Regenerative γ-Lactone Annulations: A Modular, Iterative Approach to Oligo-tetrahydrofuran Molecular Stairs and Related Frameworks

Abstract

A unified, stereocontrolled, regenerative γ-butyrolactone annulation approach has been conceptualized and validated through syntheses of a range of oligo-THFs. The new protocol is short (four steps), simple (table-top reagents), and efficient (50-61% overall yields). Although the scope of this approach is unlimited, it has been demonstrated up to five iterations on commercial γ-butyrolactone to assemble six fused tetrahydrofuran moieties in a staircase-like architecture. A selection of exploratory transformations is presented to exemplify the potential applications of this protocol.

Synthesis of All Stereoisomers of RK460 and Evaluation of Their Activity and Selectivity as Abscisic Acid Receptor Antagonists

“…The remaining isomer rac ‐ 5 a was synthesized by inverting the stereochemistry of alcohol 5 b with the Mitsunobu reaction . Protection of the secondary alcohol of 5 with SEM (trimethylsilylethoxymethyl), reduction of lactone to lactol with DIBAL‐H, Lemieux–Johnson oxidation of terminal olefin to afford lactol with a 6,5‐ cis ‐bicyclic skeleton, and PDC (pyridinium dichromate) oxidation of lactol were separately conducted to provide the lactones 4 ( rac ‐ 4 a , rac ‐ 4 b , rac ‐ 4 c , and rac ‐ 4 d ) . Final stereo‐diversification was performed by Davis oxidation .…”

“…[24] Protection of the secondary alcohol of 5 with SEM (trimethylsilylethoxymethyl), reduction of lactone to lactol with DIBAL-H, Lemieux-Johnson oxidation of terminal olefin to afford lactol with a6 ,5-cisbicyclic skeleton, and PDC (pyridinium dichromate) oxidation of lactol were separately conducted to provide the lactones 4 (rac-4a, rac-4b, rac-4c,a nd rac-4d). [25] Final stereo-diversification was performed by Davis oxidation. [26] Despite the nature 65 equiv), MS4,C H 2 Cl 2 ,RT, 12 h(66 %f or rac-4a over 4steps, 70 %f or rac-4b over 4s teps, 36 %f or rac-4c over 4steps, 56 %for rac-4d over 4s teps);j )KHMDS (potassium bis(trimethylsilyl)amide)( 1.5 equiv), Davis reagent (2.0 equiv), THF, À78 8C, 4h(50 %f or rac-3a,20% for rac-3b,3 1% for rac-3c,4 8% for rac-3d,81% for rac-3e,4%f or rac-3f79 %f or rac-3g); k) Tf 2 O(1.1 equiv), pyridine(2.4 equiv), CH 2 Cl 2 , À40 8C, 4h;l)sodium trifluoroacetate (2.0 equiv), DMF (N,N-dimethylformamide), 60 8C, 2d,t hen MeOH (60 %o ver 2s teps).…”

Platanic Acid‐Aryl Enones as Potential Anticancer Compounds: Synthesis and Biological Profiling against Breast, Prostate and Lung Cancer Cell Lines

“…In continuation of our deep interests in natural products total synthesis, [34][35][36][37][38][39] and their exploitation in medicinal chemistry, [40,41] platanic acid derived from betulinic acid was taken as a starting point for structural reformations. Based on the literature precedence, structural analoguing was executed on the side chain which is considered as one of the molecule's hot spots.…”

The distinctively singular self-assembly of a “molecular stair”: observation of a quadrilateral C–H⋯O hydrogen bonding cycle in the crystal structure of a tetracyclic oligo-tetrahydrofuran

“…The initial impetus for undertaking such a comparative case study came from the ready availability of single crystal X-ray diffraction data of anti-fused oligotetrahydrofurans, such as 7-9, that were afforded from our own recently concluded synthetic endeavour towards "molecular stairs" based on a regenerative γ-butyrolactone annulation stratagem. 2 We recognized that besides the obvious lack of any C(sp 2 )-H donor, the unsymmetrical oligotetrahydrofurans 7-9 differ from the C 2 /C s symmetric Werz variants 1-3 by bearing an additional C-H•••O acceptor (in form of a γ-lactone) on one of the peripheral rings. Since this feature invariably leads to a dissymmetry in the potential Hbond donors and acceptors in 7-9, we opted to make our postulated comparative study more holistic by including a The tetracyclic lactone 8 was crafted as a racemic modification from γ-butyrolactone 11 with an overall yield of around 13% via a four step iterative protocol, namely (a) LiHMDS mediated α-alkenylation of the lactone with allyl bromide, (b) DIBAL-H mediated reduction of the lactone moiety, (c) Lemieux-Johnson oxidation of the allyl side-arm and subsequent in situ oligoacetal formation and (d) Jones oxidation of the newly created hemiacetal moiety.…”

“…The tetracyclic anti-fused oligo-tetrahydrofuran 10 was readily crystalline and best suited our needs in this regard. 2 The present communication is therefore an initial endeavour to compare the molecular packing of three structurally related "molecular stairs", viz. 2, 8 and 10, and throw a spotlight en route on the distinctively singular crystal structure observed for 8.…”