Diels-Alder Reaction steroid synthesis

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. " ... 

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. 

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... 

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 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... 

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. 

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]. 

C Application Diels-Alder Reaction in the Synthesis of Steroids... 

The synthesis of steroids by Diels-Alder reactions (Section 16.14C)... 

This ester was used in the synthesis of steroids (Chapter 51) by the Diels-Alder reaction (Chapter 35) Z. Valenta and group, Can,... 

Hydrophenanthrenes are known to be useful intermediates in the total synthesis of diterpenes and steroids. The Diels-Alder reaction of heteroannular bicyclic dienone 8 with ( )-piperylene (9a) and 2,3-dimethyl-l,3-butadiene (9b)... 

The Diels-Alder reaction occupies a cherished place in the hearts of organic synthetic chemists, not only in the synthesis of steroids [45] but far and wide in the synthesis of structurally complex natural products [46]. The Diels-Alder... 

Alkylation of the metallated enol derived from 52 with m-methoxy-phenylethyl-iodide to afford the tricyclic jj-keto ester 53, followed by cationic cydization of this to furnish the steroid derivative 54, warrants particular attention. Corey and colleagues have recently published another total synthesis of 40 [82], beginning with an enantioselective Diels-Alder reaction between Dane s diene 14 and dienophile 61. An oxazaborolidinium salt (see Section 1.3.2.3) was used as an efficient catalyst (Scheme 1-14). 

Intramolecular Diels-Alder reactions of orr/jo-quinodimethanes have been used widely in the synthesis of natural products, particularly in the steroid and alkaloid fields. orr/ o-Quinodimethanes are reactive dienes and evenunreactive dienophiles can be used to form cycloadducts. The diene is prepared in situ, using one of a number of procedures (see Section 3.1.2) such as the thermal ring-opening of benzocyclobutenes. One method makes use of the ready loss of sulfur dioxide from a sulfone such as 103 (3.83). Thus, heating the sulfone 103 gave the intermediate orr/jo-quinodimethane 104, which cyclized to the tetracycle 105. This product can be converted readily into the steroid (-f)-estradiol. 

An important electrocyclic reaction is the ring-opening of benzocyclobutenes to give o-quinodimethanes. The resulting diene is an excellent substrate for reaction with a dienophile in a Diels-Alder reaction (see Section 3.1.2). For example, in a synthesis of the steroid estrone, the benzocyclobutane 337, prepared by a cobalt-mediated cyclotrimerizafion, was converted on heating to the o-quinodimethane... 

It is striking that Diels and Alder finally received the Nobel Prize in chemistry in 1950, more than two decades after their initial publication. The science of total synthesis of natural products was slow to advance and was hindered by World War II. These factors perhaps explain the delay in fuUy appreciating the impact of the Diels-Alder reaction. The modem era of total organic synthesis is generally considered to have started during the 1940s. In 1952, Robert Bums ( R. B. ) Woodward (1917-79) at Harvard would employ the Diels-Alder reaction to brilliant effect en route to total syntheses of the steroids cortisone and cholesterol. 

The Pd-catalyzed reactions of a-heterosubstituted alkenylzincs containing alkoxy and thioalkoxy groups were developed with the goal of synthesizing heterosubstituted conjugated dienes for the Diels-Alder reaction (Scheme 56). The use of the parent aUcenyllithiums did not produce the desired dienes in detectable amounts. This reaction has been applied to the synthesis of steroidal a-hydroxy enones (Scheme 57). It should be noted that Zn has been shown to be decidedly superior to Sn as the countercation. 

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