Jumreang Tummatorn

Strain-promoted azide-alkyne cycloadditions of benzocyclononynes.

Preliminary studies related to the design and development of new cycloalkyne reagents for metal-free click coupling are reported. Cyclononynes are more stable than cyclooctynes, and the robust benzocyclononyne platform offers spontaneous reactivity toward azides at rates competitive with other azidophiles that have been employed for metal-free click coupling. Benzocyclononynes (e.g., 1) provide valuable insight into the design of new cycloalkynes for strain-promoted azide-alkyne cycloaddition (SPAAC) couplings for applications in which side reactions and decomposition of the reagent must be kept to a minimum.

Generation of medium-ring cycloalkynes by ring expansion of vinylogous acyl triflates.

Reductive cyclization of aryl and vinyl iodides tethered to vinylogous acyl triflates (VATs) induces a ring-expanding fragmentation to provide cyclic alkynyl ketones, including strained nine-membered cycloalkynes, in fair to excellent yield. The tandem cyclization/C-C bond-cleavage is initiated under carefully optimized conditions by halogen-metal exchange in the presence of carbonyl and vinyl triflate functionality. A modified protocol for alkylation of 1,3-cyclohexanedione is described for preparing the relevant VAT substrates.

A convergent general strategy for the functionalized 2-aryl cycloalkyl-fused chromans: intramolecular hetero-Diels-Alder reactions of ortho-quinone methides.

adduct isolated from Brosimum rubescens, showed potent inhibition of the binding of 5a-dihydrotestosterone (DHT) with the androgen receptor. Parvifolol A (2 ; Scheme 1), a natural product isolated from Gnetum parvifolium, was evaluated for the inhibitory activity in the Maillard reaction (protein glycation) associated with diabetic complications and aging of the skin. Compound 3 was synthesized and studied as an estradiol analogue. Some tricyclic 2-aryl-3,4cycloalkyl-fused benzopyrans (4, 5 ; Scheme 1) were synthesized and investigated for their high affinity to and selectivity for the estrogen receptor b over the a. Some synthetic methods have been developed for chromans by hetero-Diels–Alder (HDA) reactions. However, despite the presence of the 2-aryl group in some natural products and synthetic compounds, the synthesis of 2-aryl3,4-cycloalkyl-fused chromans has been relatively unexplored, partly due to the susceptible nature of styrenes to polymerization. To date, the reported syntheses have been largely performed for the 2-alkylcycloalkyl-fused chromans and pyranobenzopyrans. In addition, modifications on the cycloalkyl-fused rings would be difficult because the cycloalkyl or pyranyl moieties are nonfunctionalized. Moreover, different strategies were required for cyclopentyland cyclohexyl-fused compounds (4, 5). Thus, developing a general synthetic strategy for the tricyclic core of 2-aryl-3,4-cycloalkyl-fused chromans with defined stereocenters (C2, C3, and C4) and functionalizable moieties on the cycloalkyl ring would be pivotal. Recently, as part of our research in the use of solid-supported reagents in organic synthesis, our group has reported the successful generation of o-QMs and their intermolecular HDA reactions with styrene derivatives under mild conditions mediated by p-toluenesulfonic acid (p-TsOH) immobilized on silica (PTS-Si) in toluene. We now envisioned that PTS-Si could be employed to generate ortho-quinone methide (o-QM), which, upon reacting intramolecularly with the tethered dienophile (i.e. , styrenes), could form the tricyclic 2-aryl-3,4-cycloalkyl-fused chroman. As shown retrosynthetically in Scheme 2, the precursors for the intramolecular HDA reactions would be derived from aldol condensation between the benzaldehyde derivative (6) and ketone (X= H; Y=Me) or the acetophenone derivative (7) and the aldehyde (X=Me; Y=H). Synthesis of these cycloalkyl-fused chroman systems would be highly convergent and requires a similar strategy to assemble the precursors for the intramolecular o-QM/HDA reactions. [a] Dr. J. Tummatorn, Prof. Dr. S. Ruchirawat, Dr. P. Ploypradith Laboratory of Medicinal Chemistry, Chulabhorn Research Institute Vipavadee-Rangsit Highway, Bangkok 10210 (Thailand) Fax: (+662) 574-2027 E-mail : poonsakdi@cri.or.th [b] Prof. Dr. S. Ruchirawat, Dr. P. Ploypradith Program in Chemical Biology, Chulabhorn Graduate Institute Vipavadee-Rangsit Highway, Bangkok 10210 (Thailand) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200902403. Scheme 1. Examples of 2-arylcycloalkyl-fused chromans (shown with relative stereochemistry).

Ring opening/fragmentation of dihydropyrones for the synthesis of homopropargyl alcohols.

Ring-opening/C-C bond cleavage reactions induced by nucleophilic addition of methyl Grignard to 5,6-dihydro-2-pyrone (DHP) triflates 1 furnish homopropargyl alcohols (1 --> 2) stereospecifically with respect to the stereochemistry of 1. Carbonyl extrusion from DHP triflates provides a unified and operationally simple strategy for preparing chiral homopropargyl alcohols.

Regioselective Synthesis of 3-Bromoquinoline Derivatives and Diastereoselective Synthesis of Tetrahydroquinolines via Acid-Promoted Rearrangement of Arylmethyl Azides

Regioselective synthesis of 3-bromoquinoline derivatives was achieved via a formal [4 + 2]-cycloaddition between N-aryliminium ion, generated from arylmethyl azides, and 1-bromoalkynes. This method could also be applied to other quinoline derivatives using appropriate alkynes. Moreover, the current strategy could be utilized for the diastereoselective synthesis of tetrahydroquinoline derivatives employing alkenyl substrates in good to excellent yields.

Stereodefined Homopropargyl Amines by Tandem Nucleophilic Addition/Fragmentation of Dihydropyridone Triflates

Dihydropyridone (DHPD) triflates undergo nucleophile-triggered fragmentation to provide homopropargyl amine derivatives, the stereochemistry of which is defined by starting from readily available β-amino esters.

Synthesis of isocryptolepine analogues and their structure–activity relationship studies as antiplasmodial and antiproliferative agents

Novel isocryptolepine analogues have been conveniently synthesized and evaluated for antimalarial and antiproliferative activities. We have found 3-fluoro-8-bromo-isocryptolepine (1n) to have the highest activities against chloroquine-resistant K1, chloroquine-sensitive 3D7, and chloroquine- and mefloquine-resistant SKF58 and SRIV35 strains. Several fluorine-substituted analogues (1b, 1n, and 1q) also showed excellent selectivities while maintaining good to excellent activities against all four Plasmodium falciparum strains. Additionally, antiproliferative properties of isocryptolepine derivatives against HepG2, HuCCA-1, MOLT-3 and A549 cancer cell lines are reported for the first time in this study. 2-Chloroisocryptolepine (1c) and benzo-fused-2-chloroisocryptolepine (1i) showed significant bioactivities whereas several novel fluorinated compounds and 2-chloro-8-bromoisocryptolepine (1f) displayed excellent selectivities.

Utility of Nitrogen Extrusion of Azido Complexes for the Synthesis of Nitriles, Benzoxazoles, and Benzisoxazoles

The utility of the nitrogen extrusion reaction of azido complexes, generated in situ from the corresponding aldehydes or ketones with TMSN3 in the presence of ZrCl4 or TfOH, has been described. These azido complexes could undergo three different pathways, depending on the substrates. First, azido methanolate complexes or imine diazonium ions could lead to benzisoxazole products via an intramolecular nucleophilic substitution. Second, imine diazonium ions could also undergo either the elimination of proton to provide nitrile products in good to excellent yields or an aryl migration, followed by an intramolecular nucleophilic addition, to give benzoxazole products in good yields.

Silver-Catalyzed Cyclization of ortho-Carbonylarylacetylenols for the Synthesis of Dihydronaphthofurans

ortho-Carbonylarylacetylenols have been employed for the synthesis of dihydronaphthofurans via AgTFA-catalyzed annulation reaction. A broad range of substrates both ortho-keto- and ortho-formylarylacetylenols could be employed in this transformation providing the desired products in good yields. However, the reaction pathways of these two substrates are different. The reaction of the ketone precursors could directly lead to the desired products in a single operation while the reaction of the aldehyde precursors required a one-pot two-step approach, without isolation of the bicyclic acetal intermediates. In addition, this method was also successfully used for the synthesis of dihydronaphthopyrans in very good yields.

Synthesis of the tricyclic core of aldingenin B by oxidative cyclo-ketalization of an alkyne-diol.

The preparation and selenium-mediated cyclo-ketalization of an alkyne-diol is described as a model study for the synthesis of aldingenin B. The oxidative cyclization is a simplifying transformation for aldingenin B, as it provides a convenient method for generating the tricylic core of the natural product from a functionalized cyclohexane.