Convenient synthesis of new pregnenolone oximinyl oxalate dimers

Abstract

Three new symmetrical pregnenolone oxyminyl oxalate dimers (8)(9)(10) were synthesized from the corresponding pregnenolone oximes (3, 5, and 7) at room temperature. All dimers were characterised by spectroscopic means, notably HRFABMS and comprehensive NMR spectroscopic data analyses.In continuation of the search for biologically active steroid-based dimers [1], we have used pregnenolone (1) as the starting substance. Pregnenolone, a well-known vertebrate hormone, is a primary steroid on the pathway from cholesterol to the androgens, estrogens, progesterone, and the corticoids, and also the starting material for several other pharmacologically active steroids [2, 3]. As part of our initiative for synthesizing new steroid dimers towards the generation of a library of steroidal dimers for relevant pharmacological screening, we now report on the synthesis of three new pregnenolone oximinyl oxalate dimers (8-10), which contain an oxalate ester linkage between the 20-one oxime positions of two molecules.Oximes, as they contain a hydroxyl group linked to nitrogen, behave like alcohols, and are considered to be important reaction intermediates for the synthesis of various nitrogen-containing compounds. To synthesize the target dimer bis(3βacetoxypregn-5-en)-20-on-oximinyl oxalate (8), it was necessary to prepare the steroid monomer 3β-acetoxypregn-5-en-20-one oxime (3). In order to functionalize C-20 of pregnenolone (1), its 3β-hydroxy group was protected by acetylation [4][5][6]. The acetylated pregnenolone 2 was treated with hydroxylamine hydrochloride to obtain 20-one oxime 3 [4]. An increase of 15 mass units in its molecular mass (compared to that of 2) obtained from the ESIMS spectrum ([M+H] + and [M+Na] + at m/z 374 and 396, respectively) confirmed the presence of a C=N-OH instead of a C=O group. The 1 H NMR showed a broad 1H singlet at δ 8.88 for hydroxyl proton, and an olefinic quaternary carbon at δ 158.7 observed in its 13 C NMR spectrum was characteristic for C=N-OH group.2, 3: R = 5-dehydro, R 1 = R 2 = H; 4, 5: R = 5-dehydro, R 1 = H, R 2 = 16-dehydro 6, 7: 5α-H, R 1 = 11α-OAc, R 2 = 16-dehydro

Design and synthesis of screening libraries based on the muurolane natural product scaffold

“…These data suggested some of the minor products included the substitution of the primary hydroxyl (14-OH) with a chlorine atom, 43,44 and the formation of oxalic acid derivatives at 14-OH. 45,46 Due to the low yields and difficulty associated with purifying these potentially unstable minor side-products, full spectroscopic characterisation was not possible. While protection chemistry was considered as an option for reducing the (COCl) 2 side products, this was not pursued due to the number of additional reaction and purification steps required, the scarcity of the NP scaffold, and our desire to generate other analogues based on the muurolane scaffold 1.…”

N,N-Bis(3β-acetoxypregn-5(6)-en-20-on-16α-yl)hydroxylamine

“…Consequently, among new steroid dimers, a number of pregnenolone derivatives were synthesized for pharmacological screening [12,13].…”