Non‐iterative Asymmetric Synthesis of C15 Polyketide Spiroketals

The 2,2′‐methylenebis[furan] ( 1 ) was converted to 1‐{(4R,6S))‐6‐[(2R)‐2,4‐dihydroxybutyl]‐2,2‐dimethyl‐1,3‐dioxan‐4‐yl}‐3‐[(2R,4R)‐tetrahydro‐4,6‐dihydroxy‐2H‐pyran‐2‐yl)propan‐2‐one ((+)‐ 18 ) and its (4S)‐epimer (?)‐ 19 with high stereo‐ and enantioselectivity (Schemes 1–3). Under acidic methanolysis, (+)‐ 18 yielded a single spiroketal, (3R)‐4‐{(1R,3S,4′R,5R,6′S,7R)‐3′,4′,5′,6′‐tetrahydro‐4′‐hydroxy‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐6′‐yl}butane‐1,3‐diol ((?)‐ 20 ), in which both O‐atoms at the spiro center reside in equatorial positions, this being due to the tricyclic nature of (?)‐ 20 (methyl pyranoside formation). Compound (?)‐ 19 was converted similarly into the (4′S)‐epimeric tricyclic spiroketal (?)‐ 21 that also adopts a similar (3S)‐configuration and conformation. Spiroketals (?)‐ 20 , (?)‐ 21 and analog (?)‐ 23 , i.e., (1R,3S,4′R,5R,6′R)‐3′,4′,5′,6′‐tetrahydro‐6′‐[(2S)‐2‐hydroxybut‐3‐enyl]‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐4′‐ol, derived from (?)‐ 20 , were assayed for their cytotoxicity toward murine P388 lymphocytic leukemia and six human cancer cell lines. Only racemic (±)‐ 21 showed evidence of cancer‐cell‐growth inhibition (P388, ED₅₀: 6.9 μg/ml).     

Total Synthesis of (−)‐Daphenylline

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (?)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO₄)₂‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (?)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.     

Catalyzed Asymmetric Diels?Alder Reactions of Benzoquinone. Total Synthesis of (−)‐Ibogamine

The Diels? Alder reaction of 1,4‐benzoquinone with 1,3‐dienes catalyzed by Mikami's [Ti{(S)‐binol(2?)}Cl₂] complex (binol=[1,1′‐binaphthalene]‐2,2′‐diol) gives cycloadducts in good yield and in high enantiomer excess. A model is proposed to explain the observed absolute configuration of cycloadducts, and the reaction is used as the key step in an asymmetric synthesis leading to the alkaloid (?)‐ibogamine.     

Concise Syntheses of bis‐Strychnos Alkaloids (−)‐Sungucine, (−)‐Isosungucine,and (−)‐Strychnogucine B from (−)‐Strychnine

The first chemical syntheses of complex, bis‐Strychnos alkaloids (?)‐sungucine ( 1 ), (?)‐isosungucine ( 2 ), and (?)‐strychnogucine B ( 3 ) from (?)‐strychnine ( 4 ) is reported. Key steps included (1) the Polonovski–Potier activation of strychnine N‐oxide; (2) a biomimetic Mannich coupling to forge the signature C23?C5′ bond that joins two monoterpene indole monomers; and (3) a sequential HBr/NaBH₃CN‐mediated reduction to fashion the ethylidene moieties in 1 – 3 . DFT calculations were employed to rationalize the regiochemical course of reactions involving strychnine congeners.     

Divergent Total Syntheses of (−)‐Daphnilongeranin B and (−)‐Daphenylline

(?)‐Daphnilongeranin B and (?)‐daphenylline are two hexacyclic Daphniphyllum alkaloids, each containing a complex cagelike backbone. Described herein are the first asymmetric total synthesis of (?)‐daphnilongeranin B and a bioinspired synthesis of (?)‐daphenylline with an unusual E ring embedded in a cagelike framework. The key features include an intermolecular [3+2] cycloaddition, a late‐stage aldol cyclization to install the F ring of daphnilongeranin B, and a bioinspired cationic rearrangement leading to the tetrasubstituted benzene ring of daphenylline.     

Enantioselective Synthesis of 3- Azabicyclo[4.3.0]nonane Alkaloids

The stereospecific synthesis of the monoterpene alkaloids (?)-α-skytanthine ((?)- 2 ), (?)-N -demethyle-δ-sky-tanthine((?)- 7 ), and (+)-epidihydrotecomanine (+)- 4 was achieved from a common intermediate 22 , which in turn was obtained from (1R,4S,1′S)-2-(1′-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene (10) ,via a ketene aza-Claisen rearrangement. The piperidine derivative (+)- 31 , formally the aza-analogue of (+)-isoiridomyrmecin, was also obtained from the same intermediate 22 .     

Reactivity and stereoselectivity of oxazolopyridines with a ring‐junction nitrogen atom

The present study demonstrates a synopsis of the scientific researches reported on the different reactions of oxazolo[3,2‐a]pyridines, besides the preparation of significant fused heterocycles up till now. The different main sections that described the reactivity of the inspected analogues include stereoselective alkylation, reactions involved oxazolidine ring, synthesis of polycyclic systems, indole alkaloids, and alkyl amines. The stereochemical selectivity of oxazolopiperidone lactams is studied, in which the configuration of the stereocenter C8a and substituents at the C8 and C8a effect on the stereoselectivity. On the other hand, the synthetic consequence of the alkylation products provides diverse routes for the synthesis of substituted enantiopure piperidines that are used for the synthesis of natural products, for example, (?)‐rhazinilam, (+)‐eburnamonine, (+)‐aspidospermidine, indole alkaloids such as dihydrocleavamine, nor‐20‐epiuleine, (+)‐dasycarpidone, (+)‐uleine, indoloquinolizidine, (+)‐dihydrocorynantheine, (?)‐dihydrocorynantheol, and indolizines, eg, octahydroindolizines, monomorine I, (?)‐S‐coniceine, and (?)‐R‐coniceine.     

Concise and Enantioselective Total Synthesis of (−)‐Mehranine, (−)‐Methylenebismehranine,and Related Aspidosperma Alkaloids

We report an efficient and highly stereoselective strategy for the synthesis of Aspidosperma alkaloids based on the transannular cyclization of a chiral lactam precursor. Three new stereocenters are formed in this key step with excellent diastereoselectivity due to the conformational bias of the cyclization precursor, leading to a versatile pentacyclic intermediate. A subsequent stereoselective epoxidation followed by a mild formamide reduction enabled the first total synthesis of the Aspidosperma alkaloids (?)‐mehranine and (+)‐(6S,7S)‐dihydroxy‐N‐methylaspidospermidine. A late‐stage dimerization of (?)‐mehranine mediated by scandium trifluoromethanesulfonate completed the first total synthesis of (?)‐methylenebismehranine.     

The first example of the stereoselective synthesis and crystal structure of a spirobicycloquinazolinone based on (–)‐fenchone and anthranilamide

The possibility of a single‐stage solvent‐free stereoselective synthesis of a spirocyclic compound from the natural bicyclic monoterpenoid (?)‐fenchone and anthranilamide has been shown for the first time. The molecular and crystal structure of (1R,2S,4S)‐1,3,3‐trimethyl‐1′H‐spiro[bicyclo[2.2.1]heptane‐2,2′‐quinazolin]‐4′(3′H)‐one, C₁₇H₂₂N₂O, was established by X‐ray diffraction though the chirality was assumed via the known reactant connectivity and ¹H and ¹³C NMR spectroscopy. It has shown that in the molecule, for steric reasons, there is an elongation of the Me₂C—C(N)N bond to 1.603 (5) Å. The formation of dimers via N—H…O=C hydrogen bonds with an interaction energy of 93.30 kJ mol^?1 and through cavities (33.7% of the unit‐cell volume) was established in the packing of the molecules. There are no π‐stacking interactions in the structure.     

Total Syntheses and Biological Evaluation of Both Enantiomers of Several Hydroxylated Dimeric Nuphar Alkaloids

Herein, we describe the first total syntheses of five members of the dimeric nuphar alkaloids: (+)‐6,6′‐dihydroxythiobinupharidine (+)‐ 1 a , (+)‐6‐hydroxythiobinupharidine (+)‐ 1 b , (?)‐6,6′‐dihydroxythionuphlutine (?)‐ 2 a , (?)‐6,6′‐dihydroxyneothiobinupharidine (?)‐ 3 a , and (+)‐6,6′‐dihydroxyneothionuphlutine (+)‐ 4 a . The latter two have not been found in nature. We have also made each of their enantiomers (?)‐ 1 a – b , (+)‐ 2 a , (+)‐ 3 a , and (?)‐ 4 a . The key step in these syntheses was the dimerization of an α‐aminonitrile (a hydrolytically stable surrogate for its corresponding hemiaminal) with chiral Lewis acid complexes. We have also reassigned the literature structures of (+)‐ 1 a – 1 b —for those instances in which the NMR spectra were obtained in CD₃OD—to their corresponding CD₃O‐adducts. Our efforts provide for the first time apoptosis data for (?)‐ 3 a , (+)‐ 4 a , and all five non‐natural enantiomers prepared. The data indicate high apoptotic activity regardless of the enantiomer or relative stereochemical configuration at C7 and C7′.     

Redox Divergent Synthesis of Fawcettimine‐Type Lycopodium Alkaloids

A new approach for synthesis of fawcettimine‐type Lycopodium alkaloids is described. A divergent strategy was achieved by applying stereoselective Diels–Alder reaction followed by redox‐controlled elaboration. Eventually, (?)‐8‐deoxyserratinine, (+)‐fawcettimine, (?)‐lycopoclavamine‐A, (?)‐serratine, (?)‐lycopoclavamine‐B and (?)‐serratanidine were successfully accessed.     

Divergent Total Synthesis of the Tricyclic Marine Alkaloids Lepadiformine,Fasicularin, and Isomers of Polycitorols by Reagent‐Controlled Diastereoselective Reductive Amination

We describe a flexible and divergent route to the pyrrolo‐/pyrido[1,2‐j]quinoline frameworks of tricyclic marine alkaloids via a common intermediate formed by the ester–enolate Claisen rearrangement of a cyclic amino acid allylic ester. We have synthesized the proposed structure of polycitorols and demonstrated that the structure of these alkaloids requires revision. In addition to asymmetric formal syntheses, stereoselective and concise total syntheses of (?)‐lepadiformine and (?)‐fasicularin were also accomplished from simple, commercially available starting materials in a completely substrate‐controlled manner. The key step in these total syntheses was the reagent‐dependent stereoselective reductive amination of the common intermediate to yield either indolizidines 55 a or 55 b . Aziridinium‐mediated carbon homologation of the hindered C‐10 group to the homoallylic group facilitated the synthesis.     

Preparation and Absolute Configuration of (−)-(E)-α-trans-Bergamotenone

The synthesis, absolute configuration, and olfactive evaluation of (?)-(E)-α-trans-bergamotenone (= (?)-(1′S,6′R,E)-5-(2′,6′-dimethylbicyclo[3.1.1]hept-2′-en-6′-yl)pent-3-en-2-one; (?)- 1 ), as well as its homologue (?)- 19 are reperted. The previously arbitrarily attributed absolute configuration of 1 and of (?)-α-trans-bergamotene (= (?)-(1 S,6R)-2,6-dimethyl-6-(4-methylpent-3-enyl)bicyclo[3.1. 1]hept-2-ene; (?)- 2 ), together with those of the structurally related aldehydes (?)- 3a,b and alcohols (?)- 4a,b , have been rigorously assigned.     

Helical Poly(α,β‐unsaturated ketone) with Bulky Pendant of Binaphthyl from Anionic Polymerization of ((−)‐Menthyl (S)‐6′‐Acrylyl‐2′‐methyloxy‐1,1′‐binaphthalene‐2‐carboxylate

((?)‐Menthyl (S)‐6′‐acrylyl‐2′‐methyloxy‐1,1′‐binaphthalene‐2‐carboxylate ( 3 ) was synthesized and anionically polymerized using n‐BuLi as an initiator in toluene. The monomer 3 was levorotatory and had an [α]_D²⁵ value of ?72.4, but its corresponding polymer poly‐ 3 was dextrorotatory and showed an [α]_D²⁵ value of +162.0. Poly‐ 3 was confirmed to exist in the form of one‐handed helical structure in solution by means of comparing the specific optical rotation and the CD spectra with that of 3 and the model compounds such as (?)‐menthyl (S)‐6′‐propionyl‐2′‐methyloxy‐1,1′‐binaphthalene‐2‐carboxylate 2b and (?)‐menthyl (S)‐6′‐heptanoyl‐2′‐methyloxy‐1,1′‐binaphthalene‐2‐carboxylate 2c . This conclusion was also confirmed by the fact that the g‐value of poly‐ 3 is about 11 times of that of monomer 3 .     

Protecting‐Group‐Free Total Synthesis of Isoquinoline Alkaloids by Nickel‐Catalyzed Annulation of o‐Halobenzaldimine with an Alkyne as the Key Step

An efficient short total synthesis of benzo[c]phenanthridine alkaloids including oxyavicine, oxynitidine, and oxysanguinarine is described. Thus, N‐methyl‐o‐bromobenzaldimines 1 b – d undergo regioselective cyclization with 4‐(benzo[d][1,3]dioxol‐5‐yl)but‐3‐yn‐1‐ol ( 2 b ) in the presence of [Ni(cod)₂] (cod=1,5‐cyclooctadiene). In situ oxidation of the resultant isoquinolinium salts gives isoquinolinone derivatives 5 b – d with benzo[d][1,3]dioxol‐5‐yl substitution at the C₃ atom and a (CH₂)₂OH group at the C₄ atom. Later, oxidation of the alcohol group in 5 b – d to the aldehyde moiety followed by acid‐catalyzed cyclization and dehydration completes the total syntheses to give oxyavicine, oxynitidine, and oxysanguinarine in 67, 65, and 60 % yields, respectively. The synthesis requires four steps from o‐bromobenzaldehyde derivatives. Transformations of these alkaloids to the other alkaloids in this family are also discussed herein.     

Palladium‐Catalyzed Enantioselective Desymmetrizing Aza‐Wacker Reaction: Development and Application to the Total Synthesis of (−)‐Mesembrane and (+)‐Crinane

Reported is an unprecedented catalytic enantioselective desymmetrizing aza‐Wacker reaction. In the presence of a catalytic amount of a newly developed Pd(CPA)₂(MeCN)₂ catalyst (CPA=chiral phosphoric acid), a pyrox ligand, and molecular oxygen, cyclization of properly functionalized prochiral 3,3‐disubstituted cyclohexa‐1,4‐dienes afforded enantioenriched cis‐3a‐substituted tetrahydroindoles in good yields with excellent enantioselectivities. A cooperative effect between the phosphoric acid and the pyrox ligand ensured efficient transformation. This reaction was tailor‐made for Amaryllidaceae and Sceletium alkaloids as illustrated by its application in the development of the concise and divergent total synthesis of (?)‐mesembrane and (+)‐crinane.     

Accelerated iterative strategy for the divergent synthesis of dendritic macromolecules using a combination of living radical polymerization and an irreversible terminator multifunctional initiator

Our laboratory has reported the elaboration of an iterative strategy for the synthesis of dendritic macromolecules from conventional monomers. This synthetic method involves a combination of self‐regulated metal‐catalyzed living radical polymerization initiated from arenesulfonyl chlorides and an irreversible terminator multifunctional initiator (TERMINI). The previous TERMINI, (1,1‐dimethylethyl)[[1‐[3,5‐bis(S‐phenyl‐4‐N,N′ diethylthiocarbamate)phenyl]ethenyl]oxy]dimethylsilane, was prepared in nine reaction steps. The replacement of the previous TERMINI with one that requires only three steps for its synthesis, diethylthiocarbamic acid S‐{3‐[1‐(tert‐butyl‐dimethyl‐silanyloxy)‐vinyl]‐5‐diethylcarbamoylsulfanyl‐phenyl} ester, and the use of the more reactive Cu₂S/2,2′‐bipyridine rather than the Cu₂O/2,2′‐bipyridine self‐regulated catalyst have generated an accelerated method for the synthesis of dendritic macromolecules. This method provides rational design strategies for the synthesis of dendritic macromolecules with different compaction by the use of a single monomer. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 4894–4906, 2005     

A Solid State Polymer‐Coated Electrode Containing a Chiral Crown Ether Derivative for Enantioselective Detection of Phenylglycine Methyl Ester Isomer

All solid‐state enantioselective electrode (ASESE) based on a newly synthesized chiral crown ether derivative ((R)‐(?)‐(3,3′‐diphenyl‐1,1′‐binaphthyl)‐23‐crown‐6 incorporating 1,4‐dimethoxybenzene) was prepared and characterized by potentiometry. The ASESE clearly showed enantiomer discrimination for methyl esters of alanine, leucine, valine, phenylalanine, and phenylglycine, where the enantioselectivity for phenylglycine methyl ester was the highest (K_R,S=8.5±7.1%). Experimental parameters of ASESE for the analysis of (R)‐(?)‐phenylglycine methyl ester were optimized. The optimized ASESE showed a slope of 55.3±0.2 mV/dec for (R)‐(?)‐phenylglycine methyl ester in the concentration range of 1.0×10^?5–1.0×10^?2 M and the detection limit was 9.0×10^?6 M. The ASESE showed good selectivity for (R)‐(?)‐phenylglycine methyl ester against inorganic cations and various amino acid methyl esters. The concentration of (R)‐(?)‐phenylglycine methyl ester was determined in the mixture of (R)‐(?) and (S)‐(+)‐phenylglycine methyl ester, which ratios varied from 2 : 1 to 1 : 9. The lifespan of the electrode was alleged to be 30 days.     

The Cobalt Way to Angucyclinones: Asymmetric Total Synthesis of the Antibiotics (+)‐Rubiginone B2, (−)‐Tetrangomycin,and (−)‐8‐O‐Methyltetrangomycin

A cobalt(I)‐mediated convergent and asymmetric total synthesis of angucyclinones with an aromatic B ring has been developed. In the course of our research, we synthesized three naturally occurring anguclinone derivatives, namely, (+)‐rubiginone B₂ ( 1 ), (?)‐8‐O‐methyltetrangomycin ( 2 ), and (?)‐tetrangomycin ( 3 ). By combining 3‐hydroxybenzoic acid, 3‐methoxybenzoic acid, citronellal, and geraniol as starting materials in a convergent way, we were able to synthesize chiral triyne chains, which were cyclized with [CpCo(C₂H₄)₂] (Cp=cyclopentadienyl) by means of an intramolecular [2+2+2] cycloaddition to their corresponding tetrahydrobenzo[a]anthracenes. Successive oxidation and deprotection steps led to the above‐mentioned natural products 1 – 3 .     

Preparation of C3‐Symmetric Homochiral syn‐Trisnorbornabenzenes through Regioselective Cyclotrimerization of Enantiopure Iodonorbornenes

C₃‐symmetric homochiral (?)‐syn‐trisoxonorbornabenzene 1 possessing a rigid cup‐shaped structure was synthesized through a novel regioselective cyclotrimerization of enantiopure iodonorbornenes catalyzed by palladium nanoclusters. The yield of the cyclotrimerization was dependent on the stability of the palladium clusters, which was ascertained from the appearance and TEM images of the reaction mixtures. The efficient preparation of (?)‐syn‐ 1 was established in short steps, including the newly developed cyclotrimerization reaction. The thus‐prepared homochiral (?)‐syn‐ 1 can serve as a key intermediate for the synthesis of C₃‐symmetric homochiral cup‐shaped molecules with a helical arrangement of substituents. Introduction of several types of substituents was well demonstrated through palladium‐catalyzed coupling reactions with the corresponding phosphate and triflate of (?)‐syn‐ 1 .