Asymmetric Synthesis of (R)‐1‐Alkyl‐Substituted Tetrahydro‐ß‐carbolines Catalyzed by Strictosidine Synthases

Stereoselective methods for the synthesis of tetrahydro‐ß‐carbolines are of significant interest due to the broad spectrum of biological activity of the target molecules. In the plant kingdom, strictosidine synthases catalyze the C?C coupling through a Pictet–Spengler reaction of tryptamine and secologanin to exclusively form the (S)‐configured tetrahydro‐ß‐carboline (S)‐strictosidine. Investigating the biocatalytic Pictet–Spengler reaction of tryptamine with small‐molecular‐weight aliphatic aldehydes revealed that the strictosidine synthases give unexpectedly access to the (R)‐configured product. Developing an efficient expression method for the enzyme allowed the preparative transformation of various aldehydes, giving the products with up to >98 % ee. With this tool in hand, a chemoenzymatic two‐step synthesis of (R)‐harmicine was achieved, giving (R)‐harmicine in 67 % overall yield in optically pure form.     

The First Modular Route to Core‐Chiral Bispidine Ligands and Their Application in Enantioselective Copper(II)‐Catalyzed Henry Reactions

The first modular and flexible synthesis of core‐chiral bispidines was achieved by using an “inside‐out” strategy. The key intermediate, a NBoc‐activated bispidine lactam, was constructed in enantiomerically pure form from a chirally modified β‐amino acid and 2‐(acetoxymethyl)acrylonitrile in just five steps and good 48 % yield. A simple addition–reduction protocol permitted a highly endo‐selective introduction of substituents and, thus, a fast and variable access to 2‐endo‐substituted and 2‐endo,N‐fused bi‐ and tricyclic bispidines. The new diamines were evaluated as the chiral ligands in asymmetric Henry reactions. Excellent enantioselectivities of up to 99 % ee and good diastereomeric ratios of up to 86:14 were reached with a copper(II) complex modified by a 2‐endo,N‐(3,3‐dimethylpyrrolidine)‐annelated bispidine. Its performance is superior to that of the well‐known bispidines (?)‐sparteine and the (+)‐sparteine surrogate.     

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 .     

Structural and Kinetic Dissection of the endo‐α‐1,2‐Mannanase Activity of Bacterial GH99 Glycoside Hydrolases from Bacteroides spp.

Glycoside hydrolase family 99 (GH99) was created to categorize sequence‐related glycosidases possessing endo‐α‐mannosidase activity: the cleavage of mannosidic linkages within eukaryotic N‐glycan precursors (Glc_1–3Man₉GlcNAc₂), releasing mono‐, di‐ and triglucosylated‐mannose (Glc_1–3‐1,3‐Man). GH99 family members have recently been implicated in the ability of Bacteroides spp., present within the gut microbiota, to metabolize fungal cell wall α‐mannans, releasing α‐1,3‐mannobiose by hydrolysing αMan‐1,3‐αMan→1,2‐αMan‐1,2‐αMan sequences within branches off the main α‐1,6‐mannan backbone. We report the development of a series of substrates and inhibitors, which we use to kinetically and structurally characterise this novel endo‐α‐1,2‐mannanase activity of bacterial GH99 enzymes from Bacteroides thetaiotaomicron and xylanisolvens. These data reveal an approximate 5 kJ mol^?1 preference for mannose‐configured substrates in the ?2 subsite (relative to glucose), which inspired the development of a new inhibitor, α‐mannopyranosyl‐1,3‐isofagomine (ManIFG), the most potent (bacterial) GH99 inhibitor reported to date. X‐ray structures of ManIFG or a substrate in complex with wild‐type or inactive mutants, respectively, of B. xylanisolvens GH99 reveal the structural basis for binding to D ‐mannose‐ rather than D ‐glucose‐configured substrates.     

Norbornane Mimics of Distorted β‐D‐Glucopyranosides – Inhibitors of β‐D‐Glucopyranosidases?

The racemic gluco‐configured norbornanes 4 and 16 were prepared and tested as inhibitors of β‐glucosidases. The known alcohol 5 was deprotected to provide the triol 6 . Silylation (→ 7 ), monobenzoylation (→ 8 / 9 ), and oxidation provided the regioisomeric ketones 10 and 11 . Reduction of 10 gave the desired endo‐alcohol 13 , albeit in low yield, while reduction of the isomeric ketone 11 provided mostly the altro‐configured endo‐alcohol 12 . The alcohol 13 was desilylated to 14 . Debenzoylation to 15 followed by hydrogenolytic deprotection gave the amino triol 4 that was reductively aminated to the benzylamine 16 . The amino triols 4 and 16 proved weak inhibitors of the β‐glucosidase from Caldocellum saccharolyticum ( 4 : IC₅₀ = 5.6 mm; 16 : IC₅₀ = 3.3 mm) and from sweet almonds ( 16 : IC₅₀ = 5.5 mm) . A comparison of 4 with the manno‐configured norbornane 3 shows that 3 is a better inhibitor of snail β‐mannosidase than 4 is of β‐glucosidases, in keeping with earlier results suggesting that these β‐glycosidases enforce a different conformational itinerary.     

Cationic Ir/Me‐BIPAM‐Catalyzed Asymmetric Intramolecular Direct Hydroarylation of α‐Ketoamides

Asymmetric intramolecular direct hydroarylation of α‐ketoamides gives various types of optically active 3‐substituted 3‐hydroxy‐2‐oxindoles in high yields with complete regioselectivity and high enantioselectivities (84–98 % ee). This is realized by the use of the cationic iridium complex [Ir(cod)₂](BAr^F₄) and the chiral O‐linked bidentate phosphoramidite (R,R)‐Me‐BIPAM.     

[2+2] Photocycloaddition of 3‐Alkenyloxy‐2‐cycloalkenones: Enantioselective Lewis Acid Catalysis and Ring Expansion

By application of substoichiometric amounts (50 mol %) of a chiral Lewis acid, the intramolecular [2+2] photocycloaddition of the title compounds was achieved with high enantioselectivity (up to 94 % ee). Upon cleavage of the cyclobutane ring the resulting tricyclic products underwent ring‐expansion reactions under acidic conditions and formed anellated seven‐ or eight‐membered‐ring systems without racemization. The ring expansion could be combined with a diastereoselective reduction (triethylsilane) or allylation (allyltrimethylsilane) upon BF₃ catalysis (48–87 % yield).     

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 of Some Novel Amino Phenols with Octahydro‐1,1′‐binaphthyl Backbone

A series of new octahydro‐1,1′‐binaphthyl derivatives, namely (R)‐(+)‐2‐(N, N‐dialkylamino)‐2′‐hydroxy‐5,5′,6,6′,7, 7′,8,8′‐octahydro‐1,1′‐binaphthyls (7,9), have been synthesized. Their asymmetric induction for enantioselective addition of Et₂Zn to benzaldehyde was examined and it was found that (R)‐(+)‐2‐(N‐cyclohexyl‐N‐methylamino)‐2′‐hydroxy‐5, 5′,6,6′,7,7′,8,8′‐octahydro‐1,1′‐binaphthyl (9c) exhibited the best asymmetric induction among the ligands prepared, up to 55% ee of 1‐phenylpropanol being obtained.     

Axially Dissymmetric Chiral (R)‐N,W‐Bis(2‐hydroxy‐3,5‐ditert‐butyl‐arylmethyl)‐1, 1′‐binaphthalene‐2,2′‐diamine as Chiral Ligands in the Reaction of Diethylzinc to Aldehydes†

Chiral ligand (A)‐N,N′‐Bis(2‐hydroxy‐3,5‐di‐tert‐butyl‐arylmethyl)‐1,1′‐binaphthalene‐2,2′‐diamine derived from the reduction of Schiff base (R)‐2,2′‐bis (3,5‐di‐tert‐butyl‐2‐hydroxybenzylideneamino)‐1, 1′‐binaphthyl with LiAlH₄, is fairly effective in the asymmetric addition reaction of diethylzinc to aldehydes by which good yields (46%‐94%) of the corresponding sec‐alcohols can be obtained in moderate ee (51%‐79%) with R configuration for a variety of aldehydes.     

Desymmetrization of 1,4‐Pentadien‐3‐ol by the Asymmetric 1,3‐Dipolar Cycloaddition of Azomethine Imines

Desymmetrization of the divinyl carbinol 1,4‐pentadien‐3‐ol was accomplished by the asymmetric 1,3‐dipolar cycloaddition of azomethine imines based on a magnesium‐mediated, multinucleating chiral reaction system utilizing diisopropyl (R,R)‐tartrate as the chiral auxiliary. The corresponding optically active trans‐pyrazolidines, each with three contiguous stereogenic centers, were obtained with excellent regio‐, diastereo‐, and enantioselectivity, with results as high as 99 % ee. This reaction was shown to be applicable to both aryl‐ and alkyl‐substituted azomethine imines. The use of a catalytic amount of diisopropyl (R,R)‐tartrate was also effective when accompanied by the addition of MgBr₂.     

Atropselective Dibrominations of a 1,1′‐Disubstituted 2,2′‐Biindolyl with Diverging Point‐to‐Axial Asymmetric Inductions. Deriving 2,2′‐Biindolyl‐3,3′‐diphosphane Ligands for Asymmetric Catalysis

On the ¹H NMR timescale, 2,2′‐biindolyls with (R)‐configured (1‐alkoxyprop)‐2‐yl, (1‐hydroxyprop)‐2‐yl, or (1‐siloxyprop)‐2‐yl substituents at C‐1 and C‐1′ are atropisomerically stable at <0 °C and interconvert at >30 °C. A 2,2′‐biindolyl (R,R)‐ 17 a of that kind and achiral (!) brominating reagents gave the atropisomerically stable 3,3′‐dibromobiindolyls (M)‐ and/or (P)‐ 18 a at best atropselectively—because of point‐to‐axial asymmetric inductions—and atropdivergently, exhibiting up to 95 % (M)‐ and as much (P)‐atropselectivity. This route to atropisomerically pure biaryls is novel and should extend to other substrates and/or different functionalizations. The dibromobiindolyls (M)‐ and (P)‐ 18 a furnished the biindolyldiphosphanes (M)‐ and (P)‐ 14 without atropisomerization. These syntheses did not require the resolution of a racemic mixture, which distinguishes them from virtually all biaryldiphosphane syntheses known to date. (M)‐ and (P)‐ 14 acted as ligands in catalytic asymmetric allylations and hydrogenations. Remarkably, the β‐ketoester rac‐ 25 c was hydrogenated trans‐selectively with 98 % ee; this included a dynamic kinetic resolution.     

Majority‐Rules‐Type Helical Poly(quinoxaline‐2,3‐diyl)s as Highly Efficient Chirality‐Amplification Systems for Asymmetric Catalysis

A highly efficient majority‐rules effect of poly(quinoxaline‐2,3‐diyl)s (PQXs) bearing 2‐butoxymethyl chiral side chains at the 6‐ and 7‐positions was established and attributed to large ΔG_h values (0.22–0.41 kJ mol^?1), which are defined as the energy difference between P‐ and M‐helical conformations per chiral unit. A PQX copolymer prepared from a monomer derived from (R)‐2‐octanol (23 % ee) and a monomer bearing a PPh₂ group adopted a single‐handed helical structure (>99 %) and could be used as a highly enantioselective chiral ligand in palladium‐catalyzed asymmetric reactions (products formed with up to 94 % ee), in which the enantioselectivity could be switched by solvent‐dependent inversion of the helical PQX backbone.     

Chemoselectivity Control in the Asymmetric Hydrogenation of γ‐ and δ‐Keto Esters into Hydroxy Esters or Diols

The asymmetric hydrogenation of aromatic γ‐ and δ‐keto esters into optically active hydroxy esters or diols under the catalysis of a novel DIPSkewphos/3‐AMIQ–Ru^II complex was studied. Under the optimized conditions (8 atm H₂ , Ru complex/t‐C₄H₉OK=1:3.5, 25 °C) the γ‐ and δ‐hydroxy esters (including γ‐lactones) were obtained quantitatively with 97–99 % ee. When the reaction was conducted under somewhat harsh conditions (20 atm H₂ , [t‐C₄H₉OK]=50 mm , 40 °C), the 1,4‐ and 1,5‐diols were obtained predominantly with 95–99 % ee. The reactivity of the ester group was notably dependent on the length of the carbon spacer between the two carbonyl moieties of the substrate. The reaction of β‐ and ?‐keto esters selectively afforded the hydroxy esters regardless of the reaction conditions. This catalyst system was applied to the enantioselective and regioselective (for one of the two ester groups) hydrogenation of a γ‐?‐diketo diester into a trihydroxy ester.     

Temperature Dual Enantioselective Control in a Rhodium‐Catalyzed Michael‐Type Friedel–Crafts Reaction: A Mechanistic Explanation

By changing the temperature from 283 to 233 K, the S (99 % ee) or R (96 % ee) enantiomer of the Friedel–Crafts (FC) adduct of the reaction between N‐methyl‐2‐methylindole and trans‐β‐nitrostyrene can be obtained by using (S_Rh,R_C)‐[(η⁵‐C₅Me₅)Rh{(R)‐Prophos}(H₂O)][SbF₆]₂ as the catalyst precursor. This catalytic system presents two other uncommon features: 1) The ee changes with reaction time showing trends that depend on the reaction temperature and 2) an increase in the catalyst loading results in a decrease in the ee of the S enantiomer. Detection and characterization of the intermediate metal–nitroalkene and metal–aci‐nitro complexes, the free aci‐nitro compound, and the FC adduct‐complex, together with solution NMR measurements, theoretical calculations, and kinetic studies have allowed us to propose two plausible alternative catalytic cycles. On the basis of these cycles, all the above‐mentioned observations can be rationalized. In particular, the reversibility of one of the cycles together with the kinetic resolution of the intermediate aci‐nitro complexes account for the high ee values achieved in both antipodes. On the other hand, the results of kinetic measurements explain the unusual effect of the increment in catalyst loading.     

Competitive Gold‐Promoted Meyer–Schuster and oxy‐Cope Rearrangements of 3‐Acyloxy‐1,5‐enynes: Selective Catalysis for the Synthesis of (+)‐(S)‐γ‐Ionone and (−)‐(2S,6 R)‐cis‐γ‐Irone

We report a simple, highly stereoselective synthesis of (+)‐(S)‐γ‐ionone and (‐)‐(2S,6R)‐cis‐γ‐irone, two characteristic and precious odorants; the latter compound is a constituent of the essential oil obtained from iris rhizomes. Of general interest in this approach are the photoisomerization of an endo trisubstituted cyclohexene double bond to an exo vinyl group and the installation of the enone side chain through a [(NHC)Au^I]‐catalyzed Meyer–Schuster‐like rearrangement. This required a careful investigation of the mechanism of the gold‐catalyzed reaction and a judicious selection of reaction conditions. In fact, it was found that the Meyer–Schuster reaction may compete with the oxy‐Cope rearrangement. Gold‐based catalytic systems can promote either reaction selectively. In the present system, the mononuclear gold complex [Au(IPr)Cl], in combination with the silver salt AgSbF₆ in 100:1 butan‐2‐one/H₂O, proved to efficiently promote the Meyer–Schuster rearrangement of propargylic benzoates, whereas the digold catalyst [{Au(IPr)}₂(μ‐OH)][BF₄] in anhydrous dichloromethane selectively promoted the oxy‐Cope rearrangement of propargylic alcohols.     

Precursor of a β‐lactamase inhibitor: allyl (4S,8S,9R)‐10‐[(E)‐ethyl­idene]‐4‐methoxy‐11‐oxo‐1‐aza­tri­cyclo­[7.2.0.03,8]­undec‐2‐ene‐2‐carboxyl­ate

The molecular structure of the title tricyclic compound, C₁₇H₂₁NO₄, which is the immediate precursor of a potent synthetic inhibitor {Lek157: sodium (8S,9R)‐10‐[(E)‐ethyl­idene]‐4‐methoxy‐11‐oxo‐1‐aza­tri­cyclo­[7.2.0.0^3,8]­undec‐2‐ene‐2‐carboxyl­ate} with remarkable potency, provides experimental evidence for the previously modelled relative position of the fused cyclo­hexyl ring and the carbonyl group of the β‐lactam ring, which takes part in the formation of the initial tetrahedral acyl–enzyme complex. In this hydro­phobic mol­ecule, the overall geometry is influenced by C—H?O intramolecular hydrogen bonds [3.046 (4) and 3.538 (6) Å, with corresponding normalized H?O distances of 2.30 and 2.46 Å], whereas the mol­ecules are interconnected through intermolecular C—H?O hydrogen bonds [3.335 (4)–3.575 (5) Å].     

Me‐BIPAM for the Synthesis of Optically Active 3‐Aryl‐3‐hydroxy‐2‐oxindoles by Ruthenium‐catalyzed Addition of Arylboronic Acids to Isatins

A chiral O‐linked C₂‐symmetric bidentate phosphoramidite (Me‐BIPAM) was found to be efficient for the ruthenium‐catalyzed addition of arylboronic acids to isatins. Asymmetric synthesis of 3‐aryl‐3‐hydroxy‐2‐oxindoles by 1,2‐addition of arylboronic acids to isatins was carried out in the presence of [RuCl₂(PPh₃)₃]/(R,R)‐Me‐BIPAM and KF, resulting in an enantioselectivity as high as 90 % ee. It was found that the reaction with N‐protected isatins proceeds with high yields and good enantioselectivities. The best protective groups on the nitrogen atom were different depending on the substituents on the aromatic ring. The use of a N‐benzyl group resulted in excellent enantioselectivities in many substrates compared with other groups.     

Regioisomeric 4‐nitroindazole N1‐ and N2‐(β‐d‐ribonucleosides)

The structures of the isomeric nucleosides 4‐nitro‐1‐(β‐d ‐ribo­furan­osyl)‐1H‐indazole, C₁₂H₁₃N₃O₆, (I), and 4‐nitro‐2‐(β‐d ‐ribo­furan­osyl)‐2H‐indazole, C₁₂H₁₃N₃O₆, (II), have been determined. For compound (I), the conformation of the gly­cosylic bond is anti [χ = −93.6 (6)°] and the sugar puckering is C2′‐exo–C3′‐endo. Compound (II) shows two conformations in the crystalline state which differ mainly in the sugar pucker; type 1 adopts the C2′‐endo–C3′‐exo sugar puckering associated with a syn base orientation [χ = 43.7 (6)°] and type 2 shows C2′‐exo–C3′‐endo sugar puckering accompanied by a somewhat different syn base orientation [χ = 13.8 (6)°].     

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).