Synthesis of Enantiomerically Pure Isoxazolidine Monomers for the Preparation of β3‐Oligopeptides by Iterative α‐Keto Acid?Hydroxylamine (KAHA) Ligations

A versatile method for the synthesis of enantiomerically pure isoxazolidine monomers for the synthesis of β³‐oligopeptides via α‐keto acid? hydroxylamine (KAHA) ligation is presented. This one‐pot synthetic method utilizes in situ generated nitrones bearing gulose‐derived chiral auxiliaries for the asymmetric 1,3‐dipolar cycloaddition with methyl 2‐methoxyacrylate. The resulting enantiomerically pure isoxazolidine monomers bearing diverse side chains (proteinogenic and non‐proteinogenic) can be synthesized in either configuration (like‐ and unlike‐configured). The scalable and enantioselective synthesis of the isoxazolidine monomers enables the use of the synthesis of β³‐oligopeptides via iterative α‐keto acid? hydroxylamine (KAHA) ligation.     

Total Synthesis of (+)-Lactacystin

A double stereodifferentiating crotylation between aldehyde 1 and silane (S)- 2 to afford homoallylic alcohol 3 is the key diastereoselective step (anti:syn >30:1) in an efficient asymmetric synthesis of (+)-lactacystin. This compound is a metabolite isolated from Streptomyces sp. OM-6519 that exhibits significant neurotrophic activity. An additional important step in the synthesis is a catalytic asymmetric aminohydroxylation used as the key step in the synthesis of the (2R,3S)-hydroxyleucine synthon.     

Intramolecular Wittig Reaction: A New Synthesis of (S)‐Pyrrolam A

A straightforward synthesis of (S)‐pyrrolam A is described. The synthesis involves in situ generation of the phosphorane 3 , followed by an intramolecular Wittig reaction to furnish (S)‐pyrrolam A.     

Synthesis of (+)-(3R,5R)-3-Hydroxy-5-decanolide and Massoialactone,and Formal Synthesis of Verbalactone

Total synthesis of (3R, 5R)-(+)-3-hydroxy-5-decanolide (1) and massoialactone (2), and formal synthesis of verbalactone (3), have been reported.     

A Total Synthesis of Aliskiren

A total synthesis of aliskiren ( 20 ) was accomplished. A key in our synthesis was to use the symmetric trans‐cisoid‐trans‐bis‐lactone 1 as a precursor. It was expediently prepared by three different routes (Scheme 2). Appending the end groups and functional group transformations completed the synthesis (Scheme 3).     

Enantioselective Synthesis of Phenyl-ethanolamines Through Application of Chiral Sulfoxide

Efficient enantioselective synthesis of (R)- and (S)-enantiomers of 2-(tert-butylamino)-1-(p-methoxyphenyl)-ethanol has been achieved in high enantiomeric excess by using asymmetric sulfoxide as a chiral auxiliary. The present synthetic approach was further extended to the asymmetric synthesis of (R)-salbutamol.     

Facile synthesis of cyclopentapeptide,cyclo[Arg(NO2)-Gly-Asp(OBn)-D-Phe-Lys(Fmoc)], and its application in synthesis of integrin-targeting anticancer conjugate

An efficient approach for integrin-targeting cRGDfK conjugate synthesis has been developed using a new protected cyclopentapeptide, cR(NO₂)GD(Bn)fK(Fmoc), as the key intermediate. cR(NO₂)GD(Bn)fK(Fmoc) was conveniently prepared in high yield. The Fmoc group of this cyclopentapeptide was selectively removed under mild conditions which makes it an ideal intermediate for cRGDfK conjugate synthesis as was well demonstrated in this paper by the synthesis of cRGDfK chlorambucil conjugate.     

Total Synthesis of Umuravumbolide

A simple and efficient stereoselective total synthesis of (+)‐umuravumbolide ( 1b ) and (?)‐deacetylumuravumbolide ( 1a ) starting from commercially available pentanal is described. The synthesis involves Sharpless asymmetric epoxidation, Jacobsen's hydrolytic kinetic resolution (HKR), and the Yamaguchi oxirane opening as key steps (Scheme 2).     

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).     

Stereoselective Total Synthesis of Xestodecalactone C

A simple and highly efficient stereoselective total synthesis of xestodecalactone C ( IIb ), a polyketide natural product, was achieved (Scheme 2). The synthesis involved Keck's asymmetric allylation, a iodine‐induced electrophilic cyclization, and an intramolecular Friedel–Crafts acylation as key steps.     

An improved synthesis of ‘octa-acid’ deep-cavity cavitand

An improved synthesis of a water-soluble deep-cavity cavitand (octa-acid, 1) is presented. Previously (Gibb, C.L.D.; Gibb, B.C. J. Am. Chem. Soc. 2004, 126, 11408–11409), we documented access to host 1 in eight (non-linear) steps starting from resorcinol; a synthesis that required four steps involving chromatographic purification. Here, we reveal a modified synthesis of host 1. Consisting of seven (non-linear) steps, this new synthesis involves only one chromatographic step, and avoids a minor impurity observed in the original approach. This improved synthesis is therefore useful for the laboratories that are investigating the properties of these types of host.     

Synthesis of (1α)‐1,25‐Dihydroxyvitamin D3 with a β‐Positioned Seven‐Carbon Side Chain at C(12)

A convergent synthesis of an analogue of (1α)‐1,25‐dihydroxyvitamin D₃ ( 1b ) with a C₇ side chain at C(12), i.e., of 5 (Fig.), is described. A key step of the synthesis is the assembly of the triene system by a Pd^II‐catalyzed ring closure of an enol triflate (‘bottom’ fragment) followed by coupling of the resulting Pd^II intermediate with an alkenylboronate (‘upper’ fragment) (Scheme 2). The synthetic strategy allows isotopic labelling at the end of the 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.     

Enantioselective Synthesis of cis-Decalin Derivatives by the Inverse-Electron-Demand Diels–Alder Reaction of 2-Pyrones

A novel strategy for the synthesis of cis-decalins by an ytterbium-catalyzed asymmetric inverse-electron-demand Diels–Alder reaction of 2-pyrones and silyl cyclohexadienol ethers is reported here. A broad range of synthetically important cis-decalin derivatives with multiple contiguous stereogenic centers and functionalities are obtained in good yields and stereoselectivities. A full set of diastereomeric substituted cis-decalin motifs are readily accessible by tuning the absolute configurations of substituted silyl cyclohexadienol ethers (R or S) as well as the ligands (R or S). The synthetic potential is showcased by the enantioselective total synthesis of 4-amorphen-11-ol, and further demonstrated by the first total synthesis of cis-crotonin.     

Studies toward the Synthesis of (R)‐(+)‐Harmicine

The study toward the total synthesis of (R)‐(+)‐harmicine is reported in this paper. The enantioselective synthesis of pyrrolidinone, the main backbone of of (R)‐(+)‐harmicine, has been completed by the methodology based on photo‐induced Wolff rearrangement of α‐diazo‐β‐carbonyl compounds.     

Synthesis of Nonsymmetrically N,N′‐Diaryl‐Substituted 4,4′‐Bipyridinium Salts with Redox‐Tunable and Titanium Dioxide (TiO2)‐Anchoring Properties

A general method for the synthesis of so far unknown nonsymmetrically substituted N‐aryl‐N′‐aryl′‐4,4′‐bipyridinium salts is presented (Scheme 1). The common intermediate in all procedures is N‐(2,4‐dinitrophenyl)‐4,4′‐bipyridinium hexafluorophosphate ( 1 ⋅ ). For the synthesis of nonsymmetric arylviologens, 1 ⋅ was arenamine‐exchanged by the Zincke reaction, and then activated at the second bipyridine N‐atom with 2,4‐dinitrophenyl 4‐methylbenzenesulfonate. The detailed preparation of the six N‐aryl‐N′‐aryl′‐viologens 21 – 26 is discussed (Scheme 2). The generality of the procedure is further exemplified by the synthesis of two nonsymmetrically substituted N‐aryl‐N′‐benzyl‐ (see 11 and 12 ), and seven N‐aryl‐N′‐alkyl‐4,4′‐bipyridinium salts (see 28 – 34 ) including substituents with metal oxide anchoring and redox tuning properties. The need for these compounds and their usage as electrochromic materials, in dendrimer synthesis, in molecular electronics, and in tunable‐redox mediators is briefly discussed. The latter adjustable property is demonstrated by the reduction potential measured by cyclic voltammetry on selected compounds (Table).     

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.     

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).     

Facile Synthesis of Metallosalphen-Based 2D Conductive Metal-Organic Frameworks for NO2 Sensing: Metal Coordination Induced Planarization

As an emerging class of promising porous materials, the development of two-dimensional conductive metal organic frameworks (2D c-MOFs) is hampered by the few categories and tedious synthesis of the specific ligands. Herein, we developed a nonplanar hexahydroxyl-functionalized Salphen ligand (6OH-Salphen) through a facile two-step synthesis, which was further applied to construct layered 2D c-MOFs through in situ one pot synthesis based on the synergistic metal binding effect of the N₂O₂ pocket of Salphen. Interestingly, the C_2v-symmetry of ligand endows Cu-Salphen-MOF with periodically heterogeneous pore structures. Benefitting from the higher metal density and shorter in-plane metal-metal distance, Cu-Salphen-MOF showcased excellent NO₂ sensing performance with good sensitivity, selectivity and reversibility. The current work opens up a new avenue to construct 2D c-MOF directly from nonplanar ligands, which greatly simplifies the synthesis and provides new possibilities for preparing different topological 2D c-MOF based functional materials.     

Carbohydrate‐Based Studies Toward the Synthesis of Hamigeromycin E: A Stereoselective Total Synthesis of an Isomer of Zeaenol

A stereoselective synthesis of 14‐membered macrolide hamigeromycin E ( 6 ) has been studied by employing ortho‐lithiated formylation, Barbier allylation, Julia–Kocienski olefination, Mitsunobu esterification, and ring‐closing metathesis (RCM) reactions. The final RCM reaction did not provide the target molecule. This study has prompted us to synthesize a stereoisomer of zeaenol and accomplish the total synthesis with the above protocols.