Synthesis of an Ursolic Acid Saponin with N-Acetylglucosamine-containing Trisaccharide Residue

The focus of this work is the synthesis of an ursolic acid saponin with an N-acetylglucosamine-containingtrisaccharide residue.Therefore,ursolic acid 3-yl α-L-arabinopyranosyl-(1→2)-α-L-arabinopyranosyl-(1→6)-2-acetamido-2-deoxy-β-D-glucopyranoside(1)was concisely synthesized in convergent synthesis with 48.0% overallyield.The structure of saponin 1 was confirmed by ~1H NMR,~(13)C NMR and mass spectra.     

First Stereoselective Synthesis of the Cytotoxic Polyketide (4R)‐1‐(3,5‐Dihydroxyphenyl)‐4‐hydroxypentan‐2‐one

The first stereoselective synthesis of the cytotoxic polyketide (4R)‐1‐(3,5‐dihydroxyphenyl)‐4‐hydroxypentan‐2‐one ( 1 ) was achieved from readily available propylene oxide and 3,5‐dimethoxybenzyl alcohol. The synthesis involves Jacobsen's hydrolytic kinetic resolution (HKR) and Grignard reaction as key steps.     

An Efficient Stereoselective Total Synthesis of Bioactive (3R,5R)‐1‐(4‐Hydroxyphenyl)‐7‐phenylheptane‐3,5‐diol via Asymmetric Aldol Reaction

An efficient stereoselective total synthesis of (3R,5R)‐1‐(4‐hydroxyphenyl)‐7‐phenylheptane‐3,5‐diol ( 1 ) is reported based on the Mukaiyama aldol reaction. The total synthesis of compound 1 was accomplished with 30% overall yield in simple eight steps from commercially available trans‐cinnamaldehyde.     

Configurational Assignment of ‘Cryptochiral’ 10‐Hydroxystearic Acid Through an Asymmetric Catalytic Synthesis

An asymmetric catalytic total synthesis of (S)‐10‐hydroxystearic acid ( 1 ) for comparison of its absolute configuration to that of samples obtained by fermentative hydration of oleic acid is reported. The synthesis involves two catalytic key‐steps, namely Ru‐catalyzed anti‐Markovnikov hydration of 9‐decynoic acid ( 7 ) to 10‐oxodecanoic acid ( 5 ), followed by titanium‐mediated asymmetric catalytic addition of dioctylzinc ( 25 ) to 5 in presence of the chiral ligand N,N’‐((1R,2R)‐cyclohexane‐1,2‐diyl)bis(1,1,1‐trifluoromethanesulfonamide) ( 6 ). The synthesis is short and efficient and avoids use of protecting groups. Ozonolysis of 10‐undecynoic acid ( 9 ) to 5 provides an alternative entry point into the synthetic route. The double dehydrobromination of (ω,ω‐1)‐dibromoalkanoic acids to ω‐alkynoic acids under a variety of conditions was investigated with 10,11‐dibromoundecanoic acid ( 11 ) as model substrate and using qNMR to quantify all reaction products. The synthetic approaches presented here have the potential to be generalized to the asymmetric catalytic synthesis of a variety of n‐hydroxy‐fatty acids.     

An improved synthesis of enantiomerically pure RWJ 69442, a development candidate for the treatment of benign prostatic hyperplasia

This report describes an improved synthesis of enantiomerically pure (S)‐2‐[4‐(Dimethylamino)phenyl]‐2,3‐dihydro‐N‐[2‐hydroxy‐3‐[4‐[2‐(1‐methylethoxy)‐phenyl]‐1‐piperazinyl]propyl]‐1,3‐dioxo‐1H‐isoindole‐5‐carboxamide (RWJ 69442), a potent and selective α_la‐adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia. The synthesis highlights less hazardous reagents, easier purification and higher enantiomeric purity. The N‐benzyl‐N—t‐butoxycarbonyl amine 6 could serve as an enantiomerically pure chiral building block for asymmetric synthesis.     

‘Click Synthesis’ of Some Novel Benzimidazol Oxime Ethers Containing Heterocycle Residues as Potential ß‐Adrenergic Blocking Agents

The ‘click synthesis’ of some novel O‐substituted oximes, 5a – 5j , which contain heterocycle residues, as new analogs of ß‐adrenoceptor antagonists is described (Scheme 1). The synthesis of these compounds was achieved in four steps. The formation of (E)‐2‐(1H‐benzo[d]imidazol‐1‐yl)‐1‐phenylethanone oxime, followed by their reaction with 2‐(chloromethyl)oxirane, afforded mixture of oil compounds 3 and 4 , which by a subsequent tetra‐n‐butylammonium bromide (TBAB)‐catalyzed reaction with N H heterocycle compounds (Scheme 1), led to the target compounds 5a – 5j in good yields.     

First Total Synthesis of N‐(3‐Guanidinopropyl)‐2‐(4‐hydroxyphenyl)‐2‐oxoacetamide

The first total synthesis of the α‐oxo amide‐based natural product, N‐(3‐guanidinopropyl)‐2‐(4‐hydroxyphenyl)‐2‐oxoacetamide ( 3 ), isolated from aqueous extracts of hydroid Campanularia sp., has been achieved. The α‐oxo amide 12 , prepared via the oxidative amidation of 1‐[4‐(benzyloxy)phenyl]‐2,2‐dibromoethanone ( 9a ) with 4‐{[(tert‐butyl)(dimethyl)silyl]oxy}butan‐1‐amine ( 10a ), has been used as the key intermediate in the total synthesis of 3 as HBr salt. On the way, an expeditious total synthesis of polyandrocarpamide C ( 2c ), isolated from marine ascidian Polyandrocarpa sp., was carried out in four steps.     

A Novel Synthesis of Quinazolines by Cyclization of 1‐(2‐Isocyanophenyl)alkylideneamines Generated by the Treatment of 2‐(1‐Azidoalkyl)phenyl Isocyanides with NaH

A new and efficient method for the synthesis of quinazolines has been developed. Thus, N‐[2‐(1‐azidoalkyl)phenyl]formamides 1 are dehydrated with POCl₃ to give the corresponding 2‐(1‐azidoalkyl)phenyl isocyanides 2 , which are then treated with NaH in DMF at 0° to give quinazolines 6 in satisfactory yields via cyclization of 1‐(2‐isocyanophenyl)alkylideneamine intermediates 4 . This methodology can be applied to the synthesis of the 7‐azaanalogs of quinazolines, i.e., pyrido[3,4‐d]pyrimidines 9 .     

A novel synthetic approach for the synthesis of pyridocarbazole alkaloids

The synthesis of 11‐methyl‐6H‐pyrido[4,3‐b]carbazole‐1(2H)‐one (5), which can be important for the synthesis of other pyridocarbazole alkaloids and especially 1‐substituted ellipticines, is described. Construction of the tetracyclic structure was achieved by a new route and two important precursor compounds (4a and 4b) for the synthesis of pyridocarbazole alkaloids and also many new tetrahydrocar‐bazole derivatives (7, 8, 9, 10, 11, 12, 13) were synthesized.     

Novel Method for the Synthesis of 6,12‐Dihydro‐2‐Methylindolo[2,3‐ b]Carbazol‐6‐Ones

A novel method for the synthesis of 6,12‐dihydro‐2‐methylindolo[2,3‐b]carbazol‐6‐ones was developed from 1‐oxo‐2,3,4,9‐tetrahydro‐1H‐carbazol‐1‐one through methyl 6‐methyl‐2‐(1‐oxo‐2,3,4,9‐tetrahydro‐1H‐carbazol‐2‐yl)oxoacetate in good yields. This method provides an alternative path for the synthesis of this product using 2‐hydroxy methylene‐2,3,4,9‐tetrahydro‐1H‐carbazol‐1‐one.     

An Improved Asymmetric Synthesis of Unusual Amino Acid (2S,3S)‐3‐Hydroxyproline

Abstract

An improved three‐steps method for the conversion of N‐benzyl (S)‐3‐hydroxypyrrolidin‐2‐one 6 to (2S,3S)‐3‐hydroxyproline 1 is reported. The key step is the reductive cyanation of 6. The synthesis of 1 constitutes a formal asymmetric synthesis of (2S,3S)‐3‐hydroxyproline betaines 2.     

A Practical and Enantiospecific Synthesis of (−)‐(R)‐ and (+)‐(S)‐Piperidin‐3‐ols

A highly enantiospecific, azide‐free synthesis of (?)‐(R)‐ and (+)‐(S)‐piperidin‐3‐ol in excellent yield was developed. The key step of the synthesis involves the enantiospecific ring openings of enantiomerically pure (R)‐ and (S)‐2‐(oxiran‐2‐ylmethyl)‐1H‐isoindole‐1,3(2H)‐diones with the diethyl malonate anion and subsequent decarboxylation.     

Synthesis of Nonsymmetrically N,N′‐Diaryl‐Substituted 4,4′‐Bipyridinium Salts with Redox‐Tunable and Titanium Dioxide (TiO2)‐Anchoring Properties

A general method for the synthesis of so far unknown nonsymmetrically substituted N‐aryl‐N′‐aryl′‐4,4′‐bipyridinium salts is presented (Scheme 1). The common intermediate in all procedures is N‐(2,4‐dinitrophenyl)‐4,4′‐bipyridinium hexafluorophosphate ( 1 ⋅ ). For the synthesis of nonsymmetric arylviologens, 1 ⋅ was arenamine‐exchanged by the Zincke reaction, and then activated at the second bipyridine N‐atom with 2,4‐dinitrophenyl 4‐methylbenzenesulfonate. The detailed preparation of the six N‐aryl‐N′‐aryl′‐viologens 21 – 26 is discussed (Scheme 2). The generality of the procedure is further exemplified by the synthesis of two nonsymmetrically substituted N‐aryl‐N′‐benzyl‐ (see 11 and 12 ), and seven N‐aryl‐N′‐alkyl‐4,4′‐bipyridinium salts (see 28 – 34 ) including substituents with metal oxide anchoring and redox tuning properties. The need for these compounds and their usage as electrochromic materials, in dendrimer synthesis, in molecular electronics, and in tunable‐redox mediators is briefly discussed. The latter adjustable property is demonstrated by the reduction potential measured by cyclic voltammetry on selected compounds (Table).     

Heterospirocyclic N‐(2H‐Azirin‐3‐yl)‐L‐prolinates: New Dipeptide Synthons

The synthesis of methyl N‐(1‐aza‐6‐oxaspiro[2.5]oct‐1‐en‐2‐yl)‐L ‐prolinate ( 1e ) has been performed by consecutive treatment of methyl N‐[(tetrahydro‐2H‐pyran‐4‐yl)thiocarbonyl]‐L ‐prolinate ( 5 ) with COCl₂, 1,4‐diazabicyclo[2.2.2]octane (DABCO), and NaN₃ (Scheme 1). As the first example of a novel class of dipeptide synthons, 1e has been shown to undergo the expected reactions with carboxylic acids and thioacids (Scheme 2). The successful preparation of the nonapeptide 16 , which is an analogue of the C‐terminal nonapeptide of the antibiotic Trichovirin I 1B, proved that 1e can be used in peptide synthesis as a dipeptide building block (Scheme 3). The structure of 7 has been established by X‐ray crystal‐structure analysis (Figs. 1 and 2).     

A Total Synthesis of Aliskiren

A total synthesis of aliskiren ( 20 ) was accomplished. A key in our synthesis was to use the symmetric trans‐cisoid‐trans‐bis‐lactone 1 as a precursor. It was expediently prepared by three different routes (Scheme 2). Appending the end groups and functional group transformations completed the synthesis (Scheme 3).     

Enantiospecific Synthesis of (R)‐3‐Amino‐4‐(2,4,5‐trifluorophenyl)butanoic Acid Using (S)‐Serine as a Chiral Pool

Starting from (S)‐serine, a new method was developed for the synthesis of the β‐amino acid part of sitagliptin in ten steps and with an overall yield of 30%. The crucial step of the synthesis was the ring opening of N‐ and O‐protected (R)‐aziridin‐2‐methanol with (2,4,5‐trifluorophenyl)magnesium bromide to give N‐ and O‐protected (R)‐2‐amino‐3‐(2,4,5‐trifluorophenyl)propan‐1‐ol.     

Synthesis of some new Pyridine‐based Heterocyclic Compounds with Anticipated Antitumor Activity

A novel class of 5‐amino‐N′‐(1‐(pyridin‐4‐yl)ethylidene)‐1H‐pyrazole‐4‐carbohydrazides and 8‐(pyridin‐4‐yl)pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidin‐5(1H)‐ones was synthesized from reaction of 2‐cyano‐N′‐(1‐(pyridin‐4‐yl)ethylidene)‐acetohydrazide and 7‐(pyridin‐4‐yl)‐2‐thioxo‐2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐one with the appropriate hydrazonoyl halides. Moreover, 2‐cyano‐N′‐(1‐(pyridin‐4‐yl)‐ethylidene)‐acetohydrazide was used for the synthesis of 2‐cyano‐N′‐(1‐(pyridin‐4‐yl)ethylidene)‐acrylohydrazides and 2‐oxo‐2‐(2‐(1‐(pyridin‐4‐yl)ethylidene)‐hydrazinyl)‐acetohydrazonoyl cyanides. The structures of the newly prepared compounds were confirmed by both elemental and spectral analyses as well as by alternate synthesis. The anticancer activities of the prepared compounds were screened against the hepatocellular carcinoma (HepG2) cell line, and the results showed that most of the compounds exhibit considerable activities.     

A New Preparation of 1,3,3‐Trimethylbicyclo[2.2.2]octan‐2,6‐dione,a Never Isolated Intermediate in a Total Synthesis of (+)‐Norpatchoulenol. Formal Total Synthesis of (±)‐Iso‐Norpatchoulenol

A new preparation and the isolation and spectroscopic characterization of 1,3,3‐trimethylbicyclo[2.2.2]octan‐2,6‐dione ( 3 ), a so far elusive key intermediate in the Liu–Ralitsch total synthesis of (+)‐norpatchoulenol ((+)‐ 1a ), is described. The preparation of 3 constitutes also a formal total synthesis of (±)‐iso‐norpatchoulenol ((±)‐ 1b ), since 3 is correlated to an intermediate in the Monti and co‐workers synthesis of (±)‐ 1b .     

Total Synthesis of Marine Eicosanoid (−)‐Hybridalactone

(?)‐Hybridalactone ( 1 ) is a marine eicosanoid isolated from the red alga Laurencia hybrida. This natural product contains cyclopropane, cyclopentane, 13‐membered macrolactone and epoxide ring systems incorporating seven stereogenic centers. Moreover, this compound has an acid‐labile skipped Z,Z‐diene motif. In this paper, we report on the total synthesis of (?)‐hybridalactone ( 1 ). The unique eicosanoid (?)‐hybridalactone ( 1 ) was synthesized starting from optically active γ‐butyrolactone 2 in a linear sequence comprising 21 steps with an overall yield of 21.9 %. A key step in the synthesis of (?)‐hybridalactone ( 1 ) is the methyl phenylsulfonylacetate‐mediated one‐pot synthesis of the cis‐cyclopropane‐γ‐lactone derivative. This reaction provided an efficient and stereoselective access to cis‐cyclopropane‐γ‐lactone 12 . Further elaboration of the latter compounds through desulfonylation, epoxidation, oxidation, Wittig olefination and Shiina macrolactonization afforded (?)‐hybridalactone.     

Asymmetric α‐Hydroxylation of a Lactone with Vinylogous Pyridone by Using a Guanidine–Urea Bifunctional Organocatalyst: Catalytic Enantioselective Synthesis of a Key Intermediate for (20S)‐Camptothecin Analogues

We have developed a catalytic asymmetric synthesis of (S)‐4‐ethyl‐6,6‐(ethylenedioxy)‐7,8‐dihydro‐4‐hydroxy‐1H‐pyrano[3,4‐f]indolizine‐3,10(4H)dione ( 5 a ), a synthetic intermediate for (20S)‐camptothecin analogues. A key step in this synthesis is an asymmetric α‐hydroxylation of a lactone with a vinylogous pyridone structure ( 8 a ) by using a guanidine–urea bifunctional organocatalyst. The present oxidation was successfully applied to the synthesis of C20‐modified derivatives of (+)‐C20‐desethylbenzylcamptothecin ( 13 ).