Huanyu Tang

Redox-neutral rhodium-catalyzed C-H functionalization of arylamine N-oxides with diazo compounds: primary C(sp(3))-H/C(sp(2))-H activation and oxygen-atom transfer.

An unprecedented rhodium(III)-catalyzed regioselective redox-neutral annulation reaction of 1-naphthylamine N-oxides with diazo compounds was developed to afford various biologically important 1H-benzo[g]indolines. This coupling reaction proceeds under mild reaction conditions and does not require external oxidants. The only by-products are dinitrogen and water. More significantly, this reaction represents the first example of dual functiaonalization of unactivated a primary C(sp(3) )H bond and C(sp(2) )H bond with diazocarbonyl compounds. DFT calculations revealed that an intermediate iminium is most likely involved in the catalytic cycle. Moreover, a rhodium(III)-catalyzed coupling of readily available tertiary aniline N-oxides with α-diazomalonates was also developed under external oxidant-free conditions to access various aminomandelic acid derivatives by an O-atom-transfer reaction.

Rh(III)-Catalyzed Intramolecular Redox-Neutral or Oxidative Cyclization of Alkynes: Short, Efficient Synthesis of 3,4-Fused Indole Skeletons

A Rh(III)-catalyzed intramolecular redox-neutral or oxidative annulation of a tethered alkyne has been developed to efficiently construct 3,4-fused indoles via a C-H activation pathway. The advantages of this process are (1) ready availability of annulation precursors; (2) broad substrate scope; (3) complete regioselectivity; (4) simple and mild reaction conditions; and (5) no need for an external oxidant or to employ molecular oxygen as the stoichiometric terminal oxidant.

Access to Six- and Seven-Membered 1,7-Fused Indolines via Rh(III)-Catalyzed Redox-Neutral C7-Selective C-H Functionalization of Indolines with Alkynes and Alkenes.

We report herein a new strategy for the Rh(III)-catalyzed redox-neutral C7-selective C-H activation/annulation of indolines to rapidly access various privileged 1,7-fused indolines by utilizing an oxidizing-directing group. For example, a Rh(III)-catalyzed redox-neutral C7-selective C-H functionalization of indolines with arylalkynes is described to directly access 7-membered 1,7-fused indolines. Moreover, an unprecedented intramolecular addition of an alkenyl-Cp*Rh(III) species to a carbamoyl moiety occurred to give 1H-pyrroloquinolinones when employing alkyl alkynes. Additionally, an efficient Rh(III)-catalyzed redox-neutral C7-selective C-H activation/alkenylation/aza-Michael addition of indolines is also developed to give 6-membered 1,7-fused indolines. The advantages of these processes are as follows: (1) mild and simple reaction conditions; (2) no need for an external oxidant; (3) broad scope of substrates; and (4) valuable six- or seven-membered 1,7-fused indolines as products.

Design, synthesis and anticancer activity evaluation of novel C14 heterocycle substituted epi-triptolide.

Two series of novel C14 heterocycle substituted epi-triptolide derivatives as potential anticancer agents were synthesized and tested for their cytotoxicity against SKOV-3 and PC-3 tumor cell lines. The introduction of C14β-aryl heterocycle aminomethyl substituent to the leading compound was found to be an effective modification method to retain the potent anticancer activity. Meanwhile, the series of epi-triptolide derivatives (21-40) with C14α-hydroxyl group, still retained the natural products cytotoxicity. This is apparently challenges the classical structure-activity relationship of triptolide that considers the C14β-hydroxyl group to be essential for its anticancer activity.

Design, synthesis and structure-activity relationships studies on the D ring of the natural product triptolide.

Triptolide is a diterpene triepoxide natural product isolated from Tripterygium wilfordii Hook F, a traditional Chinese medicinal herb. Triptolide has previously been shown to possess antitumor, anti‐inflammatory, immunosuppressive, and antifertility activities. Earlier reports suggested that the five‐membered unsaturated lactone ring (D ring) is essential for potent cytotoxicity, however, to the best of our knowledge, systematic structure–activity relationship studies have not yet been reported. Here, four types of D ring‐modified triptolide analogues were designed, synthesized and evaluated against human ovarian (SKOV‐3) and prostate (PC‐3) carcinoma cell lines. The results suggest that the D ring is essential to potency, however it can be modified, for example to C18 hydrogen bond acceptor and/or donor furan ring analogues, without complete loss of cytotoxic activity. Interestingly, evaluation of the key series of C19 analogues showed that this site is exquisitely sensitive to polarity. Together, these results will guide further optimization of this natural product lead compound for the development of potent and potentially clinically useful triptolide analogues.

Divergent Total Synthesis of Triptolide, Triptonide, Tripdiolide, 16-Hydroxytriptolide, and Their Analogues

A divergent route was developed for the formal total synthesis of triptolide, triptonide, and tripdiolide, as well as a total synthesis of 16-hydroxytriptolide and their analogues in an enantioselective form. Common advanced intermediate 5 was concisely assembled by employing an indium(III)-catalyzed cationic polycyclization reaction and a palladium-catalyzed carbonylation-lactone formation reaction as key steps. This advanced intermediate was readily converted to the above natural products by using palladium-catalyzed cross-coupling or the Claisen rearrangement reaction as key steps. Additionally, preliminary structure-cytotoxic activity relationship studies of C13 suggested that it might be a new modification site that could still retain the cytotoxicity.

Semisynthesis of triptolide analogues: Effect of B-ring substituents on cytotoxic activities

A series of B-ring modified analogues of triptolide were synthesized and tested for their cytotoxicity against two human tumor cell lines (U251 and PC-3). From the current investigation, the structure-cytotoxic activity relationships of these analogues suggested that the introduction of hydroxyl, epoxide, halogen or olefinic groups on C5 and/or C6 could still retain the cytotoxicity, albeit a little less potency, and the C7,C8-β-epoxide group of triptolide was essential to its potent cytotoxic activity.

A diastereoselective synthesis of 7α-nitromethyl steroid derivative and its use for an efficient synthesis of eplerenone

A novel and efficient method of stereoselectively introducing α-nitromethyl group to C-7 position of 11α-hydroxyl canrenone 4 was described. In addition, this method was successfully applied in a total synthesis of Eplerenone 8. The route was characteristic of simple operation, moderate reaction conditions with 5 steps and 55% total yield, at the same time, without any expensive or toxic reagent in use.