Diverse synthesis of the C ring fragment of bryostatins via Zn/Cu-promoted conjugate addition of α-hydroxy iodide with enone

A convergent approach to 1,5-hydroxy ketones,the general precursors for constructing the C ring of bryostatins,has been developed via a Zn/Cu-promoted conjugate addition of a-hydroxy iodides with enones.The reaction leads to direct formation of the C21-C22 bond and tolerates diverse functionalities at the C17-,C18-and C24-positions.The approach also enables a more concise synthesis of the known C ring intermediate(10 longest linear steps and 14 total steps),in contrast to its previous synthesis(17 longest linear steps and 22 total steps) in our total synthesis of bryostatin 8.     

An efficient photoinduced iodoperfluoroalkylation of carbon-carbon unsaturated compounds with perfluoroalkyl iodides

Dependent on the selection of the light sources employed, the photoinduced iodoperfluoroalkylation of a variety of unsaturated compounds takes place efficiently via a radical mechanism. Upon irradiation with a xenon lamp through Pyrex (hnu >300 nm), terminal alkenes (R-CH=CH2) and alkynes (R-C triple bond CH) undergo iodoperfluoroalkylation with perfluoroalkyl iodides (RF-I) regioselectively, providing R-CH(I)-CH2-RF and R-C(I)=CH-RF, respectively. In the case of terminal allenes (R-CH=C=CH2), the photoinduced iodoperfluoroalkylation occurs selectively at the terminal double bond, giving the corresponding beta-perfluoroalkylated vinylic iodides (R-CH=C(I)-CH2-RF) in good yields. The photoinitiated reaction of vinylcyclopropanes (c-C3H5-C(R)=CH2) with RF-I proceeds via the rearrangement of cyclopropylcarbinyl radical intermediates to the homoallylic radical intermediates, and the corresponding 1,5-iodoperfluoroalkylated products (I-(CH2)2CH=C(R)-CH2-RF) are obtained in high yields. Isocyanides (R-NC), as C-N unsaturated compounds, also undergo the xenon-lamp-irradiated iodoperfluoroalkylation to provide the corresponding 1,1-adducts (R-N=C(I)-RF) in good yields. Furthermore, the present photoinitiation procedure can be applied to the iodotrifluoromethylation of unsaturated compounds, when the xenon-lamp-irradiated reactions are conducted under the refluxing conditions of excess CF3-I.     

A mechanistic and synthetic study of organocopper substitution reactions with some homoallylic and cyclopropylcarbinyl substrates : Application to isoprenoid synthesis

The double bond of cholesteryl and 5-norbornen-2-yl tosylates and the cyclopropane ring of cyclopropylmethylcarbinyl tosylate participate in organocuprate substitution reactions; retention of configuration at the nucleofugal sp³-C atom and skeletal reorganizations are observed. A plausible mechanism for these reactions is discussed. Coupling of homogeranyl iodide with a four-carbon, functionalized, vinylic cuprate reagent is applied to stereospecific synthesis of trans, trans-farnesol.     

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.     

Vinyl-aziridines and cyclopropanes in Pd-catalyzed (3+2)-cycloaddition reactions with cyclic N-sulfonyl imines

Efficient palladium-catalyzed (3 + 2)-cycloaddition reactions of cyclic N-sulfonyl imines and vinyl-aziridines (or cyclopropanes) have been achieved. The reactions, with either vinylic substrate, proceed with excellent yields affording highly functionalized imidazolidine and pyrrolidine derivatives. The cycloadditions take place via the reaction of zwitterionic π-allyl palladium intermediates with cyclic N-sulfonyl imines through i) the formation of two NC bonds in the presence of vinylaziridines (synthesis of imidazolidines) and ii) one CC bond and one NC bond in the presence of vinylcyclopropanes (synthesis of pyrrolidines). Following on preliminary works on the diastereoselective synthesis of imidazolidines, herein we wish to give a broader view on the subject by describing derivatization reactions and attempts towards an enantioselective version. Moreover, we describe and discuss the behavior of each vinylic substrate (aziridine or cyclopropane) on the (3 + 2)-cycloaddition reactions. Mechanistic and (intriguing) selectivity outcomes are also going to be discussed.     

Stereoselective synthesis of C5-C20 and C21-C34 subunits of the core structure of the aplyronines. Applications of enantioselective additions of chiral allenylindium reagents to chiral aldehydes

The stereoselective synthesis of a C5-C20 and a C21-C34 subunit of the aplyronine family of polyketide marine macrolides has been achieved. These subunits contain all 15 stereocenters of the core structure. Six of the 15 stereocenters were introduced through enantioselective and diastereoselective additions of chiral allenylindium reagents to alpha-methyl-beta-oxygenated propionaldehydes. The products of these additions were further transformed by reactions involving the terminal alkynyl substituent produced in the addition reactions. Unlike previous applications of this methodology, the present synthesis employs Pd(0)-catalyzed transmetalations of chiral allenylpalladium intermediates to generate the chiral allenylindium reagents in situ.     

Electrophilic Substitution of Hydrogen in Betulin and Diacetylbetulin

Betulin and diacetylbetulin, which can be regarded as sterically hindered alkenes, reacted with N-chloro-, N-bromo-, and N-iodosuccinimides to give products of allylic and vinylic substitution in quantitative overall yield. The contribution of allylic substitution increases in the series Cl < Br < I. Quantum chemical simulation of the reactions of diacetylbetulin with N-halosuccinimides showed that, regardless of the electrophile power, all reactions involve open-chain carbocationic intermediates. The direction of deprotonation of the latter with formation of allylic or vinylic substitution products is determined by preferential orientation of the vacant orbital and C–Hlg bond.     

Stereocontrolled total synthesis of (+)-concanamycin F: the strategic use of boron-mediated aldol reactions of chiral ketones

A highly stereocontrolled total synthesis of the 18-membered macrolide (+)-concanamycin F, a potent inhibitor of vacuolar ATPases, is described that proceeds in 5.8% yield over 26 steps. The three key fragments, C1-C13 vinyl iodide, C14-C22 vinyl stannane and C23-C28 aldehyde, were efficiently constructed using asymmetric boron-mediated aldol reactions of appropriate chiral ketone building blocks. The nature of the silyl protection of the C7/C9 hydroxyls proved to be critical for achieving macrocyclisation, with TES ethers being superior to a cyclic silylene derivative. Following a Liebeskind-Stille cross-coupling reaction between the C1-C13 vinyl iodide and C14-C22 vinyl stannane fragments to assemble the (12E,14E)-diene, a modified Yamaguchi macrolactonisation delivered the requisite 18-membered macrocyclic core. This advanced intermediate was also obtained by an alternative sequence using an esterification step to connect the C1-C13 and C14-C22 fragments followed by a Pd-catalysed intramolecular Stille reaction to install the (12E,14E)-diene. Conversion of the resulting macrocyclic intermediate into a methyl ketone then enabled a highly diastereoselective Mukaiyama aldol coupling of the derived silyl enol ether with the C13-C28 aldehyde fragment to install the fully elaborated side chain, whereby subsequent global deprotection of the resulting β-hydroxyketone under suitable conditions (TASF followed by p-TsOH) afforded (+)-concanamycin F.     

Total synthesis of epothilones B and D: stannane equivalents for beta-keto ester dianions

Studies leading to a total synthesis of epothilones B and D are described. The overall synthetic plan was based on late-stage fragment assembly of two segments representing C(1)-C(9) and C(10)-C(21) of the structure. The C(1)-C(9) fragment was prepared by elaboration of commercially available (2R)-3-hydroxy-2-methylpropanoate at both ends of the three-carbon unit. Introduction of carbons 1-4 containing the gem-dimethyl unit was achieved in a convergent manner using a diastereoselective addition of a stannane equivalent of a beta-keto ester dianion. An enantioselective addition of such a stannane equivalent for a beta-keto ester dianion was also used to fashion one version of the C(10)-C(21) subunit; however, the fragment assembly (using bimolecular esterification followed by ring-closing metathesis) with this subunit failed. Therefore, fragment assembly was achieved using a Wittig reaction; this was followed by macrolactonization to close the macrocycle. The C(10)-C(21) subunit needed for this approach was prepared in an efficient manner using the Corey-Kim reaction as a key element. Other key reactions in the synthesis include a stereoselective SmI(2) reduction of a beta-hydroxy ketone and a critical opening of a valerolactone with aniline which required extensive investigation.     

A preliminary evaluation of a metathesis approach to bryostatins

Preliminary investigations into the synthesis of bryostatins using ring-closing metathesis to form the C(16)-C(17) double bond led to a synthesis of the bryostatin analogue 51; precursors 26 and 52, which possess the geminal dimethyl group at C-18, did not undergo the required ring-closing metathesis.     

Studies towards the total synthesis of cruentaren A and B: Stereoselective synthesis of fragments C1-C11, C12-C22 and C23-C28

A convergent and stereoselective approach for the synthesis of C1-C11, C12-C22, and C23-C28 fragments of cytotoxic natural products cruentaren A and B are accomplished. Highlights of the strategy include a Sharpless epoxidation followed by a regioselective opening of epoxide to generate anti and syn-stereochemistry at C9-C10 and C15-C16, an Alder-Rickert reaction between a 1,5-dimethoxy-1,4-cyclohexadiene and dienophile to construct the aromatic ring, and a lithium-mediated aldol reaction to install the C17-C18 anti-stereochemistry. The synthesis of C1-C11 and C12-C22 fragments proceed with a longest linear sequence of 10 and 17 steps from commercially available 2-butyne-1,4-diol and cis-2-butene-1,4-diol respectively.     

Toward the synthesis of reidispongiolide a: stereocontrolled synthesis of the C17-C22 and C23-C35 degradation fragments

[structure: see text] By relying on the asymmetric aldol reactions of chiral ketones, a highly stereocontrolled synthesis of each of the C(17)-C(22) and C(23)-C(35) degradation fragments of reidispongiolide A has been achieved. This permits a configurational assignment of the complete C(17)-C(36) region of this antimitotic macrolide, along with providing advanced intermediates for a projected total synthesis.     

Generation and Rearrangement of N,O‐Dialkenylhydroxylamines for the Synthesis of 2‐Aminotetrahydrofurans

A new diastereoselective route to 2‐aminotetrahydrofurans has been developed from N,O‐dialkenylhydroxylamines. These intermediates undergo a spontaneous C?C bond‐forming [3,3]‐sigmatropic rearrangement followed by a C?O bond‐forming cyclization. A copper‐catalyzed N‐alkenylation of an N‐Boc‐hydroxylamine with alkenyl iodides, and a base‐promoted addition of the resulting N‐hydroxyenamines to an electron‐deficient allene, provide modular access to these novel rearrangement precursors. The scope of this de novo synthesis of simple nucleoside analogues has been explored to reveal trends in diastereoselectivity and reactivity. In addition, a base‐promoted ring‐opening and Mannich reaction has been discovered to covert 2‐aminotetrahydrofurans to cyclopentyl β‐aminoacid derivatives or cyclopentenones.     

Study of Two Puzzled Questions on the Fullerene C_（70）：A First-principles Study

The cycloaddition reactions of NH to different bonds on C70 have been studied by the first-principles calculations.The results indicate that the reactivity of cycloaddition reactions is determined by the directional curvature,KD,and the larger binding energy of Eb on the bond C5-C'5 can be ascribed to the unique bond which can be treated as the shortest bond of(5.5)-SWCNT in the four [6,6] ring fusion bonds.This work also discloses that the energy gap of different spin states is decided by the electronic density,and that of the frontier obitals for the bond C5-C'5 is larger than the value for the C4-C'4 bond.Furthermore,the transition state investigation of the two bond addition reactions provides a reaction barrier of 11.10 kcal/mol for the NH cycloaddition to the C5-C'5 bond;whereas,the addition reaction on C4-C'4 is a spontaneous pathway.Herein,the dynamics effect illustrates the [2+1] cycloaddition reaction on the equatorial C5-C'5 bond to be unfavorable.     

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.     

Catalytic asymmetric hydrometallation of cyclobutenes with salicylaldehydes

Chiral, substituted cyclobutanes are common motifs in bioactive compounds and intermediates in organic synthesis but few asymmetric routes for their synthesis are known. Herein we report the Rh-catalyzed asymmetric hydrometallation of a range of meso-cyclobutenes with salicylaldehydes. The ortho-phenolic group promotes hydroacylation and can be used as a handle for subsequent transformations. The reaction proceeds via asymmetric hydrometallation of the weakly activated cyclobutene, followed by a C–C bond forming reductive elimination. A prochiral, spirocyclic cyclobutene undergoes a highly regioselective hydroacylation. This report will likely inspire the development of other asymmetric addition reactions to cyclobutenes via hydrometallation pathways.

Chiral, substituted cyclobutanes are common motifs in bioactive compounds and intermediates in organic synthesis but few asymmetric routes for their synthesis are known.     

L-cysteine as sustainable and effective sulfur source in the synthesis of diaryl sulfides and heteroarenethiols

L-cysteine, a natural and essential amino acid, was employed as novel sulfur source in the synthesis of symmetrical diaryl sulfides from a variety of aryl iodides in moderate to excellent yields. A tandem three steps’ reactions including C(sp²)-S bond formation, C(sp³)-S bond cleavage and another C(sp²)-S bond formation were proposed to be involved in this conversion. This protocol was featured by broad substrate scope and good functional group tolerance. In addition, heteroarenes including benzothiazoles and benzoxazoles were successfully converted into the corresponding heteroarenethiols using L-cysteine as C-H mercaptalization reagent.     

Recent development of ortho-C–H functionalization of aryl sulfoxides through [3,3] sigmatropic rearrangement

Sulfoxide-promoted ortho-C–H functionalization reactions of aromatic compounds have emerged as powerful tools for organic synthesis. Among them, [3,3] sigmatropic rearrangement induced by interrupted Pummerer reaction or electrophilic activation of sulfoxides has proved to be a fruitful strategy due to its versatility and high reaction efficiency. This digest paper mainly focuses on recent progress on C–H functionalization reactions of aryl sulfoxides via [3,3] sigmatropic rearrangement of sulfonium-tethered intermediates.     

Synthesis of bi- and tetracatenar highly fluorinated compounds for grafting on silicone materials

A series of highly fluorinated compounds bearing two or four perfluoroalkyl (R_F) chains, with a flexible or rigid core have been synthesized. Radical additions, nucleophilic addition or condensation reactions were implemented for these synthesis, using perfluoroalkylated iodides and alcohols and various type of substrates: bis(allylic) derivatives, epichlorhydrin, diacid derivatives. All compounds contain an unsaturated moiety (vinyl, allyl or internal double bond) to be grafted on silicone materials by a catalyzed hydrosilylation reaction.     

Tellurium in organic synthesis: synthesis of bioactive butenolides

Reduction of (Z)-β-butyltelluro-enones gives the corresponding γ-hydroxy vinylic tellurides with retention of the double bond configuration. Reaction of γ-hydroxy vinylic tellurides with 2 equiv of n-butyllithium produces 1,4-C,O-dianions, which on reaction with carbon dioxide give the corresponding butenolides.