Synthesis of Steroidal D‐Ring‐Fused Pyrrolidines of Dehydroepiandrosterone

Abstract

The commercially available steroid dehydroepiandrosterone 3‐acetate (DHEA) was converted into steroidal D‐ring‐fused pyrrolidines that combine two privileged structures: a steroid and a (2‐arylethyl)amine. The three‐step transformations proceeded through conversion of the C‐17 ketone into an enol ether, followed by high‐pressure‐mediated cascade [4+2]/[3+2] cycloadditions with two nitroalkenes ([4+2]) and five dipolarophiles ([3+2]) to yield azonite intermediates. Finally, reduction of these azonites formed the new azasteroids, which are suitable for further derivatization.

Hyperbaric reactions in organic synthesis. Progress from 2006 to 2021

“…In modelled experiments, it was shown that a 15 kbar cascade 3CR between enol 128 , ( E )-(2-nitrovinyl)benzene, and monosubstituted olefins 127 allows one to obtain azonites 129 as mixtures of only two diastereoisomers (all- cis -isomers are strongly predominant in all cases) in considerable yields (Scheme 39). 87 The sequence of steps includes the initial dipolar endo -[4 + 2] cycloaddition of a nitrostyrene molecule at the activated double bond of the cyclopentene ring in 128 , followed by an exo -(3 + 2) cycloaddition of the intermediate azinate 130 to alkenes 127 . Both types of olefins, with donor and acceptor substituents R 1 , were equally suitable for the last stage.…”

“…In the presence of nitroalkenes 131 and alkenes 132 , the same high-pressure-promoted cascade of successive cycloaddition reactions transforms the D-ring of steroid 133 into azonites 134 (Scheme 40). 87 In spite of the fact that mixtures of two or three diastereoisomers occur, only the major product possessing the all- cis configuration of the substituents H, OMe, R 1 , and Ar 1 in rings E and F was isolated in good yields. E and F fragments in cycloadducts 134 may be reduced (H 2 , Ra–Ni) to furnish steroidal D-ring-fused pyrrolidines that combine two privileged steroid and 2-arylethyl amine scaffolds in one molecule.…”

“…In modelled experiments, it was shown that a 15 kbar cascade 3CR between enol 128, (E)-(2-nitrovinyl)benzene, and monosubstituted olefins 127 allows one to obtain azonites 129 as mixtures of only two diastereoisomers (all-cis-isomers are strongly predominant in all cases) in considerable yields (Scheme 39). 87 The sequence of steps includes the initial dipolar endo- Then, the identified conditions were used for a postmodification of the structure of the semi-synthetic steroid enol 133 derived from commercially available dehydroepiandrosterone 3-acetate (see Scheme 27 also). In the presence of nitroalkenes 131 and alkenes 132, the same high-pressure-promoted cascade of successive cycloaddition reactions transforms the D-ring of steroid 133 into azonites 134 (Scheme 40).…”

Library Synthesis of Cyclobutanol Derivatives by Hyperbaric [2+2] Cycloaddition Reactions

“…Hyperbaric reactions, typically carried out between 10 and 15 kbar, provide attractive synthetic opportunities to perform cycloadditions of compounds that are unreactive under conventional conditions. [6,7,8,9,10] Herein we present a general, highpressure-mediated [2 + 2] cycloaddition pathway for the synthesis of a modest library of novel cyclobutanols 1 with different (arenesulfonyl)methyl and amino groups at the 3position to expand the coverage of the chemical space (Figure 2). These compounds offer exciting potential for various applications in drug development.…”

Nitronate-aryne cycloaddition as a concise route to stereochemically complex fused benzisoxazolines and amino alcohols

“…8 These strategies allow rapid generation of molecular and stereochemical complexity, while the resulting bicylic nitroso acetals can be converted to aminoalcohols, that are precursors of natural products (such as pyrrolizidine and indolizidine alkaloids). 1 i – l ,9…”