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.     

Practical Enzymatic Desymmetrization of 2‐(Ethoxycarbonyl)propane‐1,3‐diyl Dihexanoate and Model Cyclization for the A–D Ring System of Lysergic Acid

Porcine pancreas lipase‐catalyzed hydrolysis of symmetrical 2‐(ethoxycarbonyl)propane‐1,3‐diyl dihexanoate, under the modified conditions of the Seebach protocol, afforded a desymmetrized monohexanoate in 40–51% yield with 91–94% ee, even in a gram‐scale reaction. The absolute configuration of a half‐hydrolyzed (?)‐product was determined to be (R) by conversion to a known 2‐methylpropane‐1,3‐diol derivative. Samarium iodide‐induced radical cyclization of 2‐oxo‐3‐phenylethylamine with a C₄ unit on the N‐atom, derived from the racemic monohexanoate, afforded a 3‐phenylpiperidine derivative as a model construction of the A–D ring system of lysergic acid.     

Novel and enantioselective syntheses of (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid: a synthon for sitagliptin and its derivatives

A new synthetic strategy for (R)- and (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid, a building block in the preparation of sitagliptin and its derivatives, was developed. Pd(OAc)₂ catalyzed coupling of 2,4,5-trifluoro-1-iodobenzene with allyl alcohol gave 3-(2,4,5-trifluorophenyl)propanal in a yield of 95%. l-Proline catalyzed reaction of the 3-phenylpropanal (in only 1.2 molar equiv) with nitrosobenzene followed by reduction with NaBH₄ and Pd/C catalyzed hydrogenation gave (R)-3-(2,4,5-trifluorophenyl)propane-1,2-diol with >99% ee and 65% yield. Selective tosylation of primary hydroxyl group of the 1,2-propandiol unit followed by cyanide displacement afforded (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanenitrile (80%). The nitrile was converted to the title β-hydroxy acid under basic hydrolysis in a yield of 90%. Thus, (R)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid was prepared enantioselectively from the starting material in four steps and 45% overall yield. The reaction sequence was repeated with d-proline as the catalyst to give (S)-3-hydroxy-4-(2,4,5-trifluorophenyl)butanoic acid in 45% overall yield and >99% enantiomeric excess.     

Stereoselective Synthesis of [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐D‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐L‐valine]cyclosporin A

Addition of various amines to the 3,3‐bis(trifluoromethyl)acrylamides 10a and 10b gave the tripeptides 11a – 11f , mostly as mixtures of epimers (Scheme 3). The crystalline tripeptide 11f ₂ was found to be the N‐terminal (2‐hydroxyethoxy)‐substituted (R,S,S)‐ester HOCH₂CH₂O‐D ‐Val(F₆)‐MeLeu‐Ala‐O^tBu by X‐ray crystallography. The C‐terminal‐protected tripeptide 11f ₂ was condensed with the N‐terminus octapeptide 2b to the depsipeptide 12a which was thermally rearranged to the undecapeptide 13a (Scheme 4). The condensation of the epimeric tripeptide 11f ₁ with the octapeptide 2b gave the undecapeptide 13b directly. The undecapeptides 13a and 13b were fully deprotected and cyclized to the [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐D ‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐L ‐valine]]cyclosporins 14a and 14b , respectively (Scheme 5). Rate differences observed for the thermal rearrangements of 12a to 13a and of 12b to 13b are discussed.     

6‐(Diazomethyl)‐1,3‐bis(methoxymethyl)uracil,Synthesis and Transformation into Annulated Pyrimidinediones

6‐(Diazomethyl)‐1,3‐bis(methoxymethyl)uracil ( 5 ) was prepared from the known aldehyde 3 by hydrazone formation and oxidation. Thermolysis of 5 and deprotection gave the pyrazolo[4,3‐d]pyrimidine‐5,7‐diones 7a and 7b . Rh₂(OAc)₄ catalyzed the transformation of 5 into to a 2 : 1 (Z)/(E) mixture of 1,2‐diuracilylethenes 9 (67%). Heating (Z)‐ 9 in 12n HCl at 95° led to electrocyclisation, oxidation, and deprotection to afford 73% of the pyrimido[5,4‐f]quinazolinetetraone 12 . The Rh₂(OAc)₄‐catalyzed reaction of 5 with 3,4‐dihydro‐2H‐pyran and 2,3‐dihydrofuran gave endo/exo‐mixtures of the 2‐oxabicyclo[4.1.0]heptane 13 (78%) and the 2‐oxabicyclo[3.1.0]hexane 15 (86%), Their treatment with AlCl₃ or Me₂AlCl promoted a vinylcyclopropane–cyclopentene rearrangement, leading to the pyrano‐ and furanocyclopenta[1,2‐d]pyrimidinediones 14 (88%) and 16 (51%), respectively. Similarly, the addition product of 5 to 2‐methoxypropene was transformed into the 5‐methylcyclopenta‐pyrimidinedione 18 (55%). The Rh₂(OAc)₄‐catalyzed reaction of 5 with thiophene gave the exo‐configured 2‐thiabicyclo[3.1.0]hexane 19 (69%). The analoguous reaction with furan led to 8‐oxabicyclo[3.2.1]oct‐2‐ene 20 (73%), and the reaction with (E)‐2‐styrylfuran yielded a diastereoisomeric mixture of hepta‐1,4,6‐trien‐3‐ones 21 (75%) that was transformed into the (1E,4E,6E)‐configured hepta‐1,4,6‐trien‐3‐one 21 (60%) at ambient temperature.     

Synthesis and characterization of block poly(ester‐ether‐urethane)s from bacterial poly(3‐hydroxybutyrate) oligomers

Telechelic hydroxylated poly(3‐hydroxybutyrate) (PHB‐diol) oligomers have been successfully synthesized in 90–95% yield from high molar mass PHB by tin‐catalyzed alcoholysis with different diols (mainly 1,4‐butanediol) in diglyme. The PHB‐diol oligomers structure was studied by nuclear magnetic resonance, Fourier transformed infrared spectroscopy MALDI‐ToF MS, and size exclusion chromatography, whereas their crystalline structures, thermal properties and thermal stability were analyzed by wide angle X‐ray scattering, DSC, and thermogravimetric analyses. The kinetic of the alcoholysis was studied and the influence of (i) the catalyst amount, (ii) the diol amount, (iii) the reaction temperature, and (iv) the diol chain length on the molar mass was discussed. The influence of the PHB‐diol molar mass on the thermal stability, the thermal properties and optical properties was investigated. Then, tin‐catalyzed poly(ester‐ether‐urethane)s (PEEU) of M_n = 15,000–20,000 g/mol were synthesized in 1,2‐dichloroethane from PHB‐diol oligomers (P_ester) with modified 4,4'‐MDI and different polyether‐diols (P_ether) (PEG‐2000, PEG‐4000, and PPG‐PEG‐PPG). The influence of the PHB‐diol chain length, the P_ether/P_ester ratio, the polyether segment nature and the PEG chain length on the thermal properties and crystalline structures of PEEUs was particularly discussed. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 1949–1961     

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.     

Chemo‐Enzymatic Synthesis of 3‐Deoxy‐β‐D‐ribofuranosyl Purines

9‐(3‐Deoxy‐β‐D ‐erythro‐pentofuranosyl)‐2,6‐diaminopurine ( 6 ) was synthesized by an enzymatic transglycosylation of 2,6‐diaminopurine ( 2 ) with 3′‐deoxycytidine ( 1 ) as a donor of 3‐deoxy‐D ‐erythro‐pentofuranose moiety. This transformation comprises i) deamination of 1 to 3′‐deoxyuridine ( 3 ) under the action of whole cell (E. coli BM‐11) cytidine deaminase (CDase), ii) the phosphorolytic cleavage of 3 by uridine phosphorylase (UPase) giving rise to the formation of uracil ( 4 ) and 3‐deoxy‐α‐D ‐erythro‐pentofuranose‐1‐O‐phosphate ( 5 ), and iii) coupling of the latter with 2 catalyzed by whole cell (E. coli BMT‐4D/1A) purine nucleoside phosphorylase (PNPase). Deamination of 6 by adenosine deaminase (ADase) gave 3′‐deoxyguanosine ( 7 ). Treatment of 6 with NaNO₂ afforded 9‐(3‐deoxy‐β‐D ‐erythro‐pentofuranosyl)‐2‐amino‐6‐oxopurine (3′‐deoxyisoguanosine; 8 ). Schiemann reaction of 6 (HF/HBF₄+NaNO₂) gave 9‐(3‐deoxy‐β‐D ‐erythro‐pentofuranosyl)‐2‐fluoroadenine ( 9 ).     

Stereoselective Synthesis of the Non‐Lactonic Portion of (Z)‐Cryptofolione and Approaches towards Its Conversion to (Z)‐Cryptofolione

The stereoselective synthesis of the non‐lactonic part of the natural G₂ checkpoint inhibitor, (Z)‐cryptofolione, has been accomplished. Butane‐1,4‐diol was used as the starting material, and the stereogenic centers were generated through L ‐proline‐catalyzed α‐aminoxylation and Maruoka asymmetric allylation. We attempted to convert this non‐lactonic moiety to (Z)‐cryptofolione via olefin cross‐metathesis reaction, but by this approach another naturally occurring lactonic compound, goniothalamin, was obtained.     

Fate of the Oxygen Atoms in the Diol‐Dehydratase‐Catalyzed Dehydration of meso‐Butane‐2,3‐diol

¹⁸O‐Substituted propane‐1,2‐diols and meso‐butane‐1,2‐diols were synthesized and fed to growing cells of Lactobacillus brevis. Propan‐1‐ol and butan‐2‐ol, prepared from such diols through diol‐dehydratase‐catalyzed dehydration followed by intracellular reduction, were analyzed for their ¹⁸O‐content. For each propane‐1,2‐diol enantiomer, partial retention or complete loss of the isotope appeared to be related to the mode of substrate binding. Specific retention of the O‐atom linked to the (R)‐configured C‐atom of meso‐butane‐1,2‐diol indicates that the diol dehydratase handles this substrate like (R)‐propane‐1,2‐diol.     

Asymmetric Hydroformylation of Vinylfurans Catalyzed by {(11bS)‐4‐{[(1R)‐2′‐Phosphino[1,1′‐binaphthalen]‐2‐yl]oxy}dinaphtho[2,1‐d:1′,2′‐f]‐ [1,3,2]dioxaphosphepin}rhodium(I) [RhI{(R,S)‐binaphos}] Derivatives

The asymmetric hydroformylation of 2‐ and 3‐vinylfurans ( 2a and 2b , resp.) was investigated by using [Rh{(R,S)‐binaphos}] complexes as catalysts ((R,S)‐binaphos = (11bS)‐4‐{[1R)‐2′‐phosphino[1,1′‐binaphthalen]‐2‐yl]oxy}dinaphtho[2,1‐d:1′,2′‐f][1,3,2]dioxaphosphepin; 1 ). Hydroformylation of 2 gave isoaldehydes 3 in high regio‐ and enantioselectivities (Scheme 2 and Table). Reduction of the aldehydes 3 with NaBH₄ successfully afforded the corresponding alcohols 5 without loss of enantiomeric purity (Scheme 3).     

Investigation of Functionalized α‐Chloroalkyllithiums for a Stereospecific Reagent‐Controlled Homologation Approach to the Analgesic Alkaloid (−)‐Epibatidine

Four putative functionalized α‐chloroakyllithiums RCH₂CHLiCl, where R=CHCH₂ ( 18 a ), CCH ( 18 b ), CH₂OBn ( 18 c ), and CH[O(CH₂)₂O] ( 18 d ), were generated in situ by sulfoxide–lithium exchange from α‐chlorosulfoxides, and investigated for the stereospecific reagent‐controlled homologation (StReCH) of phenethyl and 2‐chloropyrid‐5‐yl ( 17 ) pinacol boronic esters. Deuterium labeling experiments revealed that α‐chloroalkyllithiums are quenched by proton transfer from their α‐chlorosulfoxide precursors and it was established that this effect compromises the yield of StReCH reactions. Use of α‐deuterated α‐chlorosulfoxides was discovered to ameliorate the problem by retarding the rate of acid‐base chemistry between the carbenoid and its precursor. Carbenoids 18 a and 18 b showed poor StReCH efficacy, particularly the propargyl group bearing carbenoid 18 b , the instability of which was attributed to a facile 1,2‐hydride shift. By contrast, 18 d , a carbenoid that benefits from a stabilizing interaction between O and Li atoms gave good StReCH yields. Boronate 17 was chain extended by carbenoids 18 a , 18 b , and 18 d in 16, 0, and 68 % yield, respectively; α‐deuterated isotopomers D ‐ 18 a and D ‐ 18 d gave yields of 33 and 79 % for the same reaction. Double StReCH of 17 was pursued to target contiguous stereodiads appropriate for the total synthesis of (?)‐epibatidine ( 15 ). One‐pot double StReCH of boronate 17 by two exposures to (S)‐D ‐ 18 a (≤66 % ee), followed by work‐up with KOOH, gave the expected stereodiad product in 16 % yield (d.r.～67:33). The comparable reaction using two exposures to (S)‐D ‐ 18 d (≤90 % ee) delivered the expected bisacetal containing stereodiad (R,R)‐DD ‐ 48 in 40 % yield (≥98 % ee, d.r.=85:15). Double StReCH of 17 using (S)‐D ‐ 18 d (≤90 % ee) followed by (R)‐D ‐ 18 d (≤90 % ee) likewise gave (R,S)‐DD ‐ 48 in 49 % yield (≥97 % ee, d.r.=79:21). (R,S)‐DD ‐ 48 was converted to a dideuterated isotopomer of a synthetic intermediate in Corey’s synthesis of 15 .     

Controllable ring‐opening copolymerization of L‐lactide and (3S)‐benzyloxymethyl‐(6S)‐methyl‐morpholine‐2,5‐dione initiated by a biogenic compound creatinine acetate

Ring‐opening copolymerization (ROCP) of L ‐lactide (L ‐LA) and (3S)‐benzyloxymethyl‐(6S)‐methyl‐morpholine‐2,5‐dione [(3S, 6S)‐BMMD] initiated by creatinine acetate, a biogenic organic compound, was performed in the bulk at 130 °C. The copolymerization was well controlled as evidenced by that both the measured values of number‐average molecular weight (M_n,NMR(OH) and M_n,NMR(COOH)) and serine molar fraction (F_Bz.ser) of synthesized copolymers were close to the corresponding theoretical values; and that the higher isotacticity of synthesized copolymers (85–86%) and lower racemization degree of the ROCP. After removing O‐benzyls of the copolymers with Et₃SiH/Et₃N/CH₂Cl₂ under catalysis of PdCl₂, functional biodegradable copolymers of L ‐lactic acid (L ‐Lac) and L ‐Ser with designed molar fraction of serine (F_ser 1.35%, 3.57%, 5.41%), narrow molecular weight distribution (polydispersity index 1.10–1.36), and improved hydrophilicity (θ_stat 82.3–89.6°) were finally obtained. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

A novel synthesis of (2S)-3-(2,4,5-trifluorophenyl)propane-1,2-diol by sharpless asymmetric epoxidation method

Synthesis of (2S)-3-(2,4,5-trifluorophenyl)propane-1,2-diol by the Sharpless asymmetric epoxidation reaction has been achieved. 2,4,5-Trifluorobenzaldehyde with methyl 2-(triphenyl-λ⁵-phosphanylidene)acetate gave methyl (E)-3-(2,4,5-trifluorophenyl)acrylate in 83% yield. The reduction of ester group with DibalH followed by Sharpless asymmetric epoxidation gave ((2R,3R)-3-(2,4,5-trifluorophenyl)oxiran-2-yl)methanol. Pd/C-catalyzed hydrogenation of epoxy alcohol furnished (2S)-3-(2,4,5-trifluorophenyl)propane-1,2-diol with >90% ee and 71% yield.     

Stereoselective Total Synthesis of (3S,5S)‐1,7‐Bis(4‐hydroxyphenyl)heptane‐3,5‐diol, (3S,5S)‐Alpinikatin,and Its Diastereoisomers

Stereoselective synthesis of the diarylheptanoids, (3S,5S)‐1,7‐bis(4‐hydroxyphenyl)heptane‐3,5‐diol ( 1 ), (3S,5S)‐alpinikatin ( 3 ), and their diastereoisomers ( 2 and 4 , resp.), was achieved from readily available 4‐hydroxybenzaldehyde. The synthetic sequences involve Browns's allylation and Et₂Zn mediated diastereoselective alkynylation reaction as key steps.     

New Optically Active Bis‐Heterocycles Derived from (S)‐Proline

Enantiomerically pure bis‐heterocycles containing a (S)‐proline moiety have been prepared starting from (S)‐N‐benzylprolinehydrazide ( 2b ). The reactions with isothiocyanates or butyl isocyanate in refluxing MeOH led to the corresponding thiosemicarbazide 5 and semicarbazide 9 with a N‐benzylprolinoyl residue. The structure of the tert‐butyl derivative 5d was established by X‐ray crystallography. Base‐catalyzed cyclization of 5 and 9 led to (S)‐3‐(pyrrolidin‐2‐yl)‐1H‐1,2,4‐triazole‐5(4H)‐thiones 6 and the corresponding 5(4H)‐one 8 , respectively, whereas, in concentrated H₂SO₄, compounds 5 undergo cyclization to give (S)‐5‐amino‐2‐(pyrrolidin‐2‐yl)‐1,3,4‐thiadiazoles 7 . Furthermore, 2b reacted with hexane‐2,5‐dione in boiling ⁱPrOH to yield the (S)‐N‐(2,5‐dimethylpyrrol‐1‐yl)prolinamide 10 . In the case of the bis‐heterocycle 8 , treatment with HCOONH₄ and Pd/C in MeOH gave the debenzylated product 12 .     

Asymmetric Henry reactions of aldehydes with various nitroalkanes catalyzed by copper(II) complexes of novel chiral N‐monoalkyl cyclohexane‐1,2‐diamines

A number of novel chiral diamines 3 , (1R,2R)‐N‐monoalkylcyclohexane‐1,2‐diamines, were designed and synthesized from trans‐cyclohexane‐1,2‐diamine and applied to the catalytic asymmetric Henry reaction of benzaldehyde and nitromethane to provide β‐nitroalcohol in high yield (up to 99%) and good enantiomeric excess (up to 89%). By using ligand (1R,2R)‐N¹‐(4‐methylpentan‐2‐yl)cyclohexane‐1,2‐diamine ( 3g ), the reaction was optimized in terms of the metal ion, temperature, solvent and base. Further experiments indicated that the complex, 3g –Cu(OAc)₂, was an efficient catalyst in the asymmetric Henry reaction between different aldehydes and nitromethane, and the desired products have been obtained with high chemical yields (up to 99%) and high enantiomeric excess (up to 93%). The optimized catalyst promoted the diastereoselective Henry reaction of various aldehyde substrates and nitroalkane, which gave the corresponding anti‐selective adduct with up to 99% yield and 83:17 anti/syn selectivity. Upon scaling up to gram quantities, the β‐nitroalcohol was obtained in good yield (96%) with excellent selectivities (93% ee). The chiral induction mechanism was tentatively explained on the basis of a previously proposed transition‐state model. Copyright © 2014 John Wiley & Sons, Ltd.     

Optical Resolution of 5‐Oxo‐1‐Phenyl‐Pyrazolidine‐3‐Carboxylic Acid as a New Organocatalyst for Organic Reactions

Optical resolution of racemic 5‐oxo‐1‐phenyl‐pyrazolidine‐3‐carboxylic acid 2 with L‐amino acid methyl ester via the diastereomers formation was investigated. Treatment of racemic 5‐oxo‐1‐phenyl‐pyrazolidine‐3‐carboxylic acid 2 with L‐valine methyl ester gave diastereomers with a total yield of 86%. The diastereomeric dipeptides can be easily separated by flash column chromatography. Acidic cleavage of the derived diastereomers gave both the optically pure (+)‐(R)‐ and (‐)‐(S)‐5‐oxo‐1‐phenyl‐pyrazolidine‐3‐carboxylic acid ((+)‐(R)‐ 2 and (‐)‐(S)‐ 2 ) with a total yield of 94% and 95%, respectively.     

Reaction of Optically Active Oxiranes with Thiofenchone and 1‐Methylpyrrolidine‐2‐thione: Formation of 1,3‐Oxathiolanes and Thiiranes

The SnCl₄‐catalyzed reaction of (?)‐thiofenchone (=1,3,3‐trimethylbicyclo[2.2.1]heptane‐2‐thione; 10 ) with (R)‐2‐phenyloxirane ((R)‐ 11 ) in anhydrous CH₂Cl₂ at ?60° led to two spirocyclic, stereoisomeric 4‐phenyl‐1,3‐oxathiolanes 12 and 13 via a regioselective ring enlargement, in accordance with previously reported reactions of oxiranes with thioketones (Scheme 3). The structure and configuration of the major isomer 12 were determined by X‐ray crystallography. On the other hand, the reaction of 1‐methylpyrrolidine‐2‐thione ( 14a ) with (R)‐ 11 yielded stereoselectively (S)‐2‐phenylthiirane ((S)‐ 15 ) in 56% yield and 87–93% ee, together with 1‐methylpyrrolidin‐2‐one ( 14b ). This transformation occurs via an S_N2‐type attack of the S‐atom at C(2) of the aryl‐substituted oxirane and, therefore, with inversion of the configuration (Scheme 4). The analogous reaction of 14a with (R)‐2‐{[(triphenylmethyl)oxy]methyl}oxirane ((R)‐ 16b ) led to the corresponding (R)‐configured thiirane (R)‐ 17b (Scheme 5); its structure and configuration were also determined by X‐ray crystallography. A mechanism via initial ring opening by attack at C(3) of the alkyl‐substituted oxirane, with retention of the configuration, and subsequent decomposition of the formed 1,3‐oxathiolane with inversion of the configuration is proposed (Scheme 5).     

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.