A Novel Asymmetric Synthesis of 3‐(1H‐Pyrrol‐1‐yl)‐Substituted β‐Lactams via a Bismuth Nitrate‐Catalyzed Reaction

The reaction of racemic α‐keto β‐lactams 5a – 5c with the commercially available chiral compound trans‐4‐hydroxy‐L ‐proline ( 6 ) in the presence of a catalytic amount of Bi(NO₃)₃?5 H₂O in EtOH gave a diastereoisomer mixture of β‐lactams with a pyrrole ring at C(3) ( 7 to 12 ). This is the first enantioselective synthesis of optically active β‐lactams (=azetidin‐2‐ones) that possess a pyrrolyl residue at C(3), in a single step.     

Microwave‐Induced Stereocontrol of β‐Lactam Formation with an N‐Benzylidene‐9,10‐dihydrophenanthren‐3‐amine via Staudinger Cycloaddition

The synthesis of 3‐substituted 4‐phenyl‐1‐(9,10‐dihydrophenanthren‐3‐yl)azetidin‐2‐ones was achieved following Staudinger cycloaddition under microwave‐induced conditions. The stereoselectivity of β‐lactam formation depended on the power level of the microwave irradiation used in the experiments.     

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.     

Analogues of α‐Campholenal (= (1R)‐2,2,3‐Trimethylcyclopent‐3‐ene‐1‐acetaldehyde) as Building Blocks for (+)‐β‐Necrodol (= (1S,3S)‐2,2,3‐Trimethyl‐4‐methylenecyclopentanemethanol) and Sandalwood‐like Alcohols

To complete our panorama in structure–activity relationships (SARs) of sandalwood‐like alcohols derived from analogues of α‐campholenal (= (1R)‐2,2,3‐trimethylcyclopent‐3‐ene‐1‐acetaldehyde), we isomerized the epoxy‐isopropyl‐apopinene (?)‐ 2d to the corresponding unreported α‐campholenal analogue (+)‐ 4d (Scheme 1). Derived from the known 3‐demethyl‐α‐campholenal (+)‐ 4a , we prepared the saturated analogue (+)‐ 5a by hydrogenation, while the heterocyclic aldehyde (+)‐ 5b was obtained via a Bayer‐Villiger reaction from the known methyl ketone (+)‐ 6 . Oxidative hydroboration of the known α‐campholenal acetal (?)‐ 8b allowed, after subsequent oxidation of alcohol (+)‐ 9b to ketone (+)‐ 10 , and appropriate alkyl Grignard reaction, access to the 3,4‐disubstituted analogues (+)‐ 4f,g following dehydration and deprotection. (Scheme 2). Epoxidation of either (+)‐ 4b or its methyl ketone (+)‐ 4h , afforded stereoselectively the trans‐epoxy derivatives 11a,b , while the minor cis‐stereoisomer (+)‐ 12a was isolated by chromatography (trans/cis of the epoxy moiety relative to the C₂ or C₃ side chain). Alternatively, the corresponding trans‐epoxy alcohol or acetate 13a,b was obtained either by reduction/esterification from trans‐epoxy aldehyde (+)‐ 11a or by stereoselective epoxidation of the α‐campholenol (+)‐ 15a or of its acetate (?)‐ 15b , respectively. Their cis‐analogues were prepared starting from (+)‐ 12a . Either (+)‐ 4h or (?)‐ 11b , was submitted to a Bayer‐Villiger oxidation to afford acetate (?)‐ 16a . Since isomerizations of (?)‐ 16 lead preferentially to β‐campholene isomers, we followed a known procedure for the isomerization of (?)‐epoxyverbenone (?)‐ 2e to the norcampholenal analogue (+)‐ 19a . Reduction and subsequent protection afforded the silyl ether (?)‐ 19c , which was stereoselectively hydroborated under oxidative condition to afford the secondary alcohol (+)‐ 20c . Further oxidation and epimerization furnished the trans‐ketone (?)‐ 17a , a known intermediate of either (+)‐β‐necrodol (= (+)‐(1S,3S)‐2,2,3‐trimethyl‐4‐methylenecyclopentanemethanol; 17c ) or (+)‐(Z)‐lancifolol (= (1S,3R,4Z)‐2,2,3‐trimethyl‐4‐(4‐methylpent‐3‐enylidene)cyclopentanemethanol). Finally, hydrogenation of (+)‐ 4b gave the saturated cis‐aldehyde (+)‐ 21 , readily reduced to its corresponding alcohol (+)‐ 22a . Similarly, hydrogenation of β‐campholenol (= 2,3,3‐trimethylcyclopent‐1‐ene‐1‐ethanol) gave access via the cis‐alcohol rac‐ 23a , to the cis‐aldehyde rac‐ 24 .     

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%).     

On the Reactivity of (−)‐(R)‐Carvone and (−)‐4aα,7α,7aβ‐Nepetalactone: Synthesis of New Heterocycles

The 1,3‐dipolar cycloaddition of 4‐chlorobenzonitrile oxide to the unsaturated system of (?)‐(R)‐carvone occurred exclusively at C(8) to give a new isoxazoline derivative. This derivative reacts with NH₂OH to yield a new heterocycle, observed for the first time. On the other hand, the addition of 4‐chlorobenzonitrile oxide to the unsaturated lactone (?)‐4aα,7α,7aβ‐nepetalactone gave, in a good yield, also a new heterocycle, again obtained for the first time. The terpenoid (?)‐(R)‐carvone and iridoid (?)‐4aα,7α,7aβ‐nepetalactone were isolated from Moroccan species Mentha viridis (L.) and Nepeta tuberosa (L.), respectively. The new heterocycles obtained were identified by combination of chromatographic and spectroscopic methods.     

Addition of isocyanides to α‐(methylthio)‐benzylidenamidinium iodides: A surprising access to 2‐(dialkylamino)imidazoles and 3,5‐diamino‐2H‐pyrrolium salts

A number of 2‐(dialkylamino)‐5‐(methylthio)imidazoles 2 are obtained by treating the formamidinium iodides 1a,b with isocyanides R³ NC under mild conditions. Reduction of these species can occur in the reaction medium to furnish the corresponding imidazoles 3 . In some cases, double cycloaddition across the imine bond of starting salts 1 also provides the (azetidin‐1‐yl‐methylene)ammonium iodides 4 . Reactions with tert‐butyl and isopropyl isocyanides in refluxing acetonitrile convert the acetamidinium iodide 1c into the 3,5‐diamino‐2H‐pyrrolium salts 7 . Mechanisms are suggested to account for these ring‐closure processes. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:370–376, 2000     

Enantioselective Synthesis of (−)‐(R)‐Cordiachromene and (−)‐(R)‐Dictyochromenol Utilizing Intramolecular SNAr Reaction

A simple and efficient enantioselective synthesis of chromene, (?)‐(R)‐cordiachromene ( 1 ), and (?)‐(R)‐dictyochromenol ( 2 ) has been accomplished. This convergent synthesis utilizes intramolecular S_NAr reaction for the formation of chroman ring, and Seebach's method of ‘self‐reproduction of chirality’ should establish the (R)‐configuration of the C(2) side chain as key steps.     

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.     

[2+2] Cycloaddition Reactions of Imines with Cyclic Ketenes: Synthesis of 1,3‐Thiazolidine Derived Spiro‐β‐lactams and Their Transformations

Unsymmetric cyclic ketenes were generated from N‐acyl‐1,3‐thiazolidine‐2‐carboxylic acids 1a – c by means of Mukaiyama's reagent, and then reacted with imines 2a – c to the new, isomeric spiro‐β‐lactams 3 and 4 via [2+2] cycloaddition (Staudinger ketene–imine reaction; Scheme 1). The reactions were stereoselective (Table 1) and mainly afforded the spiro‐β‐lactams with a relative trans configuration. The spiro‐β‐lactams could be transformed into the corresponding monocyclic β‐lactams by means of thiazolidine ring opening or into substituted thiazolidines via hydrolysis of the β‐lactam ring.     

The First Stereoselective Total Synthesis of Naturally Occurring,Bioactive (3R,5R)‐1‐(4‐Hydroxyphenyl)‐7‐phenylheptane‐3,5‐diol and the Synthesis of Its Enantiomer

The first stereoselective total synthesis of the naturally occurring anti‐emetic diarylheptanoid (3R,5R)‐1‐(4‐hydroxyphenyl)‐7‐phenylheptane‐3,5‐diol ( 1 ) was accomplished starting from 4‐hydroxybenzaldehyde and involving a Sharpless kinetic resolution and an asymmetric epoxidation as the key steps (Scheme 2). The enantiomer 1a of this compound was also simultaneously prepared.     

Synthesis and α‐Mannosidase Inhibitory Evaluation of (2R,3R,4S)‐ and (2S,3R,4S)‐2‐(Aminomethyl)pyrrolidine‐3,4‐diol Derivatives

The synthesis of 46 derivatives of (2R,3R,4S)‐2‐(aminomethyl)pyrrolidine‐3,4‐diol is reported (Scheme 1 and Fig. 3), and their inhibitory activities toward α‐mannosidases from jack bean (B) and almonds (A) are evaluated (Table). The most‐potent inhibitors are (2R,3R,4S)‐2‐{[([1,1′‐biphenyl]‐4‐ylmethyl)amino]methyl}pyrrolidine‐3,4‐diol ( 3fs ; IC₅₀(B)=5 μM , K_i=2.5 μM ) and (2R,3R,4S)‐2‐{[(1R)‐2,3‐dihydro‐1H‐inden‐1‐ylamino]methyl}pyrrolidine‐3,4‐diol ( 3fu ; IC₅₀(B)=17 μM , K_i=2.3 μM ). (2S,3R,4S)‐2‐(Aminomethyl)pyrrolidine‐3,4‐diol ( 6 , R?H) and the three 2‐(N‐alkylamino)methyl derivatives 6fh, 6fs , and 6f are prepared (Scheme 2) and found to inhibit also α‐mannosidases from jack bean and almonds (Table). The best inhibitor of these series is (2S,3R,4S)‐2‐{[(2‐thienylmethyl)amino]methyl}pyrrolidine‐3,4‐diol ( 6o ; IC₅₀(B)=105 μM , K_i=40 μM ). As expected (see Fig. 4), diamines 3 with the configuration of α‐D ‐mannosides are better inhibitors of α‐mannosidases than their stereoisomers 6 with the configuration of β‐D ‐mannosides. The results show that an aromatic ring (benzyl, [1,1′‐biphenyl]‐4‐yl, 2‐thienyl) is essential for good inhibitory activity. If the C‐chain that separates the aromatic system from the 2‐(aminomethyl) substituent is longer than a methano group, the inhibitory activity decreases significantly (see Fig. 7). This study shows also that α‐mannosidases from jack bean and from almonds do not recognize substrate mimics that are bulky around the O‐glycosidic bond of the corresponding α‐D ‐mannopyranosides. These observations should be very useful in the design of better α‐mannosidase inhibitors.     

(3R,4S)‐3‐Phenyl‐1‐[(R)‐1‐phenyl­ethyl]‐4‐[(R)‐1‐phenylethyliminomethyl]azetidin‐2‐one

The configuration of the chiral ring atoms of the title compound, C₂₆H₂₆N₂O, obtained in an enantioselective synthesis, has been established relative to the known R configuration of the α‐methyl­benzyl moieties. The crystal packing involves a two‐dimensional network of C—H?π interactions between the aromatic rings.     

Studies toward the Synthesis of (R)‐(+)‐Harmicine

The study toward the total synthesis of (R)‐(+)‐harmicine is reported in this paper. The enantioselective synthesis of pyrrolidinone, the main backbone of of (R)‐(+)‐harmicine, has been completed by the methodology based on photo‐induced Wolff rearrangement of α‐diazo‐β‐carbonyl compounds.     

Synthesis of 3‐Carbamoyl β‐Lactams via Manganese(III)‐Promoted Cyclization of N‐Alkenylmalonamides

Manganese(III)‐promoted cyclization of N‐alkenylmalonamides (=N‐alkenylpropanediamides) gave 3‐(aryl/(alkylamino)carbonyl) β‐lactams as well as 3‐(aryl/(alkylamino)thiocarbonyl) β‐lactams. The relative configuration of the obtained products was unambiguously determined by X‐ray crystallography. The proposed method is very useful for the one‐pot synthesis of a number of 3‐(aryl/(alkylamino)carbonyl) β‐lactams, especially those containing an amino(thiocarbonyl) moiety, which are not selectively accessible by other methods.     

Efficient Synthesis of (−)‐(R)‐Muscone by Enantioselective Protonation

A new synthesis of (?)‐(R)‐muscone ((R)‐ 1 ) by means of enantioselective protonation of a bicyclic ketone enolate as the key step (see 6 →(S)‐ 4 in Scheme 2) is presented. The C₁₅ macrocyclic system is obtained by ozonolysis (Scheme 7).     

Synthesis of Novel β‐Lactams from Phenothiazin‐10‐ylacetic Acid

The first synthesis of 3‐phenothiazine‐β‐lactams is herein reported. Thirteen new derivatives of β‐lactams were synthesized using various Schiff bases and (phenothiazin‐10‐yl)acetic acid, which in turn was prepared starting from phenothiazine. The sole product of the Staudinger ketene–imine [2 + 2] cycloaddition reaction is the trans‐β‐lactam. All the synthesized compounds were characterized by elemental analyses and spectral (IR, ¹H‐NMR, and ¹³C‐NMR) data.     

Highly Diastereoselective,Biogenetically Patterned Synthesis of (+)‐(1S,6R)‐Volvatellin (=(+)‐(4R,5S)‐5‐Hydroxy‐4‐(5‐methyl‐1‐methylenehex‐4‐en‐2‐ynyl)cyclohex‐1‐ene‐1‐carbaldehyde)

The synthesis of volvatellin ( 4a ), previously isolated from a herbivorous marine mollusk, was achieved with high diastereoselectivity from putative dietary oxytoxin‐1 ( 2 ). A biogenetically patterned carbonyl‐ene route was chosen, proceeding from 2 predominantly via the trans cyclization product 3 without the use of enzymes. This challenges the involvement of enzymes in the formation of 4a in nature. The optical purity and absolute configuration (1S,4S,6R), assigned to 3 from high‐field ¹H‐NMR examination of its Mosher (MTPA) esters 6 , was retained on its chemical conversion to (+)‐(1S,6R)‐configured 4a and is consistent with the (4S) configuration previously established for caulerpenyne ( 1 ).     

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.     

A Novel Procedure to Synthesize 3‐Chloro‐1‐(4a,10b‐diazaphenanthrene‐2‐yl)‐4‐phenyl Azetidin‐2‐ones and Exploration of Their Anti‐Inflammatory Activity

Some new derivatives of 3‐chloro‐1‐(4a,10b‐diazaphenanthrene‐2‐yl)‐4‐phenyl azetidin‐2‐one were synthesized through the reaction of N‐{4‐[phenyldiazenyl] phenyl}‐N‐[phenyl methylene] amine with 4‐[phenyldiazenyl] aniline. The resulting 3‐chloro‐4‐phenyl‐1‐{4‐[phenyldiazenyl] phenyl} azetidin‐2‐one intermediate in benzene was irradiated in a Pyrex vessel with 350 nm UV light in a photochemical reactor to give the desired derivatives (4a–j) . Structures of the new compounds were verified on the basis of spectral and elemental methods of analyses. Nine of the prepared compounds were tested for their anti‐inflammatory effects; most of these compounds showed potent and significant results compared with indomethacin.