Total synthesis of leustroducsin B

Leustroducsin B was synthesized via a convergent route based on division of the leustroducsin molecule into three segments A, B, and C. Two coupling reactions (Julia coupling reaction and Nozaki-Hiyama-Kishi (NHK) reaction) were employed for coupling of segments A and B: segment A1 for the Julia coupling reaction was prepared by a combination of Sharpless asymmetric epoxidation and an epoxide-cleavage reaction with an organoaluminum reagent, while segment A2 for the NHK reaction was synthesized from optically active alcohol that had previously been prepared by lipase-catalyzed kinetic resolution. Segment B, whose structure was modified with some functional groups, was synthesized from (R)-malic acid by a combination of Wittig reaction and Sharpless asymmetric dihydroxylation, and segment C, containing a cyclohexane moiety, was prepared by asymmetric Diels-Alder reaction. Segment B was first coupled with segment A1 via the Julia coupling reaction, but the yield was low due to unexpected epimerization. The NHK reaction of segment A2 proceeded to give the coupling product in good yield. This product was coupled with segment C via Wittig and Stille coupling reactions, and finally, phosphorylation was carried out by partial hydrolysis of a cyclic phosphate to give leustroducsin B.     

Total synthesis of scytophycin C. 2. Coupling reaction of the C(1)-C(18) segment and the C(19)-C(31) segment, a key macrolactonization, and the crucial terminal amidation reaction

[reaction: see text] Stereoselective syntheses of the C(1)-C(18) segment (segment A) and the C(19)-C(31) segment (segment B) are described in the preceding paper. This paper reports the key coupling reaction of both segments, 22-membered lactonization, and the crucial terminal amidation reaction culminating in the total synthesis of scytophycin C.     

Total synthesis of the antitumor acetogenin mosin B: desymmetrization approach to the stereodivergent synthesis of threo/trans/erythro-type acetogenins

A total synthesis of the threo/trans/erythro-type acetogenin mosin B and one of its diastereomers has been achieved. The carbon skeleton is assembled in a convergent fashion from two segments (a THF ring segment and a gamma-lactone segment) through the Nozaki-Hiyama-Kishi reaction. The THF ring segment was stereoselectively constructed by a stereodivergent synthesis starting from a common intermediate (4-cyclohexene-1,2-diol) based on a desymmetrization strategy. The gamma-lactone segment was synthesized by coupling a triflate and a chiral alpha-sulfenyl gamma-lactone. By virtue of these synthetic results, we suggest that the absolute configuration of natural mosin B is 1 a. Antiproliferative effects of 1 a and 1 b were also investigated.     

Stereoselective synthesis of premisakinolide A, the monomeric counterpart of the marine 40-membered dimeric macrolide misakinolide A

[structure: see text] The first synthesis of premisakinolide A, the monomeric counterpart of misakinolide A, the marine 40-membered macrolide displaying potent activity against a variety of human carcinoma cell lines, has been reported. The strategy was highlighted by a crucial coupling of a tetrahydropyran fragment and an alkynylaluminum reagent having a polypropionate chain, the highly stereoselective cross aldol reaction of segment A and segment B, and the stereospecific construction of the polypropionate structure based on original acyclic stereocontrol.     

Total synthesis of an antitumor antibiotic,Fostriecin (CI-920)

The total synthesis of an antitumor antibiotic, fostriecin (CI-920), via a highly convergent route is described. A characteristic feature of the present total synthesis is that the synthesis was achieved via a coupling procedure of three segments A, B, and C. The unsaturated lactone moiety of fostriecin, corresponding to segment A, was constructed from a known Horner-Emmons reagent, and the stereochemistry of the C-5 position was introduced by asymmetric reduction with (R)-BINAl-H. Segment B having a series of stereogenic centers was synthesized from (R)-malic acid and the stereogenic centers at the C-8 and C-9 positions were prepared by a combination of Wittig reaction and Sharpless asymmetric dihydroxylation reaction. The conjugated Z,Z,E-triene moiety of fostriecin, corresponding to segment C, was eventually constructed by Wittig reaction and Stille coupling reaction. The phosphate moiety, which is known to be essentially important for the antitumor activity, was introduced via two routes: (i) direct phosphorylation of the monohydroxyl derivative in which other hydroxyl groups are protected with silyl groups; (ii) cyclic phosphorylation and selective cleavage of the cyclic phosphate derivative. Although the former route is basically the same as those reported by other groups, the latter route is novel and more effective than the former one. The present total synthesis would serve as a versatile synthetic route to not only fostriecin, but also its various analogues including stereoisomers.     

Total Synthesis of Siomycin A: Completion of the Total Synthesis

The total synthesis of siomycin A ( 1 ), a representative compound of the thiostrepton family of peptide antibiotics, was achieved by incorporating the five synthetic segments A ( 2 ), B ( 3 ), C ( 4 ), D ( 5 ), and E ( 6 ). The dehydropiperidine segment A ( 2 ) was esterified with the dihydroquinoline segment C ( 4 ), and the subsequent coupling with the β‐phenylselenoalanine dipeptide segment D ( 5 ) at the segment C portion followed by lactamization between the segments A and D gave segment A‐C‐D ( 27 ). This was amidated with the pentapeptide segment B ( 3 ) at the segment A portion followed by one‐pot cyclization (between segments A and B) and elongation (with the β‐phenylselenoalanine dipeptide segment E ( 6 ) at the segment A portion), thus furnishing siomycin A ( 1 ).     

提高接肽缩合率的研究进展

本文针对多肽合成中缩合反应存在"困难肽段"的情况, 反析了影响缩合率的原因,归纳了改善缩合率的措施。 它们对提高经典液相法及固相法肽合成的质量均有实际意义。     

A strategy for the asymmetric aminohomologation of alpha, beta-dihydroxy aldehydes: application to the synthesis of the southwest tripeptide segment of echinocandin B

The synthesis of the (2S,3S,4S)-3,4-dihydroxyhomotyrosine amino acid segment, present in echinocandin B, in its activated form ready for peptide coupling is described. The key steps of the approach are the enantioselective AD reaction of 4-methoxycinnamic acid methyl ester, a completely diastereoselective [2 + 2] hydroxyketene-imine cycloaddition, and the TEMPO-assisted cycloexpansion of the resulting 3-hydroxy beta-lactam to the corresponding alpha-amino acid N-carboxy anhydride (NCA). The smooth opening of the latter upon treatment with L-Thr(OSi(t)BuPh(2))OMe and further acylation with the N-Cbz protected L-4-tert-butyldiphenylsilyloxy proline rendered the southwest portion of echinocandin B.     

Asymmetric Ni(II)/Cr(II)-mediated coupling reaction: catalytic process

[reaction: see text] The stable, crystalline Cr(III)/sulfonamide complex 1a is shown to be an effective catalyst for the Ni/Cr-mediated coupling reaction. A possible mechanism is suggested for the process. 1a is also effective for other Cr-mediated coupling reactions. With this catalyst, a concise and efficient synthesis of the C14-C26 segment of halichondrins has been developed.     

Convergent synthesis of pyragonicin

This paper describes a second-generation synthesis of an antitumor tetrahydropyran (THP) acetogenin, pyragonicin. The key step involved an olefin cross-metathesis between the THP segment and the terminal gamma-lactone residue. The coupling reaction in the presence of Grubbs' second-generation catalyst resulted in an unseparable mixture of a desired coupling product and its one-carbon eliminated product while the use of Grubbs' first-generation catalyst afforded the former exclusively. A novel MOM-migrating reaction found in a cyclization reaction is also discussed.     

Synthesis of novel oligoester‐block‐polyacrylate‐block‐oligoester ABA triblock copolymers by coupling methods

An original approach based on coupling methodology was used to prepare novel well‐defined ABA triblock copolymers, made of polyester‐type chain ends (A) associated with a polyacrylate midblock (B). Poly(ethylene terephthalate)‐block‐poly(lauryl acrylate)‐block‐poly(ethylene terephthalate) (PET‐b‐PLAc‐b‐PET) copolymers were achieved from poly(ethylene terephthalate)‐b‐poly(lauryl acrylate) (PET‐b‐PLAc) diblock ones. The first step consisted in the synthesis of diblock copolymers by atom transfer radical polymerization of lauryl acrylate starting from PET segment as a macroinitiator. In the second step, the coupling of diblock copolymers was achieved using four different methods, which were evaluated and compared: atom transfer radical coupling, “click” chemistry using the Huisgen's reaction, and coupling via a dithiol reagent or a diisocyanate molecule. Coupling using the Huisgen's reaction or a diisocyanate spacer proved to be the most efficient techniques. Even if these methods showed limitation and were only adapted for copolymers with low molecular weights, we managed to successfully prepare ABA triblock copolymers involving a polyester segment as end blocks and a polyacrylate moiety as midblock. To our knowledge, such kind of chemical structure has never been reported before and would be useful, possibly affording physical networks leading to rheological modification, for instance. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Microstructure effect in the coupling reactions of polymeric organolithium compounds using chlorosilanes

The most important variable affecting the yield in the coupling reactions of polymeric organolithium compounds with chlorosilane compounds has been investigated through size-exclusion chromatographic (SEC) analysis. The coupling reaction of poly(styryl)lithium with dichlorodimethylsilane as a silane-coupling agent provided 44 wt % of the coupling yield. The coupling yield, depending on the chain end reactivity of active polymers, was not greatly affected. The addition of a Lewis base such as N,N,N′,N′-tetramethylethylenediamine (TMEDA) even after complete polymerization of the dienes in hydrocarbon seems to affect the coupling reaction, resulting in decreasing the yield. The 1,2- or 3,4-enchain contents in the polydiene backbones affected the reduction of the linking efficiency in the coupling of the poly(dienyl)lithiums with chlorosilanes as the linking agent. The linking yields of the active polymers including over 75 mol % of 1,2- or 3,4-enchainment on the polydiene segment were below 20 wt %. The linking yields exhibited a dependence not only on the steric requirement of the chain end, but also the microstructure of the polydiene segment. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 1743–1753, 1998     

Synthetic studies toward biselides. Part 1: synthesis of the core carbon framework of biselides A,B, and E using Stille coupling

Biselides A and B are cytotoxic marine polyketides. We have achieved synthesis of the C-1–C-15 segment of biselides A and B by using Stille coupling and regioselective oxidative cleavage as key steps. Furthermore, we constructed the α,β-unsaturated lactone part of biselide E by using a similar strategy.     

A practical semi-synthesis of tautomycin using a hydrolysate of natural tautomycin

A useful and brief semi-synthesis of tautomycin, which can be supplied a large quantity, has been achieved through the coupling reaction of the C21-C26 segment (an epoxide) with the C1-C20 segment (a dithiane), which was derived from the degradation of natural tautomycin, toward the conformational analysis of the C21-C26 moiety and the exploration of structure-activity relationships.     

Synthesis of the C6-C21 segment of amphidinolide E

[reaction: see text] A convergent approach to a C6-C21 segment of the polyketide amphidinolide E has been developed through combination of three subunits by allenylindium bromide-aldehyde addition and Suzuki sp2-sp3 coupling.     

Total synthesis of the epidermal growth factor inhibitor (-)-reveromycin B

The total synthesis of the epidermal growth factor inhibitor reveromycin B (2) in 25 linear steps from chiral methylene pyran 13 is described. The key steps involved an inverse electron demand hetero-Diels-Alder reaction between dienophile 13 and diene 12 to construct the 6,6-spiroketal 11 which upon oxidation with dimethyldioxirane and acid catalyzed rearrangement gave the 5,6-spiroketal aldehyde 9. Lithium acetylide addition followed by oxidation/reduction and protective group manipulation provided the reveromycin B spiroketal core 8 which was converted into the reveromycin A (1) derivative 6 in order to confirm the stereochemistry of the spiroketal segment. Introduction of the C1-C10 side chain began with sequential Wittig reactions to form the C8-C9 and C7-C6 bonds, and a tin mediated asymmetric aldol reaction installed the C4 and C5 stereocenters. The final key steps to the target molecule 2 involved a Stille coupling to introduce the C21-C22 bond, succinoylation, selective deprotection, oxidation, and Wittig condensation to form the final C2-C3 bond. Deprotection was effected by TBAF in DMF to afford reveromycin B (2) in 72% yield.     

Total Synthesis of Siomycin A: Construction of Synthetic Segments

The five practical segments for the total synthesis of siomycin A, that is, the dehydropiperidine segment A ( 5 ), the pentapeptide segment B ( 3 ), the dihydroquinoline segment C ( 6 ), and the β‐phenylselenoalanine dipeptide segments D ( 7 ) and E ( 4 ), were synthesized. Segment A ( 5 ) was constructed by the coupling of the azomethine ylide and the chiral sulfinimine, followed by the stereoselective reduction of the six‐membered imine function. Segment B ( 3 ) was synthesized by the phenylselenylation of the β‐lactone, stereoselective vinylzinc addition to the chiral sulfinimine, and oxazoline–thioamide conversion. Segment C ( 6 ) was prepared by the one‐pot olefination of the tetrahydroquinoline N‐oxide using triflic anhydride and triethylamine, stereoselective reduction of the methyl ketone function, and regioselective Yb(OTf)₃‐catalyzed epoxide opening by the amino group. Segments D ( 7 ) and E ( 4 ) were synthesized by coupling of the properly protected β‐phenylselenoalanines.     

A convergent and stereoselective synthesis of a seco-precursor of macrolactin A

A seco-precursor of macrolactin A was synthesized by coupling two advanced segments. Wittig reaction and Horner-Emmons reaction were utilized to construct the three characteristic E,Z and E,E dienes. The C₁-C₁₀ segment was synthesized through Horner-Emmons reaction with phosphonate reagent. The α-alkylation of sulfone stabilized anion with allyl bromide followed by desulfonation gave the C₁₁-C₂₄ segment.     

Construction of the DEF-ring system of nogalamycin and menogaril via an efficient Suzuki-Miyaura reaction

A new approach to the total synthesis of anthracycline natural products, nogalamycin and menogaril, was explored. The goal was to enable late-stage introduction of the EF-ring segment. The new synthetic route has been developed through strategic application of a Suzuki-Miyaura reaction as the key step, which coupled the EF-ring segment with the D-ring to give a 1,1′-disubsitituted alkene in good yield under biphasic conditions. Further manipulation of the coupling product completed the construction of the DEF-ring system.