Stille/Diels−Alder Reaction Sequences:  Diversity-Oriented Access to Novel Steroids

Abstract

[reaction: see text] An efficient, diversity-oriented approach to novel steroid analogues possessing a C-5beta configuration begins with the Stille cross-coupling of enantiomerically pure cycloalkenylstannane trans-2 and enol triflate 3. The resulting diene trans-4 engages in Diels-Alder cycloaddition reactions with a range of dienophiles to give, after removal of protecting groups, biologically interesting 6,7-disubstituted steroid analogues.

The Diels–Alder Reaction in Steroid Synthesis

“…Wulff's 1991 DA-double intramolecular two alkyne annulation approach to the steroid skeleton A different steroid B-ring-forming DA reaction was employed by the de Meijere research group in 2008 (Scheme 17). 41,42 A heat-promoted DA reaction between diene 73generated via a Stille coupling between enol triflate 71 and alkenyl stannane 72 -and dimethyl acetylenedicarboxylate (DMAD) as dienophile gave tetracycle 74 in good yield. The dienophile approaches diene 73 from the opposite face to the methyl and tert-butyloxy substituents.…”

Transition‐Metal‐Mediated or ‐Catalyzed Syntheses of Steroids and Steroid‐Like Compounds

“…Stille coupling of 15 and 16 (Scheme 7) was used by de Meijere et al for preparation of intermediates such as 17 (77 %), containing the A and C/D rings and a conjugated 1,3-diene moiety, as building blocks for the synthesis of steroid derivatives. [25] Later, another procedure based on a domino Stille coupling/Heck reaction sequence was developed. [26] In this instance the cross-coupling was carried out between 15 and 18 (Scheme 8), forming the bromodiene 19 (95 %), which was then subjected to a Heck reaction with acrylate to yield the conjugated triene 20 in 90 % yield.…”

Diversity‐Oriented Synthesis of Enantiomerically Pure Steroidal Tetracycles Employing Stille/Diels–Alder Reaction Sequences

“…[23] (6S,7S,5R,8S,13R,14S,17S)-17-tert-Butoxy-13-methyl-spiro ( 3,4,5,6,7,8,11,12,13,14,15,16,17- ; the X-ray crystal structure analysis of trans-22 has previously been published. [23] (3 aR,3 bS,9 aS,10 S,12 aS,12 bR,12 cS)-10-tert-Butoxy-2,9 a-dimethyl- 3 b,6,7,8,9,9 a,10,11,12,12 (5R,8S,13S,14S,17S)-Spiro(1',3'-dioxolane-[2',3]-17-tert-butoxy-6-chloro-13-methyl-2, 3,4,5,6,7,8,11,12,13,14,15,16,17- 24.75 (À, CH 2 ), 25.13 (À, CH 2 ), 25.59 (À, CH 2 ), 25.74 (À, CH 2 ), 25.94 (À, CH 2 ), 26.80 (À, CH 2 ), 28.67 (+ , 3C, CA C H T U N G T R E N N U N G (CH 3 ) 3 ), 29.24 (À, CH 2 ), 31.11 (À, CH 2 ), 31.21 (À, CH 2 ), 34.45 (+ , CH), 35.13 (À, CH 2 ), 35.48 (À, CH 2 ), 35.66 (À, CH 2 ), 37.40 (À, CH 2 ), 40.79 (À, CH 2 ), 41.42 (À, CH 2 ), 41.56 (À, CH 2 ), 41.82 (À, CH 2 ), 42.70 (À, C quat ), 43.41 (À, C quat (5R,6S,7S,8S,13S,14S,17S)-17-tert-Butoxy-13-methyl-3-oxo-2, 3,4,5,6,7,8,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-6,7-dicarbonitrile (trans-32): p-Toluenesulfonic acid (80.0 mg, 0.402 mmol) was added to a solution of the steroid analogue trans-22 (330 mg, 777 mmol) in acetone (15.0 mL) and water (0.050 mL). The resulting solution was stirred at 23 8C for 24 h. After this time, the reaction mixture was concentrated in vacuo, and the residue was taken up in diethyl ether (55 mL).…”

“…The absolute configuration of trans-21 was established by an X-ray crystal structure analysis [19] (see Figure 1), and the same was done for the single diastereomer trans-22 that was formed in 84 % yield upon cycloaddition of fumaronitrile onto trans-19 which occurred in toluene at 110 8C (Scheme 5). [23] 4-Phenyl-1,2,4-triazoline-3,5-dione, which is well known for its high dienophilicity, reacted with trans-19 in methylene chloride at ambient temperature to yield trans-26 (77 %), also as a single diastereomer. The less reactive dimethyl acetylenedicarboxylate (DMAD), like the other dienophiles employed, required heating in benzene and gave trans-24…”