NaBH4‐I2 mediated chemoselective reduction of γ‐lactam and thio‐γ‐lactam in presence of gem‐dicarboxylates: An easy access to 1,3‐diaryl pyrrolidines

Substituted pyrrolidine derivatives were synthesized in high yield by NaBH₄/I₂ mediated chemoselective reduction of N‐aryl‐γ‐lactam and N‐aryl‐thio‐γ‐lactam‐2,2‐dicarboxylate. With excess NaBH₄/I₂, carbonyl functionality of the ester groups remained unchanged. J. Heterocyclic Chem., (2011).     

Total Synthesis of Diaporthichalasin by Using the Intramolecular Diels–Alder Reaction of an α,β‐Unsaturated γ‐Hydroxylactam in Aqueous Media

The first total synthesis of diaporthichalasin has been successfully achieved and complete structure elucidation, including the absolute configuration, was also accomplished. The intramolecular Diels–Alder (IMDA) reaction between the diene side chain on the decalin skeleton and α,β‐unsaturated γ‐hydroxy‐γ‐lactam in aqueous media was effectively employed as the key step. From this synthetic study, we found that α,β‐unsaturated γ‐hydroxy‐γ‐lactam is an essential precursor for the construction of the diaporthichalasin‐type pentacyclic skeleton. This important finding strongly suggests that this route is involved in the biosynthetic pathway for diaporthichalasin.     

Tandem IBX‐Promoted Primary Alcohol Oxidation/Opening of Intermediate β,γ‐Diolcarbonate Aldehydes to (E)‐γ‐Hydroxy‐α,β‐enals

A tandem IBX‐promoted oxidation of primary alcohol to aldehyde and opening of intermediate β,γ‐diolcarbonate aldehyde to (E)‐γ‐hydroxy‐α,β‐enal has been developed. Remarkably, the carbonate opening delivered exclusively (E)‐olefin and no over‐oxidation of γ‐hydroxy was observed. The method developed has been extended to complete the stereoselective total synthesis of both (S)‐ and (R)‐coriolides and d ‐xylo‐ and d ‐arabino‐C‐20 guggultetrols.     

Synthesis of Epigoitrin from (R)‐(+)‐4‐Hydroxy‐γ‐butyrolactone

Epigoitrin is one of the major components of several natural species, including Isatis indigotica Fort, turnip, and cabbage. It presents antithyroid and antivirus activities. Here, we report an efficient and practical method for the chemical synthesis of epigoitrin from commercially available (R)‐(+)‐4‐hydroxy‐γ‐butyrolactone.     

The homo‐PADAM Protocol: Stereoselective and Operationally Simple Synthesis of α‐Oxo‐ or α‐Hydroxy‐γ‐acylaminoamides and Chromanes

A straightforward and fully stereoselective synthesis of a new class of peptidomimetics, that is α‐oxo‐γ‐acylaminoamides, was achieved starting from various benzaldehydes by a sequence of 1) an asymmetric organocatalytic Mannich reaction, 2) a Passerini multicomponent reaction, 3) an amine deprotection–acyl migration protocol, and 4) a final oxidation. The whole sequence can be performed without purification of the intermediates and represents the first example of a homo‐Passerini–amine deprotection–acyl migration (PADAM) strategy. Highly stereoselective reduction of the α‐oxo‐γ‐acylaminoamides afforded α‐hydroxy‐γ‐acylaminoamides as well. In some cases both diastereomers were obtained by simply changing the reducing agent. Finally, starting from protected salicylaldehyde, the same sequence, followed by a Mitsunobu cyclization, afforded highly substituted chromanes.     

Synthesis of Glycaro‐1,5‐lactams and Tetrahydrotetrazolopyridine‐5‐carboxylates: Inhibitors of β‐D‐Glucuronidase and α‐L‐Iduronidase

The known glucaro‐1,5‐lactam 8 , its diastereoisomers 9 – 11 , and the tetrahydrotetrazolopyridine‐5‐carboxylates 12 – 14 were synthesised as potential inhibitors of β‐D ‐glucuronidases and α‐L ‐iduronidases. The known 2,3‐di‐O‐benzyl‐4,6‐O‐benzylidene‐D ‐galactose ( 16 ) was transformed into the D ‐galactaro‐ and L ‐altraro‐1,5‐lactams 9 and 11 via the galactono‐1,5‐lactam 21 in twelve steps and in an overall yield of 13 and 2%, respectively. A divergent strategy, starting from the known tartaric anhydride 41 , led to the D ‐glucaro‐1,5‐lactam 8 , D ‐galactaro‐1,5‐lactam 9 , L ‐idaro‐1,5‐lactam 10 , and L ‐altraro‐1,5‐lactam 11 in ten steps and in an overall yield of 4–20%. The anhydride 41 was transformed into the L ‐threuronate 46 . Olefination of 46 to the (E)‐ or (Z)‐alkene 47 or 48 followed by reagent‐ or substrate‐controlled dihydroxylation, lactonisation, azidation, reduction, and deprotection led to the lactams 8 – 11 . The tetrazoles 12 – 14 were prepared in an overall yield of 61–81% from the lactams 54, 28 , and 67 , respectively, by treatment with Tf₂O and NaN₃, followed by saponification, esterification, and hydrogenolysis. The lactams 8 – 11 and 40 and the tetrazoles 12 – 14 are medium‐to‐strong inhibitors of β‐D ‐glucuronidase from bovine liver. Only the L ‐ido‐configured lactam 10 (K_i = 94 μM ) and the tetrazole 14 (K_i = 1.3 mM ) inhibit human α‐L ‐iduronidase.     

An Efficient New Route for the Synthesis of Some 3‐Hterocyclylquinolinones via Novel 3‐(1,2‐Dihydro‐4‐hydroxy‐1‐methyl‐2‐oxoquinolin‐3‐yl)‐3‐oxopropanal and Their Antioxidant Screening

3‐(4‐hydroxy‐1‐methylquinoline‐3‐yl)‐3‐oxoproponal ( 5 ) was synthesized from 3‐[(E)‐3‐(dimethylamino)‐2‐propenoyl]‐4‐hydroxy‐1‐methyl‐2(1H )‐quinolinone ( 3 ) and was utilized as a starting precursor material. A convenient new route to functionalized 3‐heterocyclyl 4‐hydroxy‐2(1H )‐quinolinones such as pyrazolyl, isoxazolyl, pyrimidinyl, azepineyl , pyridonyl, and pyranyl heterocycles was described via cyclization of compound 5 with some N and C ‐nucleophiles. The newly synthesized aldehyde 5 showed only one ring closure possibility with maximum yield instead of using compound 3 that exhibited different regioselective ring closure routes with minimum yields. All newly synthesized products were structurally elucidated on the basis of their relevant spectroscopic data and elemental microanalyses. The antioxidant activity of the products was screened in a series of in vitro tests.     

Synthesis of 3,4‐Fused γ‐Lactone‐γ‐Lactam Bicyclic Moieties as Multifunctional Synthons for Bioactive Molecules

A short approach for the synthesis of 3,4‐fused γ‐lactone‐γ‐lactam bicyclic systems ( 1 ) in diastereomeric mixtures from chiral D ‐alanine methyl ester hydrochloride is described. The key step towards lactonisation is the reduction of the carbonyl ketone of the 5R‐configured 3,5‐dimethylpyrrolidine‐2,4‐dione diastereomers ( 8 ) via sodium borohydride in the presence of hydrochloric acid. With the presence of ethyl acetyl functionality at C3‐position, ester hydrolysis of 8 occurred concomitantly with keto reduction leading to lactonisation and eventually affording the anticipated (3S,4S,5R), (3R,4R,5R), (3R,4S,5R) and (3S,4R,5R) bicyclic moieties. The formation of the fused systems was confirmed by mass spectroscopy (MS) and nuclear magnetic resonance (NMR) analyses.     

Synthesis and Analysis of the Conformational Preferences of 5‐Aminomethyloxazolidine‐2,4‐dione Scaffolds: First Examples of β2‐ and β2, 2‐Homo‐Freidinger Lactam Analogues

Constrained peptidomimetic scaffolds are of considerable interest for the design of therapeutically useful analogues of bioactive peptides. We present the single‐step cyclization of (S)‐ or (R)‐α‐hydroxy‐β²‐ or α‐substituted‐α‐hydroxy‐β^{2, 2}‐amino acids already incorporated within oligopeptides to 5‐aminomethyl‐oxazolidine‐2,4‐dione (Amo) rings. These scaffolds can be regarded as unprecedented β²‐ or β^{2, 2}‐homo‐Freidinger lactam analogues, and can be equipped with a proteinogenic side chain at each residue. In a biomimetic environment, Amo rings act as inducers of extended, semi‐bent or folded geometries, depending on the relative stereochemistry and the presence of α‐substituents.     

Synthesis of 15‐Cyano‐12‐oxopentadecano‐15‐lactone and 15‐Cyano‐ 12‐oxopentadecano‐15‐lactam

15‐Cyano‐12‐oxopentadecano‐15‐lactone was synthesized in 59% total yield starting from 2‐nitrocyclododecanone by Michael addition to acrylaldehyde, followed by reaction with trimethylsilylcyanide, hydrolysis, ring‐expansion, and Nef reaction. A two‐step, one‐pot synthesis of intermediate 2‐hydroxy‐4‐(1‐nitro‐2‐oxycyclododecyl)butanenitrile from 3‐(1‐nitro‐2‐oxocyclododecyl)propanal was developed and the conditions for the Nef reaction were studied. 15‐Cyano‐12‐oxopentadecano‐15‐lactam was synthesized in 40% total yield starting from 2‐nitrocyclododecanone by Michael addition to acrylaldehyde, followed by Strecker reaction, ring‐expansion, and Nef reaction. The conditions for the Strecker and Nef reactions were studied. The structures of the target compounds, intermediates, and by‐product were characterized by IR, ¹H‐ and ¹³C‐NMR, and elemental analysis or MS.     

Synthesis of (E)‐1,1‐Diethoxy‐3‐(3‐hydroxy‐3‐arylfuro[2,3‐b]quinoxalin‐2(3H)‐ylidene)propan‐2‐ones via Acid‐Catalyzed,Stereoselective 5‐Exo‐Dig Cyclization

A number of 3‐(4,4,5,5‐tetraethoxy‐1‐hydroxy‐1‐arylpent‐2‐ynyl)quinoxalin‐2(1H)‐ones, obtained by reacting the lithium acetylide of 3,3,4,4‐tetraethoxybut‐1‐yne (TEB) with 3‐aroylquinoxalin‐2(1H)‐ones, appeared to undergo stereoselective cyclization in the 5‐exo‐Dig manner when heated at reflux in acidic, aqueous THF. In each case, the products were the corresponding (E)‐1,1‐diethoxy‐3‐(3‐hydroxy‐3‐arylfuro[2,3‐b]quinoxalin‐2(3H)‐ylidene)propan‐2‐ones and 1,1‐diethoxy‐3‐hydroxy‐3‐(3‐arylfuro[2,3‐b]quinoxalin‐2‐yl)propan‐2‐one, which were isolated in an approximate ratio of 2:1 in high total yield. Irrespective of the structure of the aryl group, both compounds were stable solids when kept in a refridgerator (3 °C), but when the latter product was dissolved in chloroform and stored at room temperature, it rearranged smoothly and quantitatively to the former compound within a few days.     

Enantioselective Syntheses of Substituted γ‐Butyrolactones

The previously described chiral 2‐acyloxathianes 5 (Scheme I) are used in two different enantioselective syntheses of γ‐butyrolactones. In one synthesis, Grignard addition, cleavage and reduction to carbinols RR'C(OH)CH₂OH is followed by tosylation, malonate homologation, lactonization, and removal of the carbomethoxy group to give optically active γ‐lactones. A modification of this synthesis (Scheme I) leads to optically active α‐methylene‐γ‐lactones. In the second synthesis, reaction of a bromomagnesium enolate with ketones 5 leads to β‐hydroxyesters, which, by appropriate sequences of reduction and cleavage (Scheme II) are converted to optically active α‐ or β‐hydroxy‐γ‐lactones.     

A Flexible Approach to the γ－Amino－β－hydroxy Acid Moiety of Hapalosin

A flexible approach to ethyl (3R,4S)-N-Boc-4-amino-3-hydroxy-5-phenylpentanoate (N-Boc-AHPPA-OEt), the γ-amino-β-hydroxy acid moiety of hapalosin is described. The synthetic method features a ring-opening ethanolysis of an activated N-Boc-lactam, which is obtained via a diastereoselective reductive-alkylation of (R)-malimide derivative. The flexibility of the method resides in the introduction of the alkyl side chain by Grignard reagent addition.     

Chemoselective Synthesis of β‐Amino Ester or β‐Lactam via Sonochemical Reformatsky Reaction

A series of β‐amino esters were synthesized by the reaction of N‐tosyl aldimine or N‐hydroxy aldimine with bromoacetate by sonochemical Reformatsky reaction. The β‐N‐hydroxyamino ester was obtained and the formed sensitive hydroxylamino functionality was resistant under the reaction condition. The β‐lactam also was synthesized by the reaction of N‐p‐methoxy aldimine as reacting substrate under this sonochemical Reformatsky reaction condition.     

Reactions of Acid Chlorides/Ketenes with 2‐Substituted 4,5‐Dihydro‐4,4‐dimethyl‐1,3‐thiazoles: Formation of Penam Derivatives

Addition reactions of acid chlorides with various 2‐substituted 4,5‐dihydro‐4,4‐dimethyl‐5‐(methylsulfanyl)‐1,3‐thiazoles under basic conditions were studied. Two kinds of products were obtained from these additions, β‐lactams and non‐β‐lactam adducts. When the reaction was carried out with 4,5‐dihydro‐1,3‐thiazoles with a Ph substituent at C(2), the reaction proceeded via formal [2+2] cycloaddition and led to the correspoding β‐lactam. On the other hand, acid chlorides and 4,5‐dihydro‐1,3‐thiazoles bearing an α‐H‐atom at the C(2)‐substituent underwent C(α)‐ and/or N‐addition reactions and furnished non‐β‐lactam adducts, i.e., C(α)‐ and/or N‐acylated 1,3‐thiazolidines. The attempted transformations of sulfonyl esters of exo‐6‐hydroxy penams to endo‐6‐azido penams failed, although they were successful with mono‐β‐lactams under the same conditions.     

Control of N‐Heterocyclic Carbene Catalyzed Reactions of Enals: Asymmetric Synthesis of Oxindole‐γ‐Amino Acid Derivatives

A strategy to control the switch between a non‐cycloaddition reaction and a cycloaddition reaction of enals, using N‐heterocyclic carbene (NHC) catalyisis, has been developed. The new scalable protocol leads to γ‐amino‐acid esters bearing a tetrasubstituted stereocenter in good yields and high stereoselectivities by homo‐Mannich reactions of enals and isatin‐derived ketimines. By simply changing the N‐ketimine substituent to an ortho‐hydroxy phenyl group, the corresponding spirocyclic oxindolo‐γ‐lactams are obtained.     

Enantioseparation of hydroxyeicosatetraenoic acids by hydroxypropyl‐γ‐cyclodextrin‐modified micellar electrokinetic chromatography

Complete resolution of hydroxyeicosatetraenoic acid (HETE) enantiomers was achieved using hydroxypropyl‐γ‐cyclodextrin (HP‐γ‐CD)‐modified MEKC. The optimum running conditions were determined to be utilizing a 30 mM phosphate–15 mM borate buffer (pH 9.0) containing 30 mM HP‐γ‐CD and 75 mM SDS as the BGE, application of +30 kV as the effective voltage, and carrying out the experiment at 15°C. The eluents were detected at 235 nm. The method was used successfully for the simultaneous separations of (S)‐ and (R)‐enantiomers of regioisomeric 8‐, 11‐, 12‐, and 15‐HETEs. Subsequently, the optimized method was applied to evaluate the stereochemistry of 8‐ and 12‐HETEs from the marine red algae, Gracilaria vermiculophylla and Gracilaria arcuata, respectively. The 8‐HETE was found to be a mixture of 98% (R)‐enantiomer and 2% (S)‐enantiomer, while the 12‐HETE was a mixture of 98% (S)‐enantiomer and 2% (R)‐enantiomer. The present study demonstrates that the HP‐γ‐CD‐modified MEKC method is simple and sensitive and provides unambiguous information on the configuration of natural and synthetic HETEs.     

Concise Synthesis of α‐Methylene‐β‐hydroxy‐γ‐carboxy‐γ‐lactams

A concise protocol for the synthesis of α‐methylene‐β‐hydroxy‐γ‐carboxy‐γ‐lactams has been described via alkylation of amino acid derived iminoesters with α‐bromomethylmethacrylate, followed by allylic hydroxylation. All the synthesized compounds have been evaluated for their cytotoxicity on multiple myeloma cancer cell lines.     

Synthesis of the Macrocyclic Spermidine Alkaloid (±)‐(2R*,3R*)‐3‐Hydroxycelacinnine

The macrocyclic lactam alkaloid (±)‐(2R*,3R*)‐3‐hydroxycelacinnine ( 1 ) derived from spermidine was synthesized via stereoselective epoxide‐ring opening with magnesium azide and cesium carbonate promoted macrocyclization of the ditosylated diamino precursor 12 with 1,4‐dibromobutane in the two key steps (Scheme 2). ¹H‐ and ¹³C‐NMR Signal assignments from COSY, HSQC, and HMBC 2D NMR data of the synthesized 1 were compared with the earlier‐described data of the natural 3‐hydroxycelacinnine. The similarity of their ¹³C‐NMR spectra point to the correctness of the proposed constitutional formula for natural 3‐hydroxycelacinnine; however, different ¹H‐NMR chemical shifts and coupling constants (J(2,3)=9.0 vs. 1.2 Hz, resp.) in the α‐hydroxy‐β‐amino lactam moiety suggest that natural 3‐hydroxycelacinnine is the 2,3‐cis‐epimer of one synthetic (±)‐ 1 .     

Synthesis anti‐fungal and anti‐bacterial screening of 3‐phenyl‐1,4,5‐trihydro‐pyrazol and 2, 4‐dihydro[ 1,2,4]‐triazol‐3‐one derivatives of 4‐hydroxy‐2‐oxo‐2H‐1‐benzopyran

4‐Hydroxy‐2‐oxo‐2H‐1‐benzopyran‐3‐carboxaldehydes 2a‐d are prepared from 4‐hydroxy‐2‐oxo‐2H‐1‐benzopyrans 1a‐d via the Vielsmeyer Haack reaction. The 4‐hydroxy‐2‐oxo‐3‐(3′oxo‐3′‐phenylprop‐1′‐enyl)‐2H‐1‐benzopyrans 3a‐d are obtained from 2a‐d via the Claisen reaction. Refluxing compounds 3a‐d with hydrazine hydrate gave the 3‐phenyl‐5‐(4‐hydroxy‐2‐oxo‐2H‐1‐benzopyran‐3‐yl)‐1,4,5‐trihydropyra‐zols 4a‐d . Stirring compounds 2a‐d with semicarbazide hydrochloride in acidic medium gave the 4‐hydroxy‐2‐oxo‐2H‐1‐benzopyran‐3‐aldehyde‐semicarbazone 5a‐d , which on cyclisation with ferric chloride hexahydrate gave the 5‐(4‐hydroxy‐2‐oxo‐2H‐1‐benzopyran‐3‐yl)‐2,4‐dihydro[1,2,4]triazol‐3‐ones 6a‐d . All these compounds show significant antibacterial activities.