Total Synthesis of Leucosceptroids A and B

Leucosceptroids A and B are sesterterpenoids with potent antifeedant and antifungal activities. A more efficient gram‐scale total synthesis of leucosceptroid B and the first total synthesis of leucosceptroid A are presented. The key transformations include an aldol reaction between a substituted dihydrofuranone and an (S)‐citronellal‐derived aldehyde, a SmI₂‐mediated intramolecular ketyl–olefin radical cyclization, and final‐stage alcohol oxidation.     

Total Synthesis of (−)‐Lundurine A and Determination of its Absolute Configuration

A 15‐step total synthesis of (?)‐lundurine A ( 1 ) from easily accessible (S)‐pyrrolidinone 18 is reported. A Simmons‐Smith reaction allows the efficient, simultaneous assembly of the cyclopropyl C ring, the six‐membered D ring, the seven‐membered E ring, and the quaternary carbon stereocenters at C2 and C7. The absolute configuration of natural (?)‐lundurine A was deduced to be 2R,7R,20R based on the stepwise construction of the stereocenters during the total synthesis.     

Synthetic Applications of the Baylis–Hillman Reaction: Simple and Convenient Synthesis of Five Important Insect Pheromones

A simple and convenient synthesis of five important insect pheromones by means of Baylis–Hillman adducts is described, i.e., of (2E,4S)‐2,4‐dimethylhex‐2‐enoic acid ( 1 ), a mandibular‐gland secretion of the male carpenter ant in the genus Camponotus, of (+)‐(S)‐manicone ( 2 ) and (+)‐(S)‐normanicone ( 3 ), two mandibular‐gland constituents of Manica ants, and of (+)‐dominicalure‐I ( 6 ) and (+)‐dominicalure‐II ( 7 ), two aggregation pheromones of the lesser grain borer Rhyzopertha dominica (F). For the first time, the potential of the Baylis–Hillman chemistry for the stereoselective synthesis of trisubstituted olefins was successfully applied to the synthesis of these pheromone compounds.     

Catalytic Asymmetric Total Synthesis of Leucinostatin A

This review describes our efforts toward achieving catalytic asymmetric total synthesis of leucinostatin A, a compound that interferes with the tumor‐stroma interaction. The synthesis utilizes four catalytic asymmetric reactions, including direct‐type reactions exemplified by high atom‐economy, and three C?C bond forming reactions. Thorough analysis of the NMR data, HPLC profiles, and biologic activity led us to unambiguously revise the absolute configuration regarding the 6‐position of the AHMOD residue side chain from S (reported) to R. Other examples of previously reported important studies on the stereoselective synthesis of HyLeu and AHMOD are also described.     

Enantioselective Syntheses of Lignin Models: An Efficient Synthesis of β‐O‐4 Dimers and Trimers by Using the Evans Chiral Auxiliary

We describe an efficient five‐step, enantioselective synthesis of (R,R)‐ and (S,S)‐lignin dimer models possessing a β‐O‐4 linkage, by using the Evans chiral aldol reaction as a key step. Mitsunobu inversion of the (R,R)‐ or (S,S)‐isomers generates the corresponding (R,S)‐ and (S,R)‐diastereomers. We further extend this approach to the enantioselective synthesis of a lignin trimer model. These lignin models are synthesized with excellent ee (>99 %) and high overall yields. The lignin dimer models can be scaled up to provide multigram quantities that are not attainable by using previous methodologies. These lignin models will be useful in degradation studies probing the selectivity of enzymatic, microbial, and chemical processes that deconstruct lignin.     

Synthesis of (‐)‐herbertenediol and (aR,aS)‐mastigophorenes A via asymmetric intramolecular heck coupling reaction

Total enantioselective synthesis of the natural (‐)‐Herbertenediol (1) was accomplished in eleven steps with an overall yield of 15% starting from the 2‐methoxy‐4‐methyl‐phenol. The total synthesis features asymmetric intramolecular Heck reaction and Wolff‐Kishner‐Huang reduction. (aR, aS)‐Mastigophorenes A was also synthesized through the oxidative coupling reaction.     

Total Synthesis of (+)‐Gracilamine Based on an Oxidative Phenolic Coupling Reaction and Determination of Its Absolute Configuration

The enantioselective total synthesis of (+)‐gracilamine ( 1 ) is described. The strategy features a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza‐Michael reaction to construct the ABCE ring system. The configuration at C3a in 1 was controlled by the stereocenter at C9a, which was selectively generated (91 % ee) by an organocatalytic enantioselective aza‐Friedel–Crafts reaction developed by our research group. This synthesis revealed that the absolute configuration of (+)‐gracilamine is 3aR, 4S, 5S, 6R, 7aS, 8R, 9aS.     

Toward the Total Synthesis of Onchidin,a Cytotoxic Cyclic Depsipeptide from a Mollusc

The total synthesis of onchidin ( 1 ), a cytotoxic, C₂‐symmetric cyclic decadepsipeptide from a marine mollusc, according to the published structure, is described. A novel β‐amino acid, (2S,3S)‐3‐amino‐2‐methyl‐7‐octynoic acid (AMO), was efficiently prepared in high yield with high diastereo‐ and enantioselectivity based on a catalytic asymmetric three‐component Mannich‐type reaction with a chiral zirconium catalyst. The formation of sterically unfavorable N‐methyl amide and hindered ester bonds were successfully demonstrated, and final macrocyclization was achieved at a secondary‐amide site. Completion of the synthesis of 1 suggested that a revision of the structure of the natural product is required. Two diastereomers were also synthesized as candidates for the actual structure of onchidin. Furthermore, efficient solid‐phase methods were employed for the combinatorial synthesis of other derivatives to clarify the real structure of onchidin. The solid‐phase assembly of a pentadepsipeptide containing all the building blocks was established followed by dimeric cyclization in solution.     

A Total Synthesis of a New Class of Biazine Thioglycosides

Abstract

A new method for the synthesis of bipyridinyl S‐glycosides 11 and 12 has provided the title compounds in a higher yield. Application of a one‐pot glycosylation methodology resulted in an efficient, high‐yield synthesis of biazine S‐glycosides 17–20 An X‐ray diffraction analysis of 11 disclosed the conformation of this glycoside as the S‐glycoside and not the corresponding N‐form.     

Asymmetric Synthesis of (R)-Fluoxetine: A Practical Approach Using Recyclable and in-situ Generated Oxazaborolidine Catalyst

A practical route for the synthesis of (R)-fluoxetine•HCl (ee＝96%) in 56% overall yield was described. The key intermediate (R)-3-chloro-1-phenyl-1-propanol was obtained by the asymmetric reduction of prochiral 3-chloropropiophenone using in-situ generated oxazaborolidine catalyst derived from (S)-α,α-diphenylprolinol. The chiral procatalyst (S)-α,α-diphenylprolinol was recovered quantitatively and recycled. An improved practical synthesis of (S)-α,α-diphenylprolinol was also discussed.     

A Stereoselective Aldol Approach for the Total Syntheses of Two 6‐Alkylated 2H‐Pyran‐2‐ones

A simple and highly efficient stereoselective total synthesis of the 6‐alkylated pyranones (6R)‐6‐[(1E,4R,6R)‐4,6‐dihydroxy‐10‐phenyldec‐1‐en‐1‐yl]‐5,6‐dihydro‐2H‐pyran‐2‐one ( 1 ) and (6S)‐5,6‐dihydro‐6‐[(2R)‐2‐hydroxy‐6‐phenylhexyl]‐2H‐pyran‐2‐one ( 2 ) was developed using Crimmins' aldol reaction, SmI₂ reduction, Grubbs‐II‐catalyzed olefin cross‐metathesis, and Still's modified Horner? Wadsworth? Emmons reaction.     

Synthesis of Glycoborine,Glybomine A and B,the Phytoalexin Carbalexin A and the β‐Adrenoreceptor Antagonists Carazolol and Carvedilol

We describe a regioselective synthesis of 4‐ or 5‐substituted carbazoles by oxidative cyclisation of meta‐oxygen‐substituted N‐phenylanilines. Using the regiodirecting effect of a pivaloyloxy group, we prepared 4‐hydroxycarbazole, a precursor for the enantiospecific synthesis of the β‐adrenoreceptor antagonists (?)‐(S)‐carazolol ( 5 ) and (?)‐(S)‐carvedilol ( 6 ). Regioselective palladium(II)‐catalysed cyclisation of different diarylamines led to total synthesis of glycoborine ( 7 ) and the first total syntheses of the phytoalexin carbalexin A ( 8 ), glybomine A ( 9 ) and glybomine B ( 10 ). For glybomine B ( 10 ), a 5‐hydroxycarbazole was converted into the corresponding triflate and utilized for introduction of a prenyl substituent.     

Olefin Cross‐Metathesis: Studies towards the Total Synthesis of (+)‐Bitungolide F

A stereoselective synthesis of (5S,6S)‐6‐[(2S,5S,7R,8E,10E)‐5‐(benzyloxy)‐7‐{[(tert‐butyl)dimethylsilyl]oxy}‐11‐phenylundeca‐8,10‐dien‐2‐yl]‐5‐ethyl‐5,6‐dihydro‐2H‐pyran‐2‐one (=(+)‐9‐O‐benzyl‐11‐O‐[(tert‐butyl)dimethylsilyl]bitungolide F) is reported. The strategy involves Gilman reaction, olefin cross‐metathesis, and Horner? Wadsworth? Emmons olefination as key steps.     

A Practical and Enantiospecific Synthesis of (−)‐(R)‐ and (+)‐(S)‐Piperidin‐3‐ols

A highly enantiospecific, azide‐free synthesis of (?)‐(R)‐ and (+)‐(S)‐piperidin‐3‐ol in excellent yield was developed. The key step of the synthesis involves the enantiospecific ring openings of enantiomerically pure (R)‐ and (S)‐2‐(oxiran‐2‐ylmethyl)‐1H‐isoindole‐1,3(2H)‐diones with the diethyl malonate anion and subsequent decarboxylation.     

Tandem IBX‐Promoted Primary Alcohol Oxidation/Opening of Intermediate β,γ‐Diolcarbonate Aldehydes to (E)‐γ‐Hydroxy‐α,β‐enals

A tandem IBX‐promoted oxidation of primary alcohol to aldehyde and opening of intermediate β,γ‐diolcarbonate aldehyde to (E)‐γ‐hydroxy‐α,β‐enal has been developed. Remarkably, the carbonate opening delivered exclusively (E)‐olefin and no over‐oxidation of γ‐hydroxy was observed. The method developed has been extended to complete the stereoselective total synthesis of both (S)‐ and (R)‐coriolides and d ‐xylo‐ and d ‐arabino‐C‐20 guggultetrols.     

An Efficient Stereoselective Approach for the Synthesis of (+)‐(4S,5S)‐Muricatacin

An efficient stereoselective total synthesis of (+)‐(4S,5S)‐muricatacin was accomplished in good yields from inexpensive, commercially available chemicals ((+)‐diethyl tartrate (DET) and undecan‐1‐ol) by utilizing Mitsunobu and Julia? Kocienski reactions, Wittig homologation, Swern oxidation, and lactonization.     

Synthesis of New C2‐Symmetric Chiral Bisamides from (1S,2S)‐Cyclohexane‐1,2‐dicarboxylic Acid

A series of new C₂‐symmetric (1S,2S)‐cyclohexane‐1,2‐dicarboxamides was synthesized from (1S,2S)‐cyclohexane‐1,2‐dicarbonyl dichloride and N‐benzyl‐substituted aromatic amines, which were prepared from 2‐aminopyridine, 2‐chloroaniline, and 2‐aminophenol via imine formation with benzaldehyde and subsequent reduction with NaBH₄. (1S,2S)‐N,N′‐Dibenzyl‐N,N′‐bis[2‐(benzyloxy)phenyl]cyclohexane‐1,2‐dicarboxamide was converted to (1S,2S)‐N,N′‐dibenzyl‐N,N′‐bis(2‐hydroxyphenyl)cyclohexane‐1,2‐dicarboxamide via hydrogenolysis in the presence of Pd(OH)₂ on active carbon powder.     

An Efficient Enantioselective Synthesis of Natural Gingerols,the Active Principles of Ginger

A straightforward synthesis of (S)‐gingerols 1 – 3 has been described. The requisite stereogenic center in the target molecules was introduced by Sharpless asymmetric dihydroxylation using a chiral complex, AD‐mix β. This route is simple and efficient to prepare the products in very good yields.     

Total Synthesis and Structure Elucidation of JBIR‐39: A Linear Hexapeptide Possessing Piperazic Acid and γ‐Hydroxypiperazic Acid Residues

The total synthesis and stereochemical structural elucidation of JBIR‐39, containing four nonproteinogenic piperazic acid (Piz) residues, is reported. The synthesis includes Sc(OTf)₃‐catalyzed acylation of a Piz(γ‐OTBS) derivative with piperazic acid chloride, providing the desired Piz‐Piz(γ‐OTBS) dipeptide in high yield without epimerization. After assembling two additional Piz moieties and (S)‐isoleucic acid at the N‐terminus, amidation with the (R)‐α‐methylserine ester at the C‐terminus, and deprotection afforded the desired (2R,8S)‐hexapeptide, which is the assumed structure of JBIR‐39. Although the spectral data of the (2R,8S)‐hexapeptide was not identical to JBIR‐39, further synthesis of three stereoisomers confirmed the stereochemical structure of JBIR‐39 to be (2S,6S,8S,11R,16S,21R,26S,27S).     

Asymmetric Proline‐Catalyzed Addition of Aldehydes to 3H‐Indol‐3‐ones: Enantioselective Synthesis of 2,3‐Dihydro‐1H‐indol‐3‐ones with Quaternary Stereogenic Centers

The proline‐catalyzed addition of various aliphatic aldehydes to sterically hindered 2‐aryl‐substituted 3H‐indol‐3‐ones affords 2,2‐disubstituted 2,3‐dihydro‐1H‐indol‐3‐one derivatives with excellent enantioselectivities. In addition, the synthesis of a chiral derivative, (S)‐2‐(2‐bromophenyl)‐2,3‐dihydro‐2‐(2‐hydroxyethyl)‐1H‐indol‐3‐one, which can be used as an intermediate for the preparation of the natural product hinckdentine A was accomplished with a high level of enantioselectivity.