Blocking the Hype-Hypocrisy-Falsification-Fakery Pathway is Needed to Safeguard Science

In chemistry and other sciences, hype has become commonplace, compounded by the hypocrisy of those who tolerate or encourage it while disapproving of the consequences. This reduces the credibility and trust upon which all science depends for support. Hype and hypocrisy are but first steps down a slippery slope towards falsification of results and dissemination of fake science. Systemic drivers in the contemporary structure of the science establishment encourage exaggeration and may lure the individual into further steps along the hype-hypocrisy-falsification-fakery continuum. Collective, concerted intervention is required to effectively discourage entry to this dangerous pathway and to restore and protect the probity and reputation of the science system. Chemists must play and active role in this effort.     

Biomimetic Self‐Healing

Self‐healing is a natural process common to all living organisms which provides increased longevity and the ability to adapt to changes in the environment. Inspired by this fitness‐enhancing functionality, which was tuned by billions of years of evolution, scientists and engineers have been incorporating self‐healing capabilities into synthetic materials. By mimicking mechanically triggered chemistry as well as the storage and delivery of liquid reagents, new materials have been developed with extended longevity that are capable of restoring mechanical integrity and additional functions after being damaged. This Review describes the fundamental steps in this new field of science, which combines chemistry, physics, materials science, and mechanical engineering.     

An Easily Accessible Ionic Aggregation‐Induced Emission Luminogen with Hydrogen‐Bonding‐Switchable Emission and Wash‐Free Imaging Ability

Ionic fluorophores are powerful tools for the study of environmental science and bio‐imaging. However, traditional ionic dyes usually require long synthetic steps and suffer from a quenching effect caused by aggregation. A water‐soluble ionic aggregation‐induced emission luminogen called DBTA is presented, which is readily accessed by a one‐step reaction. The switchable emission manipulated by hydrogen bonding provided solid evidence for the restriction of intramolecular motions as the mechanism of aggregation‐induced emission. DBTA can not only differentiate solvents with different H‐bond donor acidities but also capable of wash‐free imaging in living HeLa cells and fish larva.     

Efficient Preparation of Pyridinyl‐1,2,4‐Triazines via Telescoped Condensation with Diversely Functionalized 1,2‐Dicarbonyls

The development of materials for efficient chemoselective extraction of minor actinides remains at the forefront of research efforts in the area of separation science. Lewis basic complexants derived from nitrogen‐donor scaffolds are often employed in this area due to favorable complexation with the transuranic element americium. In the present work an efficient procedure for the preparation of eight useful 3‐pyridin‐2‐yl‐1,2,4‐triazines (2 novel) is demonstrated via telescoped condensation with the requisite 1,2‐dicarbonyl in two‐pots without additives, differentially extractive work‐up procedures, or recrystallization. Additional efforts in this area have demonstrated the utility of polar aprotic solvents for the preparation of nine functionalized pyridinyl‐2,6‐bis‐1,2,4‐triazines (4 novel) directly from the requisite 2,6‐pyridine dicarbonitrile in 49–99% yield over four total steps. The streamlined preparation of these important materials and detailed synthetic procedures is reported herein.     

Efficient Synthesis of 1,2,3,4,6‐Penta‐O‐acetyl‐L‐idopyranose

An efficient synthesis of 1,2,3,4,6‐penta‐O‐acetyl‐L ‐idopyranose 2 from 3,5‐O‐benzylidene‐1,2‐O‐isopropylidene‐α‐D ‐glucofuranose in five steps in 45% overall yield via hydroboration of enol ether, hydrolysis of L ‐idofuranosyl sugar and acetolysis of 1,6‐anhydro‐β‐L ‐idopyranose as key steps is described here.     

An Alternative Synthesis of the Dopaminergic Drug 2‐Amino‐1,2,3,4‐tetrahydronaphthalene‐5,6‐diol (5,6‐ADTN)

Racemic 2‐amino‐1,2,3,4‐tetrahydronaphthalene‐5,6‐diol (5,6‐ADTN; 4 ) was synthesized from 5,6‐dimethoxynaphthalene‐2‐carboxylic acid ( 14 ) in four steps (60% overall yield; Scheme). The crucial steps of the synthesis are Birch reduction of 14 to the valuable synthon 15 , Curtius reaction and carbamate formation ( 16 ), hydrogenolysis ( 17 ), and demethylation to the biologically active hydrobromide salt 18 of 4 .     

Multi‐Gram Scale Synthesis of Chiral 3‐Methyl‐2,5‐trans‐tetrahydrofurans

In this article, we report the rapid and facile synthesis of chiral 3‐methyl‐2,5‐trans‐tetrahydrofurans. This reaction utilizes cheap and easily available starting materials. A domino hydrolysis and intramolecular Michael‐type ring closure reaction was the key step. As a result, synthesis of the desired 3‐methyl‐2,5‐trans‐tetrahydrofurans could be achieved in gram‐scale over seven linear steps with high chemical yield and high diastereoselectivity.     

New and Practical Synthesis of N‐(3‐Cyano‐7‐ethoxy‐4‐oxo‐1,4‐dihydroquinolin‐6‐yl)acetamide

New and practical synthetic route of N‐(3‐cyano‐7‐ethoxy‐4‐oxo‐1,4‐dihydroquinolin‐6‐yl)acetamide ( 1 ) is described, through the cyclization of 2‐aminophenyl‐ethanone ( 12 ) with N,N‐dimethylformamide dimethylacetal. The overall yield of 1 obtained from this process is 46% (five steps) with a purity of >99% (HPLC).     

A facile synthesis of substituted 3‐amino‐1H‐quinazoline‐2,4‐diones

A new synthesis of a series of 3‐amino‐1H‐quinazoline‐2,4‐diones is described. The 1H‐quinazoline‐2,4‐dione 10 was made starting with fluorobenzoic acid in three high yielding steps. The key step of this synthesis involved the generation of the dianion of urea 7 and the subsequent intramolecular nucleophilic displacement of the 2‐fluoro to form the quinazolinedione ring. The 3‐amino moiety was incorporated using (2,4‐dinitro‐phenyl)‐hydroxylamine as the aminating reagent.     

Diversity‐Oriented Synthesis of Drug‐Like Macrocyclic Scaffolds Using an Orthogonal Organo‐ and Metal Catalysis Strategy

Small‐molecule modulators of biological targets play a crucial role in biology and medicine. In this context, diversity‐oriented synthesis (DOS) provides strategies toward generating small molecules with a broad range of unique scaffolds, and hence three‐dimensionality, to target a broad area of biological space. In this study, an organocatalysis‐derived DOS library of macrocycles was synthesized by exploiting the pluripotency of aldehydes. The orthogonal combination of multiple diversity‐generating organocatalytic steps with alkene metathesis enabled the synthesis of 51 distinct macrocyclic structures bearing 48 unique scaffolds in only two to four steps without the need for protecting groups. Furthermore, merging organocatalysis and alkene metathesis in a one‐pot protocol facilitated the synthesis of drug‐like macrocycles with natural‐product‐like levels of shape diversity in a single step.     

Enantioselective Synthesis of (−)‐(19R)‐Ibogamin‐19‐ol

The first total synthesis of the natural product (?)‐(19R)‐ibogamin‐19‐ol ((?)‐ 1 ) is reported (biogenetic atom numbering). Starting with L ‐glutamic acid from the chiral pool and (2S)‐but‐3‐en‐2‐ol, the crucial aliphatic isoquinuclidine (= 2‐azabicyclo[2.2.2]octane) core containing the entire configurational information of the final target was prepared in 15 steps (overall yield: 15%). The two key steps involved a highly effective, self‐immolating chirality transfer in an Ireland–Claisen rearrangement and an intramolecular nitrone‐olefin 1,3‐dipolar cycloaddition reaction (Scheme 3). Onto this aliphatic core was grafted the aromatic moiety in the form of N(1)‐protected 1H‐indole‐3‐acetic acid by application of the dicyclohexylcarbodiimide (DCC) method (Scheme 4). Four additional steps were required to adjust the substitution pattern at C(16) and to deprotect the indole subunit for the closure of the crucial 7‐membered ring present in the targeted alkaloid family (Schemes 4 and 5). The spectral and chiroptical properties of the final product (?)‐ 1 matched the ones reported for the naturally occurring alkaloid, which had been isolated from Tabernaemonatana quadrangularis in 1980. The overall yield of the entire synthesis involving a linear string of 20 steps amounted to 1.9% (average yield per step: 82%).     

Improved Synthesis of Phytosphingosine and Dihydrosphingosine from 3,4,6‐Tri‐O‐benzyl‐D‐galactal

An efficient and facile synthesis of phytosphingosine and dihydrosphingosine derivatives is described with less steps and in improved overall yield (66–72%) starting from commercially available tri‐O‐benzyl‐D ‐galactal. The key steps include Wittig reaction, Mitsunobu transformation, reduction, and deprotection.     

Ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylates by a tandem addition‐elimination‐SNAr reaction

The ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate ring structure, important in several drug compounds, has been prepared in two steps from ethyl 2‐(2‐fluorobenzoyl)acetate. Treatment of this β‐ketoester with N,N‐dimethylformamide dimethyl acetal gives a 97% yield of the 2‐dimethylaminomethylene derivative. Reaction of this β‐enaminone with primary amines in N,N‐dimethylformamide at 140°C for 48 h then affords the 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate esters in 60–74% yields by a tandem addition‐elimination‐S_NAr reaction. The synthesis of the starting material as well as procedural details and a mechanistic scenario are presented. J. Heterocyclic Chem., (2011).     

A scalable Nenitzescu synthesis of 2‐methyl‐4‐(trifluoromethyl)‐1H‐indole‐5‐carbonitrile

2‐Methyl‐4‐(trifluoromethyl)‐1H‐indole‐5‐carbonitrile is a key intermediate in the synthesis of selective androgen receptor modulators discovered in these laboratories. A practical and convergent synthesis of the title compound starting from 4‐nitro‐3‐(trifluoromethyl)phenol and tert‐butyl acetoacetate was developed, including a telescoped procedure for synthesis (without isolation) and Nenitzescu reaction of 2‐trifluoromethyl‐1,4‐benzoquinone. Conversion of the known Nenitzescu indole product to a novel triflate intermediate followed by palladium‐catalyzed cyanation afforded a penultimate carbonitrile. Removal of the C‐3 tert‐butyl ester group on the indole through a decarboxylative pathway completed the synthesis of the title compound in six steps (27% overall yield) from 4‐nitro‐3‐(trifluoromethyl)phenol (five steps, 37% overall yield from tert‐butyl acetoacetate). J. Heterocyclic Chem., (2011).     

Facile access to 6‐substituted 1,4,5,7‐tetrahydropyrrolo[3,4‐b]‐pyridines via hantzsch type dimethyl 4‐aryl‐2‐formyl‐6‐methyl‐1,4‐dihydropyridine‐3,5‐dicarboxylates

Efficient assembly of 6‐substituted 4‐aryl‐5‐oxo‐1,4,5,7‐tetrahydropyrrolo[3,4‐b]pyridines (7a‐f) is described according to a Hantzsch type reaction from formyl‐ester 4 by imination, borohydride reduction and intramolecular thermal amino‐ester cyclization. The starting compound 4 was prepared in three steps from the readily available formyl derivative 1, methyl 4,4‐dimethoxy‐3‐oxobutanoate and methyl 3‐aminocrotonate.     

Ethyl 1,4‐Dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylates by a Tandem SNAr‐Addition‐Elimination Reaction

A series of N‐substituted 1,4‐dihydro‐4‐oxo‐1,8‐naphthyridine‐3‐carboxylate esters has been prepared in two steps from ethyl 2‐(2‐chloronicotinoyl)acetate. Treatment of the β‐ketoester with N,N‐dimethylformamide dimethyl acetal in N,N‐dimethylformamide (DMF) gave a 95% yield of the 2‐dimethylaminomethylene derivative. Subsequent reaction of this β‐enaminone with primary amines in DMF at 120^oC for 24 h then afforded the target compounds in 47–82% yields by a tandem S_NAr‐addition‐elimination reaction. Synthetic and procedural details as well as a mechanistic rationale are presented.     

First Synthesis of a C‐Homosteroid from Pregn‐4‐ene‐3,11,20‐trione

(3α,5α)‐3‐Hydroxy‐C‐homopregnane‐11,20‐dione ( 3 ) was prepared in eleven steps from the commercially available pregn‐4‐ene‐3,11,20‐trione ( 4 ) via the 11‐oxo‐13‐formyl‐12,13‐secopregnane intermediate 11 (Scheme 2). Subjection of this secopregnane to an intramolecular aldol condensation afforded the α,β‐unsaturated key intermediate C‐homopregn‐12‐en‐11‐one 12 .     

(-)-（3S, 6R）-3, 6-羟基-10-甲基十一酸及其三聚体的全合成

以廉价易得的异戊基溴为起始原料,以烯丙基二异松莰烷基硼烷参与的不对称烯丙基化反应和Yamaguchi酯化反应为关键步骤,实现了对(-)-(3S,6R)-3,6-二羟基-10-甲基十一酸(总收率27.5％)及其三聚体(总收率24.5％)的不对称全合成。     

Practical Synthesis of (20S)‐10‐(3‐Aminopropyloxy)‐7‐ethylcamptothecin,a Water‐Soluble Analogue of Camptothecin

A robust, practical synthesis of (20S)‐10‐(3‐aminopropyloxy)‐7‐ethylcamptothecin (T‐2513, 5 ), which is a water‐soluble analogue of camptothecin, has been developed. The key step in this synthesis is a highly diastereoselective ethylation at the C20 position by using N‐arylsulfonyl‐(R)‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid ester as a chiral auxiliary, which affords the key intermediate ethyl‐(S)‐2‐acyloxy‐2‐(6‐cyano‐5‐oxo‐1,2,3,5‐tetrahydroindolizin‐7‐yl)butanoate ( 8 k ) in 93 % yield and 87 % de. Optically pure compound 8 k was obtained by a single recrystallization from acetone and its further elaboration through Friedlander condensation afforded compound 5 . This synthesis does not require any chromatographic purification steps and can provide compound 5 on a multi‐gram scale in 6.3 % overall yield (16 steps).