Synthesis of the Spermidine Alkaloids (−)‐(2R,3R)‐ and (−)‐(2R,3S)‐3‐Hydroxycelacinnine: Macrocyclization with Oxirane‐Ring Opening and Inversion via Cyclic Sulfamidates

The two epimers (?)‐ 1a and (?)‐ 1b of the macrocyclic lactam alkaloid 3‐hydroxycelacinnine with the (2R,3R) and (2R,3S) absolute configurations, respectively, were synthesized by an alternative route involving macrocyclization with the regio‐ and stereoselective oxirane‐ring opening by the terminal amino group (Schemes 2 and 6). Properly N‐protected chiral trans‐oxirane precursors provided (2R,3R)‐macrocycles after a one‐pot deprotection‐macrocyclization step under moderate dilution (0.005–0.01M ). The best yields (65–85%) were achieved with trifluoroacetyl protection. Macrocyclization of the corresponding cis‐oxiranes was unsuccessful for steric reasons. Inversion at OH? C(3) via nucleophilic displacement of the cyclic sulfamidate derivative with NaNO₂ led to (2R,3S)‐macrocycles. The synthesized (?)‐(2R,3S)‐3‐hydroxycelacinnine ((?)‐ 1b ) was identical to the natural alkaloid.     

(1R,3R,4S)‐1‐Benzyl‐3‐(tert‐butyldimethylsilyloxy)‐4‐(hydroxymethyl)pyrrolidine–borane: novel B—H...H—O hydrogen bonding

The absolute configuration of the title cis‐(1R,3R,4S)‐pyrrolidine–borane complex, C₁₈H₃₄BNO₂Si, was confirmed. Together with the related trans isomers (3S,4S) and (3R,4R), it was obtained unexpectedly from the BH₃·SMe₂ reduction of the corresponding chiral (3R,4R)‐lactam precursor. The phenyl ring is disordered over two conformations in the ratio 0.65:0.35. The crystallographic packing is dominated by the rarely found donor–acceptor hydroxy–borane O—H...H—B hydrogen bonds.     

Stereo‐Inversion in the (4R)‐γ‐Decanolactone Synthesis by Saccharomyces cerevisiae: (2E,4S)‐4‐Hydroxydec‐2‐enoic Acid Acts as a Key Intermediate

Methyl (2E,4R)‐4‐hydroxydec‐2‐enoate, methyl (2E,4S)‐4‐hydroxydec‐2‐enoate, and ethyl (±)‐(2E)‐4‐hydroxy[4‐²H]dec‐2‐enoate were chemically synthesized and incubated in the yeast Saccharomyces cerevisiae. Initial C‐chain elongation of these substrates to C₁₂ and, to a lesser extent, C₁₄ fatty acids was observed, followed by γ‐decanolactone formation. Metabolic conversion of methyl (2E,4R)‐4‐hydroxydec‐2‐enoate and methyl (2E,4S)‐4‐hydroxydec‐2‐enoate both led to (4R)‐γ‐decanolactone with >99% ee and 80% ee, respectively. Biotransformation of ethyl (±)‐(2E)‐4‐hydroxy(4‐²H)dec‐2‐enoate yielded (4R)‐γ‐[²H]decanolactone with 61% of the ²H label maintained and in 90% ee indicating a stereoinversion pathway. Electron‐impact mass spectrometry analysis (Fig. 4) of 4‐hydroxydecanoic acid indicated a partial C(4)→C(2) ²H shift. The formation of erythro‐3,4‐dihydroxydecanoic acid and erythro‐3‐hydroxy‐γ‐decanolactone from methyl (2E,4S)‐4‐hydroxydec‐2‐enoate supports a net inversion to (4R)‐γ‐decanolactone via 4‐oxodecanoic acid. As postulated in a previous work, (2E,4S)‐4‐hydroxydec‐2‐enoic acid was shown to be a key intermediate during (4R)‐γ‐decanolactone formation via degradation of (3S,4S)‐dihydroxy fatty acids and precursors by Saccharomyces cerevisiae.     

Diastereoselective Electrophilic Amination of Chiral 1‐Benzoyl‐2,3,5,6‐tetrahydro‐3‐methyl‐2‐(1‐methylethyl)pyrimidin‐4(1H)‐one for the Asymmetric Syntheses of α‐Substituted α,β‐Diaminopropanoic Acids

The chiral compounds (R)‐ and (S)‐1‐benzoyl‐2,3,5,6‐tetrahydro‐3‐methyl‐2‐(1‐methylethyl)pyrimidin‐4(1H)‐one ((R)‐ and (S)‐ 1 ), derived from (R)‐ and (S)‐asparagine, respectively, were used as convenient starting materials for the preparation of the enantiomerically pure α‐alkylated (alkyl=Me, Et, Bn) α,β‐diamino acids (R)‐ and (S)‐ 11 – 13 . The chiral lithium enolates of (R)‐ and (S)‐ 1 were first alkylated, and the resulting diasteroisomeric products 5 – 7 were aminated with ‘di(tert‐butyl) azodicarboxylate’ (DBAD), giving rise to the diastereoisomerically pure (≥98%) compounds 8 – 10 . The target compounds (R)‐ and (S)‐ 11 – 13 could then be obtained in good yields and high purities by a hydrolysis/hydrogenolysis/hydrolysis sequence.     

Ring‐Opening Reactions of 3‐Aryl‐1‐benzylaziridine‐2‐carboxylates and Application to the Asymmetric Synthesis of an Amphetamine‐Type Compound

Nucleophilic ring‐opening reactions of 3‐aryl‐1‐benzylaziridine‐2‐carboxylates were examined by using O‐nucleophiles and aromatic C‐nucleophiles. The stereospecificity was found to depend on substrates and conditions used. Configuration inversion at C(3) was observed with O‐nucleophiles as a major reaction path in the ring‐opening reactions of aziridines carrying an electron‐poor aromatic moiety, whereas mixtures containing preferentially the syn‐diastereoisomer were generally obtained when electron‐rich aziridines were used (Tables 1–3). In the reactions of electron‐rich aziridines with C‐nucleophiles, S_N2 reactions yielding anti‐type products were observed (Table 4). Reductive ring‐opening reaction by catalytic hydrogenation of (+)‐trans‐(2S,3R)‐3‐(1,3‐benzodioxol‐5‐yl)aziridine‐2‐carboxylate (+)‐trans‐ 3c afforded the corresponding α‐amino acid derivative, which was smoothly transformed into (+)‐tert‐butyl [(1R)‐2‐(1,3‐benzodioxol‐5‐yl)‐1‐methylethyl]carbamate((+)‐ 14 ) with high retention of optical purity (Scheme 6).     

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 .     

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.     

Artabotryols A – E,New Lanostane Triterpenes from the Seeds of Artabotrys odoratissimus

Six new lanostane triterpenes, artabotryols A, B, C1, C2, D, and E ( 1, 2, 3a, 3b, 4 , and 5 , resp.) have been isolated from the seeds of Artabotrys odoratissimus (Annonaceae). Their structures have been established as (3α,22S,25R)‐3‐hydroxy‐22,26‐epoxylanost‐8‐en‐26‐one ( 1 ), (3α,22S,25R)‐22,26‐epoxylanost‐8‐ene‐3,26‐diol ( 2 ), (3α,22S,25R,26R)‐26‐methoxy‐22,26‐epoxylanost‐8‐en‐3‐ol ( 3a ), (3α,22S,25R, 26S)‐26‐methoxy‐22,26‐epoxylanost‐8‐en‐3‐ol ( 3b ), (3α,22S,25R)‐3,22‐dihydroxylanost‐8‐en‐26‐oic acid ( 4 ) and (3α,7α,11α,22S,25R)‐3,7,11‐trihydroxy‐22,26‐epoxylanost‐8‐en‐26‐one ( 5 ) by spectroscopic studies and chemical correlations.     

Stereoselective and Enantioselective Syntheses of the Four Stereoisomers of Muscol from (3RS)‐Muscone

Two trans stereoisomers of 3‐methylcyclopentadecanol (=muscol), (1R,3R)‐ 2 and (1S,3S)‐ 2 , were efficiently synthesized from (3RS)‐3‐methylcyclopentadecanone (=muscone; (3RS)‐ 1 ) by a highly stereoselective reduction (Scheme). L‐Selectride^® (=lithium tri(sec‐butyl)borohydride) was used, followed by the enantiomer resolution by lipase QLG (Alcaligenes sp.). The cis stereoisomers of muscol, (1S,3R)‐ 2 and (1R,3S)‐ 2 , were obtained by the Mitsunobu inversion of (1R,3R)‐ 2 and (1S,3S)‐ 2 , respectively (Scheme). The absolute configuration of (1R,3R)‐ 2 was determined by X‐ray crystal‐structure analysis of its 3‐nitrophthalic acid monoester, 2‐[(1R,3R)‐3‐methylcyclopentadecyl hydrogen benzene‐1,2‐dicarboxylate ((1R,3R)‐ 3b ), and by oxidation of (1R,3R)‐ 2 to (3R)‐muscone.     

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.     

Total Synthesis of the Spermidine Alkaloid 13‐Hydroxyisocyclocelabenzine

A convergent total synthesis of 13‐hydroxyisocyclocelabenzine was developed. (3S)‐Methyl 3‐amino‐3‐phenylpropanoate ( 4 ) was used as the chiral building block. The 3,4‐dihydro‐4‐hydroxyisoquinolin‐1(2H)‐one derivative ( 5 ), the key fragment for the total synthesis, was prepared by a novel base‐catalyzed lactone‐lactam ring enlargement (Scheme 3). The resulting target C(13) epimers 3a / 3b from macrocyclization (Scheme 4) were separated by repeated flash chromatography. The absolute configuration of the synthetic alkaloid was determined by an X‐ray crystal‐structure analysis, which enabled us to determine the absolute configuration (9S,13R) for natural 3a with positive [α]_D.     

Enantioselective Synthesis of 2‐(2‐Arylcyclopropyl)glycines: Conformationally Restricted Homophenylalanine Analogs

Starting from simple aromatic aldehydes and acetylfuran, (E)‐1‐(furan‐2‐yl)‐3‐arylprop‐2‐en‐1‐ones ( 2 ) were synthesized in high yields. Cyclopropanation of the C?C bond with trimethylsulfoxonium iodide (Me₃SO⁺I^?) furnished (furan‐2‐yl)(2‐arylcyclopropyl)methanones 3 in 90–97% yields. Selective conversion of cyclopropyl ketones to their (E)‐ and (Z)‐oxime ethers 5 and oxazaborolidine‐catalyzed stereoselective reduction of the C?N bond followed by separation of the formed diastereoisomers, furnished (2‐arylcyclopropyl)(furan‐2‐yl)methanamines 6 in optically pure form and high yield. Oxidation of the furan ring of (S,S,S)‐, (S,R,R)‐, (R,S,S)‐, and (R,R,R)‐ 6a afforded the four stereoisomers of α‐(2‐phenylcyclopropyl) glycine ( 1a ).     

Helical Structures of Bicyclic α‐Amino Acid Homochiral Oligomers with the Stereogenic Centers at the Side‐Chain Fused‐Ring Junctions

Chiral bicyclic α‐amino acid (R,R)‐Ab_5,6=c with stereogenic centers at the γ‐position of fused‐ring junctions, and its enantiomer (S,S)‐Ab_5,6=c, were synthesized. The CD spectra of (R,R)‐Ab_5,6=c oligomers indicated that the (R,R)‐Ab_5,6=c hexapeptide formed a mixture of right‐handed (P)‐ and left‐handed (M)‐3₁₀‐helices, while, in the (R,R)‐Ab_5,6=c nonapeptide, a right‐handed (P)‐3₁₀‐helix slightly dominated over the (M)‐helix. X‐Ray crystallographic analyses of (S,S)‐tripeptide and (R,R)‐hexapeptide revealed that both the tripeptide and hexapeptide formed a mixture of (P)‐ and (M)‐3₁₀‐helices, respectively. These results indicated that the side‐chain environments around the stereogenic centers are particularly important to control the helical‐screw handedness of foldamers.     

Stereoselective Reduction of `Capsanthol‐3′‐ones' (=3,6′‐Dihydroxy‐β,κ‐caroten‐3′‐ones) by Complex Hydrides

The (3R,5′R,6′R)‐ and (3R,5′R,6′S)‐capsanthol‐3′‐one (=3,6′‐dihydroxy‐β,κ‐caroten‐3′‐one; 4 and 5 , resp.) were reduced by different complex metal hydrides containing organic ligands. The ratio of the thus obtained diastereoisomeric (3′S)‐capsanthols 2 and 3 or (3′R)‐capsanthols 6 and 7 , respectively, was investigated. Four complex hydrides showed remarkable stereoselectivity and produced the (3′R,6′S)‐capsanthol ( 6 ) in 80 – 100% (see Table 1). The starting materials and the products were characterized by UV/VIS, CD, ¹H‐ and ¹³C‐NMR, and mass spectra.     

Conformation of Peptides Containing a Chiral α‐Ethylated α,α‐Disubstituted α‐Amino Acid: (S)‐α‐Ethylleucine (=(2S)‐2‐Amino‐2‐ethyl‐4‐methylpentanoic Acid) within Sequences of Dimethylglycine and Diethylglycine Residues

An optically active (S)‐α‐ethylleucine ((S)‐αEtLeu) as a chiral α‐ethylated α,α‐disubstituted α‐amino acid was synthesized by means of a chiral acetal auxiliary of (R,R)‐cyclohexane‐1,2‐diol. The chiral α‐ethylated α,α‐disubstituted amino acid (S)‐αEtLeu was introduced into the peptides constructed from 2‐aminoisobutyric acid (=dimethylglycine, Aib), and also into the peptide prepared from diethylglycine (Deg). The X‐ray crystallographic analysis revealed that both right‐handed (P) and left‐handed (M) 3₁₀‐helical structures exist in the solid state of CF₃CO‐(Aib)₂‐[(S)‐αEtLeu]‐(Aib)₂‐OEt ( 14 ) and CF₃CO‐[(S)‐αEtLeu]‐(Deg)₄‐OEt ( 18 ), respectively. The IR, CD, and ¹H‐NMR spectra indicated that the dominant conformation of pentapeptides 14 and CF₃CO‐[(S)‐αEtLeu]‐(Aib)₄‐OEt ( 16 ) in solution is a 3₁₀‐helical structure, and that of 18 in solution is a planar C₅ conformation. The conformation of peptides was also studied by molecular‐mechanics calculations.     

Naphthyl Groups in Chiral Recognition: Structures of Salts and Esters of 2‐Methoxy‐2‐naphthylpropanoic Acids

The crystal structures of salt 8 , which was prepared from (R)‐2‐methoxy‐2‐(2‐naphthyl)propanoic acid ((R)‐MβNP acid, (R)‐ 2 ) and (R)‐1‐phenylethylamine ((R)‐PEA, (R)‐ 6 ), and salt 9 , which was prepared from (R)‐2‐methoxy‐2‐(1‐naphthyl)propanoic acid ((R)‐MαNP acid, (R)‐ 1 ) and (R)‐1‐(p‐tolyl)ethylamine ((R)‐TEA, (R)‐ 7 ), were determined by X‐ray crystallography. The MβNP and MαNP anions formed ion‐pairs with the PEA and TEA cations, respectively, through a methoxy‐group‐assisted salt bridge and aromatic CH???π interactions. The networks of salt bridges formed 2₁ columns in both salts. Finally, (S)‐(2E,6E)‐(1‐²H₁)farnesol ((S)‐ 13 ) was prepared from the reaction of (2E,6E)‐farnesal ( 11 ) with deuterated (R)‐BINAL‐H (i.e., (R)‐BINAL‐D). The enantiomeric excess of compound (S)‐ 13 was determined by NMR analysis of (S)‐MαNP ester 14 . The solution‐state structures of MαNP esters that were prepared from primary alcohols were also elucidated.     

Enzyme‐Mediated Preparation of (+)‐ and (−)‐β‐Irone and (+)‐ and (−)‐cis‐γ‐Irone from Irone alpha®

The (−)‐ and (+)‐β‐irones ((−)‐ and (+)‐ 2 , resp.), contaminated with ca. 7 – 9% of the (+)‐ and (−)‐trans‐α‐isomer, respectively, were obtained from racemic α‐irone via the 2,6‐trans‐epoxide (±)‐ 4 (Scheme 2). Relevant steps in the sequence were the LiAlH₄ reduction of the latter, to provide the diastereoisomeric‐4,5‐dihydro‐5‐hydroxy‐trans‐α‐irols (±)‐ 6 and (±)‐ 7 , resolved into the enantiomers by lipase‐PS‐mediated acetylation with vinyl acetate. The enantiomerically pure allylic acetate esters (+)‐ and (−)‐ 8 and (+)‐ and (−)‐ 9 , upon treatment with POCl₃/pyridine, were converted to the β‐irol acetate derivatives (+)‐ and (−)‐ 10 , and (+)‐ and (−)‐ 11 , respectively, eventually providing the desired ketones (+)‐ and (−)‐ 2 by base hydrolysis and MnO₂ oxidation. The 2,6‐cis‐epoxide (±)‐ 5 provided the 4,5‐dihydro‐4‐hydroxy‐cis‐α‐irols (±)‐ 13 and (±)‐ 14 in a 3 : 1 mixture with the isomeric 5‐hydroxy derivatives (±)‐ 15 and (±)‐ 16 on hydride treatment (Scheme 1). The POCl₃/pyridine treatment of the enantiomerically pure allylic acetate esters, obtained by enzymic resolution of (±)‐ 13 and (±)‐ 14 , provided enantiomerically pure cis‐α‐irol acetate esters, from which ketones (+)‐ and (−)‐ 22 were prepared (Scheme 4). The same materials were obtained from the (9S) alcohols (+)‐ 13 and (−)‐ 14 , treated first with MnO₂, then with POCl₃/pyridine (Scheme 4). Conversely, the dehydration with POCl₃/pyridine of the enantiomerically pure 2,6‐cis‐5‐hydroxy derivatives obtained from (±)‐ 15 and (±)‐ 16 gave rise to a mixture in which the γ‐irol acetates 25a and 25b and 26a and 26b prevailed over the α‐ and β‐isomers (Scheme 5). The (+)‐ and (−)‐cis‐γ‐irones ((+)‐ and (−)‐ 3 , resp.) were obtained from the latter mixture by a sequence involving as the key step the photochemical isomerization of the α‐double bond to the γ‐double bond. External panel olfactory evaluation assigned to (+)‐β‐irone ((+)‐ 2 ) and to (−)‐cis‐γ‐irone ((−)‐ 3 ) the strongest character and the possibility to be used as dry‐down note.     

Syntheses and Glycosidase Inhibitory Activities of 2‐(Aminomethyl)‐5‐(hydroxymethyl)pyrrolidine‐3,4‐diol Derivatives

New 2‐(aminomethyl)‐5‐(hydroxymethyl)pyrrolidine‐3,4‐diol derivatives were synthesized from (5S)‐5‐[(trityloxy)methyl]pyrrolidin‐2‐one ( 6 ) (Schemes 1 and 2) and their inhibitory activities toward 25 glycosidases assayed (Table). The influence of the configuration of the pyrrolidine ring on glycosidase inhibition was evaluated. (2R,3R,4S,5R)‐2‐[(benzylamino)methyl]‐5‐(hydroxymethyl)pyrrolidine‐3,4‐diol ((+)‐ 21 ) was found to be a good and selective inhibitor of α‐mannosidase from jack bean (K_i=1.2 μM ) and from almond (K_i=1.0 μM ). Selectivity was lost for the non‐benzylated derivative (2R,3R,4S,5R)‐2‐(aminomethyl)‐5‐(hydroxymethyl)pyrrolidine‐3,4‐diol ((+)‐ 22 ) which inhibited α‐galactosidases, β‐galactosidases, β‐glucosidases, and α‐N‐acetylgalactosaminidase as well.     

Preparation and structural analysis of (±)‐cis‐ethyl 2‐sulfanylidenedecahydro‐1,6‐naphthyridine‐6‐carboxylate and (±)‐trans‐ethyl 2‐oxooctahydro‐1H‐pyrrolo[3,2‐c]pyridine‐5‐carboxylate

Bicycle ring closure on a mixture of (4aS,8aR)‐ and (4aR,8aS)‐ethyl 2‐oxodecahydro‐1,6‐naphthyridine‐6‐carboxylate, followed by conversion of the separated cis and trans isomers to the corresponding thioamide derivatives, gave (4aSR,8aRS)‐ethyl 2‐sulfanylidenedecahydro‐1,6‐naphthyridine‐6‐carboxylate, C₁₁H₁₈N₂O₂S. Structural analysis of this thioamide revealed a structure with two crystallographically independent conformers per asymmetric unit (Z′ = 2). The reciprocal bicycle ring closure on (3aRS,7aRS)‐ethyl 2‐oxooctahydro‐1H‐pyrrolo[3,2‐c]pyridine‐5‐carboxylate, C₁₀H₁₆N₂O₃, was also accomplished in good overall yield. Here the five‐membered ring is disordered over two positions, so that both enantiomers are represented in the asymmetric unit. The compounds act as key intermediates towards the synthesis of potential new polycyclic medicinal chemical structures.     

Asymmetric Syntheses of New Polyhydroxylated Quinolizidines: Cross‐Aldol Reactions of 7‐Oxabicyclo[2.2.1]heptan‐2‐one and 3a,4a,7a,7b‐Tetrahydro[1,3]dioxolo[4,5]furo[2,3‐d]isoxazole‐3‐carbaldehyde Derivatives

The cross‐aldolization of (−)‐(1S,4R,5R,6R)‐6‐endo‐chloro‐5‐exo‐(phenylseleno)‐7‐oxabicyclo[2.2.1]heptan‐2‐one ((−)‐ 25 ) and of (+)‐(3aR,4aR,7aR,7bS)‐ ((+)‐ 26 ) and (−)‐(3aS,4aS,7aS,7bR)‐3a,4a,7a,7b‐tetrahydro‐6,6‐dimethyl[1,3]dioxolo[4,5]furo[2,3‐d]isoxazole‐3‐carbaldehyde ((−)‐ 26 ) was studied for the lithium enolate of (−)‐ 25 and for its trimethylsilyl ether (−)‐ 31 under Mukaiyama's conditions (Scheme 2). Protocols were found for highly diastereoselective condensation giving the four possible aldols (+)‐ 27 (`anti'), (+)‐ 28 (`syn'), 29 (`anti'), and (−)‐ 30 (`syn') resulting from the exclusive exo‐face reaction of the bicyclic lithium enolate of (−)‐ 25 and bicyclic silyl ether (−)‐ 31 . Steric factors can explain the selectivities observed. Aldols (+)‐ 27 , (+)‐ 28 , 29 , and (−)‐ 30 were converted stereoselectively to (+)‐1,4‐anhydro‐3‐{(S)‐[(tert‐butyl)dimethylsilyloxy][(3aR,4aR,7aR,7bS)‐3a,4a,7a,7b‐tetrahydro‐6,6‐dimethyl[1,3]dioxolo[4,5]‐furo[2,3‐d]isoxazol‐3‐yl]methyl}‐3‐deoxy‐2,6‐di‐O‐(methoxymethyl)‐α‐D ‐galactopyranose ((+)‐ 62 ), its epimer at the exocyclic position (+)‐ 70 , (−)‐1,4‐anhydro‐3‐{(S)‐[(tert‐butyl)dimethylsilyloxy][(3aS,4aS,7aS,7bR)‐3a,4a,7a,7b‐tetrahydro‐6,6‐dimethyl[1,3]dioxolo[4,5]furo[2,3‐d]isoxazol‐3‐yl]methyl}‐3‐deoxy‐2,6‐di‐O‐(methoxymethyl)‐α‐D ‐galactopyranose ((−)‐ 77 ), and its epimer at the exocyclic position (+)‐ 84 , respectively (Schemes 3 and 5). Compounds (+)‐ 62 , (−)‐ 77 , and (+)‐ 84 were transformed to (1R,2R,3S,7R,8S,9S,9aS)‐1,3,4,6,7,8,9,9a‐octahydro‐8‐[(1R,2R)‐1,2,3‐trihydroxypropyl]‐2H‐quinolizine‐1,2,3,7,9‐pentol ( 21 ), its (1S,2S,3R,7R,8S,9S,9aR) stereoisomer (−)‐ 22 , and to its (1S,2S,3R,7R,8S,9R,9aR) stereoisomer (+)‐ 23 , respectively (Schemes 6 and 7). The polyhydroxylated quinolizidines (−)‐ 22 and (+)‐ 23 adopt `trans‐azadecalin' structures with chair/chair conformations in which H−C(9a) occupies an axial position anti‐periplanar to the amine lone electron pair. Quinolizidines 21 , (−)‐ 22 , and (+)‐ 23 were tested for their inhibitory activities toward 25 commercially available glycohydrolases. Compound 21 is a weak inhibitor of β‐galactosidase from jack bean, of amyloglucosidase from Aspergillus niger, and of β‐glucosidase from Caldocellum saccharolyticum. Stereoisomers (−)‐ 22 and (+)‐ 23 are weak but more selective inhibitors of β‐galactosidase from jack bean.