Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• potentially favourable profile for prostate cancer therapy. Spirolactam steroids Steroidal spirolactams were obtained by Fousteris et al. in a five-step reaction sequence from 3β-benzyloxy-12β-hydroxydehydroepiandrosterone (118) [59]. The protected DHEA derivative was initially condensed with (R)-(+)-tert

• -II) afforded the corresponding 17-spirolactams 123a,b in 71–73% yield (Scheme 34). Notably, when (S)-(+)-tert-butylsulfinamide was used in the initial step of the reaction sequence, the allylation of the resulting imine proceeded diastereoselectively, yielding the 17-allyl-17-sulfinamido compound as

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• -cycloalkenylmethyl substituents provided spirolactams 12m,n in good yields, but with overall low diastereoselectivity. In the cyclization of 9m lactams 12mA and 12mB with trans orientation at C4 and the newly introduced aminoxy group at C5 were the major diastereomers, which results in an overall 4.5:1 trans/cis

• diastereomeric ratios. To confirm enolate formation, lactam 12f was deprotonated by LDA at −78 °C and quenched with D2O, resulting in lactam 12f with 86% deuterium incorporation, but no change in the diastereomeric ratio. Spirolactams 12m,n were also subjected to epimerization (Scheme 4). The change of the

• diastereomeric mixture of lactam 12lA,B gave two trans-diastereomers of 13lA,B in an unchanged 1.2:1 ratio. Their opposite relative configuration at C3 and C4 was established by NOE experiments (see Supporting Information File 1). The rather complex diastereomeric mixture of spirolactams equil-12m,nA–D

Bifurcated synthesis of methylene-lactone- and methylene-lactam-fused spirolactams via electrophilic amide allylation of γ-phenylthio-functionalized γ-lactams

• Tetsuya Sengoku,
• Koki Makino,
• Ayumi Iijima,
• Toshiyasu Inuzuka and
• Hidemi Yoda

Beilstein J. Org. Chem. 2020, 16, 2769–2775, doi:10.3762/bjoc.16.227

• 501-1193, Japan 10.3762/bjoc.16.227 Abstract New synthetic methods for spirolactams bearing an α-methylene-γ-butyrolactone or its analogous methylene-lactam have been developed. The allylation of γ-phenylthio-functionalized γ-lactams with 2-(acetoxy)methyl acrylamides was accomplished by using 2.5

• equivalents of NaH to give the corresponding adducts in excellent yields. The remaining phenylthio group was substituted with a hydroxy group by treatment with CuBr, and the resulting γ-hydroxyamides were cyclized under acidic conditions to afford the corresponding methylene-lactam-fused spirolactams in high

• yields. On the other hand, methylene-lactone-fused spirolactams could be delivered from the allyl adducts in high yields through a sequential N-Boc protection/desulfinative lactonization. Keywords: bifurcated synthesis; electrophilic amide allylation; α-methylene-γ-butyrolactam; α-methylene-γ

Synthesis of spirocyclic scaffolds using hypervalent iodine reagents

• Fateh V. Singh,
• Priyanka B. Kole,
• Saeesh R. Mangaonkar and
• Samata E. Shetgaonkar

Beilstein J. Org. Chem. 2018, 14, 1778–1805, doi:10.3762/bjoc.14.152

• 2.5 h (Scheme 11). Additionally, the synthesized spirocyclic precursor 16 was transfered to (−)-tuberostemonine (40) in three chemical steps. 3. Synthesis of spirolactams 3.1. Using stoichiometric amounts of iodine(III) reagents In 1998, Ciufolini and co-workers [80] reported the oxidative cyclization

• of tyrosine derivatives to spirolactams using iodine(III) reagents. In this reaction, oxazoline derivatives 41 were cyclized to spirocyclic products 42 using PIDA (15) as an electrophile in trifluoroethanol at room temperature for 30 minutes. The desired products 42 were isolated in moderate yields

• β-substituted 3-(methoxyphenyl)-N-methoxypropionamides 46 with [bis(trifluoroacetoxy)iodo]benzene (PIFA, 31) in dichloromethane (Scheme 14). The reactions were carried out at low temperature and spirolactams 47 were achieved in high yields with up to 96% enantiomeric excess. Furthermore, these