Described herein is the enantioselective syntheses of (+)‐ and (−)‐rishirilide B from the corresponding optically active β‐substituted tetralones, which were obtained by oxidative kinetic resolution based on α‐hydroxylation in the presence of a chiral guanidine‐bisurea bifunctional organocatalyst. Benzylic oxidation of the tetralones at C1 followed by regioselective isomerization of the oxabenzonorbornadiene structure led to rishirilide B. Our findings lead to the revision of the previously proposed (2R,3R,4R) absolute configuration of (+)‐rishirilide B to (2S,3S,4S).

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A series of guanidine–bisurea bifunctional organocatalysts 4, with chiral centres located outside the urea groups, were synthesized. The novel catalyst 4 is conformationally more flexible than the original catalyst 1. In α-hydroxylation of tetralone- derived β-keto esters, 4 afforded the corresponding alcohols in high yields with moderate enantioselectivity.

Described herein is the enantioselective syntheses of (+)- and (-)-rishirilide B from the corresponding optically active β-substituted tetralones, which were obtained by oxidative kinetic resolution based on α-hydroxylation in the presence of a chiral guanidine-bisurea bifunctional organocatalyst. Benzylic oxidation of the tetralones at C1 followed by regioselective isomerization of the oxabenzonorbornadiene structure led to rishirilide B. Our findings lead to the revision of the previously proposed (2R,3R,4R) absolute configuration of (+)-rishirilide B to (2S,3S,4S).

Dehydroxymethylepoxyquinomycin (DHMEQ, 1) is well known to inhibit nuclear factor-kappa B (NF-κB), which is closely associated with immune, inflammatory, and apoptotic processes as an inducible transcription factor. The inhibitory effect seems to be the result of the ring opening of an epoxide of 1 with Cys 38 of p65. We have synthesized an analog 4 containing a cyclopropanated quinol skeleton and examined its ability to inhibit NF-κB. Surprisingly, 4 showed no remarkable NF-κB inhibitory activity as determined through expression of cyclooxygenase-2 (COX-2) in an RAW264.7 macrophage cell line.Key words dehydroxymethylepoxyquinomycin (DHMEQ); cyclopropane; nuclear factor-kappa B (NF-κB); cyclooxygenase-2 (COX-2); RAW264.7The recent growth in molecular biology has generated new drug targets causing a dramatic paradigm shift in the chemotherapeutics of cancer (e.g., molecularly targeted therapeutics). Recently, much attention has been concentrated on nuclear factor-kappa B (NF-κB), which belongs to a family of transcription factors associated with immune and inflammatory processes. NF-κB is a homo-or heterodimer of Rel family proteins including p65 (RelA), p50, RelB, c-Rel, and p52. Among them, p65 (RelA), c-Rel, and p52 have a transactivation domain. Continuous activation of NF-κB is known to occur in various types of human tumors, and is correlated with inactivation of apoptosis via transcriptional misregulation. NF-κB inhibitors are thus expected to be prominent candidates for anticancer drugs.1) Dehydroxymethylepoxyquinomycin (DHMEQ, 1), first synthesized by Umezawa and colleagues on the basis of a structural modification of epoxyquinomycin C (Chart 1), shows a potent NF-κB inhibitory effect with little toxicity.2) The careful matrix assisted laser desorption ionization-time of flight (MALDI-TOF)-MS analysis by Umezawa and colleagues of chymotrypsin-treated p65 peptide clarified that the bioactivity of 1 is a result of coupling with Cys 38 of p65.3) To specify the covalent bond formed, they conducted a reaction of 1 with N-Boc-L-Cys methyl ester. The resulting conjugate was identified as 2 based on its mass and NMR spectra. Although the regioselective ring opening of the epoxide is essential for the additional inhibitory effect of 1 against p65, it has not yet been completely confirmed whether a similar chemical binding occurs in biological processes. In this paper, we describe the synthesis of a new DHMEQ analog 4 with a cyclopropane ring instead of an epoxide and the evaluation of its NF-κB inhibitory activity to clarify the significance of the epoxide in 1 using a structure-activity relationship study. Results and DiscussionBecause 3b also inhibits NF-κB activation, 4) synthesis of its analog 8 was initially conducted as shown in Chart 2. Dienone 5 was prepared from 2,5-dimethoxyaniline following a known procedure.5) Treatment of dienone 5 with trimethylsulfoxonium iodide in the presence of NaH resulted in selective cyclopropanation at the C 4,5 double bond to generate 6 in 77% yield. 6,7)Deacetalization of ...