s a hydrogen atom from the thiol to give hydroperoxide 96 and a thiyl radical, which propagates the chain. Hydroperoxide 96 is reduced in the presence of triphenyl phosphine to give the corresponding alcohol 91. The preference for the formation of cis-3,5-disubstituted 1,2-dioxolanes is in agreement with the Beckwith−Houk transition state model for 5-exo-trig cyclizations. Similarly, the addition of thiophenol onto 5methylhepta-1,3,6-triene 97 under an atmosphere of oxygen led to 1,2-dioxolane 98, isolated in 49% as a single diastereoisomer after treatment with triphenyl phosphine, together with minor amounts of linear alcohols 99 and 100 (Scheme 49, eq b). This reaction is remarkable for a number of reasons. First, the addition of the thiyl radical occurs exclusively at the terminal position of the conjugated diene system and not at the terminal alkene, thus highlighting the higher reactivity of conjugated dienes as compared to isolated alkenes. Second, intermolecular trapping of the resulting allyl radical is reversible and regioselective under these reaction conditions. Because of the reversibility of the reaction between the allyl radical and molecular oxygen, both ratios 1,4/1,2-addition and 1,2dioxolane/linear alcohols strongly depend upon the initial concentration in thiol. Accordingly, the 1,2-dioxolanes were obtained in good yields only in highly diluted solutions. Finally, the 5-exo-trig cyclization occurs in a completely stereoselective manner, with only one of the two diastereomeric peroxyl radical intermediates (101) undergoing cyclization, while the other one (102) either leads to linear alcohol 99 or fragments back the allyl radical (Scheme 49, eq b). The reversible reaction of allyl radicals with molecular oxygen was also demonstrated for carotenoid-derived carbon-centered radical generated by Scheme 47 Scheme 48. Application to the Preparation of Functionalized 1,2,4-Trioxanes Chemical Reviews Review dx.doi.org/10.1021/cr400441m | Chem. Rev. XXXX, XXX, XXX−XXX X addition of a thiyl radical to the conjugated polyene carotene. This process has been extended to include the more challenging 1,5-dienes, from which six-membered ring endoperoxides can be obtained. Bachi and co-workers applied the thiol−olefin cooxidation process to the total synthesis of antimalarial agent yingzhaosu A (Scheme 50) and its C14epimer, as well as the preparation of a series of active analogues, from readily available limonene 103. The overall process is extremely challenging in this case due to the particular structure of the diene, with the 6-exo-cyclization process being in competition with intermolecular hydrogen atom abstraction from the thiol, and also potentially with intramolecular hydrogen abstraction from the activated allylic position by the reactive oxygen-centered radical. As previously observed, addition of the thiyl radical takes place at the less hindered position, and due to the lack of stereocontrol during the trapping of the resulting carbon-centered radical, peroxyl radical 105 is formed as a 1:1 mixture of diastereoisomers (Scheme 50). The latter undergoes 6-exo-trig cyclization to give carbon-centered radical 106. Unlike the initial trapping with molecular oxygen, the 2,3-dioxabicyclo[3.3.1]nonane system of 106 allows a highly diastereoselective reaction for the second trapping with molecular oxygen from the less hindered face to give 107. Alcohol 104 is then obtained following hydrogen abstraction from the thiol by peroxyl radical 107 and reduction of the resulting hydroperoxide with triphenylphosphine. The yields of endoperoxides remain relatively low (ca. 20−30%, calculated on the diene); however, considering the accessibility and the cost of the reactants (thiophenol, limonene, and oxygen), this approach represents a very attractive access to these structurally complex endoperoxides, some of which exhibit very promising activity for the treatment of malaria. 3.3.2. Intramolecular Trapping of the Carbon-Centered Radical. 3.3.2.a. Fragmentation Reaction: RingOpening of Vinyl Cyclopropanes. The carbon-centered radicals generated by addition of a thiyl radical onto the C C bond of vinylcypropanes have been shown to undergo cyclopropane ring-opening. The resulting radical species can then be trapped by hydrogen abstraction from the thiol. This fragmentation is a very fast process with rate constants in the range 10−10 s−1 (310 K) for most of the cyclopropylcarbinyl radicals, which allows for the fragmentation process to compete favorably with intermolecular reactions, as well as with most intramolecular processes. Alternatively, the carboncentered radical resulting from the β-fragmentation of the cyclopropylmethyl radical can engage further in carbon−carbon bond-forming processes. The allylsulfide moiety allows for the addition of radicals with concomitant release of a thiyl radical, and very elegant processes using only substoichiometric amounts of a source of thiyl radicals have been developed for the rearrangement of vinylcyclopropanes (see section 5.2.1.e). In particular, under nonreducing conditions and in the presence of an external olefin, efficient annulation reactions have been achieved, giving access to polycyclic compounds. The carboncentered radicals generated by the thiol-mediated ring-opening Scheme 49 Scheme 50 Chemical Reviews Review dx.doi.org/10.1021/cr400441m | Chem. Rev. XXXX, XXX, XXX−XXX Y of vinylcyclopropanes could also be trapped to form a new carbon−heteroatom bond. Here again, annulations taking advantage of the allylsulfide moiety have been developed (see section 5.2.1.e). Landais, Renaud, and co-workers used vinyl cyclopentenes such as 108, easily prepared by monocyclopropanation of silylcyclopentadienes, as radical acceptors for photogenerated thiyl radicals. The reversible addition of the thiyl radical onto the CC bond of 108 leads eventually to cyclopropylcarbinyl radical 110, which undergoes fragmentation to give carboncentered radical 111, stabilized by the neighboring ester group. Hydrogen atom abstraction from the thiol then furnishes cyclopentene 109 and regenerates a thiyl radical that propagates the chain (Scheme 51, eq a). The addition of the thiyl radical at the β-carbon center takes place in a highly stereoselective manner, opposite to the bulky silyl group. The fate of the stabilized carbon-centered radical resulting from the fragmentation process depends upon the reaction conditions. For instance, Naito and co-workers reported the use of vinylcylopropyl oxime ethers such as 112 in domino reactions promoted by a thiol or a disulfide in the presence of triethylborane. The ring-opening of the cyclopropyl moiety is initiated by addition of a thiyl radical onto the terminal position of vinylcyclopropyl oxime ether 112. The stabilized carboncentered radical resulting from the fragmentation process reacts with triethylborane to form a boryl enamine 115 (Scheme 51, eq b). Depending on the reaction conditions, the latter can engage further in a radical oxygenation process, leading eventually to α-hydroxy oxime ether 113 after reduction of peroxyl radical 116 by the thiol (Scheme 51, eq b). Alternatively, 113 can react with aldehydes in an ionic aldol process to give β-hydroxy oxime ethers in a stereoselective manner, as illustrated by the preparation of 117 from 112 (Scheme 51, eq c). In the aforementioned reactions, the allylsulfide moieties generated upon addition of a thiyl radical onto the vinylcyclopropane unit remain intact at the end of the reaction. However, radical reactions taking advantage of the fragmentation of allyl sulfides upon addition of radical species are also well documented. Some examples of intermolecular additions, as well as cyclization and annulation processes, will be described in section 5.2.1.e. 3.3.2.b. Rearrangement and Cyclization of Nonconjugated Dienes. In the addition of thiyl radicals onto nonconjugated dienes, the CC bonds can either react independently or lead to rearrangements through intramolecular trapping of the carbon-centered radical generated in the initial addition step. In many cyclic dienes, addition occurs selectively at the more strained double bond, and products resulting from rearrangements are often observed. For example, the addition of thiophenol to 5-methylene-norbornene led to the exo addition products 118 and 119, together with tricyclic adduct 120. The latter results from the rearrangement of homoallyl radical intermediate 121 into cyclopropylcarbinyl radical 122 (Scheme 52). Similar rearrangements have been observed in norbornadiene derivatives where substitution at C-7 can influence facial selectivity, while substitution of the methylene bridge in 7,7-dimethylnorbornene proved to have no effect in directing the addition of thiophenol. The formation of cyclopropylcarbinyl radical intermediates in norbornadiene derivatives can also lead to other skeletal rearrangements, as illustrated by the addition of thiophenol to hexachloronorbornadiene 123, which results in the formation of 125, beside the expected 1:1 addition product 124 (Scheme 53, eq a). Following addition of the thiyl radical, presumably from the less hindered endo-face, and subsequent 3-exo-trig cyclization onto the neighboring CC bond, cyclopropylcarbinyl radical 126 undergoes fragmentation to give the more stable α-chlorosubScheme 51 Scheme 52 Chemical Reviews Review dx.doi.org/10.1021/cr400441m | Chem. Rev. XXXX, XXX, XXX−XXX Z stituted carbon-centered radical 127. The latter then abstracts a hydrogen atom from the thiol to give 125 (relative configuration not established) and a thiyl radical, which goes on to propagate the chain. Similar rearrangement was observed i n t h e add i t i on o f t BuSH on to 1 , 2 , 3 , 4 , 7 , 7 hexamethylbicyclo[2.2.1]heptadiene. Likewise, Hodgson and co-workers have observed complete skeletal rearrangements in the addition of thiophenol to 7-azabicyclo[2.2.1]heptadienes such as 128 (Scheme 53, eq b). Transa

Thiyl Radicals in Organic Synthesis

Carbon−Carbon Bond Formations Involving Organochromium(III) Reagents

This review article is an attempt to sketch the important developments in organic synthesis during the past 25 years, and to project them into the future.—The primary motivations that once induced chemists to undertake natural product syntheses no longer exist. Instead of target structures themselves, molecular function and activity now occupy center stage. Thus, inhibitors with an affinity for all the important natural enzymes and receptors have moved to the fore as potential synthetic targets.—New synthetic methods are most likely to be encountered in the fields of biological and organometallic chemistry. Enzymes, whole organisms, and cell cultures for enan-tioselective synthesis of specific substances have already been incorporated into the synthetic arsenals of both research laboratories and industry. In addition, designing appropriate analogues to transition states and intermediates should soon make it possible, with the aid of the mammalian immune system and gene technology, to prepare catalytically active monoclonal antibodies for almost any reaction; perhaps, more important, such processes will increasingly come to be applied on an industrial scale.-The discovery of truly new reactions is likely to be limited to the realm of transition-metal organic chemistry, which will almost certainly provide us with additional “miracle reagents” in the years to come. As regards main group elements (“organoelemental chemistry”), we can surely anticipate further stepwise improvements in experimental procedures and the broader application of special techniques, leading to undreamed of efficiency and selectivity with respect to known procedures. The primary center of attention for all synthetic methods will continue to shift toward catalytic and enantioselective variants; indeed, it will not be long before such modifications will be available with every standard reaction for converting achiral educts into chiral products. Analysis, spectroscopy, structure determination, theory, and electronic data processing have all become indispensable in organic synthesis. Only with the aid of these “tools” will the methods of organic chemistry permit selective syntheses of ever larger and more complex systems on both the molecular and supramolecular levels.—Examples have been introduced throughout this discourse to illustrate its many themes, and a very comprehensive bibliography should help the interested reader become more familiar with important keywords and authors.[1 ]—This article will have served its intended purpose if it changes the minds of some of those who claim organic chemistry is a mature science, and if it causes students to discover the vitality and forcefulness with which organic synthesis is meeting new challenges and attempting to fulfill old dreams.



Er zeigt uns so in seinem wissenschaftlichen Leben, das die Chemie nicht von einer Theorie, nicht von einer Methode aus zu erschopfen ist, und das Erkenntnis und Nutzen in ihr untrennbar verwoben sind.1



R. Koch, writing about Louis Pasteur

Organic Synthesis—Where now?

Preface. Contributors. Solid--Phase Carbohydrate Synthesis: The Early Work (W.--C. Haase & P. Seeberger). The Glycal Assembly Method on Solid Supports: Synthesis of Oligosaccharides and Glycoconjugates (P. Cirillo & S. Danishefsky). The Sulfoxide Glycosylation Method and its Application to Solid--Phase Oligosaccharide Synthesis and the Generation of Combinatorial Libraries (C. Taylor). The Use of O--Glycosyl Trichloroacetimidates for the Polymer--Supported Synthesis of Oligosaccharides (L. Knerr & R. Schmidt). Synthesis of Oligosaccharides on Solid Support Using Thioglycosides and Pentenyl Glycosides (V. Wittmann). Solid--Phase Oligosaccharide Synthesis Using Glycosyl Phosphates (W.--C. Haase, et al.). Stereoselective beta--Mannosylation on Polymer Support (Y. Ito & H. Ando). Tools for "On--Bead" Monitoring and Analysis in Solid--Phase Oligosaccharide Synthesis (W.--C. Haase, et al.). Polyethyleneglycol omega--Monomethylether (MPEG)--Supported Solution--Phase Synthesis of Oligosaccharides (J. Krepinsky & S. Douglas). Two--Direction Glycosylations for the Preparation of Libraries of Oligosaccharides (G.--J. Boons & T. Zhu). Carbohydrate Libraries in Solution Using Thioglycosides: From Multistep Synthesis to Programmable, One--Pot Synthesis (E. Simanek & C.--H. Wong). Carbohydrate Libraries by the Random Glycosylation Approach (O. Kanie & O. Hindsgaul). Solid--Phase Synthesis of Biologically Important Glycopeptides (N. Bezay & H. Kunz). Preparation and Screening of Glycopeptide Libraries (P. St. Hilaire, et al.). Index.

Solid-phase oligosaccharide synthesis and combinatorial carbohydrate libraries.

Advances in the chemical synthesis of C-pyranosides/furanosides are summarized, covering the literature from 2000 to 2016. The majority of the methods take advantage of the construction of the glycosidic C—C bond. These C-glycosylation methods are categorized herein in terms of the glycosyl donor precursors, which are commonly used in O-glycoside synthesis and are easily accessible to nonspecialists. They include glycosyl halides, glycals, sugar acetates, sugar lactols, sugar lactones, 1,2-anhydro sugars, thioglycosides/sulfoxides/sulfones, selenoglycosides/telluroglycosides, methyl glycosides, and glycosyl imidates/phosphates. Mechanistically, C-glycosylation reactions can involve glycosyl electrophilic/cationic species, anionic species, radical species, or transition-metal complexes, which are discussed as subcategories under each type of sugar precursor. Moreover, intramolecular rearrangements, such as the Claisen rearrangement, Ramberg–Backlund rearrangement, and 1,2-Wittig rearrangement, which usuall...

Recent Advances in the Chemical Synthesis of C-Glycosides

Cyclisation en presence d'ions Ag + ; obtention de dipyranno [3,2,2-b:2',3'-g] oxocinnes; methode pouvant etre applicable a la synthese de brevetoxines A et B

Cyclizations of hydroxy dithioketals. New synthetic technology for the construction of oxocenes and related medium-ring systems

A new synthetic strategy for the regio- and stereo-specific synthesis of tetrahydropyran systems involving 6-endo epoxide openings and its applicaiton to the construction of the ABC ring system of brevetoxin B are described.

Activation of 6-endo over 5-exo epoxide openings. Ring-selective formation of tetrahydropyran systems and stereocontrolled synthesis of the ABC ring framework of brevetoxin B

A partir de penta-O-acetyl mannopyranose, synthese stereoselective du squelette dipyranno [2,3-b:2',3'-e]pyranne de la brevetoxine β

Synthesis of the brevetoxin B IJK ring system

The second generation strategy for the total synthesis of brevetoxin B (1) is presented. According to this •strategy, the heptacyclic (ABCDEFG) phosphonium iodide 4 and the tricyclic (UK) aldehyde 3 were defined as the precursors for the brevetoxin B skeleton. The Yamaguchi lactonization was successfully applied for the formation of the (EFG) and (DEFG) lactones (15 -* 7) and (29 6), respectively. The required appendage on ring (E) was efficiently introduced via a Murai coupling, involving addition of a higher order organocuprate derived from iodide 20 to the lactone-derived enol triflate 16 (16 — 25). The minor epimer of the resulting product 6fi was then converted to the desired isomer 6 a via hydrogenation using an Ir(I) catalyst. A number of approaches were considered for further elaboration of lactone 6. Among them a convienient Cr/Ni-promoted coupling' reaction was developed and applied to the introduction of the side chain on ring D. The scope and generality of this reaction was examined with a variety of aldehydes (e.g., 39, 59, and 62). Construction of 38 was thus achieved from vinyl triflate 36 and the ring B aldehyde 39. However, the projected intramolecular Michael addition (41 — ■ 1 42) and reductive hydroxy ketone cyclization (47 48) failed to yield ring C. Fetizon cyclization afforded the pentacyclic lactone (CDEFG) (51 — * 52), which resisted further useful functionalization, Using the more elaborate aldehyde 62, the Cr/Ni coupling reaction afforded allylic alcohol 64, which then served as a precursor to the pentacyclic lactol 80. The latter compound also resisted advancement to more elaborate intermediates, leading to abandonment of this approach and the formulation of a new strategy.

/pdf/total-synthesis-of-brevetoxin-b-2-2nd-generation-strategies-npm62613oe.pdf

Total Synthesis of Brevetoxin-B .2. 2nd Generation Strategies and Construction of the Dioxepane Region [Defg]

La synthese du squelette pyranno [2,3-b] pyranne de la brevetoxine B est effectuee; le compose obtenu comporte un phosphonium quaternaire

Synthesis of the ABC ring system of brevetoxin B

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