Syntheses of Enantiomerically Pure 2‐Substituted Pyrrolidin‐3‐ones via Lithiated Alkoxyallenes – An Auxiliary‐Based Synthesis of both Enantiomers of the Antibiotic Anisomycin

The hydrochlorides of both enantiomers of the antibiotic anisomycin were prepared starting with the ‘diacetone‐fructose’‐substituted allene 1 and the N‐Boc‐protected imine precursor 2a . Addition of an excess of lithiated 1 to 2a provided a 2 : 1 mixture 3a of diastereoisomers, which were cyclized to 4a under base promotion (Scheme 2). The two diastereoisomers of 4a were separated and converted into enantiomerically pure pyrrolidin‐3‐ones (2R)‐ 5a and (2S)‐ 5a . A similar sequence yielded the N‐Tos‐protected compounds (2R)‐ 5b and (2S)‐ 5b . Compounds 5a were converted into silyl enol ethers 6 and by subsequent regio‐ and stereoselective hydroboration into pyrrolidine derivatives 7 (Scheme 3). Straightforward functional‐group transformations led to the hydrochlorides 9 of anisomycin (Scheme 3). The (2R) series provided the hydrochloride (2R)‐ 9 of the natural occurring enantiomer, whereas the (2S) series furnished the antipode (2S)‐ 9 . The overall sequence to the natural product involved ten steps with eight purified intermediates and afforded an overall yield of 8%. Our stereochemically divergent approach to this type of hydroxylated pyrrolidines is highly flexible and should easily allow preparation of many analogues.     

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 of the 2‐Alkenyl‐4‐alkylidenebut‐2‐eno‐4‐lactone (=α‐Alkenyl‐γ‐alkylidenebutenolide) Core Structure of the Carotenoid Pyrrhoxanthin via the Regioselective Dihydroxylation of Hepta‐2,4‐diene‐5‐ynoic Acid Esters

A new strategy for the stereoselective synthesis of 4‐alkylidenebut‐2‐eno‐4‐lactones (=γ‐alkylidenebutenolides) with (Z)‐configuration of the exocyclic CC bond at C(4) was developed. It is exemplified by the synthesis of 4‐alkylidenebutenolactone 31 (Scheme 4), which constitutes a substructure of the carotenoids pyrrhoxanthin ( 1 ) and peridinin. The formation of the precursor 4‐(1‐hydroxyalkyl)butenolactone 29 was accomplished either by cyclocarbonylation of the prop‐2‐yn‐1‐ol moiety of 27 (→ 29 ) or by hydrostannylation of the isopropylidene‐protected alkynoic acid ester 26 (→ 28 ) followed by transacetalization/transesterification (→ 30 ). The 4‐alkylidenebutenolactone was formed by the anti‐selective Mitsunobu dehydration 29 → 31 .     

7‐Halogenated 7‐Deazapurine 2′‐Deoxyribonucleosides Related to 2′‐Deoxyadenosine, 2′‐Deoxyxanthosine,and 2′‐Deoxyisoguanosine: Syntheses and Properties

A series of 7‐fluorinated 7‐deazapurine 2′‐deoxyribonucleosides related to 2′‐deoxyadenosine, 2′‐deoxyxanthosine, and 2′‐deoxyisoguanosine as well as intermediates 4b – 7b, 8, 9b, 10b , and 17b were synthesized. The 7‐fluoro substituent was introduced in 2,6‐dichloro‐7‐deaza‐9H‐purine ( 11a ) with Selectfluor (Scheme 1). Apart from 2,6‐dichloro‐7‐fluoro‐7‐deaza‐9H‐purine ( 11b ), the 7‐chloro compound 11c was formed as by‐product. The mixture 11b / 11c was used for the glycosylation reaction; the separation of the 7‐fluoro from the 7‐chloro compound was performed on the level of the unprotected nucleosides. Other halogen substituents were introduced with N‐halogenosuccinimides ( 11a → 11c – 11e ). Nucleobase‐anion glycosylation afforded the nucleoside intermediates 13a – 13e (Scheme 2). The 7‐fluoro‐ and the 7‐chloro‐7‐deaza‐2′‐deoxyxanthosines, 5b and 5c , respectively, were obtained from the corresponding MeO compounds 17b and 17c , or 18 (Scheme 6). The 2′‐deoxyisoguanosine derivative 4b was prepared from 2‐chloro‐7‐fluoro‐7‐deaza‐2′‐deoxyadenosine 6b via a photochemically induced nucleophilic displacement reaction (Scheme 5). The pK_a values of the halogenated nucleosides were determined (Table 3). ¹³C‐NMR Chemical‐shift dependencies of C(7), C(5), and C(8) were related to the electronegativity of the 7‐halogen substituents (Fig. 3). In aqueous solution, 7‐halogenated 2′‐deoxyribonucleosides show an approximately 70% S population (Fig. 2 and Table 1).     

A New Method for the Construction of Macrolides Stereoselective Synthesis of (±)-Phoracantholide J. Preliminary communication

Starting from 5-chloro-2-pentanone ( 1 ) the naturally occurring 10-membered lactone phoracantholide J ( 8a ) has been synthesized as its racemate in a sequence of six steps (Scheme 2). Salient features of the syntheis include an internal selenium assisted acetal formation ( 4→5 ) and a stereoselective Claisen rearrangement ( 6→7→8 ). This general synthetic strategy offers an alternative approach towards the construction of macrocyclic lactones.     

Toward the Synthesis of Modified Carbohydrates by Conjugate Addition of Propane‐1,3‐dithiol to α,β‐Unsaturated Ketones

Selected 5‐substituted derivatives 4 of 1,1‐diethoxy‐5‐hydroxypent‐3‐yn‐2‐one were treated with propane‐1,3‐dithiol under various conditions. The unprotected hydroxy ketones underwent cyclization during the dithiol addition and gave the corresponding 3‐(diethoxymethyl)‐2‐oxa‐6,10‐dithiaspiro[4.5]decan‐3‐ols 5 in 80–90% yield as the only products (Scheme 3 and Table 1). These products can be regarded as partly modified carbohydrates in the furanose form. When the benzyl‐protected analogues 10‐Bn of the 1,1‐diethoxy‐5‐hydroxypent‐3‐yn‐2‐one derivatives were treated with the same dithiol, however, no cyclization occurred; instead the corresponding 3‐{2‐[(benzyloxy)methyl]‐1,3‐dithian‐2‐yl}‐1,1‐diethoxypropan‐2‐one derivatives 11‐Bn were formed in good yield (up to 99%; Table 4). These 1,3‐dithianes were and are in the process of being converted to a number of new carbohydrate analogues, and here are reported high‐yield syntheses of functionalized molecules 17 belonging to the 5,5‐diethoxy‐1,4‐dihydroxypentan‐2‐one family of compounds (Table 7), via 15‐Bn (Table 5) and 16‐Bn (Table 6 and Scheme 8).     

Synthesis and Reactions of 2‐[1‐Methyl‐1‐(pyrrolidin‐2‐yl)ethyl]‐1H‐pyrrole and Some Derivatives with Aldehydes: Chiral Structures Combining a Secondary‐Amine Group with an 1H‐Pyrrole Moiety as Excellent H‐Bond Donor

The synthesis of compound 2 and its derivatives 6 and 8 combining a pyrrolidine ring with an 1H‐pyrrole unit is described (Scheme 2). Their attempted usability as organocatalysts was not successful. Reacting these simple pyrrolidine derivatives with cinnamaldehyde led to the tricyclic products 3b, 9b , and 10b first (Scheme 1, Fig. 2). The final, major products were the pyrrolo‐indolizidine tricycles 3a, 9a , and 10a obtained via the iminium ion reacting intramolecularly with the nucleophilic β‐position of the 1H‐pyrrole moiety (cf. Scheme 1).     

Synthesis of Derivatives of the Optically Active β‐Amino Acids from (+)‐Car‐2‐ene

The reaction of (+)‐car‐2‐ene ( 4 ) with chlorosulfonyl isocyanate (=sulfuryl chloride isocyanate; ClSO₂NCO) led to the tricyclic lactams 6 and 8 corresponding to the initial formation both of the tertiary carbenium and α‐cyclopropylcarbenium ions (Scheme 2). A number of optically active derivatives of β‐amino acids which are promising compounds for further use in asymmetric synthesis were synthesized from the lactams (see 16, 17 , and 19 – 21 in Scheme 3).     

Stereoselective Total Synthesis of (11β)‐11‐Methoxycurvularin

A simple and highly efficient stereoselective total synthesis of (11β)‐11‐methoxycurvularin ( 5 ), a polyketide natural product, was achieved. The synthesis commenced with a Cu‐mediated regioselective opening of (2S)‐2‐methyloxirane ( 6 ) and comprised a Keck asymmetric allylation and intramolecular Friedel–Crafts acylation as key steps (Scheme 2).     

Divergent Synthesis of 3‐Deoxy‐d‐manno‐oct‐2‐ulosonic Acid (Kdo) Glycosides Containing α‐(2→4)‐Linked Kdo‐Kdo Unit

A convenient and divergent approach was developed to prepare diverse bacterial 3‐deoxy‐d ‐manno‐oct‐2‐ulosonic acid (Kdo) oligosaccharides containing a Kdo‐α‐(2→4)‐Kdo fragment. The orthogonal protected α‐(2→4) linked Kdo‐Kdo disaccharide 3 , serving as a common precursor, was divergently transformed into the corresponding 8‐, 8′‐, and 4′‐hydroxy disaccharides 5 , 7 , and 14 , respectively. Then, these alcohols were glycosylated, respectively, with the 5,7‐O‐di‐tert‐butylsilylene (DTBS) protected Kdo thioglycoside donors 1 or 2 in an α‐stereoselective and high‐yielding manner to afford a range of Kdo oligosaccharides. Finally, removal of all protecting groups of the newly formed glycosides resulted in the desired free Kdo oligomer.     

Synthesis of (2′S)‐2′‐Deoxy‐2′‐C‐methylpurine Nucleosides and Their Phosphoramidites

We describe the stereoselective synthesis of (2′S)‐2′‐deoxy‐2′‐C‐methyladenosine ( 12 ) and (2′S)‐2′‐deoxy‐2′‐C‐methylinosine ( 14 ) as well as their corresponding cyanoethyl phosphoramidites 16 and 19 from 6‐O‐(2,6‐dichlorophenyl)inosine as starting material. The methyl group at the 2′‐position was introduced via a Wittig reaction (→ 3 , Scheme 1) followed by a stereoselective oxidation with OsO₄ (→ 4 , Scheme 2). The primary‐alcohol moiety of 4 was tosylated (→ 5 ) and regioselectively reduced with NaBH₄ (→ 6 ). Subsequent reduction of the 2′‐alcohol moiety with Bu₃SnH yielded stereoselectively the corresponding (2′S)‐2′‐deoxy‐2′‐C‐methylnucleoside (→ 8a ).     

Synthesis and Reactivity of π‐Electron‐Deficient (Arylsulfonyl)acetates

Different π‐electron‐deficient (arylsulfonyl)acetates 9 were synthesized (Scheme 1, Table 1), and their behavior as soft nucleophiles in the dialkylation reaction under phase‐transfer catalysis conditions was studied (Schemes 2 and 3, Tables 2 and 3). The [3,5‐bis(trifluoromethyl)phenyl]sulfonyl group was shown to be the best substituent for the stereoselective synthesis of (E)‐aconitates 18 via an alkylation hydro‐sulfonyl‐elimination integrated process under very mild phase‐transfer‐catalysis conditions (Scheme 5, Table 4). Sulfonylacetates 9h , i also underwent smooth Diels‐Alder reactions with acyclic and cyclic dienes via in situ formation of the appropriate dienophile through a Knoevenagel condensation with paraformaldehyde (Scheme 6). Reductive desulfonylation with Zn and NH₄Cl in THF was shown to be an efficient method for removal of the synthetically useful sulfonyl moiety (Scheme 7).     

Regioselective Synthesis of the 5,6‐Dihydro‐4H‐furo[2,3‐c]pyrrol‐4‐one Skeleton: A New Class of Compounds

We hereby report the first preparation of the 5,6‐dihydro‐4H‐furo[2,3‐c]pyrrol‐4‐one ( 3 ) and its derivatives starting from methyl 3‐(methoxycarbonyl)furan‐2‐acetate ( 8 ). The ester functionality connected to the methylene group was regiospecifically converted to the desired monohydrazide 9 . Conversion of 9 into the acyl azide 10 followed by Curtius rearrangement gave the corresponding isocyanate derivative 11 (Scheme 2). Reaction of 11 with different nucleophiles produced urethane and urea derivatives (Scheme 3). Intramolecular cyclization reactions provided the target compounds (Scheme 5). Removal of the amine‐protecting group formed the title compound 3 .     

Isocyanide‐Based Three‐Component Synthesis of Highly Substituted 1,6‐Dihydro‐6,6‐dimethylpyrazine‐2,3‐dicarbonitrile, 3,4‐Dihydrobenzo[g]quinoxalin‐2‐amine,and 3,4‐Dihydro‐3,3‐dimethyl‐quinoxalin‐2‐amine Derivatives

A novel and efficient isocyanide‐based multicomponent reaction between alkyl or aryl isocyanides 1 , 2,3‐diaminomaleonitrile ( 2 ), naphthalene‐2,3‐diamines ( 6 ) or benzene‐1,2‐diamine ( 9 ), and 3‐oxopentanedioic acid ( 3 ) or Meldrum's acid ( 4 ) or ketones 7 was developed for the ecologic synthesis, at room temperature under mild conditions, of 1,6‐dihydropyrazine‐2,3‐dicarbonitriles 5a – 5f in H₂O without using any catalyst, and of 3,4‐dihydrobenzo[g]quinoxalin‐2‐amine and 3,4‐dihydro‐3,3‐dimethyl‐quinoxalin‐2‐amine derivatives 8a – 8g and 10a – 10e , respectively, in the presence of a catalytic amount of p‐toluenesulfonic acid (TsOH) in EtOH, in good to excellent yields (Scheme 1).     

Low‐Temperature Olefin Syntheses in View of Parent Fulvenes and Fulvalenes

Parent fulvenes and fulvalenes are thermally unstable cross‐conjugated olefins for which low‐temperature syntheses are indispensable. In this review 5 syntheses (in the temperature range between ?100 and ?10°) are discussed: 1. Reaction of sodium cyclopentadienide with 1‐acetoxy‐1‐chloroalkanes or 1‐acetoxy‐1‐bromoalkanes ( 26 ) gives acetoxy‐alkyl‐cyclopentadienes ( 27 ) which are easily converted to pentafulvenes ( 2 ) by low‐temperature HOAc‐elimination with NEt₃. This synthesis has been applied to parent pentafulvene ( 2a ), heptafulvene ( 3a ), nonafulvene ( 4a ) and sesquifulvalene ( 19a ) (Schemes 8–11). 2. Based on a nearly quantitative oxidative coupling of cyclononatetraenide ( 8 ) to give dihydrononafulvalene ( 38 ) (Scheme 10), a general synthetic plan for fulvalenes has been outlined (Scheme 11) and applied to the synthesis of pentafulvalene ( 12 ), nonapentafulvalene ( 16 ) and nonafulvalene ( 14 ). Several applications of oxidative couplings of Hückel anions are discussed (Schemes 20 and 21). 3. Trifunctional cyclopropanes 67 (in most cases 1,1‐dibromo‐2‐X‐cyclopropanes) are attractive precursors of parent triafulvene ( 1a ) and calicene ( 17 ) (Scheme 18). Contrary to classical procedures they are transformed into nucleophiles ( 67 → 68 ) by halogen‐lithium exchange, methylation ( 68 → 69 ) and HBr‐elimination to give 1‐methylidene‐2‐X‐cyclopropanes of type 71 . By subsequent HX‐elimination triafulvene ( 1a ) has been synthesized and trapped as a [4+2]‐cycloadduct 73 (Scheme 20). Furthermore, calicene precursors 77 are available by using cyclopentenone as an electrophilic cyclopentadiene equivalent. 4. Similarly, 1‐lithio‐1‐bromo‐2‐X‐cyclopropanes 68 are directly transformed into triafulvalene precursors 81 (Scheme 26) by a novel CuCl₂‐catalyzed oxidative coupling. 5. In view of the synthesis of parent triafulvene ( 1a ), triafulvalene ( 11 ) and calicene ( 17 ), retro‐Diels? Alder reactions of stable precursors – prepared by low‐temperature reactions (described in chapters 3 and 4 ) – have been explored.     

Process‐Scale Total Synthesis of Nature‐Identical (−)‐(S,S)‐7‐Hydroxycalamenal in High Enantiomeric Purity through Catalytic Enantioselective Hydrogenation

A process‐scale stereoselective synthesis of nature‐identical (−)‐(S,S)‐7‐hydroxycalamenal (=(−)‐(5S,8S)‐5,6,7,8‐tetrahydro‐3‐hydroxy‐5‐methyl‐8‐(1‐methylethyl)naphthalene‐2‐carbaldehyde; (−)‐ 1a ) in 96% enantiomeric excess (ee) with the aid of chiral Ru complexes has been developed. The key step was the enantioselective hydrogenation of easily accessible 2‐(4‐methoxyphenyl)‐3‐methylbut‐2‐enoic acid ( 10 ) to (+)‐ 11 in a 86% ee (Scheme 5 and Table 1). A substantial increase in optical purity (96% ee) was achieved by induced crystallization of the intermediate (+)‐3,4‐dihydro‐4‐(1‐methylethyl)‐7‐methoxy‐2H‐naphthalen‐1‐one ((+)‐ 3 ). Computational conformation analysis carried out on the analog (−)‐ 9 rationalized the high diastereoselectivity achieved in the catalytic hydrogenation of the CC bond.     

Total Synthesis of Leiocarpin C and (+)‐Goniodiol via an Olefin Cross‐Metathesis Protocol

A stereoselective total synthesis of leiocarpin C ( 2 ) and (+)‐Goniodiol ( 1 ) by applying olefin cross‐metathesis and substrate directed dihydroxylation as the key steps is reported (Scheme 3).     

Stereoselective Total Synthesis of the Natural Oxylipin (6R,7E,9R,10S)‐6,9,10‐Trihydroxyoctadec‐7‐enoic Acid

The stereoselective total synthesis of the natural oxylipin, (6R,7E,9R,10S)‐6,9,10‐trihydroxyoctadec‐7‐enoic acid, has been accomplished using nonanal and hexane‐1,6‐diol as the starting materials. The synthesis involves Sharpless kinetic resolution, asymmetric epoxidation, and olefin cross‐metathesis as the key steps.     

The Total Synthesis of (±)-Isocomene by an Intramolecular Ene Reaction. Preliminary communication

The racemic sesquiterpene isocomene ( 1 ) has been synthesized starting from 1,7-octadien-3-one ( 2 ) in a stereoselective manner (Scheme 2). In the key step 4 → 5 the C(7), C(8)-bond was formed by an intramolecular thermal ene reaction. Further elaboration of 5 involved the ring contraction 6 → 7 , the elimination 8 → 9 and the final olefin isomerization 9 → 1 .     

Modular Stereoselective Synthesis of (1→2)‐C‐Glycosides based on the sp2–sp3 Suzuki–Miyaura Reaction

This work reports a modular and rapid approach to the stereoselective synthesis of a variety of α‐ and β‐(1→2)‐linked C‐disaccharides. The key step is a Ni‐catalyzed cross‐coupling reaction of D ‐glucal pinacol boronate with alkyl halide glycoside easily prepared from commercially available D ‐glucal. The products of this sp²–sp³ cross‐coupling reaction can be converted to glucopyranosyl, mannopyranosyl, or 2‐deoxy‐glucopyranosyl C‐mannopyranosides by one‐ or two‐step stereoselective oxidative–reductive transformations. To the best of our knowledge, we demonstrated the first synthetic application of a challenging sp²–sp³ Suzuki‐Miyaura cross‐coupling reaction in carbohydrate chemistry.