Investigation of the Cyclopentenone Formation via the α-Alkynone Cyclisation: Synthesis of the Acorone Intermediate 8-Methylspiro[4.5]deca-3,7-dien-2-one

As a further application of the cyclopentenone formation A→C via the thermal α-alkynone cyclisation B→C and in order to test the fate of an isolated C,C-double bond within a molecule under these conditions, we investigated the synthesis of the acorone intermediate 3 starting from the known carboxylic acid 1 . The α-alkynone 2 was obtained from 1 via the acyl chloride 6 and a Pd(II)-catalysed route (22%). The thermolysis of 2 at 550° provided the target molecule 3 (48%) together with the product 9 (20%) of a competing intramolecular ene reaction and its dimer 10 (4%). At a higher thermolysis temperature (650°), the spiro ketone 3 was found to be unstable, affording the retro-Diels-Alder fragments 4-methylidene-2-cyclopentenone ( 12 ) (33%) and isoprene (32%). A further example of the influence of an isolated double bond on the yield of the cyclopentenone-formation sequence A→C was provided by the comparison of the annelation 14→20 (5% overall with Pd(II)-catalysed acylation) with that of its non-olefinic analogue 17→21 (53% overall with Friedel-Crafts acylation).     

L‐Lysine/imidazole‐catalyzed Multicomponent Cascade Reaction: Facile Synthesis of C5‐substituted 3‐Methylcyclohex‐2‐enones

A facile and simple route for the direct preparation of substituted 3‐methylcyclohex‐2‐enone via Aldol‐Robinson cascade reaction of aldehydes and acetones catalyzed by the new catalytic system of L‐lysine/imidazole in n‐heptane with 0.5% water was reported. A variety of substrates can participate in the process efficiently. The merits of this method included inexpensive and easily available starting materials and catalyst, the good yield of products and the straightforward work‐up.     

A Negishi cross-coupling reaction enables the total synthesis of (+)-stachyflin

We present a full account on the development of the total synthesis of the antiviral meroterpenoid (+)-stachyflin. The decalin subunit is rapidly accessed by an exo-selective Diels–Alder reaction, whereas the isonindolinone was synthesized via a highly efficient and practical de novo route starting from dimedone. A challenging sp²–sp³ Negishi cross-coupling reaction enabled construction of the crucial C15–C16 bond that connects the arene with the decalin subunit. For the final installation of the cis-decalin framework, a Lewis acid-catalyzed cyclization was applied.     

Practical and efficient synthesis of gefitinib through selective O-alkylation: A novel concept for a transient protection group

A practical process that includes a simple four-step procedure for the preparation of gefitinib (1), a tyrosine kinase inhibitor that targets the epidermal growth factor receptor, is described. Dramatic improvements over previously reported conventional synthetic procedures were achieved. We found effective coupling conditions to minimize the inevitable production of an N-alkylated side product, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)-quinazoline-4-amine (3) using a transient trimethylsilyl protecting group. We synthesized gefitinib in an 81.1% overall yield from a commercially available starting material on a multigram scale using a route that did not require work-up of any of the reaction steps.     

Stereoselective Conversion of Campholene- to Necrodane-Type Monoterpenes. Novel Access to (−)-(R,R)- and (R,S)-α-Necrodol and the Enantiomeric γ-Necrodols

Naturally occurring (?)-(R,R)-α-necrodol ((?)- 1 ) and its C(4)-epimer (?)- 2 are obtained in 84 and 44% yields, respectively, by lithium ethylenediamide (LEDA) treatment of the corresponding β-necrodols (?)- 3 and (?)- 4 (Scheme 1, Table), both readily available from (?)-campholenyl acetate ((?)- i ) by an efficient stereoselective synthesis. The thermodynamically preferred (?)-(R)-γ-necrodol ((?)- 5 ) becomes the major product (≥ 80% yield) after either prolonged treatment with LEDA or exposure of α- and β-necrodols to BF₃·Et₂O. In an alternative route, (+)- 5 is prepared starting from (+)-campholenal ((+)- ii ) via Pd-catalysed decarbonylation to (?)-(S)-1,4,5,5-tetramethylcyclopent-l-ene ((?)- 6 ) and subsequent application of an acid-catalysed CH₂O-addition/rearrangement sequence (Scheme 2).     

Synthesis of Macrocyclic Insect‐Derived Alkaloids

Macrocyclic lactonic alkaloids found in the pupal secretions of two species of a coccinellid beetle (genus Epilachna) were prepared in enantiomerically pure form via an efficient synthetic route using enantiomerically pure α‐amino acids as chiral‐pool starting materials. Macrocycles with rings containing up to 98 atoms were synthesized in good yield using Mukaiyama's macrolactonization conditions.     

Synthesis of a novel pyrrolo-benzoxaborole scaffold and its derivatization via Friedel–Crafts reaction catalyzed by anhydrous stannic chloride

A novel pyrrolo-benzoxaborole, 6-(pyrrol-1-yl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, was synthesized with 27% overall yield over six steps from 2-bromo-1-methyl-4-nitrobenzene as starting material. Its derivatization was achieved via Friedel–Crafts reaction catalyzed by anhydrous stannic chloride with various acyl chlorides giving 3-acyl-1-phenylpyrroles as the main products.     

A facile synthesis of imino-protected cyclic guanidine derivatives from diamines

A convenient one-step synthesis of five-membered or six-membered imino-protected cyclic guanidine via an intramolecular ring-closure reaction of alkyl diamine(2a-2g) with 1,3-diamino-protected methylisothiourea(1a and 1b) was established and investigated.Amino guanidine such as 3-(2-aminoethyl)-1,2-dibenzyloxycarbonylguanidine(4a) has been proved to be the intermediate of the reaction via utilizing mono-protected diamine as starting material.The intramolecular ring closure of 4a results in 2-benzyloxycarbonyliminoimidazolidine(3a).This new one-step synthesis has advantages of simple condition,easy workup procedure and reasonable yield.     

Route Scouting towards a Methyl Jasmonate Precursor

For the synthesis of methyl jasmonate ( 1 ), via the strategic intermediates 3, 4 , and 6a , we constructed a synthetic network via the diverse intermediates 7 – 10, 13, 14, 17 , and 18 . This allowed us to compare the efficiency of more than 20 novel routes. The most productive pathway with a total yield of 38% is represented by the sequence→ 5a → 5m → 13b → 13a → 6a → 4 and proceeds via sequential bromination, basic elimination, decarbomethoxylation, isomerization, and finally Lindlar hydrogenation. The shortest selective way, 2a →[(E,E)‐ 12b ]→ 3 → 4 , is a two‐pot sequence using a modification of Naef's method, based on an aldol condensation between inexpensive cyclopentanone ( 2a ) and crotonaldehyde, with in situ Corey? Chaykovsky cyclopropanation under phase transfer conditions. The key intermediate 3 was then simply pyrolyzed to afford 4 in 27% total yield. The alternative isomerization method via the six‐step deviation→ 5a → 5c → 8c → 13a → 6a → 4 was longer, although more efficient, with a total yield of 32%. Alternatively, a yield of 34% was obtained via the five‐step sequence→ 5a → 5c → 2h → 2i → 4 . Another favored six‐step pathway,→ 5a → 5c → 2h → 17a → 14a → 4 afforded the target compound in 35% total yield.     

Studies of spiro-chlorin formation using porphyrin amides

Syntheses of 7-(3-ethoxycarbonylpropyl)-2,3,5-triethyl-1,4,6,8-tetramethylporphyrin ( 8 ) (via the MacDonald dipyrrylmethane route) and 2-(2-chloroethyl)-4-ethyl-6-methoxycarbonyl-7-(3-methoxy-carbonylpropyl)-1,3,5,8-tetramethylporphyrin ( 22 ) (via the tripyrrene route) are described. The corresponding pyrrolidides of these compounds were cyclized in high yield to furnish the spiro imines ( 20 and 30 respectively), but attempts to hydrolyze these imines to the appropriate spiroketochlorins were largely unsuccessful. A small amount of the spiroketochlorin 9 (from 8 ) was obtained, and this was successfully hydrogenated to give the dihydro derivative 21 . The major problem in imine hydrolysis was observed to be reversion to the parent porphyrin through simple bond migration and spiro ring cleavage. A successful transformation of protoporphyrin-IX dimethyl ester ( 31 ) into mesoporphyrin-IX dimethyl ester ( 32 ) using di-imide generated from dipotassium azodicarboxylate is described.     

Synthesis und thermisches Verhalten von exo-3-Methylidentricyclo[3.2.1.02,4]oct-6-en

Synthesis and Thermal Behaviour of exo-3-Methylidenetricyclo[3.2.1.0^2,4]oct-6-ene The title compound 3 has been prepared in 16% yield starting from 8,9,10-trinorborna-2,5-diene. Heating 3 at 140° for 4 h does not give triafulvene and cyclopentadiene by Diels-Alder cycloreversion, instead the tetracyclic compound 10 has been isolated (81%), which is presumably formed via the diradical 11.     

Synthesis of the Cellulose Model Compound Methyl 4″-O-Methyl-β-D-Cellotrioside

A high-yield synthetic route towards methyl 4″-O-methyl-β-D -cellotrioside ( 17 ) via cellobioside acceptor 8 and glucosyl fluoride donor 15 was established. The former was synthesized from cellobiose peracetate in 7 steps and 21% overall yield, while the latter was obtained from methyl β-D -glucopyranoside in a 6-step-synthesis with 19% yield. Glycosidation afforded 13% of α-compound besides the desired β-isomer (31%). The target compound, being the higher homologue of the recently prepared 4′-O-methyl-β-D -cellobioside ( 1 ), is required to study by solid-state techniques the hydrogen bond network in cellodextrins and cellulose, and its changes upon swelling and dissolution.     

Synthesis of dendritic polyamide with protected amino functional groups in the periphery

A homologous series of first-to third-generation dendritic polyamides 2a, 3, and 5 with tris(aminoethyl) amine (TREA) as the core and the protected amino functional groups at the periphery were synthesized via active ester route from “Schlüter” type dendron 1a. Their structures were characterized by ¹H-NMR and mass spectra. Based on the efficient synthesis of the first generation dendrimer 2a (yield 75%), the synthesis of second-generation dendrimer 3 was found to be more efficient via the convergent method (yield 69%), while the mixed strategy was applied efficiently for the synthesis of the higher generation dendrimer 5 (yield 37%). The overall yield for the third generation dendrimer 5 from Schlüter dendron is 12%. __________ Translated from Huaxue Tongbao (Chemistry), 2005, 68(12) (in Chinese)     

The synthesis of 1,3-dihydro-1-[1-[(4-methyl-4H-6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)methyl]-4-piperidinyl]-2H-benzimidazol-2-one (1:1) maleate (CGS 9343 B,potent calmodulin inhibitor)

A practical synthesis of the title compound 7b is described in seven steps in approximately 10% overall yield. The key step in the synthesis is the formation of the unusual tricyclic ring system 4 via acid catalyzed cyclization.     

First Total Synthesis of Prionoid E,A Bioactive Rearranged Secoabietane Diterpene Quinone from Salvia prionitis

The first total synthesis of prionoid E ( 1 ), a rearranged secoabietane diterpene quinone isolated from Salvia prionitis, was achieved efficiently by means of Wacker oxidation (Scheme 5) and aldol condensation (Scheme 7) as the key steps in the synthetic sequence. Thus 1 was prepared in 15 steps in 3.7% yield starting on one hand from anisole (=methoxybenzene) and methylsuccinic anhydride (=dihydro‐3‐methylfuran‐2,5‐dione) via 4 (Scheme 3 and 5), and on the other hand from 2‐hydroxy‐2‐methylpropanoic acid via 5 (Scheme 6).     

Synthese von (±) Seychellen

A four step synthesis of Seychellene ( 1 ) is described. Intramolecular Diels-Alder reaction of dienon 2 furnished the tricyclic ketones 3 and 4 in good yield. Hydrogenation of 3 gave 5 and 6 . The higher reactivity of 6 with methyllithium compared to 5 allowed the selective preparation of 8 , which, on subsequent acid-catalyzed rearrangment afforded Seychellen in 57,5% yield. In an analogues manner epi-Seychellene was synthetized via the intermediates 5 and 7 .     

Thallium(III) p-Tosylate Mediated Oxidative 2,3-Aryl Rearrangement: A New Useful Route to Ipriflavone and Its Analogs

A new route for the synthesis of ipriflavone, an antiosteoporotic agent, is described that has four steps and 60% yields starting from resacetophenone (2). The key step of the present methodology is thallium(III) p-tosylate mediated oxidative 2,3-aryl rearrangement of flavanone to generate the isoflavone ring system of ipriflavone in a highly efficient manner.     

Synthesis of 3,4‐dihydro‐1(2H)‐isoquinolinonesxs

Approaches toward the preparative‐scale synthesis of target 3,4‐dihydro‐1(2H)‐isoquinolinones 1–3 are presented. Compounds 1 and 2 were prepared via a Schmidt rearrangement on easily obtained indanone precursors, but in low overall yield. A better method to make this class of compounds is exemplified by the large‐scale synthesis of 2 via a Curtius rearrangement sequence. Thus, high‐temperature thermal cyclization of an in situ formed styryl isocyanate from precursor 8 in the presence of tributylamine gave the corresponding 1(2H)‐isoquinolinone ( 9 ). Catalytic hydrogenation of 9 provided the desired 3,4‐dihydro‐5‐methyl‐1(2H)‐isoquinolinone ( 2 ) in 65 % overall yield. Similar reduction of a commercially available 5‐hydroxy‐1(2H)‐isoquinolinone precursor 10 followed by an O ‐alkylation/amination sequence gave target 3 in good overall yield. The route proceeding via the Curtius rearrangement is recommended for large scale synthesis of other 3,4‐dihydro‐1(2H)‐isoquinolinones. Only when deactivating substituents or sensitive functionality within the benzenoid ring render the high temperature ring closure of the intermediate isocyanate inefficient might a Schmidt rearrangement protocol be the method of choice.     

Synthesis of [3,3′‐Di‐sec‐butyl‐4′‐(2‐dimethylaminoethoxy)biphenyl‐4‐yl‐oxy]acetic Acid

A modified synthetic route of [3,3′‐di‐sec‐butyl‐4′‐(2‐dimethylaminoethoxy)biphenyl‐4‐yloxy]acetic acid ( 1 ) with high total yield of 44% from biphenyl‐4,4′‐diol ( 2 ) is described.     

A New Sterically Highly Hindered 7‐Membered Cyclic Nitroxide for the Controlled Living Radical Polymerization

The synthesis of a new sterically highly hindered 7‐membered alkoxyamine, 2,2,7,7‐tetraethyl‐1‐(1‐phenylethoxy)‐1,4‐diazepan‐5‐one ( 4 ), starting from known 2,2,6,6‐tetraethyl‐1‐(1‐phenylethoxy)piperidin‐4‐one ( 3 ) via a Beckmann‐type rearrangement is presented. It is shown that ring‐enlargement by insertion of an NH moiety in going from 3 to 4 leads to a more efficient regulator for nitroxide‐mediated controlled living radical styrene (= ethenylbenzene) and butyl acrylate (= butyl prop‐2‐enoate) polymerization. In addition to the polymerization experiments, kinetic data on the reversible C? O bond homolysis of alkoxyamines 3 and 4 are presented.