Atropo-Enantioselective Synthesis of the Natural Bicoumarin (+)-Isokotanin A via a Configurationally Stable Biaryl Lactone

Abstract

The atropo‐enantioselective total synthesis of the axially chiral bicoumarin (+)‐isokotanin A (1) is described. Key steps were the formation of a configurationally stable seven‐membered biaryl lactone and its kinetic resolution by atroposelective ring cleavage. The previous assignment of the absolute configuration of (+)‐isokotanin A (1) (and its synthetic precursors) was confirmed by quantum chemical CD calculations. (© Wiley‐VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Atroposelective Synthesis of Axially Chiral Biaryl Compounds

“…The interconversion rate of 276 is too slow ( τ 298 K ≈10 days) to be used in a dynamic kinetic deracemization, but a normal (i.e. nondynamic) kinetic resolution with subsequent thermal recycling of the unconverted starting material is possible 245. 246 Thus, reduction of racemic 276 with borane in the presence of the ( S )‐CBS reagent (( S )‐ 267 ) delivered the diol ( M )‐ 277 in 46 % yield with 75 % ee (95 % ee after crystallization) and the lactone ( P )‐ 276 in 43 % yield with 96 % ee , when the reaction was quenched at 56 % conversion.…”

Selective opioid growth factor receptor antagonists based on a stilbene isostere

“…According to the published procedures,[72, 73, 86] to a stirred solution of methyl 3,5-dimethoxybenzoate (2.0 g, 10 mmol) in CH 3 CN (100 mL) at 0 °C was added N -bromosuccinimide (2.0 g, 11.2 mmol). After the addition was complete, the solution was allowed to equilibrate to room temperature and stirred for an additional 3.5 hours.…”

“…In this case, regiocontrolled introduction of the geranyl group could be achieved through the aryl bromide 17 , which was readily prepared by bromination of the corresponding methyl benzoate with NBS. [72, 73] Although it may not be common, halogen-metal exchange in the presence of an ester group is known,[74] and the presence of adjacent polar functionality can facilitate metalation. [75] In this specific case, treatment of the aryl bromide 17 with n -BuLi and CuBr·DMS followed by reaction with geranyl bromide gave the desired alkylation product 18 in good yield.…”

Synthesis of bicoumarin thiophosphate derivatives as steroid sulfatase inhibitors

“…Many synthetic methods for the preparation of the bicoumarin exist, which include the reaction of 4-hydroxycoumarin with substituted Meldrum acids [20], the Knoevenagel condensation of (coumarin-4-yl)acetic acids and their esters with substituted salicylic aldehydes [21], and the oxidative coupling of 7-methoxy-4-methyl coumarin with Mn(OAc) 3 /HCIO 4 [22]. Other oxidative coupling conditions have been used in the multistep synthesis of naturally occurring bicoumarins, such as the Büchi synthesis of racemic kotanin (oxidation of the organolithium derivative with cupric chloride) [23], the Lin asymmetric synthesis of the kotanin (oxidative coupling using CuCN/TMEDA) [24], the Hüttel total synthesis of kotanin, isokotanin A, and desertorin C using oxidative phenol coupling (FeCl 3 /SiO 2 ) [25], and the Bringmann atropo-enantioselective synthesis of (D)-isokotanin A (oxidative coupling with Cu/DMF) [26].…”