intramolecular Diels-Alder reaction, producing 230, having a tetracyclic steroidal skeleton, in a single operation (Scheme 20.47) [33, 34], The fused tetracyclic 5,6,6,5-ring system was likewise produced from 34f and 34g. 

In an ingenious application of the extrusion reaction, 1-alkenyl-1,3-dihydro-benzo[c]thiophene 2,2-dioxides have been thermolyzed the diene system so generated undergoes an intramolecular Diels-Alder reaction with the isolated double bond in the side chain (79HCA2017). An (E) configuration of the diene is necessary for this purpose (Scheme 233). The by-products are styrenes arising from the (Z)-isomer. The same approach has also been used to prepare a steroid derivative (Scheme 233) (80JOC1463). 

Scheme 2.2 One pot Stille and Diels-Alder reaction generating steroidal substrates.

The chiral organocopper compound (186) adds diastereoselectively to 2-methyl-2-cyclopentenone, allowing the preparation of optically active steroid CD-ring building blocks (Scheme 68).202-204 A related method was applied to a synthesis of the steroid skeleton via an intramolecular (transannular) Diels-Alder reaction of a macrocyclic precursor.203 Chiral acetone anion equivalents based on copper azaeno-lates derived from acetone imines were shown to add to cyclic enones with good selectivity (60-80% ee, after hydrolysis).206-208 Even better ee values are obtained with the mixed zincate prepared from (187) and dimethylzinc (Scheme 69). Other highly diastereoselective but synthetically less important 1,4-additions of chiral cuprates to prochiral enones were reported.209-210... 

Scheme 26 One-pot Stille coupling/Diels-Alder reaction of steroidal alkenyl halides...

Steroidal, alicyclic or aromatic annulated pyridines were prepared via a microwave-assisted, base-catalyzed Henry reaction of /1-formyl enamides and nitromethane on an alumina support [97]. Highly substituted tri- and tetrasubstituted pyridines were synthesized in a Bohlmann-Rahtz reaction from ethyl /3-amino crotonate and various alkynones. The reaction involved a Michael addition-cyclodehydration sequence and was effected in a single synthetic step under microwave heating conditions [98]. An alternative approach towards polysubstituted pyridines was based on a reaction sequence involving an inverse electron-demand Diels-Alder reaction between various enamines 45 and 1,2,4-triazines 44 (Sect. 3.6), followed by loss of nitrogen and subsequent elimination-aromatization. Enamines 45 were formed in situ from various ketones and piperidine under one-pot microwave dielectric heating conditions [99]. Furthermore, a remarkable acceleration of the reaction speed (from hours and days to minutes) was observed in a microwave-assisted cycloaddition. Unsymmetrically substituted enamines 45 afforded mixtures of regioisomers (Scheme 35). 

Macrocyclic azodicarboxylates containing a steroid skeleton were also synthe-tized using a similar synthetic route [52]. These compounds were trapped by Diels-Alder reaction with cyclopentadiene. 

The inverse electron demand hetero Diels-Alder reaction of 1-oxa-l,3-butadienes and electron-rich dienophiles is an extremely versatile tool in natural product synthesis. This cycloaddition represents the key step of numerous approaches not only to carbohydrates, but also to terpenes, alkaloids, polyethers, steroid derivatives and various biologically active metabolites. 

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]. 

Most examples of quinone dehydrogenations adjacoit to have been earned out on steroidal ketones and are essentially limited to readily enolizable species. Reactions on esters and amides (Table 8) are far less common and, because of their relatively low ease of enolization, require hanh conditions. Thus, unless stabilization of the intermediate carbonium ion is possible, - elevated temperatures and prolonged reaction times are required (Table 8), which increases the incidence of unwanted side reactions. Frequent by-products are those arising as a result of Diels-Alder reactions or Michael addition to the quinone." Allylic alcohols may be rapidly oxidized to aldehydes or ketones under these conditions and requite prior protection. 

One important application of the Diels-Alder reaction is the introduction of a trifluoromethyl group at an angular position in polycyclic systems, in particular in steroids. 

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