Efficient Synthesis of Substituted Indene Derivatives …

Our retrosynthetic analysis of 2 () features a late-stage disconnection to indene 5, which offers a potential solution to the construction of terpenoid frameworks that incorporate a fused [5–6] bicyclic ring system. An appealing aspect of our approach was that the indene cyclization precursor 5 could be readily constructed in a convergent manner from vinyl triflate 6 and boronic ester 7.

In summary, we report the first synthesis of the tetracyclic core of the neomangicols via an efficient indene alkylation strategy. This design provides a starting point for the syntheses of the biosynthetically related neomangicol and mangicol natural products by utilizing a powerful alternative to enolate chemistry in the synthesis of this subset of terpenes. Current efforts are focused on advancing 17 to neomangicols A–C.

Synthesis of indene derivatives via electrophilic cyclization.

Our synthetic studies commenced with the preparation of boronic ester 7 as illustrated in . The sequence began with Knoevenagel condensation of 2-bromo-5-methoxybenzaldehyde (8) and the sodium salt of Meldrum’s acid (9), which provided adduct 10 in 85% yield. Of note, numerous attempts to effect the Knoevenagel condensation using the conditions of Fillion (cat. pyrrolidinium acetate), which work well for electron-rich aryl aldehydes, resulted in lower yields. A conjugate reduction of alkylidene 10 was effected with sodium triacetoxyborohydride (STAB) and the resulting Meldrum’s acid derivative was methylated under standard conditions (K₂CO₃, MeI). At this stage, a formal Friedel-Crafts acylation using polyphosphoric acid (PPA) proceeded with concomitant loss of acetone and carbon dioxide to yield indanone 11 in 83% yield over the three steps.

Despite their relatively small size, the neomangicols and mangicols possess several challenging features from a synthetic standpoint. For example, these natural product families possess nine and eleven stereocenters, respectively. Additionally, the vinyl halide moiety present in neomangicols A and B is highly unusual in sesterterpene natural products. Our initial studies have focused on the neomangicols and specifically the tetracyclic core of neomangicol C. This presents an opportunity to investigate the potential application of indene alkylation chemistry to the synthesis of these highly complex rearranged sesterterpenoids. Importantly, the core of neomangicol C will serve as a starting point for the synthesis of neomangicols A and B, as well as the mangicols.

Rhenium-catalyzed synthesis of indene derivatives via C …

Historically, the carbon framework of terpenoid natural products has proven to be a synthetic challenge due to the lack of functional groups on these molecules that can direct C-C bond formation. As a result, synthetic chemists must design strategies for terpenoid syntheses that maximize carbon-carbon bond formation. Enolate methodology has been featured prominently in a wide range of C-C bond forming cyclization tactics (e.g., intramolecular aldol and Dieckmann reactions) en route to terpene natural products, which often necessitate the removal of the enolate carbonyl oxygen at a late stage. In the context of [5–6] bicyclic ring-containing terpene natural products, we envisioned that indenes, which possess acidities comparable to carbonyl compounds (e.g., ketones), could serve as enolate equivalents in late-stage bond-forming events. In this communication, we present the application of this tactic to the synthesis of the tetracyclic core of the natural product neomangicol C (2, ).

AB - The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs). Combination of salient structural features associated with colchicine and CA4 led to the design and synthesis of a variety of fused aryl-cycloalkyl and aryl-heterocyclic compounds that function as inhibitors of tubulin polymerization. Prominent among these compounds is a benzosuberene analogue (referred to as KGP18), which demonstrates sub-nM cytotoxicity against human cancer cell lines and functions (when administered as a water-soluble prodrug salt) as a VDA in mouse models. Structure activity relationship considerations led to the evaluation of benzocyclooctyl [6,8 fused] and indene [6,5 fused] ring systems. Four benzocyclooctene and four indene analogues were prepared and evaluated biologically. Three of the benzocyclooctene analogues were active as inhibitors of tubulin polymerization (IC50

SYNTHESIS OF AMINO DERIVATIVE OF INDENE AND …

N2 - The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs). Combination of salient structural features associated with colchicine and CA4 led to the design and synthesis of a variety of fused aryl-cycloalkyl and aryl-heterocyclic compounds that function as inhibitors of tubulin polymerization. Prominent among these compounds is a benzosuberene analogue (referred to as KGP18), which demonstrates sub-nM cytotoxicity against human cancer cell lines and functions (when administered as a water-soluble prodrug salt) as a VDA in mouse models. Structure activity relationship considerations led to the evaluation of benzocyclooctyl [6,8 fused] and indene [6,5 fused] ring systems. Four benzocyclooctene and four indene analogues were prepared and evaluated biologically. Three of the benzocyclooctene analogues were active as inhibitors of tubulin polymerization (IC50

Indene synthesis - Organic chemistry

Indene is an important building block for many compounds, playing a vital role in the formation of pharmaceuticals and some bio-active chemicals. Though frequently involved in many production activities, the cost for making indene is not cheap yet. The most common way to produce indene is synthesis. Then only by replacing the expensive materials with cheaper ones, the general cost of the indene synthesis can be decreased, whilst if the synthesis process can be simplified, it will be ideal. The research team led by Bas De Bruin made this. They developed a new catalyst to substitute the traditional ones, and at the same time decreased the steps for the whole synthesis.

of phenyl-substituted allylic cations

Scientists Bas de Bruin from Amsterdam and his research team release the cost of indene synthesis by replacing the noble metal catalysis with cheap and widely accessible metals, vastly decreasing the cost for commonly needed indene. Particularly, the method may be mimicked by other chemistry synthesis and the team is probing more about the possibility of the method, as well as new catalysts.

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