Syntheses of (+)-30-epi-, (−)-6-epi-, (±)-6,30-epi-13,14-Didehydroxyisogarcinol and (±)-6,30-epi-Garcimultiflorone A Utilizing Highly Diastereoselective, Lewis Acid-Controlled Cyclizations

Abstract

The first syntheses of 13,14-didehydroxyisogarcinol (6) and garcimultiflorone A (5) stereoisomers are reported in six steps from a commercially available phloroglucinol. Lewis acid-controlled, diastereoselective cationic oxycyclizations enabled asymmetric syntheses of (−)-6-epi-6 and (+)-30-epi-6. A similar strategy enabled production of the meso-dervied isomers (±)-6,30-epi-6 and (±)-6,30-epi-5. Finally, a convenient strategy for gram scale synthesis was developed utilizing diastereomer separation at a later stage in the synthesis that minimized the number of necessary synthetic operations to access all possible stereoisomers.

Synthesis and Multiplexed Activity Profiling of Synthetic Acylphloroglucinol Scaffolds

“…Lactone 12 may also be an intermediate to (AE)-10,( AE)-11,a nd (AE)-13.T he 2-oxo-tetrahydro-2Hchromene core present in 10-13 is also found in PPAP natural products (e.g.t heoliolides Aa nd B; mahureones A-E) and asynthetic derivative (Figure 2b). [6a,b,d] We also found that (+ +)-18, [23] ad iastereomer of 9, underwent as imilar rearrangement in formic acid providing the bioactive[3.3.1]-bicyclic lactone (À)-19 (a diastereomer of 10)in9%yield (Table 2, entry 1);its relative stereochemistry was unambiguously confirmed by X-ray crystal structure analysis. [16,25] Relative to its diastereomer 9,t he product diversity resulting from rearrangement of 18 is significantly decreased.…”

“…At the outset of our investigation, we discovered that formic-acid-promoted rearrangement of pyranodienone substrate (AE)-9 [23] led to production of the fused lactones (AE)-10, (AE)-11,( AE)-12,( AE)-13,a nd (AE)-14 (Table 1, entry 1), four of which had notable activity (vide infra). Table 1s hows as election of conditions from an extensive reaction screen to optimize product selectivity for active compounds.A ll rearrangement products (10)(11)(12)(13)(14)deriving from (AE)-9 could be obtained in formic acid over 72 h( Table 1, entry 1).…”

“…We have previously noted that cyclizations of compounds 9 and 18 to [3.3.1]-bicyclic scaffolds do not proceed in dry TFA. [23] However, such cyclizations could be achieved in the presence of 1% water which may serve as an appropriate nucleophile for hemiketal formation or contribute to enhanced stability of cationic intermediates leading to these products.T he results described in Tables 1a nd 2a re in agreement with our proposed mechanism and are supported by stereochemical and DFT-optimized, orbital-alignment analysis (Figures S1-S4). [16] Figure 2.…”

“…Due to the interesting activities of isogarcinol (2)a nd garcinol (4), the diverse SASs from this study merited abroad and unbiased investigation of their potential biological activities. [8i, 16,23] We utilized MAP to perform comparative assays of these compounds in the context of reported activities for 2 and 4. MAP is multiplexed in two distinct ways:1 )multiple biological readouts are assessed simultaneously at single-cell resolution using panels of fluorophoreconjugated antibodies,a nd 2) the assay utilizes fluorescent cell barcoding (FCB) [15] to enable robust large-scale screening of multiple treatment conditions,i ncluding different compounds,doses,ortimepoints.F or biological evaluation of the novel SASs produced, the primary panel included markers for apoptosis and homeostasis,s uch as cleaved caspase-3 Tabelle 3: Cyclization of O-alkylated, dearomatized acylphloroglucinols.…”

Acid-catalyzed chemoselective C- and O- prenylation of cyclic 1,3-diketones

“…Derivatives of 5-chromenone are common among natural products, particularly in medicinal plants [1][2][3][4]. For example, tomentodiones H and J, which are two syncarpic acid-conjugated terpenoids (SACTs) isolated from the traditional Chinese medicinal plant Rhodomyrtus tomentosa, contain multi-substituted 5-chromenone scaffolds (Scheme 1) [5].…”