Synthetic study of azaspiracid-1: synthesis of the EFGHI-ring fragment

Here, we report a synthesis of the lower half C21-C40 fragment of the shellfish toxin, azaspiracid-1. The C28-C40 fragment was synthesized by a coupling between the C28-C35 epoxide and the C36-C40 dithioacetal anion, followed by the HI-ring spiroaminal formation. An aldehyde corresponding to the C28-C40 fragment was then coupled with the C21-C27 allylic stannane by using InCl3. Finally, the FG-ring was constructed by HF.pyridine to accomplish the synthesis of the suitably protected C21-C40 fragment.     

Synthetic studies of the 18-membered antitumor macrolide, tedanolide. 3. Stereocontrolled synthesis of the C1-C12 part via a synthesis of the C1-C7 fragment by a mismatched but efficient sharpless dihydroxylation and its coupling with the C8-C11 fragment

The C1-C12 part (4) of tedanolide (1) was synthesized starting from methyl (R)-3-hydroxy-2-methylpropionate (11a) via a coupling between the C1-C7 aldehyde (6) and the C8-C11 iodoalkene (7a). For a synthesis of 6, a mismatched but highly efficient Sharpless dihydroxylation of the alpha, beta-unsaturated ester (15) with AD-mix-alpha was successfully applied. Compound 7a was synthesized using hydrozirconation to the alkyne (32).     

Total Synthesis of Pulvomycin D

A synthetic route to the pulvomycin class of natural products is presented, which culminated in the first synthesis of a pulvomycin, pulvomycin D. Key elements of the strategy include a pivotal aldol reaction which led to bond formation between the C24-C40 and the C8-C23 fragment. The remaining C1-C7 fragment was attached by a Yamaguchi esterification completing the assembly of the 40 carbon atoms within the main skeleton. Ring closure to the 22-membered lactone ring was achieved in the final stages of the synthesis by a Heck reaction. The completion of the synthesis required the removal of six silyl protecting groups in combination with olefin formation at C26-C27 by a Peterson elimination.     

Total synthesis of mycalamide A

This communication describes a concise and efficient total synthesis of mycalamide A by the convergent coupling of pederic acid unit with the mycalamine unit. The left-half, (+)-7-benzoylpederic acid, was synthesized from (2R,3R)-3-methylpent-4-en-2-ol in seven steps and 34.6% overall yield through a route that features a one-step Pd(II)-catalyzed tandem Wacker/Heck cyclization reaction to prepare the tetrahydropyran ring system. The right-half, the mycalamine unit, was synthesized in 21 steps and 10.5% overall yield from diethyl d-tartrate. Effective, stereoselective methods were developed for the assembly of the two parts to yield either mycalamide A or C(10)-epi-mycalamide A.     

The first total synthesis of concanamycin f (concanolide a)

A highly stereoselective total synthesis of the macrolide antibiotic concanamycin F (1), a specific and potent inhibitor of vacuolar H(+)-ATPase, has been achieved by a convergent route involving the synthesis and coupling of its 18-membered tetraenic lactone and beta-hydroxyl hemiacetal side chain subunits. The C1-C19 18-membered lactone aldehyde 4 was synthesized through the intermolecular Stille coupling of the C5-C13 vinyl iodide 24 and the C14-C19 vinyl stannane 25, followed by construction of the C1-C4 diene and macrolactonization. Synthesis of 4 via a second convergent route including the esterification of the C1-C13 vinyl iodide 45 and the C14-C19 vinyl stannane 47 followed by the intramolecular Stille coupling was also realized. The highly stereoselective aldol coupling of 4 and the C20-C28 ethyl ketone 5 followed by desilylation provided 1 which was identical with natural concanamycin F.     

Expedient access to the okadaic acid architecture: a novel synthesis of the C1-C27 domain.

A newly designed synthetic entry to the C1-C27 domain of okadaic acid has been developed. This incorporates substantial improvements in the preparations of the key okadaic acid building blocks representing the C3-C8, C9-C14, and C16-C27 portions. The synthesis of the C3-C8 lactone used (R)-glycidol as the origin of the C4 stereogenic center and featured a late-stage optional incorporation of the C7 hydroxyl group. The complementary C9-C14 fragment was synthesized in a concise route from (R)-3-tert-butyldimethylsilyloxy-2-methylpropanal and propargyl bromide. Assembly of the C3-C14 spiroketal-containing intermediate from the constitutent fragments revealed a dramatic effect of C7 functionalization upon spiroketalization efficiency. In contrast, both (9E)- and (9Z)-enones converged readily to the C8 spiroketal upon treatment with acid. Modifications to the central C16-C27 fragment of okadaic acid included the early replacement of benzylic protecting groups by more suitable functionalities to facilitate both the generation of the C15-C27 intermediate and the deprotection of the final products. These modular building blocks were deployed for the synthesis of the C1-C27 scaffold of 7-deoxyokadaic acid. This work demonstrates improvements in the formation of versatile okadaic acid intermediates, as well as a reordering of fragment couplings. This alternative order of coupling was designed to promote the late stage incorporation of nonnatural lipophilic extensions from the C27 terminus.     

Crystal structures of n-alkanes with branches of different size in the middle

We synthesized four branched n-alkane samples C35-C1, C35-C4, C35-C6, and C35-C4Ph with the same number of carbons as the main chain, n = 35, to which the methyl, butyl, hexyl, and butyl phenyl groups were respectively attached at the middle, and also the corresponding linear homologue of C35, and studied their crystalline structures from DSC, IR, and Raman spectroscopy, X-ray diffraction measurement, and computer simulation. Solid-solid phase transitions characteristic of linear alkane C35 are not observed for any branched alkanes, and their melting temperatures Tm are lowered to 325.2, 318.5, 314.3, and 314.1K, respectively. Main chains of branched alkane molecules are not folded, irrespective of length and chemical structure of branches, but are extended to take the planar zigzag form in the solid state. The branches of C35-C4 and C35-C6 are also aligned inside the crystal in the extended form. Data analyses on solution-grown crystallized samples reveal that, with increasing the branch length, their crystal structures transform from polymorphic forms of the orthorhombic (P2(1)2(1)2(1)) and the triclinic (P) for C35-C1 and C35-C4 to the unique triclinic form for C35-C6 and C35-C4Ph, so as to minimize extra surface energy invoked by introduction of long branches.     

The stereocontrolled total synthesis of spirastrellolide A methyl ester. Expedient construction of the key fragments

Due to a combination of their promising anticancer properties, limited supply from the marine sponge source and their unprecedented molecular architecture, spirastrellolides represent attractive and challenging synthetic targets. A modular strategy for the synthesis of spirastrellolide A methyl ester, which allowed for the initial stereochemical uncertainties in the assigned structure was adopted, based on the envisaged sequential coupling of a series of suitably functionalised fragments; in this first paper, full details of the synthesis of these fragments are described. The pivotal C26-C40 DEF bis-spiroacetal was assembled by a double Sharpless asymmetric dihydroxylation/acetalisation cascade process on a linear diene intermediate, configuring the C31 and C35 acetal centres under suitably mild acidic conditions. A C1-C16 alkyne fragment was constructed by application of an oxy-Michael reaction to introduce the A-ring tetrahydropyran, a Sakurai allylation to install the C9 hydroxyl, and a 1,4-syn boron aldol/directed reduction sequence to establish the C11 and C13 stereocentres. Two different coupling strategies were investigated to elaborate the C26-C40 DEF fragment, involving either a C17-C25 sulfone or a C17-C24 vinyl iodide, each of which was prepared using an Evans glycolate aldol reaction. The remaining C43-C47 vinyl stannane fragment required for introduction of the unsaturated side chain was prepared from (R)-malic acid.     

Halichondrin B: synthesis of the C1-C22 subunit

[Reaction: see text]. Two efficient routes to the C1-C22 subunit of halichondrin B are described. The cage ketal 7, which contains 11 asymmetric centers embedded within the ABCDEF-ring framework, was assembled from (+)-conduritol E (27) in 18 steps and 4% overall yield. In a separate route, 7 was also synthesized in 18 steps and 2% overall yield from a derivative of alpha-d-glucoheptonic acid gamma-lactone (62). While the former route installs the fully elaborated C-ring endowed with the correct C12 stereochemistry early in the synthesis, the latter features a late-stage introduction of the C12 stereocenter during the ultimate one-pot Michael addition/ketalization cascade to form the CDE-ring system of the cage. The importance of the C12 stereocenter to the crucial ketalization event is discussed through comparison of these two strategies.     

Total synthesis of resolvin E1

Resolvin E1 (RvE1), which is an endogenous mediator to resolve inflammation, was synthesized by Wittig reaction between the C15-C20 aldehyde and the C10-C14 phosphonium salt possessing the vinyl iodo moiety followed by Suzuki-Miyaura coupling of the resulting vinyl iodide with the vinyl borane of the C1-C9 part, which was derived from the corresponding acetylene by hydroboration. The C5 and C18 chiral centers in these parts were created by the kinetic resolution of the racemic γ-TMS allylic alcohols using the asymmetric epoxidation, while that of the C10-C14 part was constructed by the asymmetric hydrogen transfer reaction of the corresponding γ-TMS acetylene ketone.     

Synthesis of the C8-C20 and C21-C30 segments of pectenotoxin 2

In this study, we synthesized the C8-C20 and C21-C30 segments of the diarrhetic shellfish toxin pectenotoxin 2. The C8-C20 segment was assembled from a phosphonate corresponding to the C8-C15 segment (prepared from l-malic acid in 19 steps) and an aldehyde corresponding to the C16-C20 segment (synthesized from 3-methyl-3-butenol in nine steps) by a twelve-step process including the Horner-Wadsworth-Emmons reaction, regio- and stereoselective reduction of the resulting enone, diastereoselective epoxidation, and 5-exo epoxide cleavage forming the C-ring. The C21-C30 segment was constructed in 13 steps from (S)-glycidol via a route involving E-ring formation by 5-exo epoxide cleavage and stereoselective methylation at C27 by the Evans method.     

Synthetic studies of halichondrin B, an antitumor polyether macrolide isolated from a marine sponge. 8. Synthesis of the lactone part (C1---C36) via horner-emmons coupling between C1---C15 and C16---C36 fragments and Yamaguchi lactonization

The lactone part (2) of halichondrin B (1) was synthesized by Yamaguchi macrolactonization of the seco-acid (3), which was synthesized via coupling of C1---C15(4) with C16---C36 (5), prepared through stereoselective construction of the E ring starting from C16---C26 (7) and C27---C36 (8).     

Synthesis of the C42-C52 part of ciguatoxin CTX3C

The C42-C52 part of ciguatoxin CTX3C (1) was synthesized from tri-O-acetyl d-glucal. The synthetic segment had a tetrahydropyran ring corresponding to the ‘C49-reduced’ L-ring of 1, designed to avoid side reactions due to acid-labile C49 acetal carbon during acidic reductive conditions planned in further synthesis toward 1. The vicinal dimethyl part at C47-C48 was constructed by a stepwise conjugate addition/methylation procedure. The C50-C52 unit was installed by Grignard addition of the C₃ unit followed by spirocyclization and reductive cleavage of the spirocyclic acetal. Stereoselective assembly of the C42-C44 part was achieved by Brown’s asymmetric crotylboration.     

Total synthesis of rutamycin B and oligomycin C

The asymmetric synthesis of the macrolide antibiotics (+)-rutamycin B (1) and (+)-oligomycin C (2) is described. The approach relied on the synthesis and coupling of the individual spiroketal fragments 3a and 3b with the C1-C17 polyproprionate fragment 4. The preparation of the spiroketal fragments was achieved using chiral (E)-crotylsilane bond construction methodology, which allowed the introduction of the stereogenic centers prior to spiroketalization. The present work details the synthesis of the C19-C28 and C29-C34 subunits as well as their convergent assembly through an alkylation reaction of the lithiated N,N-dimethylhydrazones 6 and 8 to afford the individual linear spiroketal intermediates 5a and 5b, respectively. After functional group adjustment, these advanced intermediates were cyclized to their respective spiroketal-coupling partners 40 and 41. The requisite polypropionate fragment was assembled in a convergent manner using asymmetric crotylation methodology for the introduction of six of the nine-stereogenic centers. The use of three consecutive crotylation reactions was used for the construction of the C3-C12 subunit 32. A Mukaiyama-type aldol reaction of 35 with the chiral alpha-methyl aldehyde 39 was used for the introduction of the C12-C13 stereocenters. This anti aldol finished the construction of the C3-C17 advanced intermediate 36. A two-carbon homologation completed the construction of the polypropionate fragment 38. The completion of the synthesis of the two macrolide antibiotics was accomplished by the union of two principal fragments that was achieved with an intermolecular palladium-(0) catalyzed cross-coupling reaction between the terminal vinylstannanes of the individual spiroketals 3a and 3b and the polypropionate fragment 4. The individual carboxylic acids 46 and 47 were cyclized to their respective macrocyclic lactones 48 and 49 under Yamaguchi reaction conditions. Deprotection of these macrolides completed the synthesis of the rutamycin B and oligomycin C.     

Asymmetric crotylation reactions in synthesis of polypropionate-derived macrolides: application to total synthesis of oleandolide

Complete details of a convergent asymmetric synthesis of oleandolide (1), the aglycon of the macrolide antibiotic oleandomycin, is described. The synthesis has been achieved through the assembly and coupling of the left- and right-hand subunits 12 and 38, respectively. These subunits were prepared from chiral silane-based asymmetric crotylation reactions to control the stereochemical relationships. The left- and right-hand subunits (C1-C7 and C8-C14) were brought together through a Pd(0)-catalyzed sp3-sp2 cross-coupling reaction between the zinc intermediate 40 and vinyl triflate 38 to give 27. This product was converted to seco acid 42a and cyclized to lactone 35 under Yamaguchi conditions. This material was then epoxidized with m-chloroperbenzoic acid (m-CPBA) to install the correct C8 epoxide as a single diastereomer, which after a short deprotection sequence completed the synthesis of oleandolide.     

Improved synthesis of C8-C20 segment of pectenotoxin-2

The C8-C20 segment of pectenotoxin-2 was efficiently synthesized in 16% overall yield in 22 steps from l-malic acid via an improved route.     

Versatile enantiocontrolled synthesis of (+)-fostriecin

Fostriecin, a potent protein phosphatase inhibitor and antitumor agent, has been enantioselectively synthesized in naturally occurring form via a versatile route, which also allows one to secure all possible stereoisomeres of the C1-C13 fragment including the C11 stereocenter and the geometry of the delta 12-double bond.     

Synthesis and Structure of 6-(4- Fluorobenzylamino)-3-methylthio-1,5- diphenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

1 INTRODUCTION It was reported that the pyrazolopyrimidinone derivatives play a very important role in the bio- chemistry of living cell. Many potential drugs[1～3] and agrochemicals[4, 5] have been modeled on the compound, and the study on derivatives …     

Synthesis and Crystal Structure of 2,3-Diethoxycarbonyl-4-phenyl-5-morpholinyl Thiophene

1INTRoDUCTIONa-Thiocarbonylthioformamidesweresynthesizedin198o[l~2i,however,thereisnoreportofthesecompoundsconcerningtheirpropertiesandreactionactivitiest33.Accordingtotheirstructure,theyseemtohavereactionwithdienophi1es,likesubsti-tutedolefinicandacetylenicdienophilestoleadcorrespondingDiels-Alderproduct.xylene(15ml),diethylbutynedioicester(O.2g,1.2mmol)wasadded,themix-turewasrefluxedfor20h,thencooledtoroomtemperatureandconcentrated.Theresiduewaspurifiedbysilicagelcolumnusingacetone/petr…     

Stereoselective synthesis of the C31-C39 unit of (+)-phorboxazoles from m-anisaldehyde

A stereoselective route for the synthesis of the C31-C39 fragment of (+)-phorboxazoles is described. The route features Birch reduction, ozonolysis and acid-catalysed cyclisation of enantiopure precursors as key transformations to give the tetrahydropyran ring, starting from m-anisaldehyde as a masked β-keto ester to obtain the pyran skeleton of compound 1.